CA1140118A - Substituted n-iminomethylpiperidines - Google Patents
Substituted n-iminomethylpiperidinesInfo
- Publication number
- CA1140118A CA1140118A CA000324324A CA324324A CA1140118A CA 1140118 A CA1140118 A CA 1140118A CA 000324324 A CA000324324 A CA 000324324A CA 324324 A CA324324 A CA 324324A CA 1140118 A CA1140118 A CA 1140118A
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- phenyl
- methyl
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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
- C07D213/06—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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- 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
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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
- C07D211/10—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
-
- 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
Abstract
ABSTRACT
SUBSTITUTED N-IMINOMETHYLPIPERIDINES
Substituted N-iminomethylpiperidines are dis-closed which are useful for the inhibition of gastric acid secretion.
SUBSTITUTED N-IMINOMETHYLPIPERIDINES
Substituted N-iminomethylpiperidines are dis-closed which are useful for the inhibition of gastric acid secretion.
Description
~401.1~3 -SUBSTITUTED N-IMINOMETXYLPIPERIDINES
. .
BACKGRO~ND o~ TEE INVENTION
.
Unsubstituted ~-iminomethylpiperidine is dis-closed in United States Patent No. 2,615,023, but said compound does not inhibit gastric acid secretion even at dose~ four times or greater than those at which the subject compounds are active. It has now surprisingly been discovered t~at certain substituted N-Lminomethyl-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 ~
R
Rl >~ NC=NR3 . A ~ R2 (I) wherein:
Rl 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-alkoxy, h~X~ and halo; ~yl(Cl~C4tloweraIkyl; l-phenyl(C7-Cg)-loweralkyl; p~enyltCl-C4Sloweralkyl and l-phenyl(C7-C9~-loweralkyl in which said phenyl is substituted with from 114V~
one to three members each selected from the group con-sisting of loweralXyl, loweralkoxy, hydroxy, halo, and phenyl, ~rovided that no more than one member is phenyl;
diphenyl(Cl-C4~loweralkyl; diphenyl(Cl-C4)loweralkyl S wherein at least one of said phenyls is substituted with from one to three memhers each selected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is pheny}; diphenylhydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyls i5 gubstituted with from one to three members each selected from the group consi~ting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
~C ~ and wherein n is 0, 1, or 2 and E is H or OH;
A t~ in~ivi~E~ly is a memker selected frcm the ~roup conslcting of ~x~en, acetyl, an~ phenyl, provided that when A is acetyl or phenyl, Rl i5 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;
Rl and A taXen together is a member selected ~rom the group consisting o~ benzhydrylidene and compounds of ~ormulae:
(C ~ and wherein n is 0, 1, or 2;
~ '~ individhally is a ms~ sel~ from the grDUD oonsi~ing of ~XX~n; methyl; diphenylmethy~; diphenyl--methyl wher~in at least one of the phenyl groups is sub-stituted with from one to three mem~ers each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; diphenylhydroxymethyl; diphenyl~
hydroxymethyl wherein at least one of said phenyls is su~stituted with from one to three members each selected from ~he group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member i~ phenyl; and a compound of formula:
~.
~C~
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
Rl' and B taken together is a member selected from the group consisting of ~enzhydrylidene and a compound of ~ormula:
(CH
wherein n i3 0, l, or 2.
Rl'taken individually is a m3mber sele~ fLal~the grou~ consistmg of hy~ , diphenylmet~yl; diphenylmethyl 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, pro-vided that no more than one m~oer is phenyl; diphenyl-hydroxymethyl; diphenylhydroxymethyl wherein at least ~40~ 18 one of sa~d phenyls is substituted with from one to three members each selected ~rom the group consisting of loweralkyl, loweralko~y, hydroxy, halo, and phenyl, provided that no more than one mernber is phenyl; and compounds of formulae:
~ H and ~ H
wherein n is 0, 1, or 2:
D taken individually is hydrogen;
Rl" and D taken together is benzhydrylidene.
R2 is a member selected from the group consisting of hydrogen and Cl-C4 loweralkyl; and R3 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(Cl-C4)10weralkyl; di-phenyl(Cl-C4)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, hydroxy, halo, and phenyl, provided that no more than one member is phenyl;
alkenyl; and alkynyl; provided that at least one of said Rl, R'l and R"l is other than hydrogen and further provided that when R"l is other than hydrogen Rl, and R'l, and A are each hydrogen; when R'l is hydrogen only one of Rl and R"l is other than hydrogen; when R'l is methyl Rl is other than hydrogen and R"l is hydrogen; and when R'l is other than hydrogen or ethyl Rl, R"l and A are each hydrogen.
As used herein~loweralkyl and loweralkoxy may 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 lower-alkyls, and, respectively, the corresponding loweralkoxys, e.g., methoxy, r~ ~
1~L~V~.18 ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and the liXe. The term "Cl-C4 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-(Cl-C4)loweralkyl" and "diphenyl(Cl-C4)loweralkyl" include only those compounds where the phenyl group( 5 ) 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 n l-phenyl-(C7-Cg)loweralkyl" includes groups having the following general formula:
~1 (C~ 2)m c~3 where m is 5, 6,~r 7. me tenm "alkyl" includes straight or branched chain saturated aliphatic hydrocarbons having up to about sixteen carbon atoms, such as for example, the a~o~e mentioned loweralkyls and fsrther 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 hydro-carbons having up to about ten carbon atoms, such as for example, cyclohexyl, adamantyl, l-adamantyl-methyl, exo-norbornyl, endo-norbornyl, noradamantyl, anti-7-norbornenyl, and the like. The terms "alkenyl" and "alkynyl" include straight and branched chain hydro-carbons having from two to about eighteen carbon atoms and at least one double or triple bond, respectively, such as for example, allyl, methallyl, l-propargyl (l-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-6ubstituted 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 ~Vt ~
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, Me30 BF4 , Et30 BF4 , (MeO)2S0 MeOS02F, POCl~, PC15 and the like.
Included in the terms n amide n and "N-acyl-piperidine" as used herein are the corresponding thio derivatives in which the carbonyl oxygen has been re-placed 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 te.g., methyl methanesulfonate) methyl trifluoromethylsulfonate, and the like.
The activated reactant o~ Formula (III) may be in either free base or acid addition salt form.
Specific preparative routes are given below:
~ ) The compounds of Formula (I) may be pre-pared by reacting the appropriately-substituted piperidine of Formula (IT) 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 oryanic solvent such as, for example, a halo-carbon (e.g., carbon tetrachloride, chloroform, 1,2-dichloroethane, and the like), a loweralkanol (e.g., methanol, ethanol, isopropanol, and the like), an aromatic hydrocar~on (e.g., benzene, xylene, toluene, and the like), dimethylsu~foxide, and the like. The temperature of the reaction is preferably from about 0 to about 25C, and in some cases may be carried out as high as 50C, but in any event the temperature of the reaction must not be high enough to decompose significant amounts of the imidate e~ter. The resulting product may be isolated and purified by techni~ues known in the art, e.g., by stripping off the solvent and recrystallizing the desired produet in the free base or acid addition salt form.
The above reaction ~cheme may be illustrated by the 1147~ 18 following~ wherein Al B, D, Rl, Rl', Rln, R2, and R3 are as previously defined, Z is selected from the group con-sisting of loweralkoxy (preferably methoxy and ethoxy), loweralkyl-S- (preferably methylthio), chloro, and C12(0)P0-, and X is a member selected from the group consisting o~ halid~, BF4, FS03, and CH30S03. Addi-tionally, when Z is loweral~yl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)S03, CH3S03, and CF3S03.
Rl' B 1 Rl~ B Ri ~ D \~ ~ D
Rl ~ NH + ZC=NR3 HX 3 ~ NC2NR3 ~ III) tI) The compounds of Formula tI) wherein R2 is hydrogen may also be-prepared ~y an analogous route by substituting an appropriate compound of Formula (IIIA) or (IIIB) for the imidate ester of Formula (III). If the former is used, the resulting thiourea is then re-duced (e.g., with Raney nickel) to give the desired com-pound. If the latter is used, silver c~loride is em-ployed as catalyst. These reaction schemes are illus-trated by the following:
....
R ' B'`l R ~
A ~ NH + R3N'C=S ~--_~thiOurcl reduction)(I) (R
(II) (IIIA) ~ ..
R ' B'`l R~
A ~ NH + R3N-C cat~l~ti~ l ) (I) (R2=H) tII) (IIIB) M~ 335 1~4V~l~
B) The compounds of Formula (I) may also be prepared by reac~i~g a suitably-substi~uted piperidine of ~ormula (II) with acetic formic anhydride or N,N-diloweralkylthioformamide (for R2=H~ or a Cl-C4 loweralkyl anhydride ~for R2=Cl-C4 loweralkyl), the anhydride pre-ferably being present in excess. The piperidine and anhydride or thio~n~m~de are combined with cooling and æe allowed to stir for about 18 hours. The resulting reac-tion mixture, either dissolved in an organic solvent ~elected from t~e aforementioned halocarhon and alipha-tic hydrocarhon ~olvents or ~ithout the addition of solvent, is then treated ~lt~ an aqueous solution of a ~eak.~ase ~.g~, sodium bicarbonatel until the aqueous layer i5 neutral Cfor the. a~ydride routel or is ~ash~ wit~
water Cfor th~. amide route.l. The organic layer i5 separated and any solvent present is removed to ohtain the respective intermediate amides CrVl, CrVAl, and CVl~
The intermediate. amide.lc treated either neat or in the prese~ce of an organic solvent such as, for example, a h~locarbon CCx~l3~ C ~ C12) or a hydrocar~on U~enzene, toluen~) at 25~ to 100C with a suitahle activating agent, 5 describ~d previously, for about t~o 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 de-sired product of Formula ~I~ which may be isolated and purified by known methods dis~ussed above. Th.e above reaction scheme may be illustrated by the following, .Rl, R1, Rl, R2, R3, A, B, D, Z, and X are as originally defined:
v~
Rl'~ D
Il ~ A~_J ~c~tl~l~t~ng IV ~nt s~ D ~1 ~ D
R ~ tC113 ) 2 ~ ~ng Rl / ~ a ~7 ~ nt ~;N~ R3N112 SVA ~ VI
R ~1~,D ~ ctl~tlng r~lcyl~ 20 ~ r~~g~nt A~ lv.l r-lJcyl R ~ 1 V 7~ NR3 ~ hen Z is Uo~eralkyl~-S-~ the compounds of Formula CI2 wherein R2SH may also be obtained iy reacting the activated intermediate ~VI) with. the appropriate isocyanate of Formula (VIII), pre~erably at the reflux temperature of the solvent (e.g., toluene) for about nine days. This reac~ion scheme is illustrated by the following:
R B Rl 1~JL---L~D
1 ~ ~ lo~eralkyl A ~ N=C' H + R3N=C=0 ~ I~R2 VI 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 , hydro-chloric, hydro~romic 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, ~enzoic, cinnamic, mandelic, methane-sulfonic, ethanesulfonic, benzenesulfonic, E~toluenesulfonic, salicylic, 2-naphthalenesulfonic or ~-aminosalicylic acid. The therapeutically active, non-toxic acid addi-tion salts of subject compounds (I) are included within the scope of the present invention.
The starting materials of Formulas ~II), ~III), (IV), (IV~), (V), (VI), (VII), and (VIII) are known or may be prepared by known methods. See generally R. C.
Elderfield, ~eterocyclic 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 R. Hoffman, Helv. Chim. Acta., 248, 2133 (1954).
Preparative methods for compounds (III) and (IV) are des-cribed 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 R. 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, Sur~ey of Or~anic Syn-theses, Cho 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 80 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 ab-domen about 1 1/2 inches in length and the stomach and duodenl~m 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 ~14V~ ~l8 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 i~b=YhIdona~ly ~d.l immediately-aft r surgery or orally (~.o~l one hcur prior bo surgery at doses gene~ally 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, Q.5% aoueous methyl cellulose.
After the surgery and (in the case of i.d. ~d-ministration~ after administration of the test compound, the abdominal wall and skin are clo~ed 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 th~ 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 sedLment. The volume is read and a 1 ml ali-quot of the sup~rnatant 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, Titrata~le Acid and Total Acid Output, where Volume equals total ml of gastric juice minus sediment;
Titratable Acid (meq/l) equals amount of O.Ol N sodium hydroxide needed to titrate the acid to pH7; and Total Acid Output equals Titratable Acid times Volume. Results are reported as the ED50 dose (mg/kg required to produce an average of 50% inhibition in Total Acid Output versus controls in all the animals tested for a particular oom-pound) and as percent inhibition. The compound~ of the invention all demonstrate a significant inhibition both i.d. an~ p.o. at less than 80 mg/kg, with preferred com pounds having an ED50 ~ less than 20 mg/kg. In con-trast, the prior art N-iminomethylpiperidine demonstrates no inhibition whatsoever at a dose of 100 mg/kg ~ o. or at 80 mg/kg id.
It is well-known that excessive se~retion of gastric hydrochloric acid leads to unneeded peptic activi-ty and endangers the mucous lining of the stomach. The use of gastric antisecretory agents is thus desirable as an aid in the prevention and amelioration of distress occasioned by high concentrations of stomach acid.
Description of the Preferred Embodiments Preferred compounds of the invention are those of Formula (I) wherein:
Rl is a ~ember selected from the group consisting of phenyl; phenyl substituted with from one to three mem-bers each selected from the group consisting of loweralkyl, loweralkoxy, halo, and phenyl, provided that no more than one member is p~enyl; phenyl(Cl-C4)loweralkyl; phenyl-(Cl-C4)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-(Cl-C4)loweralkyl and diphenyl(Cl-C4)loweralkyl wherein at least on~ of said phenyls is substituted with from one to three members each selected from the group con-sisting 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;
R3 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 consis-ting of loweralkyl, loweralkoxy, and halo; alkenyl, and alkynyl; and Rl', Rl", A, B, and D are each hydrogen.
More preferred compounds of the invention are those of Formula ~I) wherein:
1~4~)~1t3 Rl 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 m~hers each selected ~rom the group consisting of lower-alkyl, lowera~oxy, and halo;
R2 is hydrogen;
R3 is a member selected ~rom the group consistingof hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl i8 substituted with from Qne to three members each selected from the group consisting of lower-alkyl, loweralkoxy, and halo; alkenyl; and alkynyl; and Rl', Rl", A, B, and D are hydrogen.
Most preferred compounds of the invention are those of Formula (I) wherein Rl is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein one of said phenyls is subs~itued in the ~
position with a mP~her selected from the group consisting of loweralkyl, loweralkoxy, and halo; R2 is hydrogen; R3 is a mem~er selected from ~he group consisting of hydrogen, straight chain alkyl, and phenylloweralkyl; and Rl', 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 met~od of inhibiting gastric acid secretion which com-prises internally admini~tering to a gastric hyperacidic subject (man or animal) an effective gastric acid secretion inhibiting amount of a substituted N-iminomethylpiperidine of Formula tI~, in base or acid addition salt form, pref-erably in admixtur~ with a pharmaceutically acce~tabl~carrier. If an acid addition sa}t form is used, said salt must of couræe ~e pharmaceutically-acceptable and non-toxic. Pharmaceutical compositions comprising a su~ject compound (I~ are also considered a further aspect of thP
3s 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 M~ 335 ll~Q1 .18 as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharma-ceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of prepara-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, lubri-cants, binders, disintegrating agents, ~nd 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 pharmaceutioal ~arriers are obviously employed.
If desired, tablets may be sugar coated or enteric coated by ~tandard techniques. For parenterals, the carrier will usually comprise sterile water, although other ingredients, for example, to aid solubility or for preservative pur-poses, 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, ~rom about ten to about five hundred milligrams of the active ingredient, and prefer-ably from about fifteen to about two hundred fifty milli-grams.
The following examples are intended to illustrate but not to limit the scope of the present invention.
EXAMPLE I
4-Diphenylmethyl-l-iminomethylpiperidine ~ ~ ochloride hydrate A suspension of 27.39g (0.25 mole) of ethyl formimidate hydrochloride ~prepared by the method of Ohme, et al., Angew. Chem. ~ntl. Ed., 6, 566(1967)] and 52.71g (0.20 mole) of diphenyl-4-piperidylmethane in 80 ml of freshly-opened absolute ethanol was stirred mag-netically 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-1-Lminomethyl-piperidine hydrochloride hydrate; m.p. 220-221C.
EXAMPLE II
Following the procedure of Example I, but sub-stituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane ~sed therein, equivalent amounts of the appropriate starting materials, there are prepared the following:
R ~
1 ~ NC=NR3 . Salt A ~ ~2 Rl 5alt A R2 R3 m.p~ (C?
~ip~P~y~ yl ~Cl H C2H5 ~ 271.5-277.5 a-(4-m~h~yniE~y1) fumarate H H H 1~9.5-192.5 b~l , ~-~,4-h~nyl)-a- HCl H H H 216 -218 hy~lr3~1 p~enyl HCl H H H 204 -205 benzyl ECl o H H H 199 -201.5 phenyl HCl C-CH3 H H 172 -175 a-U~on~E~ ~rate H H H 192.5-194.5 ~yl l8 EXAMPLE III
4-(DiphPnylmethyl)-l-N-ethyliminomethyl-pip~ridine oxalate hemihydrate A mixture of 8.00g (0.029 mole) of N-formyl-4-diphenylmethy~piperidine and 3.51g (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 li~uid. Treat-ment of this material in isopropanol with 3.26g of oxalicacid dihydrate afforded 5.0g of white solid m.p. 165-175C. Recrystallization from isopropanol afforded pure 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate hemihydrate as a white solid; m.p. 185-187C.
EXAMPLE IV
Following the procedure of Example III, but substituting for the ~-formyl-4-diphenylme~hylpiperidine and ethylamine used therein, e~uivalent amounts of the appropriate starting materials, there are prepared the following:
R1 ~ NC=NR3 Salt \J R2 _ R2 ~ Salt m.p. (C) dipheny~ yl H -C~2C~=CX2 cycld~ane 179.5-181 ~amate n H i-p~l fumarate 175 -178 ~ H n-butyl " 193.5-195 H n-hexyl ~ 179 -181.5 n H _-hepkyl ~ 175 -178 H n~x~yI " 157 -159 " H t-octyl " 227 -229 " H n-nonyl " 142 -144.5 ~14V~
R2 R3 Salt m.p. ( diphenylmEthyl ~ nrdecyl succ~nate 106 -109 n H ~ 1 ~umarate 143 -145.5 ~dra~e ~ H l-~mantyl fumarate 275 -276 n ~ benzyl cy~lohexane 164.5-166.5 n H ~1 n 141 -144 n H ~ 1 2-nLç~ ene 222 -224 ~ul~anate n H ~ 1 n 110.5-112.5 a- (4-r~eY~D~npYenyl) H n-octyl (E)-2-butene- 154.5-156 b~l dioate 10a- (4-methy1pheny1) H n-octyl n 161 -163.5 diphenylmethyl H 4 m~thyltEnzyl pt5~ or3te 242 -244 n H phenyl 4-tDluene- 285 -286 sulfonate EXAMPLE IVA
A mixture of 4-[(4-methoxyphenyl)phenylmethyl]-l-[~octylimino)methyl]piperidine (1.9Og, 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 a~ueous sodium bicar~onate, dried and evaporated. The residue, 4-[(4-hydroxyphenyl)-phenylmethyl]-l-[(octylLmino)methyl]piperidine was con-verted to its 2~naphthalenesulfonio acid salt, m.p.
177.5-180C.
XAMPLE V
4-(Diphenylmethyl)-l-[(octyl$mino)methyl]-Pi~eridine Fumarate Hvdrate ", , _ A ~olution of triethyl oxonium fluoroborate [prepared from 104.6g (0.737 mole) of boron trifluoride etherate and 56.04g ~47.37 ml, 0.606 mole) of epichloro-hydrin] was dissolved in 800 ml of anhydrous methylene chloride and the resulting solution treated with 81.0g (0.516 mole) of N-(n-octyl) formamide and stirred over-nigh~ at 25$. 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, r~
the filtrate made basic with 3 N sodium hydroxide solu-tion, separated, dried over potassium carbonate and evaporated to a yellow oil. This material was dissolved in isopropanol and treated with 6~g of fumaric acid with warming. Addition of an equal volume of aceto~e followed by ether caused a solid to form affording two crops of material m.p. 152-157C. These were combined and re-crystallized from ethanol-water to give two crops of 4-~diphenylmethyl)-1-[~octylimino)methyl]piperidine fumarate hydrate: m.p. 157-159C.
EXAMPLE VI
. . .
4-(Diphenylmethyl)-l-pipe-r-idinecarbothioaldehyd-e A solution o~ 20.0g (0.08 mole) of 4-diphenyl-methylpiperidine, 14.2g (0.16 mole) of N,N-dimethylthio-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-phenylmethyl)-l-piperidinecarbothioaldehyde, m.p. 152-154C.
EXAMPLE VII
. .
Following the above procedure, but substituting for 4-diphenylmethylpiperidine used therein, an equiva-lent amount of an appropriate piperidine, there are pre-pared the following: R ' Rl / \ S
A ~ NCH
/ , .
Rl A Rl' m p. (C) 9-fluorenyl H H 142 - 146 H H Ph2CH 115 - 120 -~ benzyhydrylidene------- H 131 - 134 diphenylhydroxymethyl H H 200 - 203 EXAMæLE VIII
4-(Diphenylmethyl) -1-N-(n-dodecyliminomethyl)piperidine fumarate 35A solution of 5.54g (0.019 mole) of 4-(diphenyl-methyl)-1-piperidinecarbothioaldehyde in 20 ml of ~l~V~ ~l8 lg chloroform was treated with 2.65g tl.l6 ml, 0.019 mole) of methyl iodide and refluxed for one hour. The result-ing 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)-l-N-(n-dodecyliminomethyl)piperidine fumarate; m.p. 143-145.5C.
EXAMPLE IX
Following the above procedure, but substituting for the 4-(diphenylmethyl)-1-p$peridinecarbothioaldehyde and n-dodecylamine used therein, equivalent amounts of the appropriate starting.materials, there are prepared 15 the following: Rl' Rl ~\
A ~ NCH=NR3 A ~' R3 Salt ~ p. ~C) H H
di~Y~lmetbyl H ( ~ )8C=C- fumara~_ ~inter (CH2)~CH3 hydrate 131 -13S
diphenylmethyl H H ~ C-CH HCl 117 -1l9 9H-flu~rg-yl H H n-C8H17 HCl 174 -177 H H diphenyl- n-C8H17 ~m~rate (sin~Pr 68.5) methyl . hylrate 70 -72 -be1~*y~ryl~ H n-C8H17 te 167 -170 diphenylhy~x3ynethyl H H n-C8H17 f~ate (.s nter 145) H H diF ~ 1- H fu~rate 185.5-187.5 methyl EXAMPLE X
Alternate Preparative Routes Illustrated for 4-(Diphenylmethyl?-l-[(octylimino)methyl]Piperidine 1) A mixture of 2.90g (0.01 mole) of 4-(di-phenylmethyl)-l-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 60 for two days. The reaction mixture was made basic ~l~V~
and concentrated to give an oil which was identified as 4-(diphenylmethyl~-1-[(octylimino)methyl]piperidine by vapor phase chromatography.
. .
BACKGRO~ND o~ TEE INVENTION
.
Unsubstituted ~-iminomethylpiperidine is dis-closed in United States Patent No. 2,615,023, but said compound does not inhibit gastric acid secretion even at dose~ four times or greater than those at which the subject compounds are active. It has now surprisingly been discovered t~at certain substituted N-Lminomethyl-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 ~
R
Rl >~ NC=NR3 . A ~ R2 (I) wherein:
Rl 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-alkoxy, h~X~ and halo; ~yl(Cl~C4tloweraIkyl; l-phenyl(C7-Cg)-loweralkyl; p~enyltCl-C4Sloweralkyl and l-phenyl(C7-C9~-loweralkyl in which said phenyl is substituted with from 114V~
one to three members each selected from the group con-sisting of loweralXyl, loweralkoxy, hydroxy, halo, and phenyl, ~rovided that no more than one member is phenyl;
diphenyl(Cl-C4~loweralkyl; diphenyl(Cl-C4)loweralkyl S wherein at least one of said phenyls is substituted with from one to three memhers each selected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is pheny}; diphenylhydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyls i5 gubstituted with from one to three members each selected from the group consi~ting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
~C ~ and wherein n is 0, 1, or 2 and E is H or OH;
A t~ in~ivi~E~ly is a memker selected frcm the ~roup conslcting of ~x~en, acetyl, an~ phenyl, provided that when A is acetyl or phenyl, Rl i5 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;
Rl and A taXen together is a member selected ~rom the group consisting o~ benzhydrylidene and compounds of ~ormulae:
(C ~ and wherein n is 0, 1, or 2;
~ '~ individhally is a ms~ sel~ from the grDUD oonsi~ing of ~XX~n; methyl; diphenylmethy~; diphenyl--methyl wher~in at least one of the phenyl groups is sub-stituted with from one to three mem~ers each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; diphenylhydroxymethyl; diphenyl~
hydroxymethyl wherein at least one of said phenyls is su~stituted with from one to three members each selected from ~he group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member i~ phenyl; and a compound of formula:
~.
~C~
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
Rl' and B taken together is a member selected from the group consisting of ~enzhydrylidene and a compound of ~ormula:
(CH
wherein n i3 0, l, or 2.
Rl'taken individually is a m3mber sele~ fLal~the grou~ consistmg of hy~ , diphenylmet~yl; diphenylmethyl 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, pro-vided that no more than one m~oer is phenyl; diphenyl-hydroxymethyl; diphenylhydroxymethyl wherein at least ~40~ 18 one of sa~d phenyls is substituted with from one to three members each selected ~rom the group consisting of loweralkyl, loweralko~y, hydroxy, halo, and phenyl, provided that no more than one mernber is phenyl; and compounds of formulae:
~ H and ~ H
wherein n is 0, 1, or 2:
D taken individually is hydrogen;
Rl" and D taken together is benzhydrylidene.
R2 is a member selected from the group consisting of hydrogen and Cl-C4 loweralkyl; and R3 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(Cl-C4)10weralkyl; di-phenyl(Cl-C4)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, hydroxy, halo, and phenyl, provided that no more than one member is phenyl;
alkenyl; and alkynyl; provided that at least one of said Rl, R'l and R"l is other than hydrogen and further provided that when R"l is other than hydrogen Rl, and R'l, and A are each hydrogen; when R'l is hydrogen only one of Rl and R"l is other than hydrogen; when R'l is methyl Rl is other than hydrogen and R"l is hydrogen; and when R'l is other than hydrogen or ethyl Rl, R"l and A are each hydrogen.
As used herein~loweralkyl and loweralkoxy may 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 lower-alkyls, and, respectively, the corresponding loweralkoxys, e.g., methoxy, r~ ~
1~L~V~.18 ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and the liXe. The term "Cl-C4 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-(Cl-C4)loweralkyl" and "diphenyl(Cl-C4)loweralkyl" include only those compounds where the phenyl group( 5 ) 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 n l-phenyl-(C7-Cg)loweralkyl" includes groups having the following general formula:
~1 (C~ 2)m c~3 where m is 5, 6,~r 7. me tenm "alkyl" includes straight or branched chain saturated aliphatic hydrocarbons having up to about sixteen carbon atoms, such as for example, the a~o~e mentioned loweralkyls and fsrther 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 hydro-carbons having up to about ten carbon atoms, such as for example, cyclohexyl, adamantyl, l-adamantyl-methyl, exo-norbornyl, endo-norbornyl, noradamantyl, anti-7-norbornenyl, and the like. The terms "alkenyl" and "alkynyl" include straight and branched chain hydro-carbons having from two to about eighteen carbon atoms and at least one double or triple bond, respectively, such as for example, allyl, methallyl, l-propargyl (l-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-6ubstituted 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 ~Vt ~
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, Me30 BF4 , Et30 BF4 , (MeO)2S0 MeOS02F, POCl~, PC15 and the like.
Included in the terms n amide n and "N-acyl-piperidine" as used herein are the corresponding thio derivatives in which the carbonyl oxygen has been re-placed 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 te.g., methyl methanesulfonate) methyl trifluoromethylsulfonate, and the like.
The activated reactant o~ Formula (III) may be in either free base or acid addition salt form.
Specific preparative routes are given below:
~ ) The compounds of Formula (I) may be pre-pared by reacting the appropriately-substituted piperidine of Formula (IT) 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 oryanic solvent such as, for example, a halo-carbon (e.g., carbon tetrachloride, chloroform, 1,2-dichloroethane, and the like), a loweralkanol (e.g., methanol, ethanol, isopropanol, and the like), an aromatic hydrocar~on (e.g., benzene, xylene, toluene, and the like), dimethylsu~foxide, and the like. The temperature of the reaction is preferably from about 0 to about 25C, and in some cases may be carried out as high as 50C, but in any event the temperature of the reaction must not be high enough to decompose significant amounts of the imidate e~ter. The resulting product may be isolated and purified by techni~ues known in the art, e.g., by stripping off the solvent and recrystallizing the desired produet in the free base or acid addition salt form.
The above reaction ~cheme may be illustrated by the 1147~ 18 following~ wherein Al B, D, Rl, Rl', Rln, R2, and R3 are as previously defined, Z is selected from the group con-sisting of loweralkoxy (preferably methoxy and ethoxy), loweralkyl-S- (preferably methylthio), chloro, and C12(0)P0-, and X is a member selected from the group consisting o~ halid~, BF4, FS03, and CH30S03. Addi-tionally, when Z is loweral~yl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)S03, CH3S03, and CF3S03.
Rl' B 1 Rl~ B Ri ~ D \~ ~ D
Rl ~ NH + ZC=NR3 HX 3 ~ NC2NR3 ~ III) tI) The compounds of Formula tI) wherein R2 is hydrogen may also be-prepared ~y an analogous route by substituting an appropriate compound of Formula (IIIA) or (IIIB) for the imidate ester of Formula (III). If the former is used, the resulting thiourea is then re-duced (e.g., with Raney nickel) to give the desired com-pound. If the latter is used, silver c~loride is em-ployed as catalyst. These reaction schemes are illus-trated by the following:
....
R ' B'`l R ~
A ~ NH + R3N'C=S ~--_~thiOurcl reduction)(I) (R
(II) (IIIA) ~ ..
R ' B'`l R~
A ~ NH + R3N-C cat~l~ti~ l ) (I) (R2=H) tII) (IIIB) M~ 335 1~4V~l~
B) The compounds of Formula (I) may also be prepared by reac~i~g a suitably-substi~uted piperidine of ~ormula (II) with acetic formic anhydride or N,N-diloweralkylthioformamide (for R2=H~ or a Cl-C4 loweralkyl anhydride ~for R2=Cl-C4 loweralkyl), the anhydride pre-ferably being present in excess. The piperidine and anhydride or thio~n~m~de are combined with cooling and æe allowed to stir for about 18 hours. The resulting reac-tion mixture, either dissolved in an organic solvent ~elected from t~e aforementioned halocarhon and alipha-tic hydrocarhon ~olvents or ~ithout the addition of solvent, is then treated ~lt~ an aqueous solution of a ~eak.~ase ~.g~, sodium bicarbonatel until the aqueous layer i5 neutral Cfor the. a~ydride routel or is ~ash~ wit~
water Cfor th~. amide route.l. The organic layer i5 separated and any solvent present is removed to ohtain the respective intermediate amides CrVl, CrVAl, and CVl~
The intermediate. amide.lc treated either neat or in the prese~ce of an organic solvent such as, for example, a h~locarbon CCx~l3~ C ~ C12) or a hydrocar~on U~enzene, toluen~) at 25~ to 100C with a suitahle activating agent, 5 describ~d previously, for about t~o 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 de-sired product of Formula ~I~ which may be isolated and purified by known methods dis~ussed above. Th.e above reaction scheme may be illustrated by the following, .Rl, R1, Rl, R2, R3, A, B, D, Z, and X are as originally defined:
v~
Rl'~ D
Il ~ A~_J ~c~tl~l~t~ng IV ~nt s~ D ~1 ~ D
R ~ tC113 ) 2 ~ ~ng Rl / ~ a ~7 ~ nt ~;N~ R3N112 SVA ~ VI
R ~1~,D ~ ctl~tlng r~lcyl~ 20 ~ r~~g~nt A~ lv.l r-lJcyl R ~ 1 V 7~ NR3 ~ hen Z is Uo~eralkyl~-S-~ the compounds of Formula CI2 wherein R2SH may also be obtained iy reacting the activated intermediate ~VI) with. the appropriate isocyanate of Formula (VIII), pre~erably at the reflux temperature of the solvent (e.g., toluene) for about nine days. This reac~ion scheme is illustrated by the following:
R B Rl 1~JL---L~D
1 ~ ~ lo~eralkyl A ~ N=C' H + R3N=C=0 ~ I~R2 VI 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 , hydro-chloric, hydro~romic 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, ~enzoic, cinnamic, mandelic, methane-sulfonic, ethanesulfonic, benzenesulfonic, E~toluenesulfonic, salicylic, 2-naphthalenesulfonic or ~-aminosalicylic acid. The therapeutically active, non-toxic acid addi-tion salts of subject compounds (I) are included within the scope of the present invention.
The starting materials of Formulas ~II), ~III), (IV), (IV~), (V), (VI), (VII), and (VIII) are known or may be prepared by known methods. See generally R. C.
Elderfield, ~eterocyclic 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 R. Hoffman, Helv. Chim. Acta., 248, 2133 (1954).
Preparative methods for compounds (III) and (IV) are des-cribed 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 R. 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, Sur~ey of Or~anic Syn-theses, Cho 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 80 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 ab-domen about 1 1/2 inches in length and the stomach and duodenl~m 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 ~14V~ ~l8 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 i~b=YhIdona~ly ~d.l immediately-aft r surgery or orally (~.o~l one hcur prior bo surgery at doses gene~ally 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, Q.5% aoueous methyl cellulose.
After the surgery and (in the case of i.d. ~d-ministration~ after administration of the test compound, the abdominal wall and skin are clo~ed 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 th~ 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 sedLment. The volume is read and a 1 ml ali-quot of the sup~rnatant 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, Titrata~le Acid and Total Acid Output, where Volume equals total ml of gastric juice minus sediment;
Titratable Acid (meq/l) equals amount of O.Ol N sodium hydroxide needed to titrate the acid to pH7; and Total Acid Output equals Titratable Acid times Volume. Results are reported as the ED50 dose (mg/kg required to produce an average of 50% inhibition in Total Acid Output versus controls in all the animals tested for a particular oom-pound) and as percent inhibition. The compound~ of the invention all demonstrate a significant inhibition both i.d. an~ p.o. at less than 80 mg/kg, with preferred com pounds having an ED50 ~ less than 20 mg/kg. In con-trast, the prior art N-iminomethylpiperidine demonstrates no inhibition whatsoever at a dose of 100 mg/kg ~ o. or at 80 mg/kg id.
It is well-known that excessive se~retion of gastric hydrochloric acid leads to unneeded peptic activi-ty and endangers the mucous lining of the stomach. The use of gastric antisecretory agents is thus desirable as an aid in the prevention and amelioration of distress occasioned by high concentrations of stomach acid.
Description of the Preferred Embodiments Preferred compounds of the invention are those of Formula (I) wherein:
Rl is a ~ember selected from the group consisting of phenyl; phenyl substituted with from one to three mem-bers each selected from the group consisting of loweralkyl, loweralkoxy, halo, and phenyl, provided that no more than one member is p~enyl; phenyl(Cl-C4)loweralkyl; phenyl-(Cl-C4)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-(Cl-C4)loweralkyl and diphenyl(Cl-C4)loweralkyl wherein at least on~ of said phenyls is substituted with from one to three members each selected from the group con-sisting 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;
R3 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 consis-ting of loweralkyl, loweralkoxy, and halo; alkenyl, and alkynyl; and Rl', Rl", A, B, and D are each hydrogen.
More preferred compounds of the invention are those of Formula ~I) wherein:
1~4~)~1t3 Rl 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 m~hers each selected ~rom the group consisting of lower-alkyl, lowera~oxy, and halo;
R2 is hydrogen;
R3 is a member selected ~rom the group consistingof hydrogen; alkyl; phenylloweralkyl; phenylloweralkyl in which said phenyl i8 substituted with from Qne to three members each selected from the group consisting of lower-alkyl, loweralkoxy, and halo; alkenyl; and alkynyl; and Rl', Rl", A, B, and D are hydrogen.
Most preferred compounds of the invention are those of Formula (I) wherein Rl is a member selected from the group consisting of diphenylmethyl and diphenylmethyl wherein one of said phenyls is subs~itued in the ~
position with a mP~her selected from the group consisting of loweralkyl, loweralkoxy, and halo; R2 is hydrogen; R3 is a mem~er selected from ~he group consisting of hydrogen, straight chain alkyl, and phenylloweralkyl; and Rl', 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 met~od of inhibiting gastric acid secretion which com-prises internally admini~tering to a gastric hyperacidic subject (man or animal) an effective gastric acid secretion inhibiting amount of a substituted N-iminomethylpiperidine of Formula tI~, in base or acid addition salt form, pref-erably in admixtur~ with a pharmaceutically acce~tabl~carrier. If an acid addition sa}t form is used, said salt must of couræe ~e pharmaceutically-acceptable and non-toxic. Pharmaceutical compositions comprising a su~ject compound (I~ are also considered a further aspect of thP
3s 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 M~ 335 ll~Q1 .18 as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharma-ceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of prepara-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, lubri-cants, binders, disintegrating agents, ~nd 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 pharmaceutioal ~arriers are obviously employed.
If desired, tablets may be sugar coated or enteric coated by ~tandard techniques. For parenterals, the carrier will usually comprise sterile water, although other ingredients, for example, to aid solubility or for preservative pur-poses, 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, ~rom about ten to about five hundred milligrams of the active ingredient, and prefer-ably from about fifteen to about two hundred fifty milli-grams.
The following examples are intended to illustrate but not to limit the scope of the present invention.
EXAMPLE I
4-Diphenylmethyl-l-iminomethylpiperidine ~ ~ ochloride hydrate A suspension of 27.39g (0.25 mole) of ethyl formimidate hydrochloride ~prepared by the method of Ohme, et al., Angew. Chem. ~ntl. Ed., 6, 566(1967)] and 52.71g (0.20 mole) of diphenyl-4-piperidylmethane in 80 ml of freshly-opened absolute ethanol was stirred mag-netically 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-1-Lminomethyl-piperidine hydrochloride hydrate; m.p. 220-221C.
EXAMPLE II
Following the procedure of Example I, but sub-stituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane ~sed therein, equivalent amounts of the appropriate starting materials, there are prepared the following:
R ~
1 ~ NC=NR3 . Salt A ~ ~2 Rl 5alt A R2 R3 m.p~ (C?
~ip~P~y~ yl ~Cl H C2H5 ~ 271.5-277.5 a-(4-m~h~yniE~y1) fumarate H H H 1~9.5-192.5 b~l , ~-~,4-h~nyl)-a- HCl H H H 216 -218 hy~lr3~1 p~enyl HCl H H H 204 -205 benzyl ECl o H H H 199 -201.5 phenyl HCl C-CH3 H H 172 -175 a-U~on~E~ ~rate H H H 192.5-194.5 ~yl l8 EXAMPLE III
4-(DiphPnylmethyl)-l-N-ethyliminomethyl-pip~ridine oxalate hemihydrate A mixture of 8.00g (0.029 mole) of N-formyl-4-diphenylmethy~piperidine and 3.51g (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 li~uid. Treat-ment of this material in isopropanol with 3.26g of oxalicacid dihydrate afforded 5.0g of white solid m.p. 165-175C. Recrystallization from isopropanol afforded pure 4-(diphenylmethyl)-1-N-ethyliminomethylpiperidine oxalate hemihydrate as a white solid; m.p. 185-187C.
EXAMPLE IV
Following the procedure of Example III, but substituting for the ~-formyl-4-diphenylme~hylpiperidine and ethylamine used therein, e~uivalent amounts of the appropriate starting materials, there are prepared the following:
R1 ~ NC=NR3 Salt \J R2 _ R2 ~ Salt m.p. (C) dipheny~ yl H -C~2C~=CX2 cycld~ane 179.5-181 ~amate n H i-p~l fumarate 175 -178 ~ H n-butyl " 193.5-195 H n-hexyl ~ 179 -181.5 n H _-hepkyl ~ 175 -178 H n~x~yI " 157 -159 " H t-octyl " 227 -229 " H n-nonyl " 142 -144.5 ~14V~
R2 R3 Salt m.p. ( diphenylmEthyl ~ nrdecyl succ~nate 106 -109 n H ~ 1 ~umarate 143 -145.5 ~dra~e ~ H l-~mantyl fumarate 275 -276 n ~ benzyl cy~lohexane 164.5-166.5 n H ~1 n 141 -144 n H ~ 1 2-nLç~ ene 222 -224 ~ul~anate n H ~ 1 n 110.5-112.5 a- (4-r~eY~D~npYenyl) H n-octyl (E)-2-butene- 154.5-156 b~l dioate 10a- (4-methy1pheny1) H n-octyl n 161 -163.5 diphenylmethyl H 4 m~thyltEnzyl pt5~ or3te 242 -244 n H phenyl 4-tDluene- 285 -286 sulfonate EXAMPLE IVA
A mixture of 4-[(4-methoxyphenyl)phenylmethyl]-l-[~octylimino)methyl]piperidine (1.9Og, 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 a~ueous sodium bicar~onate, dried and evaporated. The residue, 4-[(4-hydroxyphenyl)-phenylmethyl]-l-[(octylLmino)methyl]piperidine was con-verted to its 2~naphthalenesulfonio acid salt, m.p.
177.5-180C.
XAMPLE V
4-(Diphenylmethyl)-l-[(octyl$mino)methyl]-Pi~eridine Fumarate Hvdrate ", , _ A ~olution 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 81.0g (0.516 mole) of N-(n-octyl) formamide and stirred over-nigh~ 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, r~
the filtrate made basic with 3 N sodium hydroxide solu-tion, separated, dried over potassium carbonate and evaporated to a yellow oil. This material was dissolved in isopropanol and treated with 6~g of fumaric acid with warming. Addition of an equal volume of aceto~e followed by ether caused a solid to form affording two crops of material m.p. 152-157C. These were combined and re-crystallized from ethanol-water to give two crops of 4-~diphenylmethyl)-1-[~octylimino)methyl]piperidine fumarate hydrate: m.p. 157-159C.
EXAMPLE VI
. . .
4-(Diphenylmethyl)-l-pipe-r-idinecarbothioaldehyd-e A solution o~ 20.0g (0.08 mole) of 4-diphenyl-methylpiperidine, 14.2g (0.16 mole) of N,N-dimethylthio-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-phenylmethyl)-l-piperidinecarbothioaldehyde, m.p. 152-154C.
EXAMPLE VII
. .
Following the above procedure, but substituting for 4-diphenylmethylpiperidine used therein, an equiva-lent amount of an appropriate piperidine, there are pre-pared the following: R ' Rl / \ S
A ~ NCH
/ , .
Rl A Rl' m p. (C) 9-fluorenyl H H 142 - 146 H H Ph2CH 115 - 120 -~ benzyhydrylidene------- H 131 - 134 diphenylhydroxymethyl H H 200 - 203 EXAMæLE VIII
4-(Diphenylmethyl) -1-N-(n-dodecyliminomethyl)piperidine fumarate 35A solution of 5.54g (0.019 mole) of 4-(diphenyl-methyl)-1-piperidinecarbothioaldehyde in 20 ml of ~l~V~ ~l8 lg chloroform was treated with 2.65g tl.l6 ml, 0.019 mole) of methyl iodide and refluxed for one hour. The result-ing 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)-l-N-(n-dodecyliminomethyl)piperidine fumarate; m.p. 143-145.5C.
EXAMPLE IX
Following the above procedure, but substituting for the 4-(diphenylmethyl)-1-p$peridinecarbothioaldehyde and n-dodecylamine used therein, equivalent amounts of the appropriate starting.materials, there are prepared 15 the following: Rl' Rl ~\
A ~ NCH=NR3 A ~' R3 Salt ~ p. ~C) H H
di~Y~lmetbyl H ( ~ )8C=C- fumara~_ ~inter (CH2)~CH3 hydrate 131 -13S
diphenylmethyl H H ~ C-CH HCl 117 -1l9 9H-flu~rg-yl H H n-C8H17 HCl 174 -177 H H diphenyl- n-C8H17 ~m~rate (sin~Pr 68.5) methyl . hylrate 70 -72 -be1~*y~ryl~ H n-C8H17 te 167 -170 diphenylhy~x3ynethyl H H n-C8H17 f~ate (.s nter 145) H H diF ~ 1- H fu~rate 185.5-187.5 methyl EXAMPLE X
Alternate Preparative Routes Illustrated for 4-(Diphenylmethyl?-l-[(octylimino)methyl]Piperidine 1) A mixture of 2.90g (0.01 mole) of 4-(di-phenylmethyl)-l-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 60 for two days. The reaction mixture was made basic ~l~V~
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-(di-phenylmethyl)-l-piperidinecar~othioaldehyde, O.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)methyl3piperidine (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-(di-phenylmethyl)-l-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-(dipheny}methyl)-1-[(octylimino)methyl]piperidine in the amount of 17% in the reaction mixture.
4) A solution of l.Og (0.0034 mole), of 4-(di-phenylmethyl)-l-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)-l-[(ootylimino)methyl]piperidine to be present.
4) A solution of l.Og (0.0034 mole), of 4-(di-phenylmethyl)-l-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)-l-[(ootylimino)methyl]piperidine to be present.
5) 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 silic~ gel using chloroform as an eluent aforded a brown oil, 4-(diphenylmethyl)-N-octyl-l-piperidinecarbothioamide. A mixture of l.Og (0.0024 mole~
of this material, 3g of Raney Nickel and 15 ml of iso-propanol was refluxed three hours, cooled, and filtered.Evaporation of the filtrate afforded an oil which was converted to a fumarate identified as 4-(diphenylmethyl)-l-[(octylimino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate by thin layer chromatography.
of this material, 3g of Raney Nickel and 15 ml of iso-propanol was refluxed three hours, cooled, and filtered.Evaporation of the filtrate afforded an oil which was converted to a fumarate identified as 4-(diphenylmethyl)-l-[(octylimino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate by thin layer chromatography.
6) A solution of N-formyl-4-diphenylmethyl-piperidine 40.0g (0.143 mole) and 50 ml of methylene chloride was treated with pho~gene 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 ~4~8 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. ~riethyl amine (28 ml) was added 510wly, 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-[(octyl-imino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate, identified by thin layer chromatography.
7) A mixture of 5.60g (0.022 mole) of 4-di-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, stripped, and the residue dissolved i~ methylene chloride.
Extraction with 10% sodium hydroxide, drying and filtra-tion of the organic layer followed by evaporation afforded 4-(diphenylmethyl) l-[(octylimino)methyl]piperidine isolated as the fumarate salt, which was identified by thin layer chromatography.
EXAMPLE XI
Following the test procedure previously des-cribed, the following compounds were tested for their antisecretory activity. The ED50 values for p.o.
administration and the percent inhibition for i.d.
administration at 20 mg/kg are tabulated below (Ri =
H except where noted):
~1 R~ R2 A~NC=NR3 . _ . . ... , _ _ _ .. _ . . , .. _ . . ~
MN
~4~ ~8 O O O O ~O O ~D ~ ~ ~ ~ a~ c o ~o o o ~ In ~
~ O O O O O 0~ G 0 t~ ~ t~ O O ~ t` ~0 o 8 '` ~ ~ co ~ .` 'D ~ ~D ~ o ~ ~ ~
u~ C ~r o o ~ CD CO ~ ~ u~ ~ CO ~ ~` ~O ~ ~ O O O
k~ ~ ~ A V
~N ~J
1 ~ t ~ I r : ~ e .
~3' r~
l.8 ~3 a ~
o ~ O N t` C~ W 0~ ~
o o In ~ co I o ~ +~+U- ~
~I cl ~14V~ ~8 2~
EXA~?LE XII
Following the procadure 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 S amides, wherein the following substituents are in the two (Rln), three ~Rl') or four ~Rl) position:
1~ Rl" , 1 ~ .NC=O
A ~ R2 Position of Substituent S~i~t ~ A
dipbeny~ yl 4 H H
c~ (4~11t~he~1)bq~1 n n n (4~rethylEiher~1) b~l n ~ n (4~1~9/~l)be~l n n n ct~ (4--chl~phe~l)}~l 3 9--fluor~l ~ n n d~hes~l n ~ n ph~yl 4 n phe~l n 4 ~ lar ~ yl " " H
4-chl~rcpheny~ " " phenyl 20 4-methcxypheny1 " " H
4-methcxyph~nyl " " phenyl 4-chlordbenzyl n n H
phenyl " methylphenyl pbenyl n n-butyL phenyl 25 o!(l,4-bipbenyl)benzyl " H H
or(l~4-biphenyl)b#nzyl " methyl o-(1,4-bipbenyl)henzyl " n-butyl n 2,2-dipheny1ethy1 " H "
2,2-diphenylethyl n methyl 30 2,2-diphenylethy1 ~ n-butyl "
10,11-cbhydrc-SH-dikenzo[a,d]-cycloheptene-S-yl 2 H "
~4V~
25 ~ositic~n of Su~tih~t Substituent ~ A
10,11~ ~5H~Z Ea~d] -qk~hept~5-yl 2 ræt~yl H
n n rs--~l~l n n- 4 H "
n " meff~yl n n--but 4,4~1-n-}~1 4 H ~
4 ~ 4~1~ l n T~l n 4 ~ 4~ l nn--butyl n 4~th~1 n H ~
benzyl - - n 9--f Lu~l n n n dip~3met~1ene n n -~-(4~1)~1 " " "
--(4~1p~yl)bOE~ n ~~ (4~1) be~ tl n n n dipe~l 3~ " "
Y~Y1 2 0 a--(4~hl~1) b~l n n n pheryl 4 n n 9--fluore~l n n n 4--chlxo~ - n 4~1 n n ~
2 5 4~c~1zyl n 1~ n 4~e~1 1~
~zyl .. .. ..
dipher~ylmethylene n n n a-(4~orc~yl)b~zyl " " "
(4~ctl~1) b~zyl ~' n ~
- (4~ret~1F~yl) b~zyl " " "
diE~henylme~yl 3 " "
9-flu~renyl 1. " "
~lw~l 4 " "
--(4--chlor~yl~b~zy1 3 n Positic~ of Substitu~t S~ entR~ A
5~o[a,d]cyc~5-yl 2 H H
n n me~l n n n--bu~yl lO,ll~ydro ~a,d] ~yc~5-yl n E~ n " " me~l "
n n n~ 5~1 n E~Tl (oc~l)mEt~l 4 H n n ~ yl n " n-h~l phe~l ~h~l)m~l ~ H
n }~1 n n n ~b~l n p~e~l n n n W~l n ~ n 4-ræ~1 n 1~ n be~l n n n Wllc~l ~I n n 4~ _1 n n n q~l 2 H n diE~yl n ~1 di~ lmethyl n n-butyl 5H~szota,d]cycloh~J~s-~-yl 4 H n 5~-d~#~c[a,d]cyclohq~5-yl n methYl n 5~d~x~o[a,d~cycJ~ en-5-yl " n-butyl 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:
,~, s~
2)n Po~ition of Substituent n R2 n n CH3 S n n n--butyl " 1 H
n ~ CH3 n n n-butyl " 2 H
n n CH3 n 1l n-butyl-n n CH3 " " n-butyl " 1 H
n n CH3 n ~ n-butyl " 2 H
" " CH3 2 0 n n n-butyl 1~4~
EXAMPLE XIV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
~,, ~ NC=O
wherein R2 = hydrogen, methyl~ or n-butyl.
EXAMPLE XV
Foll~wing the procedure of Example XIII, there are prepared the following piperidine amides:
(C6HS)2C ~\
~`NC80 10Position of Substituent R2 " CH3 " n-butyl n CH3 n n-butyl " CH3 n n-butyl 1~4~.8 EXAMPLE XVI
Following procedures describPd in the references given above for compounds o~ Formula ~III), the following are prepared: 1l IH
~2 R3 H -(CH2)llCH3 (CH2)7CH3 H -(CH2)l4CH3 H -(CH2~4CH-CHCH CH
Hcls-(cH2)5cH=cH(cH2)locH3 ( 2)6C_CH
H 4-ClPh-H 4-MeOPh-H 4-MePh-H -C~2C--CH
~ exo-2-norbornyl H endo-2-norbornyl Hl-decahydronaphthyl H l-adamantyl H2-bicyclo[2.2.2]octyl Hanti-7-norbornenyl Hendo-bicyclo[3.2.lloctyl Hl-adamantylmethyl Me H
Me -C2H5 Me -(CH2)5CH3 Me -(CH2)7CH3 Me -(CH2)l4CH3 Me-(CH2)4CH=CHCH2cH3 Meclg-(CH2)5CH=CH(CH2)loCH3 Me -CH~C-CH
Me (CH2)6C--CH
Me Ph Me 4-ClPh-Me 4-MeOPh-Me 4-MePh-Me PhCH2-Me 4-ClPhCH2-Me 4-MePhCH2-M~ 335 ~4(~
Me 4-MeOPhC~2-Me 2CH2 Me exo-2-norbornyl M~ endo-2-norbornyl Me l-decahydronaphthyl ~e l-adamantyl Me 2-bicyclo[2.2.2]octyl Me anti-7-norbornenyl Me endo-bicyclol3.2.1]octyl Me 1-adamantylmethyl n-Butyl H
l-nBU" ) Bu C2H5 Bu -CH2CH=CH2 Bu (CH2)7CH3 Bu (CH2)14CH3 Bu -(CH2)4CH=C~C2~5 Bu cis-(cH2)5C~=CH(cH2)locH3 Bu CH2C-CH
Bu ( 2)6C-H
Bu 4-ClPh Bu 4-MeOPh Bu 4-MePh Bu Ph Bu PhCH2 Bu 4-ClPhCH2-Bu 4-MePhCH2-~u 4-MeOPhCH2-Bu PhCH2CH2 ~u exo-2-norbornyl Bu endo-2-norbornyl Bu l-decahydronaphthyl Bu l-adamantyl Bu . 2-bicyclo[2.2.2]octyl Bu anti-7-norbornenyl Bu endo-bicyclo[3.2.1]octyl Bu l-adamantylmethyl H diphenylmethyl Me diphenylmethyl Bu diphenylmethyl H 3,3-diphenyl-n-propyl Me 3,3-diphenyl-n-propyl Bu 3,3-diphenyl-n-propyl ~40~ 18 EXAMPLE XVII
Following the procedure of either Example I or Example III, bu~ substituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane or N-formyl-4-diphenylmetXylpiperidine 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 su~sti~uents are in the two (Rln), three (Rl'), or four (Rl) positions:
Rl l Rl n Rl ~<
A--\_~NC=NR3 Posi--tion of S~x*itNent S~x~i-~ ', or ~n) uent ~ R3 A
d~nylmethyl 2 H H H
dipheny~ yl 3 n ~ n 15 9-fluorenyl " n n n c~--(4~1)berlz~1 n n n "
di~ f~Nymethyl 4 " " n 10,11-dihy~x~5~ ~zo "
[a,d]cycloh~en-5-yl 4--chlon~x~y1 n n 20 4~o~enyl dipheny~E~l n n (~)11CH3 4~hlD~l n a-(4-methylphenyl)benzyl " " " "
4-chlorokenzyl n n n ~--(4~hl~1)--tY-- l~ n ~ydm~1 a-(4-~ophenyl)ben2yl 3 " " "
9-fluorenyl ~ n 4-metbI~uy1 4 " -(CH2)7CH3 9-~luorenyl 3 " n dipbenyl~y~s~ymethyl 2 a-(4~o~pY~y1)benzyl 3 " n 1~4V~
Posi--~ o n ) uent R2 R3 A
diph~nylhy~raxy~yl 4 H - (CH2) 7CH3 H
51~dikG~o[a,d3 n ~yc~hep~-5-yl yl n d~l (CH2) 14CH3 ~1 cr ~4--chlon~pherlyl ) b~lzyl 3 " " n 9-flu~renyl 4 " " "
~ 14-methyl~henyl)benzy1 "
4~hloq:c~1 n n n n ~1 " l~ ,. "
di~henylmet~yl " -(CH2)4C~I2CH3 ~E~l)benzyl n d~l8~t~1 3 10~11~5~ y_ ~
5}~dil~lzo [a,d] cyt:ld~5-yl 9--fll~lyl n ~ n di~ly~ret~lyl 4 ph~yl " " " "
~ ~l n ~ n diphenyl~ thyl n ~ CLs--(CEI2) cE~(CH2)10CH3 c~~ (4~hla~?he~1)b~zyl 3 9-~9-flUDl~T1 4 --(4~hl~lyl) ~~ I- ~ n n ~1 4~et~:yl " " " "
2 5 berlzyl ll ll ll n cr (4~1~ yl)be~1 n dip~Iylmethyl n " (CH2) 6C{~
a- (4-chlor~pbenyl) benzyl " " " "
~1 3 0 9-fluar~nyl 3 " " "
a-(4-chlorop~enyl)benzyl " " " "
dip~ylTrethyl 2 .. " n Posi--~ o S~nt S~
, R~ ', or Rln) uent ~2 .R3 A
}~1 4 H (C~z) 6C-CH . H
4--~leth~l n " n n d~T~ E~l n n --CH2C ~{ H n a--(4--leti~l)b~l n n a--(4~tly1p~1) ~-- n ~ n n ~1 --(4~L)berlzyl 3 " n n 9--fll~l 4 n n n [a,d] ~c1~5-y1 10 4~ethNyE~h~l n n n E~yl 4~hlo~c~1 n ~ n H
dipb~ n n exc~--2~1y1 n a- (4~et~y1p~1) b~1 " " ~ n a--(4~1)--a-- n n n n ~1 diF~lmet~l 3 n n n 9--flu~l ,. n E~yl 4 " n n 4-chLor~ibenzyl n n ~ n ~-(4~hlar~yl)b~zy1 " " en~2-nor~ornyl "
diphe~ethyl " n n di~enyl~ ~ethyl a-(4-chlorop}~yl)benzyl 3 9--flu~l ~ .. n n 4~y~yl 4 " " "
b~zyl ~ .. "
di~enylIrethyl ~ nl--deca~ydr~phthyl n a- (4~yl) b~zyl " n ~- (4-methylp~yl)--a- n ~b~l dipheny~thyl 3 "
9--fluorenyl ~ .- n ~
p~enyl 4 " " "
4-chlor~l ~- (4-meth~yl)benzyl " " l~nantyl "
~14 Posi-tian o~
Sl~bstituent Su~
(Rl, Rl', ar Rln) uent R2 R3 A
10 ,11--di3y~5-~dr~ 4 H1-ad~nan~yl H
5}}di~ ta,drc~yc~5-yl ~~ (4~hlo~l)_a_ n n ~ n ~1 a--(4~1)b0zy1 3 n n 9--flg~l n ~-4--chl~l 4 n n F~l n n n El diph~et~l n n2-bic~yclo~2.2.2]oc~1 -(4-~retl~1)~enzy1 " " " "
d~ ~Crc~l " n n n diphen~l 3 n n n 9--fluore~l 4 n n E~l .. n n 4~etho~1 ~ n n n 15 dip} ~ ~rethS~l n a ~ -7-I
-~4-c~lk=~ enyl)benzyl " n n ~-(4 m~Lhylphenyl)-~- n n ~1 dipheny~mEthyl 3 n n -9-fluorenyl " " " "
20 phenyl 4 n n 4-~hlorobenzy1 " " " "
diphenylmethyl " " enlo-bicy~10[3.2.1]octyl o-(4-methylpheny1)benzy1 " " n n diphenyIhydroxy=ethyl n n n ~
25 ~-(4-chlorcpbeny1)benzyl 3 " " "
9-fluorenyl n n dipbenyIhydr=xymethyl 2 " " "
4-methcxypbenyl 4 " " "
b ~ zyl " n n 30 diphenylmethyl " "l-adamantylmethyl "
-(4-methcxyph~=yl)benzyl " " n n a-(4-chlo ~ 1)_o_ n n hydrax ~ l a-(4-chlorc~henyl)benzyl 3 V~ ~ ~
Posi--tion o 9-flu~l , 3 Hl-adamantyl~1 H
phe~l 4 n ~ . n 4--sw~l n ~ n n diE~3~1m~1 laeth~l H n --(4~1)~1 n n ~ n a--(4--chl~Yl)~~ n n n n ~1 5--~51~di~1zo n n n n [a,d] c:ycl~-5-yl ~ (4~yl)ber~ 1 3 ~ n 9--fluorer~1 n n n diEhel~lmeff~l 2 n n ~
4--chlcl~l 4 n n 1 be~l n n 11 n t~ (4--llethc~phe~l)be~l ~I n n n a--(4~ylpt~nyl)--a-- n n ~ n ~1 dip~yl~ }~l 3 n 1~ n 9--h~r~9--flua~l 4 n n ~
4~th~y~yl " " " "
2 0 10 ,11 di~yd~5i}di~eDzo [a,d] cycl~-5-yl b~lzyl ~- n (~(4~1phe~lyl)be~lzyl n --(CH2)7CH
dipher~llyd~ynet~yl n a- (4~hlo~1)~1 3 n 2 5 9--fluor~l p}~l 4 " " "
be2~zyl ~ n n dipheny~nethyl " "(~ H2) 14CH3 a- (4~hl~phen~1)benzy1 " " "
3 0 a- (4~ret~y1) ~ " "
hydm~yl dipherlyln~l 3 " " "
9-fluoren~l " " "
Posi ti~l of o~ Rln)uent R2 R3 4~etlcyphenyl, 4 I~etl~l(CH2) 14CH~ H
4--chlorobenzyl " n n n d:i~y~hyl " n--CH2CE~=CH2 n a--(4--~l~ti~l)b~ln n n n l n r n Eh ~1 n n ~ H
a-~4~1)bq!1 3 " " n 9--flu~re~yl n n Il n 4--chlor~henyl 4 bq~l " " " "
dipe~lllet~l n n~ (CH2 ) 4CE~H2CH3 a--(4~ethylphe~1)be~1 n n n n a--(.4~bl~Y1)~-- n u n n ~1 di.E~ylIIethyl 3 n n n 9~fluorenyl l 4 n n n 4-chlorobenzyl " ~ n n diphenylmeth yl ~- n Cis--(CH2~5C~=CH( ~ )10 3 a-(4-methDxyphenyl~ken2yl" " " n diphenYlhydroxymethyl " " " "
g-flu~renyl 3 n a-~4-chl~opheny1)benzyl " " n 4--me~/l 4 ~ n 25 b~lzyl ll 1' ~I ll a--(4-methylphenyl)benzyl n l~ n a-(4-chlorcphenyl)-a_ " "
}~1 phenYlmethyl 3 " n ll 30 g-hydroxy-9-fluorenyl 4 " " "
~yl "
4-metho~ybenzy1 dipbenylmethyl n n~ (CH2) 6C---CH n a-(4-chlorophenyl)benzyl " " n diphenyIhy~roYymet~yl " " " "
l8 Posi-tion of S~b~t S~
(R~., Rl', or Rl") uent ~ R3 A
dip~y~e~l 3 nE~yl--(CH2)6C~CH H
9--f luorer~l n n n n diFbe~lly~3~1e~1 2 " n n 4~hlc3~ 4 ~ n diphe~l~E*}~l n n benzyl n a-(4~p~1)benzy1 " " 4-chlc~e~1 "
diphe~Tlh~ 4~
diEihe~y~l 3 " 4~1b~1 "
10 ~ dih~5--~n n n n 5}}dib~zo [a,d3 c:yc1at~5-yl 9--fluor~Tl - n "
-(4~yp~1)~enzyl 4 " 4~ora}~nzyl "
4--chlor~benzyl " ' benzyl n diph~ny~ yl " " ~2~ ornyl n a--~4~eth~1pbenyl) b~zyl n 1- n n ~Iyl ~ n n p~ enyl diphe~ynet~l n ~ n H
diph~nylmRthyl 3 2 0 Eiber~l 4 n n 9--fluorenyl 3 ~. n ~1 4 ~ n 10,~ ydr~5E~dib~zo [a,d] c~clo~p~-~yl dip~ny~rethyl ~ " ~2-n~ornyl "
a-(4 chlorc~henyl)benzyl " " " "
--(4~net~1ph~nyl)~- n n n h~dra~l diF~y~rethyl 3 " " "
9--fluorenyl n n n n 4~reth~p~enyl 4 " " n 3 o 4~or~zy1 " " " "
dip~yl~thyl " " l--decalyd~p~thyl n - (4-~y~l)benzyl " " " "
dip~y~t~l " " "
-(4 chl~1)benzyl 3 " " "
~ 335 1~4~
Posi-ti~ of Substituent Sl~bSti-(Rl, Rl', or RLn) uent R2 R3 A
4~hlQ~yl 4 n n n 4--net~yb~1 n n n n 5di~lmet~l n n1 a~~
~- (4~hlom~y1~benzy1 n ~ n n --(4t~ n n ll n h~drax~l dip~ylIl~l 3 n n n 9--flu~r~yl " " n n E~l 4 " " "
benzyl diphe~et~l n n2--bi~yclo[2.2.2]oc~yl "
dip~Dydr~l " " n n 15--(4--chlor~enyllbenzyl 3 "
9-flu~r~nyl 4 " "
4--chloropher~1 n n n n 4~ff~ny1 n n n n dipher~y~rethyl " anti--7--r~yl ..
a--(4-methylphenyl)benzyl " n n 1-diph~yllllet}~l 2 a- (4-chl~yl)b~1 3 phe~l 4 " " n 9--fluorenyl 3 4--me~1 4 " n diphenylIrethyl " "d~icyclo[3.2.1]oct~
p~yl " " " p~wlyl a--(4~hlo~yl) benzyl n n n H
3 0 diE~nylhy~t~yl " n n dipl~y~rethyl 3 "
9--flucxrenyl n n n 4--chlor~yl 4 " n b~yl " " " "
3 5 diph~ny~lrethyl 1~ "l-a~nnanty~thyl "
~3 Posi-~ o~
- (4~ylp~yl)benzyl 4 met~l l-adanantylnethyl H
c~--(4--chl~Yi) ~-- n n n n h~l diF~l 3 n n ~
9--~qUQ~l n n n n 4~t~ypl~yl 4 n n n W~l n n d:iph~ eth~ 1~1 H l~
--(4--ll~th~l)bel~l n n n n dipbe~l 3 n n n 9--fluor~l n n n n pb~yl 4 ll ~ n 4~yl ll n ll diE~y~et~Lyl " -C2H5 n he~ yl n n n ~yl a- (4~1) b~zyl " " " . H
a--(4--chl~yl)--a~ n n n n ~1 di~yl~thyl 2 " n n ~--(4--chlor~?henyl)b~1 3 n n n 9-fluorenyl ~ - n 4~t~ypenyl 4 " " "
n ll ll n diph~ylmethyl " " --(CH ) 7CH n c~--(4--chlo~henyl)b~zyl " n 3 d:i.Fberly~:e~Tl ~ n n ~-dipherlyl~ thyl 3 9--flut~ren~l ~yl 4 n n 3 0 b~zyl d:ipheI~yl~thyl " ' - (CH2) 4CH
a-(4-srethylph~yl)benzyl " " 1 3 cc--( 4--chlo~ophenyl ) b~l 3 3 5 9-fluDrenyl " " " "
. _ . . . _ .
M~ 335 ~ 14V~.~8 Posi--tio l o~
Substitu~nt Substi-(Rl Rl' or Rln) uent . R~ R3 A
10,11 dilyd~ 3 n~ut~rl (C~2)14CEI3 H
5~di~z= [a,d] ~c~eptcr~yi 4~e1~ ~1 4 ~ n n 4~cro~zyl n n n n d~henylmethyl ~2CE~=CH2 n a--(4~hlcrc~yl)b~zyl n n n n di.p}~y~d~l~l n n n n --(4--chl~1)b~1 3 n n n 9--flu~yl n n n n 4~c~ henyl 4 n n n b~l n n n n d:i.ph2n~1mPthyl ~ C~2) 4 2~5 5--h~d~5E~di~o n [a,d] cy~:lc~5-yl a--(4--srethylp~yl)b~nzyl n n n ~
a--(4~y1)~ n n n ~yd~l dipheny~ yl 3 n n n 9--fluorenyl " n 1~ I~
E~enyl 4 " " "
4--chlo~1 .. .. n . n diph~Iyl~ ncis--(CH2)5C~H(CH2)10CH3 a--(4~71phenyl)b~rl n l~ n l~
dip}~31ydr~1 " " " "
a- (4-chlo~p~enyl)b~zSr1 3 " n 1~
9--flu~renyl " n ~ n 2 5 phenyl 4 ~ .. ..
4--~y~l " n n n diPh~Y~rethyl " l-CH2C~
a--(4--Irethylp}~yl)benzyl n n n diPhe~llyd~ycet~yl " " " "
3 0 10 ~ dilyd~5H-dib~zo n n n [a,d] :yclo~5-yl dip~31rethyl 3 " n 9--fluarenyl " " n 1~
4-n~h~yp~:yl 4 " " "
~ll401 ,~l8 Posi-~ o~
&b~tituerltSl~bsti-(Rl RL~ 0~ Rln) t~t R2 R3 A
benz5~1 ~ 4 n~ CH2C-~ H
d~et~l n ~ CH2) 6C~
a- (4~10r~1)benzyl S phe~l n n 1~ phe~l ~ (4~tb~1)-a-- n n n H
~yl a--(4--chlor~1)benzy1 3 n n n 9--flu~rl n n n l~
~yl 4 n n n 4~ n ~
d~l n ~ ?l n a- (4-met}~tlphe~l)b~ylzyl n ~l 4-chlor~1 ..
a- (4~1O~-yl) ~- " n4-sr~Yl~Zyl "
~dss:~yl di l~yl~ 1 2 . n d~ ret~l 3 " 4~h~ny1 9--flua~enyl n n 1~ n yl 4 b~tl n 4~reth~1 " "4~thylbenzy1 "
diph~l " " phenethyl --(4--Iletb~l)benzyl " " n ~1 3 ~ n 9--~dr~9--fluorenyl 4 ~ yl ~- n n n 2 5 4-chlor~benzyl dip~lyllllethyl n n ex~2~ yl ~~(4~ylE~he~1)be~1zyl diFa~y~EI hyl n ~I n n a- (4-chlor~r1)b~zyl 3 " "
3 o 9--fluore~l n n 4~ cyE~yl 4 b~lzyl ~ n diF~exlyl~l~thyl n 1~eI~2--rx)~o~lyl ~- (4-chl~1)benzyl " " " "
~ M~ 335 ~L4~
tion of tR~., R~', o~ Rln) uent_ R2 R3 A
a- (4-met~ 4n-}~u~l erx~2-nor~ l H
dip~ln~yl 3 " "
9--fluor~yl n n n n 5 Ehe~l 4 n 1~ n ~h5~1 n ~ n n dip~nethyl n n l~th~l n a--u~l)b~Tl " n n 1~
~x--(4~ph~lyl ) ~-- n n n n 10 phenyl .. n 1~ phenyl o~--(4~1~æhenyl) ben~l 3 n n H
9--fluorenyl n n n n p~l 4 n n n benzyl n n n n 15 dipeny~Ilet~l " " l-a~an~tyl n a--(4~eth~phes~1)benzyl " n n n di~iheny1lyd~et~ n diE~y~et hyl 3 n 9--f lul~renyl n n l~
20 4-chlor~yl 4 " " "
4--chl~yl " ~I - n dip~yl~et}~l ~I n2--biCyclo[2.2~2]octyl --(4~hylp~enyl)ben~1 " n ll n a- t4-chl~rcphen~l)-a- " " "
~1 25 a- (4-chl~r~yl)b~zyl 3 n ll ll 9-flu~enyl " " " "
phE~lyl 4 n n n 4~e~1 1~ n dip~ly~I~etbyl ~ ~ ~-7-~ yl 30 a-(4~l~1p~1yl)benzyl n ll dip~eny~ rethyl " " n diEibenyl~rethyl 3 " " "
9-flu~enyl ethyl 2 n r~
1~4V~
Posi--tiOIl of Substil:uentSubsti-(Rl, Rl', c~r Rl") uent R2 R3 A
4tret~=y~y1 4 ~utyl an~i-7~y1 EI
4~hl~yl n n n diFb~;ylllethyl " endo~i~yclo[3.2.11a~
--(4-ilet~E~l)~eslzyl n n n n a--~4--Irethylphe~71~---- n n n n IydmY~l , a--(4--chlarc~l)~lzyl 3 n n n 9--flu~c)~l n E~yl 4 " n n 4--*eth~1 n " n n dipb~yllr~thyl " "l--ad~ntyllrethyl ~~ (4--~letb~l)b~lzyl n l~
dipheny3~yd ~ y ~ ~hyl " " " n diphenylmethyl 3 " n "
15 9~fluorenyl n ll phenyl 4 ~ n bg~z~l n n n n ~-(1,4-biphenyl)benzyl " H H "
~-~1,4-biphenyl)benzyl n C~ ~(CH2)7CH3 "
20 -(1,4-biphenyl)benzyl "n-butyl phenethyl n 2,2-dipbeny1ethy1 " H H "
2,2-diphenylethyl n CH3 -(CH2)7CH3 2,2-dipheny1ethyl "_-butyl phenethyl "
4,4-diphenyl-n-butyl " H H "
4,4-dip~enyl-nrbutyl n CH3 -(CH2)~CH3 "
4,4-diphenyl-n-butyl "nrbutylphenethyl "
diphenylmethyl " Hdiphenylmethyl phenyl 3 CH3 " "
9-fluorenyl 4n-butyl " n 30 4-chic~obenzy1 " H3,3-diphenyl-n-prcpyl "
diphenylmethyl 3 CH3 " "
diphenyIhyd mxymethyl 4 n-butyl Posi-tion of Sub6tit~ent Substi-~ ', or ~ ~) uent ~ ~ A
phenyl(octyl)methyl 4 H H H
10,11-dihydro-5H-dltenzo 2 " -( ~ ) ~ n [a,d]eyclcheF~er-S-yl 3 5~-diben~o[a,d] n ~ n eye1 ~ 5-yl 5 pbenylnhByl)methyl 4 n (~) 6 n E~l (hexyl)~l n mB~yl~ (C82) 4CE~ OE H2CH3 n 10,11-dbhy~e-5H ~ o 2 " -(C ~) C~rH "
[a,d]eye1 ~ -5-yl 6 5E-dlte~zo[a,d] " " " n eyelQheptEn-5-y1 lO,ll~yd~5E~di~zD n ~h~l ~2C3 n [a~d]cyclohept2nr5-yl 10 5H-dikenzo[a,d] " " n cyclQhept~n-5-yl phe~yl(octyl)~ethyl 4 " F~ yl n ~ 5 ~40~l.8 4s Example XVIII
Following t~Q procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-5 4-diphenylmethylpiperidine and ethylamine, respectively, used therein, e~uivalent amounts of the appropriate starting materials suc~ as described in Examples XIII
and XVI, there are prepared the following:
(C~2)n ~
~ ~ NC-NR
Position of 10 Su~stituent n ~ R
_ 2 3 3 0 H n-octyl 3 0 H _-dodecyl 4 0 H n-hexadecyl 4 CH3 n-octyl 4 0 n-butyl n-octyl 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 Z H n-octyl 3 2 H n-dodecyl 4 2 H n-hexadecyl 4 2 CH3 n-octyl 4 2 n-butyl n-octyl ~4~
EXAMPLE XIX
Following the procPdure of either Example I or Example III, but suhstituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, equival~nt amounts of the appropriate starting materials such as descri~ed in Examples XIV
and XVI, there are prepared the following:
\ /
. A~
~ NC--NR3 ~O>
~ H
H n-octyl H n-dodecyl H n-hexadecyl c~3 n-octyl n-butyl n-octyl H H
H n-octyl H n-dodecyl H n-hexadecyl CH3 n-octyl n-butyl n-octyl H H
H n-octyl ~ n-dodecyl H n-hexadecyl CH3 n-octyl n-butyl n-octyl MN.335 1~4V1 18 EXAMPLE XX
Following ~he procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and ~-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, e~uivalent amounts of the appropriate starting materials suc~ as described in Examples XV and XVI, there are prepared the following:
(C6H5) 2C~\
\ NC=NR3 Position of 10 Substituent n R2 R3 2 0 H _-octyl 3 0 H _-dodecyl 3 0 H n-hexadecyl 4 0 CH3 n-octyl 4 0 n-butyl n-octyl 2 1 H _-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 n-octyl 3 2 H n-dodecyl 3 2 . H n-hexadecyl 4 2 c~3 n-octyl 4 2 n-butyl n-octyl 114() EXAMPLE XXI
N-[4-(Diphenylmethyl3-1-piperidinyl]
methYlene benzenebutanamine (E)-2-Butenedioate Hvdrate , A ~ixture of 4.40g (0.016 mole) of N-formyl-4-(diphenylmethyl)piperidine and 1.47 ml (2.00g, 0.015 mole) of dimethyl sulfate was heated in a steam bath for three hours at 100C under anhydrous conditions until homo-geneous. The mixture was cooled, dissolved in 30 ml of methylene chloride and treated with 2.50 ml (2.36 g, O.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 wa~ separated, dried over potassium carbonate, filtered and evaporated ~o 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-14-(diphenylmethyl)-1-piperidinyl]-methylene benzenebutanamine (E)-2-butenedioate hydrate as a white crystalline solid, m.p. 207-208.5C.
EXAMPLE XXII
~-(Diphenylmethyl)-l- l-[me~hyl(octylimino) methyl]-piperidine Monoperchlorate .
A mixture of the fluoroborate salt of N-octyl-acetimidic acid ethyl ester ~generated from 5.68g [Q~04 molel of boron trifluoride etherate, 2.77g [0.03 mole]
of epichlorohydrin, and 5,80g t~.~34 mole] of N-octyl acetamide) and 5~ ml of ether was treated with 4 ml ~2.92g, 0.029 mole~ of triethyl amine~ Filtratio~ and evaporation of the filtrate afforded a liquid residue whic~ ~as 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 50C
over 4A molecular sieves under a nitrogen atmosphere for four days. The reaction mixture was cooled and neutralized by ~haking with 3 N sodium hydroxide solu-tion. The organic layer was separated, dried over X2C03, filtered and stripped to an oil which was distilled.
M~ 33s l~LV~
4g The pot residue was dissolved in ether and perchloric acid and methanol added. Cooling the solution pro-duced a solid fraction. Filtration afforded a crystal-line solid whi.ch was recrystallized three times from S methanol to give 4-(Diphenylmethyl)-l- l-[methyl(octylimino)-methy]~piperidine Monoperchlorate as a white crystalline solid, m.p. 119-121.5C.
EXAMPLE XXIII
a-(4-Methylphenyl ? -a-Phenvl-4-~yridine Methanol A solution of 0.05 le of 4-methylphenyl magnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in S00 ml anhydrous ether.
After stirring the n~lting m~re for 1.5 hc~rs at 25, an ~æ~s soluticn of a~L~ium ~ik~ide was ~ causing a solid to form which waQ filtered. Recrystallization of thi~ material ~rom 95% ethanol afforded the desired ~-(4-methylphenyl)-a-phenyl-4-pyridine methanol, ~.p. 192-135C. The corresponding 4-chlorophenyl (~.p. 198-202C) and 4-methoxyphenyl (~pO 204-206C) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
EXAMPLE XXIV
x-(4-Methylphenyl)-a-Phenyl-4-Piperidine A solution of 25~0g (0.09 mole) a-(4-methyl-phenyl~-a-phenyl-4-pyridine methanol, 55 ml of 47-Sl~
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 60-65C in acetic acid following the method of United States Patent No. 3,267,108. The excess acid was removed and the residue made ba~ic to give a-(4-methylphenyl)-a-phenyl-4-piperidine which was characterized as its fumarate salt, m.p. 157.5-161.5C (Hoover). The corresponding 4-chlorophenyl (m.p. 175-178C; fumarate salt) and ~, ~14 sn 4-methoxyphenyl (m.p. 94-98C; free base3 derivatives were also prepared by the same method, using equivalent amounts of the appropriate star~ing materials.
. EXAMPLE XXV
s -(1,4'-Biphenyl)~l--phenyl-4-pyridinemethanol A solution of 111.0g (0.50 ~ole) of 4-biphenyl bromide in 200 ml of dry ~etrahydrofuran ~THF) was added slowly to a mixture of 12.10g (0.5 gram-atom) of mag-nesium, 2 ml o~ ethylenedibromide and 200 ml of T~F 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 25C 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 ~rom ethanol, chloroform, and finally toluene to give a-(1,4'-biphenyl)-yl-a-phenyl-4-pyridin methanol as a white solid, m.p.
after drying in vacuo at 70C; 173.5-175.5C.
EXAMPLE XXVI
_ a-(1~4'-Biphenyl)yl-a-phenyl-4-~iperidinemethanol A solution of 10.00g (0.030 mole) of a-(1,4'-biphenyl)yl-a-phenyl-4-pyridine and 160 ml of acetic acid was hydrogenated in the presence of platinum oxide (1.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 was slurried in water, made basic with 3 N NaOH and ex-tracted 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-lized from toluene to give a-~1,4'-biphenyl)yl-a-phenyl-4-piperidinemethanol as a white solid; m.p. 185-186.5C.
481.1)3 EXAMPLE XXVII
9-(4'-~ eridinYll-9-fluorenol A sslution of 13.0g (0.05 mole) of 9-(4'-pyridyl)-9-flu~renol 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 bas~c affording 9-(4'-piperidinyl)-9-fluorenol.
EXAMPLE XXVIII
4-Fluorenylidenepiperidine A suspen~ion of 13.0g (0.05 mole) of 9-(4'-piperidinyl)-9-fluorenol in 70 ml of 48% sulfuric acid was heated on a steam bath for ~even 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 qeparated, dried over potassium carbonate, filtered and stripped to give 4-fluorenylidenepiperidine.
EXAMPLE XXIX
9-(4'-Pyridyl)fluorene A solution of 1.35g (0.005 mole1 of ~,a diphenyl-4-pyridine methanol in 18.5 ml of 97% formic acid was treated dropwise with 8 ml of concentrated sulfuric acid.
The r~action 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 me~hanol to give 9-(4'-pyridyl)fluorene, m.p. 141-143C (Hoover).
EXAMPLE_XXX
9-(4'-PiPeridYl)fluorene fumarate A solution of 54.75g (0.225 mole) of 9-(4'-pyridyl)fluorene in 600 ml of acetic acid was hydro-genated over S.Og of platinum oxide at 40 psi and 25C.
The mixture was filtered, stripped and made basic, afford-ing 9-(4'-piperidyl)fluorene, which was crystallized as the fumarate salt, m.p. 228-230C (dec).
isonitrile, 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 i~ methylene chloride.
Extraction with 10% sodium hydroxide, drying and filtra-tion of the organic layer followed by evaporation afforded 4-(diphenylmethyl) l-[(octylimino)methyl]piperidine isolated as the fumarate salt, which was identified by thin layer chromatography.
EXAMPLE XI
Following the test procedure previously des-cribed, the following compounds were tested for their antisecretory activity. The ED50 values for p.o.
administration and the percent inhibition for i.d.
administration at 20 mg/kg are tabulated below (Ri =
H except where noted):
~1 R~ R2 A~NC=NR3 . _ . . ... , _ _ _ .. _ . . , .. _ . . ~
MN
~4~ ~8 O O O O ~O O ~D ~ ~ ~ ~ a~ c o ~o o o ~ In ~
~ O O O O O 0~ G 0 t~ ~ t~ O O ~ t` ~0 o 8 '` ~ ~ co ~ .` 'D ~ ~D ~ o ~ ~ ~
u~ C ~r o o ~ CD CO ~ ~ u~ ~ CO ~ ~` ~O ~ ~ O O O
k~ ~ ~ A V
~N ~J
1 ~ t ~ I r : ~ e .
~3' r~
l.8 ~3 a ~
o ~ O N t` C~ W 0~ ~
o o In ~ co I o ~ +~+U- ~
~I cl ~14V~ ~8 2~
EXA~?LE XII
Following the procadure 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 S amides, wherein the following substituents are in the two (Rln), three ~Rl') or four ~Rl) position:
1~ Rl" , 1 ~ .NC=O
A ~ R2 Position of Substituent S~i~t ~ A
dipbeny~ yl 4 H H
c~ (4~11t~he~1)bq~1 n n n (4~rethylEiher~1) b~l n ~ n (4~1~9/~l)be~l n n n ct~ (4--chl~phe~l)}~l 3 9--fluor~l ~ n n d~hes~l n ~ n ph~yl 4 n phe~l n 4 ~ lar ~ yl " " H
4-chl~rcpheny~ " " phenyl 20 4-methcxypheny1 " " H
4-methcxyph~nyl " " phenyl 4-chlordbenzyl n n H
phenyl " methylphenyl pbenyl n n-butyL phenyl 25 o!(l,4-bipbenyl)benzyl " H H
or(l~4-biphenyl)b#nzyl " methyl o-(1,4-bipbenyl)henzyl " n-butyl n 2,2-dipheny1ethy1 " H "
2,2-diphenylethyl n methyl 30 2,2-diphenylethy1 ~ n-butyl "
10,11-cbhydrc-SH-dikenzo[a,d]-cycloheptene-S-yl 2 H "
~4V~
25 ~ositic~n of Su~tih~t Substituent ~ A
10,11~ ~5H~Z Ea~d] -qk~hept~5-yl 2 ræt~yl H
n n rs--~l~l n n- 4 H "
n " meff~yl n n--but 4,4~1-n-}~1 4 H ~
4 ~ 4~1~ l n T~l n 4 ~ 4~ l nn--butyl n 4~th~1 n H ~
benzyl - - n 9--f Lu~l n n n dip~3met~1ene n n -~-(4~1)~1 " " "
--(4~1p~yl)bOE~ n ~~ (4~1) be~ tl n n n dipe~l 3~ " "
Y~Y1 2 0 a--(4~hl~1) b~l n n n pheryl 4 n n 9--fluore~l n n n 4--chlxo~ - n 4~1 n n ~
2 5 4~c~1zyl n 1~ n 4~e~1 1~
~zyl .. .. ..
dipher~ylmethylene n n n a-(4~orc~yl)b~zyl " " "
(4~ctl~1) b~zyl ~' n ~
- (4~ret~1F~yl) b~zyl " " "
diE~henylme~yl 3 " "
9-flu~renyl 1. " "
~lw~l 4 " "
--(4--chlor~yl~b~zy1 3 n Positic~ of Substitu~t S~ entR~ A
5~o[a,d]cyc~5-yl 2 H H
n n me~l n n n--bu~yl lO,ll~ydro ~a,d] ~yc~5-yl n E~ n " " me~l "
n n n~ 5~1 n E~Tl (oc~l)mEt~l 4 H n n ~ yl n " n-h~l phe~l ~h~l)m~l ~ H
n }~1 n n n ~b~l n p~e~l n n n W~l n ~ n 4-ræ~1 n 1~ n be~l n n n Wllc~l ~I n n 4~ _1 n n n q~l 2 H n diE~yl n ~1 di~ lmethyl n n-butyl 5H~szota,d]cycloh~J~s-~-yl 4 H n 5~-d~#~c[a,d]cyclohq~5-yl n methYl n 5~d~x~o[a,d~cycJ~ en-5-yl " n-butyl 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:
,~, s~
2)n Po~ition of Substituent n R2 n n CH3 S n n n--butyl " 1 H
n ~ CH3 n n n-butyl " 2 H
n n CH3 n 1l n-butyl-n n CH3 " " n-butyl " 1 H
n n CH3 n ~ n-butyl " 2 H
" " CH3 2 0 n n n-butyl 1~4~
EXAMPLE XIV
Following the procedure of Example XIII, there are prepared the following piperidine amides:
~,, ~ NC=O
wherein R2 = hydrogen, methyl~ or n-butyl.
EXAMPLE XV
Foll~wing the procedure of Example XIII, there are prepared the following piperidine amides:
(C6HS)2C ~\
~`NC80 10Position of Substituent R2 " CH3 " n-butyl n CH3 n n-butyl " CH3 n n-butyl 1~4~.8 EXAMPLE XVI
Following procedures describPd in the references given above for compounds o~ Formula ~III), the following are prepared: 1l IH
~2 R3 H -(CH2)llCH3 (CH2)7CH3 H -(CH2)l4CH3 H -(CH2~4CH-CHCH CH
Hcls-(cH2)5cH=cH(cH2)locH3 ( 2)6C_CH
H 4-ClPh-H 4-MeOPh-H 4-MePh-H -C~2C--CH
~ exo-2-norbornyl H endo-2-norbornyl Hl-decahydronaphthyl H l-adamantyl H2-bicyclo[2.2.2]octyl Hanti-7-norbornenyl Hendo-bicyclo[3.2.lloctyl Hl-adamantylmethyl Me H
Me -C2H5 Me -(CH2)5CH3 Me -(CH2)7CH3 Me -(CH2)l4CH3 Me-(CH2)4CH=CHCH2cH3 Meclg-(CH2)5CH=CH(CH2)loCH3 Me -CH~C-CH
Me (CH2)6C--CH
Me Ph Me 4-ClPh-Me 4-MeOPh-Me 4-MePh-Me PhCH2-Me 4-ClPhCH2-Me 4-MePhCH2-M~ 335 ~4(~
Me 4-MeOPhC~2-Me 2CH2 Me exo-2-norbornyl M~ endo-2-norbornyl Me l-decahydronaphthyl ~e l-adamantyl Me 2-bicyclo[2.2.2]octyl Me anti-7-norbornenyl Me endo-bicyclol3.2.1]octyl Me 1-adamantylmethyl n-Butyl H
l-nBU" ) Bu C2H5 Bu -CH2CH=CH2 Bu (CH2)7CH3 Bu (CH2)14CH3 Bu -(CH2)4CH=C~C2~5 Bu cis-(cH2)5C~=CH(cH2)locH3 Bu CH2C-CH
Bu ( 2)6C-H
Bu 4-ClPh Bu 4-MeOPh Bu 4-MePh Bu Ph Bu PhCH2 Bu 4-ClPhCH2-Bu 4-MePhCH2-~u 4-MeOPhCH2-Bu PhCH2CH2 ~u exo-2-norbornyl Bu endo-2-norbornyl Bu l-decahydronaphthyl Bu l-adamantyl Bu . 2-bicyclo[2.2.2]octyl Bu anti-7-norbornenyl Bu endo-bicyclo[3.2.1]octyl Bu l-adamantylmethyl H diphenylmethyl Me diphenylmethyl Bu diphenylmethyl H 3,3-diphenyl-n-propyl Me 3,3-diphenyl-n-propyl Bu 3,3-diphenyl-n-propyl ~40~ 18 EXAMPLE XVII
Following the procedure of either Example I or Example III, bu~ substituting for the ethyl formimidate hydrochloride and diphenyl-4-piperidylmethane or N-formyl-4-diphenylmetXylpiperidine 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 su~sti~uents are in the two (Rln), three (Rl'), or four (Rl) positions:
Rl l Rl n Rl ~<
A--\_~NC=NR3 Posi--tion of S~x*itNent S~x~i-~ ', or ~n) uent ~ R3 A
d~nylmethyl 2 H H H
dipheny~ yl 3 n ~ n 15 9-fluorenyl " n n n c~--(4~1)berlz~1 n n n "
di~ f~Nymethyl 4 " " n 10,11-dihy~x~5~ ~zo "
[a,d]cycloh~en-5-yl 4--chlon~x~y1 n n 20 4~o~enyl dipheny~E~l n n (~)11CH3 4~hlD~l n a-(4-methylphenyl)benzyl " " " "
4-chlorokenzyl n n n ~--(4~hl~1)--tY-- l~ n ~ydm~1 a-(4-~ophenyl)ben2yl 3 " " "
9-fluorenyl ~ n 4-metbI~uy1 4 " -(CH2)7CH3 9-~luorenyl 3 " n dipbenyl~y~s~ymethyl 2 a-(4~o~pY~y1)benzyl 3 " n 1~4V~
Posi--~ o n ) uent R2 R3 A
diph~nylhy~raxy~yl 4 H - (CH2) 7CH3 H
51~dikG~o[a,d3 n ~yc~hep~-5-yl yl n d~l (CH2) 14CH3 ~1 cr ~4--chlon~pherlyl ) b~lzyl 3 " " n 9-flu~renyl 4 " " "
~ 14-methyl~henyl)benzy1 "
4~hloq:c~1 n n n n ~1 " l~ ,. "
di~henylmet~yl " -(CH2)4C~I2CH3 ~E~l)benzyl n d~l8~t~1 3 10~11~5~ y_ ~
5}~dil~lzo [a,d] cyt:ld~5-yl 9--fll~lyl n ~ n di~ly~ret~lyl 4 ph~yl " " " "
~ ~l n ~ n diphenyl~ thyl n ~ CLs--(CEI2) cE~(CH2)10CH3 c~~ (4~hla~?he~1)b~zyl 3 9-~9-flUDl~T1 4 --(4~hl~lyl) ~~ I- ~ n n ~1 4~et~:yl " " " "
2 5 berlzyl ll ll ll n cr (4~1~ yl)be~1 n dip~Iylmethyl n " (CH2) 6C{~
a- (4-chlor~pbenyl) benzyl " " " "
~1 3 0 9-fluar~nyl 3 " " "
a-(4-chlorop~enyl)benzyl " " " "
dip~ylTrethyl 2 .. " n Posi--~ o S~nt S~
, R~ ', or Rln) uent ~2 .R3 A
}~1 4 H (C~z) 6C-CH . H
4--~leth~l n " n n d~T~ E~l n n --CH2C ~{ H n a--(4--leti~l)b~l n n a--(4~tly1p~1) ~-- n ~ n n ~1 --(4~L)berlzyl 3 " n n 9--fll~l 4 n n n [a,d] ~c1~5-y1 10 4~ethNyE~h~l n n n E~yl 4~hlo~c~1 n ~ n H
dipb~ n n exc~--2~1y1 n a- (4~et~y1p~1) b~1 " " ~ n a--(4~1)--a-- n n n n ~1 diF~lmet~l 3 n n n 9--flu~l ,. n E~yl 4 " n n 4-chLor~ibenzyl n n ~ n ~-(4~hlar~yl)b~zy1 " " en~2-nor~ornyl "
diphe~ethyl " n n di~enyl~ ~ethyl a-(4-chlorop}~yl)benzyl 3 9--flu~l ~ .. n n 4~y~yl 4 " " "
b~zyl ~ .. "
di~enylIrethyl ~ nl--deca~ydr~phthyl n a- (4~yl) b~zyl " n ~- (4-methylp~yl)--a- n ~b~l dipheny~thyl 3 "
9--fluorenyl ~ .- n ~
p~enyl 4 " " "
4-chlor~l ~- (4-meth~yl)benzyl " " l~nantyl "
~14 Posi-tian o~
Sl~bstituent Su~
(Rl, Rl', ar Rln) uent R2 R3 A
10 ,11--di3y~5-~dr~ 4 H1-ad~nan~yl H
5}}di~ ta,drc~yc~5-yl ~~ (4~hlo~l)_a_ n n ~ n ~1 a--(4~1)b0zy1 3 n n 9--flg~l n ~-4--chl~l 4 n n F~l n n n El diph~et~l n n2-bic~yclo~2.2.2]oc~1 -(4-~retl~1)~enzy1 " " " "
d~ ~Crc~l " n n n diphen~l 3 n n n 9--fluore~l 4 n n E~l .. n n 4~etho~1 ~ n n n 15 dip} ~ ~rethS~l n a ~ -7-I
-~4-c~lk=~ enyl)benzyl " n n ~-(4 m~Lhylphenyl)-~- n n ~1 dipheny~mEthyl 3 n n -9-fluorenyl " " " "
20 phenyl 4 n n 4-~hlorobenzy1 " " " "
diphenylmethyl " " enlo-bicy~10[3.2.1]octyl o-(4-methylpheny1)benzy1 " " n n diphenyIhydroxy=ethyl n n n ~
25 ~-(4-chlorcpbeny1)benzyl 3 " " "
9-fluorenyl n n dipbenyIhydr=xymethyl 2 " " "
4-methcxypbenyl 4 " " "
b ~ zyl " n n 30 diphenylmethyl " "l-adamantylmethyl "
-(4-methcxyph~=yl)benzyl " " n n a-(4-chlo ~ 1)_o_ n n hydrax ~ l a-(4-chlorc~henyl)benzyl 3 V~ ~ ~
Posi--tion o 9-flu~l , 3 Hl-adamantyl~1 H
phe~l 4 n ~ . n 4--sw~l n ~ n n diE~3~1m~1 laeth~l H n --(4~1)~1 n n ~ n a--(4--chl~Yl)~~ n n n n ~1 5--~51~di~1zo n n n n [a,d] c:ycl~-5-yl ~ (4~yl)ber~ 1 3 ~ n 9--fluorer~1 n n n diEhel~lmeff~l 2 n n ~
4--chlcl~l 4 n n 1 be~l n n 11 n t~ (4--llethc~phe~l)be~l ~I n n n a--(4~ylpt~nyl)--a-- n n ~ n ~1 dip~yl~ }~l 3 n 1~ n 9--h~r~9--flua~l 4 n n ~
4~th~y~yl " " " "
2 0 10 ,11 di~yd~5i}di~eDzo [a,d] cycl~-5-yl b~lzyl ~- n (~(4~1phe~lyl)be~lzyl n --(CH2)7CH
dipher~llyd~ynet~yl n a- (4~hlo~1)~1 3 n 2 5 9--fluor~l p}~l 4 " " "
be2~zyl ~ n n dipheny~nethyl " "(~ H2) 14CH3 a- (4~hl~phen~1)benzy1 " " "
3 0 a- (4~ret~y1) ~ " "
hydm~yl dipherlyln~l 3 " " "
9-fluoren~l " " "
Posi ti~l of o~ Rln)uent R2 R3 4~etlcyphenyl, 4 I~etl~l(CH2) 14CH~ H
4--chlorobenzyl " n n n d:i~y~hyl " n--CH2CE~=CH2 n a--(4--~l~ti~l)b~ln n n n l n r n Eh ~1 n n ~ H
a-~4~1)bq!1 3 " " n 9--flu~re~yl n n Il n 4--chlor~henyl 4 bq~l " " " "
dipe~lllet~l n n~ (CH2 ) 4CE~H2CH3 a--(4~ethylphe~1)be~1 n n n n a--(.4~bl~Y1)~-- n u n n ~1 di.E~ylIIethyl 3 n n n 9~fluorenyl l 4 n n n 4-chlorobenzyl " ~ n n diphenylmeth yl ~- n Cis--(CH2~5C~=CH( ~ )10 3 a-(4-methDxyphenyl~ken2yl" " " n diphenYlhydroxymethyl " " " "
g-flu~renyl 3 n a-~4-chl~opheny1)benzyl " " n 4--me~/l 4 ~ n 25 b~lzyl ll 1' ~I ll a--(4-methylphenyl)benzyl n l~ n a-(4-chlorcphenyl)-a_ " "
}~1 phenYlmethyl 3 " n ll 30 g-hydroxy-9-fluorenyl 4 " " "
~yl "
4-metho~ybenzy1 dipbenylmethyl n n~ (CH2) 6C---CH n a-(4-chlorophenyl)benzyl " " n diphenyIhy~roYymet~yl " " " "
l8 Posi-tion of S~b~t S~
(R~., Rl', or Rl") uent ~ R3 A
dip~y~e~l 3 nE~yl--(CH2)6C~CH H
9--f luorer~l n n n n diFbe~lly~3~1e~1 2 " n n 4~hlc3~ 4 ~ n diphe~l~E*}~l n n benzyl n a-(4~p~1)benzy1 " " 4-chlc~e~1 "
diphe~Tlh~ 4~
diEihe~y~l 3 " 4~1b~1 "
10 ~ dih~5--~n n n n 5}}dib~zo [a,d3 c:yc1at~5-yl 9--fluor~Tl - n "
-(4~yp~1)~enzyl 4 " 4~ora}~nzyl "
4--chlor~benzyl " ' benzyl n diph~ny~ yl " " ~2~ ornyl n a--~4~eth~1pbenyl) b~zyl n 1- n n ~Iyl ~ n n p~ enyl diphe~ynet~l n ~ n H
diph~nylmRthyl 3 2 0 Eiber~l 4 n n 9--fluorenyl 3 ~. n ~1 4 ~ n 10,~ ydr~5E~dib~zo [a,d] c~clo~p~-~yl dip~ny~rethyl ~ " ~2-n~ornyl "
a-(4 chlorc~henyl)benzyl " " " "
--(4~net~1ph~nyl)~- n n n h~dra~l diF~y~rethyl 3 " " "
9--fluorenyl n n n n 4~reth~p~enyl 4 " " n 3 o 4~or~zy1 " " " "
dip~yl~thyl " " l--decalyd~p~thyl n - (4-~y~l)benzyl " " " "
dip~y~t~l " " "
-(4 chl~1)benzyl 3 " " "
~ 335 1~4~
Posi-ti~ of Substituent Sl~bSti-(Rl, Rl', or RLn) uent R2 R3 A
4~hlQ~yl 4 n n n 4--net~yb~1 n n n n 5di~lmet~l n n1 a~~
~- (4~hlom~y1~benzy1 n ~ n n --(4t~ n n ll n h~drax~l dip~ylIl~l 3 n n n 9--flu~r~yl " " n n E~l 4 " " "
benzyl diphe~et~l n n2--bi~yclo[2.2.2]oc~yl "
dip~Dydr~l " " n n 15--(4--chlor~enyllbenzyl 3 "
9-flu~r~nyl 4 " "
4--chloropher~1 n n n n 4~ff~ny1 n n n n dipher~y~rethyl " anti--7--r~yl ..
a--(4-methylphenyl)benzyl " n n 1-diph~yllllet}~l 2 a- (4-chl~yl)b~1 3 phe~l 4 " " n 9--fluorenyl 3 4--me~1 4 " n diphenylIrethyl " "d~icyclo[3.2.1]oct~
p~yl " " " p~wlyl a--(4~hlo~yl) benzyl n n n H
3 0 diE~nylhy~t~yl " n n dipl~y~rethyl 3 "
9--flucxrenyl n n n 4--chlor~yl 4 " n b~yl " " " "
3 5 diph~ny~lrethyl 1~ "l-a~nnanty~thyl "
~3 Posi-~ o~
- (4~ylp~yl)benzyl 4 met~l l-adanantylnethyl H
c~--(4--chl~Yi) ~-- n n n n h~l diF~l 3 n n ~
9--~qUQ~l n n n n 4~t~ypl~yl 4 n n n W~l n n d:iph~ eth~ 1~1 H l~
--(4--ll~th~l)bel~l n n n n dipbe~l 3 n n n 9--fluor~l n n n n pb~yl 4 ll ~ n 4~yl ll n ll diE~y~et~Lyl " -C2H5 n he~ yl n n n ~yl a- (4~1) b~zyl " " " . H
a--(4--chl~yl)--a~ n n n n ~1 di~yl~thyl 2 " n n ~--(4--chlor~?henyl)b~1 3 n n n 9-fluorenyl ~ - n 4~t~ypenyl 4 " " "
n ll ll n diph~ylmethyl " " --(CH ) 7CH n c~--(4--chlo~henyl)b~zyl " n 3 d:i.Fberly~:e~Tl ~ n n ~-dipherlyl~ thyl 3 9--flut~ren~l ~yl 4 n n 3 0 b~zyl d:ipheI~yl~thyl " ' - (CH2) 4CH
a-(4-srethylph~yl)benzyl " " 1 3 cc--( 4--chlo~ophenyl ) b~l 3 3 5 9-fluDrenyl " " " "
. _ . . . _ .
M~ 335 ~ 14V~.~8 Posi--tio l o~
Substitu~nt Substi-(Rl Rl' or Rln) uent . R~ R3 A
10,11 dilyd~ 3 n~ut~rl (C~2)14CEI3 H
5~di~z= [a,d] ~c~eptcr~yi 4~e1~ ~1 4 ~ n n 4~cro~zyl n n n n d~henylmethyl ~2CE~=CH2 n a--(4~hlcrc~yl)b~zyl n n n n di.p}~y~d~l~l n n n n --(4--chl~1)b~1 3 n n n 9--flu~yl n n n n 4~c~ henyl 4 n n n b~l n n n n d:i.ph2n~1mPthyl ~ C~2) 4 2~5 5--h~d~5E~di~o n [a,d] cy~:lc~5-yl a--(4--srethylp~yl)b~nzyl n n n ~
a--(4~y1)~ n n n ~yd~l dipheny~ yl 3 n n n 9--fluorenyl " n 1~ I~
E~enyl 4 " " "
4--chlo~1 .. .. n . n diph~Iyl~ ncis--(CH2)5C~H(CH2)10CH3 a--(4~71phenyl)b~rl n l~ n l~
dip}~31ydr~1 " " " "
a- (4-chlo~p~enyl)b~zSr1 3 " n 1~
9--flu~renyl " n ~ n 2 5 phenyl 4 ~ .. ..
4--~y~l " n n n diPh~Y~rethyl " l-CH2C~
a--(4--Irethylp}~yl)benzyl n n n diPhe~llyd~ycet~yl " " " "
3 0 10 ~ dilyd~5H-dib~zo n n n [a,d] :yclo~5-yl dip~31rethyl 3 " n 9--fluarenyl " " n 1~
4-n~h~yp~:yl 4 " " "
~ll401 ,~l8 Posi-~ o~
&b~tituerltSl~bsti-(Rl RL~ 0~ Rln) t~t R2 R3 A
benz5~1 ~ 4 n~ CH2C-~ H
d~et~l n ~ CH2) 6C~
a- (4~10r~1)benzyl S phe~l n n 1~ phe~l ~ (4~tb~1)-a-- n n n H
~yl a--(4--chlor~1)benzy1 3 n n n 9--flu~rl n n n l~
~yl 4 n n n 4~ n ~
d~l n ~ ?l n a- (4-met}~tlphe~l)b~ylzyl n ~l 4-chlor~1 ..
a- (4~1O~-yl) ~- " n4-sr~Yl~Zyl "
~dss:~yl di l~yl~ 1 2 . n d~ ret~l 3 " 4~h~ny1 9--flua~enyl n n 1~ n yl 4 b~tl n 4~reth~1 " "4~thylbenzy1 "
diph~l " " phenethyl --(4--Iletb~l)benzyl " " n ~1 3 ~ n 9--~dr~9--fluorenyl 4 ~ yl ~- n n n 2 5 4-chlor~benzyl dip~lyllllethyl n n ex~2~ yl ~~(4~ylE~he~1)be~1zyl diFa~y~EI hyl n ~I n n a- (4-chlor~r1)b~zyl 3 " "
3 o 9--fluore~l n n 4~ cyE~yl 4 b~lzyl ~ n diF~exlyl~l~thyl n 1~eI~2--rx)~o~lyl ~- (4-chl~1)benzyl " " " "
~ M~ 335 ~L4~
tion of tR~., R~', o~ Rln) uent_ R2 R3 A
a- (4-met~ 4n-}~u~l erx~2-nor~ l H
dip~ln~yl 3 " "
9--fluor~yl n n n n 5 Ehe~l 4 n 1~ n ~h5~1 n ~ n n dip~nethyl n n l~th~l n a--u~l)b~Tl " n n 1~
~x--(4~ph~lyl ) ~-- n n n n 10 phenyl .. n 1~ phenyl o~--(4~1~æhenyl) ben~l 3 n n H
9--fluorenyl n n n n p~l 4 n n n benzyl n n n n 15 dipeny~Ilet~l " " l-a~an~tyl n a--(4~eth~phes~1)benzyl " n n n di~iheny1lyd~et~ n diE~y~et hyl 3 n 9--f lul~renyl n n l~
20 4-chlor~yl 4 " " "
4--chl~yl " ~I - n dip~yl~et}~l ~I n2--biCyclo[2.2~2]octyl --(4~hylp~enyl)ben~1 " n ll n a- t4-chl~rcphen~l)-a- " " "
~1 25 a- (4-chl~r~yl)b~zyl 3 n ll ll 9-flu~enyl " " " "
phE~lyl 4 n n n 4~e~1 1~ n dip~ly~I~etbyl ~ ~ ~-7-~ yl 30 a-(4~l~1p~1yl)benzyl n ll dip~eny~ rethyl " " n diEibenyl~rethyl 3 " " "
9-flu~enyl ethyl 2 n r~
1~4V~
Posi--tiOIl of Substil:uentSubsti-(Rl, Rl', c~r Rl") uent R2 R3 A
4tret~=y~y1 4 ~utyl an~i-7~y1 EI
4~hl~yl n n n diFb~;ylllethyl " endo~i~yclo[3.2.11a~
--(4-ilet~E~l)~eslzyl n n n n a--~4--Irethylphe~71~---- n n n n IydmY~l , a--(4--chlarc~l)~lzyl 3 n n n 9--flu~c)~l n E~yl 4 " n n 4--*eth~1 n " n n dipb~yllr~thyl " "l--ad~ntyllrethyl ~~ (4--~letb~l)b~lzyl n l~
dipheny3~yd ~ y ~ ~hyl " " " n diphenylmethyl 3 " n "
15 9~fluorenyl n ll phenyl 4 ~ n bg~z~l n n n n ~-(1,4-biphenyl)benzyl " H H "
~-~1,4-biphenyl)benzyl n C~ ~(CH2)7CH3 "
20 -(1,4-biphenyl)benzyl "n-butyl phenethyl n 2,2-dipbeny1ethy1 " H H "
2,2-diphenylethyl n CH3 -(CH2)7CH3 2,2-dipheny1ethyl "_-butyl phenethyl "
4,4-diphenyl-n-butyl " H H "
4,4-dip~enyl-nrbutyl n CH3 -(CH2)~CH3 "
4,4-diphenyl-n-butyl "nrbutylphenethyl "
diphenylmethyl " Hdiphenylmethyl phenyl 3 CH3 " "
9-fluorenyl 4n-butyl " n 30 4-chic~obenzy1 " H3,3-diphenyl-n-prcpyl "
diphenylmethyl 3 CH3 " "
diphenyIhyd mxymethyl 4 n-butyl Posi-tion of Sub6tit~ent Substi-~ ', or ~ ~) uent ~ ~ A
phenyl(octyl)methyl 4 H H H
10,11-dihydro-5H-dltenzo 2 " -( ~ ) ~ n [a,d]eyclcheF~er-S-yl 3 5~-diben~o[a,d] n ~ n eye1 ~ 5-yl 5 pbenylnhByl)methyl 4 n (~) 6 n E~l (hexyl)~l n mB~yl~ (C82) 4CE~ OE H2CH3 n 10,11-dbhy~e-5H ~ o 2 " -(C ~) C~rH "
[a,d]eye1 ~ -5-yl 6 5E-dlte~zo[a,d] " " " n eyelQheptEn-5-y1 lO,ll~yd~5E~di~zD n ~h~l ~2C3 n [a~d]cyclohept2nr5-yl 10 5H-dikenzo[a,d] " " n cyclQhept~n-5-yl phe~yl(octyl)~ethyl 4 " F~ yl n ~ 5 ~40~l.8 4s Example XVIII
Following t~Q procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-5 4-diphenylmethylpiperidine and ethylamine, respectively, used therein, e~uivalent amounts of the appropriate starting materials suc~ as described in Examples XIII
and XVI, there are prepared the following:
(C~2)n ~
~ ~ NC-NR
Position of 10 Su~stituent n ~ R
_ 2 3 3 0 H n-octyl 3 0 H _-dodecyl 4 0 H n-hexadecyl 4 CH3 n-octyl 4 0 n-butyl n-octyl 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 Z H n-octyl 3 2 H n-dodecyl 4 2 H n-hexadecyl 4 2 CH3 n-octyl 4 2 n-butyl n-octyl ~4~
EXAMPLE XIX
Following the procPdure of either Example I or Example III, but suhstituting for the ethyl formimidate hydrochloride and 4-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, equival~nt amounts of the appropriate starting materials such as descri~ed in Examples XIV
and XVI, there are prepared the following:
\ /
. A~
~ NC--NR3 ~O>
~ H
H n-octyl H n-dodecyl H n-hexadecyl c~3 n-octyl n-butyl n-octyl H H
H n-octyl H n-dodecyl H n-hexadecyl CH3 n-octyl n-butyl n-octyl H H
H n-octyl ~ n-dodecyl H n-hexadecyl CH3 n-octyl n-butyl n-octyl MN.335 1~4V1 18 EXAMPLE XX
Following ~he procedure of either Example I or Example III, but substituting for the ethyl formimidate hydrochloride and ~-diphenylmethylpiperidine or N-formyl-4-diphenylmethylpiperidine and ethylamine, respectively, used therein, e~uivalent amounts of the appropriate starting materials suc~ as described in Examples XV and XVI, there are prepared the following:
(C6H5) 2C~\
\ NC=NR3 Position of 10 Substituent n R2 R3 2 0 H _-octyl 3 0 H _-dodecyl 3 0 H n-hexadecyl 4 0 CH3 n-octyl 4 0 n-butyl n-octyl 2 1 H _-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 n-octyl 3 2 H n-dodecyl 3 2 . H n-hexadecyl 4 2 c~3 n-octyl 4 2 n-butyl n-octyl 114() EXAMPLE XXI
N-[4-(Diphenylmethyl3-1-piperidinyl]
methYlene benzenebutanamine (E)-2-Butenedioate Hvdrate , A ~ixture of 4.40g (0.016 mole) of N-formyl-4-(diphenylmethyl)piperidine and 1.47 ml (2.00g, 0.015 mole) of dimethyl sulfate was heated in a steam bath for three hours at 100C under anhydrous conditions until homo-geneous. The mixture was cooled, dissolved in 30 ml of methylene chloride and treated with 2.50 ml (2.36 g, O.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 wa~ separated, dried over potassium carbonate, filtered and evaporated ~o 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-14-(diphenylmethyl)-1-piperidinyl]-methylene benzenebutanamine (E)-2-butenedioate hydrate as a white crystalline solid, m.p. 207-208.5C.
EXAMPLE XXII
~-(Diphenylmethyl)-l- l-[me~hyl(octylimino) methyl]-piperidine Monoperchlorate .
A mixture of the fluoroborate salt of N-octyl-acetimidic acid ethyl ester ~generated from 5.68g [Q~04 molel of boron trifluoride etherate, 2.77g [0.03 mole]
of epichlorohydrin, and 5,80g t~.~34 mole] of N-octyl acetamide) and 5~ ml of ether was treated with 4 ml ~2.92g, 0.029 mole~ of triethyl amine~ Filtratio~ and evaporation of the filtrate afforded a liquid residue whic~ ~as 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 50C
over 4A molecular sieves under a nitrogen atmosphere for four days. The reaction mixture was cooled and neutralized by ~haking with 3 N sodium hydroxide solu-tion. The organic layer was separated, dried over X2C03, filtered and stripped to an oil which was distilled.
M~ 33s l~LV~
4g The pot residue was dissolved in ether and perchloric acid and methanol added. Cooling the solution pro-duced a solid fraction. Filtration afforded a crystal-line solid whi.ch was recrystallized three times from S methanol to give 4-(Diphenylmethyl)-l- l-[methyl(octylimino)-methy]~piperidine Monoperchlorate as a white crystalline solid, m.p. 119-121.5C.
EXAMPLE XXIII
a-(4-Methylphenyl ? -a-Phenvl-4-~yridine Methanol A solution of 0.05 le of 4-methylphenyl magnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in S00 ml anhydrous ether.
After stirring the n~lting m~re for 1.5 hc~rs at 25, an ~æ~s soluticn of a~L~ium ~ik~ide was ~ causing a solid to form which waQ filtered. Recrystallization of thi~ material ~rom 95% ethanol afforded the desired ~-(4-methylphenyl)-a-phenyl-4-pyridine methanol, ~.p. 192-135C. The corresponding 4-chlorophenyl (~.p. 198-202C) and 4-methoxyphenyl (~pO 204-206C) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
EXAMPLE XXIV
x-(4-Methylphenyl)-a-Phenyl-4-Piperidine A solution of 25~0g (0.09 mole) a-(4-methyl-phenyl~-a-phenyl-4-pyridine methanol, 55 ml of 47-Sl~
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 60-65C in acetic acid following the method of United States Patent No. 3,267,108. The excess acid was removed and the residue made ba~ic to give a-(4-methylphenyl)-a-phenyl-4-piperidine which was characterized as its fumarate salt, m.p. 157.5-161.5C (Hoover). The corresponding 4-chlorophenyl (m.p. 175-178C; fumarate salt) and ~, ~14 sn 4-methoxyphenyl (m.p. 94-98C; free base3 derivatives were also prepared by the same method, using equivalent amounts of the appropriate star~ing materials.
. EXAMPLE XXV
s -(1,4'-Biphenyl)~l--phenyl-4-pyridinemethanol A solution of 111.0g (0.50 ~ole) of 4-biphenyl bromide in 200 ml of dry ~etrahydrofuran ~THF) was added slowly to a mixture of 12.10g (0.5 gram-atom) of mag-nesium, 2 ml o~ ethylenedibromide and 200 ml of T~F 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 25C 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 ~rom ethanol, chloroform, and finally toluene to give a-(1,4'-biphenyl)-yl-a-phenyl-4-pyridin methanol as a white solid, m.p.
after drying in vacuo at 70C; 173.5-175.5C.
EXAMPLE XXVI
_ a-(1~4'-Biphenyl)yl-a-phenyl-4-~iperidinemethanol A solution of 10.00g (0.030 mole) of a-(1,4'-biphenyl)yl-a-phenyl-4-pyridine and 160 ml of acetic acid was hydrogenated in the presence of platinum oxide (1.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 was slurried in water, made basic with 3 N NaOH and ex-tracted 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-lized from toluene to give a-~1,4'-biphenyl)yl-a-phenyl-4-piperidinemethanol as a white solid; m.p. 185-186.5C.
481.1)3 EXAMPLE XXVII
9-(4'-~ eridinYll-9-fluorenol A sslution of 13.0g (0.05 mole) of 9-(4'-pyridyl)-9-flu~renol 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 bas~c affording 9-(4'-piperidinyl)-9-fluorenol.
EXAMPLE XXVIII
4-Fluorenylidenepiperidine A suspen~ion of 13.0g (0.05 mole) of 9-(4'-piperidinyl)-9-fluorenol in 70 ml of 48% sulfuric acid was heated on a steam bath for ~even 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 qeparated, dried over potassium carbonate, filtered and stripped to give 4-fluorenylidenepiperidine.
EXAMPLE XXIX
9-(4'-Pyridyl)fluorene A solution of 1.35g (0.005 mole1 of ~,a diphenyl-4-pyridine methanol in 18.5 ml of 97% formic acid was treated dropwise with 8 ml of concentrated sulfuric acid.
The r~action 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 me~hanol to give 9-(4'-pyridyl)fluorene, m.p. 141-143C (Hoover).
EXAMPLE_XXX
9-(4'-PiPeridYl)fluorene fumarate A solution of 54.75g (0.225 mole) of 9-(4'-pyridyl)fluorene in 600 ml of acetic acid was hydro-genated over S.Og of platinum oxide at 40 psi and 25C.
The mixture was filtered, stripped and made basic, afford-ing 9-(4'-piperidyl)fluorene, which was crystallized as the fumarate salt, m.p. 228-230C (dec).
Claims (42)
1. A process for preparing a member selected from the group consisting of a substituted N-iminomethyl-piperidine of formula (I):
(I) and the corresponding non-toxic acid addition salts thereof, 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, loweralkoxy, hydroxy and halo; phenyl (C1-C4) lower-alkyl; l-phenyl (C7-C9) loweralkyl; phenyl (C1-C4) loweralkyl and l-phenyl (C7-C9) loweralkyl in which said phenyl is substi-tuted 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; diphenyl (C1-C4) loweralkyl; diphenyl-(C1-C4) loweralkyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, lower-alkoxy, 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 compounds of formulae and wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, R1 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;
R1 and A taken together is a member selected from the group consisting of benzhydrylidene and compounds of formulae:
and wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the group consisting of hydrogen; methyl; diphenylmethyl; diphenyl-methyl wherein at least one of the phenyl groups is substituted with from 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; diphenylhydroxy-methyl; diphenylhydroxymethyl wherein at least one of said phenyls is substituted with from one to three members each sel-ected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is phenyl; and a compound of formula:
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
R1' and s taken together is a member selected from the group consisting of benzhydrylidene and a compound of formula:
wherein n is 0, 1, or 2.
R1" taken individually is a member selected from the group consisting of hydrogen, diphenylmethyl; 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, 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 compounds of formulae:
and wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R1" and D taken together is benzhydrylidene;
R2 is a member selected from the group consisting of hydrogen and C1-C4 loweralkyl; and R3 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 members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, and halo; diphenyl (C1-C4) loweralkyl; di-phenyl (C1-C4) 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 R1, R1' and R1" is other than hydrogen, and further provided that when R1" is other than hydrogen R1 and R'1 and A are each hydro-gen; when R'1 is hydrogen only one of R1 and R"1 is other than hydrogen; when R'1 is other than hydrogen and R"1 is hydrogen;
and when R'1 is other than hydrogen or ethyl R1, R"1 and A are each hydrogen, characterized by a) i) reacting a compound of formula (II) with a compound of the formula Z? = NR3 (III) or the acid addition salt form of the latter, namely, Z? = NR3 - HX
in a suitable organic solvent at a temperature between 0°C and 50°C, wherein A, B, D, R1, R1', R1, R2, and R3 are as previously defined, Z is selected from the group consisting of loweralkoxy, loweralkyl-S-, chloro, and C12(O)PO-, and X is a member selected from the group consisting of halide, BF4, FSO3, and CH3OSO3, and additionally, when Z is loweralkyl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)SO3, CH3SO3, and CF3SO3 in order to prepare a compound of the formula (I);
or ii) reacting a compound of formula (II) with a compound of the formula R3N=C=S (IIIA) under similar reaction conditions to step a) i) in order to prepare the corresponding thiourea which is then reduced in order to prepare a compound of the formula (I), wherein R2 is hydrogen;
or iii) reacting a compound of formula (II) with a compound of the formula R3N=C (IIIB) in the presence of silver chloride as a catalyst in order to prepare a compound of the formula (I), wherein R2 is hydrogen; or b) i) reacting a compound of the formula X-with a compound of the formula R3NH2 (VII), wherein R1, R1', R1, R2, R3, A, B, D, Z, and X are as defined above, in order to prepare a compound of the formula (I); or ii) in the instance wherein Z in compound (VI) is (loweralkyl)-S- and R2 is H, re-acting said compound of the formula with a compound of the formula R3N=C-O (VIII) in a suitahle solvent, preferably at reflux temperature, in order to prepare a compound of the formula (I), wherein R2 is hydrogen;
and, if desired, preparing non-toxic acid addition salts thereof.
(I) and the corresponding non-toxic acid addition salts thereof, 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, loweralkoxy, hydroxy and halo; phenyl (C1-C4) lower-alkyl; l-phenyl (C7-C9) loweralkyl; phenyl (C1-C4) loweralkyl and l-phenyl (C7-C9) loweralkyl in which said phenyl is substi-tuted 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; diphenyl (C1-C4) loweralkyl; diphenyl-(C1-C4) loweralkyl wherein at least one of said phenyls is substituted with from one to three members each selected from the group consisting of loweralkyl, lower-alkoxy, 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 compounds of formulae and wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, R1 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;
R1 and A taken together is a member selected from the group consisting of benzhydrylidene and compounds of formulae:
and wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the group consisting of hydrogen; methyl; diphenylmethyl; diphenyl-methyl wherein at least one of the phenyl groups is substituted with from 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; diphenylhydroxy-methyl; diphenylhydroxymethyl wherein at least one of said phenyls is substituted with from one to three members each sel-ected from the group consisting of loweralkyl, loweralkoxy, halo, hydroxy, and phenyl, provided that no more than one member is phenyl; and a compound of formula:
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen;
R1' and s taken together is a member selected from the group consisting of benzhydrylidene and a compound of formula:
wherein n is 0, 1, or 2.
R1" taken individually is a member selected from the group consisting of hydrogen, diphenylmethyl; 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, 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 compounds of formulae:
and wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R1" and D taken together is benzhydrylidene;
R2 is a member selected from the group consisting of hydrogen and C1-C4 loweralkyl; and R3 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 members each selected from the group consisting of loweralkyl, loweralkoxy, hydroxy, and halo; diphenyl (C1-C4) loweralkyl; di-phenyl (C1-C4) 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 R1, R1' and R1" is other than hydrogen, and further provided that when R1" is other than hydrogen R1 and R'1 and A are each hydro-gen; when R'1 is hydrogen only one of R1 and R"1 is other than hydrogen; when R'1 is other than hydrogen and R"1 is hydrogen;
and when R'1 is other than hydrogen or ethyl R1, R"1 and A are each hydrogen, characterized by a) i) reacting a compound of formula (II) with a compound of the formula Z? = NR3 (III) or the acid addition salt form of the latter, namely, Z? = NR3 - HX
in a suitable organic solvent at a temperature between 0°C and 50°C, wherein A, B, D, R1, R1', R1, R2, and R3 are as previously defined, Z is selected from the group consisting of loweralkoxy, loweralkyl-S-, chloro, and C12(O)PO-, and X is a member selected from the group consisting of halide, BF4, FSO3, and CH3OSO3, and additionally, when Z is loweralkyl-S-, X may also be a member selected from the group consisting of (4-methylphenyl)SO3, CH3SO3, and CF3SO3 in order to prepare a compound of the formula (I);
or ii) reacting a compound of formula (II) with a compound of the formula R3N=C=S (IIIA) under similar reaction conditions to step a) i) in order to prepare the corresponding thiourea which is then reduced in order to prepare a compound of the formula (I), wherein R2 is hydrogen;
or iii) reacting a compound of formula (II) with a compound of the formula R3N=C (IIIB) in the presence of silver chloride as a catalyst in order to prepare a compound of the formula (I), wherein R2 is hydrogen; or b) i) reacting a compound of the formula X-with a compound of the formula R3NH2 (VII), wherein R1, R1', R1, R2, R3, A, B, D, Z, and X are as defined above, in order to prepare a compound of the formula (I); or ii) in the instance wherein Z in compound (VI) is (loweralkyl)-S- and R2 is H, re-acting said compound of the formula with a compound of the formula R3N=C-O (VIII) in a suitahle solvent, preferably at reflux temperature, in order to prepare a compound of the formula (I), wherein R2 is hydrogen;
and, if desired, preparing non-toxic acid addition salts thereof.
2. A process for preparing a member selected from the group consisting of 4-diphenylmethyl-1-iminomethylpiperidine and the non-toxic acid addition salts thereof, characterized by reacting ethyl formimidate with diphenyl-4-piperidylmethane.
3. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1-[(isopropylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, char-acterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethylsulfate and reacting the product with isopropylamine.
4. A process for preparing a member selected from the group consisting of l-[N-(benzyl)iminomethyl]-4-diphenylmethylpiper-idine and the non-toxic acid addition salts thereof, characterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethyl-sulfate and reacting the product with benzylamine.
5. A process for preparing a member selected from the group consisting of l-[N-(phenethyl)iminomethyl]-4-diphenylmethylpiper-idine and the non-toxic acid addition salts thereof, character-ized by reacting N-formyl-4-diphenylmethylpiperidine with di-methyl sulfate and then reacting the product with phenethylamine.
6. A process for preparing a member selected from the group consisting of 1-[N-(n-decyl)iminomethyl]-4-diphenylmethylpiper-idine and the non-toxic acid addition salts thereof, character-ized by reacting N-formyl-4-diphenylmethylpiperidine with di-methyl sulfate and then reacting the product with n-decylamine.
7. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1 [octylimino)methyl]piperidine and the non-toxic acid addition salts thereof, characterized by reacting N-formyl-4-diphenylmethylpiperidine with phosgene and then reacting the product with octylamine.
8. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1-[(2-propynylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, char-acterized by reacting 4-(diphenylmethyl)-1-piperidinocarbothioal-dehyde with methyl iodide and reacting the product with 2-propy-nylamine.
9. A process for preparing a member selected from the group consisting of 4-benzhydrylidene-1-[(octylimino)methy] piperidine and the non-toxic acid addition salts thereof, characterized by reacting 4-benzhydrylidene-1-piperidinecarbothioaldehyde with methyl iodide and then reacting the product with n-octylamine.
10. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1-[(ethylimino)methyl] piper-idine and the non-toxic acid addition salts thereof, character-ized by reacting ethylpropionimidate hydrochloride with diphenyl-4-piperidylmethane.
11. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1-[(hexylimino)methyl] piperidine and the non-toxic acid addition salts thereof, characterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethyl sul-fate and then reacting the product with hexylamine.
12. A process for preparing a member selected from the group consisting of 1-[(4-chlorobenzylimino)methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof, char-acterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethyl sulfate and then reacting the product with 4-chloro-benzylamine.
13. A process for preparing a member selected from the group consisting of 4[1-(4-methoxyphenyl)benzyl]-1-[(octylimino)-methyl]-piperidine and the non-toxic acid addition salts there-of, characterized by reacting N-formyl-4 [1-(4-methoxyphenyl)-benzyl] -piperidine with dimethyl sulfate and then reacting the product with octylamine.
14. A process for preparing a member selected from the group consisting of 4[l-[4-chlorophenyl)benzyl]-l-iminomethylpiperi-dine and the non-toxic acid addition salts thereof, character-ized by reacting ethyl formidate hydrochloride with 4-[.alpha.-(4-chlorophenyl)benzyl] piperidine.
15. A process for preparing a member selected from the group consisting of 4(9-fluorenyl)-1-[(octylimino)methyl]piperidine and the non-toxic acid addition salts thereof, characterized by reacting 4(9-fluorenyl)-1-piperidinecarbothioaldehyde with methyl iodide and then reacting the product with octylamine.
16. A process for preparing a member selected from the group consisting of 4-(diphenylmethyl)-1-[methyl(octylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, char-acterized by reacting triethyloxoniumfluoroborate with N-(n-octyl)acetamide and reacting the product with 4-diphenylmethyl-piperidine.
17. A process for preparing a member selected from the group consisting of N-[4-(diphenylmethyl)-1-piperidinyl]methylene benzenebutylimine and the non-toxic acid addition salts thereof, characterized by reacting N-formyl-4-diphenylmethylpiperidine with dimethyl sulfate and then reacting the product with phenyl-butylamine.
18 . A process for preparing a member selected from the group consisting of 3-(diphenylmethyl)-1-[(octyl-imino)methyl]piperidine and the non-toxic acid addition salts thereof, characterized by reacting 3-(diphenyl-methyl)-l-piperidinecarbothioaldehyde with methyliodide and then reacting the product with octylamine.
19. A process for preparing 4-(hydroxydiphenylmethyl)-1-[(octylimino)methyl]piperidine(E)-2-butenedioate, characterized by reacting 4-(hydroxydiphenylmethyl)-1-piperidinecarbothioaldehyde with methyliodide and then reacting the product with octylamine.
20. A process for preparing 3-(diphenylmethyl)-1-(iminomethyl)piperidine(E)-2-butenedioate hydrate, characterized by reacting 3-(diphenylmethyl)-1-piperidinecarbothioaldehyde with methyl iodide and aminating the product.
21. A process for preparing 4-[4-hydroxyphenyl)phenyl-methyl]-1-[octylimino)methyl]piperidine 2-naphthalene-sulfonate, characterized by treating 4-[(4-methoxyphenyl) phenylmethyl]-1-[(octylimino)methyl]piperidine with hydrobromic acid and converting the obtained product to its 2-naphthalenesulfonic acid salt.
22. A member selected from the group consisting of a substituted N-iminomethylpiperidine of formula (I):
(I) and the corresponding non-toxic acid addition salts thereof, 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-alkoxy, hydroxy and halo; phenyl (C1-C4)loweralkyl;
l-phenyl(C7-C9)loweralkyl; phenyl(C1-C4)lowaralkyl and l-phenyl(C7-C9)loweralkyl in which said phenyl is sub-stituted 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; diphenyl(C1-C4)loweralkyl; diphenyl-(C1-C4)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; 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, loweralXoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
and wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, R1 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;
R1 and A taken together is a member selected from the group consisting of benzhydrylidene and compounds of formulae:
and wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the group consisting of hydrogen; methyl; diphenylmethyl, diphenyl-methyl wherein at least one of the phenyl groups is sub-stituted 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; diphenylhydroxymethyl; 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 compound of formula:
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen R1' and B taken together is a member selected from the group consisting of benzhydrylidene and a compound of formula wherein n i8 0, 1, or 2 R1" taken individually is a member selected from the group consisting of hydrogen, diphenylmethyl; 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, halo, hydroxy, and phenyl, pro-vided that no more than one member is phenyl; diphenyl-hydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyls is substituted with from one of three members each selected from the group consisting of lower-alkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
and wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R; and D taken together is benzhydrylidene;
R2 is a member selected from the group con-sisting of hydkogen and C1-C4 loweralkyl; and R3 is a member selected from the group con-sisting 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; di-phenyl(C1-C4)loweralkyl; diphenyl(C1-C4)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 R1, R1', and R1" is other than hydrogen and further provided that when R1" is other than hydrogen R1, and R'1, and A are each hydrogen; when R'1 is hydrogen only one of R1 and R"1 is other than hydrogen; when R'1 is other than hydrogen or ethyl R1, R"1 and A are each hydrogen whenever prepared or produced by the process of claim 1 or by any chemical equivalent thereof.
(I) and the corresponding non-toxic acid addition salts thereof, 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-alkoxy, hydroxy and halo; phenyl (C1-C4)loweralkyl;
l-phenyl(C7-C9)loweralkyl; phenyl(C1-C4)lowaralkyl and l-phenyl(C7-C9)loweralkyl in which said phenyl is sub-stituted 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; diphenyl(C1-C4)loweralkyl; diphenyl-(C1-C4)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; 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, loweralXoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
and wherein n is 0, 1, or 2 and E is H or OH;
A taken individually is a member selected from hydrogen, acetyl, and phenyl, provided that when A is acetyl or phenyl, R1 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;
R1 and A taken together is a member selected from the group consisting of benzhydrylidene and compounds of formulae:
and wherein n is 0, 1, or 2;
R1' taken individually is a member selected from the group consisting of hydrogen; methyl; diphenylmethyl, diphenyl-methyl wherein at least one of the phenyl groups is sub-stituted 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; diphenylhydroxymethyl; 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 compound of formula:
wherein n is 0, 1, or 2 and E is H or OH;
B taken individually is hydrogen R1' and B taken together is a member selected from the group consisting of benzhydrylidene and a compound of formula wherein n i8 0, 1, or 2 R1" taken individually is a member selected from the group consisting of hydrogen, diphenylmethyl; 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, halo, hydroxy, and phenyl, pro-vided that no more than one member is phenyl; diphenyl-hydroxymethyl; diphenylhydroxymethyl wherein at least one of said phenyls is substituted with from one of three members each selected from the group consisting of lower-alkyl, loweralkoxy, hydroxy, halo, and phenyl, provided that no more than one member is phenyl; and compounds of formulae:
and wherein n is 0, 1, or 2;
D taken individually is hydrogen;
R; and D taken together is benzhydrylidene;
R2 is a member selected from the group con-sisting of hydkogen and C1-C4 loweralkyl; and R3 is a member selected from the group con-sisting 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; di-phenyl(C1-C4)loweralkyl; diphenyl(C1-C4)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 R1, R1', and R1" is other than hydrogen and further provided that when R1" is other than hydrogen R1, and R'1, and A are each hydrogen; when R'1 is hydrogen only one of R1 and R"1 is other than hydrogen; when R'1 is other than hydrogen or ethyl R1, R"1 and A are each hydrogen whenever prepared or produced by the process of claim 1 or by any chemical equivalent thereof.
23. A member selected from the group consisting of 4-diphenyl-methyl-l-iminomethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 2 or by any chemical equivalent thereof.
24. A member selected from the group consisting of 4-(diphenyl-methyl-l- [(isopropylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 3 or by any chemical equivalent thereof.
25. A member selected from the group consisting of l-[N-(benzyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 4 or by any chemical equivalent thereof.
26. A member selected from the group consisting of l-[N-(phenethyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 5 or by any chemical equivalent thereof.
27. A member selected from the group consisting of l-[N-(n-decyl)iminomethyl]-4-diphenylmethylpiperidine and the non-toxic acid additions salts thereof, whenever prepared or produced by the process of Claim 6 or by any chemical equivalent thereof.
28. A member selected from the group consisting of 4-(diphenyl-methyl)-l- [(octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 7 or by any chemical equivalent thereof.
29. A member selected from the group consisting of 4-(diphenyl-methyl)-l-[(ethylimino)methyl]piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 10 or by any chemical equivalent thereof.
30. A member selected from the group consisting of 4-(diphenyl-methyl)-l-[(hexylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 11 or by any chemical equivalent thereof.
31. A member selected from the group consisting of 1-[(4-chlorobenzylimino)methyl]-4-(diphenylmethyl)-piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 12 or by any chemical equivalent thereof.
32. A member selected from the group consisting of 4-(diphenyl-methyl)-l-[(2-propynylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 8 or by any chemical equivalent thereof.
33. A member selected from the group consisting of 4[1-(4-methoxyphenyl)benzyl]-1-[(octylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, whenever prepared or pro-duced by the process of Claim 13 or by any chemical equivalent thereof.
34. A member selected from the group consisting of 4[1-(4-chlorophenyl)benzyl]-l-iminomethylpiperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Clalm 14 or by any chemical equivalent thereof.
35. A member selected from the group consisting of 4(9-fluo-renyl)-l-[(octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 15 or by any chemical equivalent thereof.
36. A member selected from the group consisting of 4-(diphenyl-methyl)-l-[methyl(octylimino)methyl]-piperidine and the non-toxic acid addition salts thereof, prepared or produced by the process of Claim 16 or by any chemical equivalent thereof.
37. A member selected from the group consisting of N-[4-(di-phenylmethyl)-l-piperidinyl] methylene benzenebutylimine and the non-toxic acid addition salts thereof, whenever prepared or pro-duced by the process of Claim 17 or by any chemical equivalent thereof.
38. A member selected from the group consisting of 4-benzhydry-lidene-l-[(octylimino)methyl]piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 9 or by any chemical equivalent thereof.
39. A member selected from the group consisting of 3-(diphenyl-methyl)-1-[(octylimino)methyl] piperidine and the non-toxic acid addition salts thereof, whenever prepared or produced by the process of Claim 18 or by any chemical equivalent thereof.
40. A member selected from the group consisting of 4-(hydroxydiphenylmethyl)-1-[(octylimino)methyl]
piperidine(E)-2-butenedioate and the non-toxic addition salts thereof , whenever prepared or produced by the process of Claim 19 or by any chemical equivalent thereof.
piperidine(E)-2-butenedioate and the non-toxic addition salts thereof , whenever prepared or produced by the process of Claim 19 or by any chemical equivalent thereof.
41. A member selected from the group consisting of 3-(diphenylmethyl)-1-(iminomethyl)piperidine(E)-2-butenedioate hydrate, and the non-toxic addition salts thereof , whenever prepared or produced by the process of Claim 20 or by any chemical equivalent thereof.
42. A member selected from the group consisting of 4-[(4-hydroxyphenyl)phenylmethyl]-1-[(octylimino)methyl]
piperidine 2-naphthalenesulfonate or the non-toxic addition salts thereof, whenever prepared or produced by the process of Claim 21 or by any chemical eauivalent thereof.
piperidine 2-naphthalenesulfonate or the non-toxic addition salts thereof, whenever prepared or produced by the process of Claim 21 or by any chemical eauivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89141978A | 1978-03-29 | 1978-03-29 | |
| US891,419 | 1978-03-29 | ||
| US1020979A | 1979-02-08 | 1979-02-08 | |
| US10,209 | 1979-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1140118A true CA1140118A (en) | 1983-01-25 |
Family
ID=26680913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000324324A Expired CA1140118A (en) | 1978-03-29 | 1979-03-28 | 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 |
|---|---|---|---|---|
| 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 |
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 DE DE19792912026 patent/DE2912026A1/en active Granted
- 1979-03-27 DK DK124979A patent/DK124979A/en not_active Application Discontinuation
- 1979-03-27 YU YU00731/79A patent/YU73179A/en unknown
- 1979-03-27 JP JP3516879A patent/JPS54132580A/en active Granted
- 1979-03-27 SE SE7902724A patent/SE7902724L/en not_active Application Discontinuation
- 1979-03-28 IL IL56962A patent/IL56962A/en unknown
- 1979-03-28 NO NO791026A patent/NO791026L/en unknown
- 1979-03-28 IT IT48515/79A patent/IT1116525B/en active
- 1979-03-28 AT AT0230979A patent/AT372081B/en not_active IP Right Cessation
- 1979-03-28 PH PH22331A patent/PH15760A/en unknown
- 1979-03-28 SU SU792745899A patent/SU1158042A3/en active
- 1979-03-28 FI FI791035A patent/FI791035A/en not_active Application Discontinuation
- 1979-03-28 CA CA000324324A patent/CA1140118A/en not_active Expired
- 1979-03-28 ES ES479033A patent/ES479033A1/en not_active Expired
- 1979-03-28 ZW ZW64/79A patent/ZW6479A1/en unknown
- 1979-03-29 GR GR58719A patent/GR65192B/en unknown
- 1979-03-29 CH CH292779A patent/CH639071A5/en not_active IP Right Cessation
- 1979-03-29 NL NL7902465A patent/NL7902465A/en not_active Application Discontinuation
- 1979-03-29 FR FR7907919A patent/FR2421169A1/en active Granted
- 1979-08-08 IE IE650/79A patent/IE47898B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PH15760A (en) | 1983-03-22 |
| ATA230979A (en) | 1983-01-15 |
| FR2421169A1 (en) | 1979-10-26 |
| IT1116525B (en) | 1986-02-10 |
| IE790650L (en) | 1979-09-29 |
| DK124979A (en) | 1979-09-30 |
| NO791026L (en) | 1979-10-02 |
| JPS6217588B2 (en) | 1987-04-18 |
| CH639071A5 (en) | 1983-10-31 |
| IE47898B1 (en) | 1984-07-11 |
| SE7902724L (en) | 1979-09-30 |
| JPS54132580A (en) | 1979-10-15 |
| GR65192B (en) | 1980-07-29 |
| DE2912026A1 (en) | 1979-10-11 |
| IT7948515A0 (en) | 1979-03-28 |
| SU1158042A3 (en) | 1985-05-23 |
| GB2017689A (en) | 1979-10-10 |
| NZ189977A (en) | 1984-05-31 |
| AU4532279A (en) | 1979-10-04 |
| ZW6479A1 (en) | 1980-11-26 |
| IL56962A0 (en) | 1979-05-31 |
| IL56962A (en) | 1983-03-31 |
| AU523867B2 (en) | 1982-08-19 |
| DE2912026C2 (en) | 1990-04-05 |
| PT69383A (en) | 1979-04-01 |
| AT372081B (en) | 1983-08-25 |
| FR2421169B1 (en) | 1983-05-27 |
| YU73179A (en) | 1983-12-31 |
| ES479033A1 (en) | 1980-06-16 |
| FI791035A (en) | 1979-09-30 |
| NL7902465A (en) | 1979-10-02 |
| GB2017689B (en) | 1982-09-02 |
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