CA2118375A1 - Cyclic amine derivatives - Google Patents
Cyclic amine derivativesInfo
- Publication number
- CA2118375A1 CA2118375A1 CA002118375A CA2118375A CA2118375A1 CA 2118375 A1 CA2118375 A1 CA 2118375A1 CA 002118375 A CA002118375 A CA 002118375A CA 2118375 A CA2118375 A CA 2118375A CA 2118375 A1 CA2118375 A1 CA 2118375A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- piperidine
- methylsulfonamidophenylethyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract Cyclic amine derivatives of the formula I
Description
12~18375 Cvclic amine derivatives The invention relates to novel cyclic amine derivatives of the formula I
~(CH23y(cH2)m ~ :
N (CH2)~
(fH2)9 ,x ~ .. ,."""`
in which Ar and Ar' are each, independently of one another, phenyl : whi~h is unsubstituted or substituted once or twice by NO" NH2, 9al, CF3, A, N~S02A or ~HAc, X and Y are each, independently of one another, O or ' ~ ~;
a bond, ,. ~'- '~
m i8 0 or 1, n i~ 0, 1 or 2, ;~ .
p i8 0, 1, 2 or 3, . ~.
, ~, ,.
q is 2 or 3, A is alkyl having 1-6 C atoms, 15 9al is F, Cl, Br or I and Ac is alkanoyl having 1-8 C atoms, aralkanoyl having 8-10 C atoms or aroyl having 7-11 C atoms, -.
'' . ~' :"
J ~ ', ~ . , `,' ~, . :
; -` 21~3~5 and their physiologically acceptable salts.
The invention was based on the object of finding novel compounds which can be used for the production of medica-ments.
It has been found that the compounds of the formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties while being well tolerated. Thus, in particular, they show antiarrhythmic effects and positive inotropic effects prolonging the refractory period of the heart.
The cardiac action can be measured, for example, on anaesthetized or conscious rats, guinea pigs, dogs, cats, monkeys or minipigs, and the positive inotropic effect can also be measured on isolated heart preparations (for example atrium, papillary muscle or perfused whole heart) of rats, guinea pigs, cats or dogs, for example by methods as described in Arzneimittelforschung, volume 31 (I) No. la (1981), pages 141 to 170, or by Schliep et al. in the 9th International Congress of Pharmacol., London (1984J, Abstracts of papers 9P.
The compounds can therefore be used as pharmaceutical active substances in human and veterinary medicine. They can furthermore be used as intermediates for preparing other pharmaceutical active substances.
' ~ ''~ . . ' "
The invention accordingly relates to the compounds of the formulà I, to their acid addition salts and to a process for their preparation, characterized in that a compound of the formula II
t ~(CH2)m HN (CH2)n in which . '.,,' ' ' ''''~ . '' '''`' ~' ' ~ ' `' -`' 211~7~~f Ar, Y, m, n and p have the stated meaning, is reacted with a compound of the formula III, Ar-X-(C~2)q~L III, in which . ;;.
5 Ar, X and q have the stated meaning, and -~
L is 0~, Cl, Br or a reactive, functionally modified 0~ group, ~.
or in that, to prepare a compound of the formula I ; :~
according to Claim 1 in which Y i6 oxygen, a compound of the formula IV
, ",, (CH23y(CH2)m , N (ff~H2)D
(fH2)q ~ .
,X ' ', ~' ''~,' ''''.`' ;"':''.'' ~''''''";''~
in which ~ ~
Ar', X, L, m, n, p and q have the stated meanings, ~.:``.:`
' i " '~
i~ reacted with a compound of the formula V
Ar-Z V, in which Ar has the stated meaning, and Z is 0~ or a reactive, functionally modified OB group, :
': :'`
211837~
including a group with salt-like characteri~tics, or in that a compound of the formula Va Ar'-Z Va, in which Ar~ and Z have the stated meanings, 5 i8 reacted with a compound of the formula Vl ~(CH2~, Y~
--(CH2)m / -- (CH2) ( ICH2)q L ;~
.. .. ~ ; ....
in which Ar, Y, L, m, n, p and q have the stated meanings, or in that a compound which corre6ponds to the formula I
but h~s in place of one or more C~2 groups one or more reducible groups i8 converted by reduction into a com~
pound of the formula I, and/or in that one or both groups Ar and Ar~ in a compound of the formula I are converted into other radicsls Ar and Ar', respectively, and/or in that a basic compound of the formula I is converted by treatment with an acid into one of its physiologically acceptable acid addition salts.
" ' ~
~ereinbefore and hereinafter, Ar, Ar~, A, Hal, L, X, Y ~ e and Z as well as the parameters m, n, p and ~ have the meanings ~tated for the formulae I, III and V unless 20 expres~ly stated otherwise.
The radical A is alkyl having 1, 2, 3, 4, 5 or 6, in ~:
particular 1, 2 or 3, C atoms, preferably methyl, as well `~
as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ~'~';
211837~
sec-butyl or tert-butyl. A in NHSOiA is preferably methyl.
The group Ac i8 preferably alkanoyl having 1-8 C atoms, in particular having l, 2, 3, 4 or 5 C atoms;
specifically, Ac i6 preferably acetyl, furthermore preferably formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl (trimethylacetyl), further-more preferably unsubstituted or optionally substituted aroyl having 7-11 C atoms, suitable ~ubstituents being, in particular, 1-3, preferably one, of the following groups: alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl having, in each case, 1-3, preferably 1 or 2, C atoms, methylenedioxy, furthermore 0~, F, Cl, Br, I, ~2~ N~2, alkyl~mino or dialkylamino having, in each case, 1-3, preferably l or 2, C atoms in the alkyl group.
Individual preferred aroyl radicals are benzoyl, o-, m-or p-toluyl, o-, m- or p-methoxybenzoyl, 2,3-, 2,4 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxybenzoyl, o-, m- or p-methylthiobenzoyl, o-, m- or p-methylsulfinyl-benzoyl, o-, m- or p-methylsulfonylbenzoyl, 2,3- or 3,4-methylenedioxybenzoyl, 1- or 2-naphthoyl. Ac may further-more be aralkanoyl having 1-10 C atoms such as, for example, phenylacetyl, 2- or 3-phenylpropionyl or 2-, 3- or 4-phenylbutyryl.
N~Ac is particularly preferably acetamido.
If one of the compounds of the formulae I to VI contains several groups A and/or Ac it i8 po6sible for the groups of the same type in each case to be identical to or different from one another.
The radicals Ar and Ar' are each, independently of one another, unsubstituted or mono- or disubstituted phenyl, but the two radicals preferably have the same substitu-tion pattern. When they are monosubstituted, the appro-priate substituent is preferably in the para position.
"~,' ':
2 ~ 7 ~
Particularly preferred substituent~ on the phenyl radical are -N~2, -NO2, -N~SO2C~3 or -NBCOC~3. ~:
Y i~ preferably oxygen, while X is preferably a bond. ~ -~he variable m i8 preferably 1, q is preferably 2, 5 whereas n i8 particularly preferably 1 or 0 and p is 1, .~
2 or 3. ~ :
~ccordingly, the invention particularly relate~ to those compounds of the formula I in which at least one of the said radicals has one of the meanings mentioned above, especially one of the preferred meanings mentioned above.
Some preferred groups of compounds can be expre3sed by the following part-formulae Ia to Ig, which correspond to the formula I and in which the undefined radicals and parameters have the meaning stated for formula I but in i 15 which ;~
~. ~ ,'.'-.
în Ia Ar and Ar' are each p-methylsulfonamidophenyl; ~:
in Ib Ar and Ar~ are each p-nitrophenyl;
in Ic Ar and Ar~ are each p-a~; nophenyl;
in Id n ~ 2 and p ~ l 80 that the heterocyclic group i8 a piperidine radical;
in Ie n - 1 and p ~ 3 80 that the heterocyclic group i8' a hexahydroazépine radical;
in If n ~ 0 and p ~ 2 80 that the heterocyclic group i8 a pyrrolidine radical;
5 in Ig q ~ 2 and m - 0, and n and p have the meaninge stated in Id to If.
Further preferred compounds are those of the .. ~ : .-'! ' , . .
211837 ~
_ 7 _ part-formulae Ih and Iah to Igh which correspond to the part-formulae I and Ia to Ig but in which additionally Y
is oxygen and X is a bond.
The compounds of the formula I are moreover prepared by methods known per se, as described in the literature (for example in the standard works such as ~ouben-Wey Methoden der 0rganischen Chem~e [~ethods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart or J. March, Adv. Org. Chem., 3rd ~d., J. Wiley ~ Sons, N.Y. (1985)), specifically under reaction conditions which are known and suitable for the said reactions. It is m~reover possible to make use of variants which are known per se but which are not mentioned in detail here.
The starting materials for the claimed proce~s can, if required, also be formed in situ in such a manner that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I.
. : . . ::
Some of the starting materials of the formula II and III
are known. Those which are unknown can be prepared by methods known per se. The compounds of the formula II in which Y i8 oxygen are prepared, for example, starting from compounds which corre~pond to the formula II per se but, in place of the radical -Y-Ar, contain, for example, an OH group, a reactive functionally modified OH group, Cl or Br and whose secondary N atom is blocked by a protective group known per se, by reac~ion with phenol or with a substituted derivative or with a corresponding pheno}ate under conditions as are known per se for ether ~ynthesis, but especially under the condition~ of the Mitsonubo reaction (J. Am. Chem. Soc. 104, 6876 (1982)).
Furthermore, certain compounds of the formula II (Y ~ a bond) c~n also be prepared, for example, starting from benzylpyrrolidines or -piperidines or phenylpyrrolidines or -piperidines by substitution on the aromatic system, in particular nitration, where appropriate with .:
211837~
A ~ - 8 -subsequent reduction and further derivatization.
The substituted phenyl compounds of the formula II are, as a rule, known or can easily be prepared in analogy to the known compounds.
S The reaction of the compounds II and III takes place by methods as are known from the literature for the alkylation of amines. It i~ possible for the components to be melted together in the absence of a solvent, where appropriate in a closed tube or in an autoclave. ~owever, it is also possible to react the compound~ in the pres-ence of an inert solvent. Examples of ~uitable solvents - are hydrocarbons such as benzene, toluene, xylene;
ketones such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as tetrahydrofuran (T~F) or dioxane; amides such as di-methylformamide (DMF) or N-methylpyrrolidine; nitriles such as acetonitrile, where appropriate also mixtures of these ~olvents with one another or mixtures with water.
~he addition of an acid acceptor, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another alkali metal or alkaline earth metal salt of a weak acid, preferably of potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amine component, may be beneficial. The reaction time depends on the condition~
employed and i5 between a few minutes and 14 days, and the reaction temperature is between about 0 and 150 normally between 20 and 130.
It is furthermore possible for the preparation of a compound of the formula I in which Y is oxygen to react a compound of the formula IV with a benzene derivative of the formula V.
Compounds of the formula IV ca~n be obtained, for example, by reacting cyclic amines such as, for example, ~ "'''"
21183~S
g piperidinols, pyrrolidinol~, prolinols or else cyclic amines which are substituted by a hydroxymethyl or halomethyl group, where halogen i8 preferably chlorine or bromine, with a phenylalkyl bromide or chloride (alkyl ethyl or propyl) or phenoxyalkyl bromide or chloride, where the aromatic system can also be substituted by one or two of the radical6 stated for Ar, so that N-alkylation takes place. - ;
The benzene derivative~ of the formula V are known as a --rule and can be prepared by the methods known per se for aromatic substitution.
The reaction of the compounds of the formula IV with those of the formula V takes place under condition~
typical for synthesizing ethers. Suitable solvents are those mentioned above for the reaction of II with III.
Likewise, the same reaction times and temperatures are suitable. Particularly preferred reaction conditions are those of the Mitsonubo reaction, using azodicarboxylic die6ter and triphenylphosphine if a compound of the formula I with Y ~ oxygen is to be prepared.
It is noteworthy that in the reaction of IV with V under "Mitsonubo conditions~ there may be a rearrangement with ring contraction or ring expansion by in each case one C atom of the cyclic A~;ne unit 80 that, for example, a 25 piperidine derivative may be produced from a pyrrolidine ~ ~;
derivative or a hexahydroazepine derivative may be produced from a piperidine derivative, or else conver~ely a pyrrolidine system'may be produced from a piperidine system.
Resulting product mixture6 of five- and six-membered rings or six- and seven-membered heterocycles can easily be separated by preparative chromatography on ~ilica gel.
Furthermore, compounds of the formula I can also be prepared by reacting benzene derivatives of the ': '~ ' :,' 211~37~
formula Va with cyclic ~m;nes of the formula VI. The compouDds of the formula Va are known per se or can be --prepared in analogy to methods known per se, for example by those of aromatic electrophilic substitution. ~ ~-Compounds of the formula VI can be prepared, for example, starting from the particular cyclic amine by etherification of the free hydroxyl group on the side chain as well a~ N-alkylation of the heterocycle, where ~ -appropriate after elimination of a necessary proteGtive group under the conditions stated above for the prepar-ation of the compounds of the formula II using those of ~-the formula III. ;~
The reaction of the compounds va with the substances of the formula VI takes place in analogy to the reaction of IV with V as stated above, although no rearrangements take place in this case.
It is furthermore possible to obtain a compound of the formula I by reducing a compound which corresponds to the formula I but contain~, in place of one or more CB2 groups, one or more reducible groups, preferably at temperatures between -80 and +250 in the presence of at least one inert solvent.
Reducible (hydrogen-replaceable) groups are, in particular, oxygen in a carbonyl group, hydroxyl, aryl-sulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl N-benzyl or O-benzyl.
It is possible in principle to convert compounts which contain only one, or those which contain two or more of the abovementioned groups side by side, by reduction into a compound of the formula I. Preferably used for this purpo6e is nascent hydrogen or complex metal hydrides, furthermore reductions with gaseous hydrogen with catalysis by transition metals.
.:, ~, -211~3~5 If nascent hydrogen i8 used a8 reducing agent~ it can be generated~ for example r by treating metals with weak acids or with bases. Thus, for examPle, a mixture of zinc with alkali metal hydroxide 801ution or of iron with S acetic acid can be used. Also guitable is the use of sodium of another alkali metal in an alcohol such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. It is furthermore poæsible to use an aluminium/
nickel alloy in alkaline aqueOus solution, where ap-propriate with the addition of ethanol. Sodium or alu-minium amalgam in aqueous/alcoholic or aqueous solution i8 also suitable for generating nascent hydrogen. The reaction can aI80 be carried out in heterogeneous phase, in which case an aqueous and a benzene or toluene phase is preferably used.
It is furthermore particularly advantageous to use complex metal hydrides such a~ LiAl~" NaB~" diisobutyl-aluminium hydride or NaAl(OC~2Q,OC~3)2H2 as well a~
diborane as reducing agents, if required with the addi-tion of catalystc such as BF3, AlC13 or LiBr. Particularlysuitable solvents for this purpose are ethers such as diethyl ether, di-n-butyl ether, ~EF, dioxane, diglyme or 1,2-dimethoxyethane as well as hydrocarbons such as benzene. Solvents primarily suitable for a reduction with NaB~, are alcohols such as methanol or ethanol, as well as water and aqueous alcohols. Reducti~n by these methods preferably takes place at temperatures between -80 and ~150, in particular between about O and about 100.
'.
The -CO- groups in the amides can be reduced to! C~z groups particularly advantageously with LiAlH, in T~F at temperatures between about O and 66.
It is furthermors possible to carry out certain reduc~
tions by using ~2 gas with the catalytic action of transition metals such as, for example, Raney Ni or Pd.
It is possible in this way, for example, to replace Cl, Br, I, S~ or, in certain case~, also OH groups by , . -. .
:
:~.. 1' .~ .. .
21~7~
hydrogen. ~ikewise, nitro groups can be converted, for exam~le, by catalytic hydrogenation with Pd/~2 in ~-methanol into NH2 groups.
- ~.
Furthermore, one compound of the formula I can be con-verted by methods known per se into a different compound of the formula I.
The phenyl rings in the compounds of the formula I can, if side reactions are to be precluded, for example be chlorinated, brominated or alkylated under the conditions of Friedel-Crafts reactions by reactinq the appropriate halogen or àlkyl chloride or alkyl bromide with catalysis by ~ewis acids such as, for example, AlC13, FeBr3 or Fe, at temperatures between 30 and 150, preferably between 50 and 150, in an inert solvent such as, for example, hydrocarbons, ~F or tetrachloromethane, with the com-pound of the formula I which i8 to be derivatized.
It is furthermore possible to convert a compound of the formula I in which Ar or Ar' is substituted by N~2 by alkylation or acylation by methods which are generally customary and known for amines into corresponding com-pounds of the formula I in which Ar or Ar' is substituted by N~A or NHAc.
, .: .
A resulting base of the formula I can be converted with an acid into the relevant acid addition salt~ Acid~
suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to.
use inorganic acid~, for example sulfuric acid, hydro-halic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, al30 organic acids, speci~
fically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, ~uch as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic ,, :
r 21~337 - 13 - ~
: ' .' acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, a~corbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acids and lauryl sulfuric acid.
The free bases of the formula I can, if required, be liberated from their salts by treatment with strong base3 such as sodium or potas~ium hydroxide, sodium or potassium carbonate, as long as no other acidic groups are present in the molecule.
he compounds of the formula I may have a centre of asymmetry. They may therefore result from their prepara~
tion as racemates or, if optically active starting materials are used, also in optically active form.
Resulting racemates can, if required, be resolved into their optical antipodes mechanically or chemically by methods known per se. Preferably, diastereomer~ are formed from the racemate by reaction with an optically active resolving agent. ~:~
Examples of suitable resolvins agents are optically active acids such a~ the D and L forms of tartaric acids, dibenzoyltartaric acid, diacetyltartaric acid, camphosulfonic acids, mandelic acid, malic acid or lactic acid. The various forms of the diastereomers can be separated in a manner known per se, for example by.
fractional crystallization, and the optically active compounds of the formula I can be liberated from the diastereomers in a manner known per se.
~ ~ -It is furthermore possible to separate the enantiomers by preparative chromatographic methods known per se. Silica gel is preferred as stationary phase. Particularly ~ ~
preferred mobile phases are mixtures oi'ethyl acetate and ~ -35 heptane or dichloromethane and methanol. ~
The invention furthermore relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by non-chemical means. For this purpo~e they can be converted together with at least one vehicle or ancillary substance and, where appro-priate, in combination with one or more other active substance(s) into a ~uitable dosage form.
The invention furthermore relates to compositions, in particular pharmaceutical preparations, containing at least one compound of the formula I and/or one of its ~s physiologically acceptable salts. These preparations can be used afi medicaments in human and veterinary medicine.
Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the n~vel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, ~ -~
gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. Tablets, coated tsblets, capsules, syrups, ~olutions, drops or suppositories are used in particular for enteral ~ :
administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants 25 are used for parenteral administration, and ointments, -creams or powders are used for topical application. The novel compounds can also be lyophilized and the resulting lyophilizates u~ed, for example, to produce products for injection. -,, , ,:
The stated preparations can be sterilized and/or contain ancillary ~ubstances such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pres~ure, buffer substances, colorants, flavourings and/or aromatizing substances.
They can, if required, also contain one or more other active substances, for example one or more vitamins.
; . .~ ~:
: ~
.~",",~.
21~37~
~he compounds of the formula I and their physiologically acceptable salts can be used for the therapeutic treat-ment of the human or anLmal body and for controlling diseases. They are particularly suitable for the treat-ment of arrhythmias and tachycardias.
For this purpose the substances according to the inven-tion are, as a rule, administered in analogy to known substances with antiarrhythmic activity, such as aprindine, flecainide or amiodarone, preferably in dosages between about 1 and 100 mg, in particular between 2 and 20 mg per dosage unit.
The daily dosage i8 preferably between about 0.02 and 2 mg/kg of body weight. The specific doæe for each particular patient depends, however, on a wide variety of factors, for example on the efficacy of the specific compound used, on the age, body weight, general state of ~ealth, sex, on the diet, on the time and route of administration, on the rate of excretion, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral a~inistration is 2referred.
In the following examples, Nusual working up" means~
If necessary, water or dilute sodium hydroxide solution i~ added, extraction is carried out with an organic solvent such as ethyl acetate, chloroform or dichloro~
methane, the organic phase is ~eparated off, dried over .
sodium sulfate, filteied and evaporated, and purificatibn ~;
is carried out by chromatography on silica gel and~or `~
crystallization. The optical rotations were measured in ~0 methanol (c ~ 1) unless ~tated otherwise. If the produc-tion of two substances is de~cribed in the individual examples, these are always separate from one another.
All temperatures are stated hereinbefore and hereinafter in degrees Celsius. ~ ;
-,, ~11837 ;i Bxample 1 4 mmol of 1-(2-p-nitrophenylethyl)-3-piperidinol [prepared from 3-piperidinol by alkylation with p-nitro-phenethyl bromide or p-nitrostyrene], 4 mmol of p-nitro-phenol, 4 mmol of triphenylphosphine and 4 mmol ofdiethyl azodicarboxylate are dissolved in 100 ml of T~F
and stirred at room temperature for 48 h. After the usual working up, the residue is chromatographed on silica gel using dichloromethane/methanol (99:1~ and ethyl acetate/
methanol (99~ uccessively as mobile phases.
The following are obtained: -,:,, a) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-pyrrolidine;
b) 1-t2-p-nitrophenylethyl)-3-(p-nitrophenoxy)- ;
piperidine. ;- ;~
~ample 2 In analogy to Example 1, starting from (-)-1-(2-p-nitro~
phenylethyl)-2-prolinol~ the following are obtained after ~;
chromatography on silica ~el using ethyl acetate/heptane (7:3) and subsequently dichloromethane/ methanol (99~
as mobile phases: `~ ; ;
a) (-)-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine ; `~
la]20~ -98.4; -; 25 b) (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine [a]'~ l37.2 The following are obtained analogously from (+)-1-(2-p-nitrophenylethyl)-2-prolinol:
':
,'';'' ~
-~ 2~1837S
a) (~t-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine [a]20D +97.8;
b) (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine [~]20D -36.6 .
Example 3 In analogy to Example 1, starting from 1-(2-p-nitro-phenylethyl)-2-hydroxymethylpiperidine, the following are ~ -obtained by reaction with p-nitrophenol with a reaction time of 60 h (purification: silica gel/methyl tert.-butyl ether and subsequently heptane/acetone (7:3)) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)- ~ ~
piperidine and ~ ;
1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine.
Subsequent reaction with fumaric acid provides after crystallization (ethyl acetate/diisopropyl ether) a) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-piperidine -m.p. (fumarate) 122;
b) l-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine m.p. (fumarate) 137.
25 Esample 4 ; ;
.'~ ' '" .'''' In analogy to Bxample 1, the following are obtained by resction of p-nitrophenol ~ ;~
with 1-(2-p-nitrophenylethyl)-3-hydroxymethylpiperidine (purification: ~ilica gel/methyl tert.-butyl ether and ~, 211~375 subsequently heptane/acetone (7:3)) 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy-methyl)piperidine;
with l-(2-p-nitrophenylethyl)-4-piperidinol (purification: silica gel/heptane:acetone (7:3) and subsequently ethyl acetate/methanol (19:1)) 1-(2-p-nitrophenylethyl)-4-(p-nitrophenoxy)~
piperidine;
with (~ (2-p-nitrophenylethyl)-3-pyrrolidinol (purification: silica gel/methyl tert.-butyl ether:petroleum ether:methanol (25:24 (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)~
pyrrolidine, m.p. 97, [a]20D - +13.8 (dioxane).
.... " ~ .. ~.~ ..
. .~'-"''~i Rxample 5 In analogy to Example 1, reaction of 1-benzhydryl-azetidine tobtainable by reaction of benzhydrylamine with 1-chloro-2,3-epoxypropane] with N-(4-hydroxyphenyl)-phthalimide results, after the usual working up, in 1-benzhydryl-3-[4-(1,3-dioxo-2-i~oindolinyl)phenoxy]-azetidine (purification: 8ilica gel~diisopropyl ether:methanol (49 Elimination of the benzhydryl group by treatment with ~2 gas/Pd on carbon (Pd content 1 %) in toluene at room~
tempe~ature p~ovides 3-[4-(1,3-dioxo-2-isoindolinyl)-phenoxy~azetidine.
Example 6 1 mmol of 3-[4-(1,3-dioxo-2-isoindolinyl)-phenoxy]-azetidine is dissolved in 40 ml of dichloromethane, 1 equivalent of p-nitrophenethyl bromide is added, and the mixture i8 stirred at room temperature for 6 h. The :: ~ :..~: .
. ~ ~
19 - 21183~
usual working up results in 1-(2-p-nitrophenylethyl)-3-14-(1,3-dioxo-2-i~oindolinyl)phenoxy]azetidine.
Example 7 0.9 g of 1-(2-p-nitrophenylethyl)-3-[4-(1,3-dioxo-2-5 i80indolinyl)phenoxy]azetidine i8 dissolved in 50 ml of THF, and 0.5 g of hydrazine i5 added. The mixture i8 boiled for 2 h and then worked up as usual. 1-(2-p-Nitrophenylethyl)-3-(p-aminophenoxy~azetidine i~
obtained.
~xamDle 8 ~ .. .: ~.
18 mmol of p-nitrophenol are dissolved in 15 ml of DMF, 22 mmol of Na~ are added, and the mixture is ~tirred at 40 for 30 min. Subsequently, 18 mmol of 1-(2-p-nitro~
phenylethyl)-2-chloromethylpiperidine tprepared from the piperidinol derivative by halogenation with thionyl chloride/DMF in dichloromethane] are dissolved in 20 ml of DMF, added to the phenolate ~olution and stirred at 90 for 4 h. The solution i~ concentrated, the re6idue i8 taken up in toluene, and the solution is washed with 2 N
sodium hydroxide solution and extracted with 2 N hydro-chloric acid. ~he usual working up and purification by chromatography (silica gel/methyl tert.-butyl ether) re~ults in : . ,: ,. '`, ' .
a) 1-(2-p-nitrophenylethyl~-2-(p-nitrophenoxymethyl)-piperidine;
., , j , b) 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine.
~xample 9 85 mmol of 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine are hydrogenated on 15 g of Raney Ni in 400 ml of ethanol and 40 ml of T~F at 20 and 3 bar ~ 211837~
for 7 h. The solution i8 concentrated and worked up as usual. 1-(2-p-Aminophenylethyl)-2-(p-aminophenoxymethyl)-pyrrolidine i8 obtained.
The following are obtained analogously by catalytic reduction with Raney Ni~
from 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)- -~
piperidine~
1-(2-p-aminophenylethyl)-3-~p-aminophenoxy)- ; ~ .
piperidine;
from (~ (2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine:
(-)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy- :~
methyl)pyrrolidine;
from (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine:
(+)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-piperidine;
from (+)-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy- ;~ :~
methyl)pyrrolidine:
(+)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy-methyl)pyrrolidine;
from (-)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine: - ::
(-)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-. : ~ ~
piperidine;~ ' ' I `; :~'' from 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-piperidine: .~
1-(2-p-aminophenylethyl)-2-( p-~mi nophenoxymethyl)- ~ `.
piperidine; ~ ~:
,,, :, ,, 211~37~
~ .
from l-(2-p-nitrophenylethyl)-3-~p-nitrophenoxy)-hexahydroazepine: ~ ~
1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- :
hexahydroazepine;
' ' .
from 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxymethyl)-piperidine: .
1-(2-p-aminophenylethyl)-3-(p-aminophenoxymethyl)- - -piperidine;
from l-(2-p-nitrophenylethyl)-4-(p-nitrophenoxy~
piperidine~
1-(2-p-aminophenylethyl)-4-(p-aminophenoxy)-piperidine;
from (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxyl)- :
pyrrolidine~
(+)-1-(2-p-aminophenylethyll-3-(p-aminophenoxy)- ~: .
pyrrolidine.
. ~
~xample 10 13 mmol of 1-(2-p-aminophenylethyl)-2-(p-aminophenoxy- ~ :
methyl)pyrrolidine are dissolved in 40 ml of dry pyridine 20 and, while stirring under an N2 atmosphere and cooling in ~ :
ice, at a temperature of 5-10 39 mmol of mesyl chloride :~
are added dropwise and the mixture i8 6tirred at the same : :
temperature for 2 h. Ethyl acetate i~ added to the solution. ~he resulting precipitate i8 separated off and taken up in ethyl acetate~Na~C03 solution. The usual .
working up and~ purification by chromatography (silica gel/dichloromethane/methanol (49:1)) results in 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamido~
phenoxymethyl)pyrrolidine, m.p. 61-63.
The following are obtainad analogou~ly by reaction with m ~yl chloride~
.. ~ .:
. ~ ;,,,:,.
. :, . . .
- . ~ .
: ": ... .
7 i . r~
from l-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~ ~ .
piperidine: :
1-(2-p-methylsulfonamidophenylethyl)-3-(p-methyl-sulfonamidophenoxy)piperidine, m.p. 148-149; ~ ~ ~
.,.:.
from (-)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy-methyl)pyrrolidine:
(-)-1-(2-p-methylsulfonamidophe~ylethyl)-2-(p- :
methylsulfonamidophenoxymethyl)pyrrolidiner [a]20 _73 go;
-: . ' 10 from (+)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~:
piperidine~
(+)-1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxy)piperidine, m.p. 168, .
[a]20D +31.8; :~
from (+)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy~
methyl)pyrrolidine:
(+)-1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)pyrrolidine, [a]~oD
-72.0; ~ ;;
from (-)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-piperidine: `
(-)-1-(2-p-methylsulfonamidophenylethyl)-3-(p- ::
methylsulfonamidophenoxyJpiperidine, m.p. 168, [a]20D -32.7; ~.
25 from 1-(2-p-aminophenylethyl)-2-(p- ~ nophenoxymethyl)- ~
piperidine: ! l ! ': "; ..
1-(2-p-methylsulfonamidophenylethyl)-2-(p-methyl-sulfonamidophenoxymethyl)piperidine;
from 1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~ ~ a hexahydroazepine~
1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxy)hexahydroazepine;
.. ~,,~;,, ~, ., ..~ i. -.". ,~.
. . ... . ~
21~37~
from l-(2-p-aminophenylethyl)-3-(p-aminophenoxymethyl)-piperidine:
1-(2-p-methylsulfon~m;dophenylethyl)-3-(p-methyl-6ulfonamidophenoxymethyl)piperidine, m.p. 199-200;
S from 1-(2-p-aminophenylethyl)-4-tp-aminophenoxy)-piperidine~
1-(2-p-methylsulfon~;dophenylethyl)-4-(p-methyl- ~-sulfonamidophenoxy)piperidine, m.p. 182-183~
from (~)-l-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- --pyrrolidine:
(+)-1-(2-p-methylsulfonamidophenylethyl)-3-(p- ~
methylsulfonamidophenoxy)pyrrolidine,m.p.l99-200, ~;
[a]20D ~7.3 (dioxane). ; -Example 11 .
10 mmol of 1-(2-p-Pm;nophenylethyl)-3-(p-aminophenoxy)- ~ f pyrrolidine are dissolved in 45 ml of dry pyridine and 45 ml of acetic anhydride and stirred at room temperature for 24 h. Water i9 added to the suspension while cooling in ice, the mixture is stirred at room temperature for 20 3 h, 2 N sodium hydroxide ~olution is added until ~;~
opalescent, and the usual working up is carried out.
Recrystallization from methanol results in 1-(2-p-acetamidophenylethyl)-3-(p-acetamidophenoxy)-pyrrolidine, m.p. 213-214. - ~ -~
The following examples relate to pharmaceutical prepara--tions. ' ! i .: ~
Esample A: Vi~
~. .........
A solution of 100 g of an active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 1 ~ ~
30 of double-distilled water is adjusted to p~ 6.5 with 2 N ~ ~`
hydrochlcric acid, sterilized by filtration, dispensed into vials, lyophilized and sealed sterile. Each vial ~ ,....,,, ,-, ...... .
:~r -~ 211~37~
contains 5 m~ of active ~ubstance.
E~ample B: Suppo~itories A mixture of 20 mg of an active substance of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and left to cool.
Each suppository contains 20 mg of active substance.
Bxample C: Solution ~-A solution i8 prepared from 1 g of an active substance of ~ ;~
the formula I, 9.38 g of Na~,PO, x 2 H~O, 28.48 g of Na2HPO~ x 12 ~2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The p~ is adjusted to 6.8, the volume i8 made up to 1 1 and the solution is ~ ~`
sterilized by radiation. This solution can be used in the form of eye drops. ~ -Example D: Ointment 500 mg of an active substance of the formula I are mixed ~;
with 99.5 g of petrolatum under aseptic conditions. ~;
Bxample B: Tablets `~
A mixture of 1 kg of active substance of the formula I, ~ -4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate i~ compressed to tablets in a conventional way ~uch that each tablet contains- il;
10 mg of active substance. :
Example F: Coated tablets ,;. i , ~ ,, ~.
Tablets are compressed in analogy to Bxample E and are then coated in a conventional way with a coating compo~ed of sucrose, potato starch, talc, tragacanth and colorant.
.', ;'.','1-.
~ 25 21~37:~.
B~ample G: Capsules 2 kg of active substance of the formula I are packed into hard gelatin capsules in a conventional way BO that each capsule contains 20 mg of the active substance.
Bsample ~: Ampoules A solution of 1 kg of active substance of the ,~ ~.
formula I in 60 1 of double-distilled water i8 dispensed ;;~
into ampoules, lyophilized under a~eptic conditions and :~
sealed sterile. Each ampoule contains 10 mq of active f~
10 substance. ;;
;;
~ ,. !
.. ' '''~
'' ~ ~" .~
"' ~: ,~ f.i, ".',,, ', .".; `' '", " " .,
~(CH23y(cH2)m ~ :
N (CH2)~
(fH2)9 ,x ~ .. ,."""`
in which Ar and Ar' are each, independently of one another, phenyl : whi~h is unsubstituted or substituted once or twice by NO" NH2, 9al, CF3, A, N~S02A or ~HAc, X and Y are each, independently of one another, O or ' ~ ~;
a bond, ,. ~'- '~
m i8 0 or 1, n i~ 0, 1 or 2, ;~ .
p i8 0, 1, 2 or 3, . ~.
, ~, ,.
q is 2 or 3, A is alkyl having 1-6 C atoms, 15 9al is F, Cl, Br or I and Ac is alkanoyl having 1-8 C atoms, aralkanoyl having 8-10 C atoms or aroyl having 7-11 C atoms, -.
'' . ~' :"
J ~ ', ~ . , `,' ~, . :
; -` 21~3~5 and their physiologically acceptable salts.
The invention was based on the object of finding novel compounds which can be used for the production of medica-ments.
It has been found that the compounds of the formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties while being well tolerated. Thus, in particular, they show antiarrhythmic effects and positive inotropic effects prolonging the refractory period of the heart.
The cardiac action can be measured, for example, on anaesthetized or conscious rats, guinea pigs, dogs, cats, monkeys or minipigs, and the positive inotropic effect can also be measured on isolated heart preparations (for example atrium, papillary muscle or perfused whole heart) of rats, guinea pigs, cats or dogs, for example by methods as described in Arzneimittelforschung, volume 31 (I) No. la (1981), pages 141 to 170, or by Schliep et al. in the 9th International Congress of Pharmacol., London (1984J, Abstracts of papers 9P.
The compounds can therefore be used as pharmaceutical active substances in human and veterinary medicine. They can furthermore be used as intermediates for preparing other pharmaceutical active substances.
' ~ ''~ . . ' "
The invention accordingly relates to the compounds of the formulà I, to their acid addition salts and to a process for their preparation, characterized in that a compound of the formula II
t ~(CH2)m HN (CH2)n in which . '.,,' ' ' ''''~ . '' '''`' ~' ' ~ ' `' -`' 211~7~~f Ar, Y, m, n and p have the stated meaning, is reacted with a compound of the formula III, Ar-X-(C~2)q~L III, in which . ;;.
5 Ar, X and q have the stated meaning, and -~
L is 0~, Cl, Br or a reactive, functionally modified 0~ group, ~.
or in that, to prepare a compound of the formula I ; :~
according to Claim 1 in which Y i6 oxygen, a compound of the formula IV
, ",, (CH23y(CH2)m , N (ff~H2)D
(fH2)q ~ .
,X ' ', ~' ''~,' ''''.`' ;"':''.'' ~''''''";''~
in which ~ ~
Ar', X, L, m, n, p and q have the stated meanings, ~.:``.:`
' i " '~
i~ reacted with a compound of the formula V
Ar-Z V, in which Ar has the stated meaning, and Z is 0~ or a reactive, functionally modified OB group, :
': :'`
211837~
including a group with salt-like characteri~tics, or in that a compound of the formula Va Ar'-Z Va, in which Ar~ and Z have the stated meanings, 5 i8 reacted with a compound of the formula Vl ~(CH2~, Y~
--(CH2)m / -- (CH2) ( ICH2)q L ;~
.. .. ~ ; ....
in which Ar, Y, L, m, n, p and q have the stated meanings, or in that a compound which corre6ponds to the formula I
but h~s in place of one or more C~2 groups one or more reducible groups i8 converted by reduction into a com~
pound of the formula I, and/or in that one or both groups Ar and Ar~ in a compound of the formula I are converted into other radicsls Ar and Ar', respectively, and/or in that a basic compound of the formula I is converted by treatment with an acid into one of its physiologically acceptable acid addition salts.
" ' ~
~ereinbefore and hereinafter, Ar, Ar~, A, Hal, L, X, Y ~ e and Z as well as the parameters m, n, p and ~ have the meanings ~tated for the formulae I, III and V unless 20 expres~ly stated otherwise.
The radical A is alkyl having 1, 2, 3, 4, 5 or 6, in ~:
particular 1, 2 or 3, C atoms, preferably methyl, as well `~
as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ~'~';
211837~
sec-butyl or tert-butyl. A in NHSOiA is preferably methyl.
The group Ac i8 preferably alkanoyl having 1-8 C atoms, in particular having l, 2, 3, 4 or 5 C atoms;
specifically, Ac i6 preferably acetyl, furthermore preferably formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl (trimethylacetyl), further-more preferably unsubstituted or optionally substituted aroyl having 7-11 C atoms, suitable ~ubstituents being, in particular, 1-3, preferably one, of the following groups: alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl having, in each case, 1-3, preferably 1 or 2, C atoms, methylenedioxy, furthermore 0~, F, Cl, Br, I, ~2~ N~2, alkyl~mino or dialkylamino having, in each case, 1-3, preferably l or 2, C atoms in the alkyl group.
Individual preferred aroyl radicals are benzoyl, o-, m-or p-toluyl, o-, m- or p-methoxybenzoyl, 2,3-, 2,4 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxybenzoyl, o-, m- or p-methylthiobenzoyl, o-, m- or p-methylsulfinyl-benzoyl, o-, m- or p-methylsulfonylbenzoyl, 2,3- or 3,4-methylenedioxybenzoyl, 1- or 2-naphthoyl. Ac may further-more be aralkanoyl having 1-10 C atoms such as, for example, phenylacetyl, 2- or 3-phenylpropionyl or 2-, 3- or 4-phenylbutyryl.
N~Ac is particularly preferably acetamido.
If one of the compounds of the formulae I to VI contains several groups A and/or Ac it i8 po6sible for the groups of the same type in each case to be identical to or different from one another.
The radicals Ar and Ar' are each, independently of one another, unsubstituted or mono- or disubstituted phenyl, but the two radicals preferably have the same substitu-tion pattern. When they are monosubstituted, the appro-priate substituent is preferably in the para position.
"~,' ':
2 ~ 7 ~
Particularly preferred substituent~ on the phenyl radical are -N~2, -NO2, -N~SO2C~3 or -NBCOC~3. ~:
Y i~ preferably oxygen, while X is preferably a bond. ~ -~he variable m i8 preferably 1, q is preferably 2, 5 whereas n i8 particularly preferably 1 or 0 and p is 1, .~
2 or 3. ~ :
~ccordingly, the invention particularly relate~ to those compounds of the formula I in which at least one of the said radicals has one of the meanings mentioned above, especially one of the preferred meanings mentioned above.
Some preferred groups of compounds can be expre3sed by the following part-formulae Ia to Ig, which correspond to the formula I and in which the undefined radicals and parameters have the meaning stated for formula I but in i 15 which ;~
~. ~ ,'.'-.
în Ia Ar and Ar' are each p-methylsulfonamidophenyl; ~:
in Ib Ar and Ar~ are each p-nitrophenyl;
in Ic Ar and Ar~ are each p-a~; nophenyl;
in Id n ~ 2 and p ~ l 80 that the heterocyclic group i8 a piperidine radical;
in Ie n - 1 and p ~ 3 80 that the heterocyclic group i8' a hexahydroazépine radical;
in If n ~ 0 and p ~ 2 80 that the heterocyclic group i8 a pyrrolidine radical;
5 in Ig q ~ 2 and m - 0, and n and p have the meaninge stated in Id to If.
Further preferred compounds are those of the .. ~ : .-'! ' , . .
211837 ~
_ 7 _ part-formulae Ih and Iah to Igh which correspond to the part-formulae I and Ia to Ig but in which additionally Y
is oxygen and X is a bond.
The compounds of the formula I are moreover prepared by methods known per se, as described in the literature (for example in the standard works such as ~ouben-Wey Methoden der 0rganischen Chem~e [~ethods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart or J. March, Adv. Org. Chem., 3rd ~d., J. Wiley ~ Sons, N.Y. (1985)), specifically under reaction conditions which are known and suitable for the said reactions. It is m~reover possible to make use of variants which are known per se but which are not mentioned in detail here.
The starting materials for the claimed proce~s can, if required, also be formed in situ in such a manner that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I.
. : . . ::
Some of the starting materials of the formula II and III
are known. Those which are unknown can be prepared by methods known per se. The compounds of the formula II in which Y i8 oxygen are prepared, for example, starting from compounds which corre~pond to the formula II per se but, in place of the radical -Y-Ar, contain, for example, an OH group, a reactive functionally modified OH group, Cl or Br and whose secondary N atom is blocked by a protective group known per se, by reac~ion with phenol or with a substituted derivative or with a corresponding pheno}ate under conditions as are known per se for ether ~ynthesis, but especially under the condition~ of the Mitsonubo reaction (J. Am. Chem. Soc. 104, 6876 (1982)).
Furthermore, certain compounds of the formula II (Y ~ a bond) c~n also be prepared, for example, starting from benzylpyrrolidines or -piperidines or phenylpyrrolidines or -piperidines by substitution on the aromatic system, in particular nitration, where appropriate with .:
211837~
A ~ - 8 -subsequent reduction and further derivatization.
The substituted phenyl compounds of the formula II are, as a rule, known or can easily be prepared in analogy to the known compounds.
S The reaction of the compounds II and III takes place by methods as are known from the literature for the alkylation of amines. It i~ possible for the components to be melted together in the absence of a solvent, where appropriate in a closed tube or in an autoclave. ~owever, it is also possible to react the compound~ in the pres-ence of an inert solvent. Examples of ~uitable solvents - are hydrocarbons such as benzene, toluene, xylene;
ketones such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as tetrahydrofuran (T~F) or dioxane; amides such as di-methylformamide (DMF) or N-methylpyrrolidine; nitriles such as acetonitrile, where appropriate also mixtures of these ~olvents with one another or mixtures with water.
~he addition of an acid acceptor, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another alkali metal or alkaline earth metal salt of a weak acid, preferably of potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amine component, may be beneficial. The reaction time depends on the condition~
employed and i5 between a few minutes and 14 days, and the reaction temperature is between about 0 and 150 normally between 20 and 130.
It is furthermore possible for the preparation of a compound of the formula I in which Y is oxygen to react a compound of the formula IV with a benzene derivative of the formula V.
Compounds of the formula IV ca~n be obtained, for example, by reacting cyclic amines such as, for example, ~ "'''"
21183~S
g piperidinols, pyrrolidinol~, prolinols or else cyclic amines which are substituted by a hydroxymethyl or halomethyl group, where halogen i8 preferably chlorine or bromine, with a phenylalkyl bromide or chloride (alkyl ethyl or propyl) or phenoxyalkyl bromide or chloride, where the aromatic system can also be substituted by one or two of the radical6 stated for Ar, so that N-alkylation takes place. - ;
The benzene derivative~ of the formula V are known as a --rule and can be prepared by the methods known per se for aromatic substitution.
The reaction of the compounds of the formula IV with those of the formula V takes place under condition~
typical for synthesizing ethers. Suitable solvents are those mentioned above for the reaction of II with III.
Likewise, the same reaction times and temperatures are suitable. Particularly preferred reaction conditions are those of the Mitsonubo reaction, using azodicarboxylic die6ter and triphenylphosphine if a compound of the formula I with Y ~ oxygen is to be prepared.
It is noteworthy that in the reaction of IV with V under "Mitsonubo conditions~ there may be a rearrangement with ring contraction or ring expansion by in each case one C atom of the cyclic A~;ne unit 80 that, for example, a 25 piperidine derivative may be produced from a pyrrolidine ~ ~;
derivative or a hexahydroazepine derivative may be produced from a piperidine derivative, or else conver~ely a pyrrolidine system'may be produced from a piperidine system.
Resulting product mixture6 of five- and six-membered rings or six- and seven-membered heterocycles can easily be separated by preparative chromatography on ~ilica gel.
Furthermore, compounds of the formula I can also be prepared by reacting benzene derivatives of the ': '~ ' :,' 211~37~
formula Va with cyclic ~m;nes of the formula VI. The compouDds of the formula Va are known per se or can be --prepared in analogy to methods known per se, for example by those of aromatic electrophilic substitution. ~ ~-Compounds of the formula VI can be prepared, for example, starting from the particular cyclic amine by etherification of the free hydroxyl group on the side chain as well a~ N-alkylation of the heterocycle, where ~ -appropriate after elimination of a necessary proteGtive group under the conditions stated above for the prepar-ation of the compounds of the formula II using those of ~-the formula III. ;~
The reaction of the compounds va with the substances of the formula VI takes place in analogy to the reaction of IV with V as stated above, although no rearrangements take place in this case.
It is furthermore possible to obtain a compound of the formula I by reducing a compound which corresponds to the formula I but contain~, in place of one or more CB2 groups, one or more reducible groups, preferably at temperatures between -80 and +250 in the presence of at least one inert solvent.
Reducible (hydrogen-replaceable) groups are, in particular, oxygen in a carbonyl group, hydroxyl, aryl-sulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl N-benzyl or O-benzyl.
It is possible in principle to convert compounts which contain only one, or those which contain two or more of the abovementioned groups side by side, by reduction into a compound of the formula I. Preferably used for this purpo6e is nascent hydrogen or complex metal hydrides, furthermore reductions with gaseous hydrogen with catalysis by transition metals.
.:, ~, -211~3~5 If nascent hydrogen i8 used a8 reducing agent~ it can be generated~ for example r by treating metals with weak acids or with bases. Thus, for examPle, a mixture of zinc with alkali metal hydroxide 801ution or of iron with S acetic acid can be used. Also guitable is the use of sodium of another alkali metal in an alcohol such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. It is furthermore poæsible to use an aluminium/
nickel alloy in alkaline aqueOus solution, where ap-propriate with the addition of ethanol. Sodium or alu-minium amalgam in aqueous/alcoholic or aqueous solution i8 also suitable for generating nascent hydrogen. The reaction can aI80 be carried out in heterogeneous phase, in which case an aqueous and a benzene or toluene phase is preferably used.
It is furthermore particularly advantageous to use complex metal hydrides such a~ LiAl~" NaB~" diisobutyl-aluminium hydride or NaAl(OC~2Q,OC~3)2H2 as well a~
diborane as reducing agents, if required with the addi-tion of catalystc such as BF3, AlC13 or LiBr. Particularlysuitable solvents for this purpose are ethers such as diethyl ether, di-n-butyl ether, ~EF, dioxane, diglyme or 1,2-dimethoxyethane as well as hydrocarbons such as benzene. Solvents primarily suitable for a reduction with NaB~, are alcohols such as methanol or ethanol, as well as water and aqueous alcohols. Reducti~n by these methods preferably takes place at temperatures between -80 and ~150, in particular between about O and about 100.
'.
The -CO- groups in the amides can be reduced to! C~z groups particularly advantageously with LiAlH, in T~F at temperatures between about O and 66.
It is furthermors possible to carry out certain reduc~
tions by using ~2 gas with the catalytic action of transition metals such as, for example, Raney Ni or Pd.
It is possible in this way, for example, to replace Cl, Br, I, S~ or, in certain case~, also OH groups by , . -. .
:
:~.. 1' .~ .. .
21~7~
hydrogen. ~ikewise, nitro groups can be converted, for exam~le, by catalytic hydrogenation with Pd/~2 in ~-methanol into NH2 groups.
- ~.
Furthermore, one compound of the formula I can be con-verted by methods known per se into a different compound of the formula I.
The phenyl rings in the compounds of the formula I can, if side reactions are to be precluded, for example be chlorinated, brominated or alkylated under the conditions of Friedel-Crafts reactions by reactinq the appropriate halogen or àlkyl chloride or alkyl bromide with catalysis by ~ewis acids such as, for example, AlC13, FeBr3 or Fe, at temperatures between 30 and 150, preferably between 50 and 150, in an inert solvent such as, for example, hydrocarbons, ~F or tetrachloromethane, with the com-pound of the formula I which i8 to be derivatized.
It is furthermore possible to convert a compound of the formula I in which Ar or Ar' is substituted by N~2 by alkylation or acylation by methods which are generally customary and known for amines into corresponding com-pounds of the formula I in which Ar or Ar' is substituted by N~A or NHAc.
, .: .
A resulting base of the formula I can be converted with an acid into the relevant acid addition salt~ Acid~
suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to.
use inorganic acid~, for example sulfuric acid, hydro-halic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, al30 organic acids, speci~
fically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, ~uch as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic ,, :
r 21~337 - 13 - ~
: ' .' acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, a~corbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acids and lauryl sulfuric acid.
The free bases of the formula I can, if required, be liberated from their salts by treatment with strong base3 such as sodium or potas~ium hydroxide, sodium or potassium carbonate, as long as no other acidic groups are present in the molecule.
he compounds of the formula I may have a centre of asymmetry. They may therefore result from their prepara~
tion as racemates or, if optically active starting materials are used, also in optically active form.
Resulting racemates can, if required, be resolved into their optical antipodes mechanically or chemically by methods known per se. Preferably, diastereomer~ are formed from the racemate by reaction with an optically active resolving agent. ~:~
Examples of suitable resolvins agents are optically active acids such a~ the D and L forms of tartaric acids, dibenzoyltartaric acid, diacetyltartaric acid, camphosulfonic acids, mandelic acid, malic acid or lactic acid. The various forms of the diastereomers can be separated in a manner known per se, for example by.
fractional crystallization, and the optically active compounds of the formula I can be liberated from the diastereomers in a manner known per se.
~ ~ -It is furthermore possible to separate the enantiomers by preparative chromatographic methods known per se. Silica gel is preferred as stationary phase. Particularly ~ ~
preferred mobile phases are mixtures oi'ethyl acetate and ~ -35 heptane or dichloromethane and methanol. ~
The invention furthermore relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by non-chemical means. For this purpo~e they can be converted together with at least one vehicle or ancillary substance and, where appro-priate, in combination with one or more other active substance(s) into a ~uitable dosage form.
The invention furthermore relates to compositions, in particular pharmaceutical preparations, containing at least one compound of the formula I and/or one of its ~s physiologically acceptable salts. These preparations can be used afi medicaments in human and veterinary medicine.
Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the n~vel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, ~ -~
gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. Tablets, coated tsblets, capsules, syrups, ~olutions, drops or suppositories are used in particular for enteral ~ :
administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants 25 are used for parenteral administration, and ointments, -creams or powders are used for topical application. The novel compounds can also be lyophilized and the resulting lyophilizates u~ed, for example, to produce products for injection. -,, , ,:
The stated preparations can be sterilized and/or contain ancillary ~ubstances such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pres~ure, buffer substances, colorants, flavourings and/or aromatizing substances.
They can, if required, also contain one or more other active substances, for example one or more vitamins.
; . .~ ~:
: ~
.~",",~.
21~37~
~he compounds of the formula I and their physiologically acceptable salts can be used for the therapeutic treat-ment of the human or anLmal body and for controlling diseases. They are particularly suitable for the treat-ment of arrhythmias and tachycardias.
For this purpose the substances according to the inven-tion are, as a rule, administered in analogy to known substances with antiarrhythmic activity, such as aprindine, flecainide or amiodarone, preferably in dosages between about 1 and 100 mg, in particular between 2 and 20 mg per dosage unit.
The daily dosage i8 preferably between about 0.02 and 2 mg/kg of body weight. The specific doæe for each particular patient depends, however, on a wide variety of factors, for example on the efficacy of the specific compound used, on the age, body weight, general state of ~ealth, sex, on the diet, on the time and route of administration, on the rate of excretion, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral a~inistration is 2referred.
In the following examples, Nusual working up" means~
If necessary, water or dilute sodium hydroxide solution i~ added, extraction is carried out with an organic solvent such as ethyl acetate, chloroform or dichloro~
methane, the organic phase is ~eparated off, dried over .
sodium sulfate, filteied and evaporated, and purificatibn ~;
is carried out by chromatography on silica gel and~or `~
crystallization. The optical rotations were measured in ~0 methanol (c ~ 1) unless ~tated otherwise. If the produc-tion of two substances is de~cribed in the individual examples, these are always separate from one another.
All temperatures are stated hereinbefore and hereinafter in degrees Celsius. ~ ;
-,, ~11837 ;i Bxample 1 4 mmol of 1-(2-p-nitrophenylethyl)-3-piperidinol [prepared from 3-piperidinol by alkylation with p-nitro-phenethyl bromide or p-nitrostyrene], 4 mmol of p-nitro-phenol, 4 mmol of triphenylphosphine and 4 mmol ofdiethyl azodicarboxylate are dissolved in 100 ml of T~F
and stirred at room temperature for 48 h. After the usual working up, the residue is chromatographed on silica gel using dichloromethane/methanol (99:1~ and ethyl acetate/
methanol (99~ uccessively as mobile phases.
The following are obtained: -,:,, a) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-pyrrolidine;
b) 1-t2-p-nitrophenylethyl)-3-(p-nitrophenoxy)- ;
piperidine. ;- ;~
~ample 2 In analogy to Example 1, starting from (-)-1-(2-p-nitro~
phenylethyl)-2-prolinol~ the following are obtained after ~;
chromatography on silica ~el using ethyl acetate/heptane (7:3) and subsequently dichloromethane/ methanol (99~
as mobile phases: `~ ; ;
a) (-)-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine ; `~
la]20~ -98.4; -; 25 b) (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine [a]'~ l37.2 The following are obtained analogously from (+)-1-(2-p-nitrophenylethyl)-2-prolinol:
':
,'';'' ~
-~ 2~1837S
a) (~t-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine [a]20D +97.8;
b) (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine [~]20D -36.6 .
Example 3 In analogy to Example 1, starting from 1-(2-p-nitro-phenylethyl)-2-hydroxymethylpiperidine, the following are ~ -obtained by reaction with p-nitrophenol with a reaction time of 60 h (purification: silica gel/methyl tert.-butyl ether and subsequently heptane/acetone (7:3)) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)- ~ ~
piperidine and ~ ;
1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine.
Subsequent reaction with fumaric acid provides after crystallization (ethyl acetate/diisopropyl ether) a) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-piperidine -m.p. (fumarate) 122;
b) l-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine m.p. (fumarate) 137.
25 Esample 4 ; ;
.'~ ' '" .'''' In analogy to Bxample 1, the following are obtained by resction of p-nitrophenol ~ ;~
with 1-(2-p-nitrophenylethyl)-3-hydroxymethylpiperidine (purification: ~ilica gel/methyl tert.-butyl ether and ~, 211~375 subsequently heptane/acetone (7:3)) 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy-methyl)piperidine;
with l-(2-p-nitrophenylethyl)-4-piperidinol (purification: silica gel/heptane:acetone (7:3) and subsequently ethyl acetate/methanol (19:1)) 1-(2-p-nitrophenylethyl)-4-(p-nitrophenoxy)~
piperidine;
with (~ (2-p-nitrophenylethyl)-3-pyrrolidinol (purification: silica gel/methyl tert.-butyl ether:petroleum ether:methanol (25:24 (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)~
pyrrolidine, m.p. 97, [a]20D - +13.8 (dioxane).
.... " ~ .. ~.~ ..
. .~'-"''~i Rxample 5 In analogy to Example 1, reaction of 1-benzhydryl-azetidine tobtainable by reaction of benzhydrylamine with 1-chloro-2,3-epoxypropane] with N-(4-hydroxyphenyl)-phthalimide results, after the usual working up, in 1-benzhydryl-3-[4-(1,3-dioxo-2-i~oindolinyl)phenoxy]-azetidine (purification: 8ilica gel~diisopropyl ether:methanol (49 Elimination of the benzhydryl group by treatment with ~2 gas/Pd on carbon (Pd content 1 %) in toluene at room~
tempe~ature p~ovides 3-[4-(1,3-dioxo-2-isoindolinyl)-phenoxy~azetidine.
Example 6 1 mmol of 3-[4-(1,3-dioxo-2-isoindolinyl)-phenoxy]-azetidine is dissolved in 40 ml of dichloromethane, 1 equivalent of p-nitrophenethyl bromide is added, and the mixture i8 stirred at room temperature for 6 h. The :: ~ :..~: .
. ~ ~
19 - 21183~
usual working up results in 1-(2-p-nitrophenylethyl)-3-14-(1,3-dioxo-2-i~oindolinyl)phenoxy]azetidine.
Example 7 0.9 g of 1-(2-p-nitrophenylethyl)-3-[4-(1,3-dioxo-2-5 i80indolinyl)phenoxy]azetidine i8 dissolved in 50 ml of THF, and 0.5 g of hydrazine i5 added. The mixture i8 boiled for 2 h and then worked up as usual. 1-(2-p-Nitrophenylethyl)-3-(p-aminophenoxy~azetidine i~
obtained.
~xamDle 8 ~ .. .: ~.
18 mmol of p-nitrophenol are dissolved in 15 ml of DMF, 22 mmol of Na~ are added, and the mixture is ~tirred at 40 for 30 min. Subsequently, 18 mmol of 1-(2-p-nitro~
phenylethyl)-2-chloromethylpiperidine tprepared from the piperidinol derivative by halogenation with thionyl chloride/DMF in dichloromethane] are dissolved in 20 ml of DMF, added to the phenolate ~olution and stirred at 90 for 4 h. The solution i~ concentrated, the re6idue i8 taken up in toluene, and the solution is washed with 2 N
sodium hydroxide solution and extracted with 2 N hydro-chloric acid. ~he usual working up and purification by chromatography (silica gel/methyl tert.-butyl ether) re~ults in : . ,: ,. '`, ' .
a) 1-(2-p-nitrophenylethyl~-2-(p-nitrophenoxymethyl)-piperidine;
., , j , b) 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-hexahydroazepine.
~xample 9 85 mmol of 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine are hydrogenated on 15 g of Raney Ni in 400 ml of ethanol and 40 ml of T~F at 20 and 3 bar ~ 211837~
for 7 h. The solution i8 concentrated and worked up as usual. 1-(2-p-Aminophenylethyl)-2-(p-aminophenoxymethyl)-pyrrolidine i8 obtained.
The following are obtained analogously by catalytic reduction with Raney Ni~
from 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)- -~
piperidine~
1-(2-p-aminophenylethyl)-3-~p-aminophenoxy)- ; ~ .
piperidine;
from (~ (2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)pyrrolidine:
(-)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy- :~
methyl)pyrrolidine;
from (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine:
(+)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-piperidine;
from (+)-1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy- ;~ :~
methyl)pyrrolidine:
(+)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy-methyl)pyrrolidine;
from (-)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxy)-piperidine: - ::
(-)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-. : ~ ~
piperidine;~ ' ' I `; :~'' from 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxymethyl)-piperidine: .~
1-(2-p-aminophenylethyl)-2-( p-~mi nophenoxymethyl)- ~ `.
piperidine; ~ ~:
,,, :, ,, 211~37~
~ .
from l-(2-p-nitrophenylethyl)-3-~p-nitrophenoxy)-hexahydroazepine: ~ ~
1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- :
hexahydroazepine;
' ' .
from 1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxymethyl)-piperidine: .
1-(2-p-aminophenylethyl)-3-(p-aminophenoxymethyl)- - -piperidine;
from l-(2-p-nitrophenylethyl)-4-(p-nitrophenoxy~
piperidine~
1-(2-p-aminophenylethyl)-4-(p-aminophenoxy)-piperidine;
from (+)-1-(2-p-nitrophenylethyl)-3-(p-nitrophenoxyl)- :
pyrrolidine~
(+)-1-(2-p-aminophenylethyll-3-(p-aminophenoxy)- ~: .
pyrrolidine.
. ~
~xample 10 13 mmol of 1-(2-p-aminophenylethyl)-2-(p-aminophenoxy- ~ :
methyl)pyrrolidine are dissolved in 40 ml of dry pyridine 20 and, while stirring under an N2 atmosphere and cooling in ~ :
ice, at a temperature of 5-10 39 mmol of mesyl chloride :~
are added dropwise and the mixture i8 6tirred at the same : :
temperature for 2 h. Ethyl acetate i~ added to the solution. ~he resulting precipitate i8 separated off and taken up in ethyl acetate~Na~C03 solution. The usual .
working up and~ purification by chromatography (silica gel/dichloromethane/methanol (49:1)) results in 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamido~
phenoxymethyl)pyrrolidine, m.p. 61-63.
The following are obtainad analogou~ly by reaction with m ~yl chloride~
.. ~ .:
. ~ ;,,,:,.
. :, . . .
- . ~ .
: ": ... .
7 i . r~
from l-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~ ~ .
piperidine: :
1-(2-p-methylsulfonamidophenylethyl)-3-(p-methyl-sulfonamidophenoxy)piperidine, m.p. 148-149; ~ ~ ~
.,.:.
from (-)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy-methyl)pyrrolidine:
(-)-1-(2-p-methylsulfonamidophe~ylethyl)-2-(p- :
methylsulfonamidophenoxymethyl)pyrrolidiner [a]20 _73 go;
-: . ' 10 from (+)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~:
piperidine~
(+)-1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxy)piperidine, m.p. 168, .
[a]20D +31.8; :~
from (+)-1-(2-p-aminophenylethyl)-2-(p-aminophenoxy~
methyl)pyrrolidine:
(+)-1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)pyrrolidine, [a]~oD
-72.0; ~ ;;
from (-)-1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)-piperidine: `
(-)-1-(2-p-methylsulfonamidophenylethyl)-3-(p- ::
methylsulfonamidophenoxyJpiperidine, m.p. 168, [a]20D -32.7; ~.
25 from 1-(2-p-aminophenylethyl)-2-(p- ~ nophenoxymethyl)- ~
piperidine: ! l ! ': "; ..
1-(2-p-methylsulfonamidophenylethyl)-2-(p-methyl-sulfonamidophenoxymethyl)piperidine;
from 1-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- ~ ~ a hexahydroazepine~
1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxy)hexahydroazepine;
.. ~,,~;,, ~, ., ..~ i. -.". ,~.
. . ... . ~
21~37~
from l-(2-p-aminophenylethyl)-3-(p-aminophenoxymethyl)-piperidine:
1-(2-p-methylsulfon~m;dophenylethyl)-3-(p-methyl-6ulfonamidophenoxymethyl)piperidine, m.p. 199-200;
S from 1-(2-p-aminophenylethyl)-4-tp-aminophenoxy)-piperidine~
1-(2-p-methylsulfon~;dophenylethyl)-4-(p-methyl- ~-sulfonamidophenoxy)piperidine, m.p. 182-183~
from (~)-l-(2-p-aminophenylethyl)-3-(p-aminophenoxy)- --pyrrolidine:
(+)-1-(2-p-methylsulfonamidophenylethyl)-3-(p- ~
methylsulfonamidophenoxy)pyrrolidine,m.p.l99-200, ~;
[a]20D ~7.3 (dioxane). ; -Example 11 .
10 mmol of 1-(2-p-Pm;nophenylethyl)-3-(p-aminophenoxy)- ~ f pyrrolidine are dissolved in 45 ml of dry pyridine and 45 ml of acetic anhydride and stirred at room temperature for 24 h. Water i9 added to the suspension while cooling in ice, the mixture is stirred at room temperature for 20 3 h, 2 N sodium hydroxide ~olution is added until ~;~
opalescent, and the usual working up is carried out.
Recrystallization from methanol results in 1-(2-p-acetamidophenylethyl)-3-(p-acetamidophenoxy)-pyrrolidine, m.p. 213-214. - ~ -~
The following examples relate to pharmaceutical prepara--tions. ' ! i .: ~
Esample A: Vi~
~. .........
A solution of 100 g of an active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 1 ~ ~
30 of double-distilled water is adjusted to p~ 6.5 with 2 N ~ ~`
hydrochlcric acid, sterilized by filtration, dispensed into vials, lyophilized and sealed sterile. Each vial ~ ,....,,, ,-, ...... .
:~r -~ 211~37~
contains 5 m~ of active ~ubstance.
E~ample B: Suppo~itories A mixture of 20 mg of an active substance of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and left to cool.
Each suppository contains 20 mg of active substance.
Bxample C: Solution ~-A solution i8 prepared from 1 g of an active substance of ~ ;~
the formula I, 9.38 g of Na~,PO, x 2 H~O, 28.48 g of Na2HPO~ x 12 ~2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The p~ is adjusted to 6.8, the volume i8 made up to 1 1 and the solution is ~ ~`
sterilized by radiation. This solution can be used in the form of eye drops. ~ -Example D: Ointment 500 mg of an active substance of the formula I are mixed ~;
with 99.5 g of petrolatum under aseptic conditions. ~;
Bxample B: Tablets `~
A mixture of 1 kg of active substance of the formula I, ~ -4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate i~ compressed to tablets in a conventional way ~uch that each tablet contains- il;
10 mg of active substance. :
Example F: Coated tablets ,;. i , ~ ,, ~.
Tablets are compressed in analogy to Bxample E and are then coated in a conventional way with a coating compo~ed of sucrose, potato starch, talc, tragacanth and colorant.
.', ;'.','1-.
~ 25 21~37:~.
B~ample G: Capsules 2 kg of active substance of the formula I are packed into hard gelatin capsules in a conventional way BO that each capsule contains 20 mg of the active substance.
Bsample ~: Ampoules A solution of 1 kg of active substance of the ,~ ~.
formula I in 60 1 of double-distilled water i8 dispensed ;;~
into ampoules, lyophilized under a~eptic conditions and :~
sealed sterile. Each ampoule contains 10 mq of active f~
10 substance. ;;
;;
~ ,. !
.. ' '''~
'' ~ ~" .~
"' ~: ,~ f.i, ".',,, ', .".; `' '", " " .,
Claims (8)
1. Cyclic amine derivatives of the formula I
I, in which Ar and Ar' are each, independently of one another, phenyl which is unsubstituted or sub-stituted once or twice by NO2, NH2, Hal, CF3, A, NHSO2A or NHAc, X and Y are each, independently of one another, O or a bond, m is 0 or 1, n is 0, 1 or 2, p is 0, 1, 2 or 3, q is 2 or 3, A is alkyl having 1-6 C atoms, Hal is F, Cl, Br or I and Ac is alkanoyl having 1-8 C atoms, aralkanoyl having 8-10 C atoms or aroyl having 7-11 C atoms, and their physiologically acceptable salts.
I, in which Ar and Ar' are each, independently of one another, phenyl which is unsubstituted or sub-stituted once or twice by NO2, NH2, Hal, CF3, A, NHSO2A or NHAc, X and Y are each, independently of one another, O or a bond, m is 0 or 1, n is 0, 1 or 2, p is 0, 1, 2 or 3, q is 2 or 3, A is alkyl having 1-6 C atoms, Hal is F, Cl, Br or I and Ac is alkanoyl having 1-8 C atoms, aralkanoyl having 8-10 C atoms or aroyl having 7-11 C atoms, and their physiologically acceptable salts.
2. An enantiomer of a compound of the formula I accord-ing to claim 1.
3. (a) 1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxy)piperidine;
(b) 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)pyrrolidine;
(c) 1-(2-p-nitrophenylethyl)-3-p-nitrophenoxy-pyrrolidine;
(d) 1-(2-p-acetamidophenylethyl)-3-p-acetamidophenoxypyrrolidine;
(e) 1-(2-p-methylsulfonamidophenylethyl)-3-p-methylsulfonamidophenoxypyrrolidine;
(f) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)piperidine;
(g) 1-(2-p-nitrophenylethyl)-3-p-nitrophenoxyhexa-hydroazepine;
(h) 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)piperidine;
(i) 1-(2-p-methylsulfonamidophenylethyl)-3-p-methylsulfonamidophenoxyhexahydroazepine;
(j) 1-(2-p-methylsulfonamidophenylethyl)-4-p-methylsulfonamidophenoxypiperidine;
(k) 1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxymethyl)piperidine.
(b) 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)pyrrolidine;
(c) 1-(2-p-nitrophenylethyl)-3-p-nitrophenoxy-pyrrolidine;
(d) 1-(2-p-acetamidophenylethyl)-3-p-acetamidophenoxypyrrolidine;
(e) 1-(2-p-methylsulfonamidophenylethyl)-3-p-methylsulfonamidophenoxypyrrolidine;
(f) 1-(2-p-nitrophenylethyl)-2-(p-nitrophenoxy-methyl)piperidine;
(g) 1-(2-p-nitrophenylethyl)-3-p-nitrophenoxyhexa-hydroazepine;
(h) 1-(2-p-methylsulfonamidophenylethyl)-2-(p-methylsulfonamidophenoxymethyl)piperidine;
(i) 1-(2-p-methylsulfonamidophenylethyl)-3-p-methylsulfonamidophenoxyhexahydroazepine;
(j) 1-(2-p-methylsulfonamidophenylethyl)-4-p-methylsulfonamidophenoxypiperidine;
(k) 1-(2-p-methylsulfonamidophenylethyl)-3-(p-methylsulfonamidophenoxymethyl)piperidine.
4. Process for the preparation of compounds of the formula I according to Claim 1, characterized in that a compound of the formula II
II, in which Ar, Y, m, n and p have the stated meaning, is reacted with a compound of the formula III, Ar-X-(CH2)q-L III, in which Ar, X and q have the stated meaning, and L is OH, Cl, Br or a reactive, functionally modified OH group, or in that, to prepare a compound of the formula I
according to Claim 1 in which Y is oxygen, a com-pound of the formula IV
IV, in which Ar, X, L, m, n, p and q have the stated meanings, is reacted with a compound of the formula V
Ar-Z V, in which Ar has the stated meaning, and Z is OH or a reactive, functionally modified OH
group, including a group with salt-like charac-teristics, or in that a compound of the formula Va Ar'-Z Va, in which Z and Ar' have the stated meanings, is reacted with a compound of the formula VI
VI, in which Ar, Y, L, m, n, p and q have the stated meanings, or in that a compound which corresponds to the formula I but has in place of one or more CH2 groups one or more reducible groups is converted by reduction into a compound of the formula I, and/or in that one or both groups Ar and Ar' in a compound of the formula I are converted into other radicals Ar and Ar', respectively, and/or in that a basic compound of the formula I is converted by treatment with an acid into one of its physiologically accept-able acid addition salts.
II, in which Ar, Y, m, n and p have the stated meaning, is reacted with a compound of the formula III, Ar-X-(CH2)q-L III, in which Ar, X and q have the stated meaning, and L is OH, Cl, Br or a reactive, functionally modified OH group, or in that, to prepare a compound of the formula I
according to Claim 1 in which Y is oxygen, a com-pound of the formula IV
IV, in which Ar, X, L, m, n, p and q have the stated meanings, is reacted with a compound of the formula V
Ar-Z V, in which Ar has the stated meaning, and Z is OH or a reactive, functionally modified OH
group, including a group with salt-like charac-teristics, or in that a compound of the formula Va Ar'-Z Va, in which Z and Ar' have the stated meanings, is reacted with a compound of the formula VI
VI, in which Ar, Y, L, m, n, p and q have the stated meanings, or in that a compound which corresponds to the formula I but has in place of one or more CH2 groups one or more reducible groups is converted by reduction into a compound of the formula I, and/or in that one or both groups Ar and Ar' in a compound of the formula I are converted into other radicals Ar and Ar', respectively, and/or in that a basic compound of the formula I is converted by treatment with an acid into one of its physiologically accept-able acid addition salts.
5. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I and/or one of its physiologically acceptable salts is converted together with at least one solid, liquid or semiliquid vehicle or ancillary substance into a suitable dosage form.
6. Pharmaceutical preparation characterized by a content of at least one compound of the formula I
and/or one of its physiologically acceptable salts.
and/or one of its physiologically acceptable salts.
7. Use of compounds of the formula I according to Claim 1 or of their physiologically acceptable salts for the production of a medicament.
8. Use of compounds of the formula I according to Claim 1 or of their physiologically acceptable salts for controlling diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4335718.0 | 1993-10-20 | ||
| DE4335718A DE4335718A1 (en) | 1993-10-20 | 1993-10-20 | Cyclic amine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2118375A1 true CA2118375A1 (en) | 1995-04-21 |
Family
ID=6500552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002118375A Abandoned CA2118375A1 (en) | 1993-10-20 | 1994-10-18 | Cyclic amine derivatives |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0649838A1 (en) |
| JP (1) | JPH07188162A (en) |
| KR (1) | KR950011408A (en) |
| CN (1) | CN1107469A (en) |
| AU (1) | AU7588394A (en) |
| CA (1) | CA2118375A1 (en) |
| CZ (1) | CZ257794A3 (en) |
| DE (1) | DE4335718A1 (en) |
| HU (1) | HUT72294A (en) |
| NO (1) | NO943961L (en) |
| PL (1) | PL305487A1 (en) |
| RU (1) | RU94038254A (en) |
| SK (1) | SK125994A3 (en) |
| TW (1) | TW275062B (en) |
| ZA (1) | ZA948211B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA9610745B (en) * | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| ZA9610741B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
| ZA9610736B (en) | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
| GB9725541D0 (en) * | 1997-12-02 | 1998-02-04 | Pharmacia & Upjohn Spa | Amino-benzothiazole derivatives |
| WO2002022572A2 (en) * | 2000-09-11 | 2002-03-21 | Sepracor, Inc. | Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission) |
| DE10135043A1 (en) * | 2001-07-11 | 2003-01-30 | Bayer Cropscience Gmbh | Substituted 3-heteroaryl (amino or oxy) pyrrolidin-2-ones, process for their preparation and use as herbicides or as plant growth regulators |
| US7812035B2 (en) | 2001-12-11 | 2010-10-12 | Sepracor Inc. | 4-substituted piperidines, and methods of use thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1219865A (en) * | 1982-05-14 | 1987-03-31 | Leo Alig | Aziridine phenethanolamine derivatives |
| DK623586A (en) * | 1985-12-27 | 1987-06-28 | Eisai Co Ltd | PIPERIDE INGREDIENTS OR SALTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE COMPOUNDS |
| GB8720910D0 (en) * | 1987-09-05 | 1987-10-14 | Pfizer Ltd | Antiarrhythmic agents |
| WO1990006303A1 (en) * | 1988-12-02 | 1990-06-14 | Pfizer Inc. | Arylpiperidine derivatives |
| GB8929331D0 (en) * | 1989-12-29 | 1990-02-28 | Shell Int Research | Piperidine derivatives |
| GB9100505D0 (en) * | 1991-01-10 | 1991-02-20 | Shell Int Research | Piperidine derivatives |
| FR2681319B1 (en) * | 1991-09-12 | 1995-02-17 | Synthelabo | 1- (PHENOXYALKYL) PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| US5202346A (en) * | 1992-02-25 | 1993-04-13 | American Home Products Corporation | Piperidinyl and piperazinyl derivatives |
-
1993
- 1993-10-20 DE DE4335718A patent/DE4335718A1/en not_active Withdrawn
-
1994
- 1994-10-10 EP EP94115921A patent/EP0649838A1/en not_active Withdrawn
- 1994-10-17 AU AU75883/94A patent/AU7588394A/en not_active Abandoned
- 1994-10-18 CA CA002118375A patent/CA2118375A1/en not_active Abandoned
- 1994-10-18 CN CN94117324A patent/CN1107469A/en active Pending
- 1994-10-18 TW TW083109667A patent/TW275062B/zh active
- 1994-10-18 JP JP6252333A patent/JPH07188162A/en active Pending
- 1994-10-18 PL PL94305487A patent/PL305487A1/en unknown
- 1994-10-18 SK SK1259-94A patent/SK125994A3/en unknown
- 1994-10-19 NO NO943961A patent/NO943961L/en unknown
- 1994-10-19 HU HU9403010A patent/HUT72294A/en unknown
- 1994-10-19 RU RU94038254/04A patent/RU94038254A/en unknown
- 1994-10-19 ZA ZA948211A patent/ZA948211B/en unknown
- 1994-10-19 KR KR1019940026700A patent/KR950011408A/en not_active Application Discontinuation
- 1994-10-19 CZ CZ942577A patent/CZ257794A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07188162A (en) | 1995-07-25 |
| SK125994A3 (en) | 1995-05-10 |
| PL305487A1 (en) | 1995-05-02 |
| AU7588394A (en) | 1995-05-11 |
| ZA948211B (en) | 1995-06-12 |
| KR950011408A (en) | 1995-05-15 |
| TW275062B (en) | 1996-05-01 |
| CZ257794A3 (en) | 1995-11-15 |
| HU9403010D0 (en) | 1994-12-28 |
| EP0649838A1 (en) | 1995-04-26 |
| HUT72294A (en) | 1996-04-29 |
| NO943961L (en) | 1995-04-21 |
| RU94038254A (en) | 1996-09-10 |
| CN1107469A (en) | 1995-08-30 |
| NO943961D0 (en) | 1994-10-19 |
| DE4335718A1 (en) | 1995-04-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |