CA1077474A - 1-aryloxy-4-amino-2-butanols - Google Patents
1-aryloxy-4-amino-2-butanolsInfo
- Publication number
- CA1077474A CA1077474A CA238,243A CA238243A CA1077474A CA 1077474 A CA1077474 A CA 1077474A CA 238243 A CA238243 A CA 238243A CA 1077474 A CA1077474 A CA 1077474A
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- Prior art keywords
- butanol
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- chloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- 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
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/196—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel 1-aryloxy-4-amino-2-butanols of the formula ArO-CH2-CHOH-CH2CH2-NR1R2 wherein Ar is 1-naphthyl, 2-naphthyl, indene-4(or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, monosubstituted phenyl or di-substituted phenyl, R1 is lower alkyl, phenyl, phenyl-alkyl, 2-hydroxymethyl-2-propyl, adamantyl or lower cycloalkyl, R2 is hydrogen or lower alkyl, wherein R1 and R2 together with the adjacent nitrogen form a heterocyclic residue and the pharmaceutically acceptable acid addition salts thereof having local anesthetic, alpha-adrenergic blocking, beta-adrenergic blocking and antiarrhythmic properties are disclosed. The compounds are prepared by reacting novel 1-aryloxy-4-chloro-2-butanols with amines. Methods for the preparation of the novel 1-aryloxy-4-chloro-2-butanol intermediates are also disclosed
Novel 1-aryloxy-4-amino-2-butanols of the formula ArO-CH2-CHOH-CH2CH2-NR1R2 wherein Ar is 1-naphthyl, 2-naphthyl, indene-4(or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, monosubstituted phenyl or di-substituted phenyl, R1 is lower alkyl, phenyl, phenyl-alkyl, 2-hydroxymethyl-2-propyl, adamantyl or lower cycloalkyl, R2 is hydrogen or lower alkyl, wherein R1 and R2 together with the adjacent nitrogen form a heterocyclic residue and the pharmaceutically acceptable acid addition salts thereof having local anesthetic, alpha-adrenergic blocking, beta-adrenergic blocking and antiarrhythmic properties are disclosed. The compounds are prepared by reacting novel 1-aryloxy-4-chloro-2-butanols with amines. Methods for the preparation of the novel 1-aryloxy-4-chloro-2-butanol intermediates are also disclosed
Description
` ~
:- 1077474 .. . .
` :. `
. j, .: The present invention relates to certain organic compounds which may be referred to as disubstituted-2-butanols and is more particularly concerned with l-aryloxy-4-amino-2-butanols and with processes for the ~,; production thereof, intermediate products useful in the preparation thereof - and with processes forthe preparation of such intermediates, compositions - :, containing the l-aryloxy-4-amino-2-butanols as active ingredients and methods for the use thereof.
Accordingly, the present invention provides a process for preparing a compound of the formula.
;` Aro-cH2-cHoH-cH2-cH2-NR R (I) i ~,;
and pharmaceutically acceptable acid addition salts thereof wherein; Ar is ~, selected from the group consisting of l-naphthyl, 2-naphthyl, inden-4~or 5-) yl, 3-(or5-)chloro-2-pyridyl, phenyl, which is unsubstituted or substituted by up to two radical selected from the group Cl 8 alkyl, Cl 8 alkoxy, trifluoromethyl, acetyl, acetylamino, halogen and phenyl; Rl is selected from the group consisting of lower alkyl having one to eight carbon atoms, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl and lower cyclo-~;i alkyl having five to seven carbon atoms, R2 is selected from hydrogen and lower alkyl, Rl and R2 together with the adjacent nitrogen form a hetero-` 20 cyclic residue which comprises reacting a compound of formula ~ Aro-cH2-cHaH-cH2-cH -X (V) ~ with a compound of the formula ,i,.'.' NHRl R2 wherein Ar, Rl and R2 are as defined above, and X is halogen, and where required preparing a pharmaceutically acceptable acid addition salt of the ~ so prepared compound.
,j~ The present invention also provides compounds of formula I as , defined above whenever prepared by the above process or by an obvious chemical equivalent thereof.
~, ' ~, ~ - 2 - ~
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... ~ The compounds of the invention having the foregoing formula I are generally characterized by important and significant pharmacological activity, which is indicative of their use in counteracting certain physiological abnormalities in an animal body. The compounds are local anesthetics, alpha-A~`,`~ adrenergic blocking agents, beta-adrenergic blocking agents ... .
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' .. '. ' ~"; ' `
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; ~ ~ _ 2 a -:., : . .:
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~ and antiarrhythmic agents.
i The prior art discloses various l-aryloxy-3-amino-2-propanols alleging beta-adrenergic blocking,anticonvulsant, sedative and tranquilizing activity. Among the United States patents disclosing the aforementioned 1,3-disubstituted-2-propanols and their pharmacological activities are U. S.
Patents 3J337~628; 3,415,873; 3,432,545 and 3,520,919. United .~ States Patent 3,337,628 in particular discloses l-isopropyl-amino-3-(1-naphthyloxy)-2-propanol which compound is a potent ' 10 beta-adrenergic blocking agent.
y`l The novel l-aryloxy-4-amino-2-butanols of the present invention were evaluated for pharmacological activity and were found to possess antiarrhythmic utility against experimentally induced cardiac arrhythmias in dogs. The prior art homolog 1, 5-disubstituted-2-propanols also have antiarrhythmic activity.
However, in contrast to the prior art 2-propanols, the novel
:- 1077474 .. . .
` :. `
. j, .: The present invention relates to certain organic compounds which may be referred to as disubstituted-2-butanols and is more particularly concerned with l-aryloxy-4-amino-2-butanols and with processes for the ~,; production thereof, intermediate products useful in the preparation thereof - and with processes forthe preparation of such intermediates, compositions - :, containing the l-aryloxy-4-amino-2-butanols as active ingredients and methods for the use thereof.
Accordingly, the present invention provides a process for preparing a compound of the formula.
;` Aro-cH2-cHoH-cH2-cH2-NR R (I) i ~,;
and pharmaceutically acceptable acid addition salts thereof wherein; Ar is ~, selected from the group consisting of l-naphthyl, 2-naphthyl, inden-4~or 5-) yl, 3-(or5-)chloro-2-pyridyl, phenyl, which is unsubstituted or substituted by up to two radical selected from the group Cl 8 alkyl, Cl 8 alkoxy, trifluoromethyl, acetyl, acetylamino, halogen and phenyl; Rl is selected from the group consisting of lower alkyl having one to eight carbon atoms, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl and lower cyclo-~;i alkyl having five to seven carbon atoms, R2 is selected from hydrogen and lower alkyl, Rl and R2 together with the adjacent nitrogen form a hetero-` 20 cyclic residue which comprises reacting a compound of formula ~ Aro-cH2-cHaH-cH2-cH -X (V) ~ with a compound of the formula ,i,.'.' NHRl R2 wherein Ar, Rl and R2 are as defined above, and X is halogen, and where required preparing a pharmaceutically acceptable acid addition salt of the ~ so prepared compound.
,j~ The present invention also provides compounds of formula I as , defined above whenever prepared by the above process or by an obvious chemical equivalent thereof.
~, ' ~, ~ - 2 - ~
. ~
i , . . .
~, . .
` ~ ~077474 :.~
. . .
... ~ The compounds of the invention having the foregoing formula I are generally characterized by important and significant pharmacological activity, which is indicative of their use in counteracting certain physiological abnormalities in an animal body. The compounds are local anesthetics, alpha-A~`,`~ adrenergic blocking agents, beta-adrenergic blocking agents ... .
, !, .
.'."
. ', ' ~,.'~" .
! ' .
,,:,, ",!..; .
'.'" :
`',''~ `
,, .
: ~ ',, .....
;.~"' ' ' '' , ;,`''.' ~ .
'`' :
~,:'. :
~:5, .:
;'"""
~' '' `' i '''' " .
, ''' '''' '~ :' :~ .
' .. '. ' ~"; ' `
."' ' .
' ' ...
,' :. ' ~.~
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:
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~ and antiarrhythmic agents.
i The prior art discloses various l-aryloxy-3-amino-2-propanols alleging beta-adrenergic blocking,anticonvulsant, sedative and tranquilizing activity. Among the United States patents disclosing the aforementioned 1,3-disubstituted-2-propanols and their pharmacological activities are U. S.
Patents 3J337~628; 3,415,873; 3,432,545 and 3,520,919. United .~ States Patent 3,337,628 in particular discloses l-isopropyl-amino-3-(1-naphthyloxy)-2-propanol which compound is a potent ' 10 beta-adrenergic blocking agent.
y`l The novel l-aryloxy-4-amino-2-butanols of the present invention were evaluated for pharmacological activity and were found to possess antiarrhythmic utility against experimentally induced cardiac arrhythmias in dogs. The prior art homolog 1, 5-disubstituted-2-propanols also have antiarrhythmic activity.
However, in contrast to the prior art 2-propanols, the novel
2-butanols of the present invention have minimal beta-adrenergic blocking activity, enabling them to be employed in controlling ~ .
moderate to serious arrhythmias without the dangers of cardiac , 20 failure and respiratory difficulties, which dangers are attendlant when the prior art 1, 3-disubstituted-2-propanols having potent , . . .
beta-adrenergic blocXing activity are used in controlling cardiac arrhythmias.
', Compounds of Formula I wherein Ar is l-naphthyl and -~RlR
is lower-alkylamino, lower cycloalkylamino wher ein lower cyclo-.
~l alkyl has from 5 to 7 carbon atoms, phenylalkylamino, 2-hydroxy-:.~
methyl-2-propylamino or phenylamino represent preferred compounds
moderate to serious arrhythmias without the dangers of cardiac , 20 failure and respiratory difficulties, which dangers are attendlant when the prior art 1, 3-disubstituted-2-propanols having potent , . . .
beta-adrenergic blocXing activity are used in controlling cardiac arrhythmias.
', Compounds of Formula I wherein Ar is l-naphthyl and -~RlR
is lower-alkylamino, lower cycloalkylamino wher ein lower cyclo-.
~l alkyl has from 5 to 7 carbon atoms, phenylalkylamino, 2-hydroxy-:.~
methyl-2-propylamino or phenylamino represent preferred compounds
- 3 -.... .
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AHR-~10-CIP
`:
;
- for their antiarrhythmic activity.
`~ Compounds of Formula I wherein Ar is a ortho-lower-`~ alkoxyphenoxy radical, particularly methoxy- and ethoxy-i~
~1 phenoxy radicals, and -NRlR2 is lower-alkylamino, lower cyclo-."
~ 5 alkylamino wherein lower cycloalkyl has from 5 to 7 carbon :
-~ atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or ' phenylamino are also of particular interest for their anti-~ .
~ arrhythmic activity.
,:
It is accordingly an object of this invention to provide novel 1-aryloxy-4-amino-2-butanols which are useful pharma-:
cologically because of their aforesaid types of activity, , ~- processes for the production thereof, and intermediate products useful in the preparation thereof and processes for the production of such intermediates which in themselves have useful pharmacological activity. A further object is to provide ;..
novel compositions containing l-aryloxy-4-amino-2-butanols as ~ .
active ingredients and methods for their use. Other objects of the invention will be apparent to one skilled in the art, : ' ~
l and still other objects will become apparent hereinafter.
rl 20 In the definitions of the symbols in foregoing Formula I
. ~, : and where they appear elsewhere throughout this specification, , .:, the terms have the following significance.
~`~ The term "lower alkyl" as used herein includes straigh*
,.. . .
,1 and branched chain radicals of up to eight carbon atoms inclusive -~ 25 and is exemplified by euch groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, - and the like.
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Tho term "lower slkoxy" has the f~rmula -0-lower alkyl.
When halogen is referred to herein, preferably but not necessarily, a halogen of atomic weight in excess of eighteen but not greater than eighty is employed.
The term "heterocyclic residue" as used herein includes basic saturated monocyclic heterocyclic radicals and basic ~, unsaturated monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower alkyl) piperidino, e.g., 2-, 3-, or 4-(lower alkyl)piperidino;
; 10 pyrrolidino; morpholino; di-(lower alkyl)morpholino, e.g., 3,5-dimethylmorpholino; 2,6-dimethylmorpholino; piperazino;
(lower alkyl)piperazino (e.g., N -methylpiperazino); phenyl-piperazino (e.g., N -phenylpiperazino); 1,2,~,4-tetrahydro-.
isoquinolyl; 1,2,5,6-tetrahydropyridino, 4-(2-pyridyl)piperazino, and phthalimido.
;' Included in the term "phenylalkyl" are groups such as " . i . .
~- benzyl, phenethyl, methylbenzyl, phenpropyl, and the like.
The term "lower cycloalkyl" includes cyclic radicals having ; up to eight carbon atoms and includes radicals such as cyclo-!'"' 20 propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and ~ cyclooctyl.
. . , The term "phenyl" includes the unsubstituted phenyl radical, the substituted phenyl radical and the disubstituted phenyl radical. Among the suitable substituted and disubstituted phenyl .~ .
~;- 25 radicals are those which are substituted by any radical or radicals which are not reactive or otherwise interfering under the . .;
. conditions of reaction in preparing the desired compound, such ..... .
... .
~ ~ - 5 -~.
`;, 1077474 AHR-310-CIP
.
radicals including lower alkylJ lower alkoxy, trifluoromethyl, acetyl, acetylamino, halo, trifluoromethyl, and phenyl. The - substituted phenyl radicals have preferably one or two substituents . ~ .
such as those given above and, furthermore, the substituents can be in various available positions of the phenyl nucleus and, ~- when more than one substituent is present, can be the same or ~ different and can be in various combinations relative to each ,: . .
other. The lower alXyl and lower alkoxy substituents each have ` preferably from one to four carbon atoms which can be arranged ; 10 as straight or branched chains. A total of nine carbon atoms in all ring substituents, making a total of fifteen carbon atoms in the radical,is the preferred maximum.
ffl e compounds of the invention are most conveniently employed in the form of pharmaceutically acceptable acid addition ,~; 15 salts. Such salts have improved water solubility over the free bases. Appropriate acid addition salts are those derived from :i mineral acids such as hydrochloric, hydrobromicJ sulfuric and ., ~ .
phosphoric; and or~anic acids such as acetic, citric, lactic, .:
, maleic, oxalic, fumaric and tartaric. The preferred acid .,.,.~ .
addition salt i8 the hydrochloride. The acid addition salts are conventionally prepared by reaction of the basic compounds with the selected acid, either or both of which may be in the form of ether, alcohol or acetone solutions.
The present invention also includes the novel l-aryloxy-
,;"
.. . ~ .
;:>
AHR-~10-CIP
`:
;
- for their antiarrhythmic activity.
`~ Compounds of Formula I wherein Ar is a ortho-lower-`~ alkoxyphenoxy radical, particularly methoxy- and ethoxy-i~
~1 phenoxy radicals, and -NRlR2 is lower-alkylamino, lower cyclo-."
~ 5 alkylamino wherein lower cycloalkyl has from 5 to 7 carbon :
-~ atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or ' phenylamino are also of particular interest for their anti-~ .
~ arrhythmic activity.
,:
It is accordingly an object of this invention to provide novel 1-aryloxy-4-amino-2-butanols which are useful pharma-:
cologically because of their aforesaid types of activity, , ~- processes for the production thereof, and intermediate products useful in the preparation thereof and processes for the production of such intermediates which in themselves have useful pharmacological activity. A further object is to provide ;..
novel compositions containing l-aryloxy-4-amino-2-butanols as ~ .
active ingredients and methods for their use. Other objects of the invention will be apparent to one skilled in the art, : ' ~
l and still other objects will become apparent hereinafter.
rl 20 In the definitions of the symbols in foregoing Formula I
. ~, : and where they appear elsewhere throughout this specification, , .:, the terms have the following significance.
~`~ The term "lower alkyl" as used herein includes straigh*
,.. . .
,1 and branched chain radicals of up to eight carbon atoms inclusive -~ 25 and is exemplified by euch groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, - and the like.
.` ' .
., .
~ ;, .
. ~ . .
~;
` 1077474 AHR-~10-CIP
Tho term "lower slkoxy" has the f~rmula -0-lower alkyl.
When halogen is referred to herein, preferably but not necessarily, a halogen of atomic weight in excess of eighteen but not greater than eighty is employed.
The term "heterocyclic residue" as used herein includes basic saturated monocyclic heterocyclic radicals and basic ~, unsaturated monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower alkyl) piperidino, e.g., 2-, 3-, or 4-(lower alkyl)piperidino;
; 10 pyrrolidino; morpholino; di-(lower alkyl)morpholino, e.g., 3,5-dimethylmorpholino; 2,6-dimethylmorpholino; piperazino;
(lower alkyl)piperazino (e.g., N -methylpiperazino); phenyl-piperazino (e.g., N -phenylpiperazino); 1,2,~,4-tetrahydro-.
isoquinolyl; 1,2,5,6-tetrahydropyridino, 4-(2-pyridyl)piperazino, and phthalimido.
;' Included in the term "phenylalkyl" are groups such as " . i . .
~- benzyl, phenethyl, methylbenzyl, phenpropyl, and the like.
The term "lower cycloalkyl" includes cyclic radicals having ; up to eight carbon atoms and includes radicals such as cyclo-!'"' 20 propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and ~ cyclooctyl.
. . , The term "phenyl" includes the unsubstituted phenyl radical, the substituted phenyl radical and the disubstituted phenyl radical. Among the suitable substituted and disubstituted phenyl .~ .
~;- 25 radicals are those which are substituted by any radical or radicals which are not reactive or otherwise interfering under the . .;
. conditions of reaction in preparing the desired compound, such ..... .
... .
~ ~ - 5 -~.
`;, 1077474 AHR-310-CIP
.
radicals including lower alkylJ lower alkoxy, trifluoromethyl, acetyl, acetylamino, halo, trifluoromethyl, and phenyl. The - substituted phenyl radicals have preferably one or two substituents . ~ .
such as those given above and, furthermore, the substituents can be in various available positions of the phenyl nucleus and, ~- when more than one substituent is present, can be the same or ~ different and can be in various combinations relative to each ,: . .
other. The lower alXyl and lower alkoxy substituents each have ` preferably from one to four carbon atoms which can be arranged ; 10 as straight or branched chains. A total of nine carbon atoms in all ring substituents, making a total of fifteen carbon atoms in the radical,is the preferred maximum.
ffl e compounds of the invention are most conveniently employed in the form of pharmaceutically acceptable acid addition ,~; 15 salts. Such salts have improved water solubility over the free bases. Appropriate acid addition salts are those derived from :i mineral acids such as hydrochloric, hydrobromicJ sulfuric and ., ~ .
phosphoric; and or~anic acids such as acetic, citric, lactic, .:
, maleic, oxalic, fumaric and tartaric. The preferred acid .,.,.~ .
addition salt i8 the hydrochloride. The acid addition salts are conventionally prepared by reaction of the basic compounds with the selected acid, either or both of which may be in the form of ether, alcohol or acetone solutions.
The present invention also includes the novel l-aryloxy-
4~chloro-2-butanols of Formula IV which are useful as inter-~ - .
, ~ .
mediates for preparing the final amine products of Formula I
'$j1 and they may be prepared by the process diagrammed in Chart I, wherein all of the symbols have the meanings given previously.
';
':
.. . . . .
; AHR-310-CIP
;~ 1077474 .~ .
~r~
t?
CH~RT I -- PREPAR~TIO~ OF STARTING
~` ` 1--ARYLoxy-4--CHLORO--2--BUTANOLS ( IV) , ~, `` ArOH + ClcH2-cHoH-cH2-cH2cl OH
`
ArO-CHz-CHOH-CH2-CH Cl The l-aryloxy-4-chloro-2-butanols (IV) are generally `i prepared by treating an aqueous basic solution or an aqueous-alcoholic basic solution of a phenol, a substituted phenol or ; an aryl compound having an acidic hydroxyl group of Formula II
with 1,4-dichloro-2-butanol III. The additio~ is carried out at or below 70 C., preferably at from about 30C. to about 65 C.
over a period of from about three hours to about eight hours.
Sub~equent to the addition the reaction mixture is heated at ; from about 50C. to about 75 C., preferably at 60 C. to 70 C~
,.,.':1 for a period of from about six hours to about forty-eight hours, usually for a period of from twelve hours to eighteen hours.
The I-aryloxy-4-chloro2 -butanol is isolated from the reaction ` 20 mixture by extraction using a suitable organic solvent as, for ,:~
example, ether, isopropyl ether or chloroform, evaporation of ' the solvent after drying to give the 2-butanol which is isolated , ~~ by suitable means such as distillation or crystallization.
,"~
Alternatively, the l-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous basic solution to a mixture of the phenol or the compound having an acidic hydroxyl group and 1,4-dichloro-2-butanol at a rate so as to maintain the reaction mixture at a pH of from about 9.0 to about 10.5, preferably at a pH of g.5 ~- -- 7 --:' ~ 1~77474 AHR-~10-CIP
:' ' ., ' ~ to 10Ø rrhe product is isolated as aescribed hereinabove.
:
- The following preparations are given by way of illustration '.. ~ only and are in no event to be construed as limiting.
.. ~
~'' :
,......... .
: ,:.,, ";
...
" .
f'`` ~ .
' ' ','I~ '~i .-, ,' ' , .
i, ' .
... .
.1., .
. ~ .
i,~,.,~,~ , .,~';Jf .,1 . ~ ., .
.'` . .
.,~,,~ , .
, ........ .
' .!
~ ' ' .
i'', .
, ........ .
;., ....
. ~ .
.... .
,;,; .
.
.. .
. .
....
_ 8 _ .
.~
., .
~ 1077474 A~R-310-CIP
,~ Preparation 1 4-Chloro-l-phenoxy2 -butanol.
~' To a mixture which contained 282 g. (3 moles) of phenol, ";,";
7''1,,`' one liter of water and 300 ml. of 50~ sodium hydroxide was ;~; added slowly with stirring at 60C. 44~.36 g. (3.1 moles)of ~ 5 1,4-dichlorobutanol. Stirring was continued at 60C. for ", 16 hr. The resulting mixture was extracted twice with one liter of ether and the combined ether extracts were washed ~;~ with water to neutrality and dried overnight over sodium sulfate. The dried ether mixture was concentrated to dryness .; ,, .
under reduced pressure. The residue was distilled and yielded 435 g. of product which was collected at 135-138 C./0.05 mm.
The product solidified and was recrystallized using pet.
ether (60-110C.) to give a white crystalline solid which melted at 52-54 C.
Analysis: Calculated for CloHl3Cl02: C,59.86; H,6.53 Found : c,59.72; H,6-37 , ~
~'!. ' ' ' . Preparation 2 4-Chloro-1-(2-chlorophenoxy~-2-butanol.
To a mixture of 129 g. (1 mole) of 2~chlorophenol, 60 g.
,................... .
'~ 20 of potassium hydroxide, 100 ml. of water and 1100 ml. of ~, isopropanol was added 1.3 moles (185.9 g.) of 1,4-dichloro-2-: butanol with stirring at 50 C. The resulting mixture was :; , 7' ;. heated in a steam bath at 65 C. overnight and extracted with 300 ml. of isopropyl ether. The ether extract was washed ; successively with 1~ sodium hydroxide, water ànd dried over sodium sulfate. The dried ether solution was concentrated . . . ~
~, ., ., . - , `: ~
~ ~ AHR-310-CIP
. . .
and the oily residue was distilled under reduced pressure yieldiny 152 g. of an oily substance (b.p. 130-131 C./0.01 mm.).
~ Analysis: Calculated for CloHlscl~2: C,51-08; H~5-15 ;. ~ . .
Found : C,51.13; H,5.14 Preparation 3 4-Chloro-1-(~,5-dimethylphenoxy)-2-butanol.
i .
To a mixture of 245 g. (2 moles) of ~,5-dimethylphenol , . .
;~ and 2 liters of 2N sodium hydroxide was added 2.5 moles of ` 1,4-dichlorobutanol with stirring at 65C. overnight. The ,~ 10 solid precipitate which separated on cooling was filtered and . . .
washed with water to neutrality. Recrystallization with ~`l isopropyl ether yielded 375 g. of white crystalline solid ~; which melted at 74-76 C.
., .
",~f,JI Analysis: Calculated for Cl2Hl7Cl02: C,62.02; H,7.49 15Found : C,63.96; H,7.66 `;l Preparation 4 r"~l 4-Chloro-1-(4-chloro-3-methylphenoxy)-2-~utanol.
~, To a mixture of 286 g. (2 moles) of 3-methyl-4-chlorophenol, "~
700 ml. of tertiary butanol, 700 ml. of water and ~.0 moles of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g.
in 700 ml. water) was added with stirring at 40C to maintain ~j a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr.; the reaction was stirred at 40 C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium ... .
hydroxide at 25 C. The chloroform extract was washed with ; sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give .; .
.. . .
"
--. 10 --~ .
: ' ~ -`' C 107747~ AHR-310-CIP
.,.
110.9 g. of the product which distilled at 135-143 C./0.007 mm.
and melted at 87-89C. after recrystallization with isopxopanol and pet. ether (30.60).
~; Analysis: Calculated for CllHl4C12O2: C,53-03; H~5.66 Found : C,53.11; H,5.61 .
Preparation 5 4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol.
4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol was prepared according to the procedure of Preparation 4 using ",.,;
1 10 105 g. (0.74 mole) of 2-methyl-4-chlorophenol, 171.5 g.
',:",'7 , ( 1.2 mole) of 1,4-dichloro-2-butanol, 50.3 g. of sodium hydroxide, 300 m~. of water and 300 ml. of tertiary butanol.
~;~ There was obtained ô4 g. (45.5~) of product which distilled at 135C./0.01 mm.
Analysis: calculated for CllHl~02Cl2: C,53.03; HJ5.66 ~i Found : C,53.41; H,5.70 Preparation 6 4-Chloro-l-(l-naphthyloxy)-2-butanol.
To a mixture of 1 mole (147 g.) of l-naphthol, 350 ml.
of water and 2 moles (112 g.) of potassium hydroxide was added ~.
at 54C. 1 mole (143 g.) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60C. during : the addition of the chlorobutanol. The reaction mixture was ;: ' heated at 65C. for 12 hF., then mixed with 500 ml. of water and 350 ml. of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated and the residual oil distilled under reduced pressure to give .. 11 . .
~ ~ ' - - .
.
.; .
1077~74 ( A~IR--3l0-CIP
.~ .
128 g. of a crystalline solid which was distilled at 162-165C./0.01 mm. The solid was recrystallized with ether and pet. ether (30-60) to give material melting at 75-77C.
Analysis: Calculated for Cl4Hl502Cl: c,67.o7; H,6.o3 ,~ 5 Found : C,67-19; H,6.19 .~ . . .
Preparation 7 4-Chloro-(4-biphenylyloxy)-2-butanol.
To a solution of 1 mole (158 g.) of 4-phenylphenol :
100 g. of sodium hydroxide and 500 ml. of water was added 1 mole (14~.02 g.) of 1,4-dichloro-2-butanol with stirring ` at 40C. The resulting mixture was heated at 68 C. in a steam bath for 6 hr., cooled and extracted with 300 ml. of . . ,.
::, :j chloroform. The chloroform extract was washed with water to ,.. .
neutrality, dried over sodium sulfate and concentrated to dryness. The solid residue was recrystallized with isopropanol .. . .
ii- and yielded 180 g. of a white crystalline solid which melted at 12~-124C.
Analysis: Calculated for Cl6Hl7Cl02: C,69.44; H,6.19 Found : C,69.79; H,6.22 ` 20 Preparation 8 . .
4-Chloro-1-(3-trifluoromethylphenox ~-2-butanol.
To a mixture of 0.5 mole (75 g.) of m-trifluoromethyl-i; ~
; phenol, 1 mole (56 g.) of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added o.6 mole (84 g.) of 1,4-dichloro-2-butanol with stirring at temperature below ` 55 C. The resulting reaction mixture was heated at 65C. for ` 20 hr., mixed with 2 liters of water, and extracted with ,,.,~
~, .
,.. .
; . -. ~ .
.'. ,, - ' ~. '' :, ' ````:``:
: C 1077474 ( AHR--310-CIP
:, -400 ml. of isopropyl ether. The ether extract was washed with `~, 0.5 N sodium hydroxide and then with water, dried over sodium ~ .
sulfate and distilled under reduced pressure. The distillate ~-: o which was collected at 120-124 C./0.01 mm. solidified at room temperature and melted at 50-52 C.
... .
Analysis: Calculated for CllHl2ClF302: C,49.18i H,4.50 ~- Found : C,49.35; H,4.47 : ` Preparation ~
4-Chloro-1-(4-chlorophenoxy)-2-butanol.
;~ 10 4-Chloro-1-(4-chlorophenoxy)-2-butanol was prepared using the procedure of Preparation 7 from 45 g. (0.5 mole) of p chloro-phenol, 72 g. (0.5 mole) of 1,4-dichloro-2-butanol, 40 g.
(1.0 mole) of sodium hydroxide and 400 ml. of water to give 85 g. (36.1%) of product which melted at 62-64 C. after recrystal-~ . . .
15 lization from isopropanol.
Analysis: Calculated for C1O~15C1OZ: C,51.09; H,5.14 Found : CJ51.76; H,5.12 Preparation 10 ....
, ..
4-Chloro-1-(2-methoxyphenoxy)-2-butanol.
.,:
To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and ; distilled under reduced pressure. The distillate which was collected at 136-138 C./0.015 mm. (396.8 g.) solidified to a , ~
. , .
.' .
:` `
-. ` r ~ AHR--3l0-cIP
~07747 ~` "
~ ;. . .
;;~ white crystalline solid which melted at 48-50 C.
~ .
~ Analysis: Calculated for C11H1403Cl: C,57.52; H,6.14 .
Found : C,57.49; H,6.54 ~,,~ . .
Using the procedures disclosed in Preparations 1-10, , 5 starting from the appropriate phenol II and 1J 4-dichloro-2-. :
i;r~l butanol III, various other l-aryloxy-4-chloro-2-butanols IV
are prepared.
Preparation 11 4-Chloro-1-(2-methyl-5-chlorophenoxy)-2-butanol, b.p.
135-8 C./0.05 mm. was prepared from 2-methyl-5-chlorophenol and l,4-dichloro-2-butanol.
~,~
~`; Preparation 12 4-Chloro-1-(2-naphthyloxy)-2-butanol, m.p. 101-102 C., ~ was prepared from 2-naphthol and 1,4-dichloro-2-butanol.
.~ .
Preparation 13 4-Chloro-1-(4-acetylaminophenoxy)-2-butanol, m.p. 125-128 C., .: .
was prepared from 4-acetylaminophenol and 1,4-dichloro-2-butanol.
,,~, .
Preparation 14 4-chloro-1-(4-methoxyphenoxy)-2-butanol, m.p. 61-6~ C., :::
.:, was prepared from 4-methoxyphenol and 1,4-dichloro-2-butanol.
Preparation 15 .j,, .
rl 4-Chloro-1-(3-chloro-2-pyridyloxy)-2-butanol, m.p. 56-58 C., was prepared from 3-chloro-2-hydroxypyridine and 1,4-dichloro-:~j .~ 2-butanol.
. . ~
~ .
, . .
~.1 ~ -14 -. ~
:'-,, `:.;` .
~, .v.
., ;~
Preparation 16 4-Chloro-l-(5-chloro-2-pyridyloxy)-2-butanolJ was prepared .~,.
-~ ~ from 5-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol.
`:; `
; ~ Preparation 17 4-Chloro-l-(inden-5-yloxy)-2-butanol, m.p. 56-58 C., was - 5prepared from 6-hydroxyindene and 1,4-dichloro-2-butanol.
Preparation 18 . ~ ... .
4-Chloro-1-(3-chlorophenoxy)-2-butanol, 60-62C., was prepared from 3-chlorophenol and 1,4-dichloro-2-butanol.
:
Preparation 19 : o , 10 4-Chloro-l-t2-ethoxyphenoxy)-2-butanol, b.p. 130-132 C./
'`., ~
0.01 mm. was prepared from 2-ethoxyphenol and 1,4-dichloro-2-~; butanol.
Preparation 20 ; 4-Chloro-1-(4-acetylphenoxy)-2-butanol, m.p. 125-128 C., was prepared from 4-acetylphenol and 1,4-dichloro-2-butanol.
, .
~, ~
Pre?aration 21 4-Chloro-l-(o-phenylphenoxy)-2-butanol, b.p. 156-160 C./
0.25 mm., was prepared from o-phenylphenol and 1,4-dichloro-, 2-butanol.
,.,;~, ~ 20 ,;. .
:; ', ' , '.`1 ~
, J: .
~ 7 .., .ij '~' '.
~c -- 15 --i ~ f ~ AHR-310-CIP
7747~ `' ~, .
The preparation of the novel l-aryloxy-4-amino-2-butanols `~ I of the present invention is designated in the following xeaction sequence:
:.:
CH~RT 2 - PREPARATIO~ OF
1-ARYL0XY-4-AMI~0-2-BUTANOLS
.,j;~,................................................ .
ArO-CH2-CHOH-CH2-CH2-Cl ~ H~RlR
. IV V
.,,.~ .
. ArO-CH2-CHOH-CH~-CH2-NR R
t"''" .
~i wherein all of the symbols have the meanings given hereinabove.
.... . . . .
~ In the reaction sequence the l-aryloxy-4-chloro-2-butanol , .. . . .
(IV) is reacted with an amine (V) to give the novel l-aryloxy-~, 4-amino-2-butanols (I). The foregoing reaction can be carried ~ 15 out by (A) heating a mixture of the chloro compound and the :'!'''' amine with a solvent in a steel bomb, (B) heating a mixture of ~:!
the chloro compound and the amine without a solvent in a steel bomb, ( C) refluxing a mixture of the chloro compound, the amine and a solvent at atmospheric pressure or (D) heating a mixture of the chloro compound and the amine without a solvent at atmospheric pressure and at a suitable temperature. The selected procedure is somewhat dependent on the nature of the amine reactant. Thus, when the amine is a low molecular volatile l ~' .
amine process A or B is preferred and the bomb contents are heated at from about 100 C. to about 150 C. ~or a period of ?i; 1~ -from about 12 hours to about 24 hours. When the amine is a `;l high molecular weight non-volatile amine or an amine having low X
( f AHR-310-CIP
` `~~ 1077~74 ~ ~ .
.~ .
volatility,process C or D is preferred and the reaction mixture ; is refluxed at the temperature of the solvent used or the mixture is heated at from about 100 C. to about 150 C. The ; reaction time can be varied, reaction times being somewhat .
æhorter when the chloro compound and the amine are reacted together in the absence of a solvent and a higher reaction . .~;
temperature is employed. The reaction product in each case is ~` isolated by conventional acid-base extraction procedures and the free base, if desired, is converted to a pharmaceutically .. ,;,. .
10 acceptable acid addition salt which is further purified by cry~tallization from a suitable solvent or solvent system.
l-Aryloxy-4-amino-2-butanols which do not form well defined -~ salts can be purified by vacuum distillation.
Examples 1-6 illustrate the prepàration of the novel 1-aryloxy-4-amino-2-butanol compounds of the present invention by one of the four optional processes. Table I summarizes the ;:;,. .
~ physical data of additional compounds within the scope of .,;, .
~`l Formula I and indicates the process used to prepare each compound.
~, Table II contains the analytical data of the compounds listed in Table I.
": '1 i 1 ' .
. ., . ..
~"
~' 17: .
: - . .. - . . .: .
~ . ... : , . : : .
. . : . . . .
.:
t, ~ l ~
{ 1077474 ~ AHR-310-CIP
..~
"'~ , .
Example 1 .
4-IsopropYlamino-l-(l-naphthyloxy) ? -butanol Hydrochloride.
A mixture of 27.1 g. (0.1 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride and 100 ml. of isopropylamine in a steel ,, ~ bomb was heated at 120C. for 24 hours. The reaction mixture ~ .
~ 5 was mixed with 300 ml. of 6N hydrochloric acid and extracted .~,r: :~
with ether at room temperature. The acidic aqueous solution was made basic, extracted with isopropyl ether, dried over , .............................. .
i~ sodium sulfate, then concentrated to dryness. The residue was ~; !
s dissolved in isopropanol and mixed with ethereal hydrogen ~ ~, ;.~ 10 chloride. The white crystalline precipitate was recrystal-,,"~ . .
lized from isopropanol and isopropyl ether to give hydrochloride salt which melted at 126-128 C.
, j, .
~i Analysis: Calculated for C 17H2~ClNO2: C,65.90; H,7.81; N,4.52 Found : C,65.67; H,7.91; N,4.34 ,,,:~.
Example 2 4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-(1-naphthyloxy)-2-butanol HYdrochloride.
A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chlorideJ 9~97 g. (0.075 mole) of 1,2,3,4-tetra-hydroisoquinoline and 300 ml. of isopropanol was refluxed for 15 hr. On standing at room temperature a crystalline precipitate formed. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The semi-solid residue which ,~.. '.1 .
crystallized was recrystallized from acetone. The 12.2 g. of crystalline solid material melted at 169-171 C.
Analysis: Calculated for C23H26C1~02: C, 71.96; H,6.83; N,3.65 Found : C,71.69; H,6.76; N~3.60 :
:
.. . .
: , :
~ `
~ ~AHR-~10-CIP
~ i~77474 ~ .. .
"`.~' . , Example 3 l-(l-~aphthyloxy)_4_phenethylamino? -butanol Hydrochloride.
.~
: .
~ A mixture of 12.5 g. (0.05 mole) of 1~ naphthyloxy)-2-.~.,; .
hydroxybutyl chloride and 14.5 g. (0.1 mole) of phenethylamine was heated at 120C. for 20 min. on a hot plate. The resulting mixture was mixed with 250 ml. of acetone, heated to boiling , , and then filtered at room temperature. The filtrate was treated `~ with 50 ml. of ethereal hydrogen chloride. The resulting white precipitate was filtered. The white crystalline solid was recrystallized from acetone and yielded 11.8 g. of the hydro-~;- 10 chloride salt which melted at 163-165 C.
` Analysis: Calculated for C22~6N02Cl: C,71.05; H,7-05; ~13 77 , ~'i Found : C,70.99; H,6.98; ~J~.61 . ' 'i .
Example l~
1-(2-Chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl~-2-butanol HYdrochloride Hydrate.
` A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-,, .
2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetra-,~ hydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N
. . .
;~ hydrochloric acid and extracted twice with 100 ml. isopropyl ~ ., ether. The aqueous acidic solution was made basic and extracted ,~; .1 .
with isopropyl ether and treated with ethereal hydrogen chloride.
Recrystallization with isopropanol yielded 6 g. of the hydro-, 25 chloride hydrate of the product which melted at 118-120C.
;~ Analysis: Calculated for ClgH~5Cl2~03: C,59.07; H,6.52; N,3.63 ~ Found : C,59.08i H,6.51; ~,~-55 . , .
~ ~ AHR-~10-CIP
` 1077474 :....
~ ... . .
~ Example 5 i ,i,~, ~; 4-(Isopropylamino)-l-(o-methoxyphenoxy~-2-butanol HYdro-~ .
n chloride~ -.;: -~ A mixture which contained 11.6 g. (0.05 mole) of 1-(2-.i.:
`~ ~ethoxyphenoxy)-2-hydroxybutyl chloride, 50 ml. of isopropyl :~, ~t:" amine and 100 ml. of n-butanol was charged in a steel bomb and ~ heated at 120 C. for 24 hr. The resulting reaction mixture ¢ was filtered. The filtrate was concentrated to dryness and ,~/;r mixed with 200 ml. of 3N hydrochloric acid, extracted with ether and the aqueous layer was made basic. The base insoluble oil was extracted into isopropyl ether, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in isopropanol and mixed with 20 ml. ethereal hydrogen chloride.
The gummy precipitate recrystallized using isopropyl ether and isopropanol. The hydrochloride (8.3 g.) melted at 83-85C.
Analysis: Calculated for Cl4E~ClN03: C,58.02; H,8.35; N/4.83 Found : C,57.44; H,8.31; N,4.72 Example 6 (o-Chlorophenoxv)-4-(4-phenyl-1-piperazinyl) 2 -butanol.
A mixture of 35.1 g. (0.15 mole) of 1-(o-chlorophenoxy)-2-~!, 20 hydroxybutyl chloride, 32.6 g. (0.2 mole) of N-phenylpiperazine and 400 ml. of isopropanol was refluxed for 48 hr. The reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and the salt precipitated by the addition of ether.
The white crystalline solid which formed was dissolved in 0.1 mole of hydrochloric ac,id and then neutralized with sodium . ~ .
~ - -20-. .
,. .... .
,... -, ... . - . - ~ . , .
., - . ~ , : ..
,... . .
. ~ .
` :`
~ ~ ( ( AHR-310-CIP
:'"' ` . .
. ~o7~7474 .
` .`
~ hydroxide producing a crystalline precipitate. This was : ;:
recrystallized with isopropanol yielding 36 g. of the free base of the product which melted at 100-101.5C.
Analysis: Calculated for C20H25~202Cl: C,66.56; H,6.98; N,7.76 ii 5 Found : C,66.49; H,7.03; N,7.86The physical constants of some representative l-aryloxy-., ~`~ 4-amino-2-butanols made from 1-aryloxy-4-chloro-2-butanols ,:., and a selected amine by processes A, B, C and D are shown in .
~ Table I and Table II.
:,", 10 . ~ .
:: .
'; ' . ~ .
.... .
, J:r, , ..... .
,, ! . .
,~, .-,. i , .,,`, , . ~'.
. .
, .
.
-2il-`
.,.
,. . .
. -. . .
. TABLE I - Examples 7 throuqh 72 ~: OH Rl -'` .Ar-O-CH2-CH-CH2-CH2-N~ 2 ,!,. ~ R
Rl .
. Example -N ~ M.P.
Number Ar ~R2 Salt C. Process 7 l-CloH7 -NHCzHs HCl 153-5 A
8 l-CloH7 -NHCeHll HCl 158-60 D
g l-CloH7 . -NOC4H~ a b ~ 54-6 D
l-CloH7 -NOC4H6(CH3)z Hcl H20 118-20 D
.~11 l-CloH7 -N(CH33C~Hll ~ 62-5 D
12 l-CloH7 -NC5Hlo c HCl 135-7 D
1~ l-CloH7 -NHCH2CsHs HCl-H20 83-5 D
14 4-CBH5-CgH4 -NHCH(CH3)2 HCl 190-2 B
3-CH3-4-ClCBH3 -NHCH(CH3)2 ~ 74-6 A
16 3-CF3C6H4 -NHCH(CH3)2 HCl 92-4 B
17 2-CH3-5-ClC6H3 -N(CHj)CH2C~H5 HCl 169-71 C
18 3-CM3-4-ClC6H3 -NH(CH2)2CBHs HCl 16~-5 A
19 2-CH3-4-ClC6H3 -NH(CH~)2C8Hs HCl 128-30 A
2-ClC~H4 -NHC(CH3)zCH20M HCl 117-119 C
21 C~H5 -NH(CH~)~C~Hc HCl 14~-4 D
~' 22 2-CH3-4-ClC~H3 -NCsH9-4-C6Hs HCl 148-50 D
t~ 23 2-CE3-4-ClC6H3 -NC4H8N-C~Hs e di-HCl 186-8 C
24 2-ClC6H4 -NC5HloC HCl 159-60 C
~,~ 25 3-CF3C~H4 -NH(CH2)2C~Hs HCl 131-3 D
26 2-CH3-5-ClCBH4 -NH(CH2)2C6H5 HCl 141 - 3 D
27 3-ClC6H4 -NH(CHz)zCsHs HCl 154-6 D
28 2-CH30CeH4 -NH(CH2)2CBH5 - 112-14 D
~; . 29 C6Hs -NHCH2C~Hs HCl 1/2HzO 108-10 D
2-CH30C8H4 -NHCBHl1 H~O C
~': 31 3-clcsH4 -NHCH2CB~I5 HCl 139-41 D
32 2-CH3-4-Clc~H3 -NcsHlof HCl 149-51 D
33 3~5~CH3CsH3 -NH(CH2)2C6Hs HCl l/2H20 117-20 D
~ 34 3,5-CH3CBH3 -NC4HaN-C8H5 e _ 88-go D
'~, 35 3,5-CH3C6H3 -NCsHlof HCl.l/2H20 141-3 D
,~ 36 3,5~CH3CsH3 -NC5H7-4-C6Hsg HCl 162-4 D
37 3~5-CH3C6H3 -N(CH~)CRHll HCl 158-60 D
8 2-ClCBH4 -NH(C~)2C6Hs h 92-4 D
39 C6H5 -NC4H8N-2-CsH4N di-maleate 123-5 DC6Hs -N(CH3)C6Hll ~ 50-2 D
;;; 41 C6H5 -N(CH3)CH2CsHs maleate 118-20 D
i~s 42 2-CH30C6H4 -N(CH3)C6Hll maleate 109-11 D
43 2-CH30C6H4 -NOC4H6(CH3)2 h ~ _ D
44 2-CH30C6H4 -NC4H8N?-C5H4N 3 HCl 1/2HzO 95-7 D
2-CH30C6H4 -NHCsHg i HCl 112-14 D
46 2-CloH7 -NC5H7-4-C6Hs HCl 168-70 C
47 2-CloH7 -NHCH(CH3)2 ~ 96-98 B
48 4-CH30C6H4 -~(CH3)C6Hll _ 50-2 C
~ (cont.) .. ; - .
.; -22-.
. . .
: -., '` ~ . :
: .
` 1~7747~
` Table I (cont.) R
Example N ~ M.P.
Number Ar R Salt C Process :., 49 4-CH3CoNHC6H4 -~IC6Hll ~ 140-2 C
4-CH3cOc6H4 -NHC6Xll ~ 93 5 C
51 l-CloH7 -NHC(CH3)2CH2OH - 98-100 C
52 3,5-CH~C6H3 -NHCloHl5~ HC1 229-31 C
53 5-CsH7 -NHC6Hll ~ 95 7 C
54 5-CsH7 -NHCH(CH3) 2 HCl H2O 103-5 C
2-CH3-5-ClC6H3 -NHC6Hll HCl 189-92 C
56 4-CH3OC6H4 -NHCloHl5~ ~ 78-80 C
57 l-CloH7 -NHCloHlsi HCl 195-7 C
58 l-CloH7 -N(CH3)CsHls HCl 143-5 C
59 4-CH3OCeH4 -NHCH(CH3)2 HCl 118-20 C
4-CH30C6H4 -NHC8Hll HCl 136-8 C
61 5-CsH7k 1 -NHC(CH3)2CH2OH - 9~-5 C
62 5-ClC5H3N -NHC6Hll HCl H20 - C
63 l-CloH7 -N(CH3)CH2CH~OHHCl 115-17 C
64 l-CloH7 1 -NHC5H9 HCl 148-50 D
, ~ .
mediates for preparing the final amine products of Formula I
'$j1 and they may be prepared by the process diagrammed in Chart I, wherein all of the symbols have the meanings given previously.
';
':
.. . . . .
; AHR-310-CIP
;~ 1077474 .~ .
~r~
t?
CH~RT I -- PREPAR~TIO~ OF STARTING
~` ` 1--ARYLoxy-4--CHLORO--2--BUTANOLS ( IV) , ~, `` ArOH + ClcH2-cHoH-cH2-cH2cl OH
`
ArO-CHz-CHOH-CH2-CH Cl The l-aryloxy-4-chloro-2-butanols (IV) are generally `i prepared by treating an aqueous basic solution or an aqueous-alcoholic basic solution of a phenol, a substituted phenol or ; an aryl compound having an acidic hydroxyl group of Formula II
with 1,4-dichloro-2-butanol III. The additio~ is carried out at or below 70 C., preferably at from about 30C. to about 65 C.
over a period of from about three hours to about eight hours.
Sub~equent to the addition the reaction mixture is heated at ; from about 50C. to about 75 C., preferably at 60 C. to 70 C~
,.,.':1 for a period of from about six hours to about forty-eight hours, usually for a period of from twelve hours to eighteen hours.
The I-aryloxy-4-chloro2 -butanol is isolated from the reaction ` 20 mixture by extraction using a suitable organic solvent as, for ,:~
example, ether, isopropyl ether or chloroform, evaporation of ' the solvent after drying to give the 2-butanol which is isolated , ~~ by suitable means such as distillation or crystallization.
,"~
Alternatively, the l-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous basic solution to a mixture of the phenol or the compound having an acidic hydroxyl group and 1,4-dichloro-2-butanol at a rate so as to maintain the reaction mixture at a pH of from about 9.0 to about 10.5, preferably at a pH of g.5 ~- -- 7 --:' ~ 1~77474 AHR-~10-CIP
:' ' ., ' ~ to 10Ø rrhe product is isolated as aescribed hereinabove.
:
- The following preparations are given by way of illustration '.. ~ only and are in no event to be construed as limiting.
.. ~
~'' :
,......... .
: ,:.,, ";
...
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i,~,.,~,~ , .,~';Jf .,1 . ~ ., .
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, ........ .
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, ........ .
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.... .
,;,; .
.
.. .
. .
....
_ 8 _ .
.~
., .
~ 1077474 A~R-310-CIP
,~ Preparation 1 4-Chloro-l-phenoxy2 -butanol.
~' To a mixture which contained 282 g. (3 moles) of phenol, ";,";
7''1,,`' one liter of water and 300 ml. of 50~ sodium hydroxide was ;~; added slowly with stirring at 60C. 44~.36 g. (3.1 moles)of ~ 5 1,4-dichlorobutanol. Stirring was continued at 60C. for ", 16 hr. The resulting mixture was extracted twice with one liter of ether and the combined ether extracts were washed ~;~ with water to neutrality and dried overnight over sodium sulfate. The dried ether mixture was concentrated to dryness .; ,, .
under reduced pressure. The residue was distilled and yielded 435 g. of product which was collected at 135-138 C./0.05 mm.
The product solidified and was recrystallized using pet.
ether (60-110C.) to give a white crystalline solid which melted at 52-54 C.
Analysis: Calculated for CloHl3Cl02: C,59.86; H,6.53 Found : c,59.72; H,6-37 , ~
~'!. ' ' ' . Preparation 2 4-Chloro-1-(2-chlorophenoxy~-2-butanol.
To a mixture of 129 g. (1 mole) of 2~chlorophenol, 60 g.
,................... .
'~ 20 of potassium hydroxide, 100 ml. of water and 1100 ml. of ~, isopropanol was added 1.3 moles (185.9 g.) of 1,4-dichloro-2-: butanol with stirring at 50 C. The resulting mixture was :; , 7' ;. heated in a steam bath at 65 C. overnight and extracted with 300 ml. of isopropyl ether. The ether extract was washed ; successively with 1~ sodium hydroxide, water ànd dried over sodium sulfate. The dried ether solution was concentrated . . . ~
~, ., ., . - , `: ~
~ ~ AHR-310-CIP
. . .
and the oily residue was distilled under reduced pressure yieldiny 152 g. of an oily substance (b.p. 130-131 C./0.01 mm.).
~ Analysis: Calculated for CloHlscl~2: C,51-08; H~5-15 ;. ~ . .
Found : C,51.13; H,5.14 Preparation 3 4-Chloro-1-(~,5-dimethylphenoxy)-2-butanol.
i .
To a mixture of 245 g. (2 moles) of ~,5-dimethylphenol , . .
;~ and 2 liters of 2N sodium hydroxide was added 2.5 moles of ` 1,4-dichlorobutanol with stirring at 65C. overnight. The ,~ 10 solid precipitate which separated on cooling was filtered and . . .
washed with water to neutrality. Recrystallization with ~`l isopropyl ether yielded 375 g. of white crystalline solid ~; which melted at 74-76 C.
., .
",~f,JI Analysis: Calculated for Cl2Hl7Cl02: C,62.02; H,7.49 15Found : C,63.96; H,7.66 `;l Preparation 4 r"~l 4-Chloro-1-(4-chloro-3-methylphenoxy)-2-~utanol.
~, To a mixture of 286 g. (2 moles) of 3-methyl-4-chlorophenol, "~
700 ml. of tertiary butanol, 700 ml. of water and ~.0 moles of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g.
in 700 ml. water) was added with stirring at 40C to maintain ~j a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr.; the reaction was stirred at 40 C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium ... .
hydroxide at 25 C. The chloroform extract was washed with ; sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give .; .
.. . .
"
--. 10 --~ .
: ' ~ -`' C 107747~ AHR-310-CIP
.,.
110.9 g. of the product which distilled at 135-143 C./0.007 mm.
and melted at 87-89C. after recrystallization with isopxopanol and pet. ether (30.60).
~; Analysis: Calculated for CllHl4C12O2: C,53-03; H~5.66 Found : C,53.11; H,5.61 .
Preparation 5 4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol.
4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol was prepared according to the procedure of Preparation 4 using ",.,;
1 10 105 g. (0.74 mole) of 2-methyl-4-chlorophenol, 171.5 g.
',:",'7 , ( 1.2 mole) of 1,4-dichloro-2-butanol, 50.3 g. of sodium hydroxide, 300 m~. of water and 300 ml. of tertiary butanol.
~;~ There was obtained ô4 g. (45.5~) of product which distilled at 135C./0.01 mm.
Analysis: calculated for CllHl~02Cl2: C,53.03; HJ5.66 ~i Found : C,53.41; H,5.70 Preparation 6 4-Chloro-l-(l-naphthyloxy)-2-butanol.
To a mixture of 1 mole (147 g.) of l-naphthol, 350 ml.
of water and 2 moles (112 g.) of potassium hydroxide was added ~.
at 54C. 1 mole (143 g.) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60C. during : the addition of the chlorobutanol. The reaction mixture was ;: ' heated at 65C. for 12 hF., then mixed with 500 ml. of water and 350 ml. of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated and the residual oil distilled under reduced pressure to give .. 11 . .
~ ~ ' - - .
.
.; .
1077~74 ( A~IR--3l0-CIP
.~ .
128 g. of a crystalline solid which was distilled at 162-165C./0.01 mm. The solid was recrystallized with ether and pet. ether (30-60) to give material melting at 75-77C.
Analysis: Calculated for Cl4Hl502Cl: c,67.o7; H,6.o3 ,~ 5 Found : C,67-19; H,6.19 .~ . . .
Preparation 7 4-Chloro-(4-biphenylyloxy)-2-butanol.
To a solution of 1 mole (158 g.) of 4-phenylphenol :
100 g. of sodium hydroxide and 500 ml. of water was added 1 mole (14~.02 g.) of 1,4-dichloro-2-butanol with stirring ` at 40C. The resulting mixture was heated at 68 C. in a steam bath for 6 hr., cooled and extracted with 300 ml. of . . ,.
::, :j chloroform. The chloroform extract was washed with water to ,.. .
neutrality, dried over sodium sulfate and concentrated to dryness. The solid residue was recrystallized with isopropanol .. . .
ii- and yielded 180 g. of a white crystalline solid which melted at 12~-124C.
Analysis: Calculated for Cl6Hl7Cl02: C,69.44; H,6.19 Found : C,69.79; H,6.22 ` 20 Preparation 8 . .
4-Chloro-1-(3-trifluoromethylphenox ~-2-butanol.
To a mixture of 0.5 mole (75 g.) of m-trifluoromethyl-i; ~
; phenol, 1 mole (56 g.) of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added o.6 mole (84 g.) of 1,4-dichloro-2-butanol with stirring at temperature below ` 55 C. The resulting reaction mixture was heated at 65C. for ` 20 hr., mixed with 2 liters of water, and extracted with ,,.,~
~, .
,.. .
; . -. ~ .
.'. ,, - ' ~. '' :, ' ````:``:
: C 1077474 ( AHR--310-CIP
:, -400 ml. of isopropyl ether. The ether extract was washed with `~, 0.5 N sodium hydroxide and then with water, dried over sodium ~ .
sulfate and distilled under reduced pressure. The distillate ~-: o which was collected at 120-124 C./0.01 mm. solidified at room temperature and melted at 50-52 C.
... .
Analysis: Calculated for CllHl2ClF302: C,49.18i H,4.50 ~- Found : C,49.35; H,4.47 : ` Preparation ~
4-Chloro-1-(4-chlorophenoxy)-2-butanol.
;~ 10 4-Chloro-1-(4-chlorophenoxy)-2-butanol was prepared using the procedure of Preparation 7 from 45 g. (0.5 mole) of p chloro-phenol, 72 g. (0.5 mole) of 1,4-dichloro-2-butanol, 40 g.
(1.0 mole) of sodium hydroxide and 400 ml. of water to give 85 g. (36.1%) of product which melted at 62-64 C. after recrystal-~ . . .
15 lization from isopropanol.
Analysis: Calculated for C1O~15C1OZ: C,51.09; H,5.14 Found : CJ51.76; H,5.12 Preparation 10 ....
, ..
4-Chloro-1-(2-methoxyphenoxy)-2-butanol.
.,:
To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and ; distilled under reduced pressure. The distillate which was collected at 136-138 C./0.015 mm. (396.8 g.) solidified to a , ~
. , .
.' .
:` `
-. ` r ~ AHR--3l0-cIP
~07747 ~` "
~ ;. . .
;;~ white crystalline solid which melted at 48-50 C.
~ .
~ Analysis: Calculated for C11H1403Cl: C,57.52; H,6.14 .
Found : C,57.49; H,6.54 ~,,~ . .
Using the procedures disclosed in Preparations 1-10, , 5 starting from the appropriate phenol II and 1J 4-dichloro-2-. :
i;r~l butanol III, various other l-aryloxy-4-chloro-2-butanols IV
are prepared.
Preparation 11 4-Chloro-1-(2-methyl-5-chlorophenoxy)-2-butanol, b.p.
135-8 C./0.05 mm. was prepared from 2-methyl-5-chlorophenol and l,4-dichloro-2-butanol.
~,~
~`; Preparation 12 4-Chloro-1-(2-naphthyloxy)-2-butanol, m.p. 101-102 C., ~ was prepared from 2-naphthol and 1,4-dichloro-2-butanol.
.~ .
Preparation 13 4-Chloro-1-(4-acetylaminophenoxy)-2-butanol, m.p. 125-128 C., .: .
was prepared from 4-acetylaminophenol and 1,4-dichloro-2-butanol.
,,~, .
Preparation 14 4-chloro-1-(4-methoxyphenoxy)-2-butanol, m.p. 61-6~ C., :::
.:, was prepared from 4-methoxyphenol and 1,4-dichloro-2-butanol.
Preparation 15 .j,, .
rl 4-Chloro-1-(3-chloro-2-pyridyloxy)-2-butanol, m.p. 56-58 C., was prepared from 3-chloro-2-hydroxypyridine and 1,4-dichloro-:~j .~ 2-butanol.
. . ~
~ .
, . .
~.1 ~ -14 -. ~
:'-,, `:.;` .
~, .v.
., ;~
Preparation 16 4-Chloro-l-(5-chloro-2-pyridyloxy)-2-butanolJ was prepared .~,.
-~ ~ from 5-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol.
`:; `
; ~ Preparation 17 4-Chloro-l-(inden-5-yloxy)-2-butanol, m.p. 56-58 C., was - 5prepared from 6-hydroxyindene and 1,4-dichloro-2-butanol.
Preparation 18 . ~ ... .
4-Chloro-1-(3-chlorophenoxy)-2-butanol, 60-62C., was prepared from 3-chlorophenol and 1,4-dichloro-2-butanol.
:
Preparation 19 : o , 10 4-Chloro-l-t2-ethoxyphenoxy)-2-butanol, b.p. 130-132 C./
'`., ~
0.01 mm. was prepared from 2-ethoxyphenol and 1,4-dichloro-2-~; butanol.
Preparation 20 ; 4-Chloro-1-(4-acetylphenoxy)-2-butanol, m.p. 125-128 C., was prepared from 4-acetylphenol and 1,4-dichloro-2-butanol.
, .
~, ~
Pre?aration 21 4-Chloro-l-(o-phenylphenoxy)-2-butanol, b.p. 156-160 C./
0.25 mm., was prepared from o-phenylphenol and 1,4-dichloro-, 2-butanol.
,.,;~, ~ 20 ,;. .
:; ', ' , '.`1 ~
, J: .
~ 7 .., .ij '~' '.
~c -- 15 --i ~ f ~ AHR-310-CIP
7747~ `' ~, .
The preparation of the novel l-aryloxy-4-amino-2-butanols `~ I of the present invention is designated in the following xeaction sequence:
:.:
CH~RT 2 - PREPARATIO~ OF
1-ARYL0XY-4-AMI~0-2-BUTANOLS
.,j;~,................................................ .
ArO-CH2-CHOH-CH2-CH2-Cl ~ H~RlR
. IV V
.,,.~ .
. ArO-CH2-CHOH-CH~-CH2-NR R
t"''" .
~i wherein all of the symbols have the meanings given hereinabove.
.... . . . .
~ In the reaction sequence the l-aryloxy-4-chloro-2-butanol , .. . . .
(IV) is reacted with an amine (V) to give the novel l-aryloxy-~, 4-amino-2-butanols (I). The foregoing reaction can be carried ~ 15 out by (A) heating a mixture of the chloro compound and the :'!'''' amine with a solvent in a steel bomb, (B) heating a mixture of ~:!
the chloro compound and the amine without a solvent in a steel bomb, ( C) refluxing a mixture of the chloro compound, the amine and a solvent at atmospheric pressure or (D) heating a mixture of the chloro compound and the amine without a solvent at atmospheric pressure and at a suitable temperature. The selected procedure is somewhat dependent on the nature of the amine reactant. Thus, when the amine is a low molecular volatile l ~' .
amine process A or B is preferred and the bomb contents are heated at from about 100 C. to about 150 C. ~or a period of ?i; 1~ -from about 12 hours to about 24 hours. When the amine is a `;l high molecular weight non-volatile amine or an amine having low X
( f AHR-310-CIP
` `~~ 1077~74 ~ ~ .
.~ .
volatility,process C or D is preferred and the reaction mixture ; is refluxed at the temperature of the solvent used or the mixture is heated at from about 100 C. to about 150 C. The ; reaction time can be varied, reaction times being somewhat .
æhorter when the chloro compound and the amine are reacted together in the absence of a solvent and a higher reaction . .~;
temperature is employed. The reaction product in each case is ~` isolated by conventional acid-base extraction procedures and the free base, if desired, is converted to a pharmaceutically .. ,;,. .
10 acceptable acid addition salt which is further purified by cry~tallization from a suitable solvent or solvent system.
l-Aryloxy-4-amino-2-butanols which do not form well defined -~ salts can be purified by vacuum distillation.
Examples 1-6 illustrate the prepàration of the novel 1-aryloxy-4-amino-2-butanol compounds of the present invention by one of the four optional processes. Table I summarizes the ;:;,. .
~ physical data of additional compounds within the scope of .,;, .
~`l Formula I and indicates the process used to prepare each compound.
~, Table II contains the analytical data of the compounds listed in Table I.
": '1 i 1 ' .
. ., . ..
~"
~' 17: .
: - . .. - . . .: .
~ . ... : , . : : .
. . : . . . .
.:
t, ~ l ~
{ 1077474 ~ AHR-310-CIP
..~
"'~ , .
Example 1 .
4-IsopropYlamino-l-(l-naphthyloxy) ? -butanol Hydrochloride.
A mixture of 27.1 g. (0.1 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride and 100 ml. of isopropylamine in a steel ,, ~ bomb was heated at 120C. for 24 hours. The reaction mixture ~ .
~ 5 was mixed with 300 ml. of 6N hydrochloric acid and extracted .~,r: :~
with ether at room temperature. The acidic aqueous solution was made basic, extracted with isopropyl ether, dried over , .............................. .
i~ sodium sulfate, then concentrated to dryness. The residue was ~; !
s dissolved in isopropanol and mixed with ethereal hydrogen ~ ~, ;.~ 10 chloride. The white crystalline precipitate was recrystal-,,"~ . .
lized from isopropanol and isopropyl ether to give hydrochloride salt which melted at 126-128 C.
, j, .
~i Analysis: Calculated for C 17H2~ClNO2: C,65.90; H,7.81; N,4.52 Found : C,65.67; H,7.91; N,4.34 ,,,:~.
Example 2 4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-(1-naphthyloxy)-2-butanol HYdrochloride.
A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chlorideJ 9~97 g. (0.075 mole) of 1,2,3,4-tetra-hydroisoquinoline and 300 ml. of isopropanol was refluxed for 15 hr. On standing at room temperature a crystalline precipitate formed. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The semi-solid residue which ,~.. '.1 .
crystallized was recrystallized from acetone. The 12.2 g. of crystalline solid material melted at 169-171 C.
Analysis: Calculated for C23H26C1~02: C, 71.96; H,6.83; N,3.65 Found : C,71.69; H,6.76; N~3.60 :
:
.. . .
: , :
~ `
~ ~AHR-~10-CIP
~ i~77474 ~ .. .
"`.~' . , Example 3 l-(l-~aphthyloxy)_4_phenethylamino? -butanol Hydrochloride.
.~
: .
~ A mixture of 12.5 g. (0.05 mole) of 1~ naphthyloxy)-2-.~.,; .
hydroxybutyl chloride and 14.5 g. (0.1 mole) of phenethylamine was heated at 120C. for 20 min. on a hot plate. The resulting mixture was mixed with 250 ml. of acetone, heated to boiling , , and then filtered at room temperature. The filtrate was treated `~ with 50 ml. of ethereal hydrogen chloride. The resulting white precipitate was filtered. The white crystalline solid was recrystallized from acetone and yielded 11.8 g. of the hydro-~;- 10 chloride salt which melted at 163-165 C.
` Analysis: Calculated for C22~6N02Cl: C,71.05; H,7-05; ~13 77 , ~'i Found : C,70.99; H,6.98; ~J~.61 . ' 'i .
Example l~
1-(2-Chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl~-2-butanol HYdrochloride Hydrate.
` A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-,, .
2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetra-,~ hydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N
. . .
;~ hydrochloric acid and extracted twice with 100 ml. isopropyl ~ ., ether. The aqueous acidic solution was made basic and extracted ,~; .1 .
with isopropyl ether and treated with ethereal hydrogen chloride.
Recrystallization with isopropanol yielded 6 g. of the hydro-, 25 chloride hydrate of the product which melted at 118-120C.
;~ Analysis: Calculated for ClgH~5Cl2~03: C,59.07; H,6.52; N,3.63 ~ Found : C,59.08i H,6.51; ~,~-55 . , .
~ ~ AHR-~10-CIP
` 1077474 :....
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~ Example 5 i ,i,~, ~; 4-(Isopropylamino)-l-(o-methoxyphenoxy~-2-butanol HYdro-~ .
n chloride~ -.;: -~ A mixture which contained 11.6 g. (0.05 mole) of 1-(2-.i.:
`~ ~ethoxyphenoxy)-2-hydroxybutyl chloride, 50 ml. of isopropyl :~, ~t:" amine and 100 ml. of n-butanol was charged in a steel bomb and ~ heated at 120 C. for 24 hr. The resulting reaction mixture ¢ was filtered. The filtrate was concentrated to dryness and ,~/;r mixed with 200 ml. of 3N hydrochloric acid, extracted with ether and the aqueous layer was made basic. The base insoluble oil was extracted into isopropyl ether, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in isopropanol and mixed with 20 ml. ethereal hydrogen chloride.
The gummy precipitate recrystallized using isopropyl ether and isopropanol. The hydrochloride (8.3 g.) melted at 83-85C.
Analysis: Calculated for Cl4E~ClN03: C,58.02; H,8.35; N/4.83 Found : C,57.44; H,8.31; N,4.72 Example 6 (o-Chlorophenoxv)-4-(4-phenyl-1-piperazinyl) 2 -butanol.
A mixture of 35.1 g. (0.15 mole) of 1-(o-chlorophenoxy)-2-~!, 20 hydroxybutyl chloride, 32.6 g. (0.2 mole) of N-phenylpiperazine and 400 ml. of isopropanol was refluxed for 48 hr. The reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and the salt precipitated by the addition of ether.
The white crystalline solid which formed was dissolved in 0.1 mole of hydrochloric ac,id and then neutralized with sodium . ~ .
~ - -20-. .
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~ hydroxide producing a crystalline precipitate. This was : ;:
recrystallized with isopropanol yielding 36 g. of the free base of the product which melted at 100-101.5C.
Analysis: Calculated for C20H25~202Cl: C,66.56; H,6.98; N,7.76 ii 5 Found : C,66.49; H,7.03; N,7.86The physical constants of some representative l-aryloxy-., ~`~ 4-amino-2-butanols made from 1-aryloxy-4-chloro-2-butanols ,:., and a selected amine by processes A, B, C and D are shown in .
~ Table I and Table II.
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. TABLE I - Examples 7 throuqh 72 ~: OH Rl -'` .Ar-O-CH2-CH-CH2-CH2-N~ 2 ,!,. ~ R
Rl .
. Example -N ~ M.P.
Number Ar ~R2 Salt C. Process 7 l-CloH7 -NHCzHs HCl 153-5 A
8 l-CloH7 -NHCeHll HCl 158-60 D
g l-CloH7 . -NOC4H~ a b ~ 54-6 D
l-CloH7 -NOC4H6(CH3)z Hcl H20 118-20 D
.~11 l-CloH7 -N(CH33C~Hll ~ 62-5 D
12 l-CloH7 -NC5Hlo c HCl 135-7 D
1~ l-CloH7 -NHCH2CsHs HCl-H20 83-5 D
14 4-CBH5-CgH4 -NHCH(CH3)2 HCl 190-2 B
3-CH3-4-ClCBH3 -NHCH(CH3)2 ~ 74-6 A
16 3-CF3C6H4 -NHCH(CH3)2 HCl 92-4 B
17 2-CH3-5-ClC6H3 -N(CHj)CH2C~H5 HCl 169-71 C
18 3-CM3-4-ClC6H3 -NH(CH2)2CBHs HCl 16~-5 A
19 2-CH3-4-ClC6H3 -NH(CH~)2C8Hs HCl 128-30 A
2-ClC~H4 -NHC(CH3)zCH20M HCl 117-119 C
21 C~H5 -NH(CH~)~C~Hc HCl 14~-4 D
~' 22 2-CH3-4-ClC~H3 -NCsH9-4-C6Hs HCl 148-50 D
t~ 23 2-CE3-4-ClC6H3 -NC4H8N-C~Hs e di-HCl 186-8 C
24 2-ClC6H4 -NC5HloC HCl 159-60 C
~,~ 25 3-CF3C~H4 -NH(CH2)2C~Hs HCl 131-3 D
26 2-CH3-5-ClCBH4 -NH(CH2)2C6H5 HCl 141 - 3 D
27 3-ClC6H4 -NH(CHz)zCsHs HCl 154-6 D
28 2-CH30CeH4 -NH(CH2)2CBH5 - 112-14 D
~; . 29 C6Hs -NHCH2C~Hs HCl 1/2HzO 108-10 D
2-CH30C8H4 -NHCBHl1 H~O C
~': 31 3-clcsH4 -NHCH2CB~I5 HCl 139-41 D
32 2-CH3-4-Clc~H3 -NcsHlof HCl 149-51 D
33 3~5~CH3CsH3 -NH(CH2)2C6Hs HCl l/2H20 117-20 D
~ 34 3,5-CH3CBH3 -NC4HaN-C8H5 e _ 88-go D
'~, 35 3,5-CH3C6H3 -NCsHlof HCl.l/2H20 141-3 D
,~ 36 3,5~CH3CsH3 -NC5H7-4-C6Hsg HCl 162-4 D
37 3~5-CH3C6H3 -N(CH~)CRHll HCl 158-60 D
8 2-ClCBH4 -NH(C~)2C6Hs h 92-4 D
39 C6H5 -NC4H8N-2-CsH4N di-maleate 123-5 DC6Hs -N(CH3)C6Hll ~ 50-2 D
;;; 41 C6H5 -N(CH3)CH2CsHs maleate 118-20 D
i~s 42 2-CH30C6H4 -N(CH3)C6Hll maleate 109-11 D
43 2-CH30C6H4 -NOC4H6(CH3)2 h ~ _ D
44 2-CH30C6H4 -NC4H8N?-C5H4N 3 HCl 1/2HzO 95-7 D
2-CH30C6H4 -NHCsHg i HCl 112-14 D
46 2-CloH7 -NC5H7-4-C6Hs HCl 168-70 C
47 2-CloH7 -NHCH(CH3)2 ~ 96-98 B
48 4-CH30C6H4 -~(CH3)C6Hll _ 50-2 C
~ (cont.) .. ; - .
.; -22-.
. . .
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: .
` 1~7747~
` Table I (cont.) R
Example N ~ M.P.
Number Ar R Salt C Process :., 49 4-CH3CoNHC6H4 -~IC6Hll ~ 140-2 C
4-CH3cOc6H4 -NHC6Xll ~ 93 5 C
51 l-CloH7 -NHC(CH3)2CH2OH - 98-100 C
52 3,5-CH~C6H3 -NHCloHl5~ HC1 229-31 C
53 5-CsH7 -NHC6Hll ~ 95 7 C
54 5-CsH7 -NHCH(CH3) 2 HCl H2O 103-5 C
2-CH3-5-ClC6H3 -NHC6Hll HCl 189-92 C
56 4-CH3OC6H4 -NHCloHl5~ ~ 78-80 C
57 l-CloH7 -NHCloHlsi HCl 195-7 C
58 l-CloH7 -N(CH3)CsHls HCl 143-5 C
59 4-CH3OCeH4 -NHCH(CH3)2 HCl 118-20 C
4-CH30C6H4 -NHC8Hll HCl 136-8 C
61 5-CsH7k 1 -NHC(CH3)2CH2OH - 9~-5 C
62 5-ClC5H3N -NHC6Hll HCl H20 - C
63 l-CloH7 -N(CH3)CH2CH~OHHCl 115-17 C
64 l-CloH7 1 -NHC5H9 HCl 148-50 D
5-ClC5H3N -NHCH(CH3)z 2HCl H20 174-77 C
66 4-C6H5-C6H4 -NHC(CH3)2CH2OHHCl 155-57 C
67 2-C2H50C6H4 -NHCH2C6H5 HCl 107-7 C
68 2 -C2 H5OC~Hg -NHC6Hll 83-5 C
69 2-C2HsOC6H4 -NC9Hl6m HCl 140-2 C
2-C2HsOC6H4 -NOC~H6(CH3)2 HCl 115-17 D
71 l-CloH7 -NHC5TI~-2-CH3 HCl 176-8 C
72 l-CloH7 -NHC6Hll 96-8 C
j., , a. morpholino b. 3,5-dimethylmorpholinyl c. piperidino d. 4-phenylpiperidino e. 4-phenylpiperazino f. 1,2,3,4-tetrahydroisoquinolyl g. 4-phenyl-1,2,3,6-tetrahydro-1-pyridino h. 4-(2-pyridyl)piperazino i-. cyclopentylamino j. l-adamantylamino k. inden-5-yl 1. 5-chloro-2-pyridyl m. l-decahydroquinoline n. 1-(2,6-dimethyl)morpholino.
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TABLE II -- Analytical Data on Examples 7 through 7?
, . .
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Example Emperical Calculated Found L,',`'`' Number Formula C H ~ C H N
.'.`~,'` .
7 cl6H23clNo2 64.75 7.81 4.7263.97 7.52 4.51 8 c20H~8clNoz 68.65 8.o7 4.oo68.46 8.16 4.03 g cl8H23No3 71.73 7.69 4.6571.59 7.70 4.58 o c20H30ClNo4 62.57 7.88 3.65 62.51 7.68 3.73 ll C21H29NO2 77.02 8.9~ 4.2876.89 8.95 4.17 12 Cl9H26clNo2 67.95 7.80 4.1767.73 7.79 4.o6 13 c2 lH26clNO3 67.10 6.97 3.7367.33 6.89 3.88 4 clgE~6clNO2 67.94 7.80 4.1767.90 7.78 3.72 Cl4H22clNO2 61.87 8.16 5.1561.13 8.os 4.99 16 C14HzlNO2F3Cl 51.30 6.46 4.2751.24 6.42 4.41 17 ClgE~5cl2No2 6l .62 6.803.78 61.42 6.77 3.88 8 ClgH29Cl2NO2 61.62 6.80 3.7861.72 6.89 3.88 9 Cl9H25Cl2NO2 61.62 6.80 3.7861.56 6.68 3.83 0 Cl4EI23NO3cl2 51.86 7.15 4.3251.85 7.17 4.40 cl8E~24No2cl 67.17 7.52 4.3567.22 7.56 4.31 c22Ek9cl2No2 64.39 7.12 3.4164.10 7.28 3.57 23 C2 lE~9cl3N2O2 56.32 6.53 6.25s6.07 6.1~7 6.24 4 clsEI23cl2NO2 56.?6 7.24 1~ 37 56.oo 7.23 4.30 cl9Ek3clF3No2 58-54 5.95 3.595~.35 6.oo 3.75 26 Cl9Ek5cl2No2 61.62 6.80 3.7861.51 6.85 3.64 cl8E~23cl2~oz 60.68 6.51 3.9360.75 6.58 3.9O
8 cl9H25NlO3 72.35 7.79 4.1~4 72.23 7.99 4.39 29 c34H46oscl2N2 64.45 7.32 4.426~.75 7.19 4.66 0 c l7EI2 gNO4 65.57 9.38 4.5065.53 8.86 4.46 31 Cl7E~lCl2NO2 59.67 6.18 4.og59.62 6.23 4.11 2 C20Hz5cl2No2 62.83 6.59 3.6662.52 6.60 3.31 33 c~O~I58cl2~2oS 66.93 8.14 ~.go67.19 8.o3 3.76 34 c2z~30N2o2 74.54 8.53 7.9074.36 8.61 8.o3 c44H58clzN2o5 6s.oo 7.63 3.6668.59 7.72 3.70 36 c23H30No2cl 71.21 7.79 3.6171.26 7.88 3.42 37 cl9H32No2cl 66.7ll 9.434.10 66.72 9.46 3.98 38 c l 8H22 N lo2 cl 1 67.60 6.93 4.38 67.28 6.96 4.37 39 c27H33N3ol0 57.96 5.94 7.5157.71 5.82 7.~0 c 17H27NO2 73.61 9.81 5.0573.32 9.64 4.94 41 c22E~7No6 65.82 6.78 3.4965.84 6.77 3.42 c22H3~No7 62.39 7.85 3.3162.15 7.68 ~ .15 43 cl7H27No4 65.99 8.80 4.5365.15 8.77 4.33 44 c20E~35cl3N3o4 49.21~ 7.238.61 49.18 6.99 8.85 cl6E~6clNo3 60.85 8.30 4.4360.71 8.12 4.34 46 c25H28clNo2 73.25 6.88 3.4272.59 6.99 3.43 47 cl7H23NO2 74.69 8.48 5.1274.21 8.50 5.02 48 cl8H29N3 70.32 9.51 4.5670.15 9.41 4.56 49 cl8E~28N2o3 67.47 8.81 8.7467.35 8.75 8.65 cl8E~7No3 70.79 8.91 4.59- 70.71 8.91 4.76 51 cl8E~5No3 71.26 8.30 4.6271.34 8.23 4.46 .,;, .
,.- I
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-~ Table II ~cont.) . . .
` Example Emperical Calculated Found : Number Formula C H N C H N
,., ~ . .
~¦ 52 Cz2H34clNo2 69.54 9.02 3.69 69.26 8.95 ~.73 ~' 53 C1sH2sN2 75-21 9.63 4.62 75-04 9.55 4.60 ;, 54 C 16H~ 8Cl~03 60.46 8.88 4.41 59-81 8.05 4.47 Cl7Hz6ClNO2 58-79 7-55 4-03 58-54 7-70 3-93 "'!.' 56 C2lH32NO4 69.58 8.90 3.86 6~.29 8.89 4.20 ~-~ 57 C24H35ClNOg 65.96 8.o7 3.20 66.~1 7-85 ~-25 ,~ 58 C23H34C1~O2 70-48 8-73 3-57 69.98 8.64 3.45 'I 59 Cl4H24clNO3 58-02 8.35 4.8~ 57-68 8.27 4.81 -~ 60 C17H~8ClNO3 61.90 8.56 4.25 61.37 8.44 4.01 61 C17H25~03 69.59 9-27 4-77 69.66 9.24 4.65 62 ClsH2ocl2No2 51.00 7.42 7-93 51.19 7.32 8.02 63 C17H24C1~O3 62.67 7.42 4.30 62.58 7.40 4.20 64 Cl9Ha~clNo2 67.94 7.80 4.17 67.76 7.78 4.21 ; 10 65 Cl2H29Cl3N203 41.22 6.63 8.01 42.27 6.27 8.og - 66 CzoH28clNo3 65.65 7-71 3.83 65.37 7-67 3-75 67 ClgH~ClNO3 64.86 7.45 3.98 64.83 7-35 4-23 68 C18H29~3 70.32 9.51 4.56 70.40 9.58 4.59 ;~ 69 C21H34ClNO3 65.69 8.93 3.65 65.78 8-77 3-60 Cl8H30ClNO~ 60.07 8.40 3.89 60.04 8.28 3.81 71 C2OH28NO2cl 68.65 8.o6 4.00 68.28 8.o6 3-85 - 72 Cl~H24NOzCl 64.53 8.12 4.70 64.40 8.17 4-55 . !
,l Example 73 ; 1-(2-Methoxyphenoxy)-4-phthalimido-2-butanol.
A mixture of 24.6 g. (0.1 mole) of 1-(2-methoxyphenoxy)-4-chloro-2-butanol, 18.5 g. (0.1 mole) of potassium phthalimido, 150 ml. of dimethylformamide and 150 ml. of toluene was refluxed f, !
! 20 for 8 hourg The cooled filtered solution was diluted with ~!
~ 500 ml. of water, the toluene layers separated and washed with '~1;
water until the washings were neutral. The product separated ¦ from the washed toluene solution as a crystalline solid which ~¦ was recrystallized from acetone. The recrystallized material ;i~ 25 melted at 108-110 C.
Analysis: Calcd. for Cl9Hl9NOs: C,66.85; H,5.61; N,4.10 Found : C,66.94; H,5.74; N,4.15 ...,~
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'X'' Example 74 1-(2-EthoxyphenoxvL-4-phthalimido-2-b-u-tanol.
~' A mixture of 30 g. (0.12 mole) of 1-(2-ethoxyphenoxy)-4-~,, `~ chloro-2-butanol and 18.5 g. (0.10 mole) of potassium phthalimide ..,,.~, .
was heated slowly to 130 C. for 10 min. and at 160 C. for one hour with stirring. The reaction mixture was extracted with 250 ml. of hot toluene. A crystalline solid separated from the toluene extract when cooled to room temperature. The solid . o was recrystallized from toluene and melted at 93-95 C.
~, Analysis: Calcd. for C20H2lN05: C,67.59; H,5.96; N,3.94 Found : C,67.78; H,6.o3; N,4.o6 ~"' ~'' ' ,, ~, ';
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: The invention further provides pharmaceutical compositions : or administration to a living animal comprising; as active ~; . .
ingredients, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds are thus presented in a fo-rm suitable - for oral, rectal, parenteral or intracardial administration.
Thus, for example, compositions for oral administration are preferably solids and can taXe the form of capsules, tablets or . . , ~ coated tablets containing carriers conveniently used in the ., , 10 pharmaceutical art. Suitable tableting excipients include lactose, potato and maize starches, talc, gelatin and stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.
For parenteral administration, the carrier or excipient can be a sterile, parenterally acceptable liquid, e.g., water, or a 15 parenterally acceptable oil, e.g., arachis oil~ contained in ampoules.
In compositions for rectal administration the carrier can ~ ~ .
comprise a suppository base, e.g., cocoa butter, or a glyceride.
Advantageously, the compositions are formulated as dosage ', 20 units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms X according to the invention. Each dosage unit adapted for oral administration may conveniently contain 10 to 40 mg. of the 25 active ingredient; each dosage unit adapted for intracardial or intravenous administration may conveniently contain 1 to 2 mg.
"
: per cc. of the active ingredient; whereas each dosage unit .
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adapted for intramuscular administration may conveniently contain 5 to 10 mg. per cc. of the active ingredient.
.~.. , - .
~ Examples of compositions within the preferred ranges ~;' given are as follows:
Capsules ~ , . .
~j~ Ingredients Per Cap.
' - 1. Active ingreaient 10.00 mg.
2. Lactose 146.000 mg.
3. Magnesium Stearate 4.000 mg.
.", .
'~Procedure 1. Blend 1, 2 and 3.
2. Mill this blend and blend again.
. This milled blend is then filled into ~1 hard gelatin capsules.
. " ,i .
Tablets Inqredients Mq./Tab.
~l 1. Active ingredient10.0 mg.
''~ 2. Corn Starch 20.0 mg.
,'~ 3. Kelacid 20.0 mg.
',' 4. Keltose 20.0 mg.
,~, 5. Magnesium Stearate1.~ mg.
. ~
~' Procedure ~,'1 1. Blend 1, 2, 3 and 4.
2. Add sufficient water portionwise to the blend from step ,j ~1 with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet ,.~",'.1. granules.
3. The wet mass is converted to yranules by passing it . ! through the oscillating granulator, using 8-mesh screen.
4. The wet granules are then dried in an oven at 140F.
.~ 5. The dried granules are then passed through an oscillating granulator, using a 10-mesh screen.
66 4-C6H5-C6H4 -NHC(CH3)2CH2OHHCl 155-57 C
67 2-C2H50C6H4 -NHCH2C6H5 HCl 107-7 C
68 2 -C2 H5OC~Hg -NHC6Hll 83-5 C
69 2-C2HsOC6H4 -NC9Hl6m HCl 140-2 C
2-C2HsOC6H4 -NOC~H6(CH3)2 HCl 115-17 D
71 l-CloH7 -NHC5TI~-2-CH3 HCl 176-8 C
72 l-CloH7 -NHC6Hll 96-8 C
j., , a. morpholino b. 3,5-dimethylmorpholinyl c. piperidino d. 4-phenylpiperidino e. 4-phenylpiperazino f. 1,2,3,4-tetrahydroisoquinolyl g. 4-phenyl-1,2,3,6-tetrahydro-1-pyridino h. 4-(2-pyridyl)piperazino i-. cyclopentylamino j. l-adamantylamino k. inden-5-yl 1. 5-chloro-2-pyridyl m. l-decahydroquinoline n. 1-(2,6-dimethyl)morpholino.
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TABLE II -- Analytical Data on Examples 7 through 7?
, . .
~.;
Example Emperical Calculated Found L,',`'`' Number Formula C H ~ C H N
.'.`~,'` .
7 cl6H23clNo2 64.75 7.81 4.7263.97 7.52 4.51 8 c20H~8clNoz 68.65 8.o7 4.oo68.46 8.16 4.03 g cl8H23No3 71.73 7.69 4.6571.59 7.70 4.58 o c20H30ClNo4 62.57 7.88 3.65 62.51 7.68 3.73 ll C21H29NO2 77.02 8.9~ 4.2876.89 8.95 4.17 12 Cl9H26clNo2 67.95 7.80 4.1767.73 7.79 4.o6 13 c2 lH26clNO3 67.10 6.97 3.7367.33 6.89 3.88 4 clgE~6clNO2 67.94 7.80 4.1767.90 7.78 3.72 Cl4H22clNO2 61.87 8.16 5.1561.13 8.os 4.99 16 C14HzlNO2F3Cl 51.30 6.46 4.2751.24 6.42 4.41 17 ClgE~5cl2No2 6l .62 6.803.78 61.42 6.77 3.88 8 ClgH29Cl2NO2 61.62 6.80 3.7861.72 6.89 3.88 9 Cl9H25Cl2NO2 61.62 6.80 3.7861.56 6.68 3.83 0 Cl4EI23NO3cl2 51.86 7.15 4.3251.85 7.17 4.40 cl8E~24No2cl 67.17 7.52 4.3567.22 7.56 4.31 c22Ek9cl2No2 64.39 7.12 3.4164.10 7.28 3.57 23 C2 lE~9cl3N2O2 56.32 6.53 6.25s6.07 6.1~7 6.24 4 clsEI23cl2NO2 56.?6 7.24 1~ 37 56.oo 7.23 4.30 cl9Ek3clF3No2 58-54 5.95 3.595~.35 6.oo 3.75 26 Cl9Ek5cl2No2 61.62 6.80 3.7861.51 6.85 3.64 cl8E~23cl2~oz 60.68 6.51 3.9360.75 6.58 3.9O
8 cl9H25NlO3 72.35 7.79 4.1~4 72.23 7.99 4.39 29 c34H46oscl2N2 64.45 7.32 4.426~.75 7.19 4.66 0 c l7EI2 gNO4 65.57 9.38 4.5065.53 8.86 4.46 31 Cl7E~lCl2NO2 59.67 6.18 4.og59.62 6.23 4.11 2 C20Hz5cl2No2 62.83 6.59 3.6662.52 6.60 3.31 33 c~O~I58cl2~2oS 66.93 8.14 ~.go67.19 8.o3 3.76 34 c2z~30N2o2 74.54 8.53 7.9074.36 8.61 8.o3 c44H58clzN2o5 6s.oo 7.63 3.6668.59 7.72 3.70 36 c23H30No2cl 71.21 7.79 3.6171.26 7.88 3.42 37 cl9H32No2cl 66.7ll 9.434.10 66.72 9.46 3.98 38 c l 8H22 N lo2 cl 1 67.60 6.93 4.38 67.28 6.96 4.37 39 c27H33N3ol0 57.96 5.94 7.5157.71 5.82 7.~0 c 17H27NO2 73.61 9.81 5.0573.32 9.64 4.94 41 c22E~7No6 65.82 6.78 3.4965.84 6.77 3.42 c22H3~No7 62.39 7.85 3.3162.15 7.68 ~ .15 43 cl7H27No4 65.99 8.80 4.5365.15 8.77 4.33 44 c20E~35cl3N3o4 49.21~ 7.238.61 49.18 6.99 8.85 cl6E~6clNo3 60.85 8.30 4.4360.71 8.12 4.34 46 c25H28clNo2 73.25 6.88 3.4272.59 6.99 3.43 47 cl7H23NO2 74.69 8.48 5.1274.21 8.50 5.02 48 cl8H29N3 70.32 9.51 4.5670.15 9.41 4.56 49 cl8E~28N2o3 67.47 8.81 8.7467.35 8.75 8.65 cl8E~7No3 70.79 8.91 4.59- 70.71 8.91 4.76 51 cl8E~5No3 71.26 8.30 4.6271.34 8.23 4.46 .,;, .
,.- I
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( 107747~ ~ AHR-3lo-cIp .
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-~ Table II ~cont.) . . .
` Example Emperical Calculated Found : Number Formula C H N C H N
,., ~ . .
~¦ 52 Cz2H34clNo2 69.54 9.02 3.69 69.26 8.95 ~.73 ~' 53 C1sH2sN2 75-21 9.63 4.62 75-04 9.55 4.60 ;, 54 C 16H~ 8Cl~03 60.46 8.88 4.41 59-81 8.05 4.47 Cl7Hz6ClNO2 58-79 7-55 4-03 58-54 7-70 3-93 "'!.' 56 C2lH32NO4 69.58 8.90 3.86 6~.29 8.89 4.20 ~-~ 57 C24H35ClNOg 65.96 8.o7 3.20 66.~1 7-85 ~-25 ,~ 58 C23H34C1~O2 70-48 8-73 3-57 69.98 8.64 3.45 'I 59 Cl4H24clNO3 58-02 8.35 4.8~ 57-68 8.27 4.81 -~ 60 C17H~8ClNO3 61.90 8.56 4.25 61.37 8.44 4.01 61 C17H25~03 69.59 9-27 4-77 69.66 9.24 4.65 62 ClsH2ocl2No2 51.00 7.42 7-93 51.19 7.32 8.02 63 C17H24C1~O3 62.67 7.42 4.30 62.58 7.40 4.20 64 Cl9Ha~clNo2 67.94 7.80 4.17 67.76 7.78 4.21 ; 10 65 Cl2H29Cl3N203 41.22 6.63 8.01 42.27 6.27 8.og - 66 CzoH28clNo3 65.65 7-71 3.83 65.37 7-67 3-75 67 ClgH~ClNO3 64.86 7.45 3.98 64.83 7-35 4-23 68 C18H29~3 70.32 9.51 4.56 70.40 9.58 4.59 ;~ 69 C21H34ClNO3 65.69 8.93 3.65 65.78 8-77 3-60 Cl8H30ClNO~ 60.07 8.40 3.89 60.04 8.28 3.81 71 C2OH28NO2cl 68.65 8.o6 4.00 68.28 8.o6 3-85 - 72 Cl~H24NOzCl 64.53 8.12 4.70 64.40 8.17 4-55 . !
,l Example 73 ; 1-(2-Methoxyphenoxy)-4-phthalimido-2-butanol.
A mixture of 24.6 g. (0.1 mole) of 1-(2-methoxyphenoxy)-4-chloro-2-butanol, 18.5 g. (0.1 mole) of potassium phthalimido, 150 ml. of dimethylformamide and 150 ml. of toluene was refluxed f, !
! 20 for 8 hourg The cooled filtered solution was diluted with ~!
~ 500 ml. of water, the toluene layers separated and washed with '~1;
water until the washings were neutral. The product separated ¦ from the washed toluene solution as a crystalline solid which ~¦ was recrystallized from acetone. The recrystallized material ;i~ 25 melted at 108-110 C.
Analysis: Calcd. for Cl9Hl9NOs: C,66.85; H,5.61; N,4.10 Found : C,66.94; H,5.74; N,4.15 ...,~
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'X'' Example 74 1-(2-EthoxyphenoxvL-4-phthalimido-2-b-u-tanol.
~' A mixture of 30 g. (0.12 mole) of 1-(2-ethoxyphenoxy)-4-~,, `~ chloro-2-butanol and 18.5 g. (0.10 mole) of potassium phthalimide ..,,.~, .
was heated slowly to 130 C. for 10 min. and at 160 C. for one hour with stirring. The reaction mixture was extracted with 250 ml. of hot toluene. A crystalline solid separated from the toluene extract when cooled to room temperature. The solid . o was recrystallized from toluene and melted at 93-95 C.
~, Analysis: Calcd. for C20H2lN05: C,67.59; H,5.96; N,3.94 Found : C,67.78; H,6.o3; N,4.o6 ~"' ~'' ' ,, ~, ';
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: The invention further provides pharmaceutical compositions : or administration to a living animal comprising; as active ~; . .
ingredients, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds are thus presented in a fo-rm suitable - for oral, rectal, parenteral or intracardial administration.
Thus, for example, compositions for oral administration are preferably solids and can taXe the form of capsules, tablets or . . , ~ coated tablets containing carriers conveniently used in the ., , 10 pharmaceutical art. Suitable tableting excipients include lactose, potato and maize starches, talc, gelatin and stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.
For parenteral administration, the carrier or excipient can be a sterile, parenterally acceptable liquid, e.g., water, or a 15 parenterally acceptable oil, e.g., arachis oil~ contained in ampoules.
In compositions for rectal administration the carrier can ~ ~ .
comprise a suppository base, e.g., cocoa butter, or a glyceride.
Advantageously, the compositions are formulated as dosage ', 20 units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms X according to the invention. Each dosage unit adapted for oral administration may conveniently contain 10 to 40 mg. of the 25 active ingredient; each dosage unit adapted for intracardial or intravenous administration may conveniently contain 1 to 2 mg.
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adapted for intramuscular administration may conveniently contain 5 to 10 mg. per cc. of the active ingredient.
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~ Examples of compositions within the preferred ranges ~;' given are as follows:
Capsules ~ , . .
~j~ Ingredients Per Cap.
' - 1. Active ingreaient 10.00 mg.
2. Lactose 146.000 mg.
3. Magnesium Stearate 4.000 mg.
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'~Procedure 1. Blend 1, 2 and 3.
2. Mill this blend and blend again.
. This milled blend is then filled into ~1 hard gelatin capsules.
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Tablets Inqredients Mq./Tab.
~l 1. Active ingredient10.0 mg.
''~ 2. Corn Starch 20.0 mg.
,'~ 3. Kelacid 20.0 mg.
',' 4. Keltose 20.0 mg.
,~, 5. Magnesium Stearate1.~ mg.
. ~
~' Procedure ~,'1 1. Blend 1, 2, 3 and 4.
2. Add sufficient water portionwise to the blend from step ,j ~1 with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet ,.~",'.1. granules.
3. The wet mass is converted to yranules by passing it . ! through the oscillating granulator, using 8-mesh screen.
4. The wet granules are then dried in an oven at 140F.
.~ 5. The dried granules are then passed through an oscillating granulator, using a 10-mesh screen.
6. Lubricate the dry granules with 0.5% magnesium stearate.
7. The lubricated granules are compressed on a suitable tablet press.
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IngreaientsPer ml, :, 1. Active ingredient1.0 mg.
2. pH 4.0 Buffer solution q.s. to 1.0 ml.
~` Procedure 1. Dissolve the active ingredient in the buffer solution.
2. Aseptically filter the solution from step ~1.
3. The sterile solution is now aseptically filled into ;~ sterile ampuls.
. The ampuls are sealed under aseptic conditions.
Intramuscular Injection , .
IngredientsPer ml.
` 1. Active ingredient5.0 mg.
2. Isotonic Buffer solution '~ 4.0 -q.s. to 1.0 ml.
:
Procedure .~, .
~ 1. Dissolve the active ingredient in the buffer solution.
;, 2. Aseptically filter the solution from step #1.
,~;,,f 3. The sterile solution is now aseptically filled into f~ sterile ampuls.
4. The ampuls are sealed under aseptic conditions.
Suppositories . ~, .
~', IngredientsPer SupP.
~'.5;
1. Active ingredient 10.0 mg.
' 2. Polyethylene Glycol 1000 1350.0 mg.
3. Polyethylene Glycol 4000 450.0 mg.
L Procedure 1. Melt 2 and 3 together and stir until uniform.
~" 2. ~issolve #1 in the molten mass from step 1 and stir until uniform.
3. Pour the molten mass from step 2 into supporitory ! molds and chill.
Il, Remove the suppositories from molds and wrap.
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1~77474 Pharmaceutical compositions having cardiac arrhythmia inhibi.ting activity and minimal ~-adrenergic blocking activity, ' - in dosage unit form, comprising a pharmaceutical carrier and a cardiac arrhythmia inhibiting amount of a compound of Formula I
~`- 5 or a pharmaceutically acceptable acid addition salt thereof are ~:: therefore one of the objects of this invention.
* Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, : method, and compositions of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.
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IngreaientsPer ml, :, 1. Active ingredient1.0 mg.
2. pH 4.0 Buffer solution q.s. to 1.0 ml.
~` Procedure 1. Dissolve the active ingredient in the buffer solution.
2. Aseptically filter the solution from step ~1.
3. The sterile solution is now aseptically filled into ;~ sterile ampuls.
. The ampuls are sealed under aseptic conditions.
Intramuscular Injection , .
IngredientsPer ml.
` 1. Active ingredient5.0 mg.
2. Isotonic Buffer solution '~ 4.0 -q.s. to 1.0 ml.
:
Procedure .~, .
~ 1. Dissolve the active ingredient in the buffer solution.
;, 2. Aseptically filter the solution from step #1.
,~;,,f 3. The sterile solution is now aseptically filled into f~ sterile ampuls.
4. The ampuls are sealed under aseptic conditions.
Suppositories . ~, .
~', IngredientsPer SupP.
~'.5;
1. Active ingredient 10.0 mg.
' 2. Polyethylene Glycol 1000 1350.0 mg.
3. Polyethylene Glycol 4000 450.0 mg.
L Procedure 1. Melt 2 and 3 together and stir until uniform.
~" 2. ~issolve #1 in the molten mass from step 1 and stir until uniform.
3. Pour the molten mass from step 2 into supporitory ! molds and chill.
Il, Remove the suppositories from molds and wrap.
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1~77474 Pharmaceutical compositions having cardiac arrhythmia inhibi.ting activity and minimal ~-adrenergic blocking activity, ' - in dosage unit form, comprising a pharmaceutical carrier and a cardiac arrhythmia inhibiting amount of a compound of Formula I
~`- 5 or a pharmaceutically acceptable acid addition salt thereof are ~:: therefore one of the objects of this invention.
* Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, : method, and compositions of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.
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Claims (154)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula ArO-CH2-CHOH-CH2-CH2-NR1R2 (I) and pharmaceutically acceptable acid addition salts thereof wherein;
Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, inden-4 (or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, which is unsubstituted or substituted by up to two radicals selected from the group C1-8 alkyl, C1-8 alkoxy, trifluoromethyl, acetyl, acetylamino, halogen and phenyl, R1 is selected from the group consisting of lower alkyl having one to eight carbon atoms, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl and lower cycloalkyl having five to seven carbon atoms, R2 is selected from hydrogen and lower alkyl, R1 and R2 together with the adjacent nitrogen form a heterocyclic residue which comprises reacting a compound of formula ArO-CH2-CHOH-CH2-CH2-X (V) with a compound of the formula NHR1,R2 wherein Ar, R1 and R2 are as defined above and X is halogen, and where required preparing a pharmaceutically acceptable acid addition salt of the so prepared compound.
Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, inden-4 (or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, which is unsubstituted or substituted by up to two radicals selected from the group C1-8 alkyl, C1-8 alkoxy, trifluoromethyl, acetyl, acetylamino, halogen and phenyl, R1 is selected from the group consisting of lower alkyl having one to eight carbon atoms, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl and lower cycloalkyl having five to seven carbon atoms, R2 is selected from hydrogen and lower alkyl, R1 and R2 together with the adjacent nitrogen form a heterocyclic residue which comprises reacting a compound of formula ArO-CH2-CHOH-CH2-CH2-X (V) with a compound of the formula NHR1,R2 wherein Ar, R1 and R2 are as defined above and X is halogen, and where required preparing a pharmaceutically acceptable acid addition salt of the so prepared compound.
2. A process according to claim 1 wherein in the starting reactants Ar is 1-naphthyl.
3. A process according to claim 1 wherein in the starting reactants Ar is monosubstituted phenyl.
4. A process according to claim 3 wherein in the starting reactants monosubstituted phenyl is 2-methoxyphenyl.
5. A process according to claim 2 wherein in the starting reactants R1 is cyclohexyl and R2 is hydrogen.
6. A process according to claim 2 wherein in the starting reactants R1 is isopropyl and R2 is hydrogen.
7. A process according to claim 2 wherein in the starting reactants R1 is cyclopentyl and R2 is hydrogen.
8. A process according to claim 3 wherein in the starting reactants the monosubstituted phenyl is 2-ethoxyphenyl and R1 and R2 together with the adjacent nitrogen is phthalimido.
9. A process according to claim 1 wherein in the starting reactants Ar is 5-chloro-2-pyridyl, R1 is isopropyl and R2 is hydrogen.
10. A process according to claim 1 wherein 1-0-chlorophenoxy-4-(4-phenyl-1-piperazinyl)-2-butanol is prepared by reacting 1-(0-chlorophenoxy)-2-hydroxybutyl chloride with N-phenylpiperazine
11. A process according to claim 1 wherein 4-morpholino-1-(1-naphthyloxy)-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with morpholine.
12. A process according to claim 1 wherein 4-(3-5-dimethylmorpholinyl)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with 3-5-dimethyl-morpholine.
13. A process according to claim 1 wherein 4-piperidino -1-(1-naphthyloxy)-2 butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with piperidine.
14. A process according to claim 1 wherein 1-(2-methyl-4-chlorophenoxy)-4-(4-phenylpiperidine)-2-butanol is prepared by reacting 1-(2-methyl-4-chlorophenoxy)-2-hydroxybutyl chloride with 4-phenylpiperidine.
15. A process according to claim 1 wherein 1-(2-chlorophenoxy)-4-(4-phenylpiperazino)-2-butanol is prepared by reacting 1-(2-chlorophenoxy-2-hydroxybutyl chloride with 4-phenylpiperazine.
16. A process according to claim-1 wherein 1-(4-chloro-2 methyl phenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol is prepared by reacting 1-(4-chloro-2-methyl phenoxy)-2-hydroxybutyl chloride with 1,2,3,4-tetrahydroisoquinoline.
17. A process according to claim 1 wherein 1-(3,5-dimethylphenoxy)-4-(phenylpiperazino)-2 butanol is prepared by reacting 1-(3,5-dimethylphenoxy)-2-hydroxybutyl chloride with 4-phenyl-piperazine.
18. A process according to claim 1 wherein 1-(3,5-dimethylphenoxy)-4-(4-phenyl-1,2,3,6-tetrahydro-1 pyridino) -2-butanol is prepared by reacting 1-(3,5-dimethylphenoxy)-2 hydroxybutyl chloride with 4-phenyl-1,2,3,6-tetrahydro-1-pyridine.
19. A process according to claim 1 wherein 1-phenoxy-4-(4-(2-pyridyl)piperazino)-2-butanol is prepared by reacting 1-phenoxy-2 hydroxybutyl chloride with 4-(2-pyridyl)-piperazine
20. A process according to claim 1 wherein 1-(2-methoxyphenoxy)-4-(4-(2-pyridyl)piperazino)-2-butanol is prepared by reacting 1-(2-methoxyphenoxy)-2-hydroxybutyl chloride with 4-(2-pyridyl)piperazine.
21. A process according to claim 1 wherein 1-(2-methoxyphenoxy)-4-cyclopentylamino-2-butanol is prepared by reacting 1-(2-methoxyphenoxy)-2-hydroxybutyl chloride with cyclopentyl-amine.
22. A process according to claim 1 wherein 1-(2-naphthyloxy)-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridino)-2-butanol is prepared by reacting 1-(2-naphthyloxy)-2-hydroxybutyl chloride with 4-phenyl-1,2,3,6-tetrahydro-1-pyridine.
23. A process according to claim 1 wherein 1-(4-methoxyphenoxy)-4-adamantylamino)-2-butanol is prepared by reacting 1-(4-methoxyphenoxy)-2-hydroxybutyl chloride with adamantylamine.
24. A process according to claim 1 wherein 1-(1-naphthyloxy)-4-adamantylamino)-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with adamantylamine.
25. A process according to claim 1 wherein 1-(2-ethoxyphenoxy)-4-(1-decahydroquinoline)-2-butanol is prepared by reacting 1-(2-ethoxyphenoxy)-2-hydroxybutyl chloride with 1-decahydroquinoline.
26. A process according to claim 1 wherein 1-(2-ethoxyphenoxy)-4-(1-(2,6-dimethyl)morpholino-2-butanol is prepared by reacting 1-(2-ethoxyphenoxy)-2-hydroxybutyl chloride with 1-(2,6-dimethyl)morpholine.
27. A compound of formula I as defined in claim 1 whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
28. 1-0-chlorophenoxy-4-(4-phenyl-1-piperazinyl)-2-butanol whenever prepared by a process according to claim 10 or by an obvious chemical equivalent thereof.
29. 4-morpholino-1-(1-naphthyloxy)-2 butanol whenever prepared by a process according to claim 11 or by an obvious chemical equivalent thereof.
30. 4-(3-5-dimethylmopholinyl)-1-(1-naphthyloxy)-2-butanol whenever prepared by a process according to claim 12 or by an obvious chemical equivalent thereof.
31. 4-piperidino-1-(1-naphthyloxy)-2 butanol whenever prepared by a process according to claim 13 or by an obvious chemical equivalent thereof.
32. 1-(2-methyl-4-chlorophenoxy)-4-(4-phenylpiperidino)-2-butanol whenever prepared by a process according to claim 14 or by an obvious chemical equivalent thereof.
33. 1-(2-chlorophenoxy)-4-(4-phenylpiperazino)-2-butanol whenever prepared by a process according to claim 15 or by an obvious chemical equivalent thereof.
34. 1-(4-chloro-2 methyl phenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol whenever prepared by a process according to claim 16 or by an obvious chemical equivalent thereof.
35. 1-(3,5-dimethylphenoxy)-4-(4-phenylpiperazino)-2-butanol whenever prepared by a process according to claim 17 or by an obvious chemical equivalent thereof.
36. 1-(3,5-dimethylphenoxy)-4-(4-phenyl-1,2,3,6-tetrahydro-1 pyridino) -2-butanol whenever prepared by a process according to claim 18 or by an obvious chemical equivalent thereof.
37. 1-phenoxy-4-(4-(2-pyridyl)piperazino)-2-butanol whenever prepared by a process according to claim 19 or by an obvious chemical equivalent thereof.
38. 1-(2-methoxyphenoxy)-4-(4-(2-pyridyl)piperazino)-2-butanol whenever prepared by a process according to claim 20 or by an obvious chemical equivalent thereof.
39. 1-(2-methoxyphenoxy)-4-cyclopentylamino-2-butanol whenever pre-pared by a process according to claim 21 or by an obvious chemical equivalent thereof.
40. 1-(2-naphthyloxy)-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridino)-2-butanol whenever prepared by a process according to claim 22 of by an obvious cnemical equivalent thereof.
41. 1-(4-methoxyphenoxy)-4-adamantylamino-2-butanol whenever pre-pared by a process according to claim 23 or by an obvious chemical equivalent thereof.
42. 1-(1-naphthyloxy)-4-adamantylamino)-2-butanol whenever prepared by a process according to claim 24 or by an obvious chemical equivalent thereof.
43. 1-(2-ethoxyphenoxy)-4-(1-decahydroquinoline)-2-butanol whenever prepared by a process according to claim 25 or by an obvious chemical equivalent thereof.
44. 1-(2-ethoxyphenoxy)-4-(1-(2,6-dimethyl)morpholino-2-butanol when-ever prepared by a process according to claim 26 or by an obvious chemical equivalent thereof.
45. A process according to claim 1 wherein 4-isopropylamino-1-(1-naphthyloxy)-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxy-butyl chloride with isopropylamine.
46. A process according to claim 1 wherein 4-(1,2,3,4-tetrahydroiso-quinolin -2-yl)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with 1,2,3,4-tetrahydroisoquinoline.
47. A process according to claim 1 wherein 1-(1-naphthyloxy)-4-phenethylamino-2-butanol is prepared by reacting 1-(1-naphthyloxy)-2-hydroxybutyl chloride with phenethylamine.
48. A process according to claim 1 wherein 1-(2-chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol is prepared by reacting 1-(2-chlorophenoxy)-2-hydroxybutyl chloride with 1,2,3,4-tetrahydroisoquinoline.
49. A process according to claim 1 wherein 4-(isopropylamino)-1-(o-methoxyphenoxy)-2-butanol is prepared by reacting 1-(2-methoxyphenoxy) -2-hydroxybutyl chloride with isopropyl amine.
50. A process according to claim 1 wherein 4-ethylamino-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with ethylamine.
51. A process according to claim 1 wherein 4-cyclohexylamino-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with cyclohexylamine.
52. A process according to claim 1 wherein 4-(N-cyclohexyl-N-methyl-amino)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with N-cyclohexyl-N-methylamine.
53. A process according to claim 1 wherein 4-(benzylamino)-1-(1-naphthloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with benzylamine.
54. A process according to claim 1 wherein 1-(4-phenylphenoxy)-4-(isopropylamine)-2-butanol is prepared by reacting 4-chloro-1-(4-phenyl-phenoxy)-2-butanol with isopropylamine.
55. A process according to claim 1 wherein 1-(4-chloro-3-methylphenoxy) -4-(isopropylamino)-2-butanol is prepared by reacting 4-chloro-1-(4-chloro-3-methylphenoxy)-2-butanol with isopropylamine.
56. A process according to claim 1 wherein 1-(3-trifluoromethylphenoxy) -4-isopropylamino-2-butanol is prepared by reacting 4-chloro-1-(3-tri-fluoromethylphenoxy)-2-butanol with isopropylamine.
57. A process according to claim 1 wherein 1-(2-methyl-5-chlorophenoxy) -4-(N-benzyl-N-methylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-methyl-5-chlorophenoxy)-2-butanol with N-benzyl-N-methylamine.
58. A process according to claim 1 wherein 1-(3-methyl-4-chlorophenoxy) -4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(3-methyl-4-chlorophenoxy)-2-butanol with phenylethylamine.
59. A process according to claim 1 wherein 1-(2-methyl-4-chlorophenoxy) -4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-methyl-4-chlorophenoxy)-2-butanol with phenylethylamine.
60. A process according to claim 1 wherein 1-(2-chlorophenoxy)-4-(t-butanolamino)-2-butanol is prepared by reacting 4-chloro-1-(2-chloro-phenoxy)-2-butanol with t-butanolamine.
61. A process according to claim 1 wherein 1-phenoxy-4-phenylethyl-amino-2-butanol is prepared by reacting 4-chloro-1-phenoxy-2-butanol with phenylethylamine.
62. A process according to claim 1 wherein 4-(phenylethylamino)-1-(3-trifluoromethylphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(3-trifluoromethylphenoxy)-2-butanol with phenylethylamine.
63. A process according to claim 1 wherein 1-(5-chloro-2-methylphenoxy) -4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(5-chloro-4-methylphenoxy)-2-butanol with phenylethylamine.
64. A process according to claim 1 wherein 1-(3-chlorophenoxy)-4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(3-chloro-phenoxy)-2-butanol with phenylethylamine.
65. A process according to claim 1 wherein 1-(2-methoxyphenoxy)-4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-methoxy-phenoxy)-2-butanol with phenylethylamine.
66. A process according to claim 1 wherein 1-phenoxy-4-phenylmethyl-amino-2-butanol is prepared by reacting 4-chloro-1-phenoxy-2-butanol with phenylmethylamine.
67. A process according to claim 1 wherein 4-cyclohexylamino-1-(2-methoxyphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(2-methoxy-phenoxy(-2-butanol with cyclohexylamine.
68. A process according to claim 1 wherein 1-(3-chlorophenoxy)-4-(phenylmethylamino)-2-butanol is prepared by reacting 4-chloro-1-(3-chlorophenoxy)-2-butanol with phenylmethylamine.
69. A process according to claim 1 wherein 1-(3,5-dimethylphenoxy)-4-phenylethylamino-2-butanol is prepared by reacting 4-chloro-1-(3,5-dimethyl-phenoxy)-2-butanol with phenylethylamine.
70. A process according to claim 1 wherein 1-(3,5-dimethylphenoxy)-4-(1,2,3,4-tetrahydroisoquinoyl)-2-butanol is prepared by reacting 4-chloro-1-(3,5-dimethylphenoxy)-2-butanol with 1,2,3,4-tetrahydroisoquinoline.
71. A process according to claim 1 wherein 1-(3,5-dimethylphenoxy)-4-(N-cyclohexyl-N-methylamino)-2-butanol is prepared by reacting 4-chloro-1-(3,5-dimethylphenoxy)-2-butanol with N-cyclohexyl-N-methylamine.
72. A process according to claim 1 wherein 1-(2-chlorophenoxy)-4-(phenylethylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-chloro-phenoxy)-2-butanol with phenylethylamine.
73. A process according to claim 1 wherein 4-(N-cyclohexyl-N-methyl-amino)-1-phenoxy-2-butanol is prepared by reacting 4-chloro-1-phenoxy-2-butanol with N-cyclohexyl-N-methylamine.
74. A process according to claim 1 wherein 4-(N-methyl-N-phenylmethyl-amino)-1-phenoxy-2-butanol is prepared by reacting 4-chloro-1-phenoxy-2-butanol with N-methyl-N-phenylmethylamine.
75. A process according to claim 1 wherein 4-(N-cyclohexyl-N-methyl-amino)-1-(2-methoxyphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(2-methoxyphenoxy)-2-butanol with N-cyclohexyl-N-methylamine.
76. A process according to claim 1 wherein 1-(2-naphthyloxy)-4-(iso-propylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-naphthyloxy)-2-butanol with isopropylamine.
77. A process according to claim 1 wherein 1-(4-methoxyphenoxy)-4-(N-cyclohexyl-N-methylamino)-2-butanol is prepared by reacting 4-chloro-1-(4-methoxyphenoxy)-2-butanol with N-cyclohexyl-N-methylamine.
78. A process according to claim 1 wherein 1-(4-acetylaminophenoxy)-4-(cyclohexylamino)-2-butanol is prepared by reacting 1-(4-acetylamino-phenoxy)-4-chloro-2-butanol with cyclohexylamine.
79. 79. A process according to claim 1 wherein 4-cyclohexylamino-1-(4-acetylphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(4-acetyl-phenoxy)-2-butanol with cyclohexylamine.
80. 80. A process according to claim 1 wherein 1-(1-naphthyloxy)-4-(t-butanolamino)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy) -2-butanol with t-butanolamine.
81. A process according to claim 1 wherein 4-(adamantylamino)-1-(3,5-dimethylphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(3,5-dimethylphenoxy)-2-butanol with adamantylamine.
82. A process according to claim 1 wherein 4-(cyclohexylamino)-1-(inden -5-yl)-2-butanol is prepared by reacting 4-chloro-1-(inden -5-yl)-2-butanol with cyclohexylamine.
83. A process according to claim 1 wherein 1-(inden -5-yl)-4-(iso-propylamino)-2-butanol is prepared by reacting 4-chloro-1-(inden -5-yl)-2-butanol with isopropylamine.
84. A process according to claim 1 wherein 4-(cyclohexylamino)-1-(5-chloro-2-methylphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(5-chloro-2-methylphenoxy)-2-butanol with cyclohexylamine.
85. A process according to-claim 1 wherein 1-(1-naphthyloxy)-4-(N-cyclooctyl-N-methylamino)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with N-cyclooctyl-N-methylamine.
86. A process according to claim 1 wherein 4-(isopropylamino)-1-(4-methoxyphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(4-methoxy-phenoxy)-2-butanol with isopropylamine.
87. A process according to claim 1 wherein 4-(cyclohexylamino)-1-(4-methoxyphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(4-methoxy-phenoxy)-2-butanol with cyclohexylamine.
88. A process according to claim 1 wherein 1-(inden -5-yl)-4-(t-butanolamino)-2-butanol is prepared by reacting 4-chloro-1-(inden -5-yl)-2-butanol with t-butanolamine.
89. A process according to claim 1 wherein 1-(5-chloro-2-pyridyl)-4-(cyclohexylamino)-2-butanol is prepared by reacting 4-chloro-1-(5-chloro-2-pyridyl)-2-butanol with cyclohexylamine.
90. A process according to claim 1 wherein 1-(1-naphthyloxy)-4-(N-methyl-N-ethanolamino)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy)-2-butanol with N-methyl-N-ethanolamine.
91. A process according to claim 1 wherein 4-(cyclopentylamino)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthyloxy) -2-butanol with cyclopentylamine.
92. A process according to claim 1 wherein 1-(-chloro-2-pyridyl)-4-(isopropylamino)-2-butanol is prepared by reacting 4-chloro-1-(5-chloro-2-pyridyl)-2-butanol with isopropylamine.
93. A process according to claim 1 wherein 1-(4-phenylphenoxy)-4-(t-butanolamino)-2-butanol is prepared by reacting 4-chloro-1-(4-phenyphenoxy) -2-butanol with t-butanolamine.
94. A process according to claim 1 wherein 1-(2-ethoxyphenoxy)-4-(phenylmethylamino)-2-butanol is prepared by reacting 4-chloro-1-(2-ethoxy-phenoxy)-2-butanol with phenylmethylamine.
95. A process according to claim 1 wherein 4-(cyclohexylamino)-1-(2-ethoxyphenoxy)-2-butanol is prepared by reacting 4-chloro-1-(2-ethoxy-phenoxy) 2-butanol with cyclohexylamine.
96. A process according to claim 1 wherein 4-(2-methylcyclopentyl-amino)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chloro-1-(1-naphthloxy)-2-butanol with 2-methylcyclopentylamine.
97. A process according to claim 1 wherein 4-(cyclohexylamino)-1-(1-naphthyloxy)-2-butanol is prepared by reacting 4-chlorc-1-(1-naphthyloxy)-2-butanol with cyclohexylamine.
98. A process according to claim 1 wherein 1-(2-methoxyphenoxy)-4-phthalimido -2-butanol is prepared by reacting 1-(2-methoxyphenoxy)-4-chloro-2-butanol with phthalimide.
99. A process according to claim 1 wherein 1-(2-ethoxyphenoxy)-4-phthalimido-2-butanol is prepared by reacting 1-(2-ethoxyphenoxy)-4-chloro -2-butanol with phthalimide.
100. 4-isopropylamino-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 45 or by an obvious chemical equivalent thereof.
101. 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 46 or by an obvious chemical equivalent thereof.
102. 1-(1-naphthyloxy)-4-phenethylamino-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 47 or by an obvious chemical equivalent thereof.
103. 1-(2-chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 48 or by an obvious chemical equivalent thereof.
104. 4-(isopropylamino)-1-(o-methoxyphenoxy)-2-butanol, and pharmaceut-ically acceptable acid addition salts thereof whenever prepared by a process according to claim 49 or by an obvious chemical equivalent thereof.
105. 4-ethylamino-1-(naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 50 or by an obvious chemical equivalent thereof.
106. 4-cyclohexylamino-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 51 or by an obvious chemical equivalent thereof.
107. 4-(N-cyclohexyl-N-methylamino)-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 52 or by an obvious chemical equivalent thereof.
108. 4-(benzylamino)-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 53 or by an obvious chemical equivalent thereof.
109. 1-(4-phenylphenoxy)-4-(isopropylamino)-2-butanol, and pharmaceutic-ally acceptable acid addition salts thereof whenever prepared by a process according to claim 54 or by an obvious chemical equivalent thereof.
110. 1-(4-chloro-3-methylphenoxy)-4-isopropylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 55 or by an obvious chemical equivalent thereof.
111. 1-(3-trifluoromethylphenoxy)-4-isopropylamino-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 56 or by an obvious chemical equivalent thereof.
112. 1-(2-methyl-5-chlorophenoxy)-4-(N-benzyl-N-methylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 57 or by an obvious chemical equivalent thereof.
113. 1-(3-methyl-4-chlorophenoxy)-4-(phenylethylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 58 or by an obvious chemical equivalent thereof.
114. 1-(2-methyl-4-chlorophenoxy)-4-(phenylethylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 59 or by an obvious chemical equivalent thereof.
115. 1-(2-chlorophenoxy)-4-(t-butanolamino)-2-butanol, and pharmaceut-ically acceptable acid addition salts thereof whenever prepared by a process according to claim 60 or by an obvious chemical equivalent thereof.
116. 1-phenoxy-4-phenylethylamino-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 61 or by an obvious chemical equivalent thereof.
117. 4-(phenylethylamino)-1-(3-trifluoromethylphenoxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 62 or by an obvious chemical equivalent thereof.
118. 1-(5-chloro-2-methylphenoxy)-4-(phenylethylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 63 or by an obvious chemical equivalent thereof.
119. 1-(3-chlorophenoxy)-4-(phenylethylamino)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 64 or by an obvious chemical equivalent thereof.
120. 1-(2-methoxyphenoxy)-4-(phenylethylamino)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 65 or by an obvious chemical equivalent thereof.
121. 1-phenoxy-4-phenylmethylamino-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 66 or by an obvious chemical equivalent thereof.
122. 4-cyclohexylamino-1-(2-methoxyphenoxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 67 or by an obvious chemical equivalent thereof.
123. 1-(3-chlorophenoxy)-4-(phenylmethylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 68 or by an obvious chemical equivalent thereof.
124. 1-(3,5-dimethylphenoxy)-4-phenylmethylamino-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 69 or by an obvious chemical equivalent thereof.
125. 1-(3,5-dimethylphenoxy)-4-(1,2,3,4-tetrahydroisoquinoyl-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 70 or by an obvious chemical equivalent thereof.
126. 1-(3,5-dimethylphenoxy)-4-(N-cyclohexyl-N-methylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever pre-pared by a process according to claim 71 or by an obvious chemical equivalent thereof.
127. 1-(2-chlorophenoxy)-4-(phenylethylamino)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 72 or by an obvious chemical equivalent thereof.
128. 4-(N-cyclohexyl-N-methylamino)-1-phenoxy-2-butanol, and pharmaceut-ically acceptable acid addition salts thereof whenever prepared by a process according to claim 73 or by an obvious chemical equivalent thereof.
129. 4-(N-methyl-N-phenylmethvlamino)-1-phenoxy-2-butanol, and pharm-aceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 74 or by an obvious chemical equivalent thereof.
130. 4-(N-cyclohexyl-N-methylamino)-1-(2-methoxyphenoxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 75 or by an obvious chemical equivalent thereof.
131. 1-(2-naphthyloxy)-4-(isopropylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 76 or by an obvious chemical equivalent thereof.
132. 1-(4-methoxyphenoxy)-4-(N-cyclohexyl-N-methylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 77 or by an obvious chemical equivalent thereof.
133. 1-(4-acetylaminophenoxy)-4-(cyclohexylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 78 or by an obvious chemical equivalent thereof.
134. 4-cyclohexylamino-1-(4-acetylphenoxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 79 or by an obvious chemical equivalent thereof.
135. 1-(1-naphthoxy)-4-(t-butanolamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 80 or by an obvious chemical equivalent thereof.
136. 4-(adamantylamino)-1-(3,5-dimethylphenoxy)-2-butanol, and pharm-aceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 81 or by an obvious chemical equivalent thereof.
137. 4-(cyclohexylamino)-1-(inden-5-yl)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 82 or by an obvious chemical equivalent thereof.
138. 1-(inden-5-yl)-4-(isopropylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 83 or by an obvious chemical equivalent thereof.
139. 4-(cyclohexylamino)-1-(5-chloro-2-methylphenoxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 84 or by an obvious chemical equivalent thereof.
140. 1-(1-naphthyloxy)-4-(N-cyclooctyl-N-methylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 85 or by an obvious chemical equivalent thereof.
141. 4-(isopropylamino)-1-(4-methoxyphenoxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 86 or by an obvious chemical equivalent thereof.
142. 4-(cyclohexylamino)-1-(4-methoxyphenoxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 87 or by an obvious chemical equivalent thereof.
143. 1-(inden-5-yl)-4-(t-butanolamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 88 or by an obvious chemical equivalent thereof.
144. 1-(5-chloro-2-pyrdiyl)-4-(cyclohexylamino)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 89 or by an obvious chemical equivalent thereof.
145. 1-(1-naphthyloxy)-4-(N-methyl-N-ethanolamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 90 or by an obvious chemical equivalent thereof.
146. 4-(cyclopentylamino)-1-(1-naphthyloxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 91 or by an obvious chemical equivalent thereof.
147. 1-(5-chloro-2-pyridyl)-4-(isopropylamino)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 92 or by an obvious chemical equivalent thereof.
148. 1-(4-phenylphenoxy)-4-(t-butanolamino)-2-butanol, and pharm-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 93 or by an obvious chemical equivalent thereof.
149. 1-(2-ethoxyphenoxy)-4-(phenylmethylamino)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 94 or by an obvious chemical equivalent thereof.
150. 4-(cyclohexylamino)-1-(2-ethoxyphenoxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 95 or by an obvious chemical equivalent thereof.
151. 4-(2-methylcyclopentylamino)-1-(1-naphthyloxy)-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 96 or by an obvious chemical equivalent thereof.
152. 4-(cyclohexylamino)-1-(1-naphthyloxy)-2-butanol, and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 97 or by an obvious chemical equivalent thereof.
153. 1-(2-methoxyphenoxy)-4-phthalamido-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 98 or by an obvious chemical equivalent thereof.
154. 1-(2-ethoxyphenoxy)-4-phthalimido-2-butanol, and pharmaceutically acceptable acid addition salts thereof whenever prepared by a process according to claim 99 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA312,946A CA1084507A (en) | 1974-10-25 | 1978-10-10 | 1-aryloxy-4-amino-2-butanols |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51812274A | 1974-10-25 | 1974-10-25 | |
| US61898475A | 1975-10-02 | 1975-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077474A true CA1077474A (en) | 1980-05-13 |
Family
ID=27059352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA238,243A Expired CA1077474A (en) | 1974-10-25 | 1975-10-24 | 1-aryloxy-4-amino-2-butanols |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS6023100B2 (en) |
| AU (1) | AU507312B2 (en) |
| BR (1) | BR7506930A (en) |
| CA (1) | CA1077474A (en) |
| CH (1) | CH612907A5 (en) |
| DE (1) | DE2547570A1 (en) |
| DK (1) | DK154288C (en) |
| ES (1) | ES442077A1 (en) |
| FI (1) | FI60201C (en) |
| FR (2) | FR2289169A1 (en) |
| GB (1) | GB1520931A (en) |
| HU (1) | HU172525B (en) |
| IE (1) | IE43402B1 (en) |
| IL (1) | IL48309A (en) |
| IN (1) | IN142736B (en) |
| NL (1) | NL7512488A (en) |
| NO (1) | NO142666C (en) |
| NZ (1) | NZ178962A (en) |
| PH (2) | PH16403A (en) |
| SE (2) | SE434047B (en) |
| YU (1) | YU39950B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE115953T1 (en) * | 1987-12-11 | 1995-01-15 | Mitsui Petrochemical Ind | AMINE AND THEIR USE. |
| DE4108527A1 (en) * | 1991-03-15 | 1992-09-17 | Basf Ag | NEW 1- (4-CYANO-4-ARYL-CYCLOHEXYL) PIPERAZINE, THEIR PRODUCTION AND USE |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1245148A (en) * | 1968-11-18 | 1971-09-08 | Pfizer Ltd | Propanolamine derivatives |
| SE384853B (en) * | 1972-04-04 | 1976-05-24 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF NEW AMINES |
| DE2001431C3 (en) * | 1970-01-06 | 1974-12-12 | Helopharm W. Petrik & Co Kg, 1000 Berlin | 2- (2'-Hydroxy-3'-alkylaminopropoxy) -Omega-phenyl-propiophenones and processes for making the same |
| HU169464B (en) * | 1974-02-20 | 1976-11-28 |
-
1975
- 1975-10-15 IL IL48309A patent/IL48309A/en unknown
- 1975-10-16 NZ NZ178962A patent/NZ178962A/en unknown
- 1975-10-16 AU AU85778/75A patent/AU507312B2/en not_active Ceased
- 1975-10-20 CH CH1358275A patent/CH612907A5/en not_active IP Right Cessation
- 1975-10-22 HU HU75RO00000864A patent/HU172525B/en unknown
- 1975-10-22 PH PH17681A patent/PH16403A/en unknown
- 1975-10-23 DE DE19752547570 patent/DE2547570A1/en not_active Ceased
- 1975-10-23 BR BR7506930*A patent/BR7506930A/en unknown
- 1975-10-23 GB GB43649/75A patent/GB1520931A/en not_active Expired
- 1975-10-23 FI FI752966A patent/FI60201C/en not_active IP Right Cessation
- 1975-10-24 SE SE7511934A patent/SE434047B/en not_active IP Right Cessation
- 1975-10-24 YU YU2694/75A patent/YU39950B/en unknown
- 1975-10-24 FR FR7532695A patent/FR2289169A1/en active Granted
- 1975-10-24 NO NO753575A patent/NO142666C/en unknown
- 1975-10-24 CA CA238,243A patent/CA1077474A/en not_active Expired
- 1975-10-24 IE IE2328/75A patent/IE43402B1/en unknown
- 1975-10-24 ES ES442077A patent/ES442077A1/en not_active Expired
- 1975-10-24 NL NL7512488A patent/NL7512488A/en not_active Application Discontinuation
- 1975-10-24 DK DK480675A patent/DK154288C/en active
- 1975-10-25 JP JP50128804A patent/JPS6023100B2/en not_active Expired
- 1975-12-30 IN IN2411/CAL/75A patent/IN142736B/en unknown
-
1976
- 1976-12-22 FR FR7638732A patent/FR2361888A1/en active Granted
-
1979
- 1979-05-04 SE SE7903894A patent/SE449357B/en not_active IP Right Cessation
-
1980
- 1980-10-02 PH PH24655A patent/PH16233A/en unknown
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