CA2065450A1 - Substituted 2-aminotetralins - Google Patents
Substituted 2-aminotetralinsInfo
- Publication number
- CA2065450A1 CA2065450A1 CA002065450A CA2065450A CA2065450A1 CA 2065450 A1 CA2065450 A1 CA 2065450A1 CA 002065450 A CA002065450 A CA 002065450A CA 2065450 A CA2065450 A CA 2065450A CA 2065450 A1 CA2065450 A1 CA 2065450A1
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- Canada
- Prior art keywords
- group
- oxygen
- compound
- propyl
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
Optically active or racemic compounds are provided having formula (I). Wherein the radicals R1, R2, R3, R4, R6, X and N
are defined in the specification. These compounds are optically active or racemic mixtures capable of binding selectively one or more dopamine D2 receptors, for instance in humans. They are useful in treatment of disorders of the central nervous, cardiovascular, and endocrine systems such as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
are defined in the specification. These compounds are optically active or racemic mixtures capable of binding selectively one or more dopamine D2 receptors, for instance in humans. They are useful in treatment of disorders of the central nervous, cardiovascular, and endocrine systems such as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
Description
WO91/00727 za ~ PCT/US~0/03761 Back~round of the Invention Field of the Invent on The invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing anorexia and weight loss in mammals.
Backaround of the Prior Art It is known that various hydroxylated 2-aminotetralins of the general formula ~ ~ 2 (OH)n where Rl and R2 are saturated alkyl groups and n i5 1 or 2, are dopamine receptor agonists (McDermed et al., J. Med.
Chem. 18, 362 (1975); Feenstra et al., Arch. Pharmacol.
313, 213 (1980).
.. . ~ . . , ~, ~ , ;, , " .:
- - : , :: . .
. ~ . . . .
- : . : ,: , , ~ ,' ,. , -- - - - - . .
WO 91/007'~7 PCr/( IS90/0376~
5~
Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Druqs of the Future, Vol. 12, No. 3, 1987, 223-253. Based upon the high activity of apomorphine, many derivatives and simplified structural analogues have been tested and found to have dopaminergic activity. For instance, some of the bicyclic analogues of dopamine, 2-amino-5,6- and 2-amino-6,7-di-hydroxytetralin, and their N-alkylated derivatives were tested and showed activity.
In addition, studies have shown that the 5-hydroxy derivatives of 2-aminotetralins possess high potency almost equivalent to that of the 5,6 catechols, with the additional advantage o~ increased stability, selectivity and duration of biochemical action. These studies have also shown that in bicyclic compounds the size of the two nitrogen substituents controls activity. ~or instznce, the N-butyl and N,N-dibutyl derivatives of 2-amino-5,6-dihydroxytetralin, dopamine and norapomorphine have little or no dopaminergic activity, while analogues having at least one N-ethyl or N-n-propyl group possess high activity~
Further studies have shown that the D2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, becaus~ of size constrain~ max.l~ ccommodates an n-propyl grollp.
Conversely, activity drops off when the propyl group is replac~d by the smaller groups ethyl or methyl. When the ,, . . , , , ::
- . . . : :
. ~ . , ~ :
.: - - . . . . . .. : .. ..... . .
wosl/oo727 2~ 5~ PCT/~S90/03761 compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
; However, the structural requirements for the second N-substituent in such compounds have not been established.
Consequently, the search continues for new and better N-substituents to enhance both dopamine receptor binding and activity, especially as shown by in vivo studies designed to test the dopaminergic activity of compounds, such as contralateral turnlng studies in 6-OH-DA-lesioned rats.
See Seiler, Max P., et al., "Structure-Activity Relationships o~ Dopaminergic 5-~ydroxy-2-aminotetralin Derivatives with Functionalized N-Al~yl Substituents." J.
Med. Chem. 1~86, 29, 912-917.
., The receptor site into which this second N-substituent is thought to interact appea~s to accommodate a wide variety of large, bulky groups having different functionalities without lcss of activity. See McDermed, J.
D., et al., J. Med. Chem. 1975, 18, 362; Cannon, J. G., et al., J. Med. Chem. 1977, 20, 1111; and Wikstroem, H., et al., J. Med. Chem. 1982, 25, 925. However, the dopaminergic activity and potency conferred upon the compound by the choice of the second N-substituent is at present, unpredictable so that the search continues for new and better dopa~ine receptor agonists, especially for compounds showing a high degree of selectivity and specificity as either Dl or D2 receptor agonists.
,.. .... .. .. . . .... .. . . . . . .
;, , , . , . ,,, ~ ,, :
-summarv of the Invention There has now been discovered certain novel compounds having dopaminergic activity and having the structural formula ,~
_ ~ .
where R2, R3 and R~ are each selected from the group con-sisting cf H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is H
or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals optionally substituted with aromatic residues (i.e. methyl, ethyl, O O
propyl, benzyl, etc.), as well as -~-R5, -CNHR5, and -C-OR5.
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl, optionally substitued with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consistiny of -CH2-, oxygen, sulfur, and nitroaen. ~ith the provision that when X is not -CH2-, R1 is selected from the group consisting of . , . .. , . ............ . : . . . .
: ~ . - ~ ~.. ., ,: - . . , , . , -. . :
. WO91/00727 2 ~ 5 ~ PCT/US90/03761 (Y)a ~ N ~
z N~(Y)a (Y) wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoro-methyl, sulfate, sulfonamido, halogen, hydrocarbyl, and :
hetero ato~-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to ~; and~with the further provision that when X is -CH2-, R1 is either -C-Aryl or -C~-Z-Aryl ~R8 IR8 Rg Rg wherein R8 is hydrogen, aryl, or R6; and further wherein Rg O O
is aryl, R6, -OH, -NH2, -OR6, -C-OR6, -OCR6 or -NtR6)2;
or Rl is (`t' ) S~lf3STlTUTE SHEE~ ~
- - . - . . . . .
- , . ~ . , . ` . .. ~ . . , . . . ~ ... . . . ..
. `~ .---, . ~ , :. . ':
.
. . . . . . :
.. . . .
-: . . :. , . .- . : , Z~5~5') wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
It is essential that the compounds in the present invention be an optically active compound or racemic mixture thereof having substantial affinity and selectivity for binding to dopamin~ D2 receptors, e.g., in a human. In particular, it is found that 2-(N-n-propyl,N-2-~phenyloxy]ethylamino)-5-hydroxytetralin is especially preferred for its hish affinity and selectivity for binding to dopamine D2 receptors.
Detailed Description of the Invention The compounds used in the present invention are selected from the group of steroisomers or mixtures thereof of compounds having dopaminergic activity represented by the formula:
.... .
~ /(cn2) where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of P~. R~ and R4 is H, that R2 and R4 are not both OA; A ic H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals, optionally w091/00727 ~ PCT/US9~/03761 substituted with aromatic residues (i.e. methyl, ethyl, o o o Il 11 ll propyl, be~zyl, etc.), -C-R5, -CNHR5, and -~OR5.
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl residues optionaliy subs~i~uted with aromatic residues and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 or 4; R6 is an al~yl chain comprising between 1 and 4 carbon atoms; X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of )~ ~ (Y)a ~ (Y)a ~ N
(Y ja 'Y' ~,11 ,~ (Y'a l~ ,~
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the arolln ~nC;c~ina of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radi~.als comprise from 1 to 12, preferably 1 to 6, carbon atoms, and a is an integer of from zexo to 3, for ~ U8 5-iiT U ~ E ~-~_E~I
. . . .: , . . .
.
.
wo 91/00727 2~;.~'-i~ PCI/IJS90/03761 instance zero to 2; and with the further provision that when X is -CH2-, R1 is either -C-Aryl or -C-Z-Aryl Rg Rg wherein R8 is hydrogen, aryl, or R6; and further wherein Rg O O
Il 11 is aryl, R6, -OH, -NH2, -OR6, -C-OR6, -OCR6 or -N(R6)2;
or R1 is O
_~ \F B
,~
~1 (Y)a wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl, t-butyl, o-methylphenyl, o-, m- or p-methoxyphenyl, p-isopropyl-phenyl or nonyl.
The more preferxed groups represented by R1 are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2-thienyl, 3-thienyl, 3-hydroxyphenyl, 4-hydroxyphenyl, etc.
In the more preferred compounds for use in the present invention n is 2, X is oxygen or ~CH2- and R2 is OA; and most preferably A is H and R6 is propyl.
~5~ ~ 5~1T ~
.. . .. . ....... :
. . . ....
WO91/00727 ~ PCT/US90/037fi~
~ 3 _g _ It is essential that the compounds herein be an optically active or racemic mixtures capable of binding selectively to one or more dopamine D2 receptors, e.g., in a human. In particular, 2-(N-n-propyl,N-2-[phenyloxy]
ethylamino)-5-hydroxytetralin is an especially preferred compound because of its high affinity and selectivity for binding to D2 dopamine receptors. Due to their high affinity for binding to D2 dopamine receptors, it is believed that the compounds herein will be useful in the treatment of disorders of the central nervous, cardiovascular, and endocrine systems. In particular it is believed that the compounds herein are useful in the treatment of such conditions in humans as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
Particularly preferred compounds are as follows:
Compounds wherein X is oxygen, nitrogen or sulfur and R
is selected from the group consisting of radicals represented by the general formula:
~ (Y)a wherein specific preferred compounds of this group include:
Backaround of the Prior Art It is known that various hydroxylated 2-aminotetralins of the general formula ~ ~ 2 (OH)n where Rl and R2 are saturated alkyl groups and n i5 1 or 2, are dopamine receptor agonists (McDermed et al., J. Med.
Chem. 18, 362 (1975); Feenstra et al., Arch. Pharmacol.
313, 213 (1980).
.. . ~ . . , ~, ~ , ;, , " .:
- - : , :: . .
. ~ . . . .
- : . : ,: , , ~ ,' ,. , -- - - - - . .
WO 91/007'~7 PCr/( IS90/0376~
5~
Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Druqs of the Future, Vol. 12, No. 3, 1987, 223-253. Based upon the high activity of apomorphine, many derivatives and simplified structural analogues have been tested and found to have dopaminergic activity. For instance, some of the bicyclic analogues of dopamine, 2-amino-5,6- and 2-amino-6,7-di-hydroxytetralin, and their N-alkylated derivatives were tested and showed activity.
In addition, studies have shown that the 5-hydroxy derivatives of 2-aminotetralins possess high potency almost equivalent to that of the 5,6 catechols, with the additional advantage o~ increased stability, selectivity and duration of biochemical action. These studies have also shown that in bicyclic compounds the size of the two nitrogen substituents controls activity. ~or instznce, the N-butyl and N,N-dibutyl derivatives of 2-amino-5,6-dihydroxytetralin, dopamine and norapomorphine have little or no dopaminergic activity, while analogues having at least one N-ethyl or N-n-propyl group possess high activity~
Further studies have shown that the D2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, becaus~ of size constrain~ max.l~ ccommodates an n-propyl grollp.
Conversely, activity drops off when the propyl group is replac~d by the smaller groups ethyl or methyl. When the ,, . . , , , ::
- . . . : :
. ~ . , ~ :
.: - - . . . . . .. : .. ..... . .
wosl/oo727 2~ 5~ PCT/~S90/03761 compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
; However, the structural requirements for the second N-substituent in such compounds have not been established.
Consequently, the search continues for new and better N-substituents to enhance both dopamine receptor binding and activity, especially as shown by in vivo studies designed to test the dopaminergic activity of compounds, such as contralateral turnlng studies in 6-OH-DA-lesioned rats.
See Seiler, Max P., et al., "Structure-Activity Relationships o~ Dopaminergic 5-~ydroxy-2-aminotetralin Derivatives with Functionalized N-Al~yl Substituents." J.
Med. Chem. 1~86, 29, 912-917.
., The receptor site into which this second N-substituent is thought to interact appea~s to accommodate a wide variety of large, bulky groups having different functionalities without lcss of activity. See McDermed, J.
D., et al., J. Med. Chem. 1975, 18, 362; Cannon, J. G., et al., J. Med. Chem. 1977, 20, 1111; and Wikstroem, H., et al., J. Med. Chem. 1982, 25, 925. However, the dopaminergic activity and potency conferred upon the compound by the choice of the second N-substituent is at present, unpredictable so that the search continues for new and better dopa~ine receptor agonists, especially for compounds showing a high degree of selectivity and specificity as either Dl or D2 receptor agonists.
,.. .... .. .. . . .... .. . . . . . .
;, , , . , . ,,, ~ ,, :
-summarv of the Invention There has now been discovered certain novel compounds having dopaminergic activity and having the structural formula ,~
_ ~ .
where R2, R3 and R~ are each selected from the group con-sisting cf H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is H
or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals optionally substituted with aromatic residues (i.e. methyl, ethyl, O O
propyl, benzyl, etc.), as well as -~-R5, -CNHR5, and -C-OR5.
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl, optionally substitued with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consistiny of -CH2-, oxygen, sulfur, and nitroaen. ~ith the provision that when X is not -CH2-, R1 is selected from the group consisting of . , . .. , . ............ . : . . . .
: ~ . - ~ ~.. ., ,: - . . , , . , -. . :
. WO91/00727 2 ~ 5 ~ PCT/US90/03761 (Y)a ~ N ~
z N~(Y)a (Y) wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoro-methyl, sulfate, sulfonamido, halogen, hydrocarbyl, and :
hetero ato~-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to ~; and~with the further provision that when X is -CH2-, R1 is either -C-Aryl or -C~-Z-Aryl ~R8 IR8 Rg Rg wherein R8 is hydrogen, aryl, or R6; and further wherein Rg O O
is aryl, R6, -OH, -NH2, -OR6, -C-OR6, -OCR6 or -NtR6)2;
or Rl is (`t' ) S~lf3STlTUTE SHEE~ ~
- - . - . . . . .
- , . ~ . , . ` . .. ~ . . , . . . ~ ... . . . ..
. `~ .---, . ~ , :. . ':
.
. . . . . . :
.. . . .
-: . . :. , . .- . : , Z~5~5') wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
It is essential that the compounds in the present invention be an optically active compound or racemic mixture thereof having substantial affinity and selectivity for binding to dopamin~ D2 receptors, e.g., in a human. In particular, it is found that 2-(N-n-propyl,N-2-~phenyloxy]ethylamino)-5-hydroxytetralin is especially preferred for its hish affinity and selectivity for binding to dopamine D2 receptors.
Detailed Description of the Invention The compounds used in the present invention are selected from the group of steroisomers or mixtures thereof of compounds having dopaminergic activity represented by the formula:
.... .
~ /(cn2) where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of P~. R~ and R4 is H, that R2 and R4 are not both OA; A ic H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals, optionally w091/00727 ~ PCT/US9~/03761 substituted with aromatic residues (i.e. methyl, ethyl, o o o Il 11 ll propyl, be~zyl, etc.), -C-R5, -CNHR5, and -~OR5.
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl residues optionaliy subs~i~uted with aromatic residues and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 or 4; R6 is an al~yl chain comprising between 1 and 4 carbon atoms; X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of )~ ~ (Y)a ~ (Y)a ~ N
(Y ja 'Y' ~,11 ,~ (Y'a l~ ,~
wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the arolln ~nC;c~ina of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radi~.als comprise from 1 to 12, preferably 1 to 6, carbon atoms, and a is an integer of from zexo to 3, for ~ U8 5-iiT U ~ E ~-~_E~I
. . . .: , . . .
.
.
wo 91/00727 2~;.~'-i~ PCI/IJS90/03761 instance zero to 2; and with the further provision that when X is -CH2-, R1 is either -C-Aryl or -C-Z-Aryl Rg Rg wherein R8 is hydrogen, aryl, or R6; and further wherein Rg O O
Il 11 is aryl, R6, -OH, -NH2, -OR6, -C-OR6, -OCR6 or -N(R6)2;
or R1 is O
_~ \F B
,~
~1 (Y)a wherein B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
Preferably, R2 is OA and A is H.
A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl, t-butyl, o-methylphenyl, o-, m- or p-methoxyphenyl, p-isopropyl-phenyl or nonyl.
The more preferxed groups represented by R1 are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2-thienyl, 3-thienyl, 3-hydroxyphenyl, 4-hydroxyphenyl, etc.
In the more preferred compounds for use in the present invention n is 2, X is oxygen or ~CH2- and R2 is OA; and most preferably A is H and R6 is propyl.
~5~ ~ 5~1T ~
.. . .. . ....... :
. . . ....
WO91/00727 ~ PCT/US90/037fi~
~ 3 _g _ It is essential that the compounds herein be an optically active or racemic mixtures capable of binding selectively to one or more dopamine D2 receptors, e.g., in a human. In particular, 2-(N-n-propyl,N-2-[phenyloxy]
ethylamino)-5-hydroxytetralin is an especially preferred compound because of its high affinity and selectivity for binding to D2 dopamine receptors. Due to their high affinity for binding to D2 dopamine receptors, it is believed that the compounds herein will be useful in the treatment of disorders of the central nervous, cardiovascular, and endocrine systems. In particular it is believed that the compounds herein are useful in the treatment of such conditions in humans as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
Particularly preferred compounds are as follows:
Compounds wherein X is oxygen, nitrogen or sulfur and R
is selected from the group consisting of radicals represented by the general formula:
~ (Y)a wherein specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[2-thienyloxyJethylamino)-5-hydroxy-tetralin, 2-(N-n-propyl-N-2-[3-thienyloxy]ethylamino)-5-hydroxy-tetralin, 2-(N-n-propyl-N-2-[2-furanyloxy]ethylamino)-5-hydroxy-tetralin, : . : , , . , ., .: : ~ , .
.
WQ91/00727 PCT/~IS90tO3761 ;~r~-4s~ 1 2-(N-n-propyl-N-2-[3-furanyloxy]ethylamino)-5-hydroxy-tetralin, 2-(N-n-propyl-N-2-[2-(4-methyl)thienyloxy]ethylamino-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(3,4,5-trimethyl)thienyloxy]
ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(5-chloro)thienyloxy]~thylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(4-bromo-5-methyl)thienyloxy]
ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(4-methyl-5-ethyl)thienyloxy]
ethylamino)-5-hydroxytetralin, Compounds wherein X is oxygen, nitrogen or sulfur and wherein R1 is selected from the group of radicals represented by the formulae: `
--~(Y~ (Y~
More preferably, in these compounds Y comprises no more than 5 carbon atoms and a is an integer from 0 to 2.
Specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[2-naphthalenyloxy]ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[4-indolyloxy]ethylamino)-5-hydroxy- :~
tetralin, 2-(N-n-propyl-N-2-[2-benzothienyloxy]ethylamino)-5-hydroxytetralin, and 2-(N-n-propyl-N-2-[3-benzothienyloxy]ethylamino)-5-hydroxytetralin;
- ~ - - -.
:, . .
,- . : : - . , .:
- ~ . . . . . . . .
.... , . ~ . . . . . . .
- WO 91tO~727 ~ 5~ PCT/US90/03761 Compounds wherein R1 is phenyl and/or substituted phenyl and is selected from the group of radicals repre-sented ~y the formula:
~ ~ (Y)a and wherein x is oxygen, nitrogen or sulfur. Specific preferred compounds of this group include:
2-(N~n-propyl-N-2-[phenyloxy~ethylamino) 5-hydroxy-tetralln, 2-(N-n-propyl-N-2-[4-hydroxyphenyloxy]ethylamino)-S-hydroxytetralin, and 2-(N-n-propyl-N-2-[3-hydroxyphenyloxy]ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-~-2-[phenyloxy]ethylamino)-5-methoxytetralin 2-(N-n-propyl-N-2-[phenylamino]ethylamino)-5-hydroxytetralin 2-(N-n-propyl-~-2-[4-hydroxyphenylamino]ethylamino)-5-hydroxytetralin 2-(N-n-propyl-~-3-[phenyloxy]propylamino)-5-hydroxytetralin ~ 2-(N-n-propyl-N-2-[2,6-dimethylphenyloxy]ethylamino)-: 5-hydroxytetralin 2-(N-n-propyl-N-2-[3,5-dimethylphenyloxy)ethylamino)-5-hydroxytetralin - Compounds wherein X is -CH2- and R1 is selected from the group consisting of radicals represented by the following formulae:
~ ~ -C Aryl, or -C-Z - Aryl R ~R8 /) ' "
~1~
(Y '`
~ 3sTllTuTE SHEET
~.. . . . ~ . ............ . .
.: `- '' . ' .. ~ . ` `:` `
:. : ,' ~ -wosl/oo727 PCT/US90/03761 ;~r~ 5-~ -and wherein B is 0, S, or H2. Specific preferred compounds in this group include:
.
WQ91/00727 PCT/~IS90tO3761 ;~r~-4s~ 1 2-(N-n-propyl-N-2-[3-furanyloxy]ethylamino)-5-hydroxy-tetralin, 2-(N-n-propyl-N-2-[2-(4-methyl)thienyloxy]ethylamino-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(3,4,5-trimethyl)thienyloxy]
ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(5-chloro)thienyloxy]~thylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(4-bromo-5-methyl)thienyloxy]
ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[2-(4-methyl-5-ethyl)thienyloxy]
ethylamino)-5-hydroxytetralin, Compounds wherein X is oxygen, nitrogen or sulfur and wherein R1 is selected from the group of radicals represented by the formulae: `
--~(Y~ (Y~
More preferably, in these compounds Y comprises no more than 5 carbon atoms and a is an integer from 0 to 2.
Specific preferred compounds of this group include:
2-(N-n-propyl-N-2-[2-naphthalenyloxy]ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-N-2-[4-indolyloxy]ethylamino)-5-hydroxy- :~
tetralin, 2-(N-n-propyl-N-2-[2-benzothienyloxy]ethylamino)-5-hydroxytetralin, and 2-(N-n-propyl-N-2-[3-benzothienyloxy]ethylamino)-5-hydroxytetralin;
- ~ - - -.
:, . .
,- . : : - . , .:
- ~ . . . . . . . .
.... , . ~ . . . . . . .
- WO 91tO~727 ~ 5~ PCT/US90/03761 Compounds wherein R1 is phenyl and/or substituted phenyl and is selected from the group of radicals repre-sented ~y the formula:
~ ~ (Y)a and wherein x is oxygen, nitrogen or sulfur. Specific preferred compounds of this group include:
2-(N~n-propyl-N-2-[phenyloxy~ethylamino) 5-hydroxy-tetralln, 2-(N-n-propyl-N-2-[4-hydroxyphenyloxy]ethylamino)-S-hydroxytetralin, and 2-(N-n-propyl-N-2-[3-hydroxyphenyloxy]ethylamino)-5-hydroxytetralin, 2-(N-n-propyl-~-2-[phenyloxy]ethylamino)-5-methoxytetralin 2-(N-n-propyl-N-2-[phenylamino]ethylamino)-5-hydroxytetralin 2-(N-n-propyl-~-2-[4-hydroxyphenylamino]ethylamino)-5-hydroxytetralin 2-(N-n-propyl-~-3-[phenyloxy]propylamino)-5-hydroxytetralin ~ 2-(N-n-propyl-N-2-[2,6-dimethylphenyloxy]ethylamino)-: 5-hydroxytetralin 2-(N-n-propyl-N-2-[3,5-dimethylphenyloxy)ethylamino)-5-hydroxytetralin - Compounds wherein X is -CH2- and R1 is selected from the group consisting of radicals represented by the following formulae:
~ ~ -C Aryl, or -C-Z - Aryl R ~R8 /) ' "
~1~
(Y '`
~ 3sTllTuTE SHEET
~.. . . . ~ . ............ . .
.: `- '' . ' .. ~ . ` `:` `
:. : ,' ~ -wosl/oo727 PCT/US90/03761 ;~r~ 5-~ -and wherein B is 0, S, or H2. Specific preferred compounds in this group include:
3-[2-[propyl(1,2,3,4-tetrahydro-5-methoxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone 3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzo~uranone 6-[[2-(1,3-dihydro-1-isobenzofuranyl)ethyl]propylamino]-5,6,7,8-tetrahydro-1-naphthalenol 2-(N-n~propyl-N-3,3,3-triphenylpropylamino)-5-hydroxy-tetralin 2-(N-n-propyl-N-2,2,2-triphenylethylamino)-5-hydroxy-tetralin 2-(N-n-propyl-N-3,3-diphenylpropylamino)-5-hydroxy-te.tralin 2-(N-n-propyl-N-2,2-diphenylethylamino)-5-hydroxy-tetralin 2-(N-n-propyl-N-2-phenylpropylamino)-5-hydroxytetralin 2-(N-n-propyl-N-2-phenylpropylamino)-5-metho~ytetralin 2-(N-n-propyl-N-2-(2-methoxy)phenethylamino)-5-hydroxy-tetralin 2-[N-n-propyl-N-2-~2-phenyloxy)propylamino]-5-hydroxy-tetralin The invention is further illustrated by the following examples which are illustrative of various aspects of t~e invention, and are not intended as limiting the scope of the inventions defined by the appended claims. :
- , : - . . ' , . . :, . . ' :
wosl/0o727 ~ PCr/US90/03761 EXA~IPLE 1 Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethylamino]-5-methoxytetralin.
A mixture of 2-(N-n-propylamino)-5-methoxytetralin (7.0 g, 0.0319 mol; prepared according to J. Che~. Soc., 1965, pp 26-36), phenoxyacetic acid (4.86 g, 0.0319 mol), and borane trimethylamine complex (2.33 g, 0.0319 mol) was refluxed in xylenes overnight. The cooled reaction ~ixture was extracted with NaHCO3 and the organic layer was dried over MgSO4, filtered and concentrated unde- reduced pressure.
The resulting oil was subjected to flash ch~omatography (silica; 9:1 pet ether/EtOAc) and product was isolated:
NMX of the free base (300 MHz, CDC13): ~ 7.3-6.6 (m, 8H), 4.0(t, 2H), 3.7(s, 3H), 3.1-2.5(m, 5H), 2.1(~, lHj, 1.7-1.4(m, 3H), 0.9(t, 3H). The free base thus isolated was converted to a hydrochloride sal_ by the addition of dry ether-HCl.
EXAM~LE 2 Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethyla~ino]-~-hydroxytetralin.
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH40H and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatogr~phy ~ re~
ethertEtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addtition of dry ! ,' ~ , ' . ' . `, , . , ' .
WO91/00727 PCT/U~90/0376l ether-HCl. Anal. Calcd. for C21H27NO2-HCl: c, 69.69; H, 7.80; N, 3.87. Found: c, 69.54; H, 7.90; N, 3.87. NMR of the ~ree base (300 MHz, CDC13): ~ 7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m, 9H), 2.1(m, lH), 1.7-1.4(m, 3H), o.s(t~
3H).
EX.~PLE_3 The product of Example 2 was also obtained by dissolving the product of Example 1 in dry dichloromethane and adding a solution of boron tribromide in dichloromethane dropwise at room temperture under nitrogen. After completion, the reac~ion was poured into a beake~ containing NU~OH and ice and stirred for 0.5 h. The organic layer was separated, and the product was purified as in Exa~,ple 2.
EXAMP_E
Preparation of 2-[N-n-propyl,N-3-(phenyloxy)pr~pylamino]-s-methoxytetralin.
In Example 1, phenoxyacetic acid can be replace~ by 3-phenoxy-propionic acid.
.
Preparation of 2-[N-n-propyl,N-3-tphenyloxy)propylamino]-5-hydroxytetralin.
The product of Example ~ can be used as the startin~
material for E~ample 2.
... .. . . . , . " .. , .,. , :.. . i: :. .:. .. , ,. :, : :, .
WO 91/00727 PCr/l lS90/03761 t5~11 EX.~MPLE 6 Preparation of 2-[N-n-propyl,N-2-(1-naphthalenyloxy) ethylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by (1-naphthoxy)-acetic acid. The resulting oil was sujbected to flash chromatography (silica; pe~ ether) and the product was isolated; characteristic peak of N~R (300 M~2, CDC13);
8.3-6.7(m,lOH), 4.2(m, 2H), 3.85(s, 3H), l.O(t, 3H).
E~MPLE 7 Preparation of 2-[N-n-~rop~-l,N-3-(~-naphthalenyloxy) propylamino]-5-hydroxytetralin.
The product of Example 6 was used as the starting material in Example 2. The resulting oil was subjected to flash chromatography and the isolated product showed characteristic peaks at : NMR (CDC13) ~ 8.3-6.6(m, lOH), 4.2(m, 2H), O.9(t,3H).
EX~PLE 8 Preparation of 3-~2-[propyl(1,2,3,4-tetrahydro-5-methoxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
In Example 1, phenoxyacetic acid was replaced by phthalide-3-acetic acid. The resulting oil was subjected to flash chromatography and the isolated product showed distinct peaks at: NMR (CDC13) ~ 8.0-6.7(m, 7H), 5.7(m, lH), 3.8(s, 3H) O.9(t, 3H). Anal. Calc. for C24H29~03 HCl: C, 69.~ ., ;, 3.37. Found: C,-69.0~ , 7.~ .2~.
WO91/1)0727 PCl/U590/03761 1 5~
EXAMPLE g Preparation of 3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
The product of Example 8 was used as the starting material for Example 3. The resulting oil after purification showed dis.inct peaks at: NMR(CDCl3) ~ 7.9-6.6(m, 7H), 5.7(m, lH), 0.95(t, 3H). Anal. Calc. for C23H27N3 ~ HCl C, 68.73; H, 7.02; N, 3.48. Found: c, 68.62; H, 7.09; N, 3.35.
EX.~ F 1 0 Preparation of 6-[[2-(1,3-dihydro-1-isobenzofuranyl) ethyl]propylamino]-5,6,7,8-tetrahyàro-1-naphthalenol.
The reduction of the product of Example 9 will result in the desired product.
EX~PLE 1i Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino)-5-methoxytetralin.
In Exàmple 1, phenoxyacetic acid was replaced by dipheny-lactic acid. The puri~ied product showed characteristic peaks at: NMR(CDCl3) ~ 7.8-6.65(m, 13H), 4.1(t, lH), 3.8(s, 3H), 3.2(d, 2H), 0.7(t, 3H).
EXP~PLE_12 Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-.ydroxytetralin.
.
.' :. ' - ' ' ' ' ' . ' . ;' ,., ' "...... '' ~ , : . ' W091/00727 PCT/US90/0376]
The product of Example 11 was used as startin~ material in Example 3. After purification the product showed distinct peaks at: NMR(CDC13) ô 7.8-6.65(m, 13~), 4.1(t, lH), 3.2 (d, 2H), 0.7(t, 3H). Anal. calc. for C27H31NO o HCl: C, 76.84; H, 7.64; N, 3.32. Observed: C, 77.00; H, 7.69; N, 3.21.
EX~MPLE 13 Preparation of 2-~N-n-propyl,N-3,3-~iphenylpropylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3-diphenylpropionic acid. The purified product sho~ed distinct peaks a': NMR(CDC13) o 7.~-7.2(m, llH), 6.65(m, 2H), 4.05(t,1H), 3.8(s, 3H), 0.9(s, 3H).
EX~PL- 14 Preparation of ~-~N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin.
The produc' of Example 13 was use- 2S sta~ting material for Exa~ple 3. The isolated product showed distinct peaks at:
NMR(CDC13) ~ 7.4-7.0(m, lH), 6.7-6.5(m, 2H), 4.0(t, lH), 0,9(t, 3H)-- .- . . - . . ~ .. . .
. : : : : . ~ . .-.:,. . . . . . . . . .
...... . : -. . ; ,.:.. : : , :
- .-, : : .: . . :
-: : : . : . : . :
:.: . . . : , ~ . . . .. - :
. .
WO91/00727 PCT/US90/03761 ~
2~?-$~
EX~MPLE 15 Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by DL-2-phenoxypropionic acid. The purified product showed distinct peaks at: NMR(CDC13) ~ 7.3-6.65(m, 8H), ~.45(m, lH), 3.8(s, 3H), O.g(t, 3H).
EXLM~1E 16 Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-hydroxytetralin.
The product of Example 15 was useà as starting material for Example 2. The isolated produc. showed characteristlc peaks at: NMR(CDC13) ~ 7.3-6.65(m, 8H), 4.45(m, lH), 0.9(t, 3H).
EX.3~lPL~ 1/
P-eparation of 2-~N-n-propyl,N-3,3,3-t~iphenylpropylami~o]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3,3-triphenylpropionic acid. The purified product showed characteristic peaks at : NMR(CDC13) ~ 7.4-6.65(m, 18H), 3.8(s, 3H), O.9(t, 3H).
.
..
W V 91/00727 PC~/~;S90/03761 5~
_~9_ Preparation of 2-[N-n-propyl,N-3,3,3-triphenylpropylamino]-5-hydroxytetralin.
The product of Example 17 was used as starting material in Example 3. After pu-ification the product sh~wed distinct peaks at: NMR(CDCl3) ~ 7.4-6.65(r, 18H), O.9(t, 3H).
EX~PLE 1g Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]-5-methoxytetralin.
In Example 1, pehnoxyacetic ~cid can be replaced by triphenylacetic acid.
EX~MPLE 20 Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]-5-hydroxytetralin.
The produc- of Exa..~le 15 can be used as th_ starting material fo~- Example 3.
, E~PLE 21 Preparation of 2-[N-n-propyl,N-2-[2-methoxy]phenethyl-amino]-5-methoxytetralin.
In Example l, phenoxyacetic acid can be replaced by ~-methoxyphenlyacetic acid.
. . ... .
. i . ,., .. , ,, " . " . .. , , . , ., . " , ,, , ,~, . . . . . . ... ..
.
- . - - , . . .
.: . . . . . .: .: .
: :: -, : . - , , . ,~, W O 91/00~27 PCT/US90/0376]
Z~$~
Preparation of 2-[N-n-propyl,N-2-(2-methoxy)phenethyl-amino]-5-hyroxytetralin.
The product of Example 21 can be used as the starting material for Example 2.
Preparation of 2-[N-n-propyl,N-(2,3-cihydro-lH-inden-l-yl)methylamino]-5-methoxytetralin.
In Example 1, phenoxyactic acid can be replaced by 1-indancarboxylic acid.
EX.~M~L~ 2~
Preparation of 2-[N-n-propyl,N-(2,3-dihydro-lH-inden-l-yl)methylamino]-5-hydroxytetralin.
The product of Example 23 can be used as the starting material fo- Example 3.
Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by 1,2,3,4-tetrahydro 2-naphthoic acid. .:
: , : . .
. - : , . ~
: . ~ , . . : . ' . .
WO91/007~7 ~ 5~ PCT/US90/03761 Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-hydroxytetralin.
The product of Example 25 can be used as the starting material for E~ample 3.
EX~M~LE 27 Preparation of 2-[N-n-propyl,N-2-(3,5-dime~hylphenyloxv) ethylamino]-5-methoxytetralin.
In Example l, phenox~acetic acid can be replaced by 3,5-dimethylphenoxyacetic acid.
EX}~
Preparation of 2-[N-n-propyl,N-2-(3,5-dimethylphenyloxy) ethylamino]-5-hydroxytetralin.
The product of Example 27 can be used as the startins ma_erial for Example 3.
EX~MPLE 29 To test the selectivity and specificity of the present compounds for binding to dopamine receptors tests were conducted using the following standard procedures.
To test binding to dopamine receptors, the bovine caudate nuclei assay was employed. ~ovine brains were obtained fresh from a local slaughterhouse. The caudate nuclQi ~_ ~ d ~ ut and homosenl~ed ir. DuL~er ~ (~û
mM Tris; 1 mM Na2-EDTA; 5 mM KCl; 1 mM MgCl2; 2 mM CaCl2;
pH 7.4) using a Brinkman Polytron. The homogenate was ~.. . . - : . .. .
.:, : -: . , . : :
; , . .
centrifuged at 40,000 x g for 20 minutes and washed on~e.
The pellett was resuspended in Buffer A, incubated at 37C
for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-lO
mg/ml in Buffer A and frozen at -70C until used.
To test binding of the compounds to ~2-adrenergic receptors, the rat cerebral cortex assay was employed.
~ale Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM ~gCl2 (pH 7.4), and centrifuged at 40,000 x g for lO minutes. The pellet was washed once, resuspended in Tris/MgCl2 and incubated with 8 units/ml adenosine deaminase at 37C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-lO mg/ml and frozen at -70C until use.
The following tritiated drugs were used as radioligands for each of the receptors tes~ed: [3H]-Spiperone 21-24 Ci/mr.ol for D2 receptors, [3H]-scH2339o 75-85 Ci/mmol for Dl receptors, and [3H]-Para aminoclonidine 48-52 Ci/mmol for ~2-adrenergic receptors. The radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of time as follows: 75 minutes at room temperature for D2 receptors, 15 minutes at 37C for D1 receptors, or 30 minutes at room temperature for ~2 receptors. Specific binding was defined using l~M butaclamol (D2), 1 ~M SCH23390 (Dl), or l ~M
yohimbine (~2) In addition the D2 assays contained 30 nM
:._.aserin in order to bloc~ the blr,ding of 3n-~p ~ peron~ IO
5HT2 receptors.
.
.. ~ . .
- ~' '. ~: . ' , . : , ,' . . : , WO91/00727 ~ ~ PCT/US90/03761 The assays were ter~inated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1~ polyethyleneimine, and the filters were washed three times by filtration of cold buffer. The filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a BecXman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980). The results are presented as Ki values if the data were best fitted to a one-site model, or as ~H and ~L values if a two-site model produced the better fit.
Results of the binding tests ~re summarized in Table 1 below:
Table 1 RECEPTOR AFFINITIES (Ki, nM) - -Example D2 (KL)D1(KL) ~2 Cor~ound 14 3401,350 2,600 2 12S12,000 500 12 47 8,96~ 11,000 9 66 2,130 100 -N-0437 1101,000 190 This table shows high dopamine D2 receptor affinities of compounds chosen from the examples above, with unexpectedly high degrees of selectivity and specificity. The compound N-0437, a potent dopamine n~ ;cl ;s included as a reference compound for comparative purposes.
. , . .. .. , ~, . .. ,. ,, . , ,, , , . .. . .. - . . . .
, . ., . ~ . - ..
- ~ - . .. : . ,. ~ .
~: ; , - . , ~ . . , , : :
: - ~ : .~ - .. , - . .
.. . ..
007~7 PCT/US~0/03761 r~
While particular embodiments of the invention have been described it will be understood of course that the invention is not limited thereto since many obvious modifications can be made and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims.
., - , . ~ , . ~ . :
:. . ... ~ . . :
.. . . ~ . ..
- : . :
~ . ~ , . .
.. .. . . . .. . .
.
- , : - . . ' , . . :, . . ' :
wosl/0o727 ~ PCr/US90/03761 EXA~IPLE 1 Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethylamino]-5-methoxytetralin.
A mixture of 2-(N-n-propylamino)-5-methoxytetralin (7.0 g, 0.0319 mol; prepared according to J. Che~. Soc., 1965, pp 26-36), phenoxyacetic acid (4.86 g, 0.0319 mol), and borane trimethylamine complex (2.33 g, 0.0319 mol) was refluxed in xylenes overnight. The cooled reaction ~ixture was extracted with NaHCO3 and the organic layer was dried over MgSO4, filtered and concentrated unde- reduced pressure.
The resulting oil was subjected to flash ch~omatography (silica; 9:1 pet ether/EtOAc) and product was isolated:
NMX of the free base (300 MHz, CDC13): ~ 7.3-6.6 (m, 8H), 4.0(t, 2H), 3.7(s, 3H), 3.1-2.5(m, 5H), 2.1(~, lHj, 1.7-1.4(m, 3H), 0.9(t, 3H). The free base thus isolated was converted to a hydrochloride sal_ by the addition of dry ether-HCl.
EXAM~LE 2 Preparation of 2-[N-n-propyl,N-2-(phenyloxy)ethyla~ino]-~-hydroxytetralin.
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH40H and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatogr~phy ~ re~
ethertEtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addtition of dry ! ,' ~ , ' . ' . `, , . , ' .
WO91/00727 PCT/U~90/0376l ether-HCl. Anal. Calcd. for C21H27NO2-HCl: c, 69.69; H, 7.80; N, 3.87. Found: c, 69.54; H, 7.90; N, 3.87. NMR of the ~ree base (300 MHz, CDC13): ~ 7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m, 9H), 2.1(m, lH), 1.7-1.4(m, 3H), o.s(t~
3H).
EX.~PLE_3 The product of Example 2 was also obtained by dissolving the product of Example 1 in dry dichloromethane and adding a solution of boron tribromide in dichloromethane dropwise at room temperture under nitrogen. After completion, the reac~ion was poured into a beake~ containing NU~OH and ice and stirred for 0.5 h. The organic layer was separated, and the product was purified as in Exa~,ple 2.
EXAMP_E
Preparation of 2-[N-n-propyl,N-3-(phenyloxy)pr~pylamino]-s-methoxytetralin.
In Example 1, phenoxyacetic acid can be replace~ by 3-phenoxy-propionic acid.
.
Preparation of 2-[N-n-propyl,N-3-tphenyloxy)propylamino]-5-hydroxytetralin.
The product of Example ~ can be used as the startin~
material for E~ample 2.
... .. . . . , . " .. , .,. , :.. . i: :. .:. .. , ,. :, : :, .
WO 91/00727 PCr/l lS90/03761 t5~11 EX.~MPLE 6 Preparation of 2-[N-n-propyl,N-2-(1-naphthalenyloxy) ethylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by (1-naphthoxy)-acetic acid. The resulting oil was sujbected to flash chromatography (silica; pe~ ether) and the product was isolated; characteristic peak of N~R (300 M~2, CDC13);
8.3-6.7(m,lOH), 4.2(m, 2H), 3.85(s, 3H), l.O(t, 3H).
E~MPLE 7 Preparation of 2-[N-n-~rop~-l,N-3-(~-naphthalenyloxy) propylamino]-5-hydroxytetralin.
The product of Example 6 was used as the starting material in Example 2. The resulting oil was subjected to flash chromatography and the isolated product showed characteristic peaks at : NMR (CDC13) ~ 8.3-6.6(m, lOH), 4.2(m, 2H), O.9(t,3H).
EX~PLE 8 Preparation of 3-~2-[propyl(1,2,3,4-tetrahydro-5-methoxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
In Example 1, phenoxyacetic acid was replaced by phthalide-3-acetic acid. The resulting oil was subjected to flash chromatography and the isolated product showed distinct peaks at: NMR (CDC13) ~ 8.0-6.7(m, 7H), 5.7(m, lH), 3.8(s, 3H) O.9(t, 3H). Anal. Calc. for C24H29~03 HCl: C, 69.~ ., ;, 3.37. Found: C,-69.0~ , 7.~ .2~.
WO91/1)0727 PCl/U590/03761 1 5~
EXAMPLE g Preparation of 3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofuranone.
The product of Example 8 was used as the starting material for Example 3. The resulting oil after purification showed dis.inct peaks at: NMR(CDCl3) ~ 7.9-6.6(m, 7H), 5.7(m, lH), 0.95(t, 3H). Anal. Calc. for C23H27N3 ~ HCl C, 68.73; H, 7.02; N, 3.48. Found: c, 68.62; H, 7.09; N, 3.35.
EX.~ F 1 0 Preparation of 6-[[2-(1,3-dihydro-1-isobenzofuranyl) ethyl]propylamino]-5,6,7,8-tetrahyàro-1-naphthalenol.
The reduction of the product of Example 9 will result in the desired product.
EX~PLE 1i Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino)-5-methoxytetralin.
In Exàmple 1, phenoxyacetic acid was replaced by dipheny-lactic acid. The puri~ied product showed characteristic peaks at: NMR(CDCl3) ~ 7.8-6.65(m, 13H), 4.1(t, lH), 3.8(s, 3H), 3.2(d, 2H), 0.7(t, 3H).
EXP~PLE_12 Preparation of 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-.ydroxytetralin.
.
.' :. ' - ' ' ' ' ' . ' . ;' ,., ' "...... '' ~ , : . ' W091/00727 PCT/US90/0376]
The product of Example 11 was used as startin~ material in Example 3. After purification the product showed distinct peaks at: NMR(CDC13) ô 7.8-6.65(m, 13~), 4.1(t, lH), 3.2 (d, 2H), 0.7(t, 3H). Anal. calc. for C27H31NO o HCl: C, 76.84; H, 7.64; N, 3.32. Observed: C, 77.00; H, 7.69; N, 3.21.
EX~MPLE 13 Preparation of 2-~N-n-propyl,N-3,3-~iphenylpropylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3-diphenylpropionic acid. The purified product sho~ed distinct peaks a': NMR(CDC13) o 7.~-7.2(m, llH), 6.65(m, 2H), 4.05(t,1H), 3.8(s, 3H), 0.9(s, 3H).
EX~PL- 14 Preparation of ~-~N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin.
The produc' of Example 13 was use- 2S sta~ting material for Exa~ple 3. The isolated product showed distinct peaks at:
NMR(CDC13) ~ 7.4-7.0(m, lH), 6.7-6.5(m, 2H), 4.0(t, lH), 0,9(t, 3H)-- .- . . - . . ~ .. . .
. : : : : . ~ . .-.:,. . . . . . . . . .
...... . : -. . ; ,.:.. : : , :
- .-, : : .: . . :
-: : : . : . : . :
:.: . . . : , ~ . . . .. - :
. .
WO91/00727 PCT/US90/03761 ~
2~?-$~
EX~MPLE 15 Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by DL-2-phenoxypropionic acid. The purified product showed distinct peaks at: NMR(CDC13) ~ 7.3-6.65(m, 8H), ~.45(m, lH), 3.8(s, 3H), O.g(t, 3H).
EXLM~1E 16 Preparation of 2-[N-n-propyl,N-2-(2-phenyloxy)propylamino]-5-hydroxytetralin.
The product of Example 15 was useà as starting material for Example 2. The isolated produc. showed characteristlc peaks at: NMR(CDC13) ~ 7.3-6.65(m, 8H), 4.45(m, lH), 0.9(t, 3H).
EX.3~lPL~ 1/
P-eparation of 2-~N-n-propyl,N-3,3,3-t~iphenylpropylami~o]-5-methoxytetralin.
In Example 1, phenoxyacetic acid was replaced by 3,3,3-triphenylpropionic acid. The purified product showed characteristic peaks at : NMR(CDC13) ~ 7.4-6.65(m, 18H), 3.8(s, 3H), O.9(t, 3H).
.
..
W V 91/00727 PC~/~;S90/03761 5~
_~9_ Preparation of 2-[N-n-propyl,N-3,3,3-triphenylpropylamino]-5-hydroxytetralin.
The product of Example 17 was used as starting material in Example 3. After pu-ification the product sh~wed distinct peaks at: NMR(CDCl3) ~ 7.4-6.65(r, 18H), O.9(t, 3H).
EX~PLE 1g Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]-5-methoxytetralin.
In Example 1, pehnoxyacetic ~cid can be replaced by triphenylacetic acid.
EX~MPLE 20 Preparation of 2-[N-n-propyl,N-2,2,2-triphenylethylamino]-5-hydroxytetralin.
The produc- of Exa..~le 15 can be used as th_ starting material fo~- Example 3.
, E~PLE 21 Preparation of 2-[N-n-propyl,N-2-[2-methoxy]phenethyl-amino]-5-methoxytetralin.
In Example l, phenoxyacetic acid can be replaced by ~-methoxyphenlyacetic acid.
. . ... .
. i . ,., .. , ,, " . " . .. , , . , ., . " , ,, , ,~, . . . . . . ... ..
.
- . - - , . . .
.: . . . . . .: .: .
: :: -, : . - , , . ,~, W O 91/00~27 PCT/US90/0376]
Z~$~
Preparation of 2-[N-n-propyl,N-2-(2-methoxy)phenethyl-amino]-5-hyroxytetralin.
The product of Example 21 can be used as the starting material for Example 2.
Preparation of 2-[N-n-propyl,N-(2,3-cihydro-lH-inden-l-yl)methylamino]-5-methoxytetralin.
In Example 1, phenoxyactic acid can be replaced by 1-indancarboxylic acid.
EX.~M~L~ 2~
Preparation of 2-[N-n-propyl,N-(2,3-dihydro-lH-inden-l-yl)methylamino]-5-hydroxytetralin.
The product of Example 23 can be used as the starting material fo- Example 3.
Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-methoxytetralin.
In Example 1, phenoxyacetic acid can be replaced by 1,2,3,4-tetrahydro 2-naphthoic acid. .:
: , : . .
. - : , . ~
: . ~ , . . : . ' . .
WO91/007~7 ~ 5~ PCT/US90/03761 Preparation of 2-[N-n-propyl,N-(tetrahydro-2-naphthyl) methylamino]-5-hydroxytetralin.
The product of Example 25 can be used as the starting material for E~ample 3.
EX~M~LE 27 Preparation of 2-[N-n-propyl,N-2-(3,5-dime~hylphenyloxv) ethylamino]-5-methoxytetralin.
In Example l, phenox~acetic acid can be replaced by 3,5-dimethylphenoxyacetic acid.
EX}~
Preparation of 2-[N-n-propyl,N-2-(3,5-dimethylphenyloxy) ethylamino]-5-hydroxytetralin.
The product of Example 27 can be used as the startins ma_erial for Example 3.
EX~MPLE 29 To test the selectivity and specificity of the present compounds for binding to dopamine receptors tests were conducted using the following standard procedures.
To test binding to dopamine receptors, the bovine caudate nuclei assay was employed. ~ovine brains were obtained fresh from a local slaughterhouse. The caudate nuclQi ~_ ~ d ~ ut and homosenl~ed ir. DuL~er ~ (~û
mM Tris; 1 mM Na2-EDTA; 5 mM KCl; 1 mM MgCl2; 2 mM CaCl2;
pH 7.4) using a Brinkman Polytron. The homogenate was ~.. . . - : . .. .
.:, : -: . , . : :
; , . .
centrifuged at 40,000 x g for 20 minutes and washed on~e.
The pellett was resuspended in Buffer A, incubated at 37C
for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-lO
mg/ml in Buffer A and frozen at -70C until used.
To test binding of the compounds to ~2-adrenergic receptors, the rat cerebral cortex assay was employed.
~ale Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM ~gCl2 (pH 7.4), and centrifuged at 40,000 x g for lO minutes. The pellet was washed once, resuspended in Tris/MgCl2 and incubated with 8 units/ml adenosine deaminase at 37C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-lO mg/ml and frozen at -70C until use.
The following tritiated drugs were used as radioligands for each of the receptors tes~ed: [3H]-Spiperone 21-24 Ci/mr.ol for D2 receptors, [3H]-scH2339o 75-85 Ci/mmol for Dl receptors, and [3H]-Para aminoclonidine 48-52 Ci/mmol for ~2-adrenergic receptors. The radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of time as follows: 75 minutes at room temperature for D2 receptors, 15 minutes at 37C for D1 receptors, or 30 minutes at room temperature for ~2 receptors. Specific binding was defined using l~M butaclamol (D2), 1 ~M SCH23390 (Dl), or l ~M
yohimbine (~2) In addition the D2 assays contained 30 nM
:._.aserin in order to bloc~ the blr,ding of 3n-~p ~ peron~ IO
5HT2 receptors.
.
.. ~ . .
- ~' '. ~: . ' , . : , ,' . . : , WO91/00727 ~ ~ PCT/US90/03761 The assays were ter~inated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1~ polyethyleneimine, and the filters were washed three times by filtration of cold buffer. The filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a BecXman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980). The results are presented as Ki values if the data were best fitted to a one-site model, or as ~H and ~L values if a two-site model produced the better fit.
Results of the binding tests ~re summarized in Table 1 below:
Table 1 RECEPTOR AFFINITIES (Ki, nM) - -Example D2 (KL)D1(KL) ~2 Cor~ound 14 3401,350 2,600 2 12S12,000 500 12 47 8,96~ 11,000 9 66 2,130 100 -N-0437 1101,000 190 This table shows high dopamine D2 receptor affinities of compounds chosen from the examples above, with unexpectedly high degrees of selectivity and specificity. The compound N-0437, a potent dopamine n~ ;cl ;s included as a reference compound for comparative purposes.
. , . .. .. , ~, . .. ,. ,, . , ,, , , . .. . .. - . . . .
, . ., . ~ . - ..
- ~ - . .. : . ,. ~ .
~: ; , - . , ~ . . , , : :
: - ~ : .~ - .. , - . .
.. . ..
007~7 PCT/US~0/03761 r~
While particular embodiments of the invention have been described it will be understood of course that the invention is not limited thereto since many obvious modifications can be made and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims.
., - , . ~ , . ~ . :
:. . ... ~ . . :
.. . . ~ . ..
- : . :
~ . ~ , . .
.. .. . . . .. . .
.
Claims (49)
1. Optically active or racemic compounds having the formula where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is H or is selected from the group consisting of hydrocarbyl radicals said hydrocarbyl radicals being further optionally substituted with radicals selected from the group consisting of aromatic residues and .
R5 is selected from the group consisting of alkyl and aromatic residues, having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of and wherein R8 is hydrogen, aryl, or R6; and further wherein R9 is aryl, R6, -OH, NH2, OR6, , <IMG or -N(R6)2; or R1 is wherein B is oxygen, sulfur or two hydrogen atoms, and a pharmaceutically acceptable salt thereof.
R5 is selected from the group consisting of alkyl and aromatic residues, having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of and wherein R8 is hydrogen, aryl, or R6; and further wherein R9 is aryl, R6, -OH, NH2, OR6, , <IMG or -N(R6)2; or R1 is wherein B is oxygen, sulfur or two hydrogen atoms, and a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein A is hydrogen or a hydxocarbyl radical having between 1 and 12 carbon atoms selected from a group consisting of phenyl, alkyl and alkyl substituted with aromatic residues.
3. The compound of claim 2 wherein A is selected from the group consisting of , , and , and R5 is selected from the group of alkyl, alkyl substituted with aryl radicals, and aryl radicals having between 1 and 12 carbon atoms.
4. The compound of claim 1 wherein R5 is selected from the group consisting of phenyl, methyl, t-butyl, o-methylphenyl, o-, m- and p-methoxyphenyl, p-isopropyl-phenyl, and nonyl.
5. The compound of claim 1 wherein X is selected from the group consisting of nitrogen, oxygen and sulfur, and R2 is OA and A is H.
6. The compound of claim 5 wherein R1 is selected from the group consisting of thienyl, phenyl, hydroxyphenyl, dimethylphenyl, furanyl and napthalenyl.
7. The compound of claim 6 wherein the R1 is selected from the group consisting of 2-thienyl, 3 thienyl, 3-hydroxyphenyl, 2,6-dimethylphenyl, and 4-hydroxyphenyl.
8. The compound of claim 1 where n is 2, X is selected from oxygen or -CH2-, and R2 is OA.
9. The compound of claim 5 wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, and carboxyamido.
10. The compound of claim 5 wherein Y is selected from the group consisting of trifluoromethyl, sulfate, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals having between 1 and 12 carbon atoms.
11. The compound of claim 10 wherein the heteroatoms are oxygen, nitrogen or sulfur.
12. The compound of claim 1 wherein R1 is selected from the group consisting of and .
13. The compound of claim 12 wherein R9 is selected from the group consisting of - or N(R6)2.
14. The compound of claim 12 wherein R9 is selected from the group consisting of aryl, -R6, -NH2, -OH and -OR6.
15. The compound of claim 1 wherein R1 is and B is selected from the group consisting of oxygen and two hydrogen atoms.
16. The compound of claim 15 wherein B is two hydrogen atoms.
17. The compound of claim 1 wherein R1 is , X is oxygen, and Z is oxygen, nitrogen or sulfur.
18. The compound of claim 1 wherein R1 is selected from the group consising of wherein X is oxygen, Y comprises 1 to 5 carbon atoms, and a is an integer from 0 to 2.
19. The compound of claim 1 wherein R1 is , X is oxygen and Y is a hydrocarbyl radical comprising 1 to 12 carbon atoms.
20. The compounds of claim 17, 18, or 19 wherein Y
comprises no more than 6 carbon atoms, and a is 0 to 2.
comprises no more than 6 carbon atoms, and a is 0 to 2.
21. The compound of claim 19 where Y is methyl and a is 2.
22. The compound of claim 19 wherein a is zero.
23. The compound of claim 20 wherein A is H and R6 is propyl.
24. The compound of claim 1 selected from the group consisting of 2-[N-n-propyl,N 3,3-diphenylpropylamino]-5-hydroxytetralin; 2-[N-n-propyl,N-(2-phenoxy)ethylamino]-5-hydroxytetralin; 2-[N-n-propyl,N-2,2-diphenylethylamino]-5-hydroxytetralin; and 3-[2-[propyl(1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl)amino]ethyl]-1(3H)-isobenzofura-none.
25. A method comprising inducing a dopaminergic response in a patient by administering a pharmacologically-effective amount of a compound represented by the formula where R2, R3 and R4 are each selected from the group consisting of H and OA with the provision that at least one of R2, R3 and R4 is H, that R2 and R4 are not both OA; A is H or is selected from the group consisting of hydrocarbyl radicals, said radicals being further optionally substituted with radicals selected from the group consisting of aromatic residues and , , and .
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of and - wherein R8 is hydrogen, aryl, or R6; and further wherein R9 is aryl, R6, -OH, -NH2, -OR6, , or -N(R6)2; or R. is wherein B is oxygen, sulfur or two hydrogen atoms, and z pharmaceutically acceptable salt thereof.
R5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12 carbon atoms; n is an integer between 1 and 4; R6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH2-, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH2-, R1 is selected from the group consisting of wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH2-, R1 is selected from a group consisting of and - wherein R8 is hydrogen, aryl, or R6; and further wherein R9 is aryl, R6, -OH, -NH2, -OR6, , or -N(R6)2; or R. is wherein B is oxygen, sulfur or two hydrogen atoms, and z pharmaceutically acceptable salt thereof.
26. The method of claim 23 wherein A is hydrogen, or a hydrocarbyl radical having between 1 and 12 carbon atoms selected from a group consisting of phenyl, alkyl and alkyl substituted with aryl radicals.
27. The method claim 24 wherein A is selected from the group consisting of , , and and R5 is selected from the group of alkyl and aryl radicals having between 1 and 12 carbon atoms.
28. The method of claim 23 wherein R5 is selected from the group consisting of phenyl, methyl, t-butyl, o-methyl-phenyl, o-, m- and p-methoxyphenyl, p-isopropylphenyl and nonyl.
29. The method of claim 23 wherein X is selected from the group consisting of oxygen, nitrbgen and sulfur, and R2 is OA and A is hydrogen.
30. The method of claim 29 wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, and carboxyamido.
31. The method of claim 29 wherein Y is selected from the group consisting of trifluoromethyl, sulfate, halogen, and hydrocarbyl and heteroatom-substituted hydrocarbyl radicals having between 1 and 12 carbon atoms.
32. The method of claim 31 wherein the heteroatoms are oxygen or sulfur.
33. The method of claim 28 wherein R1 is selected from and wherein X is -CH2-.
34. The method of claim 33 wherein R9 is selected from the group consisting of , and -N(R6)2.
35. The method of claim 34 wherein R9 is selected from the group consisting of aryl, R6, -NH2, -OH, and -OR6.
36. The method of claim 23 wherein R1 is and X is oxygen, and B is selected from the group consisting of oxygen and two hydrogen atoms.
37. The method of claim 36 wherein B is two hydrogen atoms.
38. The method of claim 36 wherein B is oxygen.
39. The method of claim 23 wherein R1 is X is oxygen, and Z is oxygen or sulfur.
WO91/00727 PCT/US90/037~L.
WO91/00727 PCT/US90/037~L.
40. The method of claim 23 wherein R1 is selected from the qroup consisting of and X is oxygen, Y comprises 1 to 5 carbon atoms, and a is 0 or 1.
41. The method of claim 23 wherein R1 is , X is oxygen, and Y is a hydrocarbyl radical comprising 1 to 12 carbon atoms.
42. The method of claim 23 wherein R1 is , Y is methyl and a is 2.
43. The method of claim 23 wherein R1 is and a is zero.
44. The method of claim 39, 40 or 41 wherein X is oxygen, Y comprises no more than 5 carbon atoms, and a is 0 to 2.
45. The method of claim 29 wherein R1 is selected from the group consisting of thienyl, phenyl, hydroxy-phenyl, furanyl and napthalenyl.
46. The method of claim 45 wherein the napthalenyl is selected from the group consisting of 2-thienyl, 3-thienyl, 3-hydroxyphenyl, and 4-hydroxyphenyl.
47. The method of claim 23 wherein n is 2, X is selected from oxygen or -CH2-, and R2 is OA.
48. The method of claim 47 wherein A is H and R6 is propyl.
49. The method of claim 23 selected from the group consisting of 2-[N-n-propyl,N-3,3-diphenylpropylamino]-5-hydroxytetralin; 2-[N-n-propyl, N-2-(2-phenoxy) ethyl-amino]-5-hydroxytetralin; 2-[N-n-propyl,N-2,2-diphenyl-ethylamino]-5-hydroxytetralin; and 3-[2 -[propyl (1,2,3,4-tetrahydro-5-hydroxy-2-naphthalenyl) amino]ethyl]-1(3H)-isobenzofuranone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37558389A | 1989-07-05 | 1989-07-05 | |
| US375,583 | 1989-07-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065450A1 true CA2065450A1 (en) | 1991-01-06 |
Family
ID=23481446
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065450A Abandoned CA2065450A1 (en) | 1989-07-05 | 1990-07-02 | Substituted 2-aminotetralins |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0463119A4 (en) |
| AU (1) | AU6072090A (en) |
| CA (1) | CA2065450A1 (en) |
| WO (1) | WO1991000727A1 (en) |
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| US5382596A (en) * | 1993-08-05 | 1995-01-17 | Whitby Research, Inc. | Substituted 2-aminotetralins |
| IT1271411B (en) * | 1993-09-14 | 1997-05-28 | Zambon Spa | 2-AMINO-1,2,3,4-TETRAIDRO-NAFTALENE DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
| SV2001000202A (en) * | 1999-10-20 | 2001-10-16 | Warner Lambert Co | USE OF (-) - 5-CETO-2-N, N-D1-N-PROPYLAMINE-TETRAHYDROTETHRALINE FOR THE TREATMENT OF PARKINSON'S EVIL |
| SE0001438D0 (en) * | 2000-04-18 | 2000-04-18 | Axon Chemicals Bv | New chemical compounds and their use in therapy |
| US7829587B2 (en) | 2008-01-09 | 2010-11-09 | Allergan, Inc. | Substituted 2-aminotetralin derivatives as selective alpha 2B agonist |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1017359A (en) * | 1972-07-03 | 1977-09-13 | Frederic P. Hauck | Substituted cyclic polymethylene phenols |
| US3930022A (en) * | 1972-07-03 | 1975-12-30 | Squibb & Sons Inc | Certain tetrahydronaphthalenes used in the treatment of cardiac arrhythmia |
| US4267373A (en) * | 1972-07-03 | 1981-05-12 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
| US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
| DE3062971D1 (en) * | 1979-09-14 | 1983-06-09 | Sandoz Ag | Derivatives of tetraline, their preparation and medicaments containing these compounds |
| US4882352A (en) * | 1986-07-28 | 1989-11-21 | Nelson Research & Development Co. | Method for treating schizophrenia |
| US4657925A (en) * | 1984-08-13 | 1987-04-14 | Nelson Research & Development Co. | Method and compositions for reducing the intraocular pressure of mammals |
| US4743618A (en) * | 1983-01-03 | 1988-05-10 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
| US4885308A (en) * | 1984-08-13 | 1989-12-05 | Nelson Research & Development Co. | Method and compositions for treatment of parkinsonism syndrome in mammals |
-
1990
- 1990-07-02 CA CA002065450A patent/CA2065450A1/en not_active Abandoned
- 1990-07-02 AU AU60720/90A patent/AU6072090A/en not_active Withdrawn
- 1990-07-02 EP EP19900911220 patent/EP0463119A4/en not_active Ceased
- 1990-07-02 WO PCT/US1990/003761 patent/WO1991000727A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0463119A1 (en) | 1992-01-02 |
| WO1991000727A1 (en) | 1991-01-24 |
| EP0463119A4 (en) | 1992-01-22 |
| AU6072090A (en) | 1991-02-06 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |