Derivatives of 2-aminotetralins and pharmaceutical analogs thereof exhibiting differential CNS receptor activity and behavior
Aminotetralin derivatives and pharmacological analogs thereof which contain an N-propynyl group exhibit differential dopaminergenic receptor activity. The subject compounds are useful in affecting dopamine receptor activity, particularly in exhibiting differing activity among the various dopamine receptor subtypes. The compounds are useful in treating CNS disorders in mammals in general, and humans in particular.
1. A compound exhibiting differential activity between dopamine receptor subtypes, said compound being an 2-aminotetralin or biosteric analog thereof containing a fused ring structure, one ring comprising an optionally ring substituted moiety
or a pharmaceutically acceptable salt of said compound, wherein
X is CH 2 , O, NH, or S,
n is 0 or 1, and
R is ethyl, butyl, or a C 5-20 hydrocarbon, each optionally substituted by one or more halo, nitro, amino, aminoalkyl, or cyano groups, or R is a halo-, nitro-, amino-, cyano- or aminoalkyl-substituted propyl group, R optionally containing one or more heteroatoms selected from the group consisting of O, N, and S, and optionally containing a keto, thio, ester, carbonate, urea, amide, or urethane group and where said optionally ring substituted moiety may contain one or two sites of ethylenic unsaturation.
2. A compound exhibiting differential activity between dopamine receptor subtypes of claim 1 , said compound comprising a compound of the formula I or a pharmaceutically acceptable salt thereof
wherein R 1 and R 2 together complete a 5 membered aromatic ring optionally containing up to 2 heteroatoms individually selected from the group consisting of O, N, and S, and optionally substituted by R 3 , R 4 , and R 5 at substitutable ring positions:
or a 6 membered aromatic ring optionally containing up to three heteroatoms individually selected from the group of O, N, and S, and optionally substituted by R 3 , R 4 , R 5 , and R 6 at substitutable ring positions:
R 3 , R 4 , R 5 , and R 6 are individually selected from H, C 1-18 alkyl, C 2-8 alkenyl, —OH, —OR 11 , NH 2 , —NHR 11 , —NHR 2 11 , —CN, —SO 2 H, ═O, ═NH, ═NR 11 , —NH—CO—NH 2 , —NH—CO—NHR 11 , and NH—CO—NR 2 11 , or any adjacent R 3 through R 6 may form a saturated, unsaturated, or aromatic 5 to 7 membered ring, optionally containing one to three heterocycles selected from the group consisting of N, O, and S, R 7 , R 8 , R 9 , and R 10 are individually selected from H, NR 2 11 , C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 aryl, C 6-14 heteroalkyl C 1-4 lower alkoxy, all of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl groups optionally substituted by R 12 or the pair R 7 and R 8 or the pair R 9 and R 10 may individually as pairs be ═O, —NH, or ═NHR 11 ,
where R 12 is —OH, —OR 11 ,
—NHR 11 ,
—SO 2 H, —SO 2 R 11 , F, Cl, Br, F 3 C—, —CN, or —NO 2 ,
where R 11 is C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, C 6-10 heteroaryl, each of R″ optionally substituted by C 1-4 lower alkyl, —OH, and —NH 2 , and wherein each alkyl, alkenyl, or cycloalkyl or alkenyl substituent may be interrupted by one or more non-adjacent heteroatoms selected from the group consisting of N, O, and S.
3. The compound of claim 2 , containing a basic ring structure selected from the group consisting of:
wherein N R represents the group
4. The compound of claim 1 , wherein R is selected from the group consisting of ethyl, 2-propyl, 1-butyl, 2-butyl, 3-cyanopropyl, 4′-fluorophenyl, and ethylthienyl.
5. The compound of claim 2 , wherein R is selected from the group consisting of ethyl, 2-propyl, 1-butyl, 2-butyl, and 3-cyanopropyl, 4′-fluorophenyl, and ethylthienyl.
6. The compound of claim 3 , wherein R is selected from the group consisting of ethyl, 2-propyl, 1-butyl, 2-butyl, 3-cyanopropyl, 4′-fluorophenyl and ethylthienyl.
7. The compound of claim 2 , having the formula
wherein X and Y are individually selected from the group consisting of
N, O, and S and X may also be CH 2 , and Y may also be CH,
R 7 , R 8 , R 9 , and R 10 , are each individually hydrogen, C 1-4 alkyl, or C 1-4 alkoxy, or either or both of the pairs R 7 and R 8 and R 9 and R 10 may be replaced by ═O, and wherein at least two of R 7 through R 10 are H, and wherein R is a C 2-8 lower alkyl, C 2-8 lower alkenyl, C 7-11 arylalkyl, C 6-10 heteroarylalkyl, said C 2-8 lower alkyl and C 2-8 lower alkenyl optionally substituted by —CN, and wherein
R 14 is C 1-8 lower alkoxy or H.
8. The compound of claim 7 wherein X is CH 2 and Y is CH, R 14 is H, each of R 7 through R 10 is H, and R is propyl, 3-cyanopropyl, 4′-fluorophenyl, or thienylethyl.
9. The compound of claim 8 which is
10. The compound of claim 8 , which is
11. A process of altering central nervous system (CNS) response in a mammalian species, said process comprising administering to said mammalian species an effective response altering amount of a differential CNS activity compound being a 2-aminotetralin or biosteric analog thereof containing a fused ring structure, one ring comprising an optionally ring substituted moiety
or a pharmaceutically acceptable salt or derivative of said compound, wherein
X is CH 2 , O, NH, or S,
n is 0 or 1, and
R is a C 2-20 hydrocarbon which optionally contains one or more heteroatoms selected from the group consisting of O, N, and S, and which may contain a keto, thio, ester, carbonate, urea, amide, or urethane group.
12. The process of claim 11 , said compound (I) comprising a compound of the formula
or a pharmaceutically acceptable salt or derivative thereof, wherein R 1 and R 2 together complete a 5 membered aromatic ring optionally containing up to 2 heteroatoms individually selected from the group consisting of O, N, and S, and optionally substituted by R 3 , R 4 , and R 5 at substitutable ring positions:
or a 6 membered aromatic ring optionally containing up to three heteroatoms individually selected from the group of O, N, and S, and optionally substituted by R 3 , R 4 , R 5 , and R 6 at substitutable ring positions:
R 3 , R 4 , R 5 , and R 6 are individually selected from H, C 1-18 alkyl, C 2-8 alkenyl, —OH, —OR 11 , NH 2 , —NHR 11 , —NHR 2 11 , —CN, —SO 2 H, ═O, ═NH, ═NR 11 , —NH—CO—NH 2 , —NH—CO—NHR 11 , and NH—CO—NR 2 11 , or any adjacent R 3 through R 6 may form a saturated, unsaturated, or aromatic 5 to 7 membered ring, optionally containing one to three heterocycles selected from the group consisting of N, O, and S, R 7 , R 8 , R 9 , and R 10 are individually selected from H, NR 2 11 , C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 aryl, C 6-14 heteroalkyl C 1-4 lower alkoxy, all of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl groups optionally substituted by R 12 or the pair R 7 and R 8 or the pair R 9 and R 10 may individually as pairs be ═O, —NH, or ═NHR 11 ,
where R 12 is
F, Cl, Br, F 3 C—, —CN, or —NO 2 ,
where R 11 is C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, C 1-10 heteroaryl, each of R″ optionally substituted by C 1-4 lower alkyl, —OH, and —NH 2 , and wherein each alkyl, alkenyl, or cycloalkyl or alkenyl substituent may be interrupted by one or more non-adjacent heteroatoms selected from the group consisting of N, O, and S.
13. A process of altering central nervous system (CNS) response in a mammalian species, said process comprising administering to said mammalian species an effective response altering amount of a differential CNS activity compound of claim 3 .
14. The process of claim 11 , wherein R is selected from the group consisting of ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-cyanopropyl, 4′-fluorophenyl, and ethylthienyl.
15. The process of claim 12 , wherein R is selected from the group consisting of ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-cyanopropyl, 4′-fluorophenyl, and ethylthienyl.
16. The process of claim 11 , wherein said compound has the formula
wherein X and Y are individually selected from the group consisting of N, O, and S and X may also be CR 2 and Y may also be CH,
R 7 , R 8 , R 9 , and R 10 , are each individually hydrogen, C 1-4 alkyl, or C 1-4 alkoxy, or either or both of the pairs R 7 and R 8 and R 9 and R 10 may be replaced by ═O, and wherein at least two of R 7 through R 10 are H, and wherein R is a C 2-8 lower alkyl, C 2-8 lower alkenyl, C 7-11 arylalkyl, C 6-10 heteroarylalkyl, said C 2-8 lower alkyl and C 2-8 lower alkenyl optionally substituted by —CN, and wherein
R 14 is C 1-8 lower alkoxy or H or a pharmaceutical salt or derivative thereof.
17. A process for altering the response of the dopamine D3 receptor to a greater degree than that of the dopamine D2 receptor, comprising administering to a mammalian species sufficient of a compound to provide a concentration of said compound of from 1 nM to 10 μM, said compound comprising an 2-aminotetralin or biosteric analog thereof containing a fused ring structure, one ring comprising an optionally ring substituted moiety
or a pharmaceutically acceptable salt or derivative of said compound, wherein
X is CH 2 , O, NH, or S,
n is 0, or 1, and
R is a C 2-20 hydrocarbon optionally containing one or more heteroatoms selected from the group consisting of O, N, and S, and optionally containing a keto, thio, ester, carbonate, urea, amide, or urethane group.
18. The process of claim 17 , wherein the ratio of differential activity of said compound, expressed as the ratio of the inhibition constants K i for the binding affinity of D2L receptors to the inhibition constant K i for the binding affinity of D3 receptors for [ 3 H]spiperone is greater than 100.
19. The process of claim 17 , wherein the ratio of differential activity of said compound, expressed as the ratio of the inhibition constants K i for the binding affinity of D2L receptors to the inhibition constant K i for the binding affinity of D3 receptors for [ 3 H]spiperone is greater than 200.
20. An aminotetralin derivative exhibiting differential binding activity with respect to D2 and D3 dopamine receptors, having the formula
wherein A is hydroxyl or an ester or ether thereof in the 5- or 7- ring positions, and B is fluoro or chloro in the 6-ring position; wherein R 14 is a hydrocarbon radical selected from the group consisting of C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, C 6-10 heteroaryl, C 7-18 alkaryl, C 7-18 aralkyl, C 7-18 alkheteroaryl, and C 7-18 heteroaralkyl, each of said hydrocarbon radicals optionally substituted by one or more substituents selected from the group consisting of hydroxyl, C 1-8 alkyl ester, halo, nitro, and cyano.
21. The amino tetralin derivative of claim 20 , wherein R 14 is 3-cyanopropyl or ethylthienyl.
22. A method of treating a central nervous system (CNS) disorder, said method comprising administrating to a mamalian patient in need of such treating, a CNS altering amount of a compound being a 2-aminotetralin or biosteric analog thereof containing a fused ring structure, one ring comprising an optionally ring substituted moiety
or a pharmaceutically acceptable salt or derivative of said compound, wherein
X is CH 2 , O, NH, or S,
n is 0 or 1, and
R is C 2-20 hydrocarbon which optionally contains one or more heteroatoms selected from the group consisting of O, N, and S, and which may contain a keto, thio, ester, carbonate, urea, amide, or urethane group.
23. The method of claim 22 , said compound (I) comprising a compound of the formula
or a pharmaceutically acceptable salt or derivative thereof,
wherein R 1 and R 2 together complete a 5 membered aromatic ring optionally containing up to 2 heteroatoms individually selected from the group consisting of O, N, and S, and optionally substituted by R 3 , R 4 , and R 5 at substitutable ring positions:
or a 6 membered aromatic ring optionally containing up to three heteroatoms individually selected from the group of O, N, and S, and optionally substituted by R 3 , R 4 , R 5 , and R 6 at substitutable ring positions:
R 3 , R 4 , R 5 , and R 6 are individually selected from H, C 1-18 alkyl, C 2-8 alkenyl, —OH, —OR 11 , NH 2 , —NHR 11 , —NHR 2 11 , —CN, —SO 2 H, ═O, ═NH, ═NR 11 , —NH—CO—NH 2 , —NH—CO—NHR 11 , and NH—CO—NR 2 11 , or any adjacent R 3 though R 6 may form a saturated, unsaturated, or aromatic 5 to 7 membered ring, optionally containing one to three heterocycles selected from the group consisting of N, O, and S, R 7 , R 8 , R 9 , and R 10 are individually selected from H, NR 2 11 , C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 aryl, C 6-14 heteroalkyl C 1-4 lower alkoxy, all of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl groups optionally substituted by R 12 or the pair R 7 and R 8 or the pair R 9 and R 10 may individually as pairs be ═O, —NH, or ═NHR 11 ,
where R 12 is
F, Cl, Br, F 3 C—, —CN, or —NO 2 ,
where R 11 is C 1-18 alkyl, C 2-18 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, C 6-10 heteroaryl, each of R″ optionally substituted by C 1-4 lower alkyl, —OH, and —NH 2 , and wherein each alkyl, alkenyl, or cycloalkyl or alkenyl substituent may be interrupted by one or more non-adjacent heteroatoms selected from the group consisting of N, O, and S.
24. The method of claim 22 , wherein said compound has the formula
wherein X and Y are individually selected from the group consisting of
N, O, and S and X may also be CH 2 , and Y may also be CH,
R 7 , R 8 , R 9 , and R 10 , are each individually hydrogen, C 1-4 alkyl, or C 1-4 alkoxy, or either or both of the pairs R 7 and R 8 and R 9 and R 10 may be replaced by ═O, and wherein at least two of R 7 through R 10 are H, and wherein R is a C 2-8 lower alkyl, C 2-8 lower alkenyl, C 7-11 arylalkyl, C 6-10 heteroarylalkyl, said C 2-8 lower alkyl and C 2-8 lower alkenyl optionally substituted by —CN, and wherein
R 14 is C 1-8 lower alkoxy or H.
25. The method of claim 24 , wherein X is CH 2 and Y is CH, R 14 is H, each of R 7 through R 10 is H, and R is propyl, 3-cyanopropyl, 4′-fluorophenyl, or thienylethyl.
26. The method of claim 22 , wherein said CNS disorder is a mental disorder.
27. The method of claim 22 , wherein said CNS disorder is schizophrenia.
28. The method of claim 22 , wherein said CNS disorder is Parkinson's disease.
29. The method of claim 22 , wherein said CNS disorder is cocaine addiction.
30. The method of claim 23 , wherein said CNS disorder is selected from the group consisting of mental disorder, schizophrenia, Parkinson's disease, and cocaine addiction.
31. The method of claim 25 , wherein said CNS disorder is selected from the group consisting of mental disorder, schizophrenia, Parkinson's disease, and cocaine addiction.