Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT
View Patent ↗The present invention relates to epiminocycloalkyl[b]indole derivatives as serotonin sub-type 6 (5-HT 6 ) modulators, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. These compounds are useful in the treatment of central nervous system disorders including obesity, metabolic syndrome, cognition, and schizophrenia. The subject compounds have the structure of formula (I) with the substituents being described herein.
1. A compound of formula (I):
wherein:
n is an integer from 1 to 2; and
R 1 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of R 1 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 2 is independently —S(O)R 8 , —S(O) 2 R 8 , C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NO 2 , C 1 -C 6 linear alkyl, and C 2 -C 6 alkenyl;
R 3 and R 6 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —O—(CH 2 ) p —C(O)NR 8 R 9 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, wherein p is an integer from 0 to 6;
R 4 and R 5 are independently H, C 1 -C 6 alkyl, halogen, or R 7 SO 2 —;
R 7 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each one of R 7 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl, each one of R 7 substituents optionally substituted from 1 to 3 times with substitutents selected from the group consisting of halogen, H, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and mono or polycyclic aryl;
R 8 and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur each one of R 8 and R 9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and a monocyclic heteroaryl; or R 8 and R 9 can combine to form a 4- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl, with the proviso that at least one of R 4 and R 5 , but not both, is R 7 SO 2 —;
or an oxide thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein n is 1.
3. The compound according to claim 2 , wherein
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 linear alkyl;
R 3 is H, C 1 -C 6 alkyl, or OR 8 ;
R 4 and R 6 are H;
R 5 is R 7 SO 2 —;
R 7 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstitued polycyclic heteroaryl; and
R 8 is C 1 -C 6 alkyl.
4. The compound according to claim 3 , wherein
R 3 is H, methyl, or ethyl.
5. The compound according to claim 2 , wherein
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 linear alkyl;
R 3 , R 4 , and R 6 are H; and
R 5 is R 7 SO 2 —.
6. The compound according to claim 5 , wherein R 1 is methyl.
7. The compound according to claim 5 , wherein R 1 is H.
8. The compound according to claim 2 , wherein
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 linear alkyl;
R 3 is Br, Cl, F, or I;
R 4 and R 6 are H; and
R 5 is R 7 SO 2 —.
9. The compound according to claim 1 , wherein n is 2.
10. The compound according to claim 9 , wherein
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 , R 4 , and R 6 are H, C 1 -C 6 alkyl, or OR 8 ; and
R 5 is R 7 SO 2 —.
11. The compound according to claim 1 , wherein
n is 1
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 linear alkyl;
R 3 , R 5 and R 6 are H; and
R 4 is R 7 SO 2 —.
12. The compound according to claim 1 , wherein
n is 2
R 1 is H or C 1 -C 6 alkyl;
R 2 is C 1 -C 6 linear alkyl;
R 3 , R 5 and R 6 are H; and
R 4 is R 7 SO 2 —.
13. The compound according to claim 1 which has the formula (Ia):
wherein
R 3 is H, Me, Et, or OR 8 ,
R 4 is H;
R 6 is H;
R 7 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl; and
R 8 is Me or Et.
14. The compound according to claim 1 , wherein R 7 is a substituted or unsubstituted monocyclic aryl.
15. The compound according to claim 14 , wherein the monocyclic aryl is a substituted or unsubstituted phenyl.
16. The compound according to claim 1 , wherein R 7 is a substituted or unsubstituted polycyclic aryl.
17. The compound according to claim 16 , wherein the substituted or unsubstituted polycyclic aryl is selected from the group consisting of naphthyl, azulenyl, fluorenyl, phenanthrenyl, anthracenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.
18. The compound according to claim 1 , wherein R 7 is a substituted or unsubstituted monocyclic heteroaryl.
19. The compound according to claim 18 , wherein the substituted or unsubstituted monocyclic heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
20. The compound according to claim 1 wherein R 7 is a substituted or unsubstituted polycyclic heteroaryl.
21. The compound according to claim 20 , wherein the substituted or unsubstituted polycyclic heteroaryl is selected from the group consisting of thienopyrrolyl, furopyrrolyl, indolyl, azaindolyl, isoindolyl, indolinyl indolizinyl, indazolyl, benzimidazolyl, imidazopyridinyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, pyrazolopyridinyl, triazolopyridinyl, thienopyridinyl, benzothiadiazolyl, benzofuyl, benzothiophenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, quinazolinyl, quinolizilinyl, phthalazinyl, benzotriazinyl, chromenyl, and naphthyridinyl.
22. The compound according to claim 1 , wherein the compound is present in the form of a pharmaceutical acceptable salt.
23. The compound according to claim 1 , wherein the compound is present in the form of an oxide.
24. The compound according to claim 1 , wherein the compound is a (+)-stereoisomer.
25. The compound according to claim 1 , wherein the compound is a (−)-stereoisomer.
26. A process for preparation of a product compound of formula (I):
wherein
n is an integer from 1 to 2; and
R 1 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of R 1 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 2 is independently —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —S(O)R 8 , —S(O) 2 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl;
R 3 and R 6 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —O—(CH 2 ) p —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, wherein p is an integer from 0 to 6;
R 4 and R 5 are independently H, C 1 -C 6 alkyl, halogen, or R 7 SO 2 —;
R 7 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each one of R 7 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and a mono or polycyclic heteroaryl, each one of substituents optionally substituted from 1 to 3 times with substitutents selected from the group consisting of halogen, H, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NHR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and mono or polycyclic aryl;
R 8 and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur each one of R 8 and R 9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and a monocyclic heteroaryl; or R 8 and R 9 can combine to form a 4- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl, with the proviso that at least one of R 4 and R 5 , but not both, is R 7 SO 2 —;
or an oxide thereof, or a pharmaceutically acceptable salt thereof said process comprising:
providing a first intermediate having the structure:
and
reacting a first intermediate with an electrophile R 1 Z under conditions effective to form the compound of formula (I), wherein Z is a leaving group.
27. The process according to claim 26 further comprising:
providing a sulfonyl epiminocycloalkyl[b]indole having the structure:
and
deprotecting the bridged amino group of a sulfonyl epiminocycloalkyl[b]indole under acidic conditions effective to form the first intermediate.
28. The process according to claim 27 , wherein said deprotecting under the acidic conditions is carried out with hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroboric acid, trifluoroacetic acid, or sulfuric acid.
29. The process according to claim 27 , wherein said providing a sulfonyl epiminocycloalkyl[b]indole comprises:
reacting a second intermediate having the structure:
with R 2 Y, wherein Y is a leaving group, and a base to produce a third intermediate having the structure:
and
subjecting the third intermediate to a reaction with arylsulfonyl salt under conditions effective to produce the sulfonyl epiminocycloalkyl[b]indole, wherein X is a leaving group.
30. The process according to claim 29 , wherein said subjecting is carried out with a palladium catalyst selected from the group consisting of bis(benzonitrile) palladium (II) chloride, palladium diacetate, palladium dibenzylidene acetone, tetrakis(triphenylphosphine) palladium, bis(triphenylphosphine) palladium (II) dichloride, bis(diphenylphosphineferrocene) palladium (II) dichloride, and bis(diphenylphosphineferrocene) palladium.
31. The process according to claim 29 , wherein the aryl sulfonyl salt is prepared by reacting an arylsulfonyl chloride having the structure:
with Na 2 SO 3 in presence of a base.
32. The process according to claim 31 , wherein the base is selected from the group consisting of sodium hydroxide and sodium bicarbonate.
33. The process according to claim 29 , wherein Y is a radical selected from the group consisting of halo, mesylate, tosylate, triflate, and acetate.
34. The process according to claim 29 further comprising:
selectively protecting a fourth intermediate having the structure:
by reacting it with Boc group containing compound under conditions effective to form the second intermediate.
35. The process according to claim 34 further comprising:
reacting a hydrazine having the structure:
with a ketone having structure:
wherein R is H or a protective group under conditions effective to form the fourth intermediate.
36. The process according to claim 35 further comprising:
reacting an aniline having the structure:
with a nitrite under conditions effective to form the hydrazine.
37. The process according to claim 36 , wherein said reacting is carried out with a Lewis acid selected from the group consisting of titanium tetrachloride, aluminum chloride, boron trifluoride, boron tribromide, dimethylboron bromide, phosphorous pentachloride, tin dichloride, and tin tetrachloride.
38. The method according to claim 36 , wherein the nitrite is selected from the group consisting of sodium nitrite, potassium nitrite, and lithium nitrite.
39. The process according to claim 36 further comprising:
reacting a nitroarene having the structure:
with a reducing agent under conditions effective to form the amine.
40. The process according to claim 27 further comprising:
sulfonylating a third intermediate having the structure:
in presence of an organolithium and sulfur dioxide under conditions effective to produce a lithium sulfinate intermediate having the structure:
and
subjecting the lithium sulfinate-intermediate to an acylation or heteroarylation with R 7 X in presence of a palladium catalyst under conditions effective to produce the sulfonyl epiminocycloalkyl[b]indole.
41. The process according to claim 40 , wherein the organolithium is selected from the group, n-butyllithium, t-butyllithium, sec-butyllithium, phenyl lithium, and lithium disopropyl amide.
42. The process according to claim 40 , wherein X is selected from the group consisting of chloro, bromo, iodo, and triflyl.
43. The process according to claim 27 further comprising:
halogenating a lithium sulfinate-intermediate having the structure:
under conditions effective to produce a halosulfonyl epiminocycloalkyl[b]indole having the structure:
wherein X 1 is Cl, Br, or I;
and
arylating the halosulfonyl epiminocycloalkyl[b]indole under conditions effective to produce the sulfonyl epiminocycloalkyl[b]indole.
44. The process according to claim 43 , wherein said halogenating is carried out with an agent selected from the group consisting of N-bromosuccinimide, N-chlorosuccinimide, and N-iodosuccinimide.
45. The process according to claim 43 , wherein said halogenating is carried out in an organic solvent which is polar, non polar, protic or aprotic.
46. The process according to claim 26 , wherein Z is selected from the group consisting of halo, mesylate, tosylate, triflate, and acetate.
47. A process for resolution of diastereomers comprising:
providing a mixture of the diastereomers of the compound of formula (II)
wherein:
R 3 and R 6 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 R 9 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl; and
X is independently chloro, bromo, iodo, or triflyl; and
subjecting the mixture to a resolution procedure under conditions effective to separate the diastereomers of the compound of formula (II) from one another.
48. The process according to claim 47 , wherein said providing comprises:
reacting a compound of formula (III):
and a cyclohexyl chloroformate having the structure:
under conditions effective to form the mixture of the diastereomers of the compound of formula (II).
49. The process according to claim 47 further comprising:
reacting one of the diastereomers of the compound of formula (II) under conditions effective to form the (−) enantiomer of a compound of formula (III)
50. The process according to claim 47 further comprising:
reacting one of the diastereomers of the compound of formula (II) under conditions effective to form a single diastereomer of the compound of formula (IV):
51. The process according to claim 50 further comprising:
protecting the single diastereomer of the compound of formula (IV) under conditions effective to form a single diastereomer of the compound of formula (II).
52. The process according to claim 51 further comprising:
reacting the single diastereomer of the compound of formula (II) under conditions effective to form the (+) enantiomer of the compound of formula (III)
53. The process of claim 26 , wherein R 2 is independently —S(O)R 8 , —S(O) 2 R 8 , C 1 -C 6 linear alkyl, straight or branched C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NO 2 , C 1 -C 6 alkyl, and C 2 -C 6 alkenyl.