US2014194435A1PendingUtilityA1
Novel substituted indolo 4,3 fg quinolines useful for treating migraine
Est. expiryDec 23, 2029(~3.5 yrs left)· nominal 20-yr term from priority
A61P 25/00A61P 25/16A61P 25/06A61P 25/24A61P 3/00C07D 519/02A61P 1/08C07D 457/04
55
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are novel ergoline derivatives and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1D and or 5-HT 1B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the 5-HT 2B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of regulating serotonin transport using the compounds and compositions disclosed herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating or preventing migraine in a patient comprising administering to the patient in need thereof a compound of Formula (I):
or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:
R 1 is (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl;
R 2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO 2 , —N 3 , —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OC(O)R 107 ;
R 3 and R 4 are independently hydrogen, deuterium, fluoro, hydroxy or methoxy;
R 5 is hydrogen, (C 1 -C 3 ) alkyl, substituted (C 1 -C 4 ) alkyl or (C 1 -C 3 ) perfluoroalkyl;
R 7 is (C 1 -C 4 ) alkyl;
R 8 is hydrogen, (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl, benzyl or substituted benzyl;
R 9 is (C 1 -C 4 ) alkyl;
R 10 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 108 or —CONR 109 R 110 ,
R 11 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 111 or —CONR 112 R 113 ,
R 12 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 114 or —CONR 115 R 116 ;
R 13 is hydrogen or halogen;
R 101 , R 102 , R 103 , R 104 , R 105 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , R 115 and R 116 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and
k is 0, 1 or 2;
n is 0, 1, 2 or 3;
provided that when R 1 and R 5 are methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not sec-butyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not n-butyl, R 8 is not methyl and R 9 is not methyl;
R 7 is not isopropyl, R 8 is not methyl and R 9 is not benzyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not n-propyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not ethyl, R 8 is not hydrogen and R 9 is not isobutyl;
provided that when R 1 and R 5 are methyl, R 3 is —OH, R 2 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not sec-butyl;
provided that when R 1 and R 5 are methyl, R 3 is —OCH 3 , R 2 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not sec-butyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not sec-butyl;
provided that when R 1 and R 5 are methyl, R 2 , R 3 , R 4 , R 10 , R 11 and R 12 are hydrogen, R 13 is bromine and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
provided that when R 1 is n-propyl, R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 and R 12 are hydrogen, R 13 is bromine and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
provided that when R 1 and R 5 are methyl, R 2 , R 3 , R 4 , R 10 , R 11 and R 12 are hydrogen, R 13 is iodine and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 1 is methyl, R 5 is n-propyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 1 is not allyl;
provided that when R 1 is ethyl, R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
provided that when R 1 is n-propyl, R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 is hydrogen and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl
provided that when R 1 is (C 1 -C 4 ) alkyl and R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen that:
R 6 is not
provided that when R 1 is CH 2 NHMe 2 , R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
provided that when R 1 is CH 2 OCOCH 3 , R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 1 is CH 2 OH, R 5 is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 1 and R 5 are methyl and R 2 , R 3 and R 4 are hydrogen that: R 6 is not
provided that when R 1 and R 5 are methyl and R 2 , R 3 and R 4 are hydrogen that: R 6 is not
provided that when R 1 and R 5 are methyl and R 2 , R 3 and R 4 are hydrogen that: R 6 is not
2 . A method of treating or preventing migraine in a patient comprising administering to the patient in need thereof a compound of Formula (II):
or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:
R 1 is (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl;
R 2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO 2 , —N 3 , —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OC(O)R 107 ;
R 5 is hydrogen, (C 1 -C 3 ) alkyl, substituted (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) perfluoroalkyl;
R 7 is (C 1 -C 4 ) alkyl;
R 8 is hydrogen, (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl, benzyl or substituted benzyl;
R 9 is (C 1 -C 4 ) alkyl;
R 10 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 108 or —CONR 109 R 110 ;
R 11 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 111 or —CONR 112 R 113 ,
R 12 is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 114 or —CONR 115 R 116 ;
R 13 is hydrogen or halogen;
R 101 , R 102 , R 103 , R 104 , R 105 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , R 115 and R 116 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and
k is 0, 1 or 2;
n is 0, 1, 2 or 3;
provided that when R 1 and R 5 are methyl, R 2 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not benzyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not methyl, R 8 is not hydrogen and R 9 is not sec-butyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not ethyl, R 8 is not hydrogen and R 9 is not isobutyl;
R 7 is not ethyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not isopropyl;
R 7 is not n-propyl, R 8 is not methyl and R 9 is not methyl;
R 7 is not isopropyl, R 8 is not methyl and R 9 is not benzyl;
R 7 is not ethyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R t is allyl, R 5 is methyl, R 2 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 1 is CH 2 OH, R 5 is methyl, R 2 , R 10 , R 11 , R 12 and R 13 are hydrogen and R 6 is
that:
R 7 is not methyl, R 8 is not hydrogen and R 9 is not benzyl;
provided that when R 1 is CH 2 OH, R 5 is methyl, R 2 , R 10 , R 11 , and R 12 are hydrogen, R 13 is bromine and R 6 is
that:
R 7 is not isopropyl, R 8 is not hydrogen and R 9 is not sec-butyl.
3 . The method of claim 1 , wherein R 6 is
R 7 is methyl, ethyl or isopropyl, R 8 is hydrogen or methyl, R 9 is n-propyl, isopropyl, isobutyl or benzyl and R 10 , R 11 and R 12 are hydrogen.
4 . The method of claim 1 , wherein R 1 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl and R 6 is
5 . The method of claim 1 , wherein R 1 is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7 or i-C 3 F 7 and R 6 is
6 . The method of claim 1 , wherein R 1 is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7 or i-C 3 F 7 , R 2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, (C 1 -C 4 ) acyl, (C 1 -C 4 ) substituted acyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OC(O)R 107 , n is 0 or 1, R 3 and R 4 are independently hydrogen or deuterium, R 5 is —CH 3 , —C 2 H 5 , —C 3 H 7 , —CF 3 , C 2 F 5 or —C 3 F 7 , R 6 is
R 10 , R 11 and R 12 are independently hydrogen, OH or (C 1 -C 4 ) alkyl; and R 13 is hydrogen or bromine.
7 . The method of claim 1 , wherein R 1 is —CH 3 , —C 2 H 5 , -nC 3 H 7 , —CF 3 , C 2 F 5 or -nC 3 F 7 , R 2 is (C 1 -C 2 ) alkyl, (C 1 -C 2 ) substituted alkyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OCOR 107 , n is 0, R 3 and R 4 are independently hydrogen or deuterium, R 5 is —CH 3 or —CF 3 , R 6 is
R 7 is methyl, ethyl or isopropyl, R 8 is hydrogen or methyl, R 9 is n-propyl, isopropyl, isobutyl or benzyl, R 10 , R 11 and R 12 are hydrogen; and R 13 is hydrogen.
8 . The method of claim 1 , wherein the compound of Formula (I) has the structure:
9 . The method of claim 1 , wherein the compound of Formula (I) has the structure:
wherein z is 5 or 8.
10 . The method of claim 1 , wherein the compound of Formula (I) has the structure:
11 . The method of claim 1 , wherein the compound of Formula (I) has the structure:
12 . The method of claim 2 , wherein R 6 is
R 7 is methyl, ethyl or isopropyl, R 8 is hydrogen or methyl, R 9 is n-propyl, isopropyl, sec-butyl, isobutyl or benzyl and R 10 , R 11 and R 12 are hydrogen.
13 . The method of claim 2 , wherein R 1 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl and R 6 is
14 . The method of claim 2 , wherein R 1 is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7 or i-C 3 F 7 and R 6 is
15 . The method of claim 2 , wherein R 1 is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7 or i-C 3 F 7 , R 2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, (C 1 -C 4 ) acyl, (C 1 -C 4 ) substituted acyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OC(O)R 107 , n is 0 or 1, R 3 and R 4 are independently hydrogen or deuterium, R 5 is —CH 3 , —C 2 H 5 , —C 3 H 7 , —CF 3 , C 2 F 5 or —C 3 F 7 , R 6 is
R 10 , R 11 and R 12 are independently hydrogen, OH or (C 1 -C 4 ) alkyl; and R 13 is hydrogen or bromine.
16 . The method of claim 2 , wherein R 1 is —CH 3 , —C 2 H 5 , -nC 3 H 7 , —CF 3 , C 2 F 5 or -nC 3 F 7 , R 2 is (C 1 -C 2 ) alkyl, (C 1 -C 2 ) substituted alkyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106 or —OC(O)R 107 , n is 0, n is 0, R 5 is —CH 3 or —CF 3 , R 6 is
R 7 is methyl, ethyl or isopropyl, R 8 is hydrogen or methyl, R 9 is n-propyl, isopropyl, sec-butyl, isobutyl or benzyl, R 10 , R 11 and R 12 are hydrogen; and R 13 is hydrogen.
17 . The method of claim 2 , wherein the compound of Formula (II) has the structure:
18 . The method of claim 2 , wherein the compound of Formula (II) has the structure:
19 . The method of claim 2 , wherein the compound of Formula (II) has the structure:
20 . The method of claim 2 , wherein the compound of Formula (II) has the structure:
wherein z is 5 or 8.
21 . The method of claim 1 , wherein the compound of Formula (I) is formulated with a pharmaceutically acceptable vehicle.
22 . The method of claim 2 , wherein the compound of Formula (II) is formulated with a pharmaceutically acceptable vehicle.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.