# US 2014/0194434 A1 · Novel substituted indolo 4,3 fg quinolines useful for treating migraine

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- Number: US 2014/0194434 A1
- Document ID: US20140194434A1
- Status: Published application
- Kind: A1
- Application number: 14/202,744
- Filed: 2014-03-10
- Published: 2014-07-10
- Earliest claimed: 2009-12-23
- Assignees: MAP Pharmaceuticals, Inc.
- Applicants: MAP Pharmaceuticals, Inc.
- Inventors: Robert O. Cook; THOMAS A. ARMER; Sergey Alexandrovich KOSAREV; Dejian Xie; Jian Zhang
- Web page: https://patentgrep.com/patent/US20140194434A1

## CPC

- C07D 519/02: Ergot alkaloids of the cyclic peptide type
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/24: Antidepressants
- C07D 457/04: with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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-HT1D and or 5-HT1B 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-HT2B 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

### Claim 1

A compound of Formula (I):
or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:
R1 is (C1-C4) alkyl or (C1-C4) perfluoroalkyl;
R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO2, —N3, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107;
R3 and R4 are independently hydrogen, deuterium, fluoro, hydroxy or methoxy;
R5 is hydrogen, (C1-C3) alkyl, substituted (C1-C4) alkyl or (C1-C3) perfluoroalkyl;
R6 is
R7 is isopropyl, sec-butyl, isobutyl, or t-butyl;
R8 is hydrogen, (C1-C4) alkyl substituted (C1-C4) alkyl, benzyl or substituted benzyl;
R9 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, (C2-C4) alkenyl or (C2-C4) alkynyl;
R10 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R108 or —CONR109R110,
R11 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R111 or —CONR112R113,
R12 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R114 or —CONR115R116;
R13 is hydrogen or halogen;
R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114, R115 and R116 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;
wherein substituted with reference to a saturated carbon atom is limited to —Ra, halo, —O−, ═O, —ORb, —SRb, —S−, ═S, —NRcRc, ═NRb, ═N—ORb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)2Rb, —S(O)2NRb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Rb is independently hydrogen or Ra; and each Rc is independently Rb or alternatively, the two Rcs are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S; and substituted with reference to an unsaturated carbon atom or an nitrogen atom in a heteroalkyl group is limited to —Ra, halo, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2Rb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc where Ra, Rb and Rc are as defined above;
provided that when R1 and R5 are methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not n-propyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 and R5 are methyl, R3 is —OCH3, R2, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 and R5 are methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is bromine and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
provided that when R1 is n-propyl, R5 is methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is bromine and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R1 is not allyl;
provided that when R1 is ethyl, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 is n-propyl, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 is hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 is CH2OCOCH3, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 is CH2OH, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that:
R6 is not
provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that:
R6 is not
provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that: R6 is not

### Claim 2 (depends on 1)

The compound of claim 1, wherein R6 is
R7 is isopropyl, R8 is hydrogen or methyl, R9 is n-propyl, isopropyl or isobutyl and R10, R11 and R12 are hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is (C1-C4) alkyl or (C1-C4) perfluoroalkyl and R6 is

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7 and R6 is

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7, R2 is (C1-C4) alkyl, (C1-C4) substituted alkyl, (C1-C4) acyl, (C1-C4) substituted acyl, halo, —NO2, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107, n is 0 or 1, R3 and R4 are independently hydrogen or deuterium, R5 is —CH3, —C2H5, —C3H7, —CF3, C2F5 or —C3F7, R6 is
R10, R11 and R12 are independently hydrogen, OH or (C1-C4) alkyl; and R13 is hydrogen or bromine.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is —CH3, —C2H5, -nC3H7, —CF3, C2F5 or -nC3F7, R2 is (C1-C2) alkyl, (C1-C2) substituted alkyl, halo, —NO2, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107, n is 0, R3 and R4 are independently hydrogen or deuterium, R5 is —CH3 or —CF3, R6 is
R7 is isopropyl, R8 is hydrogen or methyl, R9 is n-propyl, isopropyl or isobutyl, R10, R11 and R12 are hydrogen; and R13 is hydrogen.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.