# US 2014/0194435 A1 · Novel substituted indolo 4,3 fg quinolines useful for treating migraine

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- Number: US 2014/0194435 A1
- Document ID: US20140194435A1
- Status: Published application
- Kind: A1
- Application number: 14/202,875
- 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/US20140194435A1

## 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 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:
R1 is (C1-C4) alkyl, substituted (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;
R7 is (C1-C4) alkyl;
R8 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl;
R9 is (C1-C4) alkyl;
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, 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;
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 methyl, R8 is not hydrogen and R9 is not sec-butyl;
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not n-butyl, R8 is not methyl and R9 is not methyl;
R7 is not isopropyl, R8 is not methyl and R9 is not benzyl;
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;
R7 is not ethyl, R8 is not hydrogen and R9 is not isobutyl;
provided that when R1 and R5 are methyl, R3 is —OH, R2, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl;
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 methyl, R8 is not hydrogen and R9 is not sec-butyl;
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 benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl;
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 methyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not isopropyl;
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 R1 and R5 are methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is iodine and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
provided that when R1 is methyl, R5 is n-propyl, 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 benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
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 (C1-C4) alkyl and R2, R3, R4, R10, R11, R12 and R13 are hydrogen that:
R6 is not
provided that when R1 is CH2NHMe2, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
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 benzyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
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;
R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl;
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;
R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
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

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:
R1 is (C1-C4) alkyl, substituted (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;
R5 is hydrogen, (C1-C3) alkyl, substituted (C1-C3) alkyl, or (C1-C3) perfluoroalkyl;
R7 is (C1-C4) alkyl;
R8 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl;
R9 is (C1-C4) alkyl;
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, 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;
provided that when R1 and R5 are methyl, R2, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl;
R7 is not methyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not ethyl, R8 is not hydrogen and R9 is not isobutyl;
R7 is not ethyl, R8 is not hydrogen and R9 is not isopropyl;
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;
R7 is not n-propyl, R8 is not methyl and R9 is not methyl;
R7 is not isopropyl, R8 is not methyl and R9 is not benzyl;
R7 is not ethyl, R8 is not hydrogen and R9 is not benzyl;
provided that when Rt is allyl, R5 is methyl, R2, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
provided that when R1 is CH2OH, R5 is methyl, R2, R10, R11, R12 and R13 are hydrogen and R6 is
that:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;
provided that when R1 is CH2OH, R5 is methyl, R2, 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 sec-butyl.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The method 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 7 (depends on 1)

The method 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 —OCOR107, n is 0, R3 and R4 are independently hydrogen or deuterium, R5 is —CH3 or —CF3, R6 is
R7 is methyl, ethyl or isopropyl, R8 is hydrogen or methyl, R9 is n-propyl, isopropyl, isobutyl or benzyl, R10, R11 and R12 are hydrogen; and R13 is hydrogen.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) has the structure:

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) has the structure:
wherein z is 5 or 8.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) has the structure:

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) has the structure:

### Claim 12 (depends on 2)

The method of claim 2, wherein R6 is
R7 is methyl, ethyl or isopropyl, R8 is hydrogen or methyl, R9 is n-propyl, isopropyl, sec-butyl, isobutyl or benzyl and R10, R11 and R12 are hydrogen.

### Claim 13 (depends on 2)

The method of claim 2, wherein R1 is (C1-C4) alkyl or (C1-C4) perfluoroalkyl and R6 is

### Claim 14 (depends on 2)

The method of claim 2, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7 and R6 is

### Claim 15 (depends on 2)

The method of claim 2, 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 16 (depends on 2)

The method of claim 2, 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, n is 0, R5 is —CH3 or —CF3, R6 is
R7 is methyl, ethyl or isopropyl, R8 is hydrogen or methyl, R9 is n-propyl, isopropyl, sec-butyl, isobutyl or benzyl, R10, R11 and R12 are hydrogen; and R13 is hydrogen.

### Claim 17 (depends on 2)

The method of claim 2, wherein the compound of Formula (II) has the structure:

### Claim 18 (depends on 2)

The method of claim 2, wherein the compound of Formula (II) has the structure:

### Claim 19 (depends on 2)

The method of claim 2, wherein the compound of Formula (II) has the structure:

### Claim 20 (depends on 2)

The method of claim 2, wherein the compound of Formula (II) has the structure:
wherein z is 5 or 8.

### Claim 21 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is formulated with a pharmaceutically acceptable vehicle.

### Claim 22 (depends on 2)

The method of claim 2, wherein the compound of Formula (II) is formulated with a pharmaceutically acceptable vehicle.