# US 5,705,519 A · Method for treating 5-HT.sub.2B receptor related conditions

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- Number: US 5,705,519 A
- Document ID: US5705519A
- Status: Granted
- Kind: A
- Application number: 08/440,013
- Filed: 1995-05-12
- Granted: 1998-01-06
- Earliest claimed: 1994-03-11
- Assignees: Eli Lilly and Company
- Inventors: James E. Audia; Marlene Cohen; Jaswant S. Gidda; David L. Nelson
- Web page: https://patentgrep.com/patent/US5705519A

## CPC

- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/42: Oxazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/48: Ergoline derivatives, e.g. lysergic acid, ergotamine
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/60: Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
- C07D 471/04: Ortho-condensed systems
- C07D 471/06: Peri-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides methods for binding a 5-HT.sub.2B receptor in mammals using a both known and novel compounds. Further, the invention provides a method for treating or preventing 5-HT.sub.2B related conditions. Finally, the invention provides an article of manufacture.

## Claims

### Claim 1

A method for treating a mammal suffering from or susceptible to a condition associated with abnormal or dysfunctional 5-HT.sub.2B receptor stimulation, comprising administering to the mammal an effective amount of a compound of the Formula ##STR193## wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.5' is C.sub.1 -C.sub.4 alkyl;
m is 1 or 2;
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.11 is C.sub.1 -C.sub.4 alkyl, OR.sub.5', fluoro, bromo, iodo, or chloro; and
R.sub.12' is hydrogen or C.sub.1 -C.sub.4 alkyl; or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein the compound is a 5-HT.sub.2B receptor antagonist.

### Claim 3 (depends on 1)

A method of claim 1 wherein the condition is urinary incontinence, bladder dysfunction, uterine dysfunction, a cardiovascular disorder, or a respiratory disorder.

### Claim 4 (depends on 3)

A method of claim 3 wherein the condition is a cardiovascular disorder.

### Claim 5 (depends on 3)

A method of claim 3 wherein the condition is a bladder dysfunction or urinary incontinence.

### Claim 6 (depends on 3)

A method of claim 3 wherein the condition is a respiratory disorder.

### Claim 7 (depends on 1)

The method of claim 1 wherein the condition is migraine headache.

### Claim 8

A method for treating a mammal suffering from or susceptible to a Functional Bowel Disorder associated with abnormal or dysfunctional 5-HT.sub.2B receptor stimulation, comprising administering to the mammal an effective amount of a compound of the Formula ##STR194## wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.5' is C.sub.1 -C.sub.4 alkyl;
m is 1 or 2;
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.11 is C.sub.1 -C.sub.4 alkyl, OR.sub.5', fluoro, bromo, iodo, or chloro; and
R.sub.12' is hydrogen or C.sub.1 -C.sub.4 alkyl; or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 9 (depends on 8)

The method of claim 8 wherein the Functional Bowel Disorder is Irritable Bowel Syndrome, ichlasia, hypertonic lower esophpageal sphincter, tachygastria, hypermotility associated with irritable bowel syndrome, or constipation.

### Claim 10

A method for blocking a 5-HT.sub.2B receptor in a mammal comprising administering to the mammal a 5-HT.sub.2B receptor-blocking dose of a compound of the Formula ##STR195## wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.5' is C.sub.1 -C.sub.4 alkyl;
m is 1 or 2;
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.11 is C.sub.1 -C.sub.4 alkyl, OR.sub.5', fluoro, bromo, iodo, or chloro; and
R.sub.12' is hydrogen or C.sub.1 -C.sub.4 alkyl; or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 11 (depends on 10)

The method of claim 10 wherein the mammal is a human.

### Claim 12

A method for selectively blocking a 5-HT.sub.2B receptor in a mammal comprising administering to the mammal a 5-HT.sub.2B selective compound of the Formula ##STR196## wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.5' is C.sub.1 -C.sub.4 alkyl;
m is 1 or 2;
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.11 is C.sub.1 -C.sub.4 alkyl, OR.sub.5', fluoro, bromo, iodo, or chloro; and
R.sub.12' is hydrogen or C.sub.1 -C.sub.4 alkyl; or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 13

An article of manufacture comprising a pharmaceutical agent of the Formula ##STR197## wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.5' is C.sub.1 -C.sub.4 alkyl;
m is 1 or 2;
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or C.sub.7 -C.sub.20 arylalkyl;
R.sub.11 is C.sub.1 -C.sub.4 alkyl, OR.sub.5', fluoro, bromo, iodo, or chloro; and
R.sub.12' is hydrogen or C.sub.1 -C.sub.4 alkyl;
or a pharmaceutically acceptable salt or solvate thereof, contained within a packaging material that has a label indicating that the pharmaceutical agent can be used for treating a condition associated with dysfunctional or abnormal 5-HT.sub.2B receptor stimulation.