2-acylaminopropanamines as tachykinin receptor antagonists

Details 2-acylaminopropanamines as tachykinin receptor antagonists 2-acylaminopropanamines as tachykinin receptor antagonists

2000-01-27

2002-01-15

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S415000, C514S339000, C514S367000, C514S380000, C514S414000, C514S470000, C548S507000, C548S225000, C548S455000, C548S159000, C549S304000, C546S173000, C546S277400

Reexamination Certificate

active

06339094

ABSTRACT:

BACKGROUND OF THE INVENTION
Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin &agr;), and neurokinin B (also known as neuromedin K and neurokinin &bgr;). See, J. E. Maggio,
Peptides
, 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see, e.g., S. L. Shepheard, et al.,
British Journal of Pharmacology
, 108.11-20 (1993); S. M. Moussaoui, et al.,
European Journal of Pharmacology
, 238:421-424 (1993); and W. S. Lee, et al.,
British Journal of Pharmacology
, 112:920-924 (1994).
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in U.S. Pat. No. 5,491,140, issued Feb. 13, 1996; U.S. Pat. No. 5,328,927, issued Jul. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S. Pat. No. 5,344,830, issued Sep. 6, 1994; U.S. Pat. No. 5,331,089, issued Jul. 19, 1994; European Patent Publication 591,040 A1, published Apr. 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published Jan. 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published Mar. 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published Jan. 21, 1993; Canadian Patent Application 2154116, published Jan. 23, 1996; European Patent Publication 693,489, published Jan. 24, 1996; and Canadian Patent Application 2151116, published Dec. 11, 1995.
U.S. Pat. No. 5,530,009, issued Jun. 25, 1996, describes a 1,2-diacylaminopropane for use in treating conditions associated with an excess of tachykinins. This patent also teaches processes for preparing this compound.
In essence, this invention provides a class of potent non-peptidyl tachykinin receptor antagonists similar to those of U.S. Pat. No. 5,530,009. By virtue of their non-peptidyl nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I
wherein:
R
1
and R
2
are independently hydrogen, halo, C
1
-C
6
alkyl, hydroxy, or C
1
-C
6
alkoxy;
R
5
, R
6
, and R
7
, are independently hydrogen, halo, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, trifluoromethyl, or hydroxy;
R
3
is hydrogen, C
2
-C
7
alkanoyl, glycyl, or dimethylglycyl;
n is 1-6;
D is —S(O)
m
—, —NH—, or —O—,
m is 0, 1, or 2; and
R
8
is a monocyclic or bicyclic carbocyclic or heterocyclic group, optionally substituted with one or more moieties selected from the group consisting of oxo, C
1
-
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halo, and trifluoromethyl;
or a pharmaceutically acceptable salt or solvate thereof
In another embodiment this invention provides methods of treating a condition associated with an excess of tachykinins, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof
This invention also provides pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example “° C.” refers to degrees Celsius; “N” refers to normal or normality; “mol” refers to mole or moles; “mmol” refers to millimole or millimoles; “g” refers to gram or grams; “kg” refers to kilogram or kilograms; “L” refers to liter or liters; “ml” means milliliter or milliliters; “M” refers to molar or molarity; “MS” refers to mass spectrometry; and “NMR” refers to nuclear magnetic resonance spectroscopy.
“C
1
-C
6
alkoxy” represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C
1
-C
6
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term “C
1
-C
6
alkoxy” includes within its definition the terms “C
1
-C
4
alkoxy” and “C
1
-C
3
alkoxy”.
As used herein, the term “C
1
-C
12
alkyl” refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C
1
-C
12
alkyl” includes within its definition the terms “C
1
-
6
alkyl” and “C
1
-C
4
alkyl”.
“C
2
-C
7
alkanoyloxy” represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom. Typical C
2
-C
7
alkanoyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.
“C
3
-C
8
cycloalkyl” represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms. Typical C
3
-C
8
cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
“Halo” represents chloro, fluoro, bromo or iodo.
“C
1
-C
6
alkylthio” represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical C
1
-C
6
alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.
“C
1
-C
12
alkylenyl” refers to a straight or branched, divalent, saturated aliphatic chain of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl. The term “C
1
-C
6
alkylenyl” is encompassed within the term “C
1
-C
12
alkylenyl”.
“C
1
-C
10
alkylamino” represents a group of the formula
—NH(C
1
-C
10
alkyl)
wherein a chain having from one to ten carbon atoms is attached to an amino group. Typical C
1
-C
4
alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
“C

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