Imidazolinyl tachykinin receptor antagonists

Details Imidazolinyl tachykinin receptor antagonists Imidazolinyl tachykinin receptor antagonists

1994-06-10

2001-01-16

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S254050, C514S393000, C514S399000, C514S400000, C514S402000, C548S312100, C548S350100, C548S354100, C548S355100

Reexamination Certificate

active

06175013

ABSTRACT:

BACKGROUND OF THE INVENTION
Tachykinins are a family of peptides which share the common amidated carboxy terminal sequence,
Phe-Xaa-Gly-Leu-Met-NH
2
hereinafter referred to as SEQ ID NO:1. 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. Substance P has the following amino acid sequence,
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH
2
hereinafter referred to as SEQ ID NO:2.
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,
Pentides,
6 (Supplement 3):237-243 (1985) for a review of these discoveries. Neurokinin A has the following amino acid sequence,
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH
2
hereinafter referred to as SEQ ID NO:3. The structure of neurokinin B is the amino acid sequence,
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH
2
hereinafter referred to as SEQ ID NO:4.
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.
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.
In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide 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 encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I
wherein:
m is 0 or 1;
n is 0 or 1;
x is —(CHR
4
)
p
—(CHR
6
)
q
—, where,
p is 0 or 1;
q is 0 or 1; and
R
4
and R
6
are independently selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
2
is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
any one of which groups may be substituted with one or two moieties independently selected from the group consisting of halo, C
1
-C
3
alkoxy, trifluoromethyl, C
1
-C
4
alkyl, phenyl-C
1
-C
3
alkoxy, and C
1
-C
4
alkanoyl groups;
R
1
is hydrogen, trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, hexamethyleneiminyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, tetrahydropyridinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C
1
-C
6
alkylidenyl)-, phenyl-(C
1
-C
4
alkoxy)-, quinolinyl-(C
1
-C
6
alkylidenyl)-, isoquinolinyl-(C
1
-C
6
alkylidenyl)-, reduced quinolinyl-(C
1
-C
6
alkylidenyl)-, reduced isoquinolinyl-(C
1
-C
6
alkylidenyl)-, benzoyl-(C
1
-C
6
alkylidenyl)-, C
1
-C
4
alkyl, or —NH—CH
2
—R
5
;
any one of which R
1
groups may be substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, amino, C
1
-C
4
alkylamino, or di(C
1
-C
4
alkyl)amino;
or any one of which R
1
groups may be substituted with phenyl, piperazinyl, C
3
-C
8
cycloalkyl, benzyl, C
1
-C
4
alkyl, piperidinyl, pyridinyl, pyrimidinyl, C
2
-C
6
alkanoylamino, pyrrolidinyl, C
2
-C
6
alkanoyl, or C
1
-C
4
alkoxycarbonyl;
any one of which groups may be substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
or R
1
is amino, a leaving group, hydrogen, C
1
-C
4
alkylamino, or di(C
1
-C
4
alkyl)amino;
R
5
is pyridyl, anilino-(C
1
-C
6
alkylidenyl)-, or anilinocarbonyl;
R
8
is hydrogen or C
1
-C
6
alkyl; and
R
3
is phenyl, phenyl-(C
1
-C
6
alkylidenyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, C
1
-C
8
alkyl, naphthyl, C
2
-C
8
alkenyl, or hydrogen;
any one of which groups except hydrogen may be substituted with one or two halo, C
1
-C
3
alkoxy, C
1
-C
3
alkylthio, nitro, trifluoromethyl, or C
1
-C
3
alkyl groups;
or a pharmaceutically acceptable salt or solvate thereof.
In other embodiments this invention encompasses the novel compounds of Formula I and the salts and solvates of those compounds, as well as pharmaceutical formulations comprising at least one compound of Formula I, or a pharmaceutically acceptable salt or solvent of said compound, in combination with one or more pharmaceutically acceptable carrier, diluents, or excipients.
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; “mmol” refers to millimole or millimoles; “g” refers to gram or grams; “ml” means milliliter or milliliters; “M” refers to molar or molarity; “MS” refers to mass spectrometry; “IR” refers to infrared spectroscopy; and “NMR” refers to nuclear magnetic resonance spectroscopy.
As used herein, the term “C
1
-C
6
alkyl” refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 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
6
alkyl” includes within its definition the term “C
1
-C
3
alkyl”.
“C
1
-C
6
alkylidenyl” refers to a straight or branched, divalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, and hexylenyl.
“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. The term “C
1
-C
6
alkylthio” includes within its definition the term “C
1
-C
3
alkylthio”.
The term “C
2
-C
8
alkenyl” as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to eight carbon atoms. Typical C
2
-C
8
alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
“C
5
-C
8
cycloalkenyl” represents a hydrocarbon ring structure containing from five to eight carbon atoms and having at least one double bond within that ring, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C
1
-C
4
)alkyl, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, carboxy, C
1
-C
4
alkoxycarbonyl, carbamoyl, N-(C
1
-C
4
)alkylcarbamoyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino or —(CH
2
)
a
—R
c

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