Hexamethyleneiminyl tachykinin receptor antagonists

Details Hexamethyleneiminyl tachykinin receptor antagonists Hexamethyleneiminyl tachykinin receptor antagonists

1993-11-17

2002-06-11

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235200, C514S254090, C514S307000, C514S314000, C514S323000, C514S339000, C514S414000, C514S415000, C514S438000, C540S602000, C544S143000, C544S373000, C546S146000, C546S175000, C546S201000, C546S277400, C548S455000, C548S491000, C548S506000

Reexamination Certificate

active

06403577

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,
Peptides
, 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, 1, 2, or 3;
n is 0 or 1;
o is 0, 1, or 2;
p is 0 or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which groups may be substituted with one or two halo, C
1
-C
3
alkoxy, trifluoromethyl, C
1
-C
4
alkyl, phenyl-C
1
-C
3
alkoxy, or C
1
-C
4
alkanoyl groups;
R
1
is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C
1
-C
4
alkyl)-, phenyl-(C
1
-C
4
alkoxy)-, quinolinyl-(C
1
-C
4
alkyl)-, isoquinolinyl-(C
1
-C
4
alkyl)-, reduced quinolinyl-(C
1
-C
4
alkyl)-, reduced isoquinolinyl-(C
1
-C
4
alkyl)-, benzoyl-(C
1
-C
3
alkyl)-, 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
alkoxy, trifluoromethyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
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
3
alkyl)-, or anilinocarbonyl;
R
2
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkylsulfonyl, carboxy-(C
1
-C
3
alkyl)-, C
1
-C
3
alkoxycarbonyl-(C
1
-C
3
alkyl)-, or —CO—R
6
;
R
6
is hydrogen, C
1
-C
4
alkyl, C
1
-C
3
haloalkyl, phenyl, C
1
-C
3
alkoxy, C
1
-C
3
hydroxyalkyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or —(CH
2
)
q
—R
7
;
q is 0 to 3;
R
7
is carboxy, C
1
-C
4
alkoxycarbonyl, C
1
-C
4
alkylcarbonyloxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, C
1
-C
6
alkoxycarbonylamino, or
phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C
1
-C
4
alkyl)-, quinolinyl-(C
1
-C
4
alkyl)-, isoquinolinyl-(C
1
-C
4
alkyl)-, reduced quinolinyl-(C
1
-C
4
alkyl)-, reduced isoquinolinyl-(C
1
-C
4
alkyl)-, benzoyl-C
1
-C
3
alkyl;
any one of which R
7
groups may be substituted with halo, trifluoromethyl, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
or any one of which R
7
groups may be substituted with phenyl, piperazinyl, C
3
-C
8
cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C
2
-C
6
alkanoyl, or C
1
-C
4
alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
R
8
is hydrogen or C
1
-C
6
alkyl;
R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, 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; and
R
4
is hydrogen or C
1
-C
3
alkyl; with the proviso that if R
1
is hydrogen or halo, R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, or naphthyl; with the proviso that if R
1
is hydrogen or halo, R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, or naphthyl; or a pharmaceutically acceptable salt thereof.
In another embodiment, this invention encompasses the novel compounds of Formula I and the pharmaceutically acceptable salts, solvates, and prodrugs thereof, as well as pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel processes for the synthesis of the compounds of Formula I.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
All temperatures stated herein are in degrees Celsius (° C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
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
4
alkyl”.
“Divalent(C
1
-C
4
)alkyl” represents a straight or branched divalent saturated aliphatic chain having from one to four carbon atoms. Typical divalent(C
1
-C
4
)alkyl groups include methylene, ethyle

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