Heterocyclic compounds

Details Heterocyclic compounds Heterocyclic compounds

2002-03-08

2004-10-12

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254090, C544S358000, C544S372000, C548S452000, C548S469000, C548S465000, C548S517000, C548S518000

Reexamination Certificate

active

06803362

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel, pharmaceutically-active fused heterocyclic compounds and methods of using them to treat or prevent disorders and conditions mediated by the histamine H
4
receptor.
BACKGROUND
Histamine was first identified as a hormone (Barger et al.,
J. Physiology
41:19-59, 1910) and has since been demonstrated to play a major role in a variety of physiological processes, including the inflammatory “triple response” via H
1
receptors (Ash et al.,
Br. J. Pharmacology
27:427-439, 1966), gastric acid secretion via H
2
receptors (Black et al.,
Nature
236:385-390, 1972), and neurotransmitter release in the central nervous system via H
3
receptors (Arrang et al.,
Nature
302: 832-837, 1983) (for review see Hill et al.,
Pharmacol. Rev
. 49: 253-278, 1997). All three histamine receptor subtypes have been demonstrated to be members of the superfamily of G-protein coupled receptors (Gantz et al.,
Proc. Natl. Acad. Sci. U.S.A
. 88:429-433, 1991; Lovenberg et al.,
Mol. Pharmacol
. 55:1101-1107, 1999; Yamashita et al.,
Proc. Natl. Acad. Sci. U.S.A
. 88:11515-11519, 1991). There are, however, additional functions of histamine that have been reported, for which no receptor has been identified. For example, in 1994, Raible et al. demonstrated that histamine and R-&agr;-methylhistamine could activate calcium mobilization in human eosinophils (Raible et al.,
Am. J. Respir. Crit. Care Med
. 149:1506-1511, 1994). These responses were blocked by the H
3
-receptor antagonist thioperamide. However, R-&agr;-methylhistamine was significantly less potent than histamine which was not consistent with the involvement of known H
3
receptor subtypes. Therefore, Raible et al. hypothesized the existence of a novel histamine receptor on eosinophils that was non-H
1
, -H
2
, or -H
3
. Most recently several groups (Oda et al.,
J. Biol. Chem
. 275(47):36781-36786, 2000; Liu et al.,
Mol. Pharmacol
. 59:420-426, 2001; Nguyen et al.,
Mol. Pharmacol
. 59:427-433, 2001; Zhu et al.,
Mol. Pharmacol
. 59(3):434-441, 2001; Morse et al.,
J. Pharmacol. Exp. Ther
. 296(3):1058-1066, 2001) have identified and characterized a fourth histamine receptor subtype, the H
4
receptor. This receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40% homology to the histamine H
3
receptor. In contrast to the H
3
receptor, which is primarily located in the brain, the H
4
receptor is expressed at greater levels in neutrophils and mast cells, among other cells, as reported by Morse et al. (see above).
Events that elicit the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function, or a combination of these. Many conditions, such as allergies, asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis, and autoimmune diseases, including rheumatoid arthritis and lupus, are characterized by excessive or prolonged inflammation. Inhibition of leukocyte recruitment can provide significant therapeutic value. Inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
Mast cell de-granulation (exocytosis) leads to an inflammatory response that may be initially characterized by a histamine-modulated wheal and flare reaction. A wide variety of immunological (e.g., allergens or antibodies) and non-immunological (e.g., chemical) stimuli may cause the activation, recruitment, and de-granulation of mast cells. Mast cell activation initiates allergic (H
1
) inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response. The histamine H2 receptors modulate gastric acid secretion, and the histamine H3 receptors affect neurotransmitter release in the central nervous system.
Examples of textbooks on the subject of inflammation include J. I. Gallin and R. Snyderman,
Inflammation: Basic Principles and Clinical Correlates
, 3
rd
Edition, (Lippincott Williams & Wilkins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin, “Inflammation and Fever”,
Pathophysiology Principles of Diseases
(Textbook for Medical Students, Academic Press, 1995); Cecil et al.,
Textbook Of Medicine
, 18
th
Edition (W. B. Saunders Company, 1988); and Steadmans Medical Dictionary.
A summary of the present invention follows.
SUMMARY OF THE INVENTION
The invention features a compound of formula (I) wherein:
Wherein R
1
is R
a
, R
a
R
b
—, R
a
—O—R
b
—, or (R
c
)(R
d
)N—R
b
—, where R
a
is H, cyano, —(C═O)N(R
c
)(R
d
), —C(═NH)(NH
2
), C
1-10
alkyl, C
3-8
alkenyl, C
3-8
cycloalkyl, C
2-5
heterocyclic radical, or phenyl; where R
b
is C
1-8
alkylene, C
2-8
alkenylene, C
3-8
cycloalkylene, bivalent C
3-8
heterocyclic radical, or phenylene; and R
c
and R
d
are each independently H, C
1-8
alkyl, C
2-8
alkenyl, C
3-8
cycloalkyl, or phenyl;
R
2
′ is H, methyl, ethyl, NR
p
R
q
, —(CO)NR
p
R
q
, —(CO)OR
r
, —CH
2
NR
p
R
q
, or CH
2
OR
r
; where R
p
, R
q
, and R
r
are independently selected from C
1-6
alkyl, C
3-6
cycloalkyl, phenyl; (C
3-6
cycloalkyl)(C
1-2
alkylene), benzyl or phenethyl; or R
p
and R
q
taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;
R
3
′ is H, methyl, ethyl, NR
s
R
t
, —(CO)NR
s
R
t
, —(CO)OR
u
, —CH
2
NR
s
R
t
, or CH
2
OR
u
; where R
s
, R
t
, and R
u
are independently selected from C
1-6
alkyl, C
3-6
cycloalkyl, phenyl; (C
3-6
cycloalkyl)(C
1-2
alkylene), benzyl or phenethyl; or R
s
and R
t
taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;
R
5
′ is methyl, ethyl, or H;
R
6
′ is methyl, ethyl, or H;
R
7
′ is methyl, ethyl, or H;
X
4
is NR
1
or S;
X
1
is CR
3
;
R
3
is F, Cl, Br, CHO, R
f
, R
f
R
g
—, R
f
—O—R
g
—, or (R
h
)(R
i
)N—R
g
—, where R
f
is H, C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, C
2-5
heterocyclic radical, or phenyl; where R
g
is C
1-6
alkylene, C
2-6
alkenylene, C
3-6
cycloalkylene, bivalent C
3-6
heterocyclic radical, or phenylene; and R
h
and R
i
are each independently H, C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, or phenyl;
X
2
is NR
e
or O, provided that X
2
is NR
e
where X
1
is N; R
e
is H or C
1-6
alkyl;
X
3
is N;
Z is ═O or ═S;
each of R
4
and R
6
is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C
1-4
alkoxy, or C
1-4
alkyl;
R
5
is H, F, Cl, Br, I, (C═O)R
j
, OH, nitro, NR
j
R
k
, cyano, phenyl, —OCH
2
—Ph, C
1-4
alkoxy, or C
1-4
alkyl;
R
7
is H, F, Cl, Br, I, (C═O)R
m
, OH, nitro, NR
l
R
m
, cyano, phenyl, —OCH
2
—Ph C
1-4
alkoxy, or C
1-4
alkyl;
wherein each of R
j
, R
k
, R
l
, and R
m
is independently selected from H, C
1-6
alkyl, hydroxy, phenyl, benzyl, phenethyl, and C
1-6
alkoxy;
each of the above hydrocarbyl (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, and so on) or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C
1-3
alkyl, halo, hydroxy, amino, and C
1-3
alkoxy;
wherein n is 0, 1, or 2; where n is 2, the moiety —(CHR
5
′)
n=2
— is —(CHR
5
′—CHR
7
′)— where CHR
5
′ is between CHR
6
′ and CHR
7
′;
provided at least one of R
1
, R
2
′, R
3
, R
4
, R
5
, R
6
, and R
7
is other than H when Z is O;
and provided, where Z is O, n=1, and each of R
4
, R
5
, R
6
, R
7
, R
2
′, R
3
′, R
5
′, and R
6
′ is H, (or at least 7, 8, or 9 of these 10 limitations apply) then (a) where X
2
is NH, then R
1
is (i) not methyl, pyridyl, phenyl, or benzyl, or (ii) is selected from the disclosed possibilities, but not C
1-2
alkyl and not a s

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