Carboxylic acid derivatives as IP antagonists

Details Carboxylic acid derivatives as IP antagonists Carboxylic acid derivatives as IP antagonists

2001-03-14

2004-02-17

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S375000, C514S365000, C514S255050, C548S235000, C548S202000, C544S238000, C544S359000

Reexamination Certificate

active

06693098

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to carboxylic acid derivatives, and associated pharmaceutically acceptable salts and solvates thereof, associated pharmaceutical compositions, and methods for use as prostaglandin IP (I
2
or PGI
2
) antagonists.
BACKGROUND OF THE INVENTION
Prostaglandins or prostanoids (PGs) are a group of bioactive compounds derived from membrane phospholipids and are formed from 20-carbon essential fatty acids containing three, four, or five double bonds, and a cyclopentane ring. They fall into several main classes designated by the letters D, E, F, G, H, or I, and they are distinguished by substitutions to the cyclopentane ring. The main classes are further subdivided by subscripts 1, 2, or 3, which reflect their fatty acid precursors. Thus, PGI
2
has a double ring structure, and the subscript 2 indicates that it is related to arachidonic acid.
PGI
2
(also known as prostacyclin) acts on platelets and blood vessels to inhibit aggregation and to cause vasodilation, and is thought to be important for vascular homeostasis. It has been suggested that PGI
2
may contribute to the antithrombogenic properties of the intact vascular wall. PGI
2
is also thought to be a physiological modulator of vascular tone that functions to oppose the actions of vasoconstrictors. The importance of these vascular actions is emphasized by the participation of PGI
2
in the hypotension associated with septic shock. Although prostaglandins do not appear to have direct effects on vascular permeability, PGI
2
markedly enhances edema formation and leukocyte infiltration by promoting blood flow in the inflamed region. Therefore, IP receptor antagonists may prevent conditions associated with excessive bleeding such as, but not limited to, hemophilia and hemorrhaging, may relieve hypotension related to septic shock, and may reduce edema formation.
Several in vivo analgesia studies in rodents suggest that PGI
2
plays a major role in the induction of hyperalgesia. Likewise, in vitro studies provide substantial evidence to suggest that “PGI
2
-preferring” (IP) receptors act as important modulators of sensory neuron function (K. Bley et al,
Trends in Pharmacological Sciences
1998, 19(4):141-147.). Since IP receptors in sensory neurons are coupled to activation of both adenylyl cyclase and phospholipase C, and hence, cAMP-dependent protein kinase and protein kinase C, these receptors can exert powerful effects on ion channel activity and thus neurotransmitter release. Evidence of a prominent role for IP receptors in inflammatory pain has been obtained from recent studies in transgenic mice lacking the IP receptor (T. Murata et al.,
Nature
1997, 388, 678-682).
In addition to being mediators of hyperalgesia, prostaglandins are known to be generated locally in the bladder in response to physiologic stimuli such as stretch of the detrusor smooth muscle, injuries of the vesical mucosa, and nerve stimulation (K. Anderson,
Pharmacological Reviews
1993, 45(3), 253-308). PGI
2
is the major prostaglandin released from the human bladder. There are some suggestions that prostaglandins may be the link between detrusor muscle stretch produced by bladder filling and activation of C-fiber afferents by bladder distension. It has been proposed that prostaglandins may be involved in the pathophysiology of bladder disorders. Therefore, antagonists of prostaglandin IP receptors are expected to be useful in the treatment of such conditions.
Antagonists of IP receptors are also expected to find a utility in respiratory allergies wherein PGI
2
production in response to an allergen is present, or in respiratory conditions such as asthma.
Additional information relating to prostaglandins and their receptors is described in Goodman & Gillman's,
The Pharmacological Basis of Therapeutics
, ninth edition, McGraw-Hill, New York, 1996, Chapter 26, pages 601-616. Thus antagonists which can selectively treat the above mentioned conditions by acting on the IP receptor, are desirable.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 5,250,517 assigned to F. Hoffmann-La Roche AG refers to certain N-hydroxyalkyl amino acid amide derivatives as inhibitors of renin for treating hypertension.
U.S. Pat. No. 5,610,176 and U.S. Pat. No. 5,981,755 assigned to Warner-Lambert refer to certain indole derivatives useful as tachykinin receptor antagonists.
EP published application EP 902018 assigned to F. Hoffmann-La Roche AG refers to certain 2-(arylphenyl)amino-imidazoline derivatives as IP antagonists.
PCT published application WO 97/19911 assigned to Thomae refers to certain amino acid derivatives as neuro-peptide Y antagonists.
Japanese patent applications JP 06184086 and JP 06072985 refer to certain tetrazolylbiphenylmethylurea derivatives as angiotensin II antagonists.
German patent application DE 1934783 assigned to Farbenfabrik Bayer AG and French patent application FR 1554051 assigned to Ciba Ltd refer to the use of biphenylisopropoxycarbonyl derivatives as amino protecting reagents in the synthesis of peptides.
Bley et al.,
Trends in Pharmacological Sciences
1998, 19 (4), 141-147 refer to the role of IP prostanoid receptors in inflammatory pain.
Smith et al.,
British Journal of Pharmacology
1998, 124(3), 513-523 refer to characterization of prostanoid receptor-evoked responses in rat sensory neurons.
Murata et al.,
Nature
1997, 388 (6643), 678-682 refer to altered pain perception and inflammatory response in mice lacking prostacyclin receptors.
Anderson et al.,
Pharmacological Reviews
1993, 45(3), 253-308 refer to Pharmacology of lower urinary tract smooth muscles and penile erectile tissues.
Coleman et al.,
Pharmacological Review
1994, 46(2), 205-229 refer to properties, distribution and structure of prostanoid receptors and their subtypes.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I:
wherein:
R
1
, R
2
, and R
3
are each independently in each occurrence optionally substituted aryl or optionally substituted heteroaryl;
R
4
is —COOH or tetrazolyl;
A is independently in each occurrence a single bond, —O(CH
2
)
p
—, —S(CH
2
)
p
—, —NR′(CH
2
)
p
—, —(CH
2
)
p
O—, —O(CH
2
)
p
O—, —(CH
2
)
p
O(CH
2
)
p
—, —(CH
2
)
n
CO(CH
2
)
n
—, —CON—, —NCO—; —(CH
2
)
p
—, —C═C—, or —C≡C—;
R′ is hydrogen or lower alkyl;
B is independently in each occurrence —(CH
2
)
q
—, —CH
2
O—, —CH
2
S— or —CH
2
N—;
m, p, and q are each independently in each occurrence an integer from 1 to 3 inclusive;
n and r are each independently in each occurrence an integer from 0 to 3 inclusive;
or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, R
4
is —COOH.
In a preferred embodiment, R
4
is —COOH, R
1
and R
2
are optionally substituted aryl; more preferably, R
4
is —COOH, R
1
and R
2
are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano; and even more preferably R
4
is —COOH, R
1
and R
2
are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is a single bond or —(CH
2
)
p
—.
In another preferred embodiment, R
4
is —COOH, R
1
and R
2
are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R
3
is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, A is a single bond, m is 1, n and r are 0, and B is —CH
2
—.
In another preferred embodiment, R
4
is —COOH, R
1
and R
2
are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is —(CH
2
)
p
O—, —O(CH
2
)
p
—, or —(CH
2
)
p
O(CH
2
)
p
—; in a more preferred embodiment, R
4
is —COOH, R
1
, R
2
and R
3
are phenyl optiona

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