H1—histamine receptor antagonists

Details H1—histamine receptor antagonists H1—histamine receptor antagonists

1999-06-07

2002-07-16

Venkat, Jyothsna (Department: 1627)

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

Organic compounds

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

C424S449000, C424S456000, C424S465000, C424S489000, C435S007100, C435S007200, C436S501000, C436S518000, C540S575000, C544S357000, C544S361000, C544S370000, C544S382000, C544S386000, C544S402000, C544S403000, C548S304700, C548S306100, C548S307400

Reexamination Certificate

active

06420560

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are H1 histamine receptor antagonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of allergic diseases such as rhinitis, urticaria, asthma, anaphylaxis, and the like.
REFERENCES
The following publications are cited in this application as superscript numbers:
1
Hypersensitivity-Type I
. In: Immunology. Chapter 19. Roitt, I., Brostoff, J., Male, D., Gower Medical Publishing. London, New York. (1995).
2 Histamine H1-receptor antagonists.
Burger's Medicinal Chemistry and Drug Discovery
. Fifth edition. Vol. 5: Wolff, M. E., Ed., John Wiley and Sons, Inc., (1997).
3 Hill, S. J. “Distribution, Properties, and Functional Characterisics of three classes of histamine receptor”.
Pharmacological Reviews.,
42(1):45 (1990).
4
Histamine, Bradykinin, and their antagonists
. In: The PharmacologicalBasis of Therapeutics. Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W. and Gilman, A. G. Ed., Chapter 25, McGraw-Hill Co., New York (1996).
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Asthma, rhinitis, urticara and anaphylaxis are common disorders that are the result of Type I hypersensitivity reactions
1
. Type I hypersensitivy reactions occur when antigens (allergens) stimulate the production of IgE antibodies by B lymphocytes
1
. The IgE, in turn binds to high affinity Fc receptors on the surface of tissue mast cells or blood basophils
1
. The binding of IgE to the Fc receptors stimulates a degranulation reaction by mast cells or blood basophils, in which chemical mediators, such as histamine are released
1
. The release of histamine causes a cascade of pathological sequela including the following
2
: 1) contraction of the smooth muscle of bronchi, which leads to obstruction of air flow to lungs; 2) relaxation of smooth muscle around in fine blood vessels, which causes vasodilation and decreases in blood pressure; 3) an increase in the permeability of the capillary walls and consequently the leakage of plasma components leading to tissue edema. The trilogy of effects of a hypersensitivity reaction result in pathologies associated with allergic diseases such as asthma, rhinitis, urticara, and anaphylaxis which are the cause of significant morbitity, and increasingly, mortality in humans
2
.
Histamine produces its pathological effects by binding to a receptor located on the membrane of cells in many tissues
2
. The receptors for histamine, which are part of a superfamily known as the G-protein coupled receptors (GPCRs), are seven transmembrane proteins
2
. Histamine receptors are further divided into subtypes, known as H1, H2 and H3. The type of histamine receptor expressed on cells is tissue specific
3
. Thus, H1 is found in smooth muscles of intestine, uterus, bronchi, urinary bladder, fine blood vessels and brain. H2 is expressed in stomach, smooth muscles of airway, and blood vessels of heart, and immunoreactive cells. H3 is expressed in brain and lung
3
. The pathological effects of histamine in hypersensitivity reactions appear primarily due to the interaction of histamine with the H1 receptor.
In order to prevent the pathological action of histamine a variety of drugs have been developed that interfere with the ability of histamine to bind to its receptor. Thus, drugs such as loratadine, terfenadine, diphenydramine, and cetirizeine, known as H1 receptor antagonists, prevent the binding of histamine to the cell and obviate the consequent synthesis and release of chemical mediators that produce the symptoms of allergy
4
. Unfortunately, these drugs do not selectively bind to H1 resulting in often severe side effects including myocardiopathies, sedation, and anticholinergic side effects. Thus there exists a need for drugs that bind with high affinity to H1 histamine receptors and provide potent, efficacious and long term effects effects.
The multibinding compounds of the present invention fulfill this need.
SUMMARY OF THE INVENTION
This invention is directed to novel multibinding compounds (agents) that are H1 histamine receptor antagonists and are therefore useful in the treatment and prevention of allergic diseases such as rhinitis, urticaria, asthma, anaphylaxis, and the like.
Accordingly, in one aspect this invention is directed to a multibinding compound comprising 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands is a H1 histamine receptor antagonist, and pharmaceutically acceptable salts thereof.
In second aspect, this invention provides a multibinding compound of Formula (I):
(L)
p
(X)
q
  (I)
wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20;
each X is independently a linker;
each ligand, L, is, independently of each other, a H1 histamine receptor antagonist; and pharmaceutically acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
More preferably, each ligand, L, that is a H1 histamine receptor antagonist is independently selected from a group consisting of:
(i) a compound of formula (a):
wherein:
n is 0, 1, or 2;
Q is carbon or nitrogen;
R
1
and R
2
are independently selected from the group consisting of hydrogen, halo, alkyl, carboxy, and alkylcarboxy;
R
3
is hydrogen or hydroxy;
R
4
is a covalent bond linking (a) to a linker;
(b) a compound of formula (b):
wherein:
— — — — is an optional bond;
R
5
is selected from the group consisting of hydrogen, halo, alkyl, carboxy, and alkylcarboxy; and
R
6
is covalent bond linking (b) to a linker;
(c) a compound of formula (c):
wherein:
n
1
is 1 or 2;
R
7
is -(alkylene)—O—R
9
where R
9
is alkyl; and
R
8
is a covalent bond linking the ligand to a linker;
(d) a compound of formula (d):
wherein:
A is nitrogen or oxygen;
R
10
is hydrogen or halo; and
R
11
is a covalent bond linking the ligand to a linker; and
(e) a compound of formula (e):
wherein:
R
12
is hydrogen or halo;
R
13
is alkyl; and
R
14
is a covalent bond linking the ligand to a linker; and pharmaceutically acceptable salts thereof.
Even more preferably, each linker, X, in the multibinding compound of Formula (I) independently has the formula:
—X
a
—Z—(Y
a
—Z)
m
—X
a
—
wherein:
m is an integer of from 0 to 20;
X
a
at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
each Y
a
at each separate occurrence is selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)
n
—, —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —NR′C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(X
a
)—NR′—, —NR′—C(X
a
)═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)
n
CR′R″—, —S(O)
n
—NR′—, —NR′—S(O)
n
—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that at least one of X
a
, Z, and Y
a
is not a covalent bond.
In a third aspect, this invention is directed to

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