U.S. patent application number 14/995616 was filed with the patent office on 2016-10-13 for 7-azoniabicyclo[2.2.1]heptane derivatives, methods of production, and pharmaceutical uses thereof.
The applicant listed for this patent is Theron Pharmaceuticals, Inc.. Invention is credited to Jurg R. PFISTER, Gwenaella RESCOURIO, Meenakshi S. VENKATRAMAN, Xiaoming ZHANG.
Application Number | 20160296497 14/995616 |
Document ID | / |
Family ID | 43928126 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160296497 |
Kind Code |
A1 |
PFISTER; Jurg R. ; et
al. |
October 13, 2016 |
7-AZONIABICYCLO[2.2.1]HEPTANE DERIVATIVES, METHODS OF PRODUCTION,
AND PHARMACEUTICAL USES THEREOF
Abstract
Muscarinic acetylcholine receptor antagonists and methods of
using them for the treatment of muscarinic acetylcholine
receptor-mediated diseases, such as pulmonary diseases, are
provided
Inventors: |
PFISTER; Jurg R.;
(Sunnyvale, CA) ; RESCOURIO; Gwenaella;
(Sunnyvale, CA) ; VENKATRAMAN; Meenakshi S.;
(Sunnyvale, CA) ; ZHANG; Xiaoming; (Sunnyvale,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Theron Pharmaceuticals, Inc. |
Sunnyvale |
CA |
US |
|
|
Family ID: |
43928126 |
Appl. No.: |
14/995616 |
Filed: |
January 14, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14252031 |
Apr 14, 2014 |
9320731 |
|
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14995616 |
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13512873 |
Oct 16, 2012 |
8742131 |
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PCT/US11/22760 |
Jan 27, 2011 |
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14252031 |
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61386450 |
Sep 24, 2010 |
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61336952 |
Jan 28, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/04 20180101; C07D
487/20 20130101; A61K 31/407 20130101; A61P 1/12 20180101; A61P
43/00 20180101; A61P 15/00 20180101; A61K 31/4188 20130101; A61P
13/10 20180101; A61K 45/06 20130101; A61P 11/00 20180101; A61P
13/02 20180101; A61P 1/00 20180101; A61P 13/00 20180101; A61P 11/06
20180101; Y02A 50/475 20180101; A61P 11/02 20180101; A61K 9/0078
20130101; C07D 487/08 20130101 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 31/4188 20060101 A61K031/4188; A61K 9/00 20060101
A61K009/00 |
Claims
1.-27. (canceled)
28. A method of making a pharmaceutical composition comprising:
combining i. a stereochemically pure compound with a stereochemical
purity of at least 80% according to formula (II) ##STR00046##
wherein, in the compound of formula (II): R.sub.1 is independently
selected from phenyl or thienyl, both optionally substituted with
an alkyl, alkoxy, halo, or COOR group; R.sub.2 is independently
selected from phenyl, thienyl, cyclopentyl, cyclohexyl,
1-alkylcyclopentyl, 1-alkylcyclohexyl, 1-hydroxycyclopentyl or
1-hydroxycyclohexyl, where phenyl, thienyl, cyclopentyl,
cyclohexyl, 1-alkylcyclopentyl, 1-alkylcyclohexyl,
1-hydroxycyclopentyl or 1-hydroxycyclohexyl are optionally
substituted with an alkyl, alkoxy, halo, or COOR group; or wherein
R.sub.1 and R.sub.2 together are 9-xanthenyl, where 9-xanthenyl is
substituted on either or both benzene rings with an alkyl, alkoxy,
halo, or COOR group; R.sub.3 is OH; R.sub.4 and R.sub.5 are
independently selected from lower alkyl, alkoxycarbonylalkyl,
aralkyl, or aryloxyalkyl, where alkoxycarbonylalkyl and/or aralkyl
are optionally substituted with an alkyl, alkoxy, halo, or COOR
group; or wherein R.sub.4 and R.sub.5 together with the ring to
which they are attached form a five- or six-membered ring
optionally substituted with aryl or aryloxy; R is a lower alkyl; *,
*, and *** are each independently a stereocenter, the stereocenters
*, ** and *** are present in one of the following combinations: (i)
* is (R), ** is (R), and *** is (S), or (ii) * is (S), ** is (S),
and *** is (R), or (iii) * is (R), ** is (S), and *** is (R), or
(iv) * is (S), ** is (R), and *** is (S); or (v) * is (S), ** is
(R), and *** is (R); or (vi) * is (R), ** is (R), and *** is (R);
or (vii) * is (R), ** is (S), and *** is (S); or (viii) * is (S),
** is (S), and *** is (S); wherein, X.sup..crclbar. represents a
pharmaceutically acceptable anion; and ii. at least one
pharmaceutically acceptable carrier or excipient.
29. The method of claim 28, wherein, in the compound of formula
(II), R.sub.1 is phenyl, optionally substituted with an alkyl,
alkoxy, halo, or COOR group.
30. The method of claim 29, wherein, in the compound of formula
(II), R.sub.1 is unsubstituted phenyl.
31. The method of claim 28, wherein, in the compound of formula
(II), R.sub.2 is cyclopentyl.
32. The method of claim 28, wherein, in the compound of formula
(II), R.sub.4 and R.sub.5 are independently C.sub.1-C.sub.4
alkyl.
33. The method of claim 32, wherein, in the compound of formula
(II), both R.sub.4 and R.sub.5 are methyl.
34. The method of claim 28, wherein, in the compound of formula
(II), R.sub.1 is unsubstituted phenyl and R.sub.2 is
cyclopentyl.
35. The method of claim 28, wherein, in the compound of formula
(II), R.sub.1 is unsubstituted phenyl, R.sub.2 is cyclopentyl, and
R.sub.4 and R.sub.5 are independently C.sub.1-C.sub.4 alkyl.
36. The method of claim 28, wherein, in the compound of formula
(II), X.sup.- is selected from the group consisting of acetate,
besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate,
bromide, calcium edentate, camphorsulfonate (camsylate), carbonate,
chloride, chlorotheophyllinate, citrate, edetate, ethanedisulfonate
(edisylate), ethanesulfonate (esylate), fumarate, gluceptate
(glucoheptonate), gluconate, glucuronate, glutamate,
hexylresorcinate, hydroxynaphthoate, hippurate, iodide,
isethionate, lactate, lactobionate, lauryl sulfate (estolate),
malate, maleate, mandelate, mesylate, methanesulfonate,
methylnitrate, methylsulfate, mucate, naphthoate, napsylate,
nitrate, octadecanoate, oleate, oxalate, pamoate, pantothenate,
phosphate, polygalacturonate, salicylate, stearate, succinate,
sulfate, sulfosalicylate, tannate, tartrate, teoclate,
toluenesulfonate (tosylate), and trifluoroacetate.
37. The method of claim 36, wherein, in the compound of formula
(II), X.sup.- is selected from the group consisting of chloride,
bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, and
toluenesulfonate.
38. The method of claim 37, wherein, in the compound of formula
(II), X.sup.- is bromide.
39. The method of claim 28, wherein the pharmaceutical composition
further comprises one or more additional therapeutic agents.
40. The method of claim 39, wherein at least one of the one or more
additional therapeutic agents is selected from the group consisting
of an anti-inflammatory agent, a bronchodilator, an antihistamine,
and an antitussive agent.
41. The method of claim 28, wherein the pharmaceutical composition
is formulated for administration by inhalation.
42. The method of claim 41, wherein the pharmaceutical composition
is in a form of an inhalable powder.
43. The method of claim 41, wherein the pharmaceutical composition
is in a form of an inhalable aerosol.
44. The method of any one of claims 41-43, wherein the
pharmaceutical composition is suitable for delivery by an
inhalation nebulizer.
45. The method of claim 28, wherein the pharmaceutically acceptable
carrier or the excipient is selected from one or more of calcium
phosphate, magnesium stearate, talc, monosaccharides,
disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium
carboxymethyl cellulose, dextrose, hydroxypropyl-3-cyclodextrin,
polyvinylpyrrolidinone, low melting waxes, or ion exchange
resin.
46. The method of claim 28, wherein the pharmaceutical composition
further comprises a preservative.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of Ser. No.
14/252,031, filed Apr. 14, 2014, which is a divisional application
of Ser. No. 13/512,873, filed Oct. 16, 2012, which is a National
Stage entry of International Application Serial No.
PCT/US11/022760, filed Jan. 27, 2011, which claims the benefit of
U.S. Provisional Application No. 61/386,450, filed Sep. 24, 2010,
and U.S. Provisional Application No. 61/336,952, filed Jan. 28,
2010, each of which applications are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to 7-azoniabicyclo[2.2.1]heptane
derivatives, pharmaceutical compositions of the derivatives, and
the use thereof in treating muscarinic acetylcholine receptor
mediated diseases of the respiratory tract.
BACKGROUND OF THE INVENTION
[0003] Acetylcholine released from cholinergic neurons in the
peripheral and central nervous systems affects many different
biological processes through interaction with two major classes of
acetylcholine receptors--the nicotinic and the muscarinic
acetylcholine receptors. Muscarinic acetylcholine receptors
(mAChRs) belong to the superfamily of G-protein coupled receptors
that have seven transmembrane domains. There are five subtypes of
mAChRs, termed M.sub.1-M.sub.5, and each is the product of a
distinct gene. Each of these five subtypes displays unique
pharmacological properties. Muscarinic acetylcholine receptors are
widely distributed in vertebrate organs where they mediate many
vital functions. Muscarinic receptors can mediate both inhibitory
and excitatory actions. For example, in smooth muscle located in
the airways, M.sub.3 mAChRs mediate contractile responses. For a
review, see Caufield, Pharmac. Ther. 58, 319 (1993).
[0004] In the lung, mAChRs have been localized to smooth muscle in
the trachea and bronchi, the submucosal glands, and the
parasympathetic ganglia. Muscarinic receptor density is greatest in
parasympathetic ganglia and then decreases in density from the
submucosal glands to tracheal and then bronchial smooth muscle.
Muscarinic receptors are nearly absent from the alveoli. For a
review of mAChR expression and function in the lungs, see Fryer and
Jacoby, Am. J. Respir. Crit. Care Med. 158, 154 (1998).
[0005] Three subtypes of mAChRs have been identified as important
in the lungs, M.sub.1, M.sub.2 and M.sub.3 mAChRs. The M.sub.3
mAChRs, located on airway smooth muscle, mediate muscle
contraction. Stimulation of M.sub.3 mAChRs activates the enzyme
phospholipase C via binding of the stimulatory G protein Gq/11
(Gs), leading to liberation of phosphatidyl
inositol-4,5-bisphosphate, resulting in phosphorylation of
contractile proteins. M.sub.3 mAChRs are also found on pulmonary
submucosal glands. Stimulation of this population of M.sub.3 mAChRs
results in mucus secretion.
[0006] M.sub.2 mAChRs make up approximately 50-80% of the
cholinergic receptor population on airway smooth muscles. Although
the precise function is still unknown, they inhibit
catecholaminergic relaxation of airway smooth muscle via inhibition
of cAMP generation. Neuronal M.sub.2 mAChRs are located on
postganglionic parasympathetic nerves. Under normal physiologic
conditions, neuronal M.sub.2 mAChRs provide tight control of
acetylcholine release from parasympathetic nerves. Inhibitory
M.sub.2 mAChRs have also been demonstrated on sympathetic nerves in
the lungs of some species. These receptors inhibit release of
noradrenaline, thus decreasing sympathetic input to the lungs.
[0007] M.sub.1 mAChRs are found in the pulmonary parasympathetic
ganglia where they function to enhance neurotransmission. These
receptors have also been localized to the peripheral lung
parenchyma, however their function in the parenchyma is
unknown.
[0008] Muscarinic acetylcholine receptor dysfunction in the lung
has been noted in a variety of different pathophysiological states.
In particular, in asthma and chronic obstructive pulmonary disease
(COPD), inflammatory conditions lead to loss of inhibitory M.sub.2
muscarinic acetylcholine autoreceptor function on parasympathetic
nerves supplying the pulmonary smooth muscle, causing increased
acetylcholine release following vagal nerve stimulation (Fryer et
al., Life Sci. 64, 449 (1999)). This mAChR dysfunction results in
airway hyperreactivity and hyperresponsiveness mediated by
increased stimulation of M.sub.3 mAChRs. Thus the identification of
potent mAChR antagonists would be useful as therapeutics in these
mAChR-mediated disease states.
[0009] COPD is an imprecise term that encompasses a variety of
progressive health problems including chronic bronchitis and
emphysema, and it is a major cause of mortality and morbidity in
the world. Smoking is the major risk factor for the development of
COPD; nearly 50 million people in the U.S. alone smoke cigarettes,
and an estimated 3,000 people take up the habit daily. As a result,
COPD is expected to rank among the top five diseases as a
world-wide health burden by the year 2020. Inhaled anticholinergic
therapy is currently considered the "gold standard" as first line
therapy for COPD (Pauwels et al., Am. J. Respir. Crit. Care Med.
163, 1256 (2001)).
[0010] Despite the large body of evidence supporting the use of
anticholinergic therapy for the treatment of airway hyperreactive
diseases such as COPD, relatively few anticholinergic compounds are
available for use in the clinic for pulmonary indications. More
specifically, in the United States, ipratropium (Atrovent; also as
Combivent in combination with albuterol) and tiotropium (Spiriva)
are currently the only inhaled anticholinergics marketed for the
treatment of hyperreactive airway diseases. While the latter is a
potent and long-acting anti-muscarinic agent, it is not available
as a combination with other pharmacological agents such as
albuterol. This appears to be due to the lack of sufficient
chemical stability of tiotropium in the presence of certain
additional agents.
[0011] Thus, there remains a need for novel anticholinergic agents,
i.e., agents that inhibit the binding of acetylcholine to its
receptors, which can be co-formulated with other pharmaceuticals
and which can be administered conveniently, such as once a day, for
the treatment of hyperreactive airway diseases such as asthma and
COPD.
[0012] Since mAChRs are widely distributed throughout the body, the
ability to apply anticholinergic agents locally and/or topically to
the respiratory tract is particularly advantageous, as it would
allow for lower doses of the drug to be utilized. Furthermore, the
ability to design topically active drugs that have long duration of
action, and in particular, are retained either at the receptor or
by the lung, would avoid unwanted side effects that may be seen
with systemic anticholinergic exposure. However, other muscarinic
acetylcholine receptor-mediated diseases respond to systemic
administration. Thus, medications useful for respiratory disorders
can be administered systemically when appropriate for treatment of
the respiratory disorder, or when appropriate for treatment of a
non-respiratory disorder.
SUMMARY OF THE INVENTION
[0013] This invention provides for compounds useful for treating,
and methods of treating, a muscarinic acetylcholine receptor
(mAChR) mediated disease, which method comprises administering an
effective amount of a stereochemically pure compound of Formula (I)
or Formula (II).
[0014] This invention also relates to compounds which inhibit the
binding of acetylcholine to its receptors. This invention also
relates to methods of inhibiting the binding of acetylcholine to
its receptors in a subject in need thereof which comprises
administering to aforementioned subject an effective amount of a
stereochemically pure compound of Formula (I) or Formula (II).
[0015] The present invention also provides for the novel
stereochemically pure compounds of Formula (I) or Formula (II), and
pharmaceutical compositions comprising a stereochemically pure
compound of Formula (I) or Formula (II), and a pharmaceutically
acceptable excipient, carrier, or diluent.
[0016] In one embodiment, the invention provides compounds having
the structures shown by Formula (I):
##STR00001##
[0017] where R.sub.1 is phenyl or thienyl, optionally substituted
with alkyl, alkoxy, halo or COOR groups;
[0018] R.sub.2 is R.sub.1, cyclopentyl, cyclohexyl,
1-alkylcyclopentyl or 1-alkylcyclohexyl;
[0019] or R.sub.1 and R.sub.2 together can be 9-xanthenyl or
9-hydroxyxanthenyl optionally substituted on either or both benzene
rings with alkyl, alkoxy, halo or COOR groups;
[0020] or the group R.sub.1R.sub.2R.sub.3C can be 10-phenothiazinyl
optionally substituted on either or both benzene rings with alkyl,
alkoxy, halo or COOR groups;
[0021] R.sub.3 is H, or OH;
[0022] R.sub.4 and R.sub.5 are lower alkyl, alkoxycarbonylalkyl,
aralkyl, or aryloxyalkyl (the latter two optionally substituted
with alkyl, alkoxy, halo or the group COOR) or together form a
five- or six-membered ring optionally substituted with aryl or
aryloxy;
[0023] R is lower alkyl; and
[0024] X.sup.- represents a pharmaceutically acceptable anion
associated with the positive charge of the N atom, including but
not limited to chloride, bromide, iodide, sulfate,
methanesulfonate, benzenesulfonate, and toluenesulfonate. X.sup.-
can be a monovalent or polyvalent anion.
[0025] In another embodiment, the invention provides a compound of
Formula (I), wherein the compound is stereochemically pure.
[0026] In one embodiment, R.sub.1 is independently selected from
phenyl, optionally substituted with alkyl, alkoxy, halo or COOR
groups, such as --C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8
alkyl, --F, --Cl, --Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4
alkyl groups. In another embodiment, R.sub.1 is unsubstituted
phenyl.
[0027] In one embodiment, R.sub.2 is cyclopentyl.
[0028] In one embodiment, R.sub.3 is OH.
[0029] In one embodiment, and R.sub.5 are independently selected
from C.sub.1-C.sub.4 alkyl. In another embodiment, both R.sub.4 and
R.sub.5 are methyl.
[0030] In one embodiment, the invention embraces an isolated
compound of Formula (I), optionally additionally comprising a
pharmaceutically acceptable carrier or excipient, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of Formula (I), optionally
additionally comprising a pharmaceutically acceptable carrier or
excipient, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0031] In one embodiment, the invention provides a stereochemically
pure compound of the structure shown by Formula (II):
##STR00002##
[0032] where A is independently selected from the group consisting
of:
[0033] --C(R.sub.1)(R.sub.2)(R.sub.3),
[0034] where R.sub.1 is independently selected from phenyl or
thienyl, optionally substituted with alkyl, alkoxy, halo or COOR
groups, such as --C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8
alkyl, --F, --Cl, --Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4
alkyl groups;
[0035] where R.sub.2 is independently selected from phenyl,
thienyl, cyclopentyl, cyclohexyl, 1-hydroxycyclopentyl or
1-hydroxycyclohexyl, where phenyl, thienyl, cyclopentyl,
cyclohexyl, 1-hydroxycyclopentyl or 1-hydroxycyclohexyl are
optionally substituted with alkyl, alkoxy, halo or COOR groups,
such as --C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8 alkyl, --F,
--Cl, --Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4 alkyl groups;
and
[0036] where R.sub.3 is H or OH;
[0037] 9-xanthenyl or 9-hydroxyxanthenyl, optionally substituted on
either or both benzene rings with alkyl, alkoxy, halo or COOR
groups, such as --C.sub.1-C.sub.8 alkyl, --O--C1-C.sub.8 alkyl,
--F, --Cl, --Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4 alkyl
groups; and
[0038] 10-phenothiazinyl, optionally substituted on either or both
benzene rings with alkyl, alkoxy, halo or COOR groups, such as
--C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8 alkyl, --F, --Cl,
--Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4 alkyl groups;
[0039] R.sub.4 and R.sub.5 are independently selected from lower
alkyl (such as C.sub.1-C.sub.4 alkyl), alkoxycarbonylalkyl (such as
--C.sub.1-C.sub.8 alkyl-O--(C.dbd.O)--C.sub.1-C.sub.8 alkyl),
aralkyl (such as --C.sub.1-C.sub.8 alkyl-C.sub.6-C.sub.10 aryl), or
aryloxyalkyl (such as --C.sub.1-C.sub.8 alkyl-O--C.sub.6-C.sub.10
aryl), where alkoxycarbonylalkyl and aralkyl can be optionally
substituted with alkyl, alkoxy, halo or the group COOR (such as
--C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8 alkyl, --F, --Cl,
--Br, --I, or --C(.dbd.O)--O--C.sub.1-C.sub.4 alkyl groups) or
together form a five- or six-membered ring optionally substituted
with aryl (such as --C.sub.6-C.sub.10 aryl) or aryloxy (such as
--O--C.sub.6-C.sub.10 aryl);
[0040] R is lower alkyl; and
[0041] X.sup.- represents a pharmaceutically acceptable anion,
including but not limited to chloride, bromide, iodide, sulfate,
methanesulfonate, benzenesulfonate, and toluenesulfonate. X.sup.-
can be a monovalent or polyvalent anion.
[0042] In one embodiment, A is the group
--C(R.sub.1)(R.sub.2)(R.sub.3). In another embodiment, R.sub.1 is
independently selected from phenyl, optionally substituted with
alkyl, alkoxy, halo or COOR groups, such --C.sub.1-C.sub.8 alkyl,
--O--C.sub.1-C.sub.8 alkyl, --F, --Cl, --Br, --I, or
--C(.dbd.O)--O--C.sub.1-C.sub.4 alkyl groups. In another
embodiment, R.sub.1 is unsubstituted phenyl.
[0043] In one embodiment, A is the group
--C(R.sub.1)(R.sub.2)(R.sub.3). In another embodiment, R.sub.2 is
cyclopentyl.
[0044] In one embodiment, A is the group
--C(R.sub.1)(R.sub.2)(R.sub.3). In another embodiment, R.sub.3 is
OH.
[0045] In one embodiment, R.sub.4 and R.sub.5 are independently
selected from C.sub.1-C.sub.4 alkyl. In another embodiment, both
R.sub.4 and R.sub.5 are methyl.
[0046] In one embodiment, the invention embraces an isolated
compound of Formula (II), optionally additionally comprising a
pharmaceutically acceptable carrier or excipient, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of Formula (II), optionally
additionally comprising a pharmaceutically acceptable carrier or
excipient, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0047] Included in the scope of this invention is each active,
stereochemically pure isomer of a compound of Formula (I) or
Formula (II), including crystalline forms, amorphous forms,
hydrates, or solvates. The invention includes each isolated,
stereochemically pure compound of Formula (I) or Formula (II).
[0048] The invention also embraces a pharmaceutical formulation
comprising a stereochemically pure compound of Formula (I) or
Formula (II) and a pharmaceutically acceptable carrier or
excipient, and optionally one or more other therapeutic agents. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents exclude(s) compounds (5), (6),
(7), and/or (8) as defined herein, or an alternate salt thereof.
The foregoing embodiments may optionally also add the proviso that
the one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0049] In one embodiment, the pharmaceutically acceptable anion
associated with any of the compounds disclosed herein is selected
from the group consisting of acetate, besylate (benzenesulfonate),
benzoate, bicarbonate, bitartrate, bromide, calcium edentate,
camphorsulfonate (camsylate), carbonate, chloride,
chlorotheophyllinate, citrate, edetate, ethanedisulfonate
(edisylate), ethanesulfonate (esylate), fumarate, gluceptate
(glucoheptonate), gluconate, glucuronate, glutamate,
hexylresorcinate, hydroxynaphthoate, hippurate, iodide,
isethionate, lactate, lactobionate, lauryl sulfate (estolate),
malate, maleate, mandelate, mesylate, methanesulfonate,
methylnitrate, methylsulfate, mucate, naphthoate, napsylate,
nitrate, octadecanoate, oleate, oxalate, pamoate, pantothenate,
phosphate, polygalacturonate, salicylate, stearate, succinate,
sulfate, sulfosalicylate, tannate, tartrate, teoclate,
toluenesulfonate (tosylate), and trifluoroacetate. The anion can be
a monovalent anion or a polyvalent anion.
[0050] The invention also embraces a method of using the present
compounds, such as a stereochemically pure compound of Formula (I)
or Formula (II), for treating a variety of indications, including
but not limited to diseases mediated by muscarinic acetylcholine
receptors.
[0051] The invention also embraces a method of using the present
compounds, such as a stereochemically pure compound of Formula (I)
or Formula (II), for treating respiratory tract disorders such as
chronic obstructive pulmonary disorder (COPD, also called chronic
obstructive lung disease), chronic bronchitis, asthma, chronic
respiratory obstruction, pulmonary fibrosis, pulmonary emphysema,
rhinorrhea, allergic rhinitis, occupational lung diseases including
pneumoconiosis (such as black lung disease, silicosis and
asbestosis), acute lung injury (ALI), and acute respiratory
distress syndrome (ARDS). Other, non-respiratory medical conditions
that can be treated with muscarinic receptor antagonists include,
but are not limited to, genitourinary tract disorders, such as
urinary urge incontinence, overactive bladder or detrusor
hyperactivity and their symptoms; gastroesophageal reflux disease
(GERD); gastrointestinal tract disorders, such as irritable bowel
syndrome, diverticular disease, achalasia, gastrointestinal
hypermotility disorders and diarrhea; and the like.
[0052] In another embodiment, the invention embraces a
stereochemically pure compound of the formula:
##STR00003##
(1 S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
##STR00004##
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
##STR00005##
(1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-; or
##STR00006##
(1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
[0053] where X.sup.- is a pharmaceutically acceptable anion.
X.sup.- can be a monovalent anion or a polyvalent anion. Each
compound can optionally additionally comprise a pharmaceutically
acceptable carrier or excipient, and optionally additionally
comprise one or more other therapeutic agents. The foregoing
embodiments may optionally also add the proviso that the one or
more other therapeutic agents exclude(s) compounds (5), (6), (7),
and/or (8) as defined herein, or an alternate salt thereof. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0054] In another embodiment, the invention embraces a
stereochemically pure compound of the formula:
##STR00007##
(1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
##STR00008##
(1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
##STR00009##
(1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
and
##STR00010##
(1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane with anion X.sup.-;
[0055] where X.sup.- is a pharmaceutically acceptable anion.
X.sup.- can be a monovalent anion or a polyvalent anion. Each
compound can optionally additionally comprise a pharmaceutically
acceptable carrier or excipient, and optionally additionally
comprise one or more other therapeutic agents. The foregoing
embodiments may optionally also add the proviso that the one or
more other therapeutic agents exclude(s) compounds (1), (2), (3),
and/or (4) as defined herein, or an alternate salt thereof. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0056] In another embodiment, the invention embraces specific
compounds of the formula:
##STR00011##
(1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00012##
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00013##
(1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide; and
##STR00014##
(1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide; in
stereochemically pure form. Each compound can optionally
additionally comprise a pharmaceutically acceptable carrier or
excipient, and optionally additionally comprise one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0057] In another embodiment, the invention embraces specific
compounds of the formula:
##STR00015##
(1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00016##
(1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00017##
(1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide; and
##STR00018##
(1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide; in
stereochemically pure form. Each compound can optionally
additionally comprise a pharmaceutically acceptable carrier or
excipient, and optionally additionally comprise one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents is
not another compound of Formula (I) and/or Formula (II).
[0058] In another embodiment, the invention embraces a composition
consisting essentially of a compound of the formula:
##STR00019##
(1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00020##
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide
##STR00021##
(1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide;
##STR00022##
(1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide; in
stereochemically pure form, or consisting essentially of a mixture
of (1), (2), (3), and (4) in any proportion, such as a 1:1:1:1
proportion. Each compound or mixture can optionally additionally
consist essentially of one or more other therapeutic agents. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents exclude(s) compounds (5), (6),
(7), and/or (8) as defined herein, or an alternate salt thereof.
The foregoing embodiments may optionally also add the proviso that
the one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0059] In one embodiment, the invention embraces an isolated
compound of formula (1), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (1), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (1), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0060] In one embodiment, the invention embraces an isolated
compound of formula (2), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (2), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (2), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0061] In one embodiment, the invention embraces an isolated
compound of formula (3), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (3), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (3), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0062] In one embodiment, the invention embraces an isolated
compound of formula (4), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (4), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (4), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents
exclude(s) compounds (5), (6), (7), and/or (8) as defined herein,
or an alternate salt thereof. The foregoing embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0063] In one embodiment, the invention embraces an isolated
compound of formula (5), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (5), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (5), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents is
not another compound of Formula (I) and/or Formula (II).
[0064] In one embodiment, the invention embraces an isolated
compound of formula (6), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (6), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (6), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents is
not another compound of Formula (I) and/or Formula (II).
[0065] In one embodiment, the invention embraces an isolated
compound of formula (7), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (7), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (7), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents is
not another compound of Formula (I) and/or Formula (II).
[0066] In one embodiment, the invention embraces an isolated
compound of formula (8), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces a stereochemically pure
compound of formula (8), optionally additionally comprising a
pharmaceutically acceptable excipient or carrier, and optionally
additionally comprising one or more other therapeutic agents. In
one embodiment, the invention embraces an isolated,
stereochemically pure compound of formula (8), optionally
additionally comprising a pharmaceutically acceptable excipient or
carrier, and optionally additionally comprising one or more other
therapeutic agents. The foregoing embodiments may optionally also
add the proviso that the one or more other therapeutic agents is
not another compound of Formula (I) and/or Formula (II).
[0067] In another embodiment, the invention comprises a method of
treating a muscarinic acetylcholine receptor (mAChR)-mediated
disease, comprising administering a therapeutically effective
amount of a stereochemically pure compound of Formula (I) or
Formula (II) to a subject in need of such treatment. In one
embodiment of the method, the compound administered is (1), that
is, the compound is (1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (1) is
isolated, and optionally combined with a pharmaceutically
acceptable excipient.
[0068] In further embodiments of the method, the compound (1) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (1) is isolated and stereochemically pure.
In further embodiments of the method, the compound (1) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (2), that is, the compound is
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (2) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (2) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (2) is isolated and stereochemically pure.
In further embodiments of the method, the compound (2) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (3), that is, the compound is
(1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (3) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (3) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (3) is isolated and stereochemically pure.
In further embodiments of the method, the compound (3) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (4), that is, the compound is
(1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (4) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (4) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method the compound (4) is isolated and stereochemically pure.
In further embodiments of the method, the compound (4) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (5), that is, the compound is
(1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (5) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (5) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (5) is isolated and stereochemically pure.
In further embodiments of the method, the compound (5) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (6), that is, the compound is
(1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (6) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (6) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (6) is isolated and stereochemically pure.
In further embodiments of the method, the compound (6) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (7), that is, the compound is
(1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (7) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (7) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (7) is isolated and stereochemically pure.
In further embodiments of the method, the compound (7) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In one embodiment of the method, the compound
administered is (8), that is, the compound is
(1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide. In further
embodiments of the method, the compound (8) is isolated, and
optionally combined with a pharmaceutically acceptable excipient.
In further embodiments of the method, the compound (8) is
stereochemically pure, and optionally combined with a
pharmaceutically acceptable excipient. In further embodiments of
the method, the compound (8) is isolated and stereochemically pure.
In further embodiments of the method, the compound (8) is isolated
and stereochemically pure, and is combined with a pharmaceutically
acceptable excipient. In any of the above embodiments, the
composition may optionally additionally comprise one or more other
therapeutic agents; such embodiments may optionally also add the
proviso that the one or more other therapeutic agents is not
another compound of Formula (I) and/or Formula (II).
[0069] In another embodiment, the invention comprises a method of
suppressing a muscarinic acetylcholine receptor (mAChR)-mediated
disease, by administering an amount of one or more compounds of
Formula (I) or Formula (II) sufficient to partially or totally
suppress the disease to a subject in need of such treatment. In one
embodiment of the method, the compound administered is (1), that
is, the compound is (1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (1) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (1) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (2), that
is, the compound is (1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (2) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (2) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (3), that
is, the compound is (1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (3) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (3) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (4), that
is, the compound is (1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method the compound (4) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (4) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (5), that
is, the compound is (1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (5) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (5) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (6), that
is, the compound is (1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (6) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (6) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (7), that
is, the compound is (1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (7) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (7) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In one
embodiment of the method, the compound administered is (8), that
is, the compound is (1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide. In further embodiments of the method, the compound (8) is
isolated and stereochemically pure. In further embodiments of the
method, the compound (8) is isolated and stereochemically pure, and
is combined with a pharmaceutically acceptable excipient. In any of
the above embodiments, the composition may optionally additionally
comprise one or more other therapeutic agents; such embodiments may
optionally also add the proviso that the one or more other
therapeutic agents is not another compound of Formula (I) and/or
Formula (II).
[0070] In any of the above methods, the muscarinic acetylcholine
receptor (mAChR)-mediated disease can be selected from the group
consisting of respiratory tract disorders such as chronic
obstructive pulmonary disorder (COPD, also called chronic
obstructive lung disease), chronic bronchitis, asthma, chronic
respiratory obstruction, pulmonary fibrosis, pulmonary emphysema,
rhinorrhea, allergic rhinitis, occupational lung diseases including
pneumoconiosis (such as black lung disease, silicosis and
asbestosis), acute lung injury (ALI), acute respiratory distress
syndrome (ARDS), genitourinary tract disorders, such as urinary
urge incontinence, overactive bladder or detrusor hyperactivity and
their symptoms; gastroesophageal reflux disease (GERD);
gastrointestinal tract disorders, such as irritable bowel syndrome,
diverticular disease, achalasia, gastrointestinal hypermotility
disorders and diarrhea; and the like.
[0071] In another embodiment, the invention embraces a composition
consisting essentially of a mixture of (1) and (4) in any
proportion, such as a 1:1 proportion. In another embodiment, the
invention embraces a composition consisting essentially of a
mixture of (2) and (3) in any proportion, such as a 1:1 proportion.
In another embodiment, the invention embraces a composition
consisting essentially of a mixture of (1) and (2) in any
proportion, such as a 1:1 proportion. In another embodiment, the
invention embraces a composition consisting essentially of a
mixture of (3) and (4) in any proportion, such as a 1:1 proportion.
Any of the foregoing compositions can additionally consist
essentially of an optional additional therapeutic agent. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents exclude(s) compounds (5), (6),
(7), and/or (8) as defined herein, or an alternate salt thereof.
The foregoing embodiments may optionally also add the proviso that
the one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0072] In another embodiment, the invention embraces a composition
consisting essentially of a mixture of (1) and (3) in any
proportion, such as a 1:1 proportion. In another embodiment, the
invention embraces a composition consisting essentially of a
mixture of (2) and (4) in any proportion, such as a 1:1 proportion.
Any of the foregoing compositions can additionally consist
essentially of an optional additional therapeutic agent. The
foregoing embodiments may optionally also add the proviso that the
one or more other therapeutic agents exclude(s) compounds (5), (6),
(7), and/or (8) as defined herein, or an alternate salt thereof.
The foregoing embodiments may optionally also add the proviso that
the one or more other therapeutic agents is not another compound of
Formula (I) and/or Formula (II).
[0073] In another embodiment, the invention comprises a compound of
the formula
##STR00023##
[0074]
exo-2-((R)-2'-cyclopentyl-2'-hydroxy-2'-phenylacetoxy)spiro[bicyclo-
-[2.2.1]heptane-7,1'-pyrrolidin]-1'-ium anion, where the anion
X.sup.- is a pharmaceutically acceptable anion.
[0075] In another embodiment, the invention comprises a compound of
the formula
##STR00024##
[0076]
(exo-2-((R)-2'-cyclopentyl-2'-hydroxy-2'-phenylacetoxy)spiro[bicycl-
o-[2.2.1]heptane-7,1'-pyrrolidin]-1'-ium bromide (9)).
[0077] In another embodiment, the invention comprises a composition
comprising the compound (9) and a pharmaceutically acceptable
excipient or carrier, and optionally additionally comprising one or
more other therapeutic agents. In one embodiment, the composition
comprising the compound (9) and a pharmaceutically acceptable
excipient or carrier also comprises one or more compounds selected
from (1), (2), (3), (4), (5), (6), (7), or (8).
[0078] The invention also embraces a method of using the compound
(9), either alone or in combination with other agents, and
optionally comprising a pharmaceutically acceptable excipient or
carrier, for treating a variety of indications, including but not
limited to diseases mediated by muscarinic acetylcholine receptors.
The invention also embraces a method of using the compound (9),
either alone or in combination with other agents, and optionally
comprising a pharmaceutically acceptable excipient or carrier, for
treating respiratory tract disorders such as chronic obstructive
pulmonary disorder (COPD, also called chronic obstructive lung
disease), chronic bronchitis, asthma, chronic respiratory
obstruction, pulmonary fibrosis, pulmonary emphysema, rhinorrhea,
allergic rhinitis, occupational lung diseases including
pneumoconiosis (such as black lung disease, silicosis and
asbestosis), acute lung injury (ALI), and acute respiratory
distress syndrome (ARDS). Other, non-respiratory medical conditions
that can be treated with muscarinic receptor antagonists include,
but are not limited to, genitourinary tract disorders, such as
urinary urge incontinence, overactive bladder or detrusor
hyperactivity and their symptoms; gastroesophageal reflux disease
(GERD); gastrointestinal tract disorders, such as irritable bowel
syndrome, diverticular disease, achalasia, gastrointestinal
hypermotility disorders and diarrhea; and the like.
[0079] Some embodiments described herein are recited as
"comprising" or "comprises" various elements. In alternative
embodiments, those elements can be recited with the transitional
phrase "consisting essentially of" or "consists essentially of" as
applied to those elements. In further alternative embodiments,
those elements can be recited with the transitional phrase
"consisting of" or "consists of" as applied to those elements.
Thus, for example, if a composition or method is disclosed herein
as comprising A and B, the alternative embodiment for that
composition or method of "consisting essentially of A and B" and
the alternative embodiment for that composition or method of
"consisting of A and B" are also considered to have been disclosed
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0080] FIG. 1 depicts the percentage of bronchoprotection in rats
provided by certain compounds of the invention.
[0081] FIG. 2 depicts the percentage of bronchoprotection in guinea
pigs provided by certain compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The invention provides compounds and methods for treating a
muscarinic acetylcholine receptor-mediated disease, such as chronic
obstructive pulmonary disease (COPD).
DEFINITIONS
[0083] By "subject," "individual," or "patient" is meant an
individual organism, preferably a mammal, most preferably a
human.
[0084] "Treating" a disease with the compounds and methods
discussed herein is defined as administering one or more of the
compounds discussed herein, with or without additional therapeutic
agents, in order to reduce or eliminate either the disease or one
or more symptoms of the disease, or to retard the progression of
the disease or of one or more symptoms of the disease, or to reduce
the severity of the disease or of one or more symptoms of the
disease. "Suppression" of a disease with the compounds and methods
discussed herein is defined as administering one or more of the
compounds discussed herein, with or without additional therapeutic
agents, in order to suppress the clinical manifestation of the
disease, or to suppress the manifestation of adverse symptoms of
the disease. The distinction between treatment and suppression is
that treatment occurs after adverse symptoms of the disease are
manifest in a subject, while suppression occurs before adverse
symptoms of the disease are manifest in a subject. Suppression may
be partial, substantially total, or total. The compounds and
methods of the invention can be administered to asymptomatic
patients at risk of developing the clinical symptoms of the
disease, in order to suppress the appearance of any adverse
symptoms.
[0085] "Therapeutic use" of the compounds discussed herein is
defined as using one or more of the compounds discussed herein to
treat or suppress a disease, as defined above. A "therapeutically
effective amount" of a compound is an amount of the compound,
which, when administered to a subject, is sufficient to reduce or
eliminate either a disease or one or more symptoms of a disease, or
to retard the progression of a disease or of one or more symptoms
of a disease, or to reduce the severity of a disease or of one or
more symptoms of a disease, or to suppress the clinical
manifestation of a disease, or to suppress the manifestation of
adverse symptoms of a disease. A therapeutically effective amount
can be given in one or more administrations.
[0086] "Alkyl" is intended to embrace a saturated linear, branched,
cyclic, or a combination of linear and/or branched and/or cyclic
hydrocarbon chain and/or ring of carbon atoms. In one embodiment,
alkyl groups have between 1 and 12 carbon atoms, that is,
C.sub.1-C.sub.12 alkyl. In another embodiment, alkyl groups have
between 1 and 8 carbon atoms, that is, C.sub.1-C.sub.8 alkyl. The
point of attachment of the alkyl group to the remainder of the
molecule can be at any chemically feasible location on the
fragment.
[0087] "Alkoxy" refers to the group --O-alkyl, for example,
--O--C.sub.1-C.sub.12 alkyl or --O--C.sub.1-C.sub.8 alkyl.
[0088] "Lower alkyl" is synonymous with "C.sub.1-C.sub.4 alkyl,"
and is intended to embrace methyl (Me), ethyl (Et), propyl (Pr),
n-propyl (nPr), isopropyl (iPr), butyl (Bu), n-butyl (nBu),
isobutyl (iBu), sec-butyl (sBu), t-butyl (tBu), cyclopropyl
(cyclPr), cyclobutyl (cyclBu), cyclopropyl-methyl (cyclPr-Me) and
methyl-cyclopropane (Me-cyclPr), where the C.sub.1-C.sub.4 alkyl
groups can be attached via any valence on the C.sub.1-C.sub.4 alkyl
groups to the remainder of the molecule.
[0089] "Halo" refers to F, Cl, Brand I.
[0090] "Aryl" refers to an aromatic hydrocarbon, such as
C.sub.6-C.sub.10 aromatic hydrocarbons including, but not limited
to, phenyl and naphthyl.
[0091] "Aryloxy" refers to the group --O-aryl.
[0092] "Aralkyl" refers to the group -alkyl-aryl.
[0093] "Aryloxyalkyl" refers to the group -alkyl-O-aryl.
[0094] "Alkoxycarbonylalkyl" refers to the group
-alkyl-(C.dbd.O)--O-alkyl.
[0095] By "isolated" is meant a compound that has been purified in
the chemical sense of reducing unwanted components. Isolation can
be about 80% pure or at least about 80% pure, about 90% pure or at
least about 90% pure, about 95% pure or at least about 95% pure,
about 98% pure or at least about 98% pure, about 99% pure or at
least about 99% pure, about 99.5% pure or at least about 99.5%
pure, or about 99.9% pure or at least about 99.9% pure. Isolation
percentages are preferably weight percent, but can also be mole
percent. Components that are desired, such as pharmaceutically
acceptable excipients, pharmaceutical carriers, or additional
therapeutic agents, are not included when calculating the
percentage of purity of isolation.
[0096] By "stereochemically pure compound" is meant a preparation
of a compound which contains primarily one stereoisomer out of two
or more possible stereoisomers. A stereochemically pure compound
has about 80% or at least about 80% of a single stereoisomer, about
90% or at least about 90% of a single stereoisomer, about 95% or at
least about 95% of a single stereoisomer, about 98% or at least
about 98% of a single stereoisomer, about 99% or at least about 99%
of a single stereoisomer, about 99.5% or at least about 99.5% of a
single stereoisomer, or about 99.9% or at least about 99.9% of a
single stereoisomer. Stereochemical purity percentages are
preferably mole percent, but can also be weight percent. Reference
to a particular stereoisomer of a compound as stereochemically
pure, or to a composition comprising, consisting essentially of, or
consisting of a stereochemically pure compound, means that the
preparation of the compound has about 80% or at least about 80% of
the referenced stereoisomer, about 90% or at least about 90% of the
referenced stereoisomer, about 95% or at least about 95% of the
referenced stereoisomer, about 98% or at least about 98% of the
referenced stereoisomer, about 99% or at least about 99% of the
referenced stereoisomer, about 99.5% or at least about 99.5% of the
referenced stereoisomer, or about 99.9% or at least about 99.9% of
the referenced stereoisomer.
[0097] As an example, the percent isolation of L-alanine, the
desired component, in a mixture containing 25 mg of beta-alanine,
25 mg of D-alanine, and 50 mg of L-alanine, where beta-alanine and
D-alanine are undesired components, would be 50%. The percent
stereochemical purity of L-alanine in that same mixture would be
66.7%, calculated with respect to the total of all stereoisomers of
2-amino propanoic acid (i.e., alanine; beta-alanine is 3-amino
propanoic acid and is not a stereoisomer of alanine). (All three
molecules have the same molecular weight, and percent by weight and
mole percent both yield the same percentages in this example.)
Addition of, for example, 1 gram of pharmaceutically acceptable
carrier and 50 mg of Vitamin C (where the pharmaceutically
acceptable carrier and Vitamin Care desired additional components
of the composition) would not affect the percent isolation or
percent stereochemical purity calculated for L-alanine.
[0098] The terms "active M.sub.3 muscarinic acetylcholine receptor
antagonist" and "active M.sub.3 mAChR antagonist" are synonymous
and are used to designate a compound having an IC.sub.50 of less
than 5 nanomolar or less than about 5 nanomolar, preferably less
than 3 nanomolar or less than about 3 nanomolar, more preferably
less than 1 nanomolar or less than about 1 nanomolar, still more
preferably less than 0.5 nanomolar or less than about 0.5
nanomolar, and yet still more preferably less than 0.3 nanomolar or
less than about 0.3 nanomolar, as measured by the Muscarinic
Receptor Radioligand Binding Assay described below in Example
2.
[0099] "An alternate salt thereof," when referring to a compound,
indicates that the counterion of the compound may be replaced with
another counterion. For example, possible alternate salts of
compound (5), (1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, include the corresponding chloride:
(1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane chloride; the
corresponding tosylate: (1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
toluenesulfonate; etc.
[0100] "Consisting essentially of" as used herein is intended as a
limitation to the specified materials or steps recited, and also
allows inclusion of any unrecited materials or steps that do not
materially affect the basic characteristics of the composition or
method. Thus, a composition consisting essentially of compound (1)
would exclude any other mAChR antagonist compound, such as
compounds (2)-(8), from being present in the mixture, but one or
more pharmaceutically acceptable excipients or carriers suitable
for the intended route of administration (e.g., a pharmaceutically
acceptable excipient or carrier for administration via inhalation,
a pharmaceutically acceptable excipient or carrier for
administration via injection, or a pharmaceutically acceptable
excipient or carrier for administration via oral administration)
would not be excluded from a composition consisting essentially of
compound (1), even if such a pharmaceutically acceptable excipient
or carrier is not explicitly recited.
[0101] It should be appreciated that the structures depicted in
Formula (I) and Formula (II) represent at least four possible
stereoisomers incorporating the four possible isomers of the
7-azabicyclo[2.2.1]heptan-2-ol moieties as illustrated.
##STR00025##
[0102] If additional stereo centers are present, for example, if
for the group --C(R.sub.1)(R.sub.2)(R.sub.3), the carbon atom
substituted by R.sub.1, R.sub.2, and R.sub.3 is asymmetric, a total
of at least eight different diastereomers will result.
[0103] If the R.sub.4 and R.sub.5 groups are different, additional
stereoisomers may be generated in the quaternization step.
[0104] Included in the scope of this invention are all active
isomers, mixtures of active isomers, crystalline forms, amorphous
forms, hydrates, or solvates of the subject compounds.
[0105] The chemical structures drawn herein and the chemical names
listed herein are to be construed as including all isotopologues.
Isotopologues are molecular entities that differ only in isotopic
composition (number of isotopic substitutions), e.g. CH.sub.4,
CH.sub.3D, CH.sub.2D.sub.2, etc., where "D" is deuterium, that is,
2H. Isotopologues can have isotopic replacements at any or at all
atoms in a structure, or can have atoms present in natural
abundance at any or all locations in a structure.
[0106] Various embodiments of the invention described herein are
recited as "comprising" or "comprises" various elements. In
alternative embodiments, those elements can be recited with the
transitional phrase "consisting essentially of" or "consists
essentially of" as applied to those elements. In further
alternative embodiments, those elements can be recited with the
transitional phrase "consisting of" or "consists of" as applied to
those elements. Thus, for example, if a composition or method is
disclosed herein as comprising A and B, the alternative embodiment
for that composition or method of "consisting essentially of A and
B" and the alternative embodiment for that composition or method of
"consisting of A and B" are also considered to have been disclosed
herein.
Methods of Preparation
[0107] The compounds of Formula (I) and Formula (II) may be
obtained by applying the appropriate synthetic procedures, some of
which are illustrated in the scheme below which is for illustrative
purposes only.
[0108] As outlined in Scheme 1, the desired compounds of Formula
(I) and certain compounds of Formula (II) can be prepared by
transesterification of ester 1 with the appropriate N-Boc protected
amino alcohol 2. Acid treatment of the resulting ester 3 provides
the secondary amine 4 which is converted to the tertiary amine 5 by
N-alkylation utilizing reductive amination procedures. Finally,
quaternization of the tertiary nitrogen of amino ester 5 with an
alkyl or aralkyl bromide furnishes the compounds of Formula
(I).
##STR00026##
[0109] Esters 1 where R.sub.1 and R.sub.2 are phenyl or 2-thienyl
and R.sub.3 is OH are commercially available. Esters 1 where
R.sub.1 is phenyl or thienyl, R.sub.2 is cycloalkyl and R.sub.3 is
OH can be prepared by reaction of an aryl glyoxylate (i.e.
PhCOCOOMe) with a cycloalkyl Grignard reagent. Esters where R.sub.3
is not OH have also been prepared. The diastereoselective addition
of such organometallics to chiral arylglyoxylates leading to
optically active products has been described (Tetrahedron Letters
29, 2175 (1988)).
[0110] Transesterification of methyl esters 1 with Boc-protected
amino alcohols 2 to form the amino esters 3 is carried out using a
catalytic amount of a strong base such as sodium hydride, sodium
methoxide and the like in a suitable inert solvent such as
n-heptane or toluene at temperatures high enough to allow
separation of the methanol formed by distillation.
[0111] In the case where the group A or R.sub.1R.sub.2R.sub.3C is
10-phenothiazinyl, the desired ester 3 is prepared by reacting
10-chlorocarbonylphenothiazine with amino alcohols 2 in the
presence of a base.
[0112] Removal of the Boc protection group is achieved by treatment
with acid to give the secondary amines 4.
[0113] The R.sub.4 group, for example methyl, is introduced by
reductive amination with formaldehyde and sodium
triacetoxyborohydride as described in J. Org. Chern. 61, 3489-3862
(1996) to furnish the tertiary amines 5.
[0114] Finally, treatment of the tertiary amines with a compound of
formula R.sub.5X in an inert solvent provides the quaternary
ammonium compounds of Formula (I).
[0115] Spiroazonia compounds where and R.sub.5 together form a 5-
or 6-membered ring can be prepared from secondary amines 4 by
treatment with a dihaloalkane such as 1,4-dichlorobutane or
1,5-dibromopentane in the presence of a base such as triethylamine
or potassium carbonate in a suitable solvent.
[0116] The methodology described in U.S. Pat. No. 4,353,922 and J.
Pharm. Sci. 74, 208-210 (1985) does not provide the compounds of
this invention, as these methods provide mixtures of compounds
rather than isolated compounds. For example, it was originally
thought this methodology produced a mixture of the compounds (3),
(4), (6), and (8) described herein. However, more recent research
has conclusively demonstrated that the crucial intramolecular
epoxide opening step proceeds via an unprecedented cis (not trans)
mechanism, leading to the exo amino alcohol intermediates; see J.
Org. Chem. 59, 1771-1778 (1994) and Org. Lett. 1, 1439-(1999).
Thus, the endo stereochemistry of compound 4 reported in J. Pharm.
Sci. 74, 208-210 (1985) (RS-11635, a mixture of four distinct
diastereomers rather than a stereochemically pure compound) is
incorrect, and compound 4 of J. Pharm. Sci. 74, 208-210 (1985) is
in fact a mixture of the compounds (1), (2), (5), and (7) described
herein.
[0117] The procedures listed in the Examples section demonstrate
for the first time how to synthesize all eight possible individual
diastereomers of Formula (I) where the carbon atom of the group
R.sub.1R.sub.2R.sub.3C is an asymmetric carbon.
Diseases Amenable to Treatment with Compounds of the Invention
[0118] The compounds and methods disclosed herein can be used to
treat various diseases, particularly diseases mediated by
muscarinic acetylcholine receptors. These diseases include, but are
not limited to, respiratory tract disorders such as chronic
obstructive pulmonary disorder (COPD, also called chronic
obstructive lung disease), chronic bronchitis, asthma, chronic
respiratory obstruction, pulmonary fibrosis, pulmonary emphysema,
rhinorrhea, allergic rhinitis. The diseases also include, but are
not limited to, occupational lung diseases including pneumoconiosis
(such as black lung disease, silicosis and asbestosis), acute lung
injury (ALI), and acute respiratory distress syndrome (ARDS).
[0119] Additional, non-respiratory medical conditions that can be
treated with muscarinic receptor antagonists include, but are not
limited to, genitourinary tract disorders, such as urinary urge
incontinence, overactive bladder or detrusor hyperactivity and
their symptoms; gastroesophageal reflux disease (GERD);
gastrointestinal tract disorders, such as irritable bowel syndrome,
diverticular disease, achalasia, gastrointestinal hypermotility
disorders and diarrhea; and the like.
Methods of Use
[0120] The compounds, pharmaceutical compositions, and methods of
the invention can be used in treatment and/or suppression of
muscarinic acetylcholine receptor mediated diseases, and in one
particular embodiment, in treatment and/or suppression of
muscarinic acetylcholine receptor mediated diseases of the
respiratory tract. In particular, the compounds, pharmaceutical
compositions, and methods of the invention can be used in treating
and/or suppressing chronic obstructive pulmonary disorder (COPD),
chronic bronchitis, and/or emphysema.
[0121] For treatment of respiratory disorders, the compounds and
pharmaceutical compositions are preferably administered in a form
that can be inhaled, such as in aerosols, mists, sprays, or
powders. In one embodiment, the compounds or pharmaceutical
compositions are delivered in a form suitable for inhalation. The
form suitable for inhalation can be particles, aerosols, powders,
or droplets with an average size of about 10 .mu.m diameter or
less, preferably in the range between about 0.1 .mu.m to about 5
.mu.m, or in the range between about 1 .mu.m to about 5 .mu.m. See,
for example, Hickey, Anthony J., ed., Pharmaceutical Inhalation
Aerosol Technology, 2nd Ed., New York: Marcel Dekker, 2004,
particularly Part Two on Methods of Generation, Administration, and
Characterization of Aerosols. Typically, about two-thirds,
preferably 80%, more preferably 90% of the particles, aerosols,
powders or droplets will fall within the size range specified. For
example, when droplets having a diameter in the range of about 1
.mu.m to about 5 .mu.m are specified, two-thirds, preferably about
80%, more preferably about 90% of the droplets will have a diameter
falling in the range of about 1 .mu.m to about 5 .mu.m.
[0122] The compounds or pharmaceutical compositions can be
delivered in a form suitable for inhalation by using various types
of inhalers, such as a nebulizing inhaler, metered-dose inhalers,
or a dry powder inhaler (DPI). The compounds or pharmaceutical
compositions can be delivered by voluntary inhalation by a subject
or patient, or by mechanical ventilation if a subject or patient
requires assistance in breathing.
[0123] The compounds described herein can be formulated as
pharmaceutical compositions by formulation with additives such as
pharmaceutically acceptable excipients, pharmaceutically acceptable
carriers, and pharmaceutically acceptable vehicles. Suitable
pharmaceutically acceptable excipients, carriers and vehicles
include processing agents and drug delivery modifiers and
enhancers, such as, for example, calcium phosphate, magnesium
stearate, talc, monosaccharides, disaccharides, starch, gelatin,
cellulose, methyl cellulose, sodium carboxymethyl cellulose,
dextrose, hydroxypropyl-.beta.-cyclodextrin,
polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and
the like, as well as combinations of any two or more thereof. Other
suitable pharmaceutically acceptable excipients are described in
"Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey
(1991), and "Remington: The Science and Practice of Pharmacy,"
Lippincott Williams & Wilkins, Philadelphia, 20th edition
(2003) and 21st edition (2005), incorporated herein by
reference.
[0124] A pharmaceutical composition can comprise a unit dose
formulation, where the unit dose is a dose sufficient to have a
therapeutic or suppressive effect. The unit dose may be sufficient
as a single dose to have a therapeutic or suppressive effect.
Alternatively, the unit dose may be a dose administered
periodically in a course of treatment or suppression of a
disorder.
[0125] Pharmaceutical compositions containing the compounds of the
invention may be in any from suitable for the intended method of
administration, including, for example, a solution, a suspension,
or an emulsion. Liquid carriers are typically used in preparing
solutions, suspensions, and emulsions. Liquid carriers contemplated
for use in the practice of the present invention include, for
example, water, saline, pharmaceutically acceptable organic
solvent(s), pharmaceutically acceptable oils or fats, and the like,
as well as mixtures of two or more thereof. The liquid carrier may
contain other suitable pharmaceutically acceptable additives such
as solubilizers, emulsifiers, nutrients, buffers, preservatives,
suspending agents, thickening agents, viscosity regulators,
stabilizers, and the like. Suitable organic solvents include, for
example, monohydric alcohols, such as ethanol, and polyhydric
alcohols, such as glycols. Suitable oils include, for example,
soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil,
and the like. For parenteral administration, the carrier can also
be an oily ester such as ethyl oleate, isopropyl myristate, and the
like. Compositions of the present invention may also be in the form
of microparticles, microcapsules, liposomal encapsulates, and the
like, as well as combinations of any two or more thereof.
[0126] Time-release or controlled release delivery systems may be
used, such as a diffusion controlled matrix system or an erodible
system, as described for example in: Lee, "Diffusion-Controlled
Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible
Systems", pp. 199-224, in "Treatise on Controlled Drug Delivery",
A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix
may be, for example, a biodegradable material that can degrade
spontaneously in situ and in vivo for, example, by hydrolysis or
enzymatic cleavage, e.g., by proteases. The delivery system may be,
for example, a naturally occurring or synthetic polymer or
copolymer, for example in the form of a hydrogel. Exemplary
polymers with cleavable linkages include polyesters,
polyorthoesters, polyanhydrides, polysaccharides,
poly(phosphoesters), polyamides, polyurethanes,
poly(imidocarbonates) and poly(phosphazenes).
[0127] The compounds of the invention may be administered
enterally, orally, parenterally, sublingually, by inhalation (e.g.
as mists or sprays), rectally, or topically in dosage unit
formulations containing conventional nontoxic pharmaceutically
acceptable carriers, adjuvants, and vehicles as desired. For
example, suitable modes of administration include oral,
subcutaneous, transdermal, transmucosal, iontophoretic,
intravenous, intraarterial, intramuscular, intraperitoneal,
intranasal (e.g. via nasal mucosa), intraocular, subdural, vaginal,
rectal, gastrointestinal, and the like, and directly to a specific
or affected organ or tissue, such as the lung or bladder. Topical
administration may also involve the use of transdermal
administration such as transdermal patches or iontophoresis
devices. The term parenteral as used herein includes subcutaneous
injections, intravenous injection, intramuscular injection,
intrasternal injection, or infusion techniques. The compounds are
mixed with pharmaceutically acceptable carriers, adjuvants, and
vehicles appropriate for the desired route of administration. The
compounds described for use herein can be administered in solid
form, in liquid form, in aerosol form, or in the form of tablets,
pills, powder mixtures, capsules, granules, injectables, creams,
solutions, suppositories, enemas, colonic irrigations, emulsions,
dispersions, food premixes, and in other suitable forms. The
compounds can also be administered in liposome formulations. The
compounds can also be administered as prodrugs, where the prodrug
undergoes transformation in the treated subject to a form which is
therapeutically effective. Additional methods of administration are
known in the art.
[0128] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in propylene glycol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0129] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose, lactose, or starch. Such dosage
forms may also comprise additional substances other than inert
diluents, e.g., lubricating agents such as magnesium stearate. In
the case of capsules, tablets, and pills, the dosage forms may also
comprise buffering agents. Tablets and pills can additionally be
prepared with enteric coatings.
[0130] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing ineli diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents,
cyclodextrins, and sweetening, flavoring, and perfuming agents.
[0131] The compounds of the present invention can also be
administered in the form of liposomes. As is known in the art,
liposomes are generally derived from phospholipids or other lipid
substances. Liposomes are formed by mono- or multilamellar hydrated
liquid crystals that are dispersed in an aqueous medium. Any
non-toxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients, and the
like. The preferred lipids are the phospholipids and phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York,
N.W., p. 33 et seq (1976).
[0132] In certain embodiments of the invention, the formulations
and preparations of the invention, and the formulations and
preparations used in the methods of the invention, are sterile.
Sterile pharmaceutical formulations are compounded or manufactured
according to pharmaceutical-grade sterilization standards (United
States Pharmacopeia Chapters 797, 1072, and 1211; California
Business & Professions Code 4127.7; 16 California Code of
Regulations 1751, 21 Code of Federal Regulations 211) known to
those of skill in the art.
[0133] The invention also provides articles of manufacture and kits
containing materials useful for treating or suppressing muscarinic
acetylcholine receptor-mediated diseases. The invention also
provides kits comprising any one or more of the compounds of the
invention. In some embodiments, the kit of the invention comprises
the container described above.
[0134] In other aspects, the kits may be used for any of the
methods described herein, including, for example, to treat an
individual with a muscarinic receptor-mediated disease, or to
suppress a muscarinic acetylcholine receptor-mediated disease in an
individual.
[0135] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host to which the active ingredient is
administered and the particular mode of administration. It will be
understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, body area, body mass index (BMI), general health, sex,
diet, time of administration, route of administration, rate of
excretion, drug combination, and the type, progression, and
severity of the particular disease undergoing therapy. The
pharmaceutical unit dosage chosen is usually fabricated and
administered to provide a defined final concentration of drug in
the blood, tissues, organs, or other targeted region of the body,
or to provide a defined dosage of the drug to a specific site, such
as the lungs. The therapeutically effective amount or effective
amount for a given situation can be readily determined by routine
experimentation and is within the skill and judgment of the
ordinary clinician.
[0136] Examples of dosages of the compounds described herein which
can be used are an effective amount within the dosage range of
about 0.1 .mu.g to about 10 mg per kilogram of body weight, about
0.1 .mu.g to about 5 mg per kilogram of body weight, about 0.1
.mu.g to about 1 mg per kilogram of body weight, about 0.1 .mu.g to
about 0.5 mg per kilogram of body weight, about 0.1 .mu.g to about
100 .mu.g per kilogram of body weight, about 0.1 .mu.g to about 50
.mu.g per kilogram of body weight, about 0.1 .mu.g to about 10
.mu.g per kilogram of body weight, or about 1 .mu.g to about 10
.mu.g per kilogram of body weight. When administered orally or by
inhalation, examples of dosages are an effective amount within the
dosage range of about 0.001 mg to about 0.01 mg, or about 0.01 mg
to about 0.1 mg, or about 0.1 mg to about 1 mg, or about 1 mg to
about 10 mg, or about 10 mg to about 100 mg, or about 100 mg to
about 1 g. Preferred fixed doses include about 0.005 mg, about 0.01
mg, about 0.018 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg,
about 0.05 mg, about 0.1 mg, about 1 mg, about 2 mg, about 5 mg,
about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 80 mg or
about 100 mg, independently of body weight. However, it is
understand that pediatric patients may require smaller dosages, and
depending on the severity of the disease and condition of the
patient, dosages may vary. The compound will preferably be
administered once daily, but may be administered two, three or four
times daily, or every other day, or once or twice per week.
[0137] Compounds of the present invention may be administered in a
single daily dose, or the total daily dosage may be administered in
divided dosage of two, three or four times daily.
[0138] When formulated as a liquid, the concentration of the
compound described herein will typically be about 0.01 mg/ml to
about 0.1 mg/ml or about 0.1 mg/ml to about 1 mg/ml, but can also
be about 1 mg/ml to about 10 mg/ml or about 10 mg/ml to about 100
mg/ml. When formulated as a solid, for example as a tablet or as a
powder for inhalation, the concentration, expressed as weight
compound divided by total weight, will typically be about 0.01% to
about 0.1%, about 0.1% to about 1%, about 1% to about 10%, or about
10% to about 100%.
[0139] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more other agents used in the treatment or
suppression of muscarinic acetylcholine receptor-mediated diseases.
Examples of additional agents that can be used in combination with
the compounds of the current invention include, but are not limited
to, other acetylcholine receptor inhibitors, such as ipratropium
and tiotropium; or one or more anti-inflammatory, bronchodilator,
antihistamine, decongestant or antitussive agents. The additional
agents can be administered simultaneously in the same
pharmaceutical composition, simultaneously in different
pharmaceutical compositions, or at different times. Specific agents
include, but are not limited to, corticosteroids such as
fluticasone propionate, budesonide, beclomethasone dipropionate,
flunisolide, triamcinolone acetonide, ciclesonide, or mometasone
furoate; f32-adrenoreceptor agonists such as albuterol, salmeterol,
and metaproterenol; antitussive agents (cough suppressants) such as
codeine or dextromorphan; and theophylline. Desired combinations
can be determined based on additional therapeutic advantages,
potential side effects, and other considerations known to the
skilled artisan. Some agents can be combined with the compounds of
the invention for administration via inhalation, while others can
be administered via other routes of administration.
[0140] When additional active agents are used in combination with
the compounds of the present invention, the additional active
agents may generally be employed in therapeutic amounts as
indicated in the Physicians' Desk Reference (PDR) 53.sup.rd Edition
(1999), which is incorporated herein by reference, or such
therapeutically useful amounts as would be known to one of ordinary
skill in the art.
[0141] The compounds of the invention and the other therapeutically
active agents can be administered at the recommended maximum
clinical dosage or at lower doses. Dosage levels of the active
compounds in the compositions of the invention may be varied so as
to obtain a desired therapeutic response depending on the route of
administration, severity of the disease and the response of the
patient. When administered in combination with other therapeutic
agents, the therapeutic agents can be formulated as separate
compositions that are given at the same time or different times, or
the therapeutic agents can be given as a single composition.
[0142] Compounds of Formula (I) and Formula (II), and compounds
(1), (2), (3), (4), (5), (6), (7), or (8), by virtue of the
quaternary nitrogen, are positively charged, and thus will have an
associated negative counterion. Any pharmaceutically acceptable
anion can be used with the compounds of the invention, such as
those described in Berge et al., J. Phmm. Sci. 66:1 (1977); Bighley
et al., "Salt Forms of Drugs and Absorption," in Swarbrick J,
Boylan J C, eds. Encyclopedia of Pharmaceutical Technology 13, New
York, N.Y.: Marcel Dekker; 1996:453-499; and Paulekuhn et al., J.
Med. Chern. 50:6665 (2007). The anion can be monovalent (i.e., a
charge of -1) or polyvalent (e.g., a charge of -2, -3, etc.).
Pharmaceutically acceptable anions include, but are not limited to,
acetate, besylate (benzenesulfonate), benzoate, besylate,
bicarbonate, bitartrate, bromide, calcium edentate,
camphorsulfonate (camsylate), cm.cndot.bonate, chlmide,
chlorotheophyllinate, citrate, edetate, ethanedisulfonate
(edisylate), ethanesulfonate (esylate), fumarate, gluceptate
(glucoheptonate), gluconate, glucuronate, glutamate,
hexylresorcinate, hydroxynaphthoate, hippurate, iodide,
isethionate, lactate, lactobionate, lauryl sulfate (estolate),
malate, maleate, mandelate, mesylate, methanesulfonate,
methylnitrate, methylsulfate, mucate, naphthoate, napsylate,
nitrate, octadecanoate, oleate, oxalate, pamoate, pantothenate,
phosphate, polygalacturonate, salicylate, stearate, succinate,
sulfate, sulfosalicylate, tannate, tmirate, teoclate,
toluenesulfonate (tosylate), and trifluoroacetate. Multiple anions
can be used in a single preparation if desired; for example, one
micromole of compound (1) can be combined with one-half micromole
of chloride ion and one-half micromole of bromide ion.
[0143] The compounds of Formula (I) and Formula (II), and compounds
(1), (2), (3), (4), (5), (6), (7), or (8), have a single formal
positive charge, i.e., they are monovalent cations. The
stoichiometry of the anion to the singly-charged (monovalent)
cation will depend on the valency of the anion; e.g., when the
anion is a monovalent anion, such as Br--, the cation:anion ratio
will be 1:1; when the anion is a divalent anion, such as sulfate
(Sol-), the cation:anion ratio will be 2:1, and so forth.
EXAMPLES
Example 1
Synthetic Methods
Example 1.1
(.+-.)-exo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
and
(.+-.)-endo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
##STR00027##
[0145] Palladium on carbon (10%, 1.55 g) and ammonium formate (2.48
g, 39.3 mmol) were added to a stirred solution of the combined
alcohols (.+-.)-exo-7-(phenylmethyl)-7-azabicyclo[2.2.1]heptan-2-ol
and (.+-.)-endo-7-(phenylmethyl)-7-azabicyclo[2.2.1]heptan-2-ol
(1.55 g, 7.63 mmol) in dry methanol (51 mL). The resulting
suspension was stirred at reflux temperature for 20-30 min. After
completion, the catalyst was removed by filtration through a pad of
Celite, which was then washed several times with methanol. The
filtrate was concentrated in vacuo and to the residue was added
anhydrous tetrahydrofuran (17 mL) followed by di-tert-butyl
dicarbonate (2.0 g, 9.16 mmol). The reaction mixture was stirred at
room temperature for 3 hrs and the solvent was concentrated in
vacuo. The residue was taken up with methylene chloride and washed
with a solution of ammonium hydroxide. The organic phase was dried
(MgSO.sub.4) and concentrated. The residue was purified by flash
column chromatography to give the alcohols
(.+-.)-exo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
and
(.+-.)-endo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
(1.50 g, 95%).
Example 1.2
(.+-.)-7-[tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-one
##STR00028##
[0147] Dess-Martin periodinane (3.83 g, 9.03 mmol) was added in
several portions under nitrogen to a stirred solution of the
alcohols
(.+-.)-exo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
and
(.+-.)-endo-7-[(tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-ol
(1.50 g, 7.04 mmol) in anhydrous methylene chloride (125 mL). The
reaction mixture was stirred overnight at room temperature. After
removal of the solvent in vacuo, the solid residue was triturated
with diethyl ether and filtrated. The solid was washed several
times with diethyl ether and the filtrate was concentrated in
vacuo. The residue was purified by flash column chromatography to
give the ketone
(.+-.)-7-[tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-one
(1.06 g, 71%).
Example 1.3
(1S,4'R,5'R)-tert-butyl
4'5'-diphenyl-7-azaspiro[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-carb-
oxylate and (1R,4'R,5'R)-tert-butyl
4',5'-diphenyl-7-azaspiro[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-car-
boxylate
##STR00029##
[0149] (R,R)-Diphenylethylenediamine (1.14 g, 5.37 mmol) was added
under nitrogen to a solution of ketone
(.+-.)-7-[tert-butoxycarbonyl]-7-azabicyclo[2.2.1]heptan-2-one
(1.06 g, 5.02 mmol) in dry methylene chloride (17 mL) containing 4
.ANG. molecular sieves. The reaction mixture was stirred at room
temperature for 24 h. Triethylamine (2.8 mL) was added and the
molecular sieves were then eliminated by filtration. The filtrate
was concentrated in vacuo and the resulting residue purified by
flash column chromatography (ether/petroleum ether/Et.sub.3N,
10:15:1 to 15:10:1) affording first (1S,4'R,5'R)-tert-butyl
4',5'-diphenyl-7-azaspiro[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-car-
boxylate (992 mg, 49%) and then (1R,4'R,5'R)-tert-butyl
4',5'-diphenyl-7-azaspiro-[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-ca-
rboxylate (0.938 g, 46%).
Example 1.4
(+)
(1S)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one
##STR00030##
[0151] A solution of (1S,4'R,5'R)-tert-butyl
4',5'-diphenyl-7-azaspiro[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-car-
boxylate (992 mg, 2.45 mmol) in 0.1 M H.sub.3PO.sub.4-THF (2:1,
14.4 mL) was stirred for 30 min at room temperature. The reaction
mixture was then diluted with water and extracted with ether. The
combined extracts were dried (MgSO.sub.4) and the solvent was
concentrated in vacuo. The resulting residue was purified by flash
column chromatography to give the ketone (+)
(1S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (496
mg, 96%); [.alpha.].sup.22.sub.D +74.2.degree. (c 0.43,
CHCl.sub.3); .sup.1H NMR .delta. (CDCl.sub.3, 400 MHz) 4.56 (t,
1H), 4.25 (d, 1H), 2.47 (dd, 1H), 1.99 (m+d, 2+1H), 1.59 (m, 2H),
1.46 (s, 9H).
Example 1.5
(-)-(1R)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one
##STR00031##
[0153] Following the procedure described for the preparation of (+)
(1S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one, the
diamine (1R,4'R,5'R)-tert-butyl
4',5'-diphenyl-7-azaspiro[bicyclo[2.2.1]heptane-2,2'-imidazolidine]-7-car-
boxylate (938 mg, 2.31 mmol) was converted to (-)
(1R)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (468
mg, 96%). [.alpha.].sup.22.sub.D -58.6.degree. (c 0.11,
CHCl.sub.3); .sup.1H NMR .delta. (CDCl.sub.3, 400 MHz) 4.56 (t,
1H), 4.25 (d, 1H), 2.47 (dd, 1H), 1.99 (m+d, 2+1H), 1.59 (m, 2H),
1.46 (s, 9H).
Example 1.6
(1S,2S)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-ol and
(1S,2R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol
##STR00032##
[0155] Platinum oxide (27 mg) followed by triethylamine (0.98 mL,
7.05 mmol) were added to a stirred solution of ketone (+)
(1S)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (496
mg, 2.35 mmol) in ethanol (1.2 mL). The flask was purged under
vacuum and was then filled with hydrogen using a balloon. The
reaction mixture was stirred at room temperature for 48 hours. The
catalyst was then removed by filtration through a pad of Celite,
which was washed several times with methanol. The filtrate was
concentrated in vacuo and the resulting residue was purified by
flash column chromatography affording first
(1S,2S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol (140
mg, 28%) and then
(1S,2R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol (160
mg, 32%).
Example 1.7
(1R,2R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol and
(1R,2S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol
##STR00033##
[0157] Following the procedure described for the preparation of
(1S,2S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol and
(1S,2R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol, the
ketone (-)
(1R)-7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (468
mg, 2.22 mmol) was converted to
(1R,2R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol (150
mg, 32%) and
(1R,2S)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ol (140
mg, 30%).
Example 1.8
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane
##STR00034##
[0159] To
(1R,2S)-2-hydroxy-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]hep-
tane (68 mg, 0.32 mmol) in 5 mL of heptane was added
(R)-methyl-2-cyclopentyl-2-hydroxy 2-phenylacetate (149 mg, 0.64
mmol) followed by cat. NaH (8 mg as a 60% dispersion in oil) and
the mixture was stirred at 100.degree. C. for 20 hrs. Water was
added and the mixture was extracted with ethyl acetate, dried over
sodium sulfate and concentrated. The residue was purified by column
chromatography on silica gel using hexane/ethyl acetate as eluent
to yield 76 mg of the desired product,
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane
as an oil.
[0160] Similarly prepared were: [0161]
(1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
[0162] (1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
[0163] (1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
[0164] (1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
[0165] (1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
[0166] (1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane,
and [0167] (1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane.
Example 1.9
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane
##STR00035##
[0169] To (1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane
(76 mg, 0.182 mmol) was added 1 mL of 4N hydrochloric acid in
dioxane and the mixture was stirred at room temperature for 0.5 hr.
The dioxane was removed under vacuum and the residue was basified
with ammonium hydroxide to pH 10 and extracted with 3.times.30 mL
of methylene chloride. The combined organic layers were dried over
sodium sulfate and concentrated to yield the crude amine. To this
amine, dissolved in 5 mL of dichloroethane, was added 0.1 mL of
formaldehyde solution (37% w/v in water) followed by sodium
triacetoxyborohydride (76 mg, 0.364 mmol) and the mixture stirred
at room temperature overnight. Water was added and the mixture was
extracted with 3.times.50 mL of methylene chloride. The combined
organic layers were dried over sodium sulfate and concentrated to
yield the crude tertiary amine which was further purified on silica
gel using methylene chloride/methanol/ammonia (90:9:1) as the
eluent to yield 46 mg of (1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2, 2, l]heptane as an
oil.
[0170] Similarly prepared were: [0171]
(1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane, [0172]
(1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane, [0173]
(1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane, [0174]
(1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane, [0175]
(1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane [0176]
(1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane, and [0177]
(1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane.
Example 1.10
(1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy 2'-phenylacetoxy)-7,
7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide (2)
##STR00036##
[0179] To (1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane (46 mg, 0.139
mmol) in acetone (2 mL) was added 1 mL of methyl bromide solution
(2M in ether). The resulting mixture was left at room temperature
for 48 hrs. The crystallized product was filtered off and dried to
yield 36 mg of (1R,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide (2) as a white crystalline solid, M.P. 233-234.degree. C.,
.sup.1HNMR: 7.6 (dd, 2H); 7.4 (m, 2H); 7.28 (m, 1H); 5.0 (m, 1H);
4.9 (m, 1H); 4.45 (m, 1H); 3.8 (s, 1H); 3.49 (s, 3H); 3.28 (s, 3H);
3.0 (m, 1H); 2.5-2.2 (m, 4H); 1.9-1.3 (m, 1OH).
[0180] Similarly prepared were:
[0181] (1), (1S,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 198-200.degree. C., .sup.1HNMR: 7.45 (dd, 2H); 7.25
(m, 2H); 7.1 (m, 1H); 5.1 (m, 1H); 4.9 (m, 1H); 4.1 (m, 1H); 3.8
(s, 1H); 3.23 (s, 3H); 3.0 (s, 3H); 2.8 (m, 1H); 2.3 (m, 4H);
2.8-1.2 (m, 10H);
[0182] (4), (1S,2S)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 210-212.degree. C., .sup.1HNMR: 7.59 (d, 2H); 7.36
(t, 2H); 7.3 (m, 1H); 5.4 (m, 1H); 4.8 (m, 1H); 5.6 (m, 1H); 3.6
(s, 1H); 3.5 (s, 6H); 2.85 (m, 2H); 2.2 (m, 2H); 1.8-1.2 (m,
9H);
[0183] (3), (1R,2R)-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 232-233.degree. C., .sup.1HNMR: 7.59 (d, 2H); 7.37
(t, 2H); 7.32 (m, 1H); 5.4 (m, 1H); 4.9 (t, 1H); 4.4 (t, 1H); 3.6
(s, 1H); 3.56 (s, 3H); 3.46 (s, 3H); 3.0 (m, 2H); 2.3 (m, 1H); 1.9
(m, 1H); 1.8-1.2 (m, 10H);
[0184] (5), (1R,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 222-224.degree. C., .sup.1HNMR: 7.6 (dd, 2H); 7.4 (m,
2H); 7.28 (m, 1H); 5.0 (m, 1H); 4.9 (m, 1H); 4.45 (m, 1H); 3.8 (s,
1H); 3.49 (s, 3H); 3.28 (s, 3H); 3.0 (m, 1H); 2.5-2.2 (m, 4H);
1.9-1.3 (m, 10H);
[0185] (7), (1S,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 231-233.degree. C., .sup.1HNMR: 7.45 (dd, 2H); 7.25
(m, 2H); 7.1 (m, 1H); 5.1 (m, 1H); 4.9 (m, 1H); 4.1 (m, 1H); 3.8
(s, 1H); 3.23 (s, 3H); 3.0 (s, 3H); 2.8 (m, 1H); 2.3 (m, 4H);
2.8-1.2 (m, 10H);
[0186] (8), (1S,2S)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 223-225.degree. C., .sup.1HNMR: 7.59 (d, 2H); 7.36
(t, 2H); 7.3 (m, 1H); 5.4 (m, 1H); 4.8 (m, 1H); 5.6 (m, 1H); 3.6
(s, 1H); 3.5 (s, 6H); 2.85 (m, 2H); 2.2 (m, 2H); 1.8-1.2 (m, 9H);
and
[0187] (6), (1R,2R)-2-((S)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7, 7-dimethyl-7-azoniabicyclo[2.2.1]heptane
bromide, M.P. 212-214.degree. C., .sup.1HNMR: 7.59 (d, 2H); 7.37
(t, 2H); 7.32 (m, 1H); 5.4 (m, 1H); 4.9 (t, 1H); 4.4 (t, 1H); 3.6
(s, 1H); 3.56 (s, 3H); 3.46 (s, 3H); 3.0 (m, 2H); 2.3 (m, 1H); 1.9
(m, 1H); 1.8-1.2 (m, 10H).
Example 1.11
Exo-2-((R)-2'-cyclopentyl-2'-hydroxy-2'-phenylacetoxy)spiro[bicyclo-[2.2.1-
]heptane-7,1'-pyrrolidin]-1'-ium bromide (9)
##STR00037##
[0189] To a solution of Exo-2-((R)-2'-cyclopentyl-2'-hydroxy
2'-phenylacetoxy)-7-azabicyclo[2.2.1]heptane (151 mg, 0.479 mmol)
in acetonitrile (3 mL) were added 1,4-dibromobutane (206 mg, 0.958
mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (109 mg, 0.717 mmol).
The resulting solution was stirred at 60.degree. C. for 20 hrs. The
cooled solution was evaporated to dryness and the residual oil was
triturated with acetone/ethyl acetate. The resulting solid was
recrystallized from acetone/ethyl acetate, filtered off and dried
to give 44 mg of the desired product, M.P. 214-217.degree. C., MS
370 (M.sup.+).
Example 2
Biological Methods
[0190] The antagonist effects of compounds at the M.sub.3 mAChR of
the present invention are determined by the following in vitro and
in vivo assays.
Muscarinic Receptor Radioligand Binding Assay:
[0191] Radioligand binding studies were carried out with M.sub.3
receptor cell homogenates as described (Peralta et al., The EMBO
Journal 6, 3923-3929, (1987)). Incubations of test ligands (or
standard) with 0.2 nM [.sup.3H]4-DAMP were incubated for 120
minutes at 22.degree. C. using human M.sub.3 receptor-expressing
cell homogenates. Specific ligand binding to the receptors was
defined as the difference between the total radioligand binding and
the nonspecific binding determined in the presence of an excess of
unlabeled ligand (10 .mu.M atropine). The results were expressed as
a percent of control specific binding ((measured specific
binding/control specific binding).times.100) obtained in the
presence of various concentrations of the test compounds.
[0192] The IC.sub.50 values (concentration causing a half-maximal
inhibition of control specific binding) and Hill coefficients (nH)
were determined by non-linear regression analysis of the
competition curves generated with mean replicate values using Hill
equation curve fitting (Y=D+[(A-D)/(1+(C/C.sub.50).sup.nH)], where
Y=specific binding, D=minimum specific binding, A=maximum specific
binding, C=compound concentration, C.sub.50=IC.sub.50, and nH=slope
factor).
[0193] The inhibition constants (K.sub.i) were calculated using the
Cheng-Prusoff equation (K.sub.i=IC.sub.50/(1+(L/K.sub.D)), where
L=concentration of radioligand in the assay, and K.sub.D=affinity
of the radioligand for the receptor). A Scatchard plot was used to
determine the radioligand K.sub.d.
[0194] When tested by the above method, the compounds of the
invention had K.sub.i values in the range of 0.1 to 100 nM, as
shown in Table 1.
TABLE-US-00001 TABLE 1 M.sub.3 (antagonist) % Inhibition of
Compound Test conc. Control Specific IC.sub.50 K.sub.i ID Structure
(nM) Binding (nM) (nM) (1) ##STR00038## 10 100 0.23 0.16 (2)
##STR00039## 10 98 0.25 0.18 (3) ##STR00040## 10 99 0.25 0.18 (4)
##STR00041## 10 100 0.3 0.22 (5) ##STR00042## 10 80 2.1 1.5 (6)
##STR00043## 10 75 2.9 2.1 (7) ##STR00044## 10 30 19 14 (8)
##STR00045## 10 9 36 26
Bronchodilator Potency and Duration of Action Studies; Rat
Einthoven Model:
[0195] The bronchodilator potency and duration of action studies
utilize male Sprague-Dawley rats (200-350 g). Animals are placed in
a dosing chamber and exposed to the aerosol generated from an LC
Star Nebulizer Set and driven by a mixture of gases (5% CO.sub.2,
20% oxygen and 75% nitrogen) by being placed for no more than 30
min in a dosing chamber. Within the dosing chamber the animals are
not restrained but are confined to a space that has an approximate
floor area of 18 square inches. The animals are acclimated to the
chamber for 10 min, then treated with test compounds which are
delivered via inhalation. Each test compound solution is nebulized
over 5 to 25 minutes. After a predetermined period, based on the
time point studied, the animals are evaluated for the
pharmacodynamic effects of the test compounds. Thirty minutes prior
to the start of pulmonary evaluation, the animals are anesthetized
with pentobarbital sodium (Nembutal, 25 mg/kg). The jugular vein is
catheterized with saline+10 U/ml heparin-filled polyethylene
catheters (PE-20) used to infuse the bronchoconstrictor
methacholine (MCh). The carotid artery is cannulated with 10 U/ml
heparin/saline-filled PE-50 catheters and connected to a pressure
transducer for the measurement of blood pressure and heart rate (CV
effects). The trachea is then dissected free and cannulated with a
14 G steel tube connected to a pressure transducer for the
measurement of pulmonary resistance and to a constant volume rodent
respirator set to deliver an appropriate tidal volume and at a rate
determined by the animal's weight. This is used for rat ventilation
during the evaluation of the pulmonary and CV effects of the test
articles. Intravenous MCh is administered at a dose sufficient to
cause 80% of the maximal pulmonary constriction in an untreated
animal (determined by experimentation in a pilot study using 4
rats). The pulmonary and CV responses to the MCh determine the
potency, safety and pharmacodynamic effects of test articles.
Rat Bronchoprotection Protocol-MCh Dose Response:
[0196] Test compounds and control (water) were administered to male
Sprague Dawley rats (200-350 g) via inhalation. Inhalation dosing
was done by placing the rats in a dosing chamber and exposing them
for 25 min to nebulized drug solutions using a Pari nebulizer. The
animals were then returned to their cages. The chamber was
decontaminated between uses by washing with water.
[0197] Twenty-four hours after dosing and thirty minutes prior to
the start of pulmonary evaluation, the animals were anesthetized
with pentobarbital sodium (Nembutal, 50 mg/mL, 1 mL/kg, IP). The
trachea was then dissected free and cannulated with a 14 G steel
tube connected to a pressure transducer (for the measurement of
pulmonary inflation pressure) and to a constant volume rodent
respirator set to deliver an appropriate tidal volume (2.5 ml) and
at a rate determined by the animal's weight (60 breath/min). The
carotid artery was cannulated with a 5 U/ml heparin/saline-filled
PE-50 cannula and connected to a pressure transducer for the
measurement of blood pressure and heart rate. The jugular vein was
catheterized with a saline filled polyethylene catheter (PE-10) and
used to deliver bolus challenges of the bronchoconstrictor
methacholine (MCh). Intravenous ascending doses of MCh (1 to 300
.mu.g/kg) were administered, after the response to the previous
dose returned to baseline. The pulmonary inflation pressure and
blood pressure were recorded using a Biopac system with the
AcqKnowledge software. The animals were euthanized upon completion
of the study by cervical dislocation followed by a thoracotomy.
[0198] The results of the bronchoprotection studies are shown in
FIG. 1. Table 2 shows the in vivo potency (24 h post inhalation)
and duration of bronchoprotective effects against
methacholine-induced bronchoconstriction in rat.
TABLE-US-00002 TABLE 2 Compound ID Potency (ID.sub.50) Duration (1)
.gtoreq.10 .mu.g/mL ++ (2) .ltoreq.3 .mu.g/mL +++ (3) .ltoreq.3
.mu.g/mL +++ (4) >10 .mu.g/mL + (5), (6), (7) & (8) >100
.mu.g/mL - - inactive 24 h post inhalation + <24 h duration ++
.gtoreq.24 h duration +++ .gtoreq.48 h duration
Bronchodilator Potency and Duration of Action Studies, Guinea Pig
Einthoven Model:
[0199] The bronchodilator potency and duration of action studies
utilize male Dunkin Hartley guinea pigs (250-350 g). Animals are
placed in a dosing chamber and exposed to the aerosol generated
from an LC Star Nebulizer Set and driven by a mixture of gases (5%
CO.sub.2, 20% oxygen and 75% nitrogen) by being placed for no more
than 30 min in a dosing chamber. Within the dosing chamber the
animals are not restrained but are confined to a space that has an
approximate floor area of 18 square inches. The animals are
acclimated to the chamber for 10 min, then treated with test
compounds which are delivered via inhalation. Each test compound
solution is nebulized over 5 to 25 minutes. After a predetermined
period, based on the time point studied, the animals are evaluated
for the pharmacodynamic effects of the test compounds. Thirty
minutes prior to the start of pulmonary evaluation, the animals are
anesthetized with intramuscular ketamine (55.8 mg/kg), xylazine
(3.9 mg/kg) and acepromazine (1 mg/kg). The jugular vein is
catheterized with saline+10 U/ml heparin-filled polyethylene
catheters (PE-20) used to infuse the bronchoconstrictor
methacholine (MCh). The carotid artery is cannulated with 10 U/ml
heparin/saline-filled PE-50 catheters and connected to a pressure
transducer for the measurement of blood pressure and heart rate (CV
effects). The trachea is then dissected free and cannulated with a
14 G steel tube connected to a pressure transducer for the
measurement of pulmonary resistance and to a constant volume rodent
respirator set to deliver an appropriate tidal volume and at a rate
determined by the animal's weight. This is used for guinea pig
ventilation during the evaluation of the pulmonary and CV effects
of the test articles. Intravenous MCh is administered at a dose
sufficient to cause 80% of the maximal pulmonary constriction in an
untreated animal (determined by experimentation in a pilot study
using 4 guinea pigs). The pulmonary and CV responses to the MCh
determine the potency, safety and pharmacodynamic effects of test
articles.
Guinea Pig Bronchoprotection Protocol-MCh Dose Response:
[0200] Test compounds and control (water) were administered to male
Dunkin Hartley guinea pigs (250-350 g) via inhalation. Inhalation
dosing was done by placing the guinea pigs in a dosing chamber and
exposing them for 25 min to nebulized drug solutions using a Pari
nebulizer. The animals were then returned to their cages. The
chamber was decontaminated between uses by washing with water.
[0201] Twenty-four hours after dosing and thirty minutes prior to
the start of pulmonary evaluation, the animals were anesthetized
with intramuscular ketamine (55.8 mg/kg), xylazine (3.9 mg/kg) and
acepromazine (1 mg/kg). The trachea was then dissected free and
cannulated with a 14 G steel tube connected to a pressure
transducer (for the measurement of pulmonary inflation pressure)
and to a constant volume rodent respirator set to deliver an
appropriate tidal volume (2.5 ml) and at a rate determined by the
animal's weight (100 breath/min). The carotid artery was cannulated
with a 5 U/ml heparin/saline-filled PE-50 cannula and connected to
a pressure transducer for the measurement of blood pressure and
heart rate. The jugular vein was catheterized with a saline filled
polyethylene catheter (PE-10) and used to deliver bolus challenges
of the bronchoconstrictor methacholine (MCh). Intravenous ascending
doses of MCh (1 to 300 .mu.g/kg) were administered, after the
response to the previous dose returned to baseline. The pulmonary
inflation pressure and blood pressure were recorded using a Biopac
system with the AcqKnowledge software. The animals were euthanized
upon completion of the study by cervical dislocation followed by a
thoracotomy.
[0202] The results of the bronchoprotection studies are shown in
FIG. 2. Table 3 shows in vivo potency (24 h post inhalation) and
duration of bronchoprotective effects against methacholine-induced
bronchoconstriction in guinea pig.
TABLE-US-00003 TABLE 3 Compound ID Potency (ID.sub.50) Duration (1)
50 .mu.g/mL +++ (2) 5 .mu.g/mL +++ (3) 3 .mu.g/mL +++ +++
.gtoreq.48 h duration
[0203] The disclosures of all publications, patents, patent
applications and published patent applications referred to herein
by an identifying citation are hereby incorporated herein by
reference in their entireties for all purposes, to the same extent
as if each individual publication, patent, patent application and
published patent application was specifically and individually
indicated to be incorporated by reference in its entirety, for all
purposes.
[0204] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is apparent to those skilled in the art that
certain changes and modifications will be practiced. Unless
otherwise apparent from the context, any step, element, embodiment,
feature or aspect of the invention can be used with any other.
Therefore, the description and examples should not be construed as
limiting the scope of the invention.
* * * * *