Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-03-25
2003-12-16
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C514S649000, C564S306000
Reexamination Certificate
active
06664424
ABSTRACT:
FIELD OF THE INVENTION
The present application provides stereoisomers with high affinity for adrenergic receptors which may be used in pharmaceutical compositions and as therapeutic agents in a variety of methods. The present stereoisomers can also be used to identify other compounds that bind to adrenergic receptors, for example, by way of competitive binding studies. The present stereoisomers can act as decongestants, bronchodilators, physiological antagonists of histamine, mydriatic agents, appetite suppressants, and be used for treating conditions typically treated with sympathomimetic drugs. These new stereoisomers are described by Formula I or Formula II.
Formula I embraces the stereoisomers depicted below:
wherein R
2
, R
3
and R
4
are independently H, OH, OCH
3
, CH
2
OH, NHCONH
2
, NH
2
, halogen or CF
3
, and R
1
is pyridine, or an amine which may be substituted with hydrogen, lower alkyl, lower alkylenearyl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, or a similar functional group. According to the present invention, the first carbon on the side chain progressing from the ring is preferably in the R-configuration.
In a preferred embodiment, the stereoisomers of the present invention are of Formula II, depicted below:
wherein R
5
is hydrogen, hydroxyl or methyl; R
6
is hydrogen, lower alkyl, lower alkylenaryl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, and the like. As for Formula I, the first chiral carbon atom on the side chain progressing from the ring in Formula II is preferably in the R-configuration. The second carbon atom on the side chain of Formula II may or may not be a chiral center, however, when the second carbon atom is a chiral center it is preferably in the S-configuration. The present invention contemplates each stereoisomer of Formula I and Formula II in substantially-pure form.
In an even more preferred embodiment, R
5
is hydroxy or methyl in the S-configuration.
In some embodiments, the compositions of the present invention preferably do not include (−)-phenylpropanolamine, (−)-phenylephrine, (−)-ephedrine, adrenaline, albuterol, ambuterol, carbuterol, clenbuterol, fenoterol, isoetharine, isoprenaline, metaproterenol, orciprenaline, pirbuterol, rimiterol, salmeterol, terbutaline, tolobuterol, salmeterol, or salbutamol. According to the present invention, the Formula I and Formula II stereoisomers can act as decongestants, bronchodilators, physiological antagonists of histamine, mydriatic agents, appetite suppressants, and be used for treating conditions typically treated with sympathomimetic drugs. However, also according to the present invention, the stereoisomers of Formula I have particular utility for binding to &bgr;
2
adrenergic receptors and for acting as bronchodilators.
BACKGROUND OF THE INVENTION
The present stereoisomers are structurally related to some sympathomimetic drugs. Generally, sympathomimetic amines act by binding to &agr;- and &bgr;-adrenergic receptors. Such receptor binding can result in vascular constriction, reduced blood flow and/or reduced secretion of fluids into the surrounding tissues, which can decrease the amount of mucous secreted into nasal passages. Sympathomimetic drugs are thus used to treat nasal congestion, allergies and colds. In addition, sympathomimetic amines may affect the cardiovascular, urinary, central nervous and endocrine systems. Johnson et al., 13 Pharmacotherapy 1105 (1993). Sympathomimetic drugs can influence the smooth muscles and the activity of the central nervous system. Thus, sympathomimetic amines are also used as bronchodilators, appetite suppressants and mydriatic agents.
According to the present invention, stereoisomers with particular structural configurations interact more selectively with the receptors involved in sympathomimetic action than do other types of stereoisomers. Compounds with more than one chiral center that differ in the configuration of some but not all of the chiral centers are called diastereomers. Compounds that have the same composition but are mirror images of each other are called enantiomers. A chiral center is an asymmetric carbon atom which can exist in two different, mirror-image configurations. Compounds with such chiral centers have the ability to rotate the plane of plane-polarized light. The prefixes d and l, or (+) and (−) identify the direction in which a stereoisomer rotates light. The d or (+)-stereoisomer is dextrorotatory. In contrast, the l or (−)-stereoisomer is levorotatory. A mixture of (+)- and (−)-enantiomers is called a racemic mixture.
An alternative classification system for stereoisomers exists where prefixes (S) and (R) are used, based on the structural configuration of the chiral center, rather than on the optical activity of the compound.
For example, (+)-pseudoephedrine is known to be a sympathomimetic amine which binds to &agr;-adrenergic receptors. The structures of (+)-pseudoephedrine and (−)-pseudoephedrine are provided below.
(+)-Pseudoephedrine is a known decongestant sold under the tradename Sudafed®. However, (+)-pseudoephedrine has undesirable side effects, including central nervous system stimulation, lightheadedness, nervousness, anxiety, paranoia, heart arrhythmia, atrial fibrillations and premature ventricular contractions. 95 A
MERICAN
H
OSPITAL
F
ORMULATORY
S
ERVICE
847-48. Moreover, (+)-pseudoephedrine unfortunately can be converted into the psychoactive drug, methamphetamine, by simply converting the hydroxyl, which is in the S-configuration, to the hydrogen found in methamphetamine. Hence, a need exists for a molecule which binds to an adrenergic receptor, has the beneficial decongestant activities of (+)-pseudoephedrine, and which reduces not only its adverse side effects, but its methamphetamine-conversion problem.
(−)-Ephedrine and the racemic mixture of (−)- and (+)-ephedrine also bind adrenergic receptors and have been used for bronchodilation. (−)-Ephedrine and the racemic mixture of (−)- and (+)-ephedrine relax smooth muscle, stimulate metabolism, stimulate the central nervous system, but can have significant cardiovascular effects. 95 A
MERICAN
H
OSPITAL
F
ORMULATORY
S
ERVICE
815. Accordingly, a need exists for molecules which bind adrenergic receptors, without the undesirable side effects of (−)-ephedrine and the racemic mixture of (−)-ephedrine and (+)-ephedrine.
Similarly, the racemic mixture of (+)- and (−)-phenylpropanolamine, is known to bind adrenergic receptors, and has been used as a decongestant or an anoretic. However, the racemic mixture has undesirable side effects—it may be contraindicated in patients having glaucoma and is known to stimulate the central nervous system. 95 A
MERICAN
H
OSPITAL
F
ORMULATORY
S
ERVICE
846. Hence, a need exists for a composition having the beneficial activities of (+)- and (−)-phenylpropanolamine, without their undesirable side effects.
SUMMARY OF THE INVENTION
The present invention is directed to a stereoscopically-pure stereoisomer of Formula I or Formula II, and a pharmaceutically acceptable carrier, with the proviso that the stereoisomer is not (−)-phenylpropanolamine, (−)-phenylephrine or (−)-ephedrine. The present stereoisomers bind to adrenergic receptors with high affinity. According to the present invention, compositions containing a stereoisomer of Formula I or Formula II have a variety of uses. For example, when provided in a therapeutically effective dosage, the stereoisomers of the present invention may be used to treat nasal congestion, bronchial congestion, asthma, attention deficit hyperactivity disorder (ADHD), inflammation caused by histamine, and other conditions treated with sympathomimetic drugs. The present stereoisomers may also be used to dilate the pupil and to suppress the appet
Booth Anthony
Caffrey James L.
Coppins Janet L
Federman Evan J.
Jacobsen Barry H.
Rotman Alan L.
Warner-Lambert & Company
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