Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-01
2002-05-21
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S312000, C514S313000, C514S314000, C544S353000, C544S354000, C544S355000, C544S356000, C546S156000
Reexamination Certificate
active
06391878
ABSTRACT:
TECHNICAL FIELD
This invention relates to certain substituted guanidinyl heterocycle compounds. The compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.
BACKGROUND OF THE INVENTION
Therapeutic indications of alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M. Stadel, & J. P. Hieble, “Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes”,
Annual Review of Pharmacology & Toxicology,
Vol. 32 (1993) pp. 243-279.
Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, “12.1 &agr;-Adrenergic Receptors”,
Comprehensive Medicinal Chemistry,
Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten,“&agr;-Adrenoceptor Agonists and Antagonists”,
Drugs of the Future,
Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, “Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the &agr;
1
and &agr;
2
-Selectivity of Test Compounds: (2) &agr;-Adrenoceptor Agonists”,
European Journal of Pharmacology,
Vol.129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P. A. van Zwieten, “Quantitative Relationships between &agr;-Adrenergic Activity and Binding Affinity of &agr;-Adrenoceptor Agonists and Antagonists”,
Journal of Medicinal Chemistry,
Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P. A. van Zwieten, “Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat”,
The Journal of Pharmacology and Experimental Therapeutics,
Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R. Stillings, “Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard &agr;-Adrenoreceptor Agents”,
European Journal of Medicinal Chemistry,
Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, “Heteroaromatic Analogues of the &agr;
2
-Adrenoreceptor Partial Agonist Clonidine”,
Journal of Medicinal Chemistry,
Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, “Effects of &agr;
2
-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets”,
British Journal of Pharmacology,
Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, many compounds related in structure to those of this invention do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoceptors.
For example, many compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia at systemically effective doses. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side effects.
OBJECTS OF THE INVENTION
It is an object of the invention to provide compounds and compositions useful in treating disorders modulated by alpha-2 adrenoceptors.
It is an object of this invention to provide novel compounds having substantial activity in preventing or treating nasal congestion, otitis media, and sinusitis, without undesired side effects.
It is also an object of this invention to provide novel compounds for treating cough, chronic obstructive pulmonary disease (COPD) and/or asthma.
It is also an object of this invention to provide novel compounds for treating diseases and disorders associated with sympathetic nervous system activity, including benign prostatic hypertrophy, cardiovascular disorders comprising myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.
It is also an object of this invention to provide novel compounds for treating ocular disorders, such as ocular hypertension, glaucoma, hyperemia, conjunctivitis and uveitis.
It is also an object of this invention to provide novel compounds for treating gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).
It is also an object of this invention to provide novel compounds for treating migraine.
It is also an object of this invention to provide novel compounds for treating pain, substance abuse and/or withdrawal.
It is a still further object of this invention to provide such compounds which have good activity from peroral, parenteral, intranasal and/or topical dosing.
SUMMARY OF THE INVENTION
This invention relates to compounds having the following structure:
a) R
1
is hydrogen; or alkyl or nil; where R
1
is nil, bond (a) is a double bond;
b) D is CR
2
and R
2
is selected from hydrogen; unsubstituted C
1
-C
3
alkanyl; amino, hydroxy, mercapto; C
1
-C
3
alkylthio or alkoxy; C
1
-C
3
alkylamino or C
1
-C
3
dialkylamino and halo; or when B is CR
3
; D may be N;
c) B is NR
9
, CR
3
=CR
8
, CR
3
=N, CR
3
, S, O, SO or SO
2
; wherein Rg is selected from hydrogen; unsubstituted C
1
-C
3
alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; and wherein R
3
and R
8
are each independently selected from hydrogen; unsubstituted C
1
-C
3
alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C
1
-C
3
alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C
1
-C
3
alkylamino or C
1
-C
3
dialkylamino and halo;
d R
4
, R
5
and R
6
are each independently selected from hydrogen; unsubstituted C
1
-C
3
alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C
1
-C
3
alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C
1
-C
3
alkylamino or C
1
-C
3
dialkylamino; halo; and NH—C(=NR
10
)NHR
11
(guanidinyl); wherein R
10
and R
11
are independently selected from hydrogen; methyl; and ethyl; and wherein one and only one of R
4
, R
5
and R
6
is guanidinyl;
e) R
7
is selected from hydrogen; unsubstituted C
1
-C
3
alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C
1
-C
3
alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C
1
-C
3
alkylamino or C
1
-C
3
dialkylamino and halo;
and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters, and pharmaceutical compositions containing such novel compounds, and the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkanyl” means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, “alkenyl” means a hydrocarbon substituent with one double bond, straight or branched chain, unsubstituted or substituted.
As used herein, “alkylthio” means a substituent having the structure Q—S—, where Q is alkanyl or alkenyl.
As used herein, “alkoxy” means a substituent having the structure Q—O—, where Q is alkanyl or alkenyl.
As used herein, “alkylamino” means a substituent having the structure Q—NH—, where Q is alkanyl or alkenyl.
As used herein, “dialkylamino” means a substituent having the structure Q
1
—N(Q
2
)—, where each Q is independently alkanyl or alkenyl.
“Guanidinyl” is defined as a radical of structure;
For purposes of exemplifying this radical, wherever it appears in a chart, it is shown as “GNDNL” for brevity.
“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo.
A “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.
Ares Jeffrey Joseph
Bogdan Sophie Eva
Cupps Thomas Lee
Henry Raymond Todd
Seibel William Lee
Clark Karen F.
McMahon Mary Pat
Seaman D. Margaret
The Procter & Gamble & Company
Upite David V.
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