U.S. patent application number 10/071284 was filed with the patent office on 2002-09-12 for guanidinyl heterocycle compounds useful as alpha-2 adrenoceptor agonists.
Invention is credited to Ares, Jeffrey Joseph, Bogdan, Sophie Eva, Cupps, Thomas Lee, Henry, Raymond Todd, Seibel, William Lee, Sheldon, Russell James.
Application Number | 20020128481 10/071284 |
Document ID | / |
Family ID | 21862692 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128481 |
Kind Code |
A1 |
Cupps, Thomas Lee ; et
al. |
September 12, 2002 |
Guanidinyl heterocycle compounds useful as alpha-2 adrenoceptor
agonists
Abstract
This invention involves compounds having the following
structure: 1 as described in the claims; and enantiomers, optical
isomers, stereoisomers, diastereomers, tautomers, addition salts,
biohydrolyzable amides and esters thereof, as well as
pharmaceutical compositions comprising such novel compounds. The
invention also relates to the use of such compounds for preventing
or treating disorders modulated by alpha-2 adrenoceptors.
Inventors: |
Cupps, Thomas Lee; (Norwich,
NY) ; Bogdan, Sophie Eva; (Maineville, OH) ;
Henry, Raymond Todd; (Pleasant Plain, OH) ; Sheldon,
Russell James; (Fairfield, OH) ; Seibel, William
Lee; (Hamilton, OH) ; Ares, Jeffrey Joseph;
(Hamilton, OH) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY
PATENT DIVISION
HEALTH CARE RESEARCH CENTER
8340 MASON-MONTGOMERY ROAD
MASON
OH
45040
US
|
Family ID: |
21862692 |
Appl. No.: |
10/071284 |
Filed: |
February 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10071284 |
Feb 8, 2002 |
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09727900 |
Dec 1, 2000 |
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09727900 |
Dec 1, 2000 |
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09308788 |
Aug 9, 1999 |
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60032023 |
Nov 25, 1996 |
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Current U.S.
Class: |
544/353 ;
544/283; 546/153; 546/159; 548/152; 548/217; 548/304.4; 548/483;
548/484 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
25/00 20180101; A61P 13/08 20180101; A61P 27/16 20180101; A61P 9/10
20180101; A61P 27/06 20180101; A61P 25/32 20180101; A61P 11/02
20180101; A61P 1/04 20180101; C07D 277/62 20130101; A61P 9/04
20180101; A61P 25/02 20180101; A61P 9/06 20180101; A61P 25/06
20180101; C07D 215/38 20130101; A61P 1/12 20180101; A61P 1/00
20180101; C07D 235/06 20130101; A61P 25/36 20180101; A61P 9/12
20180101; A61P 27/02 20180101 |
Class at
Publication: |
544/353 ;
546/153; 546/159; 544/283; 548/152; 548/217; 548/304.4; 548/483;
548/484 |
International
Class: |
C07D 277/62; C07D
215/36; C07D 263/52; C07D 209/40 |
Claims
What is claimed is:
1. A compound of formula; 15wherein; a) R.sub.1 is hydrogen; or
alkyl or nil; where R.sub.1 is nil, bond (a) is a double bond; b) D
is CR.sub.2 and R.sub.2 is selected from hydrogen; unsubstituted
C.sub.1-C.sub.3 alkanyl; amino, hydroxy, mercapto; C.sub.1-C.sub.3
alkylthio or alkoxy; C.sub.1-C.sub.3 alkylamino or C.sub.1-C.sub.3
dialkylamino and halo; or when B is CR.sub.3; D may be N; c) B is
NR.sub.9, CR.sub.3.dbd.CR.sub.8, CR.sub.3.dbd.N, CR.sub.3, S, O, SO
or SO.sub.2; wherein R.sub.9 is selected from hydrogen; and
unsubstituted C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl;
cycloalkanyl, cycloalkenyl; and wherein R.sub.3 and R.sub.8 are
each independently selected from hydrogen; unsubstituted
C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl; cycloalkanyl,
cycloalkenyl; unsubstituted C.sub.1-C.sub.3 aikylthio or alkoxy;
hydroxy; thio; nitro; cyano; amino; C.sub.1-C.sub.3 alkylamino or
C.sub.1-C.sub.3 dialkylamino and halo; d) R.sub.4, R.sub.5 and
R.sub.6 are each independently selected from hydrogen;
unsubstituted C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl;
cycloalkanyl, cycloalkenyl; unsubstituted C.sub.1-C.sub.3 alkylthio
or alkoxy; hydroxy; thio; nitro; cyano; amino; C.sub.1-C.sub.3
alkylamino or C.sub.1-C.sub.3 dialkylamino; halo; and
NH--C(.dbd.NR.sub.10)NHR.sub.1 1 (guanidinyl); wherein R.sub.10 and
R.sub.11 are independently selected from hydrogen; methyl; and
ethyl; and wherein one and only one of R.sub.4, R.sub.5 and R.sub.6
is guanidinyl; e) R.sub.7 is selected from hydrogen; unsubstituted
C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl; cycloalkanyl,
cycloalkenyl; unsubstituted C.sub.1-C.sub.3 alkylthio or alkoxy;
hydroxy; thio; nitro; cyano; amino; C.sub.1-C.sub.3 alkylamino or
C.sub.1-C.sub.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.
2. A compound according to claim 1 wherein R.sub.6 is guanidinyl
and R11 is hydrogen.
3. A compound according to claim 2 wherein B is
CR.sub.3.dbd.CR.sub.8, D is CR.sub.2 and R.sub.1 is nil.
4. A compound according to claim 3 wherein: R.sub.2, R.sub.3,
R.sub.5 and R.sub.8 are hydrogen. R.sub.4 is selected from
hydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano; R.sub.7
is selected from methyl, chloro, and bromo; and R.sub.10 is
hydrogen or methyl.
5. A compound according to claim 2 wherein B is NR.sub.9 and D is
CR.sub.2.
6. A compound according to claim 5 wherein: R.sub.2, R.sub.9 and
R.sub.10 are each independently chosen from hydrogen and methyl;
R.sub.4 is selected from hydrogen, methyl, methoxy, fluoro, chloro,
bromo and cyano; R.sub.5 is hydrogen; and R.sub.7 is selected from
methyl, chloro, and bromo.
7. A compound according to claim 2 wherein B is S and D is
CR.sub.2, and R.sub.1 is nil.
8. A compound according to claim 7 wherein R.sub.2 and R.sub.10 are
each independently selected from hydrogen and methyl; R.sub.4 is
selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and
cyano; R.sub.5 is hydrogen; and R.sub.7 is selected from methyl,
chloro, and bromo.
9. A compound according to claim 7 wherein R.sub.2 and R.sub.10 are
each independently selected from hydrogen and methyl; R.sub.4 is
selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and
cyano; R.sub.5 is methyl, chloro or bromo; and R.sub.7 is
hydrogen.
10. The compound according to claim 2, wherein: R.sub.4 is selected
from hydrogen; unsubstituted C.sub.1-C.sub.3 alkanyl, alkenyl or
alkynyl; unsubstituted C.sub.1-C.sub.3 alkylthio or alkoxy;
hydroxy; thio; nitro; cyano; amino; and C.sub.1-C.sub.2 alkylamino
or C.sub.1-C.sub.2 dialkylamino and halo; R.sub.5 is hydrogen; and
R.sub.7 is selected from hydrogen; unsubstituted C.sub.1-C.sub.3
alkanyl, alkenyl or alkynyl; unsubstituted C.sub.1-C.sub.3
alkylthio or alkoxy; and C.sub.1-C.sub.2 alkylamino or
C.sub.1-C.sub.2 dialkylamino; and halo.
11. The compound according to claim 1, wherein R.sub.5 is
guanidinyl and R.sub.11 is hydrogen.
12. A compound according to claim 11 wherein B is
CR.sub.3.dbd.CR.sub.8 and D is CR.sub.2.
13. A compound according to claim 12 wherein: R.sub.2 and R.sub.6
are hydrogen; R.sub.3 is methyl, bromo, fluoro or hydrogen; R.sub.4
is selected from methyl, chloro and bromo; R.sub.7 is selected from
methyl, chloro, bromo, cyano, and methoxy; R.sub.8 is methyl,
bromo, chloro, fluoro, cyano, methoxy or hydrogen; and R.sub.10 is
hydrogen or methyl.
14. A compound according to claim 11 wherein B is S and D is
CR.sub.2 and R.sub.1 is nil.
15. A compound according to claim 14 wherein R.sub.2 and R.sub.10
are each independently selected from hydrogen and methyl; R.sub.4
is selected from methyl, chloro, and bromo; R.sub.6 is hydrogen;
and R.sub.7 is selected from methyl, methoxy, chloro, bromo, and
cyano.
16. The compound according to claim 1, wherein R.sub.4 is
guanidinyl.
17 The compound of claim 16 wherein B is chosen from NR.sub.9,
CR.sub.3.dbd.CR.sub.8 and S.
18. The compound according to claim 17, wherein: R.sub.5, R.sub.6
and R.sub.7 are each independently selected from hydrogen; methyl;
ethyl; methoxy; methylthio; thio; cyano; amino; and halo; and
R.sub.2 is hydrogen.
19. The compound according to claim 1, wherein the compound is:
(4,7-Dimethylbenzimidazol-5-yl)guanidine;
(2,4-Dimethylbenzimidazol-5-yl)- guanidine;
(1,4-Dimethylbenzimidazol-5-yl)guanidine;
(4-Bromobenzimidazol-5-yl)guanidine;
N.sup.1-Methyl-N.sup.2-(4-methylbenz- imidazol-5-yl)guanidine;
(8Methylquinolin-7-yl)guanidine; (8-Bromoquinolin-7-yl)guanidine;
(6-Methylbenzothiazol-5-yl)guanidine; or
(4-Bromobenzothiazol-5-yl)guanidine.
20. The compound according to claim 1, wherein the compound is:
(4-Methylbenzimidazol-5-yl)guanidine;
21. A pharmaceutical composition comprising: (a) a safe and
effective amount of a compound of any of claims 1, 2, 11, 16, 19 or
20; and (b) a pharmaceutically-acceptable carrier.
22. A pharmaceutical composition comprising the compound of claim 1
and one or more actives chosen from the group consisting of an
antihistamine, antitussive, mast cell stabilizer, leukotriene
antagonist, expectorant/mucolytic, antioxidant or radical
inhibitor, steroid, bronchodilator, antiviral, analgesic,
antiinflammatory, gastrointestinal and ocular active.
23. A pharmaceutical composition according to claim 21 further
comprising an antihistamine.
24. A pharmaceutical composition according to claim 21 further
comprising an antiinflammatory.
25. A method for preventing or treating a disorder modulated by
alpha-2 adrenoceptors, by administering to a mammal in need of such
treatment, a safe and effective amount of an alpha-2 adrenoceptor
agonist compound according to claim 1.
26. A method for preventing or treating a disorder modulated by
alpha-2 adrenoceptors, wherein the disorder is chosen from the
groups comprising, nasal congestion, otitis media, sinusitis,
asthma, pain, migraine, substance abuse and addiction,
gastrointestinal disorder, ulcer, stomach hyperacidity, benign
prostatic hypertrophy, by administering to a mammal in need of such
treatment, a safe and effective amount of an alpha-2 adrenoceptor
agonist compound according to claim 1.
27. A method of treating or preventing nasal congestion by
administering to a mammal in need of such treatment a safe and
effective amount of a compound according to claim 1.
28. A method of treating or preventing nasal congestion by
administering to a mammal in need of such treatment a safe and
effective amount of a compound according to claims 19 or 20.
29. The method of claim 26, wherein the disorder is otitis
media.
30. The method of claim 26, wherein the disorder is sinusitis.
31. A method for preventing or treating a respiratory disorder,
wherein the disorder is chosen from the group comprising cough,
chronic obstructive pulmonary disease and asthma, by administering
to a mammal in need of such treatment, a safe and effective amount
of a compound according to claim 1.
32. A method for preventing or treating a respiratory disorder
according to claim 31, wherein the disorder is asthma.
33. A method for preventing or treating disorders mediated by
sympathetic activity and modulated by alpha-2 adrenoceptors by
administering to a mammal in need of such treatment, a safe and
effective amount of an alpha-2 adrenoceptor agonist compound
according to claim 1.
34. A method of treating a disorder according to claim 33, wherein
the disorder is chosen from the group comprising benign prostatic
hypertrophy, myocardial ischemia, cardiac reperfusion injury,
angina, cardiac arrhythmia, heart failure and hypertension.
35. The method of claim 34, wherein the disorder is heart
failure.
36. A method for preventing or treating an ocular disorder
modulated by alpha-2 adrenoceptors, by administering to a mammal in
need of such treatment, a safe and effective amount of a compound
according to claim 1.
37. A method for preventing or treating an ocular disorder
according to claim 36 wherein the disorder is chosen from the group
comprising ocular hypertension, glaucoma, hyperemia,
conjunctivitis, and uveitis and glaucoma.
38. A method for preventing or treating an ocular hypertensive
disorder according to claim 37 wherein the disorder is
glaucoma.
39. A method for preventing or treating a gastrointestinal disorder
modulated by alpha-2 adrenoceptors by administering to a mammal in
need of such treatment, a safe and effective amount of an alpha-2
adrenoceptor agonist compound according to claim 1.
40. A method for preventing or treating a gastrointestinal
disorder, according to claim 39, wherein the disorder is chosen
from the group comprising diarrhea and irritable bowel
syndrome.
41. A method for preventing or treating a gastrointestinal
disorder, according to claim 40, wherein the disorder is
diarrhea.
42. A method for preventing or treating migraine by administering
to a mammal in need of such treatment, a safe and effective amount
of a compound according to claim 1.
43. A method for preventing or treating pain by administering to a
mammal in need of such treatment, a safe and effective amount of a
compound according to claim 1.
44. A method for treating substance abuse by administering to a
mammal in need of such treatment, a safe and effective amount of a
compound according to claim 1.
Description
CROSS REFERENCE
[0001] This application claims priority under Title 35, United
States Code 119(e) from Provisional Application Ser. No.
60/032,023, filed Nov. 25, 1996.
TECHNICAL FIELD
[0002] 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
[0003] 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.
[0004] 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 .alpha.-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,
".alpha.-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 .alpha..sub.1 and
.alpha..sub.2-Selectivity of Test Compounds: (2)
.alpha.-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 .alpha.-Adrenergic
Activity and Binding Affinity of .alpha.-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 .alpha.-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 .alpha..sub.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 .alpha..sub.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.
[0005] 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
[0006] It is an object of the invention to provide compounds and
compositions useful in treating disorders modulated by alpha-2
adrenoceptors.
[0007] 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.
[0008] It is also an object of this invention to provide novel
compounds for treating cough, chronic obstructive pulmonary disease
(COPD) and/or asthma.
[0009] 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.
[0010] 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.
[0011] 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).
[0012] It is also an object of this invention to provide novel
compounds for treating migraine.
[0013] It is also an object of this invention to provide novel
compounds for treating pain, substance abuse and/or withdrawal.
[0014] 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
[0015] This invention relates to compounds having the following
structure: 2
[0016] a) R.sub.1 is hydrogen; or alkyl or nil; where R.sub.1 is
nil, bond (a) is a double bond;
[0017] b) D is CR.sub.2 and R.sub.2 is selected from hydrogen;
unsubstituted C.sub.1-C.sub.3 alkanyl; amino, hydroxy, mercapto;
C.sub.1-C.sub.3 alkylthio or alkoxy; C.sub.1-C.sub.3 alkylamino or
C.sub.1-C.sub.3 dialkylamino and halo; or when B is CR.sub.3; D may
be N;
[0018] c) B is NR.sub.9, CR.sub.3.dbd.CR.sub.8, CR.sub.3.dbd.N,
CR.sub.3, S, O, SO or SO.sub.2; wherein R.sub.9 is selected from
hydrogen; unsubstituted C.sub.1-C.sub.3 alkanyl, alkenyl or
alkynyl; cycloalkanyl, cycloalkenyl; and wherein R.sub.3 and
R.sub.8 are each independently selected from hydrogen;
unsubstituted C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl;
cycloalkanyl, cycloalkenyl; unsubstituted C.sub.1-C.sub.3 alkylthio
or alkoxy; hydroxy; thio; nitro; cyano; amino; C.sub.1-C.sub.3
alkylamino or C.sub.1-C.sub.3 dialkylamino and halo;
[0019] d R.sub.4, R.sub.5 and R.sub.6 are each independently
selected from hydrogen; unsubstituted C.sub.1-C.sub.3 alkanyl,
alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted
C.sub.1-C.sub.3 alkylthio or alkoxy; hydroxy; thio: nitro; cyano;
amino; C.sub.1-C.sub.3 alkylamino or C.sub.1-C.sub.3 dialkylamino;
halo; and NH--C(.dbd.NR.sub.10)NHR.sub.11 (guanidinyl); wherein
R.sub.10 and R.sub.11 are independently selected from hydrogen;
methyl; and ethyl; and wherein one and only one of R.sub.4, R.sub.5
and R.sub.6 is guanidinyl;
[0020] e) R.sub.7 is selected from hydrogen; unsubstituted
C.sub.1-C.sub.3 alkanyl, alkenyl or alkynyl; cycloalkanyl,
cycloalkenyl; unsubstituted C.sub.1-C.sub.3 alkylthio or alkoxy;
hydroxy; thio; nitro; cyano; amino; C.sub.1-C.sub.3 alkylamino or
C.sub.1-C.sub.3 dialkylamino and halo;
[0021] 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
[0022] As used herein, "alkanyl" means a saturated hydrocarbon
substituent, straight or branched chain, unsubstituted or
substituted.
[0023] As used herein, "alkenyl" means a hydrocarbon substituent
with one double bond, straight or branched chain, unsubstituted or
substituted.
[0024] As used herein, "alkylthio" means a substituent having the
structure Q--S--, where Q is alkanyl or alkenyl.
[0025] As used herein, "alkoxy" means a substituent having the
structure Q--O--, where Q is alkanyl or alkenyl.
[0026] As used herein, "alkylamino" means a substituent having the
structure Q--NH--, where Q is alkanyl or alkenyl.
[0027] As used herein, "dialkylamino" means a substituent having
the structure Q.sub.1--N(Q.sub.2)--, where each Q is independently
alkanyl or alkenyl.
[0028] "Guanidinyl" is defined as a radical of structure; 3
[0029] For purposes of exemplifying this radical, wherever it
appears in a chart, it is shown as "GNDNL" for brevity.
[0030] "Halo", "halogen", or "halide" is a chloro, bromo, fluoro or
iodo.
[0031] A "pharmaceutically-acceptable salt" is a cationic salt
formed at any acidic (e.g., carboxyl) group, or an anionic salt
formed at any basic (e.g., amino) group. Many such salts are known
in the art, as described in World Patent Publication 87/05297,
Johnston et al., published Sep. 11, 1987, incorporated by reference
herein. Preferred cationic salts include the alkali metal salts
(such as sodium and potassium), alkaline earth metal salts (such as
magnesium and calcium) and organic salts. Preferred anionic salts
include halides, sulfonates, carboxylates, phosphates, and the
like. Clearly contemplated in such salts are addition salts that
may provide an optical center, where once there was none. For
example, a chiral tartrate salt may be prepared from the compounds
of the invention, and this definition includes such chiral
salts.
[0032] The compounds of the invention are sufficiently basic to
form acid-addition salts. The compounds are useful both in the free
base form and the form of acid-addition salts, and both forms are
within the purview of the invention. The acid-addition salts are in
some cases a more convenient form for use. In practice, the use of
the salt form inherently amounts to the use of the base form of the
active. Acids used to prepare acid-addition salts include
preferably those which produce, when combined with the free base,
medicinally acceptable salts. These salts have anions that are
relatively innocuous to the animal organism, such as a mammal, in
medicinal doses of the salts so that the beneficial property
inherent in the free base are not vitiated by any side effects
ascribable to the acid's anions.
[0033] Examples of appropriate acid-addition salts include, but at
not limited to hydrochloride, hydrobromide, hydroiodiode, sulfate,
hydrogensulfate, acetate, trifluoroacetate, nitrate, maleate,
citrate, fumarate, formate, stearate, succinate, mallate, malonate,
adipate, glutarate, lactate, propionate, butyrate, tartrate,
methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
dodecyl sulfate, cyclohexanesulfamate, and the like. However, other
appropriate medicinally acceptable salts within the scope of the
invention are those derived from other mineral acids and organic
acids. The acid-addition salts of the basic compounds are prepared
by several methods. For example the free base can be dissolved in
an aqueous alcohol solution containing the appropriate acid and the
salt is isolated by evaporation of the solution. Alternatively,
they may be prepared by reacting the free base with an acid in an
organic solvent so that the salt separates directly. Where
separation of the salt is difficult, it can be precipitated with a
second organic solvent, or can be obtained by concentration of the
solution.
[0034] Although medicinally acceptable salts of the basic compounds
are preferred, all acid-addition salts are within the scope of the
present invention. All acid-addition salts are useful as sources of
the free base form, even if the particular salt per se is desired
only as an intermediate product. For example, when the salt is
formed only for purposes of purification or identification, or when
it is used as an intermediate in preparing a medicinally acceptable
salt by ion exchange procedures, these salts are clearly
contemplated to be a part of this invention.
[0035] "Biohydrolyzable amide" refers to an amide of the compound
of the invention that is readily converted in vivo by a mammal
subject to yield an active compound of the invention.
[0036] A "biohydrolyzable ester" refers to an ester of the compound
of the invention that is readily converted by a mammal subject to
yield an active compound of the invention.
[0037] "Optical isomer", "stereoisomer", "enantiomer,"
"diastereomer," as referred to herein have the standard art
recognized meanings (Cf., Hawleys Condensed Chemical Dictionary,
11th Ed.). Of course, an addition salt may provide an optical
center, where once there was none. For example, a chiral tartrate
salt may be prepared from the compounds of the invention, and this
definition includes such chiral salts. It will be apparent to the
skilled artisan that disclosure of the racemic mixture alone
discloses any enantiomers therein. Thus by one disclosure, more
than one compound is taught.
[0038] As used herein "animal" includes "mammals" which includes
"humans".
[0039] The skilled artisan will appreciate that tautomeric forms
will exist in certain compounds of the invention. For example, when
R.sub.2 is hydroxy and bond (a) is a double bond, it is understood
to include the keto form of that molecule, where R.sub.2 is oxo,
and bond (a) is a single bond, though not specifically described.
Thus, in this description the disclosure of one tautomeric form
discloses each and all of the tautomers, Similarly, when tautomer A
of the molecule is shown, it is understood to include tautomers B
and C of that molecule although not specifically depicted. 4
[0040] The illustration of specific protected forms and other
derivatives of the Formula (I) compounds is not intended to be
limiting. The application of other useful protecting groups, salt
forms, etc. is within the ability of the skilled artisan.
[0041] As defined above and as used herein, substituent groups may
themselves be substituted. Such substitution may be with one or
more substituents. Such substituents include those listed in C.
Hansch and A. Leo, Substituent Constants for Correlation Analysis
in Chemistry and Biology (1979), incorporated by reference herein.
Preferred substituents include (for example) alkyl, alkenyl,
alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl,
etc.), cyano, halo, carboxy, alkoxyacetyl (e.g., carboethoxy,
etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g.,
piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo,
hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
[0042] For the purposes of nomenclature, as shown in the following
example, the location of the guanidinyl radical is: 5
[0043] It is recognized that where B is CR.sub.3.dbd.CR.sub.8 and
the like, this numbering is not in strict compliance with IUPAC
nomenclature. It is used for illustration of synthetic methods
only; examples of compounds have names which more closely resemble
IUPAC nomenclature.
[0044] Compounds
[0045] This invention includes compounds having the following
structure: 6
[0046] as described in the Summary of the Invention.
[0047] In the above structure, when the guanidinyl is at the
6-position, preferably R.sub.7 is selected from hydrogen;
unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon
atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3
carbon atoms; hydroxy; thiol; cyano; and halo. R.sub.4 is
preferably hydrogen, cyano, halo or methyl. R.sub.7 is also
preferably alkanyl, more preferably methyl or ethyl, most
preferably methyl. R.sub.7 which is alkylthio or alkoxy is
preferably saturated, also preferably C.sub.1 or C.sub.2, most
preferably methylthio or methoxy. R.sub.7 which is halo is
preferably chloro or bromo.
[0048] In the above structure, when the guanidinyl is at the
5-position, preferably R.sub.4 is selected from hydrogen;
unsubstituted alkanyl or alkenyl having 1 to about 3 carbon atoms;
unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon
atoms; hydroxy; thiol; cyano; and halo. R.sub.7 is preferably
alkanyl or halo. R.sub.4 and R.sub.7 are most preferably
methyl.
[0049] In the above structure, when the guanidinyl is at the
4-position, preferably R.sub.7 is selected from hydrogen;
unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon
atoms; hydroxy; thiol; cyano; and halo. R.sub.7 which is alkanyl,
is preferably methyl or ethyl, more preferably methyl. R.sub.7
which is halo is preferably chloro or bromo. R.sub.6 is preferably
hydrogen; alkanyl; cyano; and halo. R.sub.6 which is alkanyl is
preferably methyl or ethyl, most preferably methyl. R.sub.5 is
preferably hydrogen; alkanyl; and halo. R.sub.5 which is alkanyl is
preferably methyl or ethyl, most preferably methyl.
[0050] Preferred compounds of this invention have the following
structure: 7
[0051] where R.sub.1 is nil, (a) is a double bond and D, B,
R.sub.4, R.sub.5, R.sub.7 and R.sub.10 are as indicated in the
following table:
1 Compound No D B R.sub.4 R.sub.5 R.sub.7 R.sub.10 1 CH NH H H Me H
2 CH NH Me H Me H 3 CH--Me NH H H Me H 4 CH N--Me H H Me H 5 CH NH
H H Br H 6 CH NH H H Me Me 7 CH CH.dbd.CH H H Me H 8 CH CH.dbd.CH H
H Br H 9 CH S H Me H H 10 CH S H H Br H
[0052] Methods of Making the Compounds of the Invention
[0053] The compounds of this invention are synthesized using the
following procedures. For purposes of this description,
6-guanidinyl compounds are shown, but the skilled artisan will
appreciate that the 4- and 5-guanidinyl compounds are prepared
similarly. The R.sub.1-R.sub.7 radicals are omitted for clarity,
unless they are prepared in that specific scheme. The skilled
artisan will appreciate that the radicals omitted are added using
techniques known in the art. The skilled artisan will also
appreciate that the methods described may be used with blocking
groups and the like, as appropriate.
[0054] Guanidinyl groups are conveniently prepared from nitro and
amino compounds via the following example synthetic sequences:
8
[0055] Preferably these compounds are made from nitro or amino
compounds. (Nitro and amino compounds are made by known processes.)
The compounds may be manipulated to result in the suitably
substituted aminoheterocycle. This aminoheterocycle is then
subjected to known methods to produce the guanidinyl derivative.
For example, the amino compound may be reacted with cyanamide
(H.sub.2NCN) in acid to provide the guanidinyl compound.
Alternatively, the amino compound may be reacted with a guanidine
precursor, such as an alkyl pseudothiourea or protected alkyl
pseudothiourea in the presence of a mercuric salt or the like.
[0056] The above starting nitro and amino compounds are obtained
via one or more synthetic steps comprising alkylations,
halogenations (usually brominations), and halogen displacement
reactions. These reaction types are summarized below;
[0057] Alkylation Reaction: 9
[0058] Fluorination: 10
[0059] Halogenation, Preferably Bromination: 11
[0060] Preferably, chlorination is accomplished using Cl.sub.2, and
iodination, by ICI using the same reactions.
[0061] Halogen Displacement Reactions: 12
[0062] It will be apparent to the skilled artisan that the
reactions illustrated above are known reactions. Furthermore, it is
within the purview of the skilled artisan to vary these reactions
to prepare compounds within the scope of the claims.
[0063] In the above schemes, where an R is alkoxy or alkylthio, the
corresponding hydroxy or thiol compounds are derived from the final
compounds by using a standard dealkylating procedure (Bhatt, et
al., "Cleavage of Ethers", Synthesis, 1983, pp. 249-281).
[0064] The starting materials used in preparing the compounds of
the invention are known, made by known methods, or are commercially
available as a starting material.
[0065] It is recognized that the skilled artisan in the art of
organic chemistry can readily carry out manipulations without
further direction, that is, it is well within the scope and
practice of the skilled artisan to carry out these manipulations.
These include reduction of carbonyl compounds to their
corresponding alcohols, oxidations, acylations, aromatic
substitutions, both electrophilic and nucileophilic,
etherifications, esterifications and saponifications and the ike.
These manipulations are discussed in standard texts such as March,
Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced
Organic Chemistry (2 vol.) and Trost and Fleming Comprehensive
Organic Synthesis (6 vol.). The skilled artisan will readily
appreciate that certain reactions are best carried out when other
functionality is masked or protected in the molecule, thus avoiding
any undesirable side reactions and/or increasing the yield of the
reaction. Often the skilled artisan utilizes protecting groups to
accomplish such increased yields or to avoid the undesired
reactions. These reactions are found in the literature and are also
well within the scope of the skilled artisan. Examples of many of
these manipulations are found, for example, in T. Greene,
[0066] Protecting Groups in Organic Synthesis.
COMPOUND EXAMPLES
[0067] The following non-limiting examples provide details for the
synthesis of guanidinyl heterocycles:
Example 1
[0068] (4-Methyl benzimidazol-5-yl)guanidine
[0069] A. 2,3-Diamino-6-nitrotoluene.
[0070] To a solution of 30 g of 3-methyl-2,4-dinitroaniline in 750
mL of boiling ethanol is added dropwise over 90 minutes a solution
of 109.6 g of sodium sulfide nonahydrate in 750 mL of water. At the
end of the addition, the mixture is heated to reflux for 30 minutes
then poured into ice (2000 g) and allowed to stand until all the
ice has melted. The mixture is then extracted with methylene
chloride and the organic layer is dried over magnesium sulfate and
rotary evaporated. The residue is purified by flash column
chromatography on silica gel, eluting with methylene chloride to
afford 2,3-diamino-6-nitrotoluene as an orange solid.
[0071] B. 4-Methyl-5-nitrobenzimidazole.
[0072] A mixture of 11.8 g of 2,3-diamino-6-nitrotoluene, 390 mL of
88% formic acid and 38 mL of 12N hydrochloric acid is heated to
reflux for 1 hour. The resulting mixture is cooled to room
temperature and rotary evaporated. The residue is diluted with 200
mL of water, then basified with ammonium hydroxide (28-30%). The
suspension is extracted with ethyl acetate (3.times.200 mL). The
combined extracts are dried over magnesium sulfate and rotary
evaporated to provide 4-methyl-5-nitrobenzimidazole as an orange
solid.
[0073] C. 1-tert-Butoxycarbonyl-4-methyl-5-nitrobenzimidazole.
[0074] A suspension of 11.2 g of 4-methyl-5-nitrobenzimidazole,
21.58 g of di-tert-butyl-dicarbonate, 11.7 mL of triethylamine and
100 mg of 4-dimethylamino-pyridine in methanol (800 mL) and ethyl
acetate (400 mL) is stirred at room temperature overnight. The
mixture is rotary evaporated and the residue purified by flash
column chromatography on silica gel, eluting with 10% ethyl acetate
in hexanes. The product-containing fractions are combined and
rotary evaporated to afford a white solid contaminated with a
yellow oil. The solid is dissolved in methylene chloride and enough
hexane is added to cause precipitation. The solid is filtered and
washed with 50% methylene chloride/hexane. The filtrate is rotary
evaporated and the process repeated until no more clean white solid
is obtained by precipitation. The combined solid fractions are
dried in vacuo to afford 1-tert-butoxycarbonyl-4-methyl-5-n-
itrobenzimidazole as a white solid.
[0075] D. 5-Amino-1-tert-butoxycarbonyl4-methylbenzimidazole.
[0076] To a solution of 8 g of
1-tert-butoxycarbonyl-4-methyl-5-nitrobenzi- midazole in 40 mL of
methanol and 400 mL of ethyl acetate are added 500 mg of
palladium-on-carbon (10%) and 7.27 g of ammonium formate. The
mixture is stirred at 50.degree. C. for 2 hours, then filtered on
Celite, with a methanol wash of the solids. The filtrate is rotary
evaporated and the residue partitioned between water and ethyl
acetate. The organic layer is washed with saturated ammonium
chloride, dried over magnesium sulfate, filtered and rotary
evaporated to afford pure 5-amino-1-tert-butoxycarbon-
yl-4-methylbenzimidazole as an off-white solid.
[0077] E.
1-(tert-Butyloxycarbonyl)-5-[N.sup.2,N.sup.3-bis(benzyloxycarbon-
yl)guanidino]-4-methybenzimidazole.
[0078] To a solution of 500 mg of
5-amino-1-(tert-butoxycarbonyl)-4-methyl- -benzimidazole in 20 mL
of tetrahydrofuran are added 753 mg of ethyl
N,N-bis(benzyloxycarbonyl)pseudothiourea and 645 mg of mercuric
acetate and the mixture is stirred at room temperature for 1
hour.
[0079] The resulting suspension is diluted with ethyl acetate and
washed with water followed by brine. The aqueous layers are
extracted with ethyl acetate; the combined organic layers are dried
over magnesium sulfate, filtered and rotary evaporated. The residue
is purified by flash column chromatography on silica gel, eluting
with 50% ethyl acetate/hexanes followed by recrystallization from
hexanes/methylene chloride to provide 927 mg of
1-(tert-butyloxycarbonyl)-5-[N.sup.2, N.sup.3-bis(benzyloxycarb-
onyl)-guanidino]4-methybenzimidazole as a white solid.
[0080] F. 5-[N.sup.2,N.sup.3-B
is(benzyloxycarbonyl)guanidino]-4-methylben- zimidazole.
[0081] To a cold (0.degree. C.) solution of 874 mg of
1-(tert-butoxycarbonyl)-5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)guanidin-
o]-4-methylbenzimidazole in 2 mL of methylene chloride is added 2
mL of trifluoroacetic acid. The resulting solution is stirred at
room temperature for 30 minutes, then rotary evaporated. The
residue is purified by flash column chromatography on silica gel,
eluting with 20% methanol/chloroform followed by recrystallization
from hexanes/methylene chloride to provide 573 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)gu-
anidino]4-methylbenzimidazole as a white solid.
[0082] G. (4-Methylbenzimidazol-5-yl)guanidine, Dihydrochloric Acid
Salt.
[0083] To a solution of 740 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl-
)guanidino]-4-methyl-benzimidazole in 20 mL of ethanol are added
240 mg of ammonium formate and a catalytic amount of
palladium-on-carbon. The resulting suspension is stirred at room
temperature for 10 hours. The reaction mixture is filtered and the
filtrate is rotary evaporated. The residue is dissolved in 25 mL of
methanol and treated with a slow stream of hydrogen chloride gas
for about 5 minutes. The resulting solution is stirred at room
temperature for 2 hours and rotary evaporated to give a pale yellow
solid. The solid is purified by recrystallization from
methanol/ethyl acetate to provide 361 mg of
(4-methylbenzimidazol-5-yl)gu- anidine, dihydrochloric acid salt as
a yellow solid.
Example 2
[0084] (4,7-Dimethylbenzimidazol-5-yl)guanidine
[0085] A. 4,7-Dimethylbenzimidazole. A mixture of 5.1 g of
2,3-diamino-p-xylene, 200 mL of 88% formic acid and 20 mL of 12N
hydrochloric acid is heated to reflux for 3 hours. The resulting
mixture is cooled to room temperature and rotary evaporated. The
residue is diluted with 100 mL of water, then basified with
ammonium hydroxide (28-30%). The suspension is extracted with ethyl
acetate (3.times.100 mL). The combined extracts are dried over
magnesium sulfate and rotary evaporated to afford
4,7-dimethylbenzimidazole as a yellow solid.
[0086] B. 4,7-Dimethyl-5-nitrobenzimidazole.
[0087] To a cold (ice bath) solution of 1 g of
4,7-dimethylbenzimidazole in 8 mL of concentrated sulfuric acid is
added dropwise concentrated nitric acid (0.37 mL), over 50 minutes.
The mixture is stirred an additional 30 minutes in the ice bath,
then poured into a mixture of crushed ice (30 mL) and ammonium
hydroxide (30 mL). The resulting mixture is extracted with ethyl
acetate. The extract is dried over magnesium sulfate and rotary
evaporated to afford 4,7-dimethyl-5-nitrobenzimidazole as a dark
tan solid.
[0088] C. 5-Amino-4,7-dimethylbenzimidazole. To a solution of 1.17
g of 4,7-dimethyl-5-nitrobenzimidazole in 150 mL of methanol are
added 160 mg of palladium-on-carbon (10%) and 1.31 g of ammonium
formate. The mixture is stirred at room temperature overnight, then
filtered on Celite, with a methanol wash of the solids. The
filtrate is rotary evaporated and the residue partitioned between
water and ethyl acetate. The organic layer is washed with saturated
ammonium chloride, dried over magnesium sulfate, filtered and
rotary evaporated to afford 5-amino-4,7-dimethylbenzimidazol- e as
a foamy reddish solid.
[0089] D.
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)guanidino]-4,7-dimethyb-
enzimidazole. To a solution of 430 mg of
5-amino-4,7-dimethylbenzimidazole in 100 mL of ethyl acetate and 10
mL of methanol are added 1 g of ethyl
N,N-bis(benzyloxycarbonyl)pseudothiourea and 855 mg of mercuric
acetate and the mixture is stirred at room temperature for 15
hours.
[0090] The mixture is rotary evaporated and the residue is purified
by flash column chromatography on silica gel, eluting with 5%
methanol/ethyl acetate to provide 1.01 g of 5-[N.sup.2,
N.sup.3-bis(benzyloxycarbonyl)gu- anidino]-4,7-dimethybenzimidazole
as a glassy solid.
[0091] E. (4,7-Dimethylbenzimidazol-5-yl)guanidine, Dihydrobromic
Acid Salt.
[0092] To a solution of 1 g of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)gu-
anidino]-4,7-dimethyl-benzimidazole in 100 mL of 1/1 ethyl
acetate/methanol is added a catalytic amount of
palladium-on-carbon. The resulting suspension is stirred at room
temperature under hydrogen at atmospheric pressure for 15 hours.
The reaction mixture is filtered on Celite with a methanol wash of
the solids and the filtrate is rotary evaporated. The residue is
dissolved in 50 mL of methanol and treated with 0.85 mL of 30%
hydrobromic acid/acetic acid for about 5 minutes. The resulting
solution is rotary evaporated and the residue is purified by
recrystallization from ethanol/ether to provide 490 mg of
(4,7-dimethylbenzimidazol-5-yl)guanidine dihydrobromic acid salt as
a white solid.
Example 3
[0093] (2.4-Dimethylbenzimidazol-5-yl)guanidine
[0094] A. 2,4-Dimethyl-5-nitrobenzimidazole. A mixture of 668 mg of
2,3-diamino-6-nitrotoluene, 20 mL of glacial acetic acid and 2 mL
of 12N hydrochloric acid is heated to reflux for 3 hours. The
resulting mixture is cooled to room temperature and rotary
evaporated. The residue is diluted with 20 mL of water, and
basified with ammonium hydroxide (28-30%). The resulting suspension
is extracted with ethyl acetate and the extracts are dried over
magnesium sulfate, filtered and rotary evaporated to provide 720 mg
of 2,4-dimethyl-5-nitrobenzimidazole as a tan solid.
[0095] B. 5-Amino-2,4-dimethylbenzimidazole.
[0096] To a solution of 700 mg of 2,4-dimethyl-5-nitrobenzimidazole
in 50 mL of methanol is added a catalytic amount of
palladium-on-carbon. The resulting suspension is stirred at room
temperature under hydrogen at atmospheric pressure for 15 hours.
The reaction mixture is filtered on Celite with a methanol wash of
the solids and the filtrate is concentrated. The residue is
purified by flash column chromatography on silica gel, eluting with
5% methanol/ethyl acetate to provide 565 mg of
5-amino-2,4-dimethybenzimidazole as a tan solid.
[0097] C. (2,4-Dimethylbenzimidazol-5-yl)guanidine, Dihydrochloric
Acid Salt.
[0098] To 565 mg of 5-amino-2,4-dimethylbenzimidazole is added 0.75
mL of concentrated hydrochloric acid and 0.38 mL of water. The
resulting mixture is stirred at room temperature for 5 minutes to
give a homogeneous paste. To this mixture are added 589 mg of
cyanamide and the mixture is stirred at 70.degree. C. for 3 hours.
The reaction mixture is cooled to 0.degree. C. and 1 mL of water
and 0.5 mL of concentrated hydrochloric acid are added. The mixture
is stirred at 0.degree. C. for 30 minutes and rotary evaporated.
The residue is dissolved in 10 mL of methanol and precipitated with
ether to provide 594 mg of
(2,4-dimethylbenzimidazol-5-yl)guanidine, dihydrochloric acid salt
as a white solid.
Example 4
[0099] (1,4-Dimethylbenzimidazol-5-yl)guanidine
[0100] A. 2.4-Dinitro-3-methyl-formanilide.
[0101] To a solution of 2 g of 2,4-dinitro-3-methylaniline in 10 mL
of 99% formic acid heated at 55.degree. C., are added dropwise 2.5
mL of acetic anhydride, over 15 minutes. The mixture is stirred for
1 hour at 55.degree. C. then cooled to room temperature and rotary
evaporated. The residue is diluted with 100 mL of ethyl acetate,
washed with saturated aqueous sodium bicarbonate, dried over
magnesium sulfate and rotary evaporated. The residue is purified by
flash column chromatography on silica gel, eluting with chloroform,
to afford 2,4-dinitro-3-methyl-forma- nilide as a white solid.
[0102] C. N,3-Dimethyl-2,4-dinitroaniline.
[0103] To a solution of 1.15 g of 2,4-dinitro-3-methyl-formanilide
in 40 mL of dry tetrahydrofuran are added 1.21 mL of
borane-dimethyl sulfide complex. The mixture is heated to reflux
for 2 hours, then cooled in an ice bath; 30 mL of methanol are
added and the stirring is maintained for 1 hour at 0.degree. C. The
mixture is acidified to pH=2 with concentrated hydrochloric acid
and heated to reflux for 1 hour, diluted with 70 mL of methanol and
rotary evaporated. The solid residue is suspended in 150 mL of
water and basified to pH=12 with concentrated sodium hydroxide. The
mixture is extracted with chloroform, and the organic layer is
dried over potassium carbonate and rotary evaporated. The residue
is purified by flash column chromatography on silica gel, eluting
with 25% ethyl acetate/hexane to afford
N,3-dimethyl-2,4-dinitroaniline as an orange solid.
[0104] D. N,3-Dimethyl-2,4-dinitroformanilide.
[0105] To a solution of 450 mg of N,3-dimethyl-2,4-dinitroaniline
in 10 mL of 99% formic acid and 4 mL of chloroform heated to
55.degree. C., is added dropwise 1 mL of acetic anhydride in two
portions at 1 hour intervals. The mixture is stirred for 5 hours at
55.degree. C., then cooled to room temperature, poured into 50 mL
of 1N sodium hydroxide and basified to pH=12 with concentrated
sodium hydroxide. The mixture is extracted with methylene chloride,
and the organic layer is dried over magnesium sulfate and rotary
evaporated. The residue is purified by flash column chromatography
on silica gel, eluting with chloroform, to afford
N,3-dimethyl-2,4-dinitroformanilide as a white solid.
[0106] E. 2,4-Diamino-N,3-dimethylformanilide.
[0107] To a solution of 440 mg of
N,3-dimethyl-2,4-dinitroformanilide in 40 mL of 3/1 methanol/ethyl
acetate are added 95 mg of palladium-on-carbon (10%) and 930 mg of
ammonium formate, and the mixture is stirred for 2 hours at room
temperature. The mixture is filtered on Celite, with a methanol
wash of the solids, and the filtrate is rotary evaporated. The
residue is partitioned between methylene chloride and water. The
aqueous layer is extracted 4 times with methylene chloride. The
combined organic layers are dried over magnesium sulfate and rotary
evaporated to afford 2,4-diamino-N,3-dimethylformanilide as a brown
solid.
[0108] F. 5-Amino-1.4-dimethylbenzimidazole.
[0109] A suspension of 240 mg of
2,4-diamino-N,3-dimethylformanilide in 10 mL of 2N hydrochloric
acid is heated to reflux for 90 minutes. The mixture is diluted
with water (50 mL), basified with 1N sodium hydroxide and extracted
with ethyl acetate. The organic layer is dried over magnesium
sulfate and rotary evaporated to afford 5-amino-1,4-dimethylben-
zimidazole.
[0110] G.
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)guanidino]-0.4-dimethyb-
enzimidazole.
[0111] To a solution of 250 mg of 5-amino-1,4-dimethylbenzimidazole
in 75 mL of ethyl acetate and 10 mL of methanol are added 789 mg of
ethyl N,N-bis(benzyloxycarbonyl)pseudothiourea and 665 mg of
mercuric acetate and the mixture is stirred at room temperature for
15 hours. The mixture is filtered on Celite and rotary evaporated.
The residue is purified by flash column chromatography on silica
gel, eluting with 5% methanol/ethyl acetate to provide 590 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl)gua-
nidino]-1,4-dimethybenzimidazole as a white solid.
[0112] H. (1.4-Dimethylbenzimidazol-5-yl)guanidine, Dihydrobromic
Acid Salt.
[0113] To a solution of 530 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl-
)guanidino]-1,4-dimethylbenzimidazole in 60 mL of 1/1 ethyl
acetate/methanol is added a catalytic amount of
palladium-on-carbon. The resulting suspension is stirred at room
temperature under hydrogen at atmospheric pressure for 15 hours.
The reaction mixture is filtered on Celite with a methanol wash of
the solids and the filtrate is rotary evaporated. The residue is
dissolved in 10 mL of methanol and treated with 0.2 mL of 30%
hydrobromic acid/acetic acid for about 5 minutes. The resulting
solution is rotary evaporated and the residue is purified by
recrystallization using ethanol/ether to provide 30 mg of
(1,4-dimethylbenzimidazol-5-yl)guanidine, dihydrobromic acid salt
as a white solid.
Example 5
[0114] (4-Bromobenzimidazol-5-yl)guanidine
[0115] A. 5-Amino4-bromobenzimidazole.
[0116] To a solution of 1.08 g of 5-aminobenzimidazole in 20 mL of
glacial acetic acid are added 2.68 g of sodium acetate. To this
solution is added dropwise 0.4 mL of bromine. The resulting brown
precipitate is stirred at room temperature for 2 hours. The
reaction mixture is rotary evaporated and the residue is diluted
with water and ethyl acetate. The mixture is basified with 1N
sodium hydroxide and decanted. The organic layer is washed with
water followed by brine. The aqueous layers are extracted with
ethyl acetate; the combined organic layers are dried over magnesium
sulfate, filtered and rotary evaporated. The residue is purified by
flash column chromatography on silica gel, eluting with 12.5 to
16.5% methanol/methylene chloride followed by recrystallization
from hexanes/ethyl acetate to provide 887 mg of
5-amino4-bromobenzimidazole as a pale brown solid.
[0117] B. (4-Bromobenzimidazol-5-yl)guanidine, Dihydrochloric Acid
Salt.
[0118] To 637 mg of 5-amino-4-bromobenzimidazole are added 0.5 mL
of concentrated hydrochloric and 0.25 mL of water. The resulting
mixture is stirred at room temperature for 5 minutes to give a
homogeneous paste. To this mixture are added 531 mg of cyanamide
and the mixture is stirred at 80.degree. C. for 1 hour. The
reaction mixture is cooled to 0.degree. C. and 0.5 mL of water and
1 mL of concentrated hydrochloric acid are added. The mixture is
stirred at 0.degree. C. for 30 minutes and rotary evaporated. The
residue is dissolved in hot methanol and precipitated using hot
ethyl acetate to provide 766 mg of (4-bromobenzimidazol-5-yl)gu-
anidine, dihydrochloric acid salt as an off-white solid.
Example 6
[0119] N.sup.1-Methyl-N.sup.2-(4-methylbenzimidazol-5-yl)
guanidine
[0120] A.
1-(tert-Butyloxycarbonyl)-5-[N.sup.2,N.sup.3-bis(benzyloxycarbon-
yl)-N.sup.2-methylguanidino]-4-methylbenzimidazole.
[0121] To a solution of 600 mg of
5-amino-1-(tert-butoxycarbonyl)4-methylb- enzoimidazole in 20 mL of
tetrahydrofuran are added 938 mg of ethyl
N,N-bis(benzyloxycarbonyl)-N-methylpseudothiourea and 773 mg of
mercuric acetate and the mixture is stirred at room temperature for
1 hour. The suspension is diluted with ethyl acetate and washed
with water followed by brine. The aqueous layers are extracted with
ethyl acetate; the combined organic layers are dried over magnesium
sulfate, filtered and rotary evaporated. The residue is purified by
flash column chromatography on silica gel, eluting with 50% ethyl
acetate/hexanes followed by recrystallization from
hexanes/methylene chloride to provide 927 mg of
1-(tert-butyloxycarbonyl)-5-[N.sup.2,
N.sup.3-bis(benzyloxycarbonyl)-N.su-
p.2-methylguanidino]-4-methylbenzimidazole as a white solid.
[0122] B.
N.sup.1-Methyl-N.sup.2-(4-methylbenzimidazol-5-yl)guanidine,
Dihydrochloric Acid Salt.
[0123] To a solution of 399 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl-
)-N.sup.2-methylguanidino]4-methylbenzimidazole in 10 mL of ethanol
are added 160 mg of ammonium formate and a catalytic amount of
palladium-on-carbon. The resulting suspension is heated to reflux
for 5 hours. The reaction mixture is filtered on Celite and the
filtrate is rotary evaporated. The residue is dissolved in 2 mL of
methanol and 0.5 mL of concentrated hydrochloric acid is added.
After 5 minutes, the mixture is rotary evaporated and dried under
vacuum. The residue is purified by recrystallization using
methanol/ethyl acetate to provide 211 mg of
N.sup.1-Methyl-N.sup.2-(4-methylbenzimidazol-5-yl)guanidine,
dihydrochloric acid salt as a solid.
[0124] D. 8-(Methylquinolin-7-yl)quanidine, Dihydrochloric Acid
Salt.
[0125] To a solution of 1.25 g of
7-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl-
)guanidino]-8-methylquinoline in 40 mL of ethanol are added 672 mg
of ammonium formate and a catalytic amount of palladium-on-carbon.
The resulting suspension is stirred at room temperature for 10
hours. The reaction mixture is filtered on Celite and the filtrate
is rotary evaporated. The residue is dissolved in 25 mL of methanol
and treated with a slow stream of hydrogen chloride gas for about 5
minutes. The resulting solution is stirred at room temperature for
2 hours and rotary evaporated to give a pale yellow solid that is
purified by recrystallization from methanol/ethyl acetate to
provide 313 mg of 8-(methylquinolin-7-yl)guanidine, dihydrochloric
acid salt as a yellow solid.
Example 8
[0126] (8-Bromoquinolin-7-yl)quanidine
[0127] A. 7-Amino-8-bromoquinoline.
[0128] To a solution of 401 mg of 7-aminoquinoline in 15 mL of
glacial acetic acid are added 913 mg of sodium acetate followed by
a solution of 0.14 mL of bromine in 5 mL of glacial acetic acid.
The resulting yellow slurry is stirred at room temperature for 2
hours. The brown mixture is rotary evaporated and the residue is
diluted with water and ethyl acetate. The mixture is basified using
1 N sodium hydroxide and decanted. The organic layer is washed with
water followed by brine. The combined aqueous layers are extracted
with ethyl acetate; the combined organic layers are dried over
magnesium sulfate and rotary evaporated. The residue is purified by
flash column chromatography on silica gel, eluting with 20% to 50%
ethyl acetate/hexanes followed by recrystallization from
hexanes/methylene chloride to provide 521 mg of
7-amino-8-bromoquinoline as a pale brown solid.
[0129] B.
7-[N.sup.2,N.sup.3-Bis(tert-butoxycarbonyl)guanidino]-8-bromoqui-
noline.
[0130] To a pale yellow solution of 0.40 g of
7-amino-8-bromoquinoline in 10 mL of tetrahydrofuran are added 1.11
g of ethyl N,N-bis(tert-butoxy carbonyl)pseudothiourea and 1.16 g
of mercuric acetate and the mixture is stirred at room temperature
for 26 hours. The suspension is diluted with ethyl acetate and
washed with water followed by brine. The aqueous layers are
extracted with ethyl acetate; the combined organic layers are dried
over magnesium sulfate and rotary evaporated. The residue is
purified by flash column chromatography on silica gel, eluting with
15% ethyl acetate/hexanes to provide 0.78 g of
7-[N.sup.2,N.sup.3-bis(tert-butoxyca-
rbonyl)guanidino]-8-bromoquinoline as a white solid.
[0131] C. (8-Bromoquinolin-7-yl)guanidine, Hydrochloric Acid
Salt.
[0132] To a cold (0.degree. C.) solution of 0.735 g of
7-[N.sup.2,N.sup.3-bis(tert-butoxy-carbonyl)guanidino]-8-bromoquinoline
in 2 mL of methylene chloride are added 2 mL of trifluoroacetic
acid. The resulting solution is stirred at room temperature for 3
hours and rotary evaporated to a viscous oil. The oil is dissolved
in 10 mL of methanol and 0.5 mL of concentrated hydrochloric acid
is added. After 5 minutes, the solution is rotary evaporated and
dried under vacuum. The solid residue is recrystallized from
methanol/ethyl acetate to provide 0.41 g of
(8-bromoquinolin-7-yl)guanidine, hydrochloric acid salt as a yellow
solid.
Example 9
[0133] (6-Methylbenzothiazol-5-yl)guanidine
[0134] A. 6-Methyl-5-nitrobenzothiazole.
[0135] A mixture of 1.6 g of 5-chloro-2,4-dinitrotoluene and 20 mL
of N,N-dimethyl-thioformamide is heated to 120.degree. C. for 16
hours. After cooling to room temperature, the mixture is purified
by flash column chromatography on silica gel, eluting with 3% to
10% ethyl acetate/hexanes to provide 0.78 g of
6-methyl-5-nitrobenzothiazole as a yellow solid.
[0136] B. 5-Amino-6-methylbenzothiazole.
[0137] A mixture of 0.78 g of 6-methyl-5-nitrobenzothiazole and
3.62 g of stannous chloride dihydrate in 25 mL of ethanol is heated
to 65.degree. C. for 4 hours. The cooled reaction mixture is poured
into 10 mL of 50% sodium hydroxide and 45 mL of brine and extracted
with ether (4.times.35 mL). The combined organic layers are washed
with brine, dried over sodium sulfate and rotary evaporated. The
residue is purified by flash column chromatography on silica gel,
eluting with 15% ethyl acetate/hexanes to provide 0.45 g of
5-amino-6-methylbenzothiazole as a yellow solid.
[0138] C.
5-[N.sup.2,N.sup.3-Bis(benzyloxycarbonyl)guanidino]-6-methylbenz-
othiazole.
[0139] To a solution of 230 mg of 5-amino-6-methylbenzothiazole in
10 mL of 1/1 ethyl acetate/methanol are added 520 mg of ethyl
N,N-bis(benzyloxycarbonyl)-pseudothiourea and 450 mg of mercuric
acetate and the mixture is stirred at room temperature for 24
hours.
[0140] The mixture is filtered on Celite and rotary evaporated. The
residue is purified by flash column chromatography on silica gel,
eluting with 20% ethyl acetate/hexanes to provide 598 mg of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyi)guanidino]-6-methybenzothiazole
as a yellow solid.
[0141] D. (6-Methylbenzothiazol-5-yl)guanidine, Trihydrobromic Acid
Salt.
[0142] To a solution of 0.58 g of
5-[N.sup.2,N.sup.3-bis(benzyloxycarbonyl-
)guanidino]-6-methylbenzothiazole in 25 mL of 1/1 methanol/ethyl
acetate is added 1 g of 10% palladium-on-carbon. The mixture is
stirred under hydrogen at atmospheric pressure for 3 days. The
mixture is filtered on Celite and rotary evaporated. The residue is
dissolved into a minimum amount of ethanol and is treated with 0.6
mL of 30% hydrobromic acid/acetic acid. Ethyl acetate is added
dropwise to the point of cloudiness and the mixture is stored in
the freezer until crystallization occurs. The solid is filtered and
dried under vacuum to provide 96 mg of
(6-methylbenzothiazol-5-yl)guanidine, trihydrobromic acid salt as a
white solid.
Example 10
[0143] (4-Bromobenzothiazol-5-yl)guanidine
[0144] A. 5-Nitrobenzothiazole.
[0145] A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20.26 g
of N,N-dimethylthioformamide is heated to 60.degree. C. for 3
hours. The resulting solid is suspended in 25 mL of xylene and the
mixture is heated to reflux for 4 hours. The mixture is allowed to
cool to room temperature and 15 mL of ethanol are added. The
resulting suspension is filtered, and the brown solid is washed
with a minimum amount of ethanol. The solid is dissolved in 120 mL
of ethanol, heated to boiling, and filtered hot to remove trace
solids. After reduction of the volume to about 100 mL, the solution
is allowed to stand overnight at room temperature. The resulting
solid is filtered and washed with ethanol to provide 4.68 g of
5-nitrobenzothiazole as reddish-brown needles.
[0146] B. 5-Aminobenzothiazole.
[0147] A mixture of 3.46 g of 5-nitrobenzothiazole and 15.7 g of
stannous chloride dihydrate in 55 mL of 2-propanol is heated to
reflux for 3 hours. The cooled reaction mixture is poured into 150
mL of ice/water and neutralized to pH 7 using solid sodium
hydroxide. The mixture is extracted with ethyl acetate (3.times.50
mL). The combined organic layers are dried over sodium sulfate,
filtered through a short pad of silica gel, and rotary evaporated
to provide 2.45 g of 5-aminobenzothiazole as a yellow-brown
solid.
[0148] C. 5-Amino4-bromobenzothiazole.
[0149] To a cooled (5.degree. C.) solution of 2.04 g of
5-aminobenzothiazole in 60 mL of chloroform are added dropwise 2.15
g of bromine while maintaining the temperature below 10.degree. C.
After completion of the addition, the reaction mixture is stirred
for 30 minutes at room temperature, then diluted with 14 mL of
concentrated ammonium hydroxide and 16 mL of methylene chloride.
The aqueous layer is washed with methylene chloride (2.times.16 mL)
and the combined organic layers are rotary evaporated. The residue
is purified by an aspirator vacuum-filtration through silica gel,
eluting with 15% to 30 ethyl acetate in hexanes to provide 2.44 g
of 5-amino-4-bromobenzothiazole as a reddish solid.
[0150] D. (4-Bromobenzothiazol-5-vi)quanidine, hydrochloric aicd
salt. A mixture of 100 mg of 5-amino-4-bromobenzothiazole, 0.05 mL
of water and 0.097 mL of concentrated hydrochloric acid is stirred
at room temperature for 5 minutes. To this mixture are added 74 mg
of cyanamide and the new mixture is stirred for 90 minutes at
70.degree. C. The reaction mixture is cooled to 0.degree. C. and
0.194 mL of water and 0.098 mL of concentrated hydrochloric acid
are added. The mixture is stirred for 30 minutes at 0.degree. C.
and rotary evaporated. The residue is diluted with 1 mL of methanol
and precipitated with ether to provide 41 mg of
(4-bromobenzothiazol-5-yl)guanidine, hydrochloric acid salt as a
white solid.
Example 11
[0151] 13
[0152] A. Methyl N,N'-dimethylthiopseudourea.
[0153] N,N'-Dimethylthioguanidine (5.0 g) is added to absolute
ethanol (40 mL) while stirring. Methyl iodide (4.3 ml, 1.4 Eq) is
rapidly added. The reaction mixture is warmed to 30-35.degree. C.
for 45 minutes. This solution is used directly in the next
reaction.
[0154] B. Methyl N-carbomethoxy-N,N'-dimethylthiopseudourea.
[0155] Potassium carbonate (10.1 g) is adued to the mixture in (A)
above, followed by addition of methyl chloroformate (4.2 mL) while
stirring. After 45 minutes, the reaction mixture is heated to
55.degree. C. and the insoluble salts are filtered off. These salts
are washed with 10 mL of absolute ethanol. The filtrate (and
ethanol wash) is cooled to -20.degree. C. and the recrystallized
product is isolated on a Buchner funnel. The product is washed with
10 mL cold (-20.degree. C.) absolute ethanol. The product is dried
overnight under vacuum at room temperature, yielding methyl
N-carbomethoxy-N,N'-dimethylthiopseudourea.
[0156] C. N,N'-Dimethyl-(8-methylquinolin-7-yl)guanidine.
[0157] The methyl N-carbomethoxy-N,N'-dimethylthiopseudourea is
combined with 8-methyl-7-nitroquinoline, as prepared in Example 7B,
in 10% acetic acid in ethanol and heated to reflux. After the
starting amine is consumed, the mixture is decolorized with carbon.
The mixture is cooled, filtered and rotary evaporated. Upon
recrystallization and drying,
N,N'-dimethyl-(8-methylquinolin-7-yl)guanidine is obtained as an
acetic acid salt.
[0158] Using the methodologies outlined and exemplified above the
following compounds are made. In these examples where R.sub.1 is
nil, (a) is a double bond, and guanidinyl is signified by GNDNL;
14
[0159] In the following table, R.sub.10=R.sub.11=hydrogen.
2 Ex- am- ple R.sub.1 D B R.sub.4 R.sub.5 R.sub.6 R.sub.7 In the
following table, R.sub.10 = R.sub.11 = hydrogen. 12 nil CH NH Cl H
GNDNL Me 13 nil CH NH Br H GNDNL Me 14 nil CH NH I H GNDNL Me 15
nil CH NH F H GNDNL Me 16 nil CH NH OMe H GNDNL Me 17 nil CH NH CN
H GNDNL Me 18 nil CH NH Cl H GNDNL Br 19 nil CH NH Br H GNDNL Br 20
nil CH NH I H GNDNL Br 21 nil CH NH F H GNDNL Br 22 nil CH NH OMe H
GNDNL Br 23 nil CH NH Me H GNDNL Br 24 nil CH NH CN H GNDNL Br 25
nil CH NH Cl H GNDNL Cl 26 nil CH NH Br H GNDNL Cl 27 nil CH NH I H
GNDNL Cl 28 nil CH NH F H GNDNL Cl 29 nil CH NH OMe H GNDNL Cl 30
nil CH NH Me H GNDNL Cl 31 nil CH NH CN H GNDNL Cl 32 nil CH NH H H
GNDNL Cl 33 nil CH NH Cl H GNDNL OMe 34 nil CH NH Br H GNDNL OMe 35
nil CH NH I H GNDNL OMe 36 nil CH NH F H GNDNL OMe 37 nil CH NH OMe
H GNDNL OMe 38 nil CH NH Me H GNDNL OMe 39 nil CH NH CN H GNDNL OMe
40 nil CH NH H H GNDNL OMe 41 nil CH NH Cl H GNDNL SMe 42 nil CH NH
Br H GNDNL SMe 43 nil CH NH I H GNDNL SMe 44 nil CH NH F H GNDNL
SMe 45 nil CH NH OMe H GNDNL SMe 46 nil CH NH Me H GNDNL SMe 47 nil
CH NH CN H GNDNL SMe 48 nil CH NH H H GNDNL SMe 49 nil CHMe NH H H
GNDNL Et 50 nil CHMe NH H H GNDNL OMe 51 nil CH S H H GNDNL Me 52
nil CH S Me H GNDNL Me 53 nil CH S OMe H GNDNL Me 54 nil CH S Br H
GNDNL Me 55 nil CH S Cl H GNDNL Me 56 nil CH S F H GNDNL Me 57 nil
CH S I H GNDNL Me 58 nil CH S CN H GNDNL Me 59 nil CH S Me H GNDNL
Br 60 nil CH S OMe H GNDNL Br 61 nil CH S Br H GNDNL Br 62 nil CH S
Cl H GNDNL Br 63 nil CH S F H GNDNL Br 64 nil CH S I H GNDNL Br 65
nil CH S CN H GNDNL Br 66 nil CH S H OMe GNDNL H 67 nil CH S H Br
GNDNL H 68 nil CH S H Me GNDNL Me 69 nil CH S H OMe GNDNL Me 70 nil
CH S H Br GNDNL Me 71 nil CH S H Me GNDNL Et 72 nil CH S H OMe
GNDNL Et 73 nil CH S H Br GNDNL Et 74 nil CH S H Me GNDNL Br 75 nil
CH S H OMe GNDNL Br 76 nil CH S H Br GNDNL Br 77 nil CH S H Me
GNDNL OMe 78 nil CH S H OMe GNDNL OMe 79 nil CH S H Br GNDNL OMe 80
nil CH S H Me GNDNL SMe 81 nil CH S H OMe GNDNL SMe 82 nil CH S H
Br GNDNL SMe 83 H CH.dbd. .dbd.CH H H GNDNL Me 84 H CH.dbd.
.dbd.C(Br) H H GNDNL Me 85 H CH.sub.2 CH.sub.2 H H GNDNL Me 86 H
N.dbd. .dbd.CH H H GNDNL Me 87 H N.dbd. .dbd.CH H H GNDNL Et 88 H
N.dbd. .dbd.CH H H GNDNL Br 89 nil CH O H H GNDNL Me 90 nil CH
CH.dbd.CH Cl H GNDNL Me 91 nil CH CH.dbd.CH Br H GNDNL Me 92 nil CH
CH.dbd.CH I H GNDNL Me 93 nil CH CH.dbd.CH F H GNDNL Me 94 nil CH
CH.dbd.CH OMe H GNDNL Me 95 nil CH CH.dbd.CH Me H GNDNL Me 96 nil
CH CH.dbd.CH CN H GNDNL Me 97 nil CH CH.dbd.CH Cl H GNDNL Br 98 nil
CH CH.dbd.CH Br H GNDNL Br 99 nil CH CH.dbd.CH I H GNDNL Br 100 nil
CH CH.dbd.CH F H GNDNL Br 101 nil CH CH.dbd.CH OMe H GNDNL Br 102
nil CH CH.dbd.CH Me H GNDNL Br 103 nil CH CH.dbd.CH CN H GNDNL Br
104 nil CH CH.dbd.CH Cl H GNDNL Cl 105 nil CH CH.dbd.CH Br H GNDNL
Cl 106 nil CH CH.dbd.CH I H GNDNL Cl 107 nil CH CH.dbd.CH F H GNDNL
Cl 108 nil CH CH.dbd.CH OMe H GNDNL Cl 109 nil CH CH.dbd.CH Me H
GNDNL Cl 110 nil CH CH.dbd.CH CN H GNDNL Cl 111 nil CH CH.dbd.CH H
H GNDNL Cl 112 nil CH CH.dbd.CH H Me GNDNL Me 113 nil CH CH.dbd.CH
H Me GNDNL Br 114 nil CH CH.dbd.CH H Me GNDNL Cl 115 nil CH
CH.dbd.CH H Me GNDNL OMe 116 nil CH CH.dbd.CH H Me GNDNL SMe 117
nil CH CH.dbd.CH H OMe GNDNL Me 118 nil CH CH.dbd.CH H OMe GNDNL Br
119 nil CH CH.dbd.CH H OMe GNDNL Cl 120 nil CH CH.dbd.CH H OMe
GNDNL OMe 121 nil CH CH.dbd.CH H OMe GNDNL SMe 122 nil CH CH.dbd.CH
H SMe GNDNL Me 123 nil CH CH.dbd.CH H SMe GNDNL Br 124 nil CH
CH.dbd.CH H SMe GNDNL Cl 125 nil CH CH.dbd.CH H SMe GNDNL OMe 126
nil CH CH.dbd.CH H SMe GNDNL SMe 127 nil CH CH.dbd.CH H Br GNDNL Me
128 nil CH CH.dbd.CH H Br GNDNL Br 129 nil CH CH.dbd.CH H Br GNDNL
Cl 130 nil CH CH.dbd.CH H Br GNDNL OMe 131 nil CH CH.dbd.CH H Br
GNDNL SMe 132 nil CH CH.dbd.CH H Cl GNDNL Me 133 nil CH CH.dbd.CH H
Cl GNDNL Cl 134 nil CH CH.dbd.CH Me Me GNDNL Me 135 nil CH
CH.dbd.CH Me Cl GNDNL Me 136 nil CH CH.dbd.CH Me Br GNDNL Me 137
nil CH CH.dbd.CH Me I GNDNL Me 138 nil CH CH.dbd.CH Me GNDNL H Cl
139 nil CH CH.dbd.CH Me GNDNL H Br 140 nil CH CH.dbd.CH Me GNDNL H
I 141 nil CH CH.dbd.CH Me GNDNL H Me 142 nil CH CH.dbd.CH Et GNDNL
H Cl 143 nil CH CH.dbd.CH Et GNDNL H Br 144 nil CH CH.dbd.CH Et
GNDNL H I 145 nil CH CH.dbd.CH Et GNDNL H Me 146 nil CH CH.dbd.CH
Br GNDNL H Cl 147 nil CH CH.dbd.CH Br GNDNL H Br 148 nil CH
CH.dbd.CH Br GNDNL H I 149 nil CH CH.dbd.CH Br GNDNL H Me 150 nil
CH CH.dbd.CH Cl GNDNL H Cl 151 nil CH CH.dbd.CH Cl GNDNL H Br 152
nil CH CH.dbd.CH Cl GNDNL H I 153 nil CH CH.dbd.CH Cl GNDNL H Me
154 nil CH CH.dbd.CH OMe GNDNL H Cl 155 nil CH CH.dbd.CH OMe GNDNL
H Br 156 nil CH CH.dbd.CH OMe GNDNL H I 157 nil CH CH.dbd.CH OMe
GNDNL H Me 158 nil CH CH.dbd.CH SMe GNDNL H Cl 159 nil CH CH.dbd.CH
SMe GNDNL H Br 160 nil CH CH.dbd.CH SMe GNDNL H I 161 nil CH
CH.dbd.CH SMe GNDNL H Me 162 nil CH CH.dbd.CH Me GNDNL Me H 163 nil
CH CH.dbd.CH Me GNDNL Br H 164 nil CH CH.dbd.CH Me GNDNL Cl H 165
nil CH CH.dbd.CH Me GNDNL OMe H 166 nil CH CH.dbd.CH Me GNDNL SMe H
167 nil CH CH.dbd.CH Et GNDNL Me H 168 nil CH CH.dbd.CH Et GNDNL Br
H 169 nil CH CH.dbd.CH Et GNDNL Cl H 170 nil CH CH.dbd.CH Et GNDNL
OMe H 171 nil CH CH.dbd.CH Et GNDNL SMe H 172 nil CH CH.dbd.CH Br
GNDNL Me H 173 nil CH CH.dbd.CH Br GNDNL Br H 174 nil CH CH.dbd.CH
Br GNDNL Cl H 175 nil CH CH.dbd.CH Br GNDNL OMe H 176 nil CH
CH.dbd.CH Br GNDNL SMe H 177 nil CH CH.dbd.CH Cl GNDNL Me H 178 nil
CH CH.dbd.CH Cl GNDNL Br H 179 nil CH CH.dbd.CH Cl GNDNL Cl H 180
nil CH CH.dbd.CH Cl GNDNL OMe H 181 nil CH CH.dbd.CH Cl GNDNL SMe H
182 nil CH CH.dbd.CH OMe GNDNL Me H 183 nil CH CH.dbd.CH OMe GNDNL
Br H 184 nil CH CH.dbd.CH OMe GNDNL Cl H 185 nil CH CH.dbd.CH OMe
GNDNL OMe H 186 nil CH CH.dbd.CH OMe GNDNL SMe H 187 nil CH
CH.dbd.CH SMe GNDNL Me H 188 nil CH CH.dbd.CH SMe GNDNL Br H 189
nil CH CH.dbd.CH SMe GNDNL OMe H 190 nil CH CH.dbd.CH SMe GNDNL SMe
H 191 nil CH CH.dbd.CH Me GNDNL Me Me 192 nil CH C(Me).dbd.CH Me
GNDNL H Me 193 nil CH C(Br).dbd.CH Me GNDNL H Me 194 nil CH
C(Cl).dbd.CH Me GNDNL H Me 195 nil CH C(F).dbd.CH Me GNDNL H Me 196
nil CH CH.dbd.C(Me) Me GNDNL H Me 197 nil CH CH.dbd.C(CN) Me GNDNL
H Me 198 nil CH CH.dbd.C(Br) Me GNDNL H Me 199 nil CH CH.dbd.C(Cl)
Me GNDNL H Me 200 nil CH CH.dbd.C(F) Me GNDNL H Me 201 nil CH S Me
GNDNL H Me 202 nil CH S Me GNDNL H Cl 203 nil CH S Me GNDNL H Br
204 nil CH S Me GNDNL H I 205 nil CH S Me GNDNL H OMe 206 nil CH S
Cl GNDNL H Me 207 nil CH S Cl GNDNL H Cl 208 nil CH S Cl GNDNL H Br
209 nil CH S Cl GNDNL H I 210 nil CH S Cl GNDNL H OMe 211 nil CH S
Br GNDNL H Me 212 nil CH S Br GNDNL H Cl 213 nil CH S Br GNDNL H Br
214 nil CH S Br GNDNL H I 215 nil CH S Br GNDNL H OMe 216 nil CH S
I GNDNL H Me 217 nil CH S I GNDNL H Cl 218 nil CH S I GNDNL H Br
219 nil CH S I GNDNL H I 220 nil CH S I GNDNL H OMe 221 nil CH S Et
GNDNL H Me 222 nil CH S Et GNDNL H Cl 223 nil CH S Et GNDNL H Br
224 nil CH S Et GNDNL H I 225 nil CH S Et GNDNL H OMe 226 nil CH S
Me GNDNL Me H 227 nil CH S Me GNDNL Cl H 228 nil CH S Me GNDNL Br H
229 nil CH S Me GNDNL I H 230 nil CH S Cl GNDNL Cl H 231 nil CH S
Me GNDNL Me Me 232 nil CH S Me GNDNL Cl Me 233 nil CH S Me GNDNL Br
Me 234 nil CH S Me GNDNL I Me 235 nil CH S Et GNDNL H Me 236 nil CH
S Et GNDNL H Me In the following table, R.sub.10 = Me and R.sub.11
= H. 237 nil CH NH H H GNDNL Br 238 nil CH CH.dbd.CH H H GNDNL Me
239 nil CH CH.dbd.CH Me GNDNL H Me 240 nil CH S H H GNDNL Me 241
nil CH S H H GNDNL Br In the following table, R.sub.10 = Et and
R.sub.11 = H. 242 nil CH N H H GNDNL Me 243 nil CH CH.dbd.CH H H
GNDNL Me 244 nil CH CH.dbd.CH Me GNDNL H Me 245 nil CH S H H GNDNL
Me 246 nil CH S H H GNDNL Br
[0160] Compositions
[0161] Another aspect of this invention is compositions which
comprise a safe and effective amount of a subject compound, or a
pharmaceutically-acceptable salt thereof, and a
pharmaceutically-acceptab- le carrier.
[0162] As used herein, "safe and effective amount" means an amount
of the subject compound sufficient to significantly induce a
positive modification in the condition to be treated, but low
enough to avoid serious side effects (at a reasonable benefit/risk
ratio), within the scope of sound medical judgment. A safe and
effective amount of the subject compound will vary with the age and
physical condition of the patient being treated, the severity of
the condition, the duration of the treatment, the nature of
concurrent therapy, the particular pharmaceutically-acceptable
carrier utilized, and like factors within the knowledge and
expertise of the attending physician.
[0163] Preparing a dosage form is within the purview of the skilled
artisan. Examples are provided for the skilled artisan, but are
non-limiting, and it is contemplated that the skilled artisan can
prepare variations of the compositions claimed.
[0164] Compositions of this invention preferably comprise from
about 0.0001% to about 99% by weight of the subject compound, more
preferably from about 0.01% to about 90% of the compound of the
invention. Depending upon the route of administration and attendant
bioavailability, solubility or dissolution characteristics of the
dosage form, the dosage form has preferably from about 10% to about
50%, also preferably from about 5% to about 10%, also preferably
from about 1% to about 5%, and also preferably from about 0.01% to
about 1% of the subject compound. The frequency of dosing of the
subject compound is dependent upon the pharmacokinetic properties
of each specific agent (for example, biological half-life) and can
be determined by the skilled artisan.
[0165] In addition to the subject compound, the compositions of
this invention contain a pharmaceutically-acceptable carrier. The
term "pharmaceutically-acceptable carrier", as used herein, means
one or more compatible solid or liquid filler diluents or
encapsulating substances which are suitable for administration to a
mammal. The term "compatible", as used herein, means that the
components of the composition are capable of being commingled with
the subject compound, and with each other, in a manner such that
there is no interaction which would substantially reduce the
pharmaceutical efficacy of the composition under ordinary use
situations. Preferably when liquid dose forms are used, the
compounds of the invention are soluble in the components of the
composition. Pharmaceutically-acceptable carriers must, of course,
be of sufficiently high purity and sufficiently low toxicity to
render them suitable for administration to the mammal being
treated.
[0166] Some examples of substances which can serve as
pharmaceutically-acceptable carriers or components thereof are
sugars, such as lactose, glucose and sucrose; starches, such as
corn starch and potato starch; cellulose and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose, and methyl
cellulose; powdered tragacanth; malt; gelatin; talc; solid
lubricants, such as stearic acid and magnesium stearate; calcium
sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame
oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the Tweens.RTM.; wetting
agents, such sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents, stabilizers; antioxidants; preservatives;
pyrogen-free water; isotonic saline; and phosphate buffer
solutions. The choice of a pharmaceutically-acceptable carrier to
be used in conjunction with the subject compound is basically
determined by the way the compound is to be administered. If the
subject compound is to be injected, the preferred
pharmaceutically-acceptable carrier is sterile, physiological
saline, with a blood-compatible suspending agent, the pH of which
has been adjusted to about 7.4.
[0167] If the preferred mode of administering the subject compound
is perorally, the preferred unit dosage form is therefore tablets,
capsules, lozenges, chewable tablets, and the like. Such unit
dosage forms comprise a safe and effective amount of the subject
compound, which is preferably from about 0.01 mg to about 350 mg,
more preferably from about 0.1 mg to about 35 mg, based on a 70 kg
person. The pharmaceutically-acceptable carrier suitable for the
preparation of unit dosage forms for peroral administration are
well-known in the art. Tablets typically comprise conventional
pharmaceutically-compatible adjuvants as inert diluents, such as
calcium carbonate, sodium carbonate, mannitol, lactose and
cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and croscarmelose;
lubricants such as magnesium stearate, stearic acid and talc.
Glidants such as silicon dioxide can be used to improve flow
characteristics of the powder mixture. Coloring agents, such as the
FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable
tablets. Capsules typically comprise one or more solid diluents
disclosed above. The selection of carrier components depends on
secondary considerations like taste, cost, and shelf stability,
which are not critical for the purposes of this invention, and can
be readily made by a person skilled in the art.
[0168] Peroral compositions also include liquid solutions,
emulsions, suspensions, and the like. The
pharmaceutically-acceptable carriers suitable for preparation of
such compositions are well known in the art. Such liquid oral
compositions preferably comprise from about 0.001% to about 5% of
the subject compound, more preferably from about 0.01% to about
0.5%. Typical components of carriers for syrups, elixirs, emulsions
and suspensions include ethanol, glycerol, propylene glycol,
polyethylene glycol, liquid sucrose, sorbitol and water. For a
suspension, typical suspending agents include methyl cellulose,
sodium carboxymethyl cellulose, Avicel.RTM. RC-591, tragacanth and
sodium alginate; typical wetting agents include lecithin and
polysorbate 80; and typical preservatives include methyl paraben
and sodium benzoate. Peroral liquid compositions may also contain
one or more components such as sweeteners, flavoring agents and
colorants disclosed above.
[0169] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual and buccal dosage forms.
Such compositions typically comprise one or more of soluble filler
substances such as sucrose, sorbitol and mannitol; and binders such
as acacia, microcrystalline cellulose, carboxymethyl cellulose and
hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners,
colorants, antioxidants and flavoring agents disclosed above may
also be included.
[0170] Compositions can also be used to deliver the compound to the
site where activity is desired: intranasal doses for nasal
decongestion, inhalants for asthma, and eye drops, gels and creams
for ocular disorders.
[0171] Preferred compositions of this invention include solutions
or emulsions, preferably aqueous solutions or emulsions comprising
a safe and effective amount of a subject compound intended for
topical intranasal administration. Such compositions preferably
comprise from about 0.001% to about 25% of a subject compound, more
preferably from about 0.01% to about 10%. Similar compositions are
preferred for systemic delivery of subject compounds by the
intranasal route. Compositions intended to deliver the compound
systemically by intranasal dosing preferably comprise similar
amounts of a subject compound as are determined to be safe and
effective by peroral or parenteral administration. Such
compositions used for intranasal dosing also typically include safe
and effective amounts of preservatives, such as benzalkonium
chloride and thimerosal and the like; chelating agents, such as
edetate sodium and others; buffers such as phosphate, citrate and
acetate; tonicity agents such as sodium chloride, potassium
chloride, glycerin, mannitol and others; antioxidants such as
ascorbic acid, acetylcystine, sodium metabisulfate and others;
aromatic agents; viscosity adjustors, such as polymers, including
cellulose and derivatives thereof, and polyvinyl alcohol and acids
and bases to adjust the pH of these aqueous compositions as needed.
The compositions may also comprise local anesthetics or other
actives. These compositions can be used as sprays, mists, drops,
and the like.
[0172] Other preferred compositions of this invention include
aqueous solutions, suspensions, and dry powders comprising a safe
and effective amount of a subject compound intended for atomization
and inhalation administration. Such compositions preferably
comprise from about 0.1% to about 50% of a subject compound, more
preferably from about 1% to about 20%; of course, the amount can be
altered to fit the circumstance of the patient contemplated and the
package. Such compositions are typically contained in a container
with attached atomizing means. Such compositions also typically
include propellants such as chlorofluorocarbons 12/11 and 12/114,
and more environmentally friendly fluorocarbons, or other nontoxic
volatiles; solvents such as water, glycerol and ethanol, these
include cosolvents as needed to solvate or suspend the active;
stabilizers such as ascorbic acid, sodium metabisulfite;
preservatives such as cetylpyridinium chloride and benzalkonium
chloride: tonicity adjustors such as sodium chloride; buffers; and
flavoring agents such as sodium saccharin. Such compositions are
useful for treating respiratory disorders, such as asthma and the
like.
[0173] Other preferred compositions of this invention include
aqueous solutions comprising a safe and effective amount of a
subject compound intended for topical intraocular administration.
Such compositions preferably comprise from about 0.0001% to about
5% of a subject compound, more preferably from about 0.01% to about
0.5%. Such compositions also typically include one or more of
preservatives, such as benzalkonium chloride, thimerosal,
phenylmercuric acetate; vehicles, such as poloxamers, modified
celluloses, povidone and purified water; tonicity adjustors, such
as sodium chloride, mannitol and glycerin; buffers such as acetate,
citrate, phosphate and borate; antioxidants such as sodium
metabisulfite, butylated hydroxy toluene and acetyl cysteine; acids
and bases may be used to adjust the pH of these formulations as
needed.
[0174] Other preferred compositions of this invention useful for
peroral administration include solids, such as tablets and
capsules, and liquids, such as solutions, suspensions and emulsions
(preferably in soft gelatin capsules), comprising a safe and
effective amount of a subject compound. Such compositions
preferably comprise from about 0.01 mg to about 350 mg per dose,
more preferably from about 0.1 mg to about 35 mg per dose. Such
compositions can be coated by conventional methods, typically with
pH or time-dependent coatings, such that the subject compound is
released in the gastrointestinal tract at various times to extend
the desired action. Such dosage forms typically include, but are
not limited to, one or more of cellulose acetate phthalate,
polyvinylacetate phthalate, hydroxypropyl methyl cellulose
phthalate, ethyl cellulose, Eudragit.RTM. coatings, waxes and
shellac.
[0175] Any of the compositions of this invention may optionally
include other drug actives. Non-limiting examples of drug actives
which may be incorporated in these compositions, include:
[0176] Antihistamines, including;
[0177] Hydroxyzine, preferably at a dosage range of from about 25
to about 400 mg; Doxylamine, preferably at a dosage range of from
about 3 to about 75 mg; Pyrilamine, preferably at a dosage range of
from about 6.25 to about 200 mg; Chlorpheniramine, preferably at a
dosage range of from about 1 to about 24 mg; Phenindamine,
preferably at a dosage range of from about 6.25 to about 150 mg;
Dexchlorpheniramine, preferably at a dosage range of from about 0.5
to about 12 mg; Dexbrompheniramine, preferably at a dosage range of
from about 0.5 to about 12 mg; Clemastine, preferably at a dosage
range of from about 1 to about 9 mg; Diphenhydramine, preferably at
a dosage range of from about 6.25 to about 300 mg; Azelastine,
preferably at a dosage range of from about 140 to about 1,680 .mu.g
(when dosed intranasally); 1 to about 8 mg (when dosed orally);
Acrivastine, preferably at a dosage range of from about 1 to about
24 mg; Levocarbastine (which can be dosed as an intranasal or
ocular medicament), preferably at a dosage range of from about 100
to about 800 mg; Mequitazine, preferably at a dosage range of from
about 5 to about 20 mg; Astemizole, preferably at a dosage range of
from about 5 to about 20 mg; Ebastine, preferably at a dosage range
of from about 5 to about 20 mg; Loratadine, preferably at a dosage
range of from about 5 to about 40 mg; Cetirizine, preferably at a
dosage range of from about 5 to about 20 mg; Terfenadine,
preferably at a dosage range of from about 30 to about 480 mg;
Terfenadine metabolites; Promethazine, preferably at a dosage range
of from about 6.25 to about 50 mg; Dimenhydrinate, preferably at a
dosage range of from about 12.5 to about 400 mg; Meclizine,
preferably at a dosage range of from about 6.25 to about 50 mg;
Tripelennamine, preferably at a dosage range of from about 6.25 to
about 300 mg; Carbinoxamine, preferably at a dosage range of from
about 0.5 to about 16 mg; Cyproheptadine, preferably at a dosage
range of from about 2 to about 20 mg; Azatadine, preferably at a
dosage range of from about 0.25 to about 2 mg; Brompheniramine,
preferably at a dosage range of from about 1 to about 24 mg;
Triprolidine, preferably at a dosage range of from about 0.25 to
about 10 mg; Cyclizine, preferably at a dosage range of from about
12.5 to about 200 mg; Thonzylamine, preferably at a dosage range of
from about 12.5 to about 600 mg; Pheniramine, preferably at a
dosage range of from about 3 to about 75 mg; Cyclizine, preferably
at a dosage range of from about 12.5 to about 200 mg and
others;
[0178] Antitussives, including;
[0179] Codeine, preferably at a dosage range of from about 2.5 to
about 120 mg; Hydrocodone, preferably at a dosage range of from
about 2.5 to about 40 mg; Dextromethorphan, preferably at a dosage
range of from about 2.5 to about 120 mg; Noscapine, preferably at a
dosage range of from about 3 to about 180 mg; Benzonatate,
preferably at a dosage range of from about 100 to about 600 mg;
Diphenhydramine, preferably at a dosage range of fr om about 12.5
to about 150 mg; Chlophedianol, preferably at a dosage range of
from about 12.5 to about 100 mg; Clobutinol, preferably at a dosage
range of from about 20 to about 240 mg; Fominoben, preferably at a
dosage range of from about 80 to about 480 mg; Glaucine;
Pholcodine, preferably at a dosage range of from about 1 to about
40 mg; Zipeprol, preferably at a dosage range of from about 75 to
about 300 mg; Hydromorphone, preferably at a dosage range of from
about 0.5 to about 8 mg; Carbetapentane, preferably at a dosage
range of from about 15 to about 240 mg; Caramiphen, preferably at a
dosage range of from about 10 to about 100 mg; Levopropoxyphene,
preferably at a dosage range of from about 25 to about 200 mg and
others;
[0180] Antiinflammatories, preferably Non-Steroidal
Anti-inflammatories. (NSAI DS) including;
[0181] Ibuprofen, preferably at a dosage range of from about 50 to
about 3,200 mg; Naproxen, preferably at a dosage range of from
about 62.5 to about 1,500 mg; Sodium naproxen, preferably at a
dosage range of from about 110 to about 1,650 mg; Ketoprofen,
preferably at a dosage range of from about 25 to about 300 mg;
Indoprofen, preferably at a dosage range of from about 25 to about
200 mg; Indomethacin, preferably at a dosage range of from about 25
to about 200 mg; Sulindac, preferably at a dosage range of from
about 75 to about 400 mg; Diflunisal, preferably at a dosage range
of from about 125 to about 1,500 mg; Ketorolac, preferably at a
dosage range of from about 10 to about 120 mg; Piroxicam,
preferably at a dosage range of from about 10 to about 40 mg;
Aspirin, preferably at a dosage range of from about 80 to about
4,000 mg; Meclofenamate, preferably at a dosage range of from about
25 to about 400 mg; Benzydamine, preferably at a dosage range of
from about 25 to about 200 mg; Carprofen, preferably at a dosage
range of from about 75 to about 300 mg; Diclofenac, preferably at a
dosage range of from about 25 to about 200 mg; Etodolac, preferably
at a dosage range of from about 200 to about 1,200 mg; Fenbufen,
preferably at a dosage range of from about 300 to about 900 mg;
Fenoprofen, preferably at a dosage range of from about 200 to about
3,200 mg; Flurbiprofen, preferably at a dosage range of from about
50 to about 300 mg; Mefenamic acid, preferably at a dosage range of
from about 250 to about 1,500 mg; Nabumetone, preferably at a
dosage range of from about 250 to about 2,000 mg; Phenylbutazone,
preferably at a dosage range of from about 100 to about 400 mg;
Pirprofen, preferably at a dosage range of from about 100 to about
800 mg; Tolmetin, preferably at a dosage range of from about 200 to
about 1,800 mg and others;
[0182] Analgesics, including;
[0183] Acetaminophen, preferably at a dosage range of from about 80
to about 4,000 mg; and others:
[0184] Expectorants/Mucolytics, including;
[0185] Guaifenesin, preferably at a dosage range of from about 50
to about 2,400 mg; N-Acetylcysteine, preferably at a dosage range
of from about 100 to about 600 mg; Ambroxol, preferably at a dosage
range of from about 15 to about 120 mg; Bromhexine, preferably at a
dosage range of from about 4 to about 64 mg; Terpin hydrate,
preferably at a dosage range of from about 100 to about 1,200 mg;
Potassium iodide, preferably at a dosage range of from about 50 to
about 250 mg and others;
[0186] Anticholinergics (e.g. Atropinics). preferably intranasally
or orally administered anticholinergics, including;
[0187] Ipratroprium (preferably intranasally), preferably at a
dosage range of from about 42 to about 252 .mu.g; Atropine sulfate
(preferably oral), preferably at a dosage range of from about 10 to
about 1,000 .mu.g; Belladonna (preferably as an extract),
preferably at a dosage range of from about 15 to about 45 mg
equivalents; Scopolamine, preferably at a dosage range of from
about 400 to about 3,200 .mu.g; Scopolamine methobromide,
preferably at a dosage range of from about 2.5 to about 20 mg;
Homatropine methobromide, preferably at a dosage range of from
about 2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably
at a dosage range of from about 125 to about 1,000 .mu.g;
Isopropramide (preferably oral), preferably at a dosage range of
from about 5 to about 20 mg; Orphenadrine (preferably oral),
preferably at a dosage range of from about 50 to about 400 mg;
Benzalkonium chloride (preferably intranasally) preferably a 0.005
to about 0.1% solution and others;
[0188] Mast Cell Stabilizers, preferably intranasally, or orally
administered mast cell stabilizers, including;
[0189] Cromalyn, preferably at a dosage range of from about 10 to
about 60 mg; Nedocromil, preferably at a dosage range of from about
10 to about 60 mg; Oxatamide, preferably at a dosage range of from
about 15 to about 120 mg; Ketotifen, preferably at a dosage range
of from about 1 to about 4 mg; Lodoxamide, preferably at a dosage
range of from about 100 to about 3,000 .mu.g and others;
[0190] Leukotriene Antagonists, including Zileuton and others;
[0191] Methylxanthines, including;
[0192] Caffeine, preferably at a dosage range of from about 65 to
about 600 mg; Theophylline, preferably at a dosage range of from
about 25 to about 1,200 mg; Enprofylline; Pentoxifylline,
preferably at a dosage range of from about 400 to about 3,600 mg;
Aminophylline, preferably at a dosage range of from about 50 to
about 800 mg; Dyphylline, preferably at a dosage range of from
about 200 to about 1,600 mg and others;
[0193] Antioxidants or radical inhibitors, including;
[0194] Ascorbic acid, preferably at a dosage range of from about 50
to about 10,000 mg; Tocopherol, preferably at a dosage range of
from about 50 to about 2,000 mg; Ethanol, preferably at a dosage
range of from about 500 to about 10,000 mg and others;
[0195] Steroids, preferably intranasally administered steroids,
including:
[0196] Beclomethasone, preferably at a dosage range of from about
84 to about 336 .mu.g; Fluticasone, preferably at a dosage range of
from about 50 to about 400 .mu.g; Budesonide, preferably at a
dosage range of from about 64 to about 256 .mu.g; Mometasone,
preferably at a dosage range of from about 50 to about 300 mg;
Triamcinolone, preferably at a dosage range of from about 110 to
about 440 .mu.g; Dexamethasone, preferably at a dosage range of
from about 168 to about 1,008 .mu.g; Flunisolide, preferably at a
dosage range of from about 50 to about 300 .mu.g; Prednisone
(preferably oral), preferably at a dosage range of from about 5 to
about 60 mg; Hydrocortisone (preferably oral), preferably at a
dosage range of from about 20 to about 300 mg and others;
[0197] Bronchodilators, preferably for inhalation, including
[0198] Albuterol, preferably at a dosage range of from about 90 to
about 1,080 .mu.g; 2 to about 16 mg (if dosed orally); Epinephrine,
preferably at a dosage range of from about 220 to about 1,320
.mu.g; Ephedrine, preferably at a dosage range of from about 15 to
about 240 mg (if dosed orally); 250 to about 1,000 .mu.g (if dosed
intranasally); Metaproterenol, preferably at a dosage range of from
about 65 to about 780 .mu.g or 10 to about 80 mg if dosed orally;
Terbutaline, preferably at a dosage range of from about 200 to
about 2,400 .mu.g; 2.5 to about 20 mg (if dosed orally);
Isoetharine, preferably at a dosage range of from about 340 to
about 1,360 .mu.g; Pirbuterol, preferably at a dosage range of from
about 200 to about 2,400 .mu.g; Bitolterol, preferably at a dosage
range of from about 370 to about 2,220 .mu.g; Fenoterol, preferably
at a dosage range of from about 100 to about 1,200 .mu.g; 2.5 to
about 20 mg (if dosed orally); Rimeterol, preferably at a dosage
range of from about 200 to about 1,600 .mu.g; Ipratroprium,
preferably at a dosage range of from about 18 to about 216 .mu.g
(inhalation) and others; and
[0199] Antivirals, including;
[0200] Amantadine, preferably at a dosage range of from about 50 to
about 200 mg; Rimantadine, preferably at a dosage range of from
about 50 to about 200 mg; Enviroxime; Nonoxinols, preferably at a
dosage range of from about 2 to about 20 mg (preferably an
intranasal form); Acyclovir, preferably at a dosage range of from
about 200 to about 2,000 mg (oral); 1 to about 10 mg (preferably an
intranasal form); Alpha-Interferon, preferably at a dosage range of
from about 3 to about 36 MIU; Beta-Interferon, preferably at a
dosage range of from about 3 to about 36 MIU and others;
[0201] Ocular Drug actives: acetylcholinesterase inhibitors, e.g.,
echothiophate from about 0.03% to about 0.25% in topical solution
and others; and
[0202] Gastrointestinal actives: antidiarrheals, e.g., loperamide
from about 0.1 mg to about 1.0 mg per dose, and bismuth
subsalicylate from about 25 mg to about 300 mg per dose and
others.
[0203] Of course, clearly contemplated and included in the
description above are the acid or base addition salts, esters,
metabolites, stereoisomers and enantiomers of these preferred
combination actives, as well as their analogues of these actives
that are safe and effective. It is also recognized that an active
may be useful for more than one of the above uses, and these uses
are clearly contemplated as well. This overlap is recognized in the
art and adjusting dosages and the like to fit the indication is
well within the purview of the skilled medical practitioner.
[0204] Methods of Use
[0205] Without being bound by theory, it is contemplated that the
primary mechanism by which alpha-2 agonists provide efficacy is by
intervening in the biological cascade responsible for disorder(s)
and/or manifestation(s) thereof. It may be that there is no deficit
in alpha-2 adrenoceptor activity: such activity may be normal.
However, administration of an alpha-2 agonist may be a useful way
of rectifying a disorder, condition or manifestation thereof.
[0206] Thus as used herein, the terms "disease," "disorder" and
"condition" are used interchangeably to refer to maladies related
to or modulated by alpha-2 adrenoceptor activity.
[0207] As used herein, a disorder described by the terms "modulated
by alpha-2 adrenoceptors," or "modulated by alpha-2 adrenoceptor
activity" refers to a disorder, condition or disease where alpha-2
adrenoceptor activity is an effective means of alleviating the
disorder or one or more of the biological manifestations of the
disease or disorder; or interferes with one or more points in the
biological cascade either leading to the disorder or responsible
for the underlying disorder; or alleviates one or more symptoms of
the disorder. Thus, disorders subject to "modulation" include those
for which:
[0208] The lack of alpha-2 activity is a "cause" of the disorder or
one or more of the biological manifestations, whether the activity
was altered genetically, by infection, by irritation, by internal
stimulus or by some other cause;
[0209] The disease or disorder or the observable manifestation or
manifestations of the disease or disorder are alleviated by alpha-2
activity. The lack of alpha-2 activity need not be causally related
to the disease or disorder or the observable manifestations
thereof;
[0210] Alpha-2 activity interferes with part of the biochemical or
cellular cascade that results in or relates to the disease or
disorder. In this respect, the alpha-2 activity alters the cascade,
and thus controls the disease, condition or disorder.
[0211] The compounds of this invention are particularly useful for
the treatment of nasal congestion associated with allergies, colds,
and other nasal disorders, as well as the sequelae of congestion of
the mucous membranes (for example, sinusitis and otitis media). At
effective doses, it has been found that undesired side effects can
be avoided.
[0212] While not limited to a particular mechanism of action, the
subject compounds are believed to provide advantages in the
treatment of nasal decongestion over related compounds through
their ability to interact with alpha-2 adrenoceptors. The subject
compounds have been found to be alpha-2 adrenoceptor agonists which
cause constriction of peripheral vascular beds in the nasal
turbinates.
[0213] Alpha-2 adrenoceptors are distributed both inside and
outside of the central nervous system. Thus, though not essential
for activity or efficacy, certain disorders preferably are treated
with compounds that act on alpha-2 adrenoceptors in only one of
these regions. Compounds of this invention vary in their ability to
penetrate into the central nervous system and, thus, to produce
effects mediated through central alpha-2 adrenoceptors. Thus, for
example, a compound which displays a higher degree of central
nervous system activity is preferred for central nervous system
indications over other compounds as described below. However, even
for compounds that exhibit primarily peripheral activity, central
nervous system actions can be evoked by an increase in the dose of
the compound. Further specificity of action of these compounds can
be achieved by delivering the agent to the region where activity is
desired (for example, topical administration to the eye, nasal
mucosa or respiratory tract).
[0214] Compounds preferred for, but not limited to, the treatment
of certain cardiovascular disorders, pain, substance abuse and/or
withdrawal, ulcer and hyperacidity include those compounds that are
centrally acting. By centrally acting what is meant is that they
have some action on the alpha-2 adrenoceptors in the central
nervous system in addition to their action at peripheral alpha-2
adrenoceptors.
[0215] Compounds preferred for, but not limited to, the treatment
of respiratory disorders, ocular disorders, migraine, certain
cardiovascular disorders, and certain other gastrointestinal
disorders are peripherally acting. By peripherally acting, what is
meant is that these compounds act primarily on alpha-2
adrenoceptors in the periphery, rather than those in the central
nervous system. Methods are available in the art to determine which
compounds are primarily peripherally acting and which are primarily
centrally acting.
[0216] Thus, compounds of the subject invention are also useful for
the treatment of ocular disorders such as ocular hypertension,
glaucoma, hyperemia, conjunctivitis, and uveitis. The compounds are
administered either perorally, or topically as drops, sprays,
mists, gels or creams directly to the surface of the mammalian
eye.
[0217] The compounds of this invention are also useful for
controlling gastrointestinal disorders, such as diarrhea, irritable
bowel syndrome, hyperchlorhydria and peptic ulcer.
[0218] The compounds of this invention are also useful for diseases
and disorders associated with sympathetic nervous system activity,
including hypertension, myocardial ischemia, cardiac reperfusion
injury, angina, cardiac arrhythmia, heart failure and benign
prostatic hypertrophy. Due to their sympatholytic effect, compounds
are also useful as an adjunct to anesthesia during surgical
procedures.
[0219] The compounds of this invention are also useful for
relieving pain associated with various disorders. The compounds are
administered perorally, parenterally, and/or by direct injection
into the cerebrospinal fluid.
[0220] The compounds of this invention are also useful for the
prophylactic or acute treatment of migraine. The compounds are
administered perorally, parenterally or intranasally.
[0221] The compounds of this invention are also useful for
treatment of substance abuse, in particular abuse of alcohol and
opiates, and alleviating the abstinence syndromes evoked by
withdrawal of these substances.
[0222] The compounds of this invention are also useful for other
diseases and disorders where vasoconstriction, particularly of
veins, would provide a benefit, including septic or cardiogenic
shock, elevated intracranial pressure, hemmorhoids, venous
insufficiency, varicose veins, and menopausal flushing.
[0223] The compounds of this invention are also useful for
neurologic diseases and disorders, including spasticity, epilepsy,
attention deficit hyperactive disorder, Tourette's syndrome, and
cognitive disorders.
[0224] The pharmacological activity and selectivity of these
compounds can be determined using published test procedures. The
alpha-2 selectivity of the compounds is determined by measuring
receptor binding affinities and in vitro functional potencies in a
variety of tissues known to possess alpha-2 and/or alpha-1
receptors. (See, e.g., The Alpha-2 Adrenergic Receptors, L. E.
Limbird, ed., Humana Press, Clifton, N.J.) The following in vivo
assays are typically conducted in rodents or other species. Central
nervous system activity is determined by measuring locomotor
activity as an index of sedation. (See, e.g., Spyraki, C. & H.
Fibiger, "Clonidine-induced Sedation in Rats: Evidence for
Mediation by Postsynaptic Alpha-2 Adrenoreceptors", Journal of
Neural Transmission, Vol. 54 (1982), pp. 153-163). Nasal
decongestant activity is measured using rhinomanometry as an
estimate of nasal airway resistance. (See, e.g., Salem, S. & E.
Elemente, "A New Experimental Method for Evaluating Drugs in the
Nasal Cavity", Archives of Otolaryngology, Vol. 96 (1972), pp.
524-529). Antiglaucoma activity is determined by measuring
intraocular pressure. (See, e.g., Potter, D., "Adrenergic
Pharmacology of Aqueous Human Dynamics", Pharmacological Reviews,
Vol. 13 (1981), pp. 133-153). Antidiarrheal activity is determined
by measuring the ability of the compounds to inhibit
prostaglandin-induced diarrhea. (See, e.g., Thollander, M., P.
Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced
Diarrhea by Alpha-2 Adrenoceptor Agonists", Alimentary Pharmacology
and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy in treating
irritable bowel syndrome is determined by measuring the ability of
compounds to reduce the stress-induced increase in fecal output.
(See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J.
Fondacaro & H. Ormsbee III, "Cold-restraint stress increases
rat fecal pellet output and colonic transit", American Journal of
Physiology, Vol. 258 (1990), pp. G329-G337). Antiulcer and
reduction of hyperchlorhydria efficacy is determined by measuring
the reduction in gastric acid secretion produced by these compounds
(See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca & C. Roze,
"Effect of .alpha.2-adrenoceptor agonists on gastric pepsin and
acid secretion in the rat", British Journal of Pharmacology, Vol.
106 (1992), pp. 790-796). Antiasthma activity is determined by
measuring the effect of the compound on bronchoconstriction
associated with pulmonary challenges such as inhaled antigens.
(See, e.g., Chang, J. J. Musser & J. Hand, "Effects of a Novel
Leukotriene D.sub.4 Antagonist with 5-Lipoxygenase and
Cyclooxygenase Inhibitory Activity, Wy45,911, on
Leukotriene-D.sub.4- and Antigen-induced Bronchoconstriction in
Guinea Pig", International Archives of Allergy and Applied
Immunology, Vol. 86 (1988), pp. 48-54; and Delehunt, J., A.
Perruchound, L. Yerger, B. Marchette, J. Stevenson & W.
Abraham, "The Role of Slow-Reacting Substance of Anaphylaxis in the
Late Bronchial Response After Antigen Challenge in Allergic Sheep",
American Reviews of Respiratory Disease, Vol. 130 (1984), pp.
748-754). Activity in cough is determined by measuring the number
and latency of the cough response to respiratory challenges such as
inhaled citric acid. (See, e.g., Callaway, J. & R. King,
"Effects of Inhaled .alpha.2-Adrenoceptor and GABA.sub.B Receptor
Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in
Guinea Pigs". European Journal of Pharmacology, Vol. 220 (1992),
pp. 187-195). The sympatholytic activity of these compounds is
determined by measuring the reduction of plasma catecholamines
(See, e.g., R. Urban, B. Szabo & K. Starke "Involvement of
peripheral presynaptic inhibition in the reduction of sympathetic
tone by moxonidine, rilmenidine and UK 14,304", European Journal of
Pharmacology, Vol. 282 (1995), pp. 29-37) or the reduction in renal
sympathetic nerve activity (See, e.g., Feng, Q., S. Carlsson, P.
Thoren & T. Hedner, "Effects of clonidine on renal sympathetic
nerve activity, natriuresis and diuresis in chronic congestive
heart failure rats", Journal of Pharmacology and Experimental
Therapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis
for their benefit in heart failure and benign prostatic
hypertrophy. The hypotensive effect of these compounds is measure
directly as a reduction in mean blood pressure (See, e.g.,
Timmermans, P. & P. Van Zwieten, "Central and peripheral
.alpha.-adrenergic effects of some imidazolidines", European
Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinical
studies have demonstrated the beneficial effect of alpha-2 agonists
in the prevention of myocardial ischemia during surgery (See, e.g.,
Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg
& D. Mangano, "Effects of Perioperative Dexmedetomidine
Infusion in Patients Undergoing Vascular Surgery", Anesthesiology,
Vol. 82 (1995), pp. 620-633) and in the prevention of angina (See,
e.g., Wright, R. A., P. Decroly, T. Kharkevitch & M. Oliver,
"Exercise Tolerance in Angina is Improved by Mivazerol--an
.alpha.2-Adrenoceptor Agonist", Cardiovascular Drugs and Therapy,
Vol. 7 (1993), pp. 929-934). The efficacy of these compounds in
cardiac reperfusion injury is demonstrated by measuring the
reduction of cardiac necrosis and neutrophil infiltration (See,
e.g., Weyrich, A., X. Ma, & A. Lefer, "The Role of L-Arginine
in Ameliorating Reperfusion Injury After Myocardial Ischemia in the
Cat", Circulation, Vol. 86 (1992), pp. 279-288). The cardiac
antiarrhythmic effect of these compounds is demonstrated by
measuring the inhibition of ouabain induced arrhythmias (See, e.g.,
Thomas, G. & P. Stephen, "Effects of Two Imidazolines (ST-91
and ST-93) on the Cardiac Arrhythmias and Lethality Induced by
Ouabain in Guinea-Pig", Asia-Pacific Journal of Pharmacology, Vol.
8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J.
Martins & H. Lee, "Electrophysiological effects of
.alpha.2-adrenergic stimulation in canine cardiac Purkinje fibers",
American Journal of Physiology, Vol. 268 (1995), pp. H2024-H2035).
The vasoconstrictor activity of these compounds is demonstrated by
measuring the contractile properties on isolated arteries and veins
in vitro (See, e.g., Flavahan, N., T. Rimele, J. Cooke & M.
Vanhoutte, "Characterization of Postjunctional Alpha-1 and Alpha-2
Adrenoceptors Activated by Exogenous or Nerve-Released
Norepinephrine in the Canine Saphenous Vein", Journal of
Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp.
699-705). The effectiveness of these compounds at reducing
intracranial pressure is demonstrated by measurement of this
property in a canine model of subarachnoid hemorrhage (See, e.g.,
McCormick, J., P. McCormick, J. Zabramski & R. Spetzler,
"Intracranial pressure reduction by a central alpha-2
adrenoreceptor agonist after subarachnoid hemorrhage",
Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibition of
menopausal flushing is demonstrated by measuring the reduction of
facial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H.
Connor & S. Brain, "The modulation of the increase in rat
facial skin blood flow observed after trigeminal ganglion
stimulation", European Journal of Pharmacology, Vol. 284 (1995),
pp. 69-76) as demonstrated for alpha-2 adrenergic agonists on
cutaneous blood flow in the tail (See, e.g., Redfern, W., M.
MacLean, R. Clague & J. McGrath, "The role of alpha-2
adrenoceptors in the vasculature of the rat tail", British Journal
of Pharmacology, Vol. 114 (1995), pp. 1724-1730). The
antinociceptive and pain reducing properties of these compounds is
demonstrated by measuring the increase in pain threshold in the
rodent writhing and hot plate antinociceptive models (See, e.g.,
Millan, M., K. Bervoets, J. Rivet, R. Widdowson, A. Renouard, S, Le
Marouille-Girardon & A. Gobert, "Multiple Alpha-2 Adrenergic
Receptor Subtypes. II. Evidence for a Role of Rat Alpha-2A
Adrenergic Receptors in the Control of Nociception, Motor Behavior
and Hippocampal Synthesis of Noradrenaline", Journal of
Pharmacology and Experimental Therapeutics, Vol. 270 (1994), pp.
958-972). The antimigraine effect of these compounds is
demonstrated by measuring the reduction of dural neurogenic
inflammation to trigeminal ganglion stimulation in the rat (See,
e.g., Matsubara, T., M. Moskowitz & Z. Huang, "UK-14,304,
R(-)-alpha-methyl-histamine and SMS 201-995 block plasma protein
leakage within dura mater by prejunctional mechanisms", European
Journal of Pharmacology, Vol. 224 (1992), pp. 145-150). The ability
of these compounds to suppress opiate withdrawal is demonstrated by
measuring the suppression of enhanced sympathetic nerve activity
(See, e.g., Franz, D., D. Hare & K. McCloskey, "Spinal
sympathetic neurons: possible sites of opiate-withdrawal
suppression by clonidine", Science, Vol. 215 (1982), pp.
1643-1645). Antiepileptic activity of these compounds is
demonstrated by measuring the inhibition of the kindling response
(See, e.g., Shouse, M., M. Bier, J. Langer, O. Alcalde, M. Richkind
& R. Szymusiak, "The .alpha.2-agonist clonidine suppresses
seizures, whereas the alpha-2 antagonist idazoxan promotes
seizures--a microinfusion study in amygdala-kindled kittens", Brain
Research, Vol. 648 (1994), pp. 352-356). The effectiveness of other
alpha-2 agonists in the management of neurologic disorders has been
demonstrated, including attention-deficit hyperactive disorder and
Tourefte's syndrome (See, e.g., Chappell P., M. Riddle, L. Scahill,
K. Lynch, R. Schultz, A. Arnsten, J. Leckman & D. Cohen,
"Guanfacine treatment of comorbid attention-deficit hyperactivity
disorder and Tourette's syndrome: preliminary clinical experience",
Journal of American Academy of Child and Adolescent Psychiatry,
Vol. 34 (1995), pp. 1140-1146), cognitive disorders (See, e.g.,
Coull, J., "Pharmacological manipulations of the
.alpha.2-noradrenergic system. Effects on cognition", Drugs and
Aging, Vol. 5 (1994), pp. 116-126), and spasticity (See, e.g.,
Eyssette, M., F. Rohmer, G. Serratrice, J. Warter & D. Boisson,
"Multicenter, double-blind trial of a novel antispastic agent,
tizanidine, in spasticity associated with multiple sclerosis",
Current Medical Research & Opinion, Vol. 10 (1988), pp.
699-708).
[0225] Another aspect of this invention involves methods for
preventing or treating nasal congestion by administering a safe and
effective amount of a subject compound to a mammal experiencing or
at risk of experiencing nasal congestion. Such nasal congestion may
be associated with human diseases or disorders which include, but
are not limited to, seasonal allergic rhinitis, acute upper
respiratory viral infections, sinusitis, perennial rhinitis, and
vasomotor rhinitis. In addition, other disorders can be generally
associated with mucous membrane congestion (for example, otitis
media and sinusitis.) Each administration of a dose of the subject
compound preferably administers a dose within the range of from
about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably
from about 0.001 mg/kg to about 0.5 mg/kg. Peroral administration
of such doses is preferred. The frequency of administration of a
subject compound according to this invention is preferably from
about once to about six times daily, more preferably from about
once to about 4 times daily. Such doses and frequencies are also
preferred for treating other respiratory conditions, such as,
cough, chronic obstructive pulmonary disease (COPD) and asthma.
Such doses and frequencies are also preferred for treating
conditions that are associated with mucous membrane congestion (for
example, sinusitis and otitis media).
[0226] Another aspect of this invention involves methods for
preventing or treating glaucoma by administering a safe and
effective amount of a subject compound to a mammal experiencing or
at risk of experiencing glaucoma. If administered systemically,
each administration of a dose of the subject compound preferably
administers a dose within the range of from about 0.0001 mg/kg to
about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg
to about 0.5 mg/kg. If intraocular dosing is used then preferably
one administers a typical volume (for example, 1 or 2 drops) of a
liquid composition, comprising from about 0.0001% to about 5% of a
subject compound, more preferably from about 0.01% to about 0.5% of
the compound. Determination of the exact dosage and regimen is
within the purview of the skilled artisan. Intraocular
administration of such doses is preferred. The frequency of
administration of a subject compound according to this invention is
preferably from about once to about six times daily, more
preferably from about once to about 4 times daily.
[0227] Another aspect of this invention involves methods for
preventing or treating gastrointestinal disorders, such as
diarrhea, irritable bowel syndrome, and peptic ulcer by
administering a safe and effective amount of a subject compound to
a mammal experiencing or at risk of experiencing gastrointestinal
disorders. Each administration of a dose of the subject compound
preferably administers a dose within the range of from about 0.0001
mg/kg to about 5 mg/kg of a compound, more preferably from about
0.001 mg/kg to about 0.5 mg/kg. Peroral administration of such
doses is preferred. The frequency of administration of a subject
compound according to this invention is preferably from about once
to about six times daily, more preferably from about once to about
4 times daily.
[0228] Another aspect of this invention involves methods for
preventing or treating migraine, by administering a safe and
effective amount of a subject compound to a mammal experiencing or
at risk of experiencing migraine. Each administration of a dose of
the subject compound preferably administers a dose within the range
of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more
preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral,
parenteral or intranasal administration of such doses is preferred.
The frequency of peroral administration of a subject compound
according to this invention is preferably from about once to about
six times daily, more preferably from about once to about 4 times
daily. The frequency of parenteral dosing of a subject compound
according to this invention is preferably from about once to about
six times daily, more preferably from about once to about 4 times
daily or by infusion to the desired effect. The frequency of
intranasal dosing of a subject compound according to this invention
is preferably from about once to about six times daily, more
preferably from about once to about 4 times daily.
[0229] Another aspect of this invention involves methods for
preventing or treating disorders related to sympathetic nervous
system activity, such as hypertension, myocardial ischemia, cardiac
reperfusion injury, angina, cardiac arrhythmia, and benign
prostatic hypertrophy, by administering a safe and effective amount
of a subject compound to a mammal experiencing or at risk of
experiencing these diseases or disorders. Each administration of a
dose of the subject compound preferably administers a dose within
the range of from about 0.0001 mg/kg to about 5 mg/kg of a
compound, more preferably from about 0.001 mg/kg to about 0.5
mg/kg. Peroral and parenteral administration of such doses are
preferred. The frequency of peroral administration of a subject
compound according to this invention is preferably from about once
to about six times daily, more preferably from about once to about
4 times daily. The frequency of parenteral dosing of a subject
compound according to this invention is preferably from about once
to about six times daily, more preferably from about once to about
4 times daily or by infusion to the desired effect.
[0230] Another aspect of this invention involves methods for
preventing or treating pain, by administering a safe and effective
amount of a subject compound to a mammal experiencing or at risk of
experiencing pain. Each administration of a dose of the subject
compound preferably administers a dose within the range of from
about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably
from about 0.001 mg/kg to about 0.5 mg/kg. Peroral or parenteral
administration of such doses is preferred. The frequency of peroral
administration of a subject compound according to this invention is
preferably from about once to about six times daily, more
preferably from about once to about 4 times daily. The frequency of
parenteral dosing of a subject compound according to this invention
is preferably from about once to about six times daily, more
preferably from about once to about 4 times daily or by infusion to
the desired effect.
[0231] Another aspect of this invention involves methods for
preventing or treating substance abuse and the abstinence syndrome
resulting from withdrawal of these substances, such as alcohol and
opiates, by administering a safe and effective amount of a subject
compound to a mammal experiencing or at risk of experiencing
substance abuse or withdrawal symptoms. Each administration of a
dose of the subject compound preferably administers a dose within
the range of from about 0.0001 mg/kg to about 5 mg/kg of a
compound, more preferably from about 0.001 mg/kg to about 0.5
mg/kg. Peroral administration of such doses is preferred. The
frequency of administration of a subject compound according to this
invention is preferably from about once to about six times daily,
more preferably from about once to about 4 times daily.
[0232] Composition and Method Examples
[0233] The following non-limiting examples illustrate the
compositions and methods of use of this invention.
Example A
[0234]
3 Oral Tablet Composition Ingredient Amount per tablet (mg) Subject
Compound 4 20.0 Microcrystalline cellulose (Avicel PH 102 .RTM.)
80.0 Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil .RTM.)
1.0 Magnesium stearate 3.0 Total = 200.0 mg
[0235] One tablet is swallowed by a patient with nasal congestion.
The congestion is substantially diminished.
[0236] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example B
[0237]
4 Chewable Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 1 15.0 Mannitol 255.6 Microcrystalline cellulose
(Avicel PH 101 .RTM.) 100.8 Dextrinized sucrose (Di-Pac .RTM.)
199.5 Imitation orange flavor 4.2 Sodium saccharin 1.2 Stearic acid
15.0 Magnesium stearate 3.0 FD&C Yellow #6 dye 3.0 Pyrogenic
silica (Cab-O-Sil .RTM.) 2.7 Total = 600.0 mg
[0238] One tablet is chewed and swallowed by a patient with nasal
congestion. The congestion is substantially reduced.
[0239] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example C
[0240]
5 Sublingual Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 5 2.00 Mannitol 2.00 Microcrystalline cellulose
(Avicel PH 101 .RTM.) 29.00 Mint flavorants 0.25 Sodium saccharin
0.08 Total = 33.33 mg
[0241] One tablet is placed under the tongue of a patient with
nasal congestion and allowed to dissolve. The congestion is rapidly
and substantially diminished.
[0242] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example D
[0243]
6 Intranasal Solution Composition Ingredient Composition (% w/v)
Subject Compound 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002
d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s.
Total = 100.00
[0244] One-tenth of a mL of the composition is sprayed from a pump
actuator into each nostril of a patient with nasal congestion. The
congestion is substantially diminished.
[0245] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example E
[0246]
7 Intranasal Gel Composition Ingredient Composition (% w/v) Subject
Compound 1 0.10 Benzalkonium chloride 0.02 Thimerosal 0.002
Hydroxypropyl methylcellulose 1.00 (Metolose 65SH4000 .RTM.)
Aromatics 0.06 Sodium chloride (0.65%) q.s. Total = 100.00
[0247] One-fifth of a mL of the composition is applied as drops
from a dropper into each nostril of a patient with nasal
congestion. The congestion is substantially reduced.
[0248] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example F
[0249]
8 Inhalation Aerosol Composition Ingredient Composition (% w/v)
Subject Compound 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1
Sodium Saccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0
[0250] Two-puffs of the aerosol composition is inhaled from a
metered-dose inhaler by a patient with asthma. The asthmatic
condition is effectively relieved.
[0251] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example G
[0252]
9 Topical Ophthalmic Composition Ingredient Composition (% w/v)
Subject Compound 5 0.10 Benzalkonium chloride 0.01 EDTA 0.05
Hydroxyethylcellulose (Natrosol M .RTM.) 0.50 Sodium metabisulfite
0.10 Sodium chloride (0.9%) q.s. Total = 100.0
[0253] One-tenth of a mL of the composition is administered
directly into each eye of a patient with glaucoma. The intraocular
pressure is substantially reduced.
[0254] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example H
[0255]
10 Oral Liquid Composition Ingredient Amount/15 mL Dose Subject
Compound 4 15 mg Chlorpheniramine maleate 4 mg Propylene glycol 1.8
g Ethanol (95%) 1.5 mL Methanol 12.5 mg Eucalyptus oil 7.55 mg
Flavorants 0.05 mL Sucrose 7.65 g Carboxymethylcellulose (CMC) 7.5
mg Microcrystalline cellulose and 187.5 mg Sodium CMC (Avicel RC
591 .RTM.) Polysorbate 80 3.0 mg Glycerin 300 mg Sorbitol 300 mg
FD&C Red #40 dye 3 mg Sodium saccharin 22.5 mg Sodium phosphate
monobasic 44 mg Sodium citrate monohydrate 28 mg Purified Water
q.s. Total = 15 mL
[0256] One 15 mL dose of the liquid composition is swallowed by a
patient with nasal congestion and runny nose due to allergic
rhinitis. The congestion and runny nose are effectively
reduced.
[0257] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example J
[0258]
11 Oral Liquid Composition Ingredient Amount/15 mL Dose Subject
Compound 2 30 mg Sucrose 8.16 g Glycerin 300 mg Sorbitol 300 mg
Methylparaben 19.5 mg Propylparaben 4.5 mg Menthol 22.5 mg
Eucalyptus oil 7.5 mg Flavorants 0.07 mL FD&C Red #40 dye 3.0
mg Sodium saccharin 30 mg Purified water q.s. Total = 15 mL
[0259] One 15 mL dose of the alcohol-free liquid medication is
swallowed by a patient with nasal congestion. The congestion is
substantially diminished.
[0260] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example K
[0261]
12 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 1 4 Microcrystalline cellulose, NF 130 Starch
1500, NF 100 Magnesium stearate, USP 2 Total = 236 mg
[0262] One tablet is swallowed by a patient with migraine. The pain
and aura of migraine is substantially diminished.
[0263] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example L
[0264]
13 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 2 12 Hydroxypropyl methylcellulose, USP 12
Magnesium stearate, USP 2 Lactose anhydrous, USP 200 Total = 226
mg
[0265] For the relief of pain. Adults 12 and over take one tablet
every twelve hours.
[0266] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example M
[0267]
14 Oral Caplet Composition Ingredient Amount per tablet (mg)
Naproxen sodium anhydrous, USP 220 Subject Compound 3 6
Hydroxypropyl methylcellulose, USP 6 Magnesium stearate, USP 2
Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF
44 Total = 300 mg
[0268] For relief of symptoms associated with the common cold,
sinusitis, or flu including nasal congestion, headache, fever, body
aches, and pains. Adults 12 and over take two caplets every twelve
hours.
[0269] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example N
[0270]
15 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 4 6 Hydroxypropyl methylcellulose, USP 6 Silicon
dioxide, colloidal, NF 30 Pregelatinized starch, NF 50 Magnesium
stearate, USP 4 Total = 96 mg
[0271] For treatment of benign prostatic hypertrophy. Take one
tablet per day.
[0272] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example O
[0273]
16 Oral Tablet Composition Ingredient Amount per caplet (mg)
Subject Compound 5 6 Hydroxypropyl methylcellulose, USP 6 Magnesium
stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline
cellulose, NF 44 Total = 80 mg
[0274] For the use in the treatment of alcoholism or opiate
addiction. Adults 12 and over take two caplets every twelve
hours.
[0275] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example P
[0276]
17 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 1 6 Hydroxypropyl methylcellulose, USP 12
Magnesium stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12
Microcrystalline cellulose, NF 44 Total = 86 mg
[0277] For the treatment of ulcer and hyperacidity. Take two
tablets as appropriate.
[0278] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example Q
[0279]
18 Oral Tablet Composition Amount per tablet (mg) Component Amount
Ingredient Subject Compound 5 10 mg/ml carrier Carrier: Sodium
citrate buffer with (percent by weight of carrier): Lecithin 0.48%
Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11
Propyl paraben 0.011 For the reduction of cardiac reperfusion
injury.
[0280] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example R
[0281]
19 Oral Liquid Composition Ingredient Amount/fl oz Dose (mg)
Acetaminophen, USP 1000 Doxylamine succinate, USP 12.5
Dextromethorphan hydrobromide, USP 30 Subject Compound 2 6 Dow
XYS-40010.00 resin 3 High fructose corn syrup 16000 Polyethylene
glycol, NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium
citrate dihydrate, USP 150 Citric acid, anhydrous, USP 50 Saccharin
sodium, USP 20 Flavor 3.5 Purified water, USP 3500 Total = 29275
mg/fl oz
[0282] For the relief of minor aches, pains, headache, muscular
aches, sore throat pain, and fever associated with a cold or flu.
Relieves nasal congestion, cough due to minor throat and bronchial
irritations, runny nose, and sneezing associated with the common
cold. Adults 12 and over take one fluid ounce every six hours.
[0283] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example S
[0284]
20 Oral Liquid Composition Ingredient Amount/fl oz Dose (mg)
Naproxen sodium anhydrous, USP 220 Doxylamine succinate, USP 12.5
Dextromethorphan hydrobromide, USP 30 Subject Compound 1 6 Dow
XYS-40010.00 resin 3 High fructose corn syrup 16000 Polyethylene
glycol, NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium
citrate dihydrate, USP 150 Citric acid, anhydrous, USP 50 Saccharin
sodium, USP 20 Flavor 3.5 Purified water, USP 3800 Total = 28795
mg/fl oz
[0285] For the relief of minor aches, pains, headache, muscular
aches, sore throat pain, and fever associated with a cold or flu.
Relieves nasal congestion, cough due to minor throat and bronchial
irritations, runny nose, and sneezing associated with the common
cold. Adults 12 and over take one fluid ounce every six hours.
[0286] Other compounds having a structure according to Formula I
are used with substantially similar results.
Composition Example T
[0287] A composition for parenteral administration, according to
this invention, is made comprising:
21 Component Amount Subject Compound 1 10 mg/ml carrier Carrier:
Sodium citrate buffer with (percent by weight of carrier): Lecithin
0.48% Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11
Propyl paraben 0.011
[0288] The above ingredients are mixed, forming a solution.
Approximately 2.0 ml of the solution is administered,
intravenously, to a human subject suffering from septic or
cardiogenic shock. The symptoms subside.
[0289] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example U
[0290]
22 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 5 10 Hydroxypropyl methylcellulose, USP 12
Magnesium stearate, USP 2 Povidone K-30, USP 10 Talc, USP 12
Microcrystalline cellulose, NF 44 Total = 90 mg
[0291] For the treatment of cardiac arrhythmia. Take as
prescribed.
[0292] Other compounds having a structure according to Formula I
are used with substantially similar results.
Example V
[0293]
23 Oral Tablet Composition Ingredient Amount per tablet (mg)
Subject Compound 1 4 Microcrystalline cellulose, NF 130 Starch
1500, NF 100 Magnesium stearate, USP 2 Total = 236 mg
[0294] For the treatment of congestive heart failure. Take as
prescribed.
[0295] Other compounds having a structure according to Formula I
are used with substantially similar results.
[0296] Modification of the preceding embodiments is within the
scope of the skilled artisan in formulation, given the guidance of
the specification in light of the state of the art.
[0297] Other examples of combination actives are contemplated.
Examples of medicaments which can be combined with the primary
active are included in U.S. Pat. No. 4,552,899 to Sunshine, et al.,
hereby incorporated by reference. All other references referred to
throughout this specification are hereby incorporated by
reference.
[0298] While particular embodiments of this invention have been
described, it will be obvious to those skilled in the art that
various changes and modifications of this invention can be made
without departing from the spirit and scope of the invention. It is
intended to cover, in the appended claims, all such modifications
that are within the scope of this invention.
* * * * *