U.S. patent application number 11/384006 was filed with the patent office on 2006-11-30 for pharmaceutically active compounds and methods of use.
This patent application is currently assigned to Scion Pharmaceuticals, Inc.. Invention is credited to Graham J. Durant, Seetharamaiyer Padmanabhan.
Application Number | 20060270741 11/384006 |
Document ID | / |
Family ID | 36272245 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270741 |
Kind Code |
A1 |
Durant; Graham J. ; et
al. |
November 30, 2006 |
Pharmaceutically active compounds and methods of use
Abstract
The present invention relates to pharmaceutically acceptable
compounds, including acylguanidine compounds, and methods of
treatment and pharmaceutical compositions that utilize or comprise
one or more such compounds. Compounds of the invention are
particularly useful for the treatment or prophylaxis of
neurological injury and neurodegenerative disorders.
Inventors: |
Durant; Graham J.;
(Plymouth, GB) ; Padmanabhan; Seetharamaiyer;
(Lexington, MA) |
Correspondence
Address: |
EDWARDS & ANGELL, LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Assignee: |
Scion Pharmaceuticals, Inc.
Medford
MA
02155
|
Family ID: |
36272245 |
Appl. No.: |
11/384006 |
Filed: |
March 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09176067 |
Oct 20, 1998 |
7041702 |
|
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11384006 |
Mar 17, 2006 |
|
|
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60064830 |
Oct 21, 1997 |
|
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|
Current U.S.
Class: |
514/614 ;
564/147 |
Current CPC
Class: |
C07D 209/14 20130101;
C07D 333/20 20130101 |
Class at
Publication: |
514/614 ;
564/147 |
International
Class: |
A61K 31/16 20060101
A61K031/16; C07C 249/02 20060101 C07C249/02 |
Claims
1-6. (canceled)
7. A compound of the following Formula: ##STR33## wherein R is an
optionally substituted cyclic alkyl; an optionally substituted
carbocyclic aryl; an optionally substituted alkylaryl; an
optionally substituted heteroaromatic or heteroalicyclic group
having from I to 3 rings, 3 to about 8 ring members in each ring
and from 1 to about 3 hetero atoms; optionally substituted aralkyl;
optionally substituted heteroaralkyl; or optionally substituted
heteroalicyclicalkyl; each R.sup.1 is independently hydrogen,
optionally substituted alkyl; optionally substituted alkenyl;
optionally substituted alkynyl; optionally substituted alkoxy;
optionally substituted alkylthio; optionally substituted
alkylsulfinyl; optionally substituted alkylsulfonyl; optionally
substituted or unsubstituted carbocyclic aryl; or an optionally
substituted heteroaromatic or heteroalicyclic group having from 1
to 3 rings, 3 to about 8 ring members in each ring and 1 to about 3
hetero atoms; each R.sup.2 and each R.sup.3 are independently
hydrogen, halogen, hydroxyl, azido, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted alkoxy,
optionally substituted alkylthio, optionally substituted
alkylsulfinyl, optionally substituted alkylsulfonyl, optionally
substituted aminoalkyl, optionally substituted carbocyclic aryl, or
optionally substituted aralkyl; W is optionally substituted
methylene, --S--, --O--, optionally substituted --N--, --S(O)-- or
--S(O.sub.2)--; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and
pharmaceutically acceptable salts thereof.
8. A compound of claim 7 wherein W is optionally substituted
methylene.
9-18. (canceled)
19. A compound of claim 7 wherein R is an optionally substituted
cyclic alkyl; optionally substituted carbocyclic aryl; optionally
substituted alkylaryl; an optionally substituted heteroaromatic or
heteroalicyclic group having from 1 to 3 rings, 3 to about 8 ring
members in each ring and from 1 to about 3 hetero atoms
20. A compound of claim 19 wherein R is optionally substituted
cyclic alkyl.
21. A compound of claim 19 wherein R is optionally substituted
carbocyclic aryl.
22. A compound of claim 21 wherein R is optionally substituted
phenyl or naphthyl.
23. A compound of claim 19 wherein R is optionally substituted
heteroaromatic or heteroalicyclic.
24. A compound of claim 19 wherein R is optionally substituted
aralkyl.
25. (canceled)
26. A compound of claim 7 wherein at least one R.sup.1 group is
hydrogen.
27. A compound of claim 7 wherein both R.sup.1 groups are
hydrogen.
28. A compound of claim 7 wherein at least one R.sup.1 group is
optionally substituted alkyl.
29. A compound of claim 7 wherein at least one R.sup.1 group is
alkyl having 1 to 3 carbon atoms.
30. A compound of claim 7 wherein both R.sup.1 groups are
optionally substituted alkyl.
31. A method of treating a nerve degeneration disease comprising
administering to a mammal suffering from or susceptible to said
disease a therapeutically effective amount of a compound of claim
7.
32. A method of treating a neurodegenerative disease comprising
administering to a mammal suffering from or susceptible to said
disease a therapeutically effective amount of a compound of claim
7.
33. A method of treating Alzheimer's disease, Parkinson's disease,
Huntington's disease, Amyotrophic Lateral Sclerosis, Down's
Syndrome or Korsakoff's disease, Cerebral Palsy, or epilepsy,
comprising administering to a mammal suffering from or susceptible
to said disease a therapeutically effective amount of a compound of
claim 7.
34. A method of treating or preventing nerve cell death or
degeneration comprising administering to a mammal suffering from or
susceptible to nerve cell death or degeneration a therapeutically
effective amount of a compound of claim 7.
35. The method of claim 34 wherein the nerve cell death or
degeneration is associated with hypoxia, hypoglycemia, brain or
spinal cord ischemia, retinal ischemia or brain or spinal cord
trauma.
36. A method of treating a mammal suffering from or susceptible to
stroke or heart attack comprising administering to the mammal a
therapeutically effective amount of a compound of claim 7.
37. A method of treating a mammal suffering from or susceptible to
brain or spinal cord trauma comprising administering to the mammal
a therapeutically effective amount of a compound of claim 7.
38. A method of treating a mammal suffering from or susceptible to
pain including chronic pain or neuropathic pain, peripheral
necropathy, migraines, shingles, emesis, narcotic withdrawal
symptoms or age-dependent dementia, comprising administering to the
mammal a therapeutically effective amount of a compound of claim
7.
39. A method of treating a mammal suffering from or susceptible
decreased blood flow or nutrient supply to retinal tissue or optic
nerve, or retinal ischemia or trauma, or optic nerve injury, or
aglaucoma, comprising administering to the mammal a therapeutically
effective amount of a compound of claim 7.
40. A method of treating a mammal suffering from or susceptible to
post-surgical neurological deficits or neurological deficits
associated with cardiac arrest, comprising administering to the
mammal a therapeutically effective amount of a compound of claim
7.
41. A method for treating an infection in a mammal, comprising
administering to a mammal suffering from or susceptible to an
infection an effective amount of an aminoglycoside antibiotic and a
compound of claim 7.
42. The method of claim 41 wherein the mammal is suffering from an
infection of a Gram negative bacteria or a Gram positive
bacteria.
43. (canceled)
44. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 7 and a pharmaceutically
acceptable carrier.
45. A compound of claim 7 that is radiolabelled.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S.
provisional application No. 60/064,830, filed Oct. 21, 1997, which
application is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to pharmaceutically active
compounds, including acylguanmine compounds, and methods of
treatment and pharmaceutical compositions that utilize or comprise
one or more such compounds. Compounds of the invention are
particularly useful for the treatment or prophylaxis of
neurological injury and neurodegenerative disorders.
[0004] 2. Background
[0005] Nerve cell death (degeneration) can cause potentially
devastating and irreversible effects for an individual and may
occur e.g. as a result of stroke, heart attack or other brain or
spinal chord ischemia or trauma. Additionally, neurodegenerative
disorders involve nerve cell death (degeneration) such as
Alzheimer's disease, Parkinson's disease, Huntington's disease,
Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff's
disease.
[0006] Therapies have been investigated to treat nerve cell
degeneration and related disorders, e.g., by limiting the extent of
nerve cell death that may otherwise occur to an individual. See,
e.g., N. L. Reddy et al., J. Med. Chem., 37:260-267 (1994); and WO
95/20950.
[0007] The compound MK-801 has exhibited good results in a variety
of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain
Metab. Rev., 2:27-57 (1990); D. Choi, Cerbrovascular Brain Metab.
Rev., 2:105-147 (1990). See also Merck Index, monograph 3392, 11th
ed., 1989. For example, MK-801 exhibits good activity in mouse
audiogenic tests, a recognized model for evaluation of
neuroprotective drugs. See, e.g., M. Tricklebank et al., European
Journal of Pharmacology, 167:127-135 (1989); T. Seyfried,
Federation Proceedings, 38(10):2399-2404 (1979).
[0008] However, MK-801 also has shown toxicity and further clinical
development of the compound is currently uncertain. See J. W. Olney
et al., Science, 244:1360-1362 (1989); W. Koek et al., J.
Pharmacol. Exp. Ther., 252:349-357 (1990); F. R. Sharp et al.,
Society for Neuroscience Abstr., abstr. no. 482.3 (1992).
[0009] It thus would be highly desirable to have new
neuroprotective agents, particularly agents to limit the extent or
otherwise treat nerve cell death (degeneration) such as may occur
with stroke, heart attack or brain or spinal cord trauma, or to
treat neurodegenerative disorders such as Alzheimer's disease,
Parkinson's disease, Huntington's disease, Amyotrophic Lateral
Sclerosis, Down's Syndrome and Korsakoff's disease.
SUMMARY OF THE INVENTION
[0010] In a first aspect, the present invention provides
acylguanidine compounds of the following Formula I: ##STR1##
[0011] wherein R is an optionally substituted cyclic alkyl
preferably having five or more carbon ring members; optionally
substituted carbocyclic aryl having at least about 6 ring carbon
atoms; optionally substituted alkylaryl preferably having from 7 to
about 18 carbon atoms; or optionally substituted heteroaromatic or
heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members
in each ring and from 1 to 3 hetero atoms;
[0012] each R.sup.1 and R.sup.2 are each independently hydrogen,
optionally substituted alkyl preferably having from 1 to about 20
carbon atoms, more preferably 1 to about 8 carbon atoms, still more
preferably 1 to about 3 carbon atoms; optionally substituted
alkenyl preferably having 2 to about 20 carbon atoms, more
preferably 2 to about 8 carbon atoms; optionally substituted
alkynyl preferably having 2 to about 20 carbon atoms, more
preferably 2 to about 8 carbon atoms; optionally substituted alkoxy
preferably having from 1 to about 20 carbon atoms, more preferably
1 to about 8 carbon atoms, still more preferably 1 to about 3
carbon atoms; optionally substituted alkylthio preferably having
from 1 to about 20 carbon atoms, more preferably 1 to about 8
carbon atoms, still more preferably 1 to about 3 carbon atoms;
optionally substituted alkylsulfinyl preferably having from 1 to
about 20 carbon atoms, more preferably 1 to about 8 carbon atoms,
still more preferably 1 to about 3 carbon atoms; optionally
substituted alkylsulfonyl preferably having from 1 to about 20
carbon atoms, more preferably 1 to about 8 carbon atoms, still more
preferably 1 to about 3 carbon atoms; optionally substituted
carbocyclic aryl having at least about 6 ring carbon atoms; or
optionally substituted heteroaromatic or heteroalicyclic group
having from 1 to 3 hetero atoms;
[0013] X is a chemical bond; optionally substituted alkylene,
alkenylene or alkenylene linkage preferably having from 1 to about
6 carbons in the linkage, more preferably from 1 to 4 carbons in
the linkage; or an optionally substituted heteroalkylene,
heteroalkenylene heteroalkynylene linkage preferably having from 1
to about 6 carbons in the linkage, more preferably from 1 to 4
carbons in the linkage; and
[0014] R.sup.3 is an optionally substituted cycloalkyl preferably
having 3 or more carbon ring members, more preferably about 5 or
more carbon ring members; optionally substituted carbocyclic aryl
having at least about 6 ring carbon atoms; optionally substituted
alkylaryl preferably having from 7 to about 18 carbon atoms; or
optionally substituted heteroaromatic or heteroalicyclic group
having from 1 to 3 rings, 3 to 8 ring members in each ring and from
1 to 3 hetero atoms; and pharmaceutically acceptable salts
thereof.
[0015] In the above Formula I, X may suitably be a chemical bond,
i.e. compounds of the following Formula IA. ##STR2##
[0016] wherein R, R.sup.1, R.sup.2 and R.sup.3 are each the same as
defined above for Formula I; and pharmaceutically acceptable salts
of those compounds.
[0017] It also has been found that compounds having X being an
alkylene linkage, particularly C.sub.1-4 alkylene, exhibit
significant biological activity as shown in the examples which
follow. Thus preferred are compounds of the following Formula IB:
##STR3##
[0018] wherein X is an optionally substituted alkylene linkage
preferably having from 1 to about 6 carbon atoms in the alkylene
chain, more preferably 1 to 4 carbon atoms in the alkylene chain,
and R, R.sup.1, R.sup.2 and R.sup.3 are each the same as defined
above for Formula I; and pharmaceutically acceptable salts of those
compounds.
[0019] Preferred compounds also include those of the above Formulae
I, IA or IB wherein one or more of each R.sup.1 and R.sup.2 are
hydrogen, including wherein each R.sup.1 and R.sup.2 are all
hydrogen. Generally preferred R.sup.2 groups of Formulae I, IA and
IB include hydrogen and optionally substituted alkyl such as
optionally substituted C.sub.1-6 alkyl, or more preferably
optionally substituted C.sub.1-3 alkyl. Preferred R.sup.3 groups of
Formula I, IA and IB include optionally substituted carbocyclic
aryl or alkaryl such as optionally substituted phenyl, naphthyl and
the like, and optionally substituted heteroalicyclic or
heteroaromatic such as indolyl and the like, or optionally
substituted cycloalkyl such as cyclohexyl and the like.
[0020] In a further aspect, the invention provides
acylimine-substituted indolinyl-type compounds, particularly
compounds of the following Formula II: ##STR4##
[0021] wherein R is an optionally substituted cyclic alkyl
preferably having five or more carbon ring members; optionally
substituted carbocyclic aryl having at least about 6 ring carbon
atoms; optionally substituted alkylaryl preferably having from 7 to
about 18 carbon atoms; or optionally substituted heteroaromatic or
heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members
in each ring and from 1 to 3 hetero atoms;
[0022] R.sup.1 is the selected from the same group defined for
R.sup.1 and R.sup.2 in Formula I;
[0023] each R.sup.2 and each R.sup.3 (i.e. substituent of the 4, 5,
6 and 7 aromatic ring positions) are each independently hydrogen,
halogen, hydroxyl, azido, optionally substituted alkyl preferably
having from 1 to about 20 carbon atoms, optionally substituted
alkenyl preferably having from 2 to about 20 carbon atoms,
optionally substituted alkynyl preferably having from 2 to about 20
carbon atoms, optionally substituted alkoxy preferably having from
1 to about 20 carbon atoms, optionally substituted aLkylthio
preferably having 1 to about 20 carbon atoms, optionally
substituted alkylsulfinyl preferably having from 1 to about 20
carbon atoms, optionally substituted alkylsulfonyl preferably
having from 1 to about 20 carbon atoms, optionally substituted
aminoalkyl preferably having from 1 to about 20 carbon atoms,
optionally substituted carbocyclic aryl having at least about 6
ring carbon atoms, or optionally substituted aralkyl having at
least about 6 ring carbon atoms;
[0024] W is optionally substituted methylene (--CH.sub.2--; i.e.
indolinyl compounds), --S-- (i.e. 3-benzothiazolinylcarboximidamide
compounds), --O--, optionally substituted --N--, --S(O)-- or
--S(O.sub.2)--;
[0025] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically
acceptable salts of those compounds.
[0026] In Formula II, generally preferred are compounds where W is
optionally substituted methylene, i.e. indolinyl compounds.
Optionally substituted phenyl, naphthyl, adamantyl and thiophenyl
and other heteroaromatic groups are preferred R groups for
compounds of Formula II. Preferred compounds of Formula II also
include those where R.sup.1 is hydrogen.
[0027] In a yet further aspect, the invention provides
acylimine-substituted tetrahydroquinolinyl-type compounds,
particularly compounds of the following Formula III: ##STR5##
[0028] wherein R is an optionally substituted cyclic alkyl
preferably having five or more carbon ring members; optionally
substituted carbocyclic aryl having at least about 6 ring carbon
atoms; optionally substituted alkylaryl preferably having from 7 to
about 18 carbon atoms; or an optionally substituted heteroaromatic
or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring
members in each ring and from 1 to 3 hetero atoms;
[0029] each R.sup.1 is selected from the same group as defined for
R.sup.1 and R.sup.2 in Formula I above;
[0030] each R.sup.2 (i.e. substituent of the 2 and 3 ring
positions) and each R.sup.3 (i.e. substituent of the 5, 6, 7 and 8
aromatic ring positions) are each independently hydrogen, halogen,
hydroxyl, azido, optionally substituted alkyl preferably having
from 1 to about 20 carbon atoms, optionally substituted alkenyl
preferably having from 2 to about 20 carbon atoms, optionally
substituted alkynyl preferably having from 2 to about 20 carbon
atoms, optionally substituted alkoxy preferably having from 1 to
about 20 carbon atoms, optionally substituted alkylthio preferably
having 1 to about 20 carbon atoms, optionally substituted
alkylsulfinyl preferably having from 1 to about 20 carbon atoms,
optionally substituted alkylsulfonyl preferably having from 1 to
about 20 carbon atoms, optionally substituted aminoalkyl preferably
having from 1 to about 20 carbon atoms, optionally substituted
carbocyclic aryl having at least about 6 ring carbon atoms, or
optionally substituted aralkyl having at least about 6 ring carbon
atoms;
[0031] Y is optionally substituted methylene (--CH.sub.2--, i.e.
1,2,3,4-tetrahydroquinolinyl compounds), --O-- (i.e.
2,3-benzmorpholinyl compounds), --S-- (i.e. 2,3-benzthiomorpholinyl
compounds), --S(O)--, --S(O.sub.2)--, or optionally substituted
--N--,
[0032] m and n are each independently 0 (i.e. the available ring
are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically
acceptable salts of those compounds.
[0033] In Formula III, generally preferred are compounds where Y is
methylene, i.e. 1,2,3,4-tetrahydroquinolinyl compounds. Optionally
substituted phenyl and naphthyl are preferred R groups for
compounds of Formula III. Preferred compounds of Formula III also
include those where R.sup.1 is hydrogen.
[0034] In a further aspect, the invention provide
acylimine-substituted tetrahydroisoquinolinyl compounds,
particularly compounds of the following Formula IV: ##STR6##
[0035] wherein R and each R.sup.1 are the same as defined above for
Formula I;
[0036] each R.sup.2 (i.e. substituent of the 1, 3 and 4
tetrahydroisoquinolinyl ring positions) and each R.sup.3 (i.e.
substituent of the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring
positions) are each independently hydrogen, halogen, hydroxyl,
azido, optionally substituted alkyl preferably having from 1 to
about 20 carbon atoms, optionally substituted alkenyl preferably
having from 2 to about 20 carbon atoms, optionally substituted
alkynyl preferably having from 2 to about 20 carbon atoms,
optionally substituted alkoxy preferably having from 1 to about 20
carbon atoms, optionally substituted alkylthio preferably having 1
to about 20 carbon atoms, optionally substituted alkylsulfinyl
preferably having from 1 to about 20 carbon atoms, optionally
substituted alkylsulfonyl preferably having from 1 to about 20
carbon atoms, optionally substituted aminoalkyl preferably having
from 1 to about 20 carbon atoms, optionally substituted carbocyclic
aryl suitably at least about 6 ring carbon atoms, or optionally
substituted aralkyl suitably having at least about 6 ring carbon
atoms;
[0037] m is 0 (i.e. the 1, 3 and 4 tetrahydroisoquinolinyl ring
positions are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; n is
0 (i.e. the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions
are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically
acceptable salts thereof.
[0038] In another aspect, the invention provides compounds of the
following Formula V: ##STR7##
[0039] wherein R and each R.sup.1 are the same as defined above for
Formula I;
[0040] each R.sup.2 and each R.sup.3 (i.e. substituent of the
aromatic positions 3-8) are each independently hydrogen, halogen,
hydroxyl, azido, optionally substituted alkyl preferably having
from 1 to about 20 carbon atoms, optionally substituted alkenyl
preferably having from 2. to about 20 carbon atoms, optionally
substituted alkynyl preferably having from 2 to about 20 carbon
atoms, optionally substituted alkoxy preferably having from 1 to
about 20 carbon atoms, optionally substituted alkylthio preferably
having 1 to about 20 carbon atoms, optionally substituted
alkylsulfinyl preferably having from 1 to about 20 carbon atoms,
optionally substituted alkylsulfonyl preferably having from 1 to
about 20 carbon atoms, optionally substituted aminoalkyl preferably
having from 1 to about 20 carbon atoms, optionally substituted
carbocyclic aryl suitably having at least about 6 ring carbon
atoms, or optionally substituted aralkyl suitably having at least
about 6 ring carbon atoms;
[0041] m is 0 (i.e. the 2-benz[cd]indolinyl position is
hydrogen-substituted), 1 or 2; and n is 0 (i.e. the available ring
are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; and
pharmaceutically acceptable salts thereof.
[0042] Still further, the invention provides compounds of the
following Formula VI: ##STR8##
[0043] wherein R and each R.sup.1 are the same as defined above for
Formula I;
[0044] each R.sup.2, each R.sup.3 (i.e. substituent of the aromatic
positions 1-4) and each R.sup.4 (i.e. substituent of the aromatic
positions 7-10) are each independently hydrogen, halogen, hydroxyl,
azido, optionally substituted alkyl preferably having from 1 to
about 20 carbon atoms, optionally substituted alkenyl preferably
having from 2 to about 20 carbon atoms, optionally substituted
alkynyl preferably having from 2 to about 20 carbon atoms,
optionally substituted alkoxy preferably having from 1 to about 20
carbon atoms, optionally substituted alkylthio preferably having 1
to about 5-20 carbon-atoms, optionally substituted alkylsulfinyl
preferably having from 1 to about 20 carbon atoms, optionally
substituted alkylsulfonyl preferably having from 1 to about 20
carbon atoms, optionally substituted aminoalkyl preferably having
from 1 to about 20 carbon atoms, optionally substituted carbocyclic
aryl suitably having at least about 6 ring carbon atoms, or
optionally substituted aralkyl suitably having at least about 6
ring carbon atoms;
[0045] m is 0 (i.e. the 5,6-dihydrophenanthridinyl ring position is
hydrogen-substituted), 1 or 2; and n and r are each independently 0
(i.e. the ring positions are each hydrogen-substituted), 1, 2, 3 or
4; and pharmaceutically acceptable salts thereof.
[0046] In an additional aspect, the invention provides compounds of
the following Formula VII: ##STR9##
[0047] wherein R, each R.sup.1, Y, each R.sup.2, each R.sup.3 and n
are the same as defined above for Formula III; and m of Formula VII
is an integer equal to 0-6, and preferably m is 0, 1 or 2; and
pharmaceutically acceptable salts thereof.
[0048] The invention also provides compounds of the following
Formula VIII: ##STR10##
[0049] wherein R, each R.sup.1, each R.sup.2, each R.sup.3 and m
are the same as defined above for Formula V; and n of Formula VIII
is an integer equal to 0-9, and preferably n is 0, 1 or 2; and
pharmaceutically acceptable salts thereof. It is understand that
each R.sup.3 can be the same or different and may be present on
either the non-aromatic or aromatic fused ring as depicted in the
above structural formula.
[0050] The invention further provides compounds of the following
Formula IX: ##STR11##
[0051] wherein R, R.sup.1, R.sup.2, R.sup.3, n and r are the same
as defined above for Formula VI, and m of Formula IX is an integer
equal to 0-4, and preferably m is 0, 1 or 2, and the dotted line in
Formula IX represents an optional carbon-carbon double bond
(endocyclic bond); and pharmaceutically acceptable salts
thereof.
[0052] In a further aspect, compounds of the following Formula X
are provided: ##STR12##
[0053] wherein R, R.sup.1, R.sup.2, R.sup.3, n and r are the same
as defined above for Formula VI, and m of Formula X is an integer
equal to 0-6 (i.e. R.sup.2 may be a substituent at any of the
available three saturated ring positions), and preferably m is 0, 1
or 2; and pharmaceutically acceptable salts thereof.
[0054] In a further aspect, the invention also provides compounds
of the Formulae I', IA', IB', II', III', IV', V', VI', VII', VIII',
IX' and X', which formulae are defined the same as Formulae I, IA,
IB, II, III, IV, V, VI, VII, VIII, IX and X respectively, except
that the substituent R may be selected from the group of an
optionally substituted cyclic alkyl preferably having five or more
carbon ring members; optionally substituted carbocyclic aryl having
at least about 6 ring carbon atoms; optionally substituted
alkylaryl preferably having from 7 to about 18 carbon atoms; or
optionally substituted heteroaromatic or heteroalicyclic group
having from 1 to 3 rings, 3 to 8 ring members in each ring and from
1 to 3 hetero (N, O or S) atoms; optionally substituted aralkyl
preferably having from 7 to about 18 carbon atoms; optionally
substituted heteroaralkyl preferably having from 5 to about 18
carbon atoms, and from 1 to 3 rings, 3 to 8 ring members in each
ring and from 1 to 3 hetero (N, 0 or S) atoms; or optionally
substituted heteroalicyclicalkyl preferably having from 5 to about
18 carbon atoms, and from 1 to 3 rings, 3 to 8 ring members in each
ring and from 1 to 3 hetero (N, O or S) atoms. For such compounds
of Formulae I', IA', IB', II', III', IV', V', VI', VII', VIII', IX'
and X', preferred R groups include optionally substituted aralkyl,
particularly optionally substituted carbocyclic aralkyl such as
optionally substituted phenalkyl, e.g. optionally substituted
phenyl(C.sub.1-8)alkyl, more typically optionally substituted
phenyl(C.sub.1-6)alkyl, still more typically optionally substituted
phenyl(C.sub.1-4)alkyl such as an optionally substituted phenacetyl
(C.sub.6H.sub.5CH.sub.2C(.dbd.O)) group and the like. Additional
particularly suitable R groups of such compounds of Formulae I',
IA', IB', II', III', IV', V', VI', VII', VIII', IX' and X' include
optionally substituted heteroaryalkyl and optionally substituted
heteroalicyclicalkyl, such as optionally substituted
heteroaryl(C.sub.1-8)alkyl or heteroalicyclic(C.sub.1-8)alkyl, more
typically optionally substituted heteroaryl(C.sub.1-6)alkyl or
heteroalicyclic(C.sub.1-6)alkyl, still more typically optionally
substituted heteroaryl(C.sub.1-4)alkyl or
heteroalicyclic(C.sub.1-4)alkyl. It also should be understood that
preferred substituents as disclosed herein of compounds of Formula
I, IA, IB, II, III, IV, V, VI, VII, VIII, IX and X are also
preferred substituents of the corresponding Formulae I', IA', IB',
II', III', IV', V', VI', VII', VIII', IX' and X', unless indicated
otherwise.
[0055] Compounds of the invention (i.e. compounds of Formulae I,
IA, IB, II, III, IV, V, VI, VII, VIII, IX and X as well as
compounds of Formulae I', IA', IB', II', III', IV', V', VI', VII',
VIII', IX' and X') are useful for a number of therapeutic
applications. In particular, the invention includes methods for
treatment and/or prophylaxis of neurological conditions/injuries
such as epilepsy, neurodegenerative conditions and/or nerve cell
death (degeneration) resulting from or associated with e.g.
hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal
ischemia, brain or spinal chord trauma or post-surgical
neurological deficits and the like as well as neuropathic pain. The
invention also includes methods for treating peripheral necropathy.
The compounds of the invention are especially useful for treatment
of a person susceptible or suffering from stroke or heart attack or
neurological deficits relating to cardiac arrest, a person
suffering or susceptible to brain or spinal cord injury, or a
person suffering from the effects of retinal ischemica or
degeneration, or a person suffering from decreased blood flow or
nutrient supply to retinal tissue or optic nerve, retinal trauma,
glaucoma or optic nerve injury. Compounds of the invention also are
useful to treat and/or prevent various neurodegenerative diseases
such as Parkinson's disease, Huntington's disease, Amyotrophic
Lateral Sclerosis, Alzheimer's disease, Down's Syndrome,
Korsakoff's disease, cerebral palsy and/or age-dependent dementia.
Compounds of the invention will be further useful to treat and/or
prevent migraines, shingles (herpes zoster), epilepsy, emesis
and/or narcotic withdrawal symptoms. Compounds of the invention
will be useful for treatment of various types of pain, including
e.g. chronic pain. The treatment methods of the invention in
general comprise administration of a therapeutically effective
amount of one or more compounds of the invention to an animal,
including a mammal, particularly a human. Particularly preferred
compounds of the invention exhibit good activity in an
anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed in
Example 1 which follows, preferably about 20% or more inhibition at
a dose of a compound of the invention of 20 mg/kg, more preferably
about 50% or more inhibition at a dose of 20 mg/kg in such an
anticonvulsant in vivo audiogenic assay.
[0056] The invention also provides pharmaceutical compositions that
comprise one or more compounds of the invention and a suitable
carrier for the compositions.
[0057] Other aspects of the invention are disclosed infra.
DETAILED DESCRIPTION OF THE INVENTION
[0058] We have now discovered that compounds of the above-defined
Formulae I (which includes Formulae IA and IB), II, III, IV, V, VI,
VII, VIII, IX and X as well as Formulae I', IA', IB', II', III',
IV', V', VI', VII', VIII', IX' and X') are useful for therapeutic
applications, including to treat neurological injury or a
neurodegenerative disorder.
[0059] Suitable halogen substituent groups of compounds of Formulae
I, IA, IB, II, III, IV, V, VI, VII, VIII, IX and X as well as
Formulae I', IA', IB', II', III', IV', V', VI', VII', VIII', IX'
and X' as defined above (i.e. compounds of the invention) include
F, Cl, Br and I. Alkyl groups of compounds of the invention
typically have from 1 to about 12 carbon atoms, more preferably 1
to about 8 carbon atoms, still more preferably 1 to about 6 carbon
atoms, even more preferably 1, 2, 3 or 4 carbon atoms, or still
more preferably 1, 2 or 3 carbon atoms. As used herein, the term
alkyl unless otherwise modified refers to both cyclic and noncyclic
groups, although of course cyclic groups will comprise at least
three carbon ring members. Preferred alkenyl and alynyl-groups of
compounds of the invention have one or more unsaturated linkages
and typically from 2 to about 12 carbon atoms, more preferably 2 to
about 8 carbon atoms, still more preferably 2 to about 6 carbon
atoms, even more preferably 1, 2, 3 or 4 carbon atoms. The terms
alkenyl and alkynyl as used herein refer to both cyclic and
noncyclic groups, although straight or branched noncyclic groups
are generally more preferred. Preferred alkoxy groups of compounds
of the invention include groups having one or more oxygen linkages
and from 1 to about 12 carbon atoms, more preferably from 1 to
about 8 carbon atoms, and still more preferably 1 to about 6 carbon
atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Preferred
alkylthio groups of compounds of the invention include those groups
having one or more thioether linkages and from 1 to about 12 carbon
atoms, more preferably from 1 to about 8 carbon atoms, and still
more preferably 1 to about 6 carbon atoms. Alkylthio groups having
1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred
alkylsulfinyl groups of compounds of the invention include those
groups having one or more sulfoxide (SO) groups and from 1 to about
12 carbon atoms, more preferably from 1 to about 8 carbon atoms,
and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl
groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred alkylsulfonyl groups of compounds of the invention
include those groups having one or more sulfonyl (SO.sub.2) groups
and from 1 to about 12 carbon atoms, more preferably from 1 to
about 8 carbon atoms, and still more preferably 1 to about 6 carbon
atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are
particularly preferred. Preferred aminoalkyl groups include those
groups having one or more primary, secondary and/or tertiary amine
groups, and from 1 to about 12 carbon atoms, more preferably 1 to
about 8 carbon atoms, still more preferably 1 to about 6 carbon
atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary
and tertiary amine groups are generally more preferred than primary
amine moieties. Suitable heteroaromatic groups of compounds of the
invention contain one or more N, O or S atoms and include, e.g.,
coumarinyl including 8-coumarinyl, quinolinyl including
8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,
thienyl, thiazolyl, oxazolyl, oxidizolyl, triazole, imidazolyl,
indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic
groups of compounds of the invention contain one or more N, O or S
atoms and include, e.g., tetrahydrofuranyl, thienyl,
tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl
groups. Suitable carbocyclic aryl groups of compounds of the
invention include single and multiple ring compounds, including
multiple ring compounds that contain separate and/or fused aryl
groups. Typical carbocyclic aryl groups of compounds of the
invention contain 1 to 3 separate or fused rings and from 6 to
about 18 carbon ring atoms. Specifically preferred carbocyclic aryl
groups include phenyl; naphthyl including 1-naphthyl and
2-naphthyl; biphenyl; phenanthryl; anthracyl; and acenaphthyl.
Substituted carbocyclic groups are particularly suitable including
substituted phenyl, such as 2-substituted phenyl, 3-substituted
phenyl, 4-substituted phenyl, 2,3-substituted phenyl,
2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted
phenyl; and substituted naphthyl, including naphthyl substituted at
the 5, 6 and/or 7 positions. Preferred substituents of such
substituted carbocyclic groups are identified below.
[0060] Suitable aralkyl groups of compounds of the invention
include single and multiple ring compounds, including multiple ring
compounds that contain separate and/or fused aryl groups. Typical
aralkyl groups contain 1 to 3 separate or fused rings and from 6 to
about 18 carbon ring atoms. Preferred aralkyl groups include benzyl
and methylenenaphthyl (--CH.sub.2-- naphthyl), and other
carbocyclic aralkyl groups, as discussed above.
[0061] Suitable he teroaralkyl groups of compounds of the invention
include single and multiple ring compounds, including multiple ring
compounds that contain separate and/or fused heteroaryl groups,
where such groups are substituted onto an alkyl linkage. More
preferably, a heteroaralkyl group contains a heteroaryl group that
has 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3
hetero (N, O or S) atoms, substituted onto an alkyl linkage.
Suitable heteroaryl groups substituted onto an alkyl linkage
include e.g., coumarinyl including 8-coumarinyl, quinolinyl
including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl,
pyrrolyl, thienyl, thiazolyl, oxazolyl, oxidizolyl, triazole,
imidazolyl, indolyl, benzofuranyl and benzothiazol, as well as such
groups fused to one or more benzene rings.
[0062] Suitable heteroalicyclicalkyl groups of compounds of the
invention include single and multiple ring compounds, where such
groups are substituted onto an alkyl linkage. More preferably, a
heteroalicralkyl group contains at least one ring that has 3 to 8
ring members from 1 to 3 hetero (N, O or S) atoms, substituted onto
an alkyl linkage. Suitable heteroalicyclic groups substituted onto
an alkyl linkage include e.g. tetrahydrofuranyl, thienyl,
tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl
groups.
[0063] As discussed above, X groups of Formula I and I' suitably
are alkylene or heteroalkylene linkages, or may contain one or more
carbon-carbon double or triple bonds, i.e. alkenylene, alkynylene,
heteroalkenylene or heteroalkynylene linkage. Such unsaturated X
groups typically contain 1, 2, 3 or 4 carbon-carbon multiple bonds,
more typically 1 or 2 carbon-carbon multiple bonds. An X group that
is heteroalkylene, heteroalkenylene or heteroalkynylene contains
one or more N, O or S atoms in the chain between amino group and
R.sup.3 group of Formula I or I', with other atoms in the chain
suitably being carbons. Typcially a heteroalkylene,
heteroalkenylene or heteroalkynylene X group contains 1-3 N, O or S
atoms in the chain, more typically 1 or 2 N, O or S atoms.
Typically an X group contains from about 1 to 6 carbon atoms.
[0064] Suitable cyclic alkyl R groups of Formulae I-X and I'-X' and
R.sup.3 groups of Formulae I, IA, IB, I', IA' and IB' include
groups having five or six or more ring carbon atoms, particularly
optionally substituted adamanyl, isobornyl, norbornyl, cyclohexyl,
cyclopentyl and the like. Generally preferred cyclic alkyl groups
have from 5 to about 10 ring members. Cyclic alkyl groups having
bridged structures, such as adamantyl, are particularly
preferred.
[0065] Generally preferred R.sup.1 groups of Formulae I through X
and I' through X' include hydrogen and alkyl such as C.sub.1-6
alkyl, more preferably alkyl having 1, 2 or 3 carbon atoms.
Suitable compounds also include those where both R.sup.1 of a
compound are hydrogen, or where at least one R.sup.1 group is
hydrogen.
[0066] As discussed above, R, R.sup.1, X, R.sup.2, R.sup.3,
R.sup.4, X, Y and W groups of compound of the invention are
optionally substituted. A "substituted" R, R.sup.1, X, R.sup.2,
R.sup.3, R.sup.4, X, Y and W group or other substituent may be
substituted at one or more available positions, typically 1 to 3 or
4 positions, by one or more suitable groups such as those disclosed
herein. Suitable groups that may be present on a "substituted" R,
R.sup.1, X, R.sup.2, R.sup.3, R.sup.4, Y and W group or other
substituent include e.g. halogen such as fluoro, chloro, bromo and
iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C.sub.1-6
alkanoyl group such as acyl and the like; carboxamido; alkyl groups
including those groups having 1 to about 12 carbon atoms or from 1
to about 6 carbon atoms and more preferably 1-3 carbon atoms;
alkenyl and alkynyl groups including groups having one or more
unsaturated linkages and from 2 to about 12 carbon or from 2 to
about 6 carbon atoms; alkoxy groups having those having one or more
oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6
carbon atoms; aryloxy such as phenoxy; alkylthio groups including
those moieties having one or more thioether linkages and from 1 to
about 12 carbon atoms or from 1 to about 6 carbon atoms;
alkylsulfinyl groups including those moieties having one or more
sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to
about 6 carbon atoms; alkylsulfonyl groups including those moieties
having one or more sulfonyl linkages and from 1 to about 12 carbon
atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as
groups having one or more N atoms and from 1 to about 12 carbon
atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6
or more carbons, particularly phenyl (e.g. an R group being a
substituted or unsubstituted biphenyl moiety); and aralkyl such as
benzyl.
[0067] Generally preferred substituents of "substituted" nitrogen
and methylene W and Y groups of compounds of Formulae II, III, VII,
II', III', and VII' include substituted and unsubstituted alkyl,
including C.sub.1-4 alkyl and halo-substituted C.sub.1-4 alkyl,
particularly fluoro-substituted C.sub.1-4 alkyl such as
trifluoromethyl, and in the case of a substituted methylene group,
halogen and alkylthio.
[0068] Preferred carbocyclic ring substituents of compounds of the
invention include halogen (F, Cl, Br and I; hydroxyl; azido;
optionally substituted alkyl having 1 to about 6 carbons such as
methyl, ethyl, propyl and butyl and branched groups such as
isopropyl, sec-butyl and tert-butyl, and including halogenated
alkyl, particularly fluoro-alkyl having 1 to about 6 carbon atoms;
optionally substituted alkoxy having 1 to about 6 carbons such as
methoxy, ethoxy, propoxy and butoxy, and including halogenated
alkoxy, particularly fluoro-alkoxy having 1 to about 6 carbon
atoms; optionally substituted alkylthio having 1 to about 6 carbons
such as methylthio and ethylthio; optionally substituted
alkylsulfinyl having 1 to about 6 carbons such as methylsulfinyl
(--S(O)CH.sub.3) and ethylsulfinyl (--S(O)CH.sub.2CH.sub.3);
optionally substituted alkylsulfonyl having 1 to about 6 carbons
such as methylsulfonyl (--S(O).sub.2CH.sub.3) and ethylsulfonyl
(--S(I).sub.2CH.sub.2CH.sub.3); and optionally substituted
arylalkoxy such as benzyloxy (C.sub.6H.sub.5CH.sub.2O--).
[0069] It should be understood that alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl and aminoalkyl substituent groups
described above include groups where a hetero atom is directly
bonded to a ring system, such as a carbocyclic aryl group or a
heterocyclic group, as well as groups where a hetero atom of the
group is spaced from such ring system by an alkylene linkage, e.g.
of 1 to about 4 carbon atoms.
[0070] Also, in the above Formulae I through X and I' through X',
additional preferred groups that may be R.sup.2, R.sup.3 and
R.sup.4 as those substituent groups are defined above, include
optionally substituted sulfonamide, optionally substituted urea and
optionally substituted thioamide.
[0071] Without wishing to be bound by theory, compounds of the
invention that contain an alkylsulfinyl and/or alkylsulfonyl group,
may be, in effect, "pro-drugs" wherein after administration of the
compound to a subject the sulfinyl or sulfonyl group(s) are
metabolized (reduced) in vivo to the corresponding sulfide
moiety.
[0072] Specifically preferred compounds of the invention include
the following: [0073]
N-(4-methylbenzoyl)-N'-methyl-N'-(3-methylthiophenyl)guanidine;
[0074]
N-(4-methylbenzoyl)-N'-methyl-N'-(3-iodophenylmethyl)guanidine;
[0075] N-(4-methylbenzoyl)-N'-(1-naphthyl)guanidine; [0076]
N-(4-methylbenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0077]
N-(4-methylbenzoyl)-N'-(4-tertbutylphenyl)guanidine; [0078]
N-(4-methylbenzoyl)-1-indolinylcarboximidamide; [0079]
N-(4-methylbenzoyl)-N'-(4-isopropylphenyl)guanidine; [0080]
N-(4-methylbenzoyl)-1-[7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline]ca-
rboximidamide; [0081]
N-(4-methylbenzoyl)-1-(1,2,3,4-tetrahydroquinoline)carboximidamide;
[0082] N-(4-methylbenzoyl)-N'-(2,5-dibromophenyl)guanidine; [0083]
N-(4-methylbenzoyl)-N'-(4-isopropoxyphenyl)guanidine; [0084]
N-(4-methylbenzoyl)-N'-(3,4,5-trimethoxyphenyl)guanidine; [0085]
N-(4-methylbenzoyl)-N'-(2-isopropylphenyl)guanidine; [0086]
N-(2,5-dichlorobenzoyl)-N'-methyl-N'-(3-iodophenyl)guanidine;
[0087] N-(2,5-dichlorobenzoyl)-
N'-methyl-N'-(3-methylthiophenyl)guanidine; [0088]
N-(2,5-dichlorobenzoyl)-N'-(1-naphthyl)guanidine; [0089]
N-(2,5-dichlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0090]
N-(2,5-dichlorobenzoyl)-N'-(4-isopropylphenyl)guanidine; [0091]
N-(2,5-dichlorobenzoyl)-N'-(4-tertbutylphenyl)guanidine; [0092]
N-(2,5-dichlorobenzoyl)-1-indolinylcarboximidamide; [0093]
N-(2,5-dichlorobenzoyl)-N'-methyl-N'-(4-isopropylphenyl)guanidine;
[0094] N-(phenylacetyl)-N'-(4-benzyloxyphenyl)guanidine; [0095]
N-(phenylacetyl)-N'-(4-isopropylphenyl)guanidine; [0096]
N-(phenylacetyl)-N'-(4-tert-butylphenyl)guanidine; [0097]
N-(phenylacetyl)-1-indolinylcarboximidamide; [0098]
N-(phenylacetyl)-1-(1,2,3,4-tetrahydroquinoline)carboximidamide;
[0099] N-(phenylacetyl)-N'-(4-isopropoxyphenyl)guanidine; [0100]
N-(phenylacetyl)-N'-(4-isopropylphenyl)-N'-methylguanidine; [0101]
N-(adamantan-1-carbonyl)-N'-methyl-N'-(3-iodophenyl)guanidine;
[0102] N-(adamantan-1-carbonyl)-N'-(1-naphthyl)guanidine; [0103]
N-(adamantan-1-carbonyl)-N'-(4-benzyloxyphenyl)guanidine; [0104]
N-(adamantan-1-carbonyl)-N'-(4-isopropylphenyl)guanidine; [0105]
N-(adamantan-1-carbonyl)-N'-(4-tert-butylphenyl)guanidine; [0106]
N-(adamantan-1-carbonyl)-1-(indolinyl)carboximidamide; [0107]
N-(adamantan-1-carbonyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0108] N-(adamantan-1-carbonyl)-N'-(2,5-dibromophenyl)guanidine;
[0109]
N-(adamantan-1-carbonyl)-N'-(4-isopropylphenyl)-N'-methyl)guanidi-
ne; [0110]
N-(4-chlorobenzoyl)-N'-methyl-N'-(3-iodophenyl)guanidine; [0111]
N-(4-chlorobenzoyl)-N'-methyl-N'-(3-methylthiophenyl)guanidine;
[0112] N-(4-chlorobenzoyl)-N'-(1-naphthyl)guanidine; [0113]
N-(4-chlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0114]
N-(4-chlorobenzoyl)-N'-(4-isopropylphenyl)guanidine; [0115]
N-(4-chlorobenzoyl)-N'-(4-tert-butylphenyl)guanidine; [0116]
N-(4-chlorobenzoyl)-1-(indolinyl)carboximidamide; [0117]
N-(4-chlorobenzoyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0118] N-(4-chlorobenzoyl)-N'-(2,5-dibromophenyl)guanidine; [0119]
N-(3,4-dichlorobenzoyl)-N'-methyl-N'-(3-iodophenyl)guanidine;
[0120] N-(3,4-dichlorobenzoyl)-N'-(1-naphthyl)guanidine; [0121]
N-(3,4-dichlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0122]
N-(3,4-dichlorobenzoyl)-N'-(4-isopropylphenyl)guanidine; [0123]
N-(3,4-dichlorobenzoyl)-N'-(4-tert-butylphenyl)guanidine; [0124]
N-(3,4-dichlorobenzoyl)-1-(indolinyl)carboximidamide; [0125]
N-(3,4-dichlorobenzoyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0126]
N-(3,4-dichlorobenzoyl)-N'-methyl-N'-(4-isopropylphenyl)guanidine-
; [0127]
N-(thiophen-2-carbonyl)-N'-methyl-N'-(3-iodophenyl)guanidine;
[0128]
N-(thiophen-2-carbonyl)-N'-methyl-N'-(3-methylthiophenyl)guanidin-
e; [0129] N-(thiophen-2-carbonyl)-N'-(1-naphthyl)guanidine; [0130]
N-(thiophen-2-carbonyl)-N'-(4-benzyloxyphenyl)guanidine; [0131]
N-(thiophen-2-carbonyl)-N'-(4-isopropylphenyl)guanidine; [0132]
N-(thiophen-2-carbonyl)-N'-(4-tert-butylphenyl)guanidine; [0133]
N-(thiophen-2-carbonyl)-1-(indolinyl)carboximidamide; [0134]
N-(thiophen-2-carbonyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0135]
N-(thiophen-2-carbonyl)-N'-methyl-N'-(4-isopropylphenyl)guanidine-
; [0136] N-(furan-2-carbonyl)-N'-methyl-N'-(3-iodophenyl)guanidine;
[0137]
N-(furan-2-carbonyl)-N'-methyl-N'-(3-methylthiophenyl)guanidine;
[0138] N-(furan-2-carbonyl)-N'-(1-naphthyl)guanidine; [0139]
N-(furan-2-carbonyl)-N'-(4-benzyloxyphenyl)guanidine; [0140]
N-(furan-2-carbonyl)-N'-(4-isopropylphenyl)guanidine; [0141]
N-(furan-2-carbonyl)-N'-(4-tert-butylphenyl)guanidine; [0142]
N-(furan-2-carbonyl)-1-(indolinyl)carboximidamide; [0143]
N-(furan-2-carbonyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0144]
N-(furan-2-carbonyl)-N'-(4-isopropylphenyl)-N'-methylguanidine;
[0145] N-(pyrdin-3-carbonyl)-N'-(1-naphthyl)guanidine; [0146]
N-(pyridin-3-carbonyl)-N'-(4-benzyloxyphenyl)guanidine; [0147]
N-(pyridin-3-carbonyl)-N'-(4-isopropylphenyl)guanidine; [0148]
N-(pyridin-3-carbonyl)-N'-(4-tert-butylphenyl)guanidine; [0149]
N-(pyridin-3-carbonyl)-1-(indolinyl) carboximidamide; [0150]
N-(pyridin-3-carbonyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
[0151] N-(4-methoxybenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0152]
N-(4-methoxybenzoyl)-N'-(4-isopropylphenyl)guanidine; [0153]
N-(4-methoxybenzoyl)-N'-(4-isopropoxyphenyl)guanidine; [0154]
N-(4-methoxybenzoyl)-N'-(3,4,5-trimethoxyphenyl)guanidine; [0155]
N-(1-naphthoyl)-N'-(4-benzyloxyphenyl)guanidine; [0156]
N-(1-naphthoyl)-N'-(4-isopropylphenyl)guanidine; [0157]
N-(1-naphthoyl)-N'-(4-isopropoxyphenyl)guanidine; [0158]
N-(3,4,5-trimethoxybenzoyl)-N'-(2-isopropylphenyl)guanidine; [0159]
N-(3,4,5-trimethoxybenzoyl)-N'-(4-isopropoxyphenyl)guanidine;
[0160] N-(4-butoxybenzoyl)-N'-(2-isopropylphenyl)guanidine; [0161]
N-(4-butoxybenzoyl)-N'-(4-isopropoxyphenyl)guanidine; [0162]
N-(4-butoxybenzoyl)-N'-(3,4,5-trimethoxyphenyl)guanidine; [0163]
N-(4-ethoxybenzoyl)-N'-(2-isopropylphenyl)guanidine; [0164]
N-(4-ethoxybenzoyl)-N'-(4-isopropoxyphenyl)guanidine; [0165]
N-(4-methylbenzoyl)-N'-(benzyl)guanidine; [0166]
N-(4-methylbenzoyl)-N'-(2-phenethyl)guanidine; [0167]
N-(4-methylbenzoyl)-N'-(3-dimethylaminopropyl)guanidine; [0168]
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)guanidine; [0169]
N-(4-methylbenzoyl)-N'-(3-phenylpropyl)guanidine; [0170]
N-(4-methylbenzoyl)-N'-(1-naphthylmethyl)guanidine; [0171]
N-(4-methylbenzoyl)-N'-(2-(4-chlorophenyl)ethyl)guanidine; [0172]
N-(4-methylbenzoyl)-N'-(5-phenylpentyl)guanidine; [0173]
N-(4-methylbenzoyl)-N'-(3-phenoxypropyl)guanidine; [0174]
N-(3,4-dichlorobenzoyl)-N'-(benzyl)guanidine; [0175]
N-(3,4-dichlorobenzoyl)-N'-(3-phenylpropyl)guanidine; [0176]
N-(4-chlorobenzoyl)-N'-(benzyl)guanidine; [0177]
N-(4-chlorobenzoyl)-N'-(2-phenethyl)guanidine; [0178]
N-(4-chlorobenzoyl)-N'-(4-phenylbutyl)guanidine; [0179]
N-(4-methoxybenzoyl)-N'-(benzyl)guanidine; [0180]
N-(4-methoxybenzoyl)-N'-(3-dimethylaminopropyl)guanidine; [0181]
N-(4-methoxybenzoyl)-N'-(2-phenethyl)guanidine; [0182]
N-(4-methoxybenzoyl)-N'-(4-phenylbutyl)guanidine; [0183]
N-(4-methoxybenzoyl)-N'-(2-(4-chlorophenylethyl)guanidine; [0184]
N-(4-methoxybenzoyl)-N'-(1-naphthylmethyl)guanidine; [0185]
N-(4-methoxybenzoyl)-N'-(3,4,5-trimethoxybenzyl)guanidine; [0186]
N-(4-ethoxybenzoyl)-N'-(4-phenylbutyl)guanidine; [0187]
N-(4-ethoxybenzoyl)-N'-(2-phenethyl)guanidine; [0188]
N-(4-ethoxybenzoyl)-N'-(2-(4-chlorophenyl)ethyl)guanidine; [0189]
N-(4-ethoxybenzoyl)-N'-(3-phenylpropyl)guanidine; [0190]
N-(4-ethoxybenzoyl)-N'-(1-naphthylmethyl)guanidine; [0191]
N-(4-butoxybenzoyl)-N'-(4-phenylbutyl)guanidine; [0192]
N-(4-butoxybenzoyl)-N'-(2-phenethyl)guanidine; [0193]
N-(4-butoxybenzoyl)-N'-(2-(4-chlorophenyl)ethyl)guanidine; [0194]
N-(4-butoxybenzoyl)-N'-(3-phenylpropyl)guanidine; [0195]
N-(4-butoxybenzoyl)-N'-(2-(3-indole)ethyl)guanidine; [0196]
N-(3,4,5-trimethoxybenzoyl)-N'-(4-phenylbutyl)guanidine; [0197]
N-(3,4,5-trimethoxybenzoyl)-N'-(2-(3-indole)ethyl)guanidine; [0198]
N-(3,4,5-trimethoxybenzoyl)-N'-(2-phenylethyl)guanidine; [0199]
N-(1-naphthoyl)-N'-(benzyl)guanidine; [0200]
N-(1-naphthoyl)-N'-(3-dimethylaminopropyl)guanidine; [0201]
N-(1-naphthoyl)-N'-(2-phenylethyl)guanidine; [0202]
N-(1-naphthoyl)-N'-(4-phenylbutyl)guanidine; [0203]
N-(thiophen-2-carbonyl)-N'-(benzyl)guanidine; [0204]
N-(thiophen-2-carbonyl)-N'-(3-dimethylaminopropyl)guanidine; [0205]
N-(thiophen-2-carbonyl)-N'-(2-phenylethyl)guanidine; [0206]
N-(thiophen-2-carbonyl)-N'-(4-phenylbutyl)guanidine; [0207]
N-(4-methylbenzoyl)-N'-(cyclohexyl)-N''-methylguanidine; [0208]
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)-N''-methylguanidine; [0209]
N-(4-methoxybenzoyl)-N'-(5-phenylpentyl)guanidine; [0210]
N-(2-methylbenzoyl)-N'-(4-phenylbutyl)guanidine; [0211]
N-(2-methylbenzoyl)-N'-(2-isopropylphenyl)guanidine; [0212]
N-(2-methylbenzoyl)-N'-(4-isopropylphenyl)guanidine; [0213]
N-(2-methylbenzoyl)-N'-(3-phenylpropyl)guanidine; [0214]
N-(4-methoxybenzoyl)-N'-(2-phenoxypropyl)guanidine; [0215]
N-(4-butoxybenzoyl)-N'-(5-phenylpentyl)guanidine; [0216]
N-(4-methylbenzoyl)-N'-(2-phenoxyethyl)guanidine; [0217]
N-(4-methoxybenzoyl)-N'-(2-phenoxyethyl)guanidine; [0218]
N-(4-ethoxybenzoyl)-N'-[(2-benzylthio)ethyl]guanidine; [0219]
N-(4-ethoxybenzoyl)-N'-(3,4,5-trimethoxyphenyl)guanidine; [0220]
and pharmaceutically acceptable salts thereof.
[0221] Additional specifically preferred compounds of the invention
include the following: [0222]
N-(2-methylbenzoyl)-N'-(2-isopropylphenyl)guanidine; [0223]
N-(2-methylbenzoyl)-N'-(4-isopropylphenyl)guanidine; [0224]
N-(4-ethoxybenzoyl)-N'-(3,4,5-trimethoxyphenyl)guanidine; [0225]
N-benzoyl-N'-(4-isopropylphenyl)guanidine; [0226]
N-benzoyl-N'-(4-isopropoxyphenyl)guanidine; [0227]
N-benzoyl-N'-(4-benzyloxyphenyl)guanidine; [0228]
N-benzoyl-N'-(2-isopropylphenyl)guanidine; [0229]
N-(2,6-dichlorophenacetyl)-N'-(4-benzyloxyphenyl)guanidine; [0230]
N-(2,6-dichlorophenacetyl)-N'-(phenyl)guanidine; [0231]
N-(2,6-dichlorophenacetyl)-N'-(4-isopropyl)phenylguanidine; [0232]
N-(2,6-dichlorophenacetyl)-1-(indolinyl)carboxamidamide; [0233]
N-(2-chlorobenzoyl)-N'-(4-isopropyl)phenylguanidine; [0234]
N-(2-chlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0235]
N-(2-chlorobenzoyl)-1-(indolinyl)carboxamidamide; [0236]
N-(2,6-dichlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0237]
N-(2,6-dichlorobenzoyl)-N'-(2-isopropylphenyl)guanidine; [0238]
N-(2,6-dichlorobenzoyl)-N'-(4-isopropylphenyl)guanidine; [0239]
N-(2,6-dichlorobenzoyl)-1-(indolinyl)carboxamidamide; [0240]
N-(2,6-dichlorobenzoyl)-N'-(trimethoxyphenyl)guanidine; [0241]
N-(2,3-dichlorobenzoyl)-N'-(4-isopropyl)phenylguanidine; [0242]
N-(2,3-dichlorobenzoyl)-1-(indolinyl)carboxamidamide; [0243]
N-(2,3-dichlorobenzoyl)-N'-(4-benzyloxyphenyl)guanidine; [0244]
N-(4-methoxybenzoyl)-N'-(5-phenylpentyl)guanidine; [0245]
N-(2-methylbenzoyl)-N'-(4-phenylbutyl)guanidine; [0246]
N-(2-methylbenzoyl)-N'-(3-phenylpropyl)guanidine; [0247]
N-(4-methoxybenzoyl)-N'-(3-phenoxypropyl)guanidine; [0248]
N-(4-butoxybenzoyl)-N'-(4-phenylbutyl)guanidine; [0249]
N-(4-methoxybenzoyl)-N'-(3-phenoxyethyl)guanidine; [0250]
N-(4-ethoxybenzoyl)-N'-(3-benzylthioethyl)guanidine; [0251]
N-benzoyl-N'-(4-phenylbutyl)guanidine; [0252]
N-benzoyl-N'-(3-phenoxypropyl)guanidine; [0253]
N-benzoyl-N'-(3,4,5-trimethoxybenzyl)guanidine; [0254]
N-benzoyl-N'-(2-benzylthioethyl)guanidine; [0255]
N-(4-methylbenzoyl)-N'-[(indol-3-yl)-2-ethyl]guanidine; [0256]
N-(4-chlorobenzoyl)-N'-[(indol-3-yl)-2-ethyl]guanidine; [0257]
N-(1-naphthoyl)-N'-[(indol-3-yl)-2-ethyl]guanidine; [0258]
N-(thiophen-2-carbonyl)-N'-[(indol-3-yl)-2-ethyl]guanidine; [0259]
N-(4-methylbenzoyl)-N'-butylguanidine; [0260]
N-(furan-2-carbonyl)-N'-(3-phenylpropyl)guanidine; [0261]
N-(4-methylbenzoyl)-N'-(2-benzylthioethyl)guanidine; [0262]
N-(4-methylbenzoyl)-N'-(1-indanyl)guanidine; [0263]
N-(N-(4-chlorobenzoyl)-N'-(1-indanyl)guanidine; [0264]
N-(3,4-dichlorobenzoyl)-N'-(1-indanyl)guanidine; [0265]
N-(1-naphthoyl)-N'-[(imidazol-1-yl)-3-propyl]guanidine; [0266]
N-(furan-2-carbonyl)-N'-[(imidazol-1-yl)-3-propyl]guanidine; [0267]
N-(4-chlorobenzoyl)-N'-(2-benzylthioethyl)guanidine; [0268]
N-(3,4-dichlorobenzoyl)-N'-(2-benzylthioethyl)guanidine; [0269]
N-(1-naphthoyl)-N'-(2-benzylthioethyl)guanidine; [0270]
N-(thiophen-2-carbonyl)-N'-(2-benzylthioethyl)guanidine; [0271]
N-(4-methylbenzoyl)-N'-[(thiophen-2-yl)-2-ethyl]guanidine; [0272]
N-(3,4-dichlorobenzoyl)-N'-[(thiophen-2-yl)-2-ethyl]guanidine;
[0273] N-(3
4,5-trimethoxybenzoyl)-N'-[(thiophen-2-yl)-2-ethyl]guanidine;
[0274] N-(furan-2-carbonyl)-N'-[(thiophen-2-yl)-2-ethyl]guanidine;
[0275]
N-(thiophen-2-carbonyl)-N'-[(thiophen-2-yl)-2-ethyl]guanidine;
[0276] N-(2,3-dichlorobenzoyl)-N'-(4-phenylbutyl]guanidine; [0277]
N-(2,5-dichlorobenzoyl)-N'-(4-phenylbutyl]guanidine; [0278]
N-(2,6-dichlorobenzoyl)-N'-(4-phenylbutyl]guanidine; [0279]
N-(2,6-dichlorophenylacetyl)-N'-benzylguanidine; [0280]
N-(4-methylbenzoyl)-N'-(2-phenoxyethylguanidine; [0281]
N-(benzoyl)-N'-[indol-3-yl-2-yl]guanidine; [0282]
N-(1-naphthoyl)-N'-(4-chlorobenzyl)guanidine; and [0283]
N-(3,4-dichlorobenzoyl)-N'-[(imidazol-1-yl)-3-propyl]guanidine;
[0284] and pharmaceutically acceptable salts thereof.
[0285] Compounds of the invention can be suitably prepared by one
or more of several routes which are generally depicted in the
following Scheme. ##STR13##
[0286] More specifically, as generally depicted in "Route a" above,
compounds of the invention can be prepared by reaction of a
suitable amine precursor compound with a suitable substituted
cyanamide compound that provides the desired R group of compounds
of Formulae I through X as well as Formulae I' through X'.
[0287] Suitable amine precursor compounds include e.g. a
substituted or unsubstituted aromatic amine, a substituted or
unsubstited arylalkylamine, a substituted or unsubstituted
indolinyl (or derivative thereof compound to prepare compounds of
Formula II or II', substituted or unsubstituted
1,2,3,4-tetrahydroquinolinyl (or derivative thereof compound to
prepare compounds of Formula III or III', or an optionally
substituted benz[cd]indolinyl compound, optionally substituted
5,6-dihydrophenanthridinyl compound, optionally substituted
2,3,4,5-tetrahydro-[1,5]-benzothiazepine compounds (or derivative
thereof, e.g. where Y is other atom),
2a,3,4,5-tetrabenz[cd]indoline compound,
5,6,11,12-tetrahydrodiben[b,f]azocine compound, etc. to prepare
compounds of Formulae III through X as well as Formulae III'
through X'. A secondary amine can be employed to prepare compounds
of Formulae I and I' where R.sup.2 is other than hydrogen. For
example, an N-methylaniline or other N-alkylaniline can be employed
to provide an alkyl R.sup.2 substituent for compounds of Formulae I
and I'.
[0288] Suitable cyanamide compounds will include aryloylcyanamide
compounds (i.e. aryl(C.dbd.O)NHCN) such as substituted or
unsubstituted benzoylcyanamide and the like; an arylalkanoyl
cyanamide such as substituted or unsubstituted
phenylacetylcyanamide (C.sub.6H.sub.5COCH.sub.2NHCN) and the like;
a cyclic alkanoyl cyanamide such as admantancarbonylcyanamide and
the like; or a heteroaromatic(carbonyl) cyanamide or a
heteroalicyclic(carbonyl) cyanamide such as
(2-thiophenecarbonyl)cyanamide, (3-thiophenecarbonyl)cyanamide,
(1-furanylcarbonyl)cyanamide, (2-furanylcarbonyl)cyanamide,
(1-pyridylcarbonyl)cyanamide, (2-pyridylcarbonyl)cyanamide,
(3-pyridylcarbonyl)cyanamide,
(1-tetrahydrofuranylcarbonyl)cyanamide,
(2-tetrahydrofuranylcarbonyl)cyanamide and the like; or (for
compounds of Formulae I' through X') an aralkyl, heteroaryl alkyl
or heteroalicyclic alkyl reagant such as e.g. methyl phenylacetate
and the like. See the examples which follow.
[0289] The cyanamide reactants can be readily prepared, e.g. by
reaction of the corresponding substituted carbonylchloride reactant
with cyanamide under suitable conditions, e.g. in the presence of
base with stirring at room temperature until reaction completion.
The reaction solution with the thus formed substituted cyanamide
then can be neutralized and the product isolated by standard
procedures. See the Examples which follow for exemplary
conditions.
[0290] Typically a salt (e.g. an HCl salt) of the amine precursor
compound is reacted with the substituted cyanamide reagent. The
amine precursor can be reacted with the substituted cyanamide
reagent in a suitable solvent such as chlorobenzene, toluene or
xylene with heating (e.g. reflux temperature) until reaction
completion, e.g. 2 or more hours.
[0291] As generally depicted in "Route b" above, compounds of the
invention also can be prepared by reaction of a substituted
carbonylisothiourea (RCONHC(.dbd.NH)SCH.sub.3 in above Route b) and
a substituted amine precursor compound, typicially a substituted
aliphatic amine such as a arylallylamine, e.g.
NH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C.sub.6H.sub.5. This "Route
b" is particularly suitable for synthesis of compounds of Formulae
I or II where the substituent X is alkylene.
[0292] The isothiourea reagent can be readily prepared by reaction
of S-methylisothiourea with a desired substituted carbonyl chloride
such as a benzoyl chloride compound in the presence of base and in
a suitable solvent such as aqueous diethyl ether at room
temperature with stirring overnight. For exemplary conditions, see
Example 5, Part I; Example 6, Part I; Example 7, Part I; and
Example 8, Part I, which follow. The thus formed isothiourea
derivative is then reacted with the substituted amine in the
presence of base such as triethylamine in a suitable solvent such
as toluene, chlorobenzene or other aromatic solvent with heating,
e.g. reflux temperature. See Example 5, Part I; Example 6, Part I;
Example 7, Part I; and Example 8, Part I, which follow for
exemplary conditions.
[0293] As generally depicted in "Route c" above, compounds of the
invention that contain an N''-substituent that is other than
hydrogen (i.e. one or both of R.sup.1 in Formulae I through X or
Formulae I' through X' is other than hydrogen) can be suitably
prepared by reaction of a substituted carbimidodithiolate
(RCON.dbd.C(SCH.sub.3).sub.2 in above Route c) and sequential
reactions of substituted amine precursor compounds. The substituted
carbimidodithiolate can be prepared by reaction of a desired
substituted amide compound with carbon disulfide in a suitable
solvent such as tetrahydrofuran and in the presence of base such as
sodium hydride. The isolated substituted carbimidodithiolate
compound is reacted with a slight molar excess of a desired
substituted amine (provides the desired R group). The resultant
thiourea is further reacted with a substituted amine to provide N''
substitution. See Example 9 which follows for exemplary
conditions.
[0294] As discussed above, the present invention includes methods
for treating preventing certain neurological disorders, including
the consequences of stroke, heart attack and traumatic head or
brain injury, epilepsy or neurodegenerative diseases comprising the
administration of an effective amount of one or more compounds of
the invention to a subject including a mammal, such as a primate,
especially a human, in need of such treatment. In particular, the
invention provides methods for treatment and/or prophylaxis of
nerve cell death (degeneration) resulting e.g. from hypoxia,
hypoglycemia, brain or spinal cord ischemia, brain or spinal cord
trauma, stroke, heart attack or drowning. Typical candidates for
treatment include e.g. heart attack, stroke and/or persons
suffering from cardiac arrest neurological deficits, brain or
spinal cord injury patients, patients undergoing major surgery such
as heart surgery where brain ischemia is a potential complication
and patients such as divers suffering from decompression sickness
due to gas emboli in the blood stream. Candidates for treatment
also will include those patients undergoing a surgical procedure
involving extra-corporal circulation such as e.g. a bypass
procedure. Subjects suffering from or susceptible to peripheral
necropathy can be treated in accordance with the invention by
administration of an effective amount of one or more compounds of
Formulae I through X or Formulae I' through X'.
[0295] The invention in particular provides methods for treatment
which comprise administration of one or more compounds of the
invention to a patient that is undergoing surgery or other
procedure where brain or spinal cord ischemia is a potential risk.
For example, carotid endarterectomy is a surgical procedure
employed to correct atherosclerosis of the carotid arteries. Major
risks associated with the procedure include intraoperative
embolization and the danger of hypertension in the brain following
increased cerebral blood flow, which may result in aneurism or
hemorrhage. Thus, an effective amount of one or more compounds of
the present invention could be administered pre-operatively or
peri-operatively to reduce such risks associated with carotid
endarterectomy, or other post-surgical neuorological deficits.
[0296] The invention further includes methods for prophylaxis
against neurological deficits resulting from e.g. coronary artery
bypass graft surgery and aortic valve replacement surgery, or other
procedure involving extra-corporal circulation. Those methods will
comprise administering to a patient undergoing such surgical
procedures an effective amount of one or more compounds of the
invention, typically either pre-operatively or
peri-operatively.
[0297] The invention also provides methods for prophylaxis and
treatment against neurological injury for patients undergoing
myocardial infarction, a procedure that can result in ischemic
insult to the patient. Such methods will comprise administering to
a patient undergoing such surgical procedure an effective amount of
one or more compounds of the invention, typically either
pre-operatively or peri-operatively.
[0298] Also provided are methods for treating or preventing
neuropathic pain such as may experienced by cancer patients,
persons having diabetes, amputees and other persons who may
experience neuropathic pain. These methods for treatment comprise
administration of an effective amount of one or more compounds of
the invention to a patient in need of such treatment.
[0299] The invention also provides methods for treatment and
prophylaxis against retinal ischemia or degeneration and resulting
visual loss. For example, a compound of the invention can be
administered parenterally or by other procedure as described herein
to a subject a suffering from or susceptible to ischemic insult
that may adversely affect retinal function, e.g., significantly
elevated intraocular pressures, diseases such as retinal artery or
vein occlusion, diabetes or other ischemic ocular-related diseases.
Post-ischemic administration also may limit retinal damage. The
invention also includes methods for treating and prophylaxis
against decreased blood flow or nutrient supply to retinal tissue
or optic nerve, or treatment or prophylaxis against retinal trauma
or optic nerve injury. Subjects for treatment according to such
therapeutic methods of the invention may be suffering or
susceptible to retinal ischemia that is associated with
atherosclerosis, venous capillary insufficiency, obstructive
arterial or venous retinopathies, senile macular degeneration,
cystoid macular edema or glaucoma, or the retinal ischemia may be
associated with a tumor or injury to the mammal. Intravitreal
injection of a compound of the invention also may be a preferred
administration route to provide more direct treatment to the
ischemic retina.
[0300] The invention also provides methods for treatment of a
subject suffering from shingles as well as treatment of a person
suffering from or susceptible to migraines, particularly to
alleviate the pain and discomfort associated with those disorders.
As discussed above, compounds of the invention are also useful to
treat persons suffering from various types of pain, including
chromic pain. These methods comprise administration of an effective
amount of one or more compounds of the invention to a patient in
need of treatment.
[0301] The invention further provides a method of treating
Korsakoff's disease, a chronic alcoholism-induced condition,
comprising administering to a subject including a mammal,
particularly a human, one or more compounds of the invention in an
amount effective to treat the disease. Compounds of the invention
are anticipated to have utility for the attenuation of cell loss,
hemorrhages and/or amino acid changes associated with Korsakoff's
disease.
[0302] As discussed above, the invention also includes methods for
treating a person suffering from or susceptible to cerebral palsy,
emesis, narcotic withdrawal symptoms and age-dependent dementia,
comprising administering to a subject including a mammal,
particularly a human, one or more compounds of the invention in an
amount effective to treat the condition.
[0303] The invention also includes methods for treatment of
infections, including Gram-negative and Gram-positive bacterial
infections, comprising administering a combination of 1) an
aminoglycoside antibiotic, and 2) a compound of Formulae I, IA, IB,
II, III, IV, V, VI, VII, VIII, IX and/or X as well as Formulae I',
IA', IB', II', III', IV', V', VI', VII', VIII', IX' and/or X' as
defined herein. A wide variety of aminoglycoside antibiotics are
suitable for use in the formulations of the invention. Typically,
suitable aminoglycoside antibiotics contain two or more amino
sugars (aminoglycosides) connected to an amino-cyclitol nucleus.
Exemplary aminoglycoside antibiotics preferred for use in
formulations of the present invention include clinical agents such
as gentamycin, amikacin, kanamycin, streptomycin, paromoycin,
neomycin, netilmicin and tobramycin. Other suitable aminoglycosides
include seldomycins, sisomycins, aurimycin, lividomycins,
streptothricins, hybrimycins, coralinomycin, butirosin,
strepomutins, nebramycins, tenebrimycins, ribostamycins,
destomycins, trehalosamines, myomycins, fortimicins, mutamicins and
kasugamycin. Suitable aminoglycoside antibiotics are also disclosed
in U.S. Pat. Nos. 5,508,269; 4,645,760; and 4,380,625. It should be
appreciated however that the present invention is not limited by
any particular aminoglycoside antibiotic, and the invention is
applicable to any aminoglycoside antibiotic now known or
subsequently discovered or developed. The aminoglycoside and one or
more compounds of the invention may be administered simultaneously,
in the same or different pharmaceutical formulations, or
sequentially. Preferably, the components of the combination are
administered substantially simultaneously, e.g. in a unitary
pharmaceutical composition containing the two components. Preferred
methods and compositions that comprise an aminoglycoside in
combination with a compound of the invention will be effective
against infections previously treated with aminoglycoside
antibiotics, but with the significant advantage of decreased
occurrence of ototoxicity relative to use of an aminoglycoside
antibiotic alone.
[0304] As discussed above, preferred compounds of the invention in
a standard anticonvulsant in vivo audiogenic test, such as the
audiogenic mouse assay of Example 11 which follows, where DBA/2
mice about 20-23 days old are injected intraperitoneally with a
test compound 30 minutes prior to being placed in a bell jar with
exposure to auditory stimulus of 12 KHz sine wave at 110-120 db.
References herein in vivo "audiogenic assay" are intended to refer
to that protocol. Generally preferred compounds exhibit 20% or more
inhibition (relative to subjects treated with vehicle control only)
at a dose of 20 mg/kg, more preferably about 50% or more inhibition
at a dose of 20 mg/kg in such an in vivo audiogenic assay. As
discussed above, activity in the audiogenic assay has been
recognized as indicative that a test compound has neuroprotective
properties. See, e.g., M. Tricklebank et al., European Journal of
Pharmacology, supra; T. Seyfried, Federation Proceedings,
supra.
[0305] The invention also provides methods for determining binding
activity of compounds of the invention as well as in vitro and in
vivo binding activity diagnostic methods using one or more
radiolabelled compounds of the invention, e.g., a compound of the
invention that is labeled with .sup.125I, tritium, .sup.32P,
.sup.99Tc, or the like, preferably .sup.125I. For instance, a
compound of the invention having a phenyl or other aryl substituent
that is ring substituted with one or more .sup.125I groups can be
administered to a mammal and the subject then scanned for binding
of the compound. Specifically, single photon emission computed
tomography ("SPECT") can be employed to detect such binding. Such
an analysis of the mammal could e.g. aid in the diagnosis and
treatment of acute cerebral ischemia. That is, a labeled compound
of the invention will selectively bind to ischemic tissue of e.g. a
subject's brain to differentiate between ischemic and non-ischemic
tissue and thereby assess trauma or other injury to the brain.
[0306] Accordingly, the invention includes compounds of the
invention that contain a radiolabel such as .sup.125I, tritium,
.sup.32P, .sup.99Tc, or the like, preferably .sup.125I. Such
radiolabelled compounds can be suitably prepared by procedures
known in the synthesis art. For example, a compound of the
invention having an aromatic group, such as phenyl, that has a
bromo or chloro ring substituent can be employed in an exchange
labeling reaction to provide the corresponding compound having an
.sup.125I ring substituent.
[0307] Compounds of the invention may be used in therapy in
conjunction with other medicaments. For example, for treatment of a
stroke victim or a person susceptible to stroke, one or more
compounds of Formula I may be suitably administered together with a
pharmaceutical targeted for interaction in the blood clotting
mechanism such as streptokinase, tPA, urokinase and other agents
that lyse clots. Also, one or more compounds of the invention may
be administered together with agents such as heparin and related
heparin-based compounds, acenocoumarol or other known
anticoagulants.
[0308] The compounds of this invention can be administered
intranasally, orally or by injection, e.g., intramuscular,
intraperitoneal, subcutaneous or intravenous injection, or by
transdermal, intraocular or enteral means. The optimal dose can be
determined by conventional means. Compounds of the invention are
suitably administered to a subject in the protonated and
water-soluble form, e.g., as a pharmaceutically acceptable salt of
an organic or inorganic acid, e.g., hydrochloride, sulfate,
hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate,
maleate, mesylate, etc.
[0309] Compounds of the invention can be employed, either alone or
in combination with one or more other therapeutic agents as
discussed above, as a pharmaceutical composition in mixture with
conventional excipient, i.e., pharmaceutically acceptable organic
or inorganic carrier substances suitable for parenteral, enteral or
intranasal application which do not deleteriously react with the
active compounds and are not deleterious to the recipient thereof.
Suitable pharmaceutically acceptable carriers include but are not
limited to water, salt solutions, alcohol, vegetable oils,
polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, petroethral fatty acid
esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds.
[0310] For parenteral application, particularly suitable are
solutions, preferably oily or aqueous solutions as well as
suspensions, emulsions, or implants, including suppositories.
Ampules are convenient unit dosages.
[0311] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
[0312] For topical applications, formulations may be prepared in a
topical ointment or cream containing one or more compounds of the
invention. When formulated as an ointment, one or more compounds of
the invention suitably may be employed with either a paraffinic or
a water-miscible base. The one or more compounds also may be
formulated with an oil-in-water cream base. Other suitable topical
formulations include e.g. lozenges and dermal patches.
[0313] Intravenous or parenteral administration, e.g.,
sub-cutaneous, intraperitoneal or intramuscular administration are
preferred. The compounds of this invention are particularly
valuable in the treatment of mammalian subjects, e.g., humans, to
provide neuroprotective therapy and/or prophylaxis. Typically, such
subjects include those afflicted with neurodegenerative diseases
such as Parkinson's disease, Huntington's disease, Amyotrophic
Lateral Sclerosis, Alzheimer's disease, Down's Syndrome and
Korsakoff's disease. Also suitable for treatment are those subjects
suffering from or likely to suffer from nervous system dysfunctions
resulting from, for example, epilepsy or nerve cell degeneration
which is the result of hypoxia, hypoglycemia, brain or spinal chord
ischemia or brain or spinal chord trauma. As discussed above,
typical candidates for treatment include heart attack, stroke,
brain or spinal cord injury patients, patients undergoing major
surgery where brain or spinal cord ischemia is a potential
complication and patients such as divers suffering from
decompression sickness due to gas emboli in the blood stream.
[0314] It will be appreciated that the actual preferred amounts of
active compounds used in a given therapy will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, the particular site of
administration, etc. Optimal administration rates for a given
protocol of administration can be readily ascertained by those
skilled in the art using conventional dosage determination tests
conducted with regard to the foregoing guidelines. In general, a
suitable effective dose of one or more compounds of the invention,
particularly when using the more potent compound(s) of the
invention, will be in the range of from 0.01 to 100 milligrams per
kilogram of bodyweight of recipient per day, preferably in the
range of from 0.01 to 20 milligrams per kilogram bodyweight of
recipient per day, more preferably in the range of 0.05 to 4
milligrams per kilogram bodyweight of recipient per day. The
desired dose is suitably administered once daily, or several
sub-doses, e.g. 2 to 4 sub-doses, are administered at appropriate
intervals through the day, or other appropriate schedule. Such
sub-doses may be administered as unit dosage forms, e.g.,
containing from 0.05 to 10 milligrams of compound(s) of the
invention, per unit dosage, preferably from 0.2 to 2 milligrams per
unit dosage.
[0315] Compounds of the invention also should be useful as rubber
accelerators. See U.S. Pat. No. 1,411,713 for a discussion of
rubber accelerator applications.
[0316] The entire text of all documents cited herein are
incorporated by reference herein. The following non-limiting
examples are illustrative of the invention.
General Comments
[0317] Melting points were determined in open capillary tubes on a
Mel-Temp II apparatus and are uncorrected. Yields are of isolated
products and were not optimized. .sup.1H-NMR were run on a Varian
Gemini 300 MHz spectrophotometer and the chemical shifts were
reported in ppm (.delta.) relative to the residual signal of
deutrated solvent (CHD.sub.2OD 3.30, CDCl.sub.3 7.26). HPLC purity
determinations were carried out using a Beckman 126 gradient system
with UV detection at 220 nm. Linear 30 minutes gradient:2 to 98%
CH.sub.3CN in H.sub.2O (0.1% TFA) Column: Ultrasphere ODS (AC-2)
Smm 4.6.times.250 mm with C-18 guard column, flow rate 1
ml/min.
EXAMPLE 1
Synthesis of N-(4-methylbenzoyl)-N'-(4-isopropylphenyl)guanidine,
hydrochloride (Formula I: hydrochloride salt of
R=4-CH.sub.3C.sub.6H.sub.4; each R.sup.1.dbd.R.sup.2.dbd.H;
X=chemical bond; R.sup.3=4-isopropylphenyl)
Part I: 4-methylbenzoylcyanamide
[0318] ##STR14##
[0319] To a solution of cyanamide (1.05 g, 0.025 mmol) in 25 ml of
sodium hydroxide (10%) was added slowly to a solution of
4-methylbenzoyl chloride (3.3 ml, 0.025 mmol) in ether (8 ml). The
reaction mixture was stirred at room temperature for 1 hour. The
reaction mixture then was cooled in ice bath and acidified with
hydrochloric acid (10%) to pH 2. The white solid separated was
filtered, washed with water, later hexanes and dried under high
vacuum to give the N-(4-methylbenzoyl)cyanamide (3.4 g); m.p.
140-142.degree. C. (lit m.p. 149-150.degree. C.); purity 88% HPLC;
.sup.1H-NMR (CD.sub.3OD) .delta. 2.42 (s, 3H, CH3), 7.38 (d, 2H,
ArH), 7.78 (d, 2H, ArH).
Part II: N-(4-methylbenzoyl)-N'-(4-isopropylphenyl)guanidine,
hydrochloride
[0320] ##STR15##
[0321] A mixture of N-(4-methylbenzoylcyanamide) (160 mg, 1 mmol)
and 4-isopropylaniline.hydrochloride (185 mg [prepared from
4-isopropylaniline and hydrogen chloride (1M in ether)]) in toluene
(4 ml) was refluxed for 3 hours. The reaction mixture was cooled to
room temperature, the precipitated white solid was filtered, washed
with toluene and finally with hexanes to afford the title product,
(268 mg, 78%); m.p. 208-210.degree. C.; purity 99.3% (HPLC);
.sup.1H-NMR (CD.sub.3OD) .delta. 1.28 (2s, 6H, CH.sub.3), 2.42 (s,
3H; Ar--CH.sub.3); 3.02 (m, 1H, CH), 7.38 (d, 2H, ArH), 7.42 (m,
4H, ArH), 8.0 (d, 2H, ArH).
EXAMPLE 2
Preparation of N-(1-adamantancarbonyl)-1-indolinylcarboxamidine,
hydrochloride ((Formula II: hydrochloride salt of R=1-adamantyl;
each R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.H)
Part I: Adamantancarbonylcyanamide
[0322] ##STR16##
[0323] To a solution of cyanamide (2.52 g, 0.06 mol) in 24 ml of
sodium hydroxide (10%) was added slowly to a solution of
1-adamantanecarbonylchloride (4g, 0.02 mol) in ether (15 ml). The
reaction mixture was stirred at room temperature overnight. The
reaction mixture was extracted with ether and the aqueous layer was
cooled in ice bath and acidified with hydrochloric acid (10%) to pH
2. The precipitated white solid was filtered, washed with water,
later hexanes and dried under high vacuum to give the
N-(1-adamantancarbonyl)cyanamide (3.2 g, 78%); m.p. 164-166.degree.
C. (lit m.p. 168-170.degree. C.); purity 94% HPLC; .sup.1H-NMR
(CD.sub.3OD) .delta. 1.45-2.16 (m, 15H, CH.sub.2 and CH).
Part II: N-(1-adamantancarbonyl)-1-indolinylcarboxamidine,
hydrochloride
[0324] ##STR17##
[0325] A mixture of N-(1-adamantanecarbonyl)cyanamide (200 mg, 0.88
mmol) and indoline hydrochloride (155 mg [prepared from indoline
and hydrogen chloride (1M in ether)]) in toluene (4 ml) was
refluxed for 3 hours. The reaction mixture was cooled to room
temperature, the precipitated white solid was filtered, washed with
toluene and finally with hexanes to afford the title product, (339
mg, 78%); m.p. 252-256.degree. C.; Purity 99% (HPLC); .sup.1H-NMR
(CD.sub.3OD) .delta. 1.65 (m, 15H, CH.sub.2 and CH), 3.2 (t, 2H,
ArCH.sub.2), 4.2 (t, 2H, NCH.sub.2), 7.25 (m, 1H, arH), 7.36 (m,
2H, ArH), 7.42 (m, 1H, ArH).
EXAMPLE 3
Preparation of N-(phenylacetyl)-N'-(4-t-butylphenyl)guanidine,
hydrochloride (Formula I: hydrochloride salt of
R.dbd.C.sub.6H.sub.5; each R.sup.1.dbd.R.sup.2.dbd.H; X=chemical
bond; R.sup.3=4-tert-butylphenyl)
Part I: Phenylacetylcyanamide
[0326] ##STR18##
[0327] This compound was prepared in 83% yield by the method
described in Example 2, Part I above using phenylacetyl chloride in
place of adamantane-1-carbonyl chloride. Phenylacetylcyanamide: a
white solid; purity 92% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta.
2.3 (s, 2H), 7.25-7.45 (m, 5H).
Part II: N-(Phenylacetyl)-N'-(4-t-butylphenyl)guanidine,
hydrochloride
[0328] ##STR19##
[0329] Synthesis of this compound was achieved by the method set
forth in Example 1, Part II above with the use of
phenylacetylcyanamide in place of 4-methylbenzoylcyanamide and
using 4-t-butylaniline hydrochloride instead of 4-isopropylaniline
hydrochloride respectively. Yield 69%; m.p. .182-186.degree. C.;
purity 86% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 1.38 (s, 9H,
CH.sub.3), 3.84 (s, 2H, CH.sub.2), 7.3 (d, 2H, ArH), 7.3-7.45 (m,
5H, ArH), 7.6 (d, 2H, ArH).
EXAMPLE 4
Preparation of
N-(2-thiophenecarbonyl)-N'-(4-benzyloxyphenyl)guanidine,
hydrochloride (Formula I: hydrochloride salt of R=2-thiophenyl;
each R.sup.1.dbd.R.sup.2.dbd.H; X=chemical bond;
R.sup.3=4-C.sub.6H.sub.5CH.sub.2OC.sub.6H.sub.4--)
Part I: (2-Thiophenecarbonyl)cyanamide
[0330] ##STR20##
[0331] This compound was prepared in 73% yield by the method
described in Example 2, Part I above using
2-thiophenecarbonylchloride in place of adamantane-1-carbonyl
chloride. N-(2-thiophenecarbonyl)cyanamide: a white solid; purity
96% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 7.2 (m, 1H), 7.8 (d,
1H), 7.9 (d, 1H).
Part II: N-(2-Thiophenecarbonyl)-N'-(4-benzyloxyphenyl)guanidine,
hydrochloride
[0332] ##STR21##
[0333] Synthesis of this compound was achieved by the method set
forth in Example 1, Part II above with the use of
N-(2-thiophenecarbonyl)cyanamide in place of
N-(4-methylbenzoylcyanamide) and using 4-benzylcyanamide and using
4-benzyloxyaniline hydrochloride instead of 4-isopropylaniline
hydrochloride respectively. Yield 61%; m.p. 198-202.degree. C.;
Purity 93% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 5.18 (s, 2H,
CH.sub.2), 7.18 (d, 2H), 7.22-7.4 (m, 6H), 7.44 (d, 2H), 7.9 (d,
1H), 8.18 (d, 1H).
EXAMPLE 5
Preparation of N-(4-methylbenzoyl)-N'-(4-phenylbutyl)guanidine,
hydrochloride (Formula I: hydrochloride salt of
R=4-CH.sub.3C.sub.6H.sub.4; each R.sup.1.dbd.R.sup.2.dbd.H;
X.dbd.CH.sub.2CH.sub.2CH.sub.2CH.sub.2;
R.sup.3.dbd.C.sub.6H.sub.5)
Part I: N-(4-Methylbenzoyl)-S-methylisothiourea
[0334] ##STR22##
[0335] A solution of 2-methyl-2-thiopseudourea sulfate (6.9 g,
0.025 mol) in 30 ml of sodium hydroxide (4%) was added a solution
of 4-methylbenzoyl chloride (3.4 g, 0.022 mol) in ether (10 ml) at
room temperature. The reaction mixture was stirred overnight and
the precipitated solid was filtered, washed with water, later
hexanes and dried under high vacuum.
N-(4-methylbenzoyl)-S-methylisothiourea: yield 4.60 g
(quantitative); purity 98% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta.
2.4 (s, 3H, CH.sub.3), 2.6 (s, 3H, SMe), 7.2 (d, 2H, ArH), 8.1 (d,
2H, ArH).
Part II: N-(4-methylbenzoyl)-N'-(4-phenylbutyl)guanidine,
hydrochloride
[0336] ##STR23##
[0337] Phenylbutyl amine (0.75 ml, 4.75 mmol) and triethylamine
(0.7 ml, 5 mmol) was added to a suspension of the thiourea
derivative (1.04 g, 5 mmol), prepared in Part I, in touene (10 ml).
The reaction mixture was heated in an oilbath to reflux and
maintained at reflux for 3 hours. The free base separated on
cooling was filtered, washed with hexanes and dried to afford the
solid (1.3 g).
[0338] The free base (1.3 g) was dissolved in methanol (30 ml) and
dichloromethane (25 ml) and cooled in an ice water bath. Hydrogen
chloride (1M in ether, 20 ml) was added, stirred for 30 minutes,
concentrated under reduced pressure.
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)guanidine, hydrochloride:
white solid (1.43 g, 84%); m.p. 166-170.degree. C.; Purity: 99%
(HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 1.74 (m, 4H, CH.sub.2),
2.43 (s, 3H, CH.sub.3), 2.69 (t, 2H, CH.sub.2), 3.38 (t, 2H,
CH.sub.2), 7.2 (m, 5H, ArH), 7.4 (d, 2H, ArH), 7.9 (d, 2H,
ArH).
EXAMPLE 6
Preparation of
N-(4-methoxybenzoyl)-N.alpha.-(4-phenylbutyl)guanidine,
hydrochloride (Formula I: hydrochloride salt of
R=4-CH.sub.3OC.sub.6H.sub.4; each R.sup.1.dbd.R.sup.2.dbd.H;
X.dbd.CH.sub.2CH.sub.2CH.sub.2CH.sub.2;
R.sup.3.dbd.C.sub.6H.sub.5)
Part I: N-(4-Methoxybenzoyl)-S-methylisothiourea
[0339] ##STR24##
[0340] Synthesis of this compound was achieved by the method set
forth in Example 5, Part I above with the use of 4-methoxybenzoyl
chloride in place of 4-methylbenzoyl chloride.
N-(4-methoxybenzoyl)-S-methylisothiourea: white solid (83% yield);
Purity 99% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 2.57 (s, 3H,
SCH.sub.3), 3.86 (s, 3H, OCH3), 6.94 (d, 2H, ArH), 8.15 (d, 2H,
ArH).
Part II: N-(4-Methoxybenzoyl)-N'-(4-phenylbutyl)guanidine,
hydrochloride
[0341] ##STR25##
[0342] Preparation of this compound was carried out by the method
as described in Example 5, Part II above using
4-methoxybenzoyl-S-methylisothiourea in place of
4-methylbenzoyl-S-methylisothiourea.
N-(4-methoxybenzoyl)-N'-(4-phenylbutyl)guanidine, hydrochloride:
white solid (55%); m.p. 172-174.degree. C.; Purity 99% (HPLC);
.sup.1H-NMR (CD.sub.3OD) .delta. 1.74 (m, 4H, CH.sub.2), 2.67 (t,
2H, CH.sub.2), 3.37 (t, 2H, CH.sub.2), 3.89 (s, 3H, OCH3), 7.10 (d,
2H, ArH), 7.22 (m, 5H, ArH), 7.97 (d, 2H, ArH).
EXAMPLE 7
N-(2-thiophenecarbonyl)-N'-(2-phenylethyl)guanidine, hydrochloride
(Formula I: hydrochloride salt of R=2-thiophenyl; each
R.sup.1.dbd.R.sup.2.dbd.H; X.dbd.CH.sub.2CH.sub.2;
R.sup.3.dbd.C.sub.6H.sub.5)
Part I: N-(2-Thiophenecarbonyl)-S-methylisothiourea
[0343] ##STR26##
[0344] Synthesis of this compound was achieved by the method set
forth in Example 5, Part I above with the use of
2-thiophenecarbonyl chloride in place of 4-methylbenzoyl chloride.
N-(2-thiophenecarbonyl)-S-methylisothiourea: white solid (73%
yield); Purity 91.2% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 2.76
(s, 3H, SCH.sub.3); 7.26 (m, 1H, ArH), 8.01 (d, 1H, ArH), 8.12 (d,
1H, ArH).
Part II: N-(2-Thiophenecarbonyl)-N'-(2-phenylethyl)guanidine,
hydrochloride
[0345] ##STR27##
[0346] Preparation of this compound was carried out by the method
as described in Example 5, Part II above using
N-(2-thiophenecarbonyl)-S-methylisothiourea in place of
4-methylbenzoyl-S-methylisothiourea and 2-phenylethylamine instead
of 4-phenylbutylamine respectively.
N-(2-thiophenecarbonyl)-N'-(2-phenylethyl)guanidine, hydrochloride:
white solid (58%); m.p. 198-200.degree. C.; Purity 97% (HPLC);
.sup.1H-NMR (CD.sub.3OD) .delta. 3.00 (t, 2H, CH.sub.2), 3.65 (t,
2H, CH.sub.2), 7.2 (d, 1H, ArH), 7.28 (m, 5H, ArH), 7.97 (d, 2H,
ArH).
EXAMPLE 8
N-(4-Butoxybenzoyl)-N'-[2-(indol-3-yl)ethyl]guanidine,
hydrochloride (Formula I: hydrochloride salt of
R=4-CH.sub.3(CH.sub.2).sub.3OC.sub.6H.sub.4; each
R.sup.1.dbd.R.sup.2.dbd.H; X.dbd.CH.sub.2CH.sub.2;
R.sup.3=3-indoly)
Part I: N-(4-Butoxybenzoyl)-S-methylisothiourea
[0347] ##STR28##
[0348] This compound was prepared following the method as described
in Example 6, Part I above using 4-butoxybenzoyl chloride in place
of 4-methoxybenzoyl chloride.
N-(4-butoxybenzoyl)-S-methylisothiourea: white solid (85%); Purity
95% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 1.0 (t, 3H, CH.sub.3),
1.50 (m, 2H, CH2), 1.78 (m, 2H, CH2), 2.56 (s, 3H, SCH.sub.3), 4.03
(t, 2H, OCH.sub.2), 6.93 (d, 2H, ArH), 8.14 (d, 2H, ArH).
Part II: N-(4-Butoxybenzoyl)-N'-[2-(indol-3-yl)ethyl]guanidine,
hydrochloride
[0349] ##STR29##
[0350] Preparation of this compound was carried out by the method
as described in Example 5, Part II above using
N-(4-butoxybenzoyl)-S-methylisothiourea in place of
4-methylbenzoyl-S-methylisothiourea and 3-(2-aminoethyl)indole
(tryptamine) instead of 4-phenylbutylamine respectively.
N-(4-butoxybenzoyl)-N'-[2-(indol-3-yl) ethyl]guanidine,
hydrochloride: solid (yield 28%); m.p. 158-162.degree. C.; Purity
95% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta. 0.99 (t, 3H, CH3),
1.49 (m, 2H, CH.sub.2), 1.76 (m, 2H, CH2), 3.28 (t, 2H, CH.sub.2),
3.69 (t, 2H, CH2), 4.05 (t, 2H, CH.sub.2), 7.04 (m, 4H, ArH), 7.2
(d, 1H), 7.32 (d, 1H, ArH), 7.56 (d, 1H, ArH), 7.86 (d, 2H,
ArH).
EXAMPLE 9
N-(4-Methylbenzoyl)-N'-(4-phenylbutyl)-N''-methylguanidine,
hydrochloride (Formula I: hydrochloride salt of
R=4-CH.sub.3C.sub.6H.sub.4; first R.sup.1.dbd.CH.sub.3, second
R.sup.1.dbd.H; R.sup.2.dbd.H;
X.dbd.CH.sub.2CH.sub.2CH.sub.2CH.sub.2;
R.sup.3.dbd.C.sub.6H.sub.5)
Part I: Dimethyl N-(4-methylbenzoylcarbimidodithiolate)
[0351] ##STR30##
[0352] A mixture of 4-methylbenzamide (1.35 g, 0.01 mol) in
anhydrous tetrahydrofuran (50 ml), carbon disulfide (3 g, 0.039
mol), and methyl iodide (4.5 g, 0.032 mol), and sodium hydride
(0.85 g, 60% dispersion in oil, 0.02 mol) was stirred at room
temperature overnight. The reaction mixture was poured onto ice,
extracted with ethyl acetate (3.times.30 ml), washed with water,
dried and concentrated to give an oil. This solidified on standing
and was crystallized from hexanes as bright yellow crystals (0.8
g); m.p. 57-59.degree. C. (lit 60-61.degree. C.); .sup.1H-NMR
(CDCl.sub.3) .delta. 2.40 (s, 3H, Ar--Me), 2.57 (s, 6H, SMe), 7.25
(d, 2H, ArH), 7.98 (d, 2H, ArH).
Part II:
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)-S-Methylthiourea
[0353] ##STR31##
[0354] A mixture of dimethyldithiolate (240 mg, mmol, prepared as
in Part I) and phenybutylamine (150 mg, mmol) in ethanol (5 ml) was
stirred overnight at room temperature. The reaction mixture was
concentrated and the oil obtained was repeatedly coevaporated with
dichloromethane, upon which solid separated. This solid was
triturated with hexanes, filtered and dried.
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)-S-Methylthiourea: white
solid (80 mg); .sup.1H-NMR (CDCl.sub.3) .delta. 1.85 (m, 4H,
CH.sub.2), 2.38 (s; 3H, ArMe), 2.61 (s and t, 5H, CH.sub.2 and
Sme), 3.35 (t, 2H, CH.sub.2), 7.2 (m, 5H, ArH), 7.28 (d, 2H, ArH),
8.12 (d, 2H, ArH).
Part III:
N-(4-Methylbenzoyl)-N'-(4-phenylbutyl)-N''-methylguanidine,
hydrochloride
[0355] ##STR32##
[0356] A solution of
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)-S-Methylthiourea (80 mg,
prepared as in Part II) in 5 ml of methylamine (2M in methanol) was
stirred at room temperature for 48 hours. After removal of the
solvent the residue was dissolved in methanol (3 ml), and a
ethereal solution of hydrogen chloride (5 ml) was added. The solid
separated was filtered, washed with ether and dried. Pale yellow
solid (50 mg); Purity: 93% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta.
1.71 (m, 4H, CH.sub.2), 2.40 (s, 3H, ArCH.sub.3), 2.65 (t, 2H,
CH.sub.2), 3.05 (s, 3H, NMe), 3.4 (t, 2H, CH2), 7.13 (m, 5H, Ar),
7.35 (d, 2H, ArH), 7.82 (d, 2H, ArH).
EXAMPLE 10
N-(2,6-Dichlorophenylacetyl)-N'-benzylguanidine hydrochloride
(Formula I': hydrochloride salt of R=2,6-di-C.sub.6H.sub.3; both
R.sup.1.dbd.H; R.sup.2.dbd.H; X.dbd.CH.sub.2;
R.sup.3.dbd.C.sub.6H.sub.5)
I: Benzylguanidine hydrochloride
[0357] A mixture of benzylamine hydrochloride (4.3g, 0.03 mol) and
cyanamide (1.3g, 0.031 mol) in xylenes (15 ml) was heated to reflux
for 6 hours. After concentration, the reaction mixture was
triturated with ether and the solid separated was filtered and
crystallized from methanol to provide a colorless solid (2.38 g);
purity: 96.8% (HPLC); 1H-NMR (CD3OD) .delta. 4.41 (s, 2H, CH2),
7.32-7.37 (m, 5H, Ar).
Part II: N-(2,6-Dichlorophenylacetyl)-N'-benzylguanidine
hydrochloride
[0358] To sodium ethoxide [prepared by reacting sodium (60 mg, 2.61
mmol) and anhydrous ethanol (5 ml)] benzylguanidine hydrochloride
(580 mg, 3.12 mmol) was added and refluxed in an oilbath for 1
hour. The reaction mixture was cooled to room temperature and
insoluble materials filtered. Methyl 2,6-dichlorophenylacetate (285
mg, 1.3 mmol) (CH.sub.3(C.dbd.O)CH2(2,6,-di-ClC.sub.6H.sub.3) was
added to the filtrate and refluxed for 2 hours. After cooling to
room temperature the reaction mixture was concentrated and
converted to the hydrochloride salt by the addition of hydrogen
chloride (1M in ether) to provide 310 mg of
N-(2,6-dichlorophenylacetyl)-N'-benzylguanidine hydrochloride as a
white solid, purity 89.3% (HPLC); .sup.1H-NMR (CD.sub.3OD) .delta.
4.38 (s, 4H, CH2), 7.32-7.41 (m, 8H, Ar).
EXAMPLE 11
In Vivo Anticonvulsant Activity in the DBA/2 Mouse Model (Mouse
Audiogenic Assay)
[0359] The in vivo potency of compounds of the invention is
exemplified by data summarized in the Table I below and obtained
pursuant to the following protocol.
[0360] Compounds were tested for their effectiveness in preventing
seizures in DBA/2 mice which have a unique sensitivity to auditory
stimulation. Exposure to loud high-frequency sounds can trigger
seizure activity in these animals. This sensitivity develops from
postnatal day 12 and peaks around day 21 and slowly diminishes as
the animals mature. The unusual response to auditory stimulation in
this strain of mouse is believed to be due to a combination of
early myelination (causing an unusually low excitatory threshold)
and delayed development of inhibitory mechanisms.
[0361] Mice were injected intraperitoneally with the compound
specified in Table I below or with vehicle control, 30 minutes
prior to being placed in a bell jar and turning on the auditory
stimulus (12 KHz sine wave at 110-120 db). Administered doses are
specified in Table I as milligram of compound per kilogram
bodyweight of mouse. The auditory stimulus was left on for 60
seconds and mice reactions were timed and recorded. Percentage
inhibition was determined with reference to vehicle controls.
Results are shown in the Table I below. All compounds were tested
in HCl salt form. TABLE-US-00001 TABLE I Audiogenic Response
Compound Dose Name (mg/kg) % Inhib. N-(4-methylbenzoyl)-N'-(4- 20
30 isopropylphenyl)guanidine
N-(4-methylbenzoyl)-N'-(4-phenylbutyl)guanidine 20 75 10 16
N-(4-methoxybenzoyl)-N'-(4-phenylbutyl)guanidine 20 42
N-(4-methoxyphenyl)-N'-(4- 20 56 isopropylphenyl)guanidine
N-(4-ethoxyphenyl)-N'-(4-phenylbutyl)guanidine 20 60
N-(4-butoxyphenyl)-N'-(4-phenylbutyl)guanidine 20 97
[0362] This invention has been described in detail with reference
to preferred embodiments thereof. However, it will be appreciated
that those skilled in the art, upon consideration of this
disclosure, may make modifications and improvements within the
spirit and scope of the invention.
* * * * *