U.S. patent application number 12/658973 was filed with the patent office on 2010-07-08 for compounds with nootropic action, their preparation, pharmaceutical compositions containing them, and use thereof.
Invention is credited to Carlo Farina, Stefania Gagliardi, Carla Ghelardini, Marisa Martinelli, Carlo Parini.
Application Number | 20100173945 12/658973 |
Document ID | / |
Family ID | 33042696 |
Filed Date | 2010-07-08 |
United States Patent
Application |
20100173945 |
Kind Code |
A1 |
Farina; Carlo ; et
al. |
July 8, 2010 |
Compounds with nootropic action, their preparation, pharmaceutical
compositions containing them, and use thereof
Abstract
Described herein are new bicyclic arylimidazolones having
nootropic action (i.e., protecting and stimulating cerebral
functions), analgesic action and anti hyperalgesic action; also
described is the process for their preparation and pharmaceutical
compositions comprising them, useful for the treatment of cognitive
deficits, and of various types of pain.
Inventors: |
Farina; Carlo; (Milano,
IT) ; Gagliardi; Stefania; (Vimercate, IT) ;
Parini; Carlo; (Magenta, IT) ; Martinelli;
Marisa; (Villa Guardia, IT) ; Ghelardini; Carla;
(Firenze, IT) |
Correspondence
Address: |
ABELMAN, FRAYNE & SCHWAB
666 THIRD AVENUE, 10TH FLOOR
NEW YORK
NY
10017
US
|
Family ID: |
33042696 |
Appl. No.: |
12/658973 |
Filed: |
February 17, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12378475 |
Feb 13, 2009 |
|
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12658973 |
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Current U.S.
Class: |
514/338 ;
514/387 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/28 20180101; A61P 1/12 20180101; A61P 9/10 20180101; A61P
25/08 20180101; A61P 25/04 20180101; A61P 25/24 20180101; C07D
487/04 20130101 |
Class at
Publication: |
514/338 ;
514/387 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/4188 20060101 A61K031/4188 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 24, 2003 |
IT |
MI2003A000573 |
Claims
1.-36. (canceled)
37. A method for the treatment of diseases requiring nootropic
and/or neuroprotective, analgesic and/or antihyperanalgesic, and
anti-emetic action, characterized by administering, to a patient in
need thereof, an effective amount of a compound of general formula
(I) ##STR00049## wherein: A is selected from the group consisting
of carbocyclic aromatic groups, heterocyclic aromatic groups, and
arylC.sub.1-4alkyl; R.sub.1 is selected from the group consisting
of: hydrogen, arylC.sub.1-7alkyl, optionally substituted on the
aryl moiety with one or more groups chosen among hydroxy,
C.sub.1-4alkoxy, halogen, haloC.sub.1-4alkyl;
heterocyclylC.sub.1-7alkyl, optionally substituted on the
heterocyclyl moiety with one or more groups chosen among
C.sub.1-4alkyl and hydroxy; and C.sub.1-7 alkyl, optionally
interrupted by an oxygen or sulphur atom or optionally substituted
at any position by one or more groups chosen among hydroxy, thio,
amino, carboxyl, aminocarbonyl, guanidinyl. R.sub.2 is selected
from the group consisting of hydrogen, C.sub.1-4alkyl,
arylC.sub.1-4alkyl and phenyl; or else R.sub.1 and R.sub.2, taken
together, form a saturated carbocyclic ring containing from 3 to 8
carbon atoms; R.sub.3 is selected from the group consisting of
hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl, CONH.sub.2 and
COOR.sub.5 in which R.sub.5 is selected from the group consisting
of hydrogen and C.sub.1-4alkyl; R.sub.4 is selected from the group
consisting of hydrogen, C.sub.1-4alkyl, aryl, arylC.sub.1-4alkyl
and heterocyclyl; n is 2, 3 or 4; in the form of a racemic mixture
or in the form of enantiomers, and pharmaceutically acceptable
salts.
38. The method according to claim 37 for the treatment of learning
and memory deficits, Alzheimer's disease, dementia, senile
dementia, post stroke vascular type dementia, epilepsy, cerebral
ischaemia, mood disorders, depression, for the treatment of
conditions of chronic paid, inflammatory pain, neuropathic pain,
visceral pain, and for the treatment of emesis.
39. The method according to claim 37, wherein said compound of
formula (I) is administered in association, concurrently or
sequentially, with one or more other active principles.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new compounds of formula
(I) appearing hereinafter, their process of preparation, the
pharmaceutical compositions containing them, and their use as
nootropic, neuroprotective, analgesic and anti-hyperalgesic
agents.
STATE OF THE ART
[0002] Compounds that possess nootropic activity are already known
in the literature.
[0003] In particular, the derivatives substituted in position 4 of
2-oxo-1-pyrrolidineacetamide are valid psychotropic agents that
re-establish damaged cognitive functions. These compounds are
described, for example, in Pharm. Res. Commun. 16, 67, 1984 by
Banfi et al. and in Drug Development Res. 2, 447, 1982 by Itil et
al.
[0004] Amongst the most widely known molecules belonging to the
class mentioned above there may be cited:
2-oxo-1-pyrrolidineacetamide (piracetam),
4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam),
2-(2-oxopyrrolidin-1-yl) butyramide (levetiracetam) and
N-(2,5-dimethylphenyl)-2-oxo-1-pyrrolidineacetamide
(nefiracetam).
[0005] Another chemical class that possesses nootropic activity is
represented by imidazolic condensed derivatives, in particular
2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole (dimiracetam),
described in EP 335483 and in WO-9309120, and in J. Med. Chem., 36,
4214, 1993 by Pinza M. et al.
[0006] Recently, it has been demonstrated that nefiracetam could be
a good therapeutic agent in the treatment of neuropathic pain. The
anti-hyperalgesic action induced by nefiracetam appears to be of
non-opioid nature and is probably due to the stimulation of the
nicotinic cholinergic system at a spinal and superspinal level
(Rashid Harunor M. D. J. Pharmacol. Exp. Ther, 303, 226, 2002).
SUMMARY OF THE INVENTION
[0007] The present applicant has now found new N-substituted
bicyclic imidazolones of formula (I), appearing hereinafter, that
have demonstrated improved psychotropic properties and more marked
analgesic and antihyperalgesic effects in numerous models of
neuropathic pain, with respect to the already known nootropic
agents.
[0008] The present compounds of formula (I) are consequently useful
in the treatment of many disorders of the central nervous system
(CNS), for example in the deterioration of learning, dysfunctions
of the cognitive sphere and of the memory, Alzheimer's disease,
dementias, including senile dementia of the Alzheimer type, post
stroke vascular type dementia, epilepsy, cerebral ischaemia, mood
disorders, including depression, chronic, inflammatory, neuropathic
and visceral pain, and emesis.
[0009] Consequently, representative of the subject of the present
invention are compounds of the general formula (I)
##STR00001##
in which: A is chosen among carbocyclic aromatic groups,
heterocyclic aromatic groups and arylC.sub.1-4alkyl; R.sub.1 is
chosen among: [0010] hydrogen, [0011] arylC.sub.1-7alkyl,
optionally substituted on the aryl moiety with one or more groups
chosen among hydroxy, C.sub.1-4alkoxy, halogen, haloC.sub.1-4alkyl;
[0012] heterocyclylC.sub.1-7alkyl, optionally substituted on the
heterocyclyl moiety with one or more groups chosen among
C.sub.1-4alkyl and hydroxy; [0013] C.sub.1-7 alkyl, optionally
interrupted by an oxygen or sulphur atom or optionally substituted
at any position by one or more groups chosen among hydroxy, thio,
amino, carboxyl, aminocarbonyl, guanidinyl. R.sub.2 is chosen among
hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl and phenyl; or else
R.sub.1 and R.sub.2, taken together, form a saturated carbocyclic
ring containing from 3 to 8 carbon atoms; R.sub.3 is chosen among
hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl, CONH.sub.2 and
COOR.sub.5 in which R.sub.5 is chosen between hydrogen and
C.sub.1-4alkyl; R.sub.4 is chosen among hydrogen, C.sub.1-4alkyl,
aryl, arylC.sub.1-4alkyl and heterocyclyl; and n is 2, 3 or 4; in
the form of a racemic mixture or in the form of enantiomers, and
pharmaceutically acceptable salts or solvates thereof.
[0014] The process of preparation of the compounds of formula (I)
appearing above, the pharmaceutical compositions containing them
and their use for the preparation of medicaments with nootropic and
neuroprotective action, with analgesic and/or anti-hyperalgesic
action, and anti-emetic action, constitute a further subject of the
invention.
[0015] Characteristics and advantages of the present compounds of
formula (I) will be illustrated in detail in the following
description.
DESCRIPTION OF THE FIGURES
[0016] FIGS. 1a, 1b: non limiting examples of aminoacids of formula
(IV), useful in the synthesis of the compounds of formula (I). The
encircled portion indicates the substituent R.sub.1.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In the framework of the present invention, the term
"carbocyclic aromatic group" means single or fused aromatic rings
with 6 to 12 ring members, optionally substituted.
[0018] The terms "heterocyclic aromatic group" and "heterocyclyl"
mean single or fused aromatic rings, each ring having 5 to 12
members and comprising up to four hetero atoms, chosen among
oxygen, sulphur and nitrogen, optionally substituted.
[0019] Whenever not otherwise specified, the term "aryl" means
single or fused unsaturated rings, each ring having from 5 to 8
members, and preferably 5 or 6 members, optionally substituted; by
the term "arylC.sub.1-4alkyl" is indicated a group having an aryl
group, as defined above, and a C.sub.1-4 alkyl moiety connecting
the aryl group to the point of substitution.
[0020] All the aforesaid C.sub.1-4 alkyl groups, including those
being part of the arylC.sub.1-4alkyl group, may be indifferently
linear or branched or cyclic (i.e cyclopropyl, cyclopropylmethyl or
methylcyclopropyl). Preferred C1-C4 alkyl groups are Me, Et, i-Pr,
i-Bu, and cyclopropylmethyl.
[0021] All the aforesaid C.sub.1-7alkyl groups, including those
being part of C.sub.1-7 alkyl-containing groups, can either be
linear, branched or cyclic, and may include double or triple bonds.
The term "C.sub.1-7 alkyl groups interrupted by oxygen or sulphur"
means, respectively, any ether and thioether groups containing from
1 to 7 carbon atoms.
[0022] By the term "heterocyclylC.sub.1-7alkyl" is indicated a
group having an heterocyclyl group, as defined above, and a
C.sub.1-7 alkyl moiety connecting the aryl group to the point of
substitution.
[0023] By the term "arylC.sub.1-7alkyl" is indicated a group having
an aryl group, as defined above, and a C.sub.1-7 alkyl moiety
connecting the aryl group to the point of substitution.
[0024] By "halogen" is meant an atom chosen among fluorine,
chlorine, bromine or iodine; by "haloC.sub.1-4alkyl" is meant a
C.sub.1-4 alkyl group substituted at any position by one or more
halogen atoms, e.g. trifluoromethyl.
[0025] Unless differently specified, "optionally substituted"
groups are groups optionally substituted with 1 to 3 substituents,
chosen preferably among Me, Et, i-Pr, OH, COOEt, COOH, CH.sub.2OH,
SO.sub.2NH.sub.2, SO.sub.2Me, OMe, Cl, F, CN and CF.sub.3, and more
preferably among Me, Et, i-Pr, OH, CN, Cl and CF.sub.3; the
substituents may be in any position of the group to be
substituted.
[0026] Preferred compounds according to the invention are the
compounds of formula (I), in which A is a optionally substituted
phenyl, optionally substituted benzyl, or else a optionally
substituted heterocyclic aromatic group with 5 or 6 members and
comprising up to two hetero atoms chosen between oxygen, sulphur
and nitrogen, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are chosen
among hydrogen, C.sub.1-4 alkyl or benzyl, and n is equal to 2 or
3.
[0027] Preferably, A is phenyl, thienyl, pyridyl, pyrimidinyl
group, optionally substituted, benzyl or 4-methylbenzyl; R.sub.1 is
hydrogen, C.sub.1-4 alkyl (for example methyl, isopropyl or
isobutyl), benzyl, --CH.sub.2OH, --CH.sub.2CH.sub.2CONH.sub.2,
--CH.sub.2COOH, indol(3-yl)methyl, R.sub.2 is hydrogen, C.sub.1-4
alkyl or benzyl, R.sub.3 and R.sub.4 are hydrogen or methyl, and n
is 2.
[0028] More preferably, A is a phenyl, optionally substituted,
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are hydrogen, and n is equal
to 2.
[0029] When R.sub.1 and R.sub.2, taken together, form a saturated
carbocyclic ring containing from 3 to 8 carbon atoms, the resulting
compound of formula (I) is a spirocyclic compound.
[0030] Preferred compounds of formula (I) according to the
invention are chosen in the group consisting of: [0031]
1-Phenyl-tetrahydro-1H-pymolo[1,2-a]imidazole-2,5-dione; [0032]
1-o-tolyl-tetrahydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione; [0033]
1-(2,6-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0034]
1-Thiophen-2-yl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0035] 1-m-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0036] 1-p-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0037]
1-(5-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione-
; [0038]
1-(3-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2-
,5-dione; [0039]
1-(2-Trifluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione-
; [0040]
1-(4-Chloro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2-
,5-dione; [0041]
1-(3-Chloro-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0042]
1-(3-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0043]
1-(3-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0044]
1-(4-Chloro-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0045]
1-(3-Hydroxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0046]
1-(3-Trifluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione-
; [0047]
1-(4-Trifluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2-
,5-dione; [0048]
1-(4-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0049]
1-(3,5-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0050]
1-(3,4-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dio-
ne; [0051]
1-Naphthalen-2-yl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0052]
1-(3-Isopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dion-
e; [0053]
1-(4-Chloro-3-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole--
2,5-dione; [0054]
3-Benzyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0055]
3-Methyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0056]
3-Isobutyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0057]
1-(3-Fluoro-5-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione-
; [0058]
1-(3-Fluoro-4-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2-
,5-dione; [0059]
7a-Methyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0060] (S)-1-o-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-d lone;
[0061] (R)-1-o-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0062]
1-(4-Ethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0063]
1-(4-Isopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0064]
1-(4-Hydroxymethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5--
dione; [0065]
4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imidazol-1-yl)-benzoic acid;
[0066] 4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imidazol-1-yl)benzoic
acid ethyl ester; [0067]
1-(4-Methanesulfonyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione-
; [0068]
1-(4-Fluoro-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0069]
1-(4-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0070] 1-Pyridin-2-yl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0071] 1-Pyridin-3-yl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0072]
1-(5-Methylpyridin-2-yl)-tetrahydropyrrolo[1,2-a]imidazole-2,5-dio-
ne; [0073]
1-(2-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione- ;
[0074]
1-(3-Fluoro-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0075] 1-Benzyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
[0076]
1-(4-methylbenzyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione.
[0077] It will be noted that some compounds of formula (I) can
contain one or more stereogenic centres. The present invention
extends to all the optical isomers of these compounds in their
forms entirely or partially resolved and in the form of racemic
mixtures.
[0078] A further subject of the invention is a process for the
preparation of the compounds of formula (I), or one of their salts,
and/or one of their solvates, comprising the reaction of a compound
of formula (II)
##STR00002##
with a compound of formula (III)
A-X (III)
in which A, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and n are defined as
above for the compounds of formula (I), and X is a halogen atom,
chosen preferably between bromine and iodine.
[0079] When A is a aromatic carbocyclic group or a heterocyclic
aromatic group as above defined, the reaction between the compounds
of formula (II) and the compound of formula (III) can be conducted
according to the appropriate conditions of the Goldberg reaction
(Angew. Chem. Int. E., 39, 4492, 2000). In particular, the
compounds of formula (II) are dissolved in a suitable solvent, such
as N-methylpyrrolidone, together with the compounds of formula
(III) in the presence of a catalytic amount of copper salt such as
copper iodide, and a base such as potassium carbonate, at any
temperature that will yield an adequate percentage of formation of
the product required, suitably at a high temperature, such as a
temperature of between 60.degree. C. and 140.degree. C., for
example at 120.degree. C. The reaction mixture is heated using a
system of conventional heating or a microwave reactor of adequate
power, for example comprised between 25 and 250 W (Tetrahedron
Letters, 43, 1101, 2002).
[0080] When A is arylC.sub.1-4alkyl, the reaction can be carried
out in a suitable solvent such as acetonitrile, methylene chloride,
acetone, in the presence of a suitable base such as triethylamine,
potassium carbonate,
2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (also known as BEMP), N,N-Diisopropylethylamine (also known as
Hunig base), at a suitable temperature such as reflux temperature
(60-140.degree. C., preferably 100.degree. C.).
[0081] The aforesaid compounds of formula (II) and the methods for
their preparation are described in the European patent application
EP-A-335483 and in the International patent application No.
WO-A-93/09120 and in J. Med. Chem., 36, 4214, 1993, by Pinza et
al.
[0082] The compounds of formula (III) are commercially available or
can be prepared from known compounds by known methods.
[0083] Alternatively, the compounds of formula (I) can be prepared
with a process comprising the following stages:
i) reaction of an aminoacid of formula (IV) or of one of its
activated derivatives
##STR00003##
with a compound of formula (V)
A-NH.sub.2 (V)
to obtain a compound of formula (VI)
##STR00004##
in which R.sub.1, R.sub.2 and A are as defined above for the
compound of formula (I), and P is H or a suitable protective group.
The activation of aminoacids is a well-known synthetic procedure;
examples of activated derivatives of the aminoacids are mixed
anhydrides, acyl chlorides and activated esters. ii) reaction of
the compound of formula (VI) obtained at stage i) with a compound
of formula (VII)
##STR00005##
to obtain a compound of formula (VIII)
##STR00006##
in which A, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and n are as defined
above for the compound of formula (I), P is defined as above, and
R' is an alkyl group; iii) possible removal of the protective group
P by means of hydrogenolysis of the compound of formula (VIII),
obtained in stage ii), to obtain the corresponding compound (VIII),
in which P is H; and iv) cyclization of the compound of formula
(VIII), in which P is H coming from stage ii) or from stage iii),
to obtain the desired compound of formula (I).
[0084] According to a preferred embodiment of the invention, the
alkyl residue R' is chosen between methyl and tert-butyl, and P is
chosen between hydrogen, a benzyl or a benzyloxycarbonyl group.
[0085] The reaction in stage i) between the compound of formula
(IV) and the compound of formula (V) can be performed:
(a) by preparing, in the first place, an acidic chloride of the
compound of formula (IV) and uniting to said acidic chloride the
compound of formula (V) in the presence of an inorganic or organic
base in an adequate aprotic solvent, such as dimethylformamide
(DMF) at a temperature of between -70.degree. C. and 50.degree. C.,
and preferably between -10.degree. C. and 20.degree. C.; or else:
(b) by reacting together the compound of formula (IV) with the
compound of formula (V) in the presence of a suitable condensating
agent, such as N,N'-carbonyl diimidazole (CDI) or a carbodiimmide
such as dicyclohexylcarbodiimmide (DCC) or
N-dimethylaminopropyl-N'-ethylcarbodiimmide, preferably in the
presence of N-hydroxybenzotriazole (HOBT) to maximize the yield and
prevent the processes of racemization (cf. Synthesis, 453, 1972),
or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), in an aprotic solvent, such as a
mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for
example, a mixture with volumetric ratio comprised between 1:9 and
7:3 (MeCN:THF), at any temperature capable of yielding an adequate
percentage of formation of the product required, such as a
temperature of between -70.degree. C. and 50.degree. C., and
preferably between -10.degree. C. and 25.degree. C.
[0086] At stage ii) of the present process, the compounds of
formula (VI) and (VII) are preferably reflux-heated in a protic
solvent, such as water or methanol, and possibly in the presence of
a base, such as NaOH, in the case where the compound of formula
(VI) is used in the form of one of its salts obtained by addition
of acid, for an adequate period of time, preferably comprised
between 2 and 24 hours.
[0087] Removal of the protective group P by means of hydrogenolysis
at stage iii) is preferably conducted using ammonium formiate as a
source of hydrogen in a suitable protic solvent, such as methanol
or a methanol-water mixture.
[0088] The cyclization reaction in stage iv) is carried out
directly on the compound of formula (VIII) coming from stage ii) if
P is H, or else, if in said compound (VIII) P is a protective
group, the first step is to remove it, as described above in stage
iii).
[0089] The cyclization reaction is conducted in drastic conditions
by conventionally heating the compound of formula (VIII) without
solvent at 120.degree. C. and in vacuum conditions, or else by
means of reflux-heating in xylene for a suitable period of time,
for example between 4 hours and 3 days, or by microwave
irradiation.
[0090] The compounds of formula (IV), (V) and (VII) are
commercially available compounds or can be prepared from known
compounds using known methods. In particular, the compounds of
formula (IV) can be conveniently selected from any naturally
occurring aminoacids or derivatives thereof. Examples of aminoacids
useful in the present invention are shown in FIG. 1, where the part
encircled corresponds to the substituent R.sub.1 of formula (IV):
accordingly, all these meanings for R.sub.1 are also preferred in
formula (I), being the object of the present invention.
[0091] The present compounds of formula (I) are useful as
therapeutic agents and in particular possess a nootropic and
neuroprotective activity, i.e., they contribute to restoring the
learning and memory functions deteriorated in the process of ageing
or on account of ischaemic traumas, and are effective in various
pathologies of the CNS, amongst which learning dysfunctions,
dysfunctions of the cognitive sphere and of the memory, Alzheimer's
disease, dementias, including senile dementia of the Alzheimer
type, post stroke vascular type dementia, epilepsy, cerebral
ischaemia, and mood disorders, including depression.
[0092] The present compounds of formula (I) moreover possess
analgesic and/or anti-hyperalgesic activity, i.e., they contribute
to combat the sensations of pain, in particular those caused by
conditions of neuropathic pain, chronic inflammatory pain and
visceral pain, and have proven their efficacy also in the treatment
of emesis.
[0093] The subject of the present invention is hence also the use
of the present compounds of formula (I) or of their
pharmaceutically acceptable salts and/or solvates for the
preparation of medicaments for recovery of difficulties of learning
and memory and for treatment of dementias, Alzheimer's disease,
post stroke vascular type dementia, epilepsy, cerebral ischaemia,
and mood disorders, including depression.
[0094] Also provided is a method to treat the aforesaid diseases
and disorders characterised by administering a pharmaceutically
active amount of a compound of formula (I) to a patient in need
thereof.
[0095] It is widely known that cognitive disorders that occur in
said pathologies are correlated to the deficit of the cerebral
cholinergic system, as emerges from morphological findings (B. E.
Tomlinson in "Biochemistry of Dementias"; P. J. Roberts Ed.; John
Wiley & Sons, New York, N.Y. pp. 15-22, 1980) and neurochemical
findings (R. T. Bartus et al. Science, 217, 408, 1982). It is
moreover well known that the significant deteriorations of
cognitive functions are the most evident and debilitating signs
observed in patients suffering from Alzheimer's disease, senile
dementias of the Alzheimer type, and dementia due to multiple
infarcts.
[0096] The activity of the compounds of formula (I) can be
determined in rats in regard to the amnesia-provoking action of
scopolamine (D. A. Drachman, Archs. Neurol., Chicago, 30, 113,
1974; D. A. Eckerman, Pharmacol. Biochem. Behav. 12, 595, 1980) on
the mnemic pathway and on the reduction of the levels of
acetylcholine in the hippocampus. The effect on memory and learning
can be evaluated in rats using the passive-avoidance test, as
described by Essman, Pharmacol. Res. Commun. 5, 295, 1973.
[0097] The subject of the present invention is, moreover, the use
of the present compounds of formula (I) or their pharmaceutically
acceptable salts or solvates in the treatment of conditions of
neuropathic pain, chronic inflammatory pain and visceral pain. Also
provided is a method to treat the aforesaid diseases characterised
by administering a pharmaceutically active amount of a compound of
formula (I) to a patient in need thereof.
[0098] It is hypothesized that the process of learning and memory
is implicated in the mechanisms of chronic pain (Flor H., Prog.
Brain Res., 129, 313, 2000), and recent evidence supports the
hypothesis that chronic inflammatory pain is an acquired
maladaptive phenomenon (Amstein P. M., J. Neurosci. Nurs. 29, 179,
1997; Kumazava T., Neurosci. Res., 32, 9, 1998). Cognitive
dysfunction has been described in various neuropathic conditions
(Kuhajda M. C., Ann. Behav. Med., 20, 31, 1998), and it has
recently been observed that nefiracetam, a nootropic agent,
alleviates neuropathic pain thanks to its specific effects on
neuropathies (Rashid Harunor M. D. J. Pharmacol. Exp. Ther., 303,
226, 2002). It has been shown that the analgesic and/or
anti-hyperalgesic effect of nefiracetam expresses itself through
stimulation of the nicotinic cholinergic receptors at the spinal
and supraspinal level, in so far as said effect is inhibited in a
dose-dependent way by mecamylamine, a known antagonist of the
nicotinic acetylcholine receptor.
[0099] The activity of the compounds of formula (I) can be
determined in mice by means of the thermal-hyperalgesia test
(paw-withdrawal test) and the mechanical-hyperalgesia test
(paw-pressure test) induced by partial ligation of the sciatic
nerve or by treatment with streptozotocine, following the protocols
described in J. Pharmacol. Exp. Ther., 303, 226, 2002 and in the
bibliography cited therein.
[0100] When used in the therapeutic treatment of humans and
animals, the compounds of formula (I) are normally formulated, in
compliance with standard pharmaceutical practice, as a
pharmaceutical composition.
[0101] Hence, a further subject of the invention is represented by
a pharmaceutical composition comprising, as active principle, a
compound of formula (I) or one of its pharmaceutically acceptable
salts or solvates, together with vectors, diluents and
pharmaceutically acceptable excipients suitable for the chosen form
of administration.
[0102] The compounds of formula (I) can be administered in a
standard way in the treatment of the disorders indicated above, for
example via oral, parenteral, rectal, transdermal route or by
administration through the mucosa (for example, the sublingual,
buccal, or nasal mucosa).
[0103] The compounds of formula (I) which are administered orally
or via sublingual route or via buccal administration, can be
formulated as syrups, tablets, capsules, and lozenges. A
formulation in the form of syrup consists generally of a suspension
or solution of the compound or of one of its salts in a liquid
vector, for example ethanol, glycerine or water with a flavouring
or colouring agent. When the composition is in the form of tablets,
it is possible to use any pharmaceutical vector used conventionally
in the preparation of solid formulations. Examples of said vectors
comprise magnesium stereate, starch, lactose and sucrose. When the
composition is in the form of capsules, any conventional method of
encapsulation is suitable, for example using the vectors mentioned
above in a capsule of hard gelatine. When the composition is in the
form of capsules made of soft gelatine, it is possible to use any
pharmaceutical vector used conventionally in the preparation of
dispersions or suspensions, for example aqueous gums, cellulose,
silicates or oils, to be incorporated into a shell made of soft
gelatine.
[0104] Typical parenteral compositions consist of a solution or
suspension of the compound of formula (I) in a aqueous or
non-aqueous sterile vector, possibly containing an oil acceptable
for the parenteral route, for example polyethylene-glycol,
polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil.
[0105] The typical formulation in suppositories comprises a
compound of formula (I), which is active if administered in this
way, with a binding and/or lubricating agent, for example polymeric
glycols, gelatine, cocoa butter, or other low-melting waxes or
vegetable fats.
[0106] Typical transdermal formulations comprise a conventional
aqueous or non-aqueous vector, for example cream, ointment; lotion
or paste, or can be in the form of medicated plasters, patches or
membranes.
[0107] Preferably, the composition is in a unit-dose form, for
example tablets or capsules, so that the patient can take a single
dose.
[0108] Oxyracetam is a compound used in the treatment of senile
dementia and of pathological conditions correlated thereto. The
compounds of formula (I) can be administered with regimes similar
to the ones established for oxyracetam with any appropriate
adjustment of the levels of dosage or of the frequency of dosage in
relation to the greater activity and to the better pharmacological
profile of the compounds of formula (I).
[0109] Each dosage unit for oral administration may expediently
contain from 0.05 mg/kg to 50 mg/kg, more expediently from 0.1
mg/kg to 25 mg/kg of a compound of formula (I). The active
ingredient can be administered from 1 to 6 times a day. The
compounds of formula (I) can be co-administered with other
pharmaceutically active compounds, for example in association,
concurrently or sequentially, in particular together with other
compounds used in the treatment of elderly patients, such as
tranquilizers, diuretics, anti-hypertensive drugs, vasodilator
drugs, and inotropic agents.
[0110] Examples of the present invention are provided in what
follows, purely for illustrative and non-limiting purposes.
EXPERIMENTAL PART
Description 1.
3-Isobutyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione
[0111] To a solution of DL-leucinamide hydrochloride (1.5 g, 9
mmol) in water (40 ml), adjusted to pH 9.5 with 10% sodium
hydroxide, ethyl-4-oxobutanoate (1 g, 7.5 mmol) was added. The
mixture was placed in a microwave oven and refluxed for 1 hour.
Water was then evaporated under vacuum and the residue was
chromatographated over silica gel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
98/2/0.1) to afford 1.1 g of the title compound.
[0112] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.48 (broad s, 1H); 5.30
(t, 1H); 4.23 (dd, 1H); 2.71-2.39 (m, 3H); 2.20-1.93 (m, 1H);
1.86-1.73 (m, 1H); 1.70-1.42 (m, 2H), 1.05 (d, 3H); 0.96 (d,
3H).
[0113] MS: EI TSQ 700; source 180 C; 70 V; 200 uA: 196 (M+),
97.
Example 1
1-Phenyl-tetrahydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione
[0114] To a solution of
tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol;
prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in
N-methylpyrrolidone (NMP, 12 cc), CuI (0.2 g, 1.05 mmol),
K.sub.2CO.sub.3 (1 g, 7.14 mmol) and iodobenzene (5 g, 24.5 mmol)
were added under stirring. The suspension was heated in a microwave
apparatus (250 Watt) for 45 min. Ethyl acetate was added to the
suspension and the solid was filtered. The organic phase was washed
with water and the aqueous phase was re-extracted with
CH.sub.2Cl.sub.2. The organic phases were gathered and dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue
was triturated with isopropyl ether. The solid was filtered,
triturated with water and filtered to yield 0.18 g of the title
compound, mp=185-188.degree. C.
[0115] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46-7.37 (m, 4H);
7.28-7.21 (m, 1H); 5.84 (m, 1H); 4.48 (d, 1H); 3.74 (d, 1H);
2.78-2.60 (m, 2H); 2.51-2.38 (m, 1H); 2.08-1.96 (m, 1H).
[0116] MS: EI TSQ 700; source 180 C; 70 V; 200 uA: 216 (M+), 160,
97.
Example 2
1-o-tolyl-tetrahydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione
[0117] To a solution of
tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol,
prepared as described in J. Med. Chem. 36, 4214, 1994) in
N-methylpyrrolidone (NMP, 12 cc), CuI (0.5 g, 2.62 mmol),
K.sub.2CO.sub.3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35
mmol) were added under stirring. The suspension was heated in a
microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to
the suspension and the solid was filtered. The organic phase was
washed with water and the aqueous phase was re-extracted with
CH.sub.2Cl.sub.2. The organic phases were gathered and dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue
was triturated with Et.sub.2O. The solid was filtered, and
crystallized the first time with iPrOH and then with AcOEt to yield
0.33 g of the title compound, mp=138-139.degree. C.
[0118] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35-7.23 (m, 4H);
7.13-7.06 (m, 1H); 5.69 (m br, 1H); 4.45 (d, 1H); 3.78 (d, 1H);
2.68 (ddd, 1H); 2.48 (ddd, 1H); 2.40-2.29 (m, 1H); 2.24 (s, 3H);
1.93 (m br, 1H).
[0119] MS: EI TSQ 700; source 180 C; 70 V; 200 uA: 230 (M+), 143,
118, 97.
Example 3-44
Table 1
General Procedure for arylation of
tetrahydro-pyrrolo[1,2-a]imidazole-2,5-diones with aryl halides
[0120] To a solution of
tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (3.5 mmol; prepared as
described in J. Med. Chem. 36, 4214-4220, 1994 or in WO-9309120),
in N-methylpyrrolidone (NMP 1 ml), CuI (0.19 g, 1 mmol),
K.sub.2CO.sub.3 (0.5 g, 3.5 mmol) and the appropriate aryl halide
(7 mmol) were added under stirring. The suspension was heated in a
microwave apparatus (25 Watt) for 20 min. Ethyl acetate (50 ml) and
water (5 ml) were added to the suspension and the mixture was
stirred for 30' in the presence of celite. The reaction was
filtered and the ethyl acetate was washed with a saturated solution
of NaCl, dried over Na.sub.2SO.sub.4, filtered and concentrated to
dryness. The residue was triturated with Et.sub.2O to give the
desired compound. Yields vary from 30% to 60%.
Example 45
1-Benzyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione
[0121] A solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione
(0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36, 4214,
1994), BEMP (2 ml, 7 mmol) and benzylbromide (0.6 ml, 5 mmol) in
CH.sub.3CN (20 ml) was refluxed for 1 hour. The reaction mixture
was concentrated to dryness; the residue was then re-dissolved in
ethyl acetate and washed with a saturated solution of NaCl, dried
over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The
residue was purified by flash chromatography over silica gel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 95/5/0.5) to afford 0.7 g of the
title compound as yellow oil.
[0122] Yield: 87%
[0123] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.10 (m, 5H); 5.03
(dd, 1H); 4.71 (d, 1H); 4.29 (d, 1H); 4.28 (d, 1H); 3.59 (d, 1H);
2.57 (ddd, 1H); 2.39-2.125 (m, 2H); 1.92-1.77 (m, 1H).
[0124] MS: EI TSQ 700; source 180 C; 70 V; 200 uA: 230.13 (M+),
174.09, 139.04, 91.03.
Example 46
1-(4-methylbenzyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione
[0125] A solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione
(0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36, 4214,
1994), BEMP (2 ml, 7 mmol) and 4-methylbenzylbromide (0.95 ml, 5
mmol) in CH.sub.3CN (20 ml) was refluxed for 1 hour. The reaction
mixture was concentrated to dryness; the residue was then
re-dissolved in ethyl acetate and washed with a saturated solution
of NaCl, dried over Na.sub.2SO.sub.4, filtered and evaporated under
vacuum. The residue was purified by flash chromatography over
silica gel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 95/5/0.5) to afford
0.8 g of the title compound as yellow oil.
[0126] Yield: 93%
[0127] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.29-7.11 (m, 4H); 5.01
(m, 1H); 4.69 (d, 1H); 4.29 (d, 1H); 4.23 (d, 1H); 3.58 (d, 1H);
2.65-2.50 (m, 1H); 2.40-2.24 (m, 2H); 2.33 (s, 3H); 1.93-1.78 (m,
1H).
[0128] MS: EI TSQ 700; source 180 C; 70 V; 200 uA: 244.13 (M+),
161.05, 105.02
TABLE-US-00001 TABLE 1 Structure, chemical name (generated by
Bellstein's Autonom), .sup.1H NMR, MS and melting point data for
compounds prepared according to the general procedure described
above. Ex. Structure Chemical name Analytical data 3 ##STR00007##
1-(2,6-Dimethyl-phenyl)- tetrahydropyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta. 7.24-7.10
(m, 3H); 5.63 (dd, 1H), 4.48 (d, 1H); 3.82 (d, 1H); 2.70 (ddd, 1H);
2.51 (ddd, 1H); 2.33-2.18 (m, 1H); 2.26 (s, 3H); 2.20 (s, 3H),
2.06-1.91 (m, 1H). MS: EI TSQ 700: source 180.degree. C.; 70 V; 200
uA: 244 (M+); 97. 4 ##STR00008## 1-Thiophen-2-yl-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.05 (dd, 1H); 6.93 (dd, 1H); 6.65 (dd, 1H);
5.67 (m, 1H); 4.49 (d, 1H); 3.77 (d, 1H); 2.88-2.69 (m, 2H);
2.58-2.45 (m, 1H); 2.33-2.21 (m, 1H). MS: EI TSQ 700; source
180.degree. C.; 70 V; 200 uA: 222 (M+); 194; 166; 97. mp:
170-171.degree. C. 5 ##STR00009## 1-m-Tolyl-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.30 (dd, 1H); 7.24 (dd, 1H); 7.13 (dd, 1H); 7.07 (dd,
1H); 5.82 (m, 1H); 4.46 (d, 1H); 3.74 (d, 1H); 2.79-2.57 (m, 2H);
2.45 (m, 1H); 2.38 (s, 3H); 1.06-1.94 (m, 1H). MS: EI TSQ 700;
source 180.degree. C.; 70 V; 200 uA: 230 (M+); 174; 97. mp:
92-93.degree. C. 6 ##STR00010## 1-p-Tolyl-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.27 (d, 2H); 7.24 (d, 2H); 5.79 (m, 1H); 4.45 (d, 1H);
3.73 (d, 1H); 2.72 (ddd, 1H); 2.70 (m, 1H); 2.47 (dd, 1H); 2.38 (s,
3H); 2.08-1.98 (m, 1H). MS: EI TSQ 700; source 180.degree. C.; 70
V; 200 uA: 230 (M+); 174; 118. mp: 117-118.degree. C. 7
##STR00011## 1-(5-Fluoro-2-methyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.28 (m, 1H); 7.02 (ddd, 1 H); 6.85 (dd, 1H); 5.64 (m br,
1H); 4.43 (d, 1H); 3.77 (d, 1H); 2.70 (dt, 1H); 2.53-2.31 (m, 2H);
2.18 (s, 3H); 1.90 (broad m, 1H). MS: EI TSQ 700; source
180.degree. C.; 70 V; 200 uA: 248(M+); 97. mp: 147-148.degree. C. 8
##STR00012## 1-(3-Fluoro-2-methyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.23 (ddd, 1H); 7.07 (dd br, 1H); 6.92 (d, 1H); 5.83-5.41
(broad m, 1H); 4.46 (d, 1H); 3.78 (d, 1H); 2.69 (ddd, 1H); 2.48
(ddd, 1H); 2.45-2.29 (m, 1H); 2.14 (d, 3H); 1.89 (broad m, 1H). MS:
EI TSQ 700; source 180.degree. C.; 70 V; 200 uA: 248 (M+); 136;
109. mp: 135-137.degree. C. 9 ##STR00013## 1-(2-Trifluoromethyl-
phenyl)-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.81(d, 1H); 7.66 (dd, 1H); 7.54 (broad dd,
1H); 7.27 (d, 1H); 5.64 (m, 1H); 4.42 (broad d, 1H); 3.72 (d, 1H);
2.63 (m, 1H); 2.48 (m, 1H); 2.28 (m, 1H); 2.03 (m, 1H). MS: EI TSQ
700; source 180.degree. C.; 70 V; 200 uA: 284 (M+); 228; 198; 10
##STR00014## 1-(4-Chloro-2-methyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.32 (d, 1H); 7.24 (dd, 1H); 7.04 (d, 1H); 5.63 (broad m,
1H); 4.44 (d, 1H); 3.77 (d, 1H); 2.69 (ddd, 1H); 2.48 (ddd, 1H);
2.35 (m, 1H); 2.22 (s, 3H); 1.92 (m, 1H). MS: EI TSQ 700; source
180.degree. C.; 70 V; 200 uA: 264 (M+); 97. mp: 122-124.degree. C.
11 ##STR00015## 1-(3-Chloro-phenyl)- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (m,
1H); 7.39-7.28 (m, 2H); 7.22 (ddd, 1H); 5.81 (m, 1H); 7.48 (d, 1H);
3.73 (d, 1H); 2.85-2.64 (m, 2H); 2.46(m, 1H); 2.03 (m, 1H). MS: EI
TSQ 700; source 180.degree. C.; 70 V; 200 uA: 250 (M+); 194, 138,
111. mp: 123-125.degree. C. 12 ##STR00016## 1-(3-Methoxy-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.31 (dd, 1H); 7.08 (dd, 1H); 6.91 (dd, 1H);
6.79 (dd, 1H); 5.80 (m, 1H); 4.46 (d, 1H); 3.82 (s, 3H); 3.73 (d,
1H); 2.79- 2.61 (m, 2H); 2.45 (m, 1H); 2.12-1.96 (m, 1H). MS: EI
TSQ 700; source 180.degree. C.; 70 V; 200 uA: 264 (M+); 190. mp:
94-95.degree. C. 13 ##STR00017## 1-(3-Cyano-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1 H-NMR
(CDCl.sub.3) .delta.: 7.73 (m, 2H); 7.52 (m, 2H); 5.81 (m, 1H);
4.51 (d, 1H); 3.73 (d, 1H); 2.84-2.65 (m, 2H); 2.47 (dd, 1H);
2.11-1.95 (m, 1H). MS: EI TSQ 700; source 180.degree. C.; 70 V; 200
uA: 241 (M+); 185, 129. mp: 128-130.degree. C. 14 ##STR00018##
1-(4-Chloro-phenyl)- tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.42-7.32 (m, 4H); 5.80 (m, 1H);
4.46 (d, 1H); 3.73 (d, 1H); 2.79-2.60 (m, 2H); 2.45 (m, 1H);
2.09-1.93 (m, 1H). MS: EI TSQ 700; source 180.degree. C.; 70 V; 200
uA: 250 (M+); 194. mp: 159-160.degree. C. 15 ##STR00019##
1-(3-Hydroxy-phenyl)- tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.16 (dd, 1H); 6.96 (dd, 1H);
6.76 (dd, 1H); 6.69 (dd, 1H); 5.74 (m, 1H); 4.38 (d, 1H); 3.67 (d,
1H); 2.74-2.55 (m, 2H); 2.38 (m, 1H); 2.07-1.90 (m, 1H). MS: EI TSQ
700; source 180.degree. C.; 70 V; 200 uA: 232(M+); 176. mp:
210-211.degree. C. 16 ##STR00020## 1-(3-Trifluoromethyl-
phenyl)-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.68 (d, 1H); 7.66 (broad s, 1H); 7.56 (dd,
1H); 7.50 (d, 1H); 5.88 (m, 1H); 4.50 (d, 1H); 3.76 (d, 1H); 2.73
(m, 2H); 2.48 (m, 1H); 2.04 (m, 1H). MS: EI TSQ 700; source
180.degree. C.; 70 V; 200 uA: 284 (M+); 228; 172; 145. mp:
124-125.degree. C. 17 ##STR00021## 1-(4-Trifluoromethyl-
phenyl)-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.68 (d, 2H); 7.57 (d, 2H); 5.88 (m, 1H);
4.50 (d, 1H); 3.75 (d, 1H); 2.82-2.67 (m, 2H); 2.48 (m, 1H);
2.12-1.96 (m, 1H). MS; EI TSQ 700; source 180.degree. C.; 70 V; 200
uA: 284 (M+); 228; 172; 145. 18 ##STR00022## 1-(Methoxy-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.28 (d, 2H); 6.95 (d, 2H); 5.74 (m, 1H);
4.44 (d, 1H); 3.81 (s, 3H); 3.73 (d, 1H); 2.79-2.39 (m, 3H);
2.08-1.94 (m, 1H). MS: EI TSQ 700; source 180.degree. C.; 70 V; 200
uA: 246 (M+); 190; 134. mp: 210-211.degree. C. 19 ##STR00023##
1-(3,5-Dimethyl-phenyl)- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 6.98 (s,
2H); 6.89 (s, 1H); 5.79 (m, 1H); 4.45 (d, 1H); 3.72 (d, 1H);
2.77-2.53 (m, 2H); 2.44 (m, 1H); 2.33 (s, 6H); 2.00 (m, 1H). MS: EI
TSQ 700; source 180.degree. C.; 70 V; 200 uA: 244 (M+); 188; 97.
mp: 103-104.degree. C. 20 ##STR00024## 1-(3,4-Dimethyl-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.18 (d, 1H); 7.16 (d, 1H); 7.04 (dd, 1H);
5.77 (dd, 1H); 4.44 (d, 1H); 3.72 (d, 1H); 2.78-2.52 (m, 2H); 2.44
(m, 1H); 2.28 (s, 3H); 2.25 (s, 3H), 2.08-1.93 (m, 1H). MS: ZQ, ESI
POS, spray 3, 25 KV; source 30 V; probe 250.degree. C.: 245 (MH+).
mp: 142-143.degree. C. 21 ##STR00025## 1-Naphthalen-2-yl-
tetrahydro-pyrrolo[1,2- a]imidazole-2.5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.90 (d, 1H); 7.83 (m, 2H); 7.76 (d, 1H);
7.61 (dd, 1H); 7.55-7.45 (m, 2H); 5.97 (m, 1H); 4.53 (d, 1H); 2.80
(d, 1H); 2.86- 2.66 (m, 2H); 2.47 (m, 1H); 2.15-1.99 (m, 1H). MS:
ZQ, ESI POS, spray 3, 25 KV; source 30 V; probe 250.degree. C.: 267
(MH+). mp; 175-176.degree. C. 22 ##STR00026##
1-(3-isopropyl-phenyl)- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 7.33 (dd,
1H); 7.27 (m, 1H); 7.17 (d br, 1H); 7.12 (broad d, 1H); 5.83 (m,
1H); 4.46 (d, 1H); 3.74 (d, 1H); 2.92 (m, 1H); 2.80-2.57 (m, 2H);
2.46 (m, 1H); 2.04 (m, 1H); 1.25 (d, 6H). MS: ZQ, ESI POS, spray 3,
25 KV; source 30 V; probe 250.degree. C.: 259 (MH+). mp:
81-82.degree. C. 23 ##STR00027## 1-(4-Chloro-3-methyl-
phenyl)-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.37 (d, 1H); 7.33 (d, 1H); 7.12 (dd, 1H);
5.79 (m, 1H); 4.46 (d, 1H); 3.72 (d, 1H); 2.79-2.56 (m, 2H);
2.52-2.37 (m, 1H); 2.40 (s, 3H); 2.09-1.93 (m, 1H). MS: ZQ, ESI
POS, spray 3, 25 KV; source 30 V; probe 250.degree. C.: 265 (MH+).
mp: 138-139.degree. C. 24 ##STR00028## 3-Benzyl-l-phenyl-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.34 (dd, 2H); 7.28-7.17 (m, 6H); 7.03 (d,
2H); 4.77 (m, 1H); 4.59 (dd, 1H); 3.32 (dd, 1H); 3.16 (dd, 1H);
2.64 (ddd, 1H); 2.46-2.27 (m, 2H); 1.81 (m, 1H). MS: AQA ESI Pos,
3.5 KV; source 30 V; probe 250.degree. C.: 307 (MH+). mp:
134-136.degree. C. 25 ##STR00029## 3-Methyl-1-phenyl-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDC1.sub.3) .delta.: 7.42 (m, 4H); 7.23 (m, 1H); 5.83 (m, 1H) 4.54
(q, 1H); 2.78-2.59 (m, 2H); 2.45 (m, 1H); 2.10-1.93 (m, 1H); 1.47
(d, 3H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe 250.degree.
C.: 231 (MH+). mp: 137-138.degree. C. 26 ##STR00030##
3-Isobutyl-1-phenyl- tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (m, 4H); 7.22 (m, 1H); 5.81
(m, 1H); 4.50 (dd, 1H); 2.78-2.58 (m, 2H); 2.45 (m, 1H); 2.07-1.65
(m, 3H); 1.54 (m, 1H); 1.08 (d, 3H); 0.98 (d, 3H). MS: AQA, ESI
Pos, 3.5 KV; source 30 V; probe 250.degree. C.: 273 (MH+). mp:
101-102.degree. C. 27 ##STR00031## 1-(3-Fluoro-5-methyl-
phenyl)-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 6.99 (m. 2H); 6.77 (d br, 1H); 5.78 (m, 1H);
4.46 (d, 1H); 3.73 (d, 1H); 2.84-2.63 (m, 2H); 2.45 (m, 1H); 2.37
(s, 3H); 2.11-1.94 (m, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V;
probe 250.degree. C.: 249 (MH+). mp: 111-113.degree. C. 28
##STR00032## 1-(3-Fluoro-4-methyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazo!e- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.32-7.18 (m, 2H); 7.05 (dd br, 1H); 5.78 (m, 1H); 4.46
(d, 1H); 3.73 (d, 1H); 2.78-2.63 (m, 2H); 2.50-2.41 (m, 1H); 2.56
(s, 3H); 2.11-1.94 (m, 1H). MS: ZQ, ESI POS, spray 3, 25 KV; source
30 V; probe 250.degree. C.: 248 (MH+), 192, 97. mp: 136-137.degree.
C. 29 ##STR00033## 7a-Methyl-1-phenyl- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 7.52-7.20
(m, 5H); 4.44 (d, 1H); 3.78 (d, 1H); 2.83-2.68 (m, 1H); 2.56-2.42
(m, 2H); 2.18-2.30 (m, 1H), 1.63 (s, 3H). MS: ZQ, ESI POS, spray 3,
25 KV; source 30 V; probe 250.degree. C.: 230 (MH+). mp:
154-155.degree. C. 30 ##STR00034## (S)-1-o-Tolyl-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.35-7.23 (m, 4H); 7.13-7.06 (m, 1H); 5.69 (m br, 1H);
4.45 (d, 1H); 3.78 (d, 1H); 2.68 (ddd, 1H); 2.48 (ddd, 1H); 2.40-
2.29 (m, 1H); 2.24 (s, 3H); 1.93 (m br, 1H). MS: AQA, ESI Pos, 3.5
KV; source 30 V; probe 250.degree. C.: 230(M+), 143, 118, 97.
[a].sub.D = -51.39 (c = 0.4, MeOH). 31 ##STR00035##
(R)-1-o-Tolyl-tetrahydro- pyrrolo[1,2-a]imidazole- 2,5-dione
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.35-7.23 (m, 4H); 7.13-7.06 (m,
1H); 5.69 (m br, 1H); 4.45 (d, 1H); 3.78 (d, 1H); 2.68 (ddd, 1H);
2.48 (ddd, 1H); 2.40- 2.29 (m, 1H); 2.24 (s, 3H); 1.93 (m br, 1H).
MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe 250.degree. C.:
230(M+), 143, 118, 97. [a].sub.D = +52.24 (c = 0.4, MeOH). 32
##STR00036## 1-(4-Ethyl-phenyl)- tetrahydro-pyrrolo[1,2-
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.29 (d, 2H); 7.25 (d, 2H); 5.80
(m, 1H); 4.45 (d, 1H); 3.74 (d, 1H); 2.78-2.56 (m, 2H); 2.65 (q,
2H); 2.51-2.38 (m, 1H); 33 ##STR00037## 1-(4-isopropyl-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.32-7.25 (m, 4H); 5.58 (m, 1H); 4.46 (d,
1H); 3.74 (d, 1H); 2.91 (m, 1H); 2.78-2.57 (m, 2H); 2.51-2.40 (m,
1H); 2.15-1.96 (m, 1H); 1.24 (d, 6H). MS: AQA, ESI Pos, 3.5 KV;
source 30 V; probe 250.degree. C.: 259.1 (MH+). mp: 124-125.degree.
C. 34 ##STR00038## 1-(4-Hydroxymethyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.41 (m, 4H); 5.83 (m, 1H); 4.70 (s, 2H); 4.47 (d, 1H);
3.74 (d, 1H); 2.79-2.59 (m, 2H); 2.52-2.37 (m, 1H); 2.10-1.93 (m,
1H); 1.72 (s br, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe
250.degree. C.: 247.1 (MH+). mp: 159-161.degree. C. 35 ##STR00039##
4-(2,5-Dioxo-hexahydro- pyrrolo[1,2-a]imidazol-1- yl)-benzoic acid
.sup.1H-NMR (CDCl.sub.3) .delta.: 8.06 (d, 2H); 7.47 (d, 2H); 5.85
(m, 1H); 4.43 (d, 1H); 3.71 (d, 1H); 2.77-2.61 (m, 2H); 2.5-2.36
(m, 1H); 2.05-1.91 (m, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V;
probe 250.degree. C.: 261.0 (MH+). mp: 252-253.degree. C. 36
##STR00040## 4-(2,5-Dioxo-hexahydro- pyrrolo[1,2-a]imidazol-1-
yl)-benzoic acid ethyl ester .sup.1H-NMR (CDCl.sub.3) .delta.: 8.10
(d, 2H); 7.52 (d, 2H); 5.88 (m, 1H); 4.50 (d, 1H); 4.38 (q, 2H);
3.75 (d, 1H); 2.82-2.66 (m, 2H); 2.56-2.38 (m, 1H); 2.12-1.94 (m,
1H); 1.39 (t, 3H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe
250.degree. C.: 289.4 (MH+), 218.4. mp: 158-159.degree. C. 37
##STR00041## 1-(4-Methanesulfonyl- phenyl)-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.98 (d, 2H); 7.65 (d, 2H); 5.90 (m, 1H); 4.52 (d, 1H);
3.77 (d, 1H); 3.05 (s, 3H); 2.84-2.68 (m, 2H); 2.57-2.42 (m, 1H);
2.11-1.93 (m, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe
250.degree. C.: 295.1 (MH+) 312.1 (MH + NH3+). mp: 143-145.degree.
C. 38 ##STR00042## 1-(4-Fluoro-phenyl)- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37 (m,
2H); 7.12 (dd, 2H); 5.78 (m, 1H); 4.47 (d, 1H); 3.74 (d, 1H);
2.80-2.56 (m, 2H); 2.46 (m, 1H); 2.08-1.93 (m, 1H). MS: AQA, ESI
Pos, 3.5 KV; source 30 V; probe 250.degree. C.: 235.1 (MH+). mp:
158-159.degree. C. 39 ##STR00043## 1-(4-Cyano-phenyl)-
tetrahydro-pyrrolo[1,2- a]imidazole-2,5-dione .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.72 (d, 2H); 7.60 (d, 2H); 5.87 (m, 1H);
4.52 (d, 1H); 3.76 (d, 1H); 2.84-2.68 (m, 2H); 2.57-2.43 (m, 1H);
2.14-1.94 (m, 1H). MS: AQA, ESI Pos, 3.5 KV;
source 30 V; probe 250.degree. C.: 242.1 (MH+). mp: 175-176.degree.
C. 40 ##STR00044## l-Pyridin-2-yl-tetrahydro-
pyrrolo[1,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3)
.delta.: 8.34 (ddd, 1H); 8.20 (ddd, 1H); 7.75 (ddd, 1H); 7.11 (ddd,
1H); 6.04 (dd, 1H); 4.52 (d, 1H); 3.79 (d, 1H); 3.09-2.97 (m, 1H);
2.75-2.84 (m, 1H); 2.41 (ddd, 1H); 2.15-2.00 (m, 1H). MS: AQA, ESI
Pos, 3.5 KV; source 30 V; probe 250.degree. C.: 218.4 (MH+). mp:
139-140.degree. C. 41 ##STR00045## 1-Pyridin-3-yl-tetrahydro-
pyrolo[l,2-a]imidazole- 2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.:
8.55 (m, 2H); 8.04 (d, 1H); 7.39 (m, 1H); 5.88 (m, 1H); 4.50 (d,
1H); 3.75 (d, 1H); 2.84-2.67 (m, 2H); 2.58-2.40 (m, 1H); 2.14-1.95
(m, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe 250.degree.
C.: 218.4 (MH+) mp: 180-182.degree. C. 42 ##STR00046##
1-(5-Methylpyridin-2-yl)- tetrahydropyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 8.15 (d.
1H); 8.07 (d, 1H); 7.55 (dd, 1H); 6.02 (dd, 1H); 4.49 (d, 1H); 3.77
(d, 1H); 3.05-2.94 (m, 1H);; 2.77-2.62 (m, 1H); 2.40 (ddd, 1H);
2.31 (s, 3H); 2.12-1.97 (m, 1H). MS: AQA, ESI Pos, 3.5 KV; source
30 V; probe 250.degree. C.: 232.1 (MH+). mp 158-159.degree. C. 43
##STR00047## l-(2-Cyano-phenyl)- tetrahydro-pyrrolo[1,2-
a]imidazole-2,5-dione .sup.1H-NMR (CDCl.sub.3) .delta.: 7.78 (d.
1H); 7.70 (dd, 1H); 7.48 (dd, 1H); 7.38 (d, 1H); 5.95 (m, 1H); 4.50
(d, 1H); 3.81 (d, 1H); 2.85-2.64 (m, 1H); 2.58- 2.41 (m, 2H);
2.08-1.93 (m, 1H). MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe
250.degree. C.: 242.1 (MH+). mp: 94-95.degree. C. 44 ##STR00048##
1-(3-Fluoro-phenyl)- tetrahydro-pyrrolo[1,2- a]imdazole-2,5-dione
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.38 (ddd, 1H); 7.29 (ddd, 1H);
7.15 (ddd, 1H); 6.95 (dddd, 1H); 5.81 (m, 1H); 4.49 (d, 1H); 3.75
(d, 1H); 2.85-2.65 (m, 2H); 2.53-2.40 (m, 1H); 2.13-1.97 (m, 1H).
MS: AQA, ESI Pos, 3.5 KV; source 30 V; probe 250.degree. C.: 235.1
(MH+). mp: 148-149.degree. C. indicates data missing or illegible
when filed
Pharmacological Methods
Chronic Constriction Injury Model
[0129] A peripheral mononeuropathy was produced in adult rats by
placing loosely constrictive ligatures around the common sciatic
nerve according to the method described by Bennett & Xie (Pain
1988, 33, 87-107).
[0130] Rats were anesthetized with chloral hydrate. The common
sciatic nerve was exposed at the level of the middle of the thigh
by blunt dissection through biceps femoris. Proximal to sciatica's
trifurcation, about 1 cm of the nerve was freed of adhering tissue
and four ligatures (3/0 silk tread) were tied loosely around it
with about 1 mm spacing. The length of the nerve thus affected was
1 cm long. Great care was taken to tie the ligatures such that the
diameter of the nerve was seen to be just barely constricted when
viewed with 40.times. magnification. The left paw was
untouched.
Paw Pressure Test
[0131] The nociceptive threshold in the rat was determined with an
analgesimeter (Ugo Basile, Varese, Italy), according to the method
described by Leighton et al. (Br. J. Pharmacol. 1988, 93, 553-560).
Rats scoring below 40 g or over 75 g during the test before drug
administration (25%) were rejected. An arbitrary cut-off value of
250 g was adopted.
[0132] All experiment were performed on rats submitted to
paw-pressure test 14 days after the operation since at this time a
significantly reduction of the pain threshold of the injured paw
(dx) was observed.
[0133] Gabapentin (30 .mu.g i.c.v.), levetiracetam (300 .mu.g
i.c.v.), dimiracetam (100 .mu.g i.c.v.), Example 1 (10 .mu.g
i.c.v.), Example 2 (10 .mu.g i.c.v.), Example 5 (3 .mu.g i.c.v.),
Example 6 (3 .mu.g i.c.v.), Example 13 (30 .mu.g i.c.v.) and
Example 22 (30 .mu.g i.c.v.) of the present invention showed an
antihyperalgic effect when compared with saline or vehicle treated
group. All compounds did not modify pain threshold in
contralateral, non operated, paw. It should be noted that all
compounds elicited their antihyperalgic effect without changing
animals' gross behavior and spontaneous motility in comparison with
saline/vehicle treated rats. Furthermore no modification of motor
coordination was revealed by the rat rota-rod test (Vaught J. et
al. Neuropharmacology 1985, 24, 211-216).
TABLE-US-00002 EFFECT OF COMPOUNDS OF THE INVENTION AND REFERENCE
COMPOUNDS (i.c.v.) IN A RAT MODEL OF MONONEUROPATHY dx EVALUATED IN
THE PAW-PRESSURE TEST Paw pressure in rats (g) Before After
TREATMENT (I.C.V.) PAW Treatment Treatment SALINE dx 24.3 .+-. 2.9
23.7 .+-. 2.5 VEHICLE dx 26.5 .+-. 3.5 22.9 .+-. 3.6 GABAPENTIN 30
.mu.g dx 24.5 .+-. 4.7 46.3 .+-. 4.2* LEVETIRACETAM 300 .mu.g dx
24.0 .+-. 3.9 37.3 .+-. 4.6{circumflex over ( )} DIMIRACETAM 100
.mu.g dx 25.1 .+-. 2.4 42.8 .+-. 2.5* EXAMPLE 1 10 .mu.g dx 26.0
.+-. 2.2 36.3 .+-. 5.1{circumflex over ( )} EXAMPLE 2 10 .mu.g dx
23.5 .+-. 4.0 42.2 .+-. 3.9* EXAMPLE 5 3 .mu.g dx 27.7 .+-. 2.8
39.3 .+-. 4.5{circumflex over ( )} EXAMPLE 6 3 .mu.g dx 26.7 .+-.
3.6 46.1 .+-. 5.0{circumflex over ( )} EXAMPLE 13 30 .mu.g dx 28.5
.+-. 2.9 55.4 .+-. 4.7* EXAMPLE 22 30 .mu.g dx 25.4 .+-. 2.7 48.5
.+-. 4.6* Each value represents the mean of at least 8 rats (two
separate experiments). All compounds were administered 30-45 min
before test. {circumflex over ( )}P < 0.05; *P < 0.01
* * * * *