U.S. patent application number 12/232399 was filed with the patent office on 2009-01-15 for n-phenylpyrrole guanidine derivatives as melanocortin receptor ligands.
This patent application is currently assigned to ACTION PHARMA A/S. Invention is credited to Per Andersson, Victor Andrianov, Arne Boman, Torbjorn Lundstedt, Elisabeth Seifert, Anna Skottner.
Application Number | 20090018183 12/232399 |
Document ID | / |
Family ID | 9919909 |
Filed Date | 2009-01-15 |
United States Patent
Application |
20090018183 |
Kind Code |
A1 |
Lundstedt; Torbjorn ; et
al. |
January 15, 2009 |
N-phenylpyrrole guanidine derivatives as melanocortin receptor
ligands
Abstract
The present invention provides novel compounds of the general
Formula (I) as ligands to the melanocortin receptors and/or for
treatment of disorders in the melanocortin system: ##STR00001##
wherein X is (CH.sub.2).sub.n where n is 0, 1 or 2; R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may be the same or different
and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon
atoms, alkoxy having 1 to 5 carbon atoms, hydroxy,
alkylsulphonyloxy, cyano, nitro, trihaloalkyl, sulpho or one of the
structures given in Scheme 1; or two of R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 may together form a methylenedioxy or
ethylenedioxy moiety; ##STR00002## R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are the same or different and are selected from hydrogen,
halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5
carbon atoms, hydroxy, amines (primary, secondary or tertiary)
having 0, 1 or 2 carbon atoms, cyano, nitro, trihaloalkyl, amide or
sulpho, and z where shown represents the point of attachment of the
residue to the phenyl or pyrrole ring; and the pharmacologically
active salts thereof.
Inventors: |
Lundstedt; Torbjorn;
(Uppsala, SE) ; Skottner; Anna; (Ekero, SE)
; Boman; Arne; (Uppsala, SE) ; Andersson; Per;
(Sollentuna, SE) ; Seifert; Elisabeth; (Uppsala,
SE) ; Andrianov; Victor; (Riga, LV) |
Correspondence
Address: |
BACON & THOMAS, PLLC
625 SLATERS LANE, FOURTH FLOOR
ALEXANDRIA
VA
22314-1176
US
|
Assignee: |
ACTION PHARMA A/S
Arthus N
DK
|
Family ID: |
9919909 |
Appl. No.: |
12/232399 |
Filed: |
September 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11374956 |
Mar 15, 2006 |
7442807 |
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12232399 |
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10484444 |
Jan 29, 2004 |
7186748 |
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PCT/GB02/03620 |
Aug 6, 2002 |
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11374956 |
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Current U.S.
Class: |
514/427 |
Current CPC
Class: |
C07D 207/36 20130101;
A61P 9/10 20180101; A61P 15/00 20180101; A61P 25/04 20180101; A61P
25/18 20180101; C07D 207/34 20130101; A61P 25/28 20180101; A61P
37/08 20180101; A61P 15/08 20180101; C07D 207/38 20130101; A61P
7/00 20180101; A61P 25/00 20180101; A61P 25/02 20180101; A61P 5/00
20180101; A61P 3/10 20180101; A61P 3/00 20180101; A61P 35/04
20180101; A61P 17/00 20180101; C07D 207/42 20130101; A61P 43/00
20180101; A61P 3/04 20180101; A61P 29/00 20180101; A61P 35/00
20180101; C07D 207/335 20130101; A61P 1/14 20180101; A61P 17/16
20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/427 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61P 3/00 20060101 A61P003/00; A61P 25/00 20060101
A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2001 |
GB |
0119172.5 |
Claims
1-59. (canceled)
60. A method of treating a disease associated with the melanocortin
receptors or related systems, e.g. the melanocyte stimulating
hormones, comprising the use or administration of an effective
amount of a compound of I formula (I), or tautomeric forms thereof:
##STR00007## wherein X is (CH.sub.2).sub.n where n is 0, 1 or 2;
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may be the same or
different and are selected from hydrogen, halogen, alkyl having 1
to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, hydroxy,
alkylsulphonyloxy, cyano, nitro, trihaloalkyl, sulpho and any of
the following structures: ##STR00008## and/or two of R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may together form a
methylenedioxy or ethylenedioxy moiety; R.sub.6, R.sub.7, R.sub.8
and R.sub.9 are the same or different and are selected from
hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having
1 to 5 carbon atoms, hydroxy, amines (primary, secondary or
tertiary) having 0, 1 or 2 carbon atoms, cyano, nitro,
trihaloalkyl, amide or sulpho, and z where shown represents the
point of attachment of the residue to the phenyl or pyrrole ring;
or a pharmaceutically acceptable salt thereon, in a
pharmaceutically acceptable carrier
61. The method as claimed in claim 60, wherein in the compound of
formula I, at least two of the substituents R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are hydrogen.
62. The method as claimed in claim 60, wherein in the compound of
formula I, wherein alkyl is methyl, ethyl, n-butyl, n-pentyl or
tert-butyl.
63. The method as claimed in claim 60, wherein in the compound of
formula I, wherein alkoxy is methoxy, ethoxy, propyloxy, butoxy or
tert-butoxy.
64. The method as claimed in claim 60, wherein in the compound of
formula I, wherein R.sub.6, R.sub.7 and R.sub.8 are hydrogen.
65. The method as claimed in claim 60, wherein in the compound of
formula I, wherein halogen is selected from fluoro, chloro or
bromo.
66. The method as claimed in claim 60, wherein in the compound of
formula I, wherein n=0.
67. The method as claimed in claim 60, wherein in the compound of
formula I, wherein R.sub.5 is hydrogen.
68. The method as claimed in claim 60, wherein in the compound of
formula I, wherein R.sub.3 is hydrogen.
69. The method as claimed in claim 60, wherein in the compound of
formula I, wherein R.sub.4 is hydrogen.
70. The method as claimed in claim 60, wherein in the compound of
formula I, wherein the --X--CH.dbd.N--NH--C(.dbd.NH)--NH.sub.2
moiety is in the 2 position of the pyrrole ring.
71. The method as claimed in claim 60, wherein in the compound of
formula I, wherein R.sub.1 and R.sub.2 are positioned in the 3, 4
or 5 position in the phenyl ring.
72. The method as claimed in claim 60, wherein in the compound of
formula I, is TABLE-US-00006 No. Name 1
N-{1-[(4-Chlorophenyl)-1H-Pyrrol-2- yl]methyleneamino}guanidine 2
N-[1-(5-propylamino-1-(2-butoxyphenyl)-1H-pyrrol-2-yl)-
methyleneamino]-guanidine 3
N-{3-[1-(2-Isobutyrylphenyl)-5-nitro-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 4
N-{1-[1-(3-Cyanophenyl)-5-trifluoromethyl-1H-pyrrol-2-yl]-
methyleneamino}-guanidine 5
N-{3-[1-(3-Fluorophenyl)-5-methyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 6
N-[1-(4-Aminophenyl)-5-hydroxy-1H-pyrrol-2-
ylmethylideneamino]-guanidine 7
N-{3-[1-(4-Chlorophenyl)-5-phenethyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 8
N-{3-[1-(4-Propylaminophenyl)-5-trichloromethyl-1H-pyrrol-3-
yl]-propylideneamino}-guanidine 9
N-(5-tert-Butyl-1-phenyl-1H-pyrrol-2-ylmethylideneamino)- guanidine
10 N-[3-(5-Methoxy-1-phenyl-1H-pyrrol-3-yl)-propylideneamino]-
guanidine 11 N-[4-Pentyl-1-(2-trichloromethylphenyl)-1H-pyrrol-3-
ylmethylideneamino]-guanidine 12
N-(4-Cyano-1-o-tolyl-1H-pyrrol-3-ylmethylideneamino)- guanidine 13
N-{3-[4-Hydroxy-1-(3-trichloromethylphenyl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 14
N-{3-[1-(3-tert-Butylphenyl)-5-isobutyryl-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 15
N-(1-Biphenyl-4-yl-4-chloro-1H-pyrrol-2-ylmethylideneamino)-
guanidine 16 N-{3-[1-(4-Bromophenyl)-4-tert-butyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 17
N-(4-Butoxy-1-phenyl-1H-pyrrol-3-ylmethylideneamino)- guanidine 18
N-[3-(4-Methoxy-1-phenyl-1H-pyrrol-2-yl)-propylideneamino]-
guanidine 19
N-{3-[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]-propylideneamino}-
guanidine 20
N-{3-[1-(2-Hydroxyphenyl)-1H-pyrrol-2-yl]-propylideneamino}-
guanidine 21
N-[1-(3-Methoxyphenyl)-1H-pyrrol-2-ylmethylideneamino]- guanidine
22 N-[1-(3-Butylaminophenyl)-1H-pyrrol-3-ylmethylideneamino]-
guanidine 23
N-[1-(4-tert-Butylphenyl)-1H-pyrrol-3-ylmethylideneamino]-
guanidine 24 N-{3-[1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 25
N-(1-Phenyl-1H-pyrrol-3-ylmethylideneamino)-guanidine 26
N-[3-(1-Phenyl-1H-pyrrol-2-yl)-propylideneamino]-guanidine 29
N-[3-(4-Methyl-1-phenyl-1H-pyrrol-3-yl)-propylideneamino]-
guanidine 30 N-[1-(3-Nitro-4-propylaminophenyl)-1H-pyrrol-3- 30
ylmethylideneamino]-guanidine 31
N-{3-[1-(3-Butylamino-4-methyl-phenyl)-4-methyl-1H-pyrrol-2- 31
yl]-propylidene}-guanidine 32
N-{3-[5-Bromo-1-(4-bromophenyl)-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 33
N-[(5-Chloro-1-(4-isobutyrylphenyl)-4-pentyl-1H-pyrrol-2-
yl)methyleneamino]-guanidine 34
N-[3-(5-Propoxy-1-m-tolyl-1H-pyrrol-2-yl)-propylideneamino]-
guanidine 35
N-[4-Methyl-5-propylamino-1-(3-trichloromethyl-phenyl)-1H-
pyrrol-3-ylmethylideneamino]-guanidine 36
N-{3-[1-(3-Nitro-biphenyl-4-yl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 37
N-{2-[4-tert-Butyl-1-(4-methoxy-2-propylaminophenyl)-1H-
pyrrol-3-yl]-ethylideneamino}-guanidine 38
N-{3-[1-(2-Bromo-3-chlorophenyl)-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 39
N-[4-Bromo-1-(2-butoxy-3-propoxyphenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 40
N-[5-Hydroxy-1-(2-hydroxyphenyl)-1H-pyrrol-3-
ylmethylideneamino]-guanidine 41
N-{3-[1-(2-tert-Butylphenyl)-4-chloro-5-methyl-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 42
N-[5-lsobutyryl-1-(2,3,4-trimethoxyphenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 43
N-{3-[5-tert-Butyl-1-(2-tert-butyl-3,4-bis-trichloromethylphenyl)-
4-trichloromethyl-1H-pyrrol-2-yl]-propylideneamino}-guanidine 44
N-{2-[1-(4-Pyrrol-1-ylphenyl)-1H-pyrrol-2-yl]-ethylideneamino}-
guanidine 45 N-[1-(4-Morpholin-4-ylphenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 46
N-[1-(4-Pyrrolidin-1-ylphenyl)-1H-pyrrol-3-ylmethylidenamino]-
guanidine 47 N-((1-Phenyl-1H-pyrrol-2-yl)methyleneamino)guanidine
48 N-[(1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine 49 N-[(1-(3-cyanophenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine 50
N-[(1-(3,5-dichlorophenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine
or a pharmacologically acceptable salt thereof.
Description
[0001] The present invention relates to phenyl pyrrole
aminoguanidines. It further relates to the use of these guanidines
for the treatment of obesity, anorexia, inflammation, mental
disorders and other diseases associated with the melanocortin
receptors or related systems, e.g. the melanocyte stimulating
hormones.
[0002] A number of large linear and cyclic peptides are known in
the art which show high specific binding to melanocortin (MC)
receptors. The agonistic and/or antagonistic properties of these
peptides are also known. See for example "Melanocortin Receptor
ligands and methods of using same" by Dooley, Girten and Houghten
(WO99/21571).
[0003] A number of low molecular weight compounds are known, e.g.
isoquinolines, spiropyridines and benzimidazoles, which show
activity on the MC-receptors. See "Isoquinoline compound
melanocortin receptor ligands and methods of using same" by Basu et
al, Trega Biosciences Inc. (WO 99/55679), "Spiropiperidine
derivatives as melanocortin receptor agonists" by Nargung, Ye,
Palucki, Bakshi, Patchett and van der Ploeg (WO 99/64002) and
"Melanocortin receptor-3 ligands to treat sexual dysfunction" by
Dines et al. (WO0105401). See also, WO0074679, WO0058361,
WO0218327, WO0212166, WO0155106, WO0155107, WO0155109, WO0211715
and WO0212178 for additional compounds acting on the melanocortin
receptors.
[0004] However, there is still a large need to provide low
molecular weight compounds showing agonistic or antagonistic
properties to the melanocortin receptors. The compounds of the
present invention are structually different from the
above-mentioned compounds and, consequently, constitute a new class
of compounds that show activity to the MC-receptors.
[0005] A compound previously known in the art, which is similar to
the presented compounds, is given below (see e.g. WO98/23267);
##STR00003##
[0006] This hydroxyguanidine has proven activity against xanthine
oxidase/xanthine dehydrogenase enzymes. Therefore it is very
surprising that the phenyl pyrrole benzylideneamino guanidine
compounds in the present invention show affinity to the
melanocortin receptors as agonists and/or antagonists.
[0007] One aspect of the present invention is therefore to provide
low molecular weight compounds showing activity on melanocortin
receptors and which may be taken up after peroral administration
and which may penetrate well through the blood brain barrier.
[0008] The present invention provides novel compounds of the
general formula (I) and their tautomeric forms:
##STR00004##
wherein X is (CH.sub.2).sub.n where n is 0, 1 or 2; R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may be the same or different
and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon
atoms, alkoxy having 1 to 5 carbon atoms, hydroxy,
alkylsulphonyloxy, cyano, nitro, trihaloalkyl, sulpho or one of the
structures given in Scheme 1; and/or two of R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 may together form a methylenedioxy or
ethylenedioxy moiety (preferably such methylenedioxy or
ethylenedioxy moieties are formed using R.sub.4 and R.sub.5 and/or
two of R.sub.1, R.sub.2 and R.sub.3);
##STR00005##
R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are the same or different and
are selected from hydrogen, halogen, alkyl having 1 to 5 carbon
atoms, alkoxy having 1 to 5 carbon atoms, hydroxy, amines (primary,
secondary or tertiary) having 0, 1 or 2 carbon atoms, cyano, nitro,
trihaloalkyl, amide or sulpho, and z where shown represents the
point of attachment of the residue to the phenyl or pyrrole ring;
and the pharmacologically active salts thereof.
[0009] The term halogen includes fluoro, chloro, bromo and
iodo.
[0010] The term "alkyl" includes straight or branched hydrocarbon
chains. The term "alkoxy" includes straight and branched chain
alkoxy groups.
[0011] Preferably, the "alkyl having 1 to 5 carbon atoms" is a
lower alkyl such as methyl, ethyl, propyl, isopropyl or
tert-butyl.
[0012] Preferably, the "alkoxy having 1 to 5 carbon atoms" is a
lower alkoxy such as methoxy, ethoxy, propoxy, iso-propoxy or
tert-butoxy.
[0013] The term trihaloalkyl includes straight or branched
hydrocarbon chains, preferably having 1 to carbon atoms, and
includes trichloroalkyl and trifluoroalkyl.
[0014] Preferably, the trihaloalkyl is trihalomethyl, trihaloethyl,
trihalopropyl or trihaloiso-propyl.
[0015] Furthermore, it should be noted that the Scheme 1 residues
may be attached to the carbon backbone of the compound of general
formula (I) at any suitable point within the compound of Scheme 1,
preferably at the 1, 2 or 3 position.
[0016] The compounds of formula (I) have basic properties and,
consequently, they may be converted to their therapeutically active
acid addition salts by treatment with appropriate physiologically
acceptable acids, e.g. inorganic acids such as hydrochloric,
hydrobromic, hydriodic, sulphuric, nitric and phosphoric acid, or
organic acids such as acetic, propanoic, glycolic, lactic, malonic,
succinic, fumaric, tartaric, citric, pamoic, oxalic and
para-toluene-sulphonic acid.
[0017] Conversely, the salt form may be converted into the free
base form by treatment with alkali.
[0018] The present invention relates to novel aromatic amines.
Compounds of the present invention have been biologically tested in
the melanocortin system and have surprisingly been shown to be
capable of binding to melanocortin receptors as well as showing
activity in functional assays.
[0019] Compounds of the present invention are either agonists or
antagonists of a specific MC-receptor or of a number of
MC-receptors, e.g. MC1, MC3, MC4 or/and MC5 receptors.
[0020] The MC-receptors belong to the class of G-protein coupled
receptors which are all built from a single polypeptide forming 7
transmembrane domains. Five such receptors types, termed MC1, MC2,
MC3, MC4 and MC5, have been described. The MC receptor's signaling
is mainly mediated via cAMP but also other signal transduction
pathways are known. They are distinctly distributed in the
body.
[0021] MC-receptors are linked to a variety of physiological
actions that are thought to be mediated by distinct subtypes of the
MC-receptors. In many cases, however, it is not entirely clear
which of the subtypes is responsible for the effect.
[0022] It has long been known that MSH-peptides may affect many
different processes such as motivation, learning, memory, behaviour
(including feeding and sexual), inflammation (including
immunostimulatory and immunosuppressive), body temperature, pain
perception, blood pressure, heart rate, vascular tone, brain blood
flow, trophic effects in different organs, nerve growth, placental
development, endocrine and exocrine functions, aldosterone
synthesis and release, thyroxin release, spermatogenesis, ovarian
weight, prolactin and FSH secretion, effects or other hormones,
uterine bleeding in women, sebum and pheromone secretion, blood
glucose levels, natriuresis, intrauterine foetal growth, as well as
other events surrounding parturition (Eberle, A N: The
melanotropins: Chemistry, physiology and mechanisms of action.
Basel: Karger, Switzerland. 1988, ISBN 3-8055-4678-5; Gruber, and
Callahan, Am. J. Physiol. 1989, 257, R681-R694; De Wildt et al., J.
Cardiovascular Pharmacology. 1995, 25, 898-905), as well as
inducing natriuresis (Lin et al., Hypertension. 1987, 10,
619-627).
[0023] It is also well-known that the immunomodulatory action of
.alpha.-MSH includes both immunostimulatory and immunosuppressive
effects. Several studies have shown that .alpha.-MSH antagonizes
the effects of pro-inflammatory cytokines such as IL-1.alpha.,
IL-1.beta., IL-6 and TNF.alpha., and induces the production of the
anti-inflammatory cytokine, IL-10 (for review see Catania &
Lipton, 1993).
[0024] Eating behaviour is regulated by a complex network of
physiological regulatory pathways that involve both the central
nervous system and peripheral sites. Factors such as leptin,
insulin, NPY (neuropeptide Y), orexins, CRF
(Corticotropin-Releasing Factor, release hormone) and melanocortic
peptides (Schwartz; Nature Medicine 1998, 4, 385-386) are known to
control the amount of food intake both during short and long term,
which may affect body weight, body fat mass and growth rate. Recent
studies have shown a role of MC-receptors, especially the MC4
receptor, for control of food intake, and there is evidence
indicating that the melanocortins and the MC4 receptor are
important factors downstream of leptin. Intracerebroventricular
injections of the melanocortic peptides .alpha.-MSH and ACTH(1-24)
have been shown to markedly inhibit feeding (Poggioli et al.,
Peptides, 1986, 7, 843-848; Vergoni et al., Neuropeptides, 1986, 7,
153-158).
[0025] The MC5-receptor has recently been attributed a role in
control of exocrine gland function (van der Kraan, et al.,
Endocrinol. 1998, 139, 2348-2355; Chen et al., Cell. 1997, 91,
789-798).
[0026] In addition, the melanocortic peptides have distinct effects
on sexual functions in that they cause erection in males (Donovan,
Psychol. Med. 1978, 8, 305-316), presumably mediated by a central
agonistic effect of the peptide on MC-receptors. It has also been
shown that a MC-receptor blocker could inhibit the erectogenic
effect of melanocortic peptides (Vergoni et al., Eur. J. Pharmacol,
1998, 362; 95-101).
[0027] Compounds of formula (I) and/or their pharmaceutically
acceptable salts have valuable pharmacological properties, making
them useful for the treatment of mental disorders such as
psychoses, depression, anxiety, senile dementia, Alzheimer's
disease, drug abuse disorders and eating disorders such as anorexia
and bulimia.
[0028] Compounds of formula (I) and/or their pharmaceutically
acceptable salts have valuable pharmacological properties, making
them useful for the treatment of dysfunctions of the endocrine
system and other hormonal systems such as excessive menstruations,
endometriosis, events related to parturition, dysfunctions related
to prolactin, dysfunctions related to growth hormone, dysfunctions
related to testosterone, dysfunctions related to estrogen,
dysfunctions related to glucocorticoids, dysfunctions related to
luteinizing hormone and follicle stimulating hormone, inducing
abortion, for prevention of abortion and/or for treatment of events
related to parturition.
[0029] Compounds of formula (I) and/or their pharmaceutically
acceptable salts have valuable pharmacological properties, making
them useful for the treatment of sexual functions/dysfunctions such
as inducing erection in man, to induce erection in animal breeding,
to stimulate intercourse in animals which are difficult to mate, in
particular rare species or valuable strains, pets, cats, dogs,
horses or to reduce sexual behaviour in animals, e.g. for pets,
cats etc., to treat impotence and disorders related to sexual
drive, including lack of sexual drive or abnormal sexual drive in
both men and women.
[0030] Compounds of formula (I) and/or their pharmaceutically
acceptable salts have valuable pharmacological properties, making
them useful for the treatment of inflammation such as inflammations
related to the production of nitric oxide, inflammation related to
increased amounts (upregulated amounts) of inducible nitric oxide
synthase, inflammation related to activation of transcriptional
activators, inflammation related to nuclear factor kappa beta,
inflammation related to macrophages, neutrophils, monocytes,
keratinocytes, fibroblasts, melanocytes, pigment cells and
endothelial cells, inflammation related to increased production
and/or release of inflammatory cytokines, such as e.g.
interleukins, in particular interleukin 1 (IL-1), interleukin 6
(IL-6) and tumor necrosis factor a (TNF-.alpha.).
[0031] In the present specification, "increased production" refers
to increased formation, increased release, or increased amount of
an endogenous compound locally, regionally or systemically in a
patient compared to the amount of said endogenous compound in a
healthy individual. In the present specification, "upregulated"
refers to an increased activity or amount of the compound compared
with that in a healthy individual.
[0032] In the present specification, "decreased production" refers
to decreased formation, decreased release, or decreased amount of
an endogenous compound in a patient compared to the amount of said
endogenous compound in a healthy individual. In the present
specification, "downregulated" refers to a decreased activity or
amount of the compound compared with that in a healthy
individual.
[0033] In particular, positive treatment effects or preventive
effects may be seen in conditions where inflammation or an
inflammatory-like condition is caused by or being associated with
one or more of the following: allergy, hypersensitivity, bacterial
infection, viral infection, inflammation caused by toxic agent,
fever, autoimmune disease, radiation damage by any source including
UV-radiation, X-ray radiation, .gamma.-radiation, .alpha.- or
.beta.-particles, sun burns, elevated temperature or mechanical
injury. Moreover, inflammation due to hypoxia, which is optionally
followed by reoxygenation of the hypoxic area, is typically
followed by severe inflammation, which condition may be positively
affected by treatment with a compound of the invention.
[0034] In very specific embodiments of the invention, a compound of
the invention may be administered for the prevention or therapeutic
treatment of inflammatory diseases of the skin (including the
dermis and epidermis) of any origin, including skin diseases having
an inflammatory component. Specific examples of this embodiment of
the invention include treatment of contact dermatitis of the skin,
sunburns of the skin, burns of any cause, and inflammation of the
skin caused by chemical agents, psoriasis, vasculitis, pyoderma
gangrenosum, discoid lupus erythematosus, eczema, pustulosis
palmo-plantaris, and phemphigus vulgaris.
[0035] Also comprised by the invention is the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of an inflammatory disease in the
abdomen, including an abdominal disease having an inflammatory
component. Specific examples of the treatment of such a disease
with a compound of the invention are gastritis, including one of
unknown origin, gastritis perniciosa (atrophic gastritis), ulcerous
colitis (colitis ulcerosa), morbus Crohn, systemic sclerosis, ulcus
duodeni, coeliac disease, oesophagitis and ulcus ventriculi.
[0036] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of systemic or general and/or local
immunological diseases, including those of an autoimmune nature,
and other inflammatory diseases of a general nature. Specific
examples include treatment of rheumatoid arthritis, psoriatic
arthritis, systemic sclerosis, polymyalgia rheumatica, Wegener's
granulomatosis, sarcoidosis, eosinophilic fasceitis, reactive
arthritis, Bechterew's disease, systemic lupus erythematosus,
arteritis temporalis, Behcet's disease, morbus Burger, Good
Pastures' syndrome, eosinophilic granuloma, fibromyalgia, myositis,
and mixed connective tissue disease. Included therein is also
arthritis, including arthritis of unknown origin.
[0037] Further included in the invention is administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of a disease of the peripheral and/or
central nervous system related to inflammation. Included in this
aspect of the invention is the treatment of cerebral vasculitis,
multiple sclerosis, autoimmune ophthalmitis and polyneuropathia.
Comprised by the invention is also the administration of a compound
of the invention for the treatment of an inflammation of the
central nervous system to prevent apoptotic cell death. Moreover,
as some of the compounds of the invention show a distinct ability
to induce nerve regeneration, positive treatment effects are often
seen in central nervous system diseases involving damage of cells
in this region. This aspect of the invention also includes
treatment of traumatic injuries to the central nervous system,
brain edema, multiple sclerosis, Alzheimer's disease, bacterial and
viral infections in the central nervous system, stroke, and
haemorrhagia in the central nervous system.
[0038] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases of the eye and tear glands
related to inflammation. Specific examples of such diseases
comprise anterior and posterior uveitis, retinal vasculitis, optic
neuritis, optic neuromyelitis, Wegener's granulomatosis, Sjogren's
syndrome, episcleritis, scleritis, sarcoidosis affecting the eye
and polychondritis affecting the eye.
[0039] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the of diseases of the ear related to inflammation,
specific examples of which include polychondritis affecting the ear
and external otitis.
[0040] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases of the nose related to
inflammation, specific examples of which are sarcoidosis,
polychondritis and mid-line granuloma of the nose.
[0041] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to inflammation of
the mouth, pharynx and salivary glands. Specific examples include
Wegener's granulomatosis, mid-line granuloma, Sjogren's syndrome
and polychondritis in these areas.
[0042] Included in the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to inflammation in
the lung. Specific examples include treatment of idiopathic
alveolitis, primary pulmonary hypertension, bronchitis, chronic
bronchitis, sarcoidosis, alveolitis in inflammatory systemic
disease, pulmonary hypertension in inflammatory systemic disease,
Wegener's granulomatosis and Good Pastures' syndrome.
[0043] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to the inflammation
of the heart. Specific examples include treatment of pericarditis,
idiopathic pericarditis, myocarditis, Takayasus' arteritis,
Kawasaki's disease, coronary artery vasculitis, pericarditis in
inflammatory systemic disease, myocarditis in inflammatory systemic
disease, endocarditis and endocarditis in inflammatory systemic
disease.
[0044] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to inflammation of
the liver. Specific examples include treatment of hepatitis,
chronic active hepatitis, biliary cirrhosis, hepatic damage by
toxic agents, interferon induced hepatitis, hepatitis induced by
viral infection, liver damage induced by anoxia and liver damage
caused by mechanical trauma.
[0045] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to inflammation of
the pancreas. Specific examples include treatment (and prevention)
of diabetes mellitus, acute pancreatitis and chronic
pancreatitis.
[0046] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to the inflammation
of the thyroidea. Specific examples of these embodiments of the
invention include treatment of thyreoiditis, autoimmune
thyreoiditis and Hashimoto's thyreoiditis.
[0047] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to inflammation of
the kidney. Specific examples include treatment of
glomerulonephritis, glomerulonephritis in systemic lupus
erythematosus, periarteritis nodosa, Wegener's granulomatosis,
Good-Pastures' syndrome, HLAb27 associated diseases, IgA nephritis
(IgA=Immunoglobulin A), pyelonephritis, chronic pyelonephritis and
interstitial nephritis.
[0048] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to the inflammation
of the joints. Specific examples include treatment of Bechterew's
disease, psoriatic arthritis, rheumatoid arthritis, arthritis in
colitis ulcerosa, arthritis in morbus Crohn, affection of joints in
systemic lupus erythematosus, systemic sclerosis, mixed connective
tissue disease, reactive arthritis, Reiter's syndrome. Moreover,
included in this embodiment of the invention is treatment of
arthrosis of any joint, in particular arthrosis of finger joints,
the knee and the hip.
[0049] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of diseases related to the inflammation
of blood vessels. Specific examples include treatment of arteritis
temporalis, periarteritis nodosa, arteriosclerosis, Takayasus'
arteritis and Kawasaki's disease. Particularly advantageous is the
capacity of some compounds of the invention to afford protection
against and prevention of arteriosclerosis. This is in part due to
the capacity of some compounds of Formula (I) or the
pharmacologically acceptable salts thereof to prevent the induction
of inducible nitric oxide synthesis (iNOS) caused by the action of
oxidized Low Density Lipoprotein on endothelial cells and blood
vessel walls.
[0050] Comprised by the invention is also the administration of a
compound of the invention for the treatment of drug-induced
disorders of the blood and lymphoid system, including the treatment
of drug-induced hypersensitivity (including drug hypersensitivity)
affecting blood cells and blood cell forming organs (e.g. bone
marrow and lymphoid tissue). Specific embodiments of this aspect of
the invention include the treatment of anemia, granulocytopenia,
thrombocytopenia, leukopenia, aplastic anemia, autoimmune hemolytic
anemia, autoimmune thrombocytopenia and autoimmune
granulocytopenia.
[0051] The compounds of the invention may also be administered for
the treatment of fast allergic disorders (Type I allergy). Included
in this embodiment of the invention is the treatment of
anaphylactic reactions, anaphylactoid reactions, asthma, asthma of
allergic type, asthma of unknown origin, rhinitis, hay fever and
pollen allergy.
[0052] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of inflammation related to infections of
any origin. Specific examples include treatment of inflammation
secondary to infection caused by virus, bacteria, helminths and
protozoae.
[0053] Comprised by the invention is also the administration of a
compound of formula (I) or a pharmacologically acceptable salt
thereof for the treatment of inflammations related to trauma and/or
tissue injury of any origin.
[0054] Compounds of formula (I) or pharmaceutically acceptable
salts thereof have valuable pharmacological properties, making them
useful for the treatment of disorders of the cardiovascular system
such as disorders related to blood pressure, heart rate, vascular
tone, natriuresis, bleeding, shock, disorders related to ischemia,
infarction, repercussion injuries, arrhythmias of the heart, in
particular during ischemia, or for the treatment of arrhythmias
associated with reoxygenation of a previously ischemic period of
the heart.
[0055] Compounds of formula (I) or the pharmaceutically acceptable
salts thereof have valuable pharmacological properties, making them
useful for the treatment of pain such as pain of central origin,
pain seen after damage to the CNS, stroke, infarction, pain of
peripheral origin, chronic pain, neuropathies and disorders where a
treatment effect is achieved by stimulation of receptors in the
periaqueductal grey area.
[0056] Because of the capacity of compounds of the invention to
stimulate pigment formation in epidermal cells, some of the
compounds of the invention may be also useful for inducing skin
tanning for cosmetic reasons, for treatment of vitiligo, or any
other condition where darkening of skin color is desired. Moreover,
because of the ability of some of the compounds of the invention to
inhibit pigment formation in cells of the skin, they may also be
useful for inducing lighter skin color for cosmetic reasons, or
during any condition where a lighter color of skin is desired.
[0057] Compounds of formula (I) or the pharmaceutically acceptable
salts thereof have valuable pharmacological properties, making them
useful to cause skin tanning, darkening the colour of the skin, to
induce melanin synthesis in the skin, to reduce skin tanning,
lightening the colour of the skin, to reduce or block melanin
synthesis in the skin, to cause anti-inflammatory actions in the
skin, to modulate epidermal growth, to improve wound healing, to
treat acne, seborrhoea, acne roseacea, conditions related to
malfunctions of the glands of the skin, e.g. sebacous glands and
over or underproduction of sebum.
[0058] Compounds of the invention are useful for inhibiting or
stimulating the in vivo formation of second messenger elements such
as cAMP. Such inhibition/stimulation may be used in cells or
crushed cell systems in vitro, e.g. for analytical or diagnostic
purposes.
[0059] For analytical and diagnostic purposes the compounds of the
invention may be used in radioactive form where they comprise one
or more radioactive labels or gamma or positron emitting isotopes,
to be used in radioligand binding for the quantification as well as
tissue localisation of MC-receptors, for analysis of
dissociation/association constants, and for imaging of in vivo
binding by the use of scintigraphy, positron emission tomography
(PEI) or single photon emission computed tomography (SPECT), or for
the diagnosis of disease and treatment of any malignancy where the
malignant cells contain MC receptors.
[0060] Alternatively the compounds of the invention can be labelled
with any other type of label that allows detection of the
respective compound, e.g. fluorescence, biotin, NMR, MRI, or labels
activated by gamma-irradiation, light photons or biochemical
processes, or by light or UV-light (the latter in order to obtain a
compound useful for covalent labelling of MC receptors by a
photoaffinity technique).
[0061] Compounds of formula (I) or the pharmacologically acceptable
salts thereof may also be tagged with a toxic agent (i.e.
doxotubicin, ricin, diphtheria toxin or other) and used for
targeted delivery to malignant cells bearing MC receptors, or
tagged with a compound capable of activating the endogenous immune
system for triggering the immune system (for example a compound,
monoclonal antibody or other, capable of binding to a T-cell
antigen, e.g. CD3 or other) for treatment of malignancies and other
MC receptor expressing diseases. The thus formed hybrid compound
will direct cytotoxic cells to the malignant melanoma cells or the
MC1-receptor bearing malignant cells and inhibit the tumor
growth.
[0062] Compounds of formula (I) or a pharmacologically acceptable
salt thereof may be attached to the antibody chemically by covalent
or non-covalent bond(s).
[0063] Compounds of the invention may be used for the treatment and
diagnosis of diseases, disorders and/or pathological conditions in
an animal, in particular in man.
[0064] The present invention also relates to a pro-drug which, upon
administration to an animal or a human, is converted to a compound
of the invention. Pro-drugs of the compounds of Formula (I) and
their pharmacologically acceptable salts may be used for the same
purposes as described in this specification for the compounds of
the invention, as well as is disclosed in the Examples given
below.
[0065] The compounds of the present invention may be bound
covalently or non-covalently to one or several of other molecule(s)
of any desired structure(s); the thus formed modified compound or
complex may be used for the same purposes as described in this
specification for the compounds of the invention, as well as is
disclosed in the Examples given below. In a particularly important
embodiment of the invention, a radioactively-labelled molecule is
covalently bound to a compound of Formula (I) or a
pharmacologically acceptable salt thereof so as to make a compound
of Formula (I) or a pharmacologically acceptable salt thereof
radioactively labelled.
[0066] Some of the compounds of the invention have an effect on
xanthine oxidase in mammals, including humans.
[0067] The invention also relates to processes for the manufacture
of and pharmaceutical preparations comprising one or more of the
compounds of the invention, as well as to their uses for various
medical and veterinary practices related to melanocyte stimulating
hormone receptors.
[0068] Compounds of the general formula II are either commercially
available or can be synthesised by methods well known in the art,
see for example "Advanced Organic Chemistry", by Jerry March or
"Organic Synthesis" by Michael B. Smith.
Methods of Preparation
[0069] We further provide a process for the preparation of a
compound of formula (I) as defined in above, in which a compound of
formula (II) wherein X, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are as previously defined, is reacted with an
aminoguanidine (III), or a salt or protected form thereof, using
procedures known per se in the art, and, following deprotection if
necessary or desired, a compound of formula (I) is obtained
##STR00006##
[0070] The following examples are intended to illustrate but not to
limit the scope of the invention, although the compounds named are
of particular interest for the intended purposes. The preparation
of the compounds of general formula (I) is presented schematically
in Example 1 below. Specific synthetic procedures are given in
methods 1-3. The compounds are numbered and listed with their
complete name below.
EXAMPLES
Example 1
[0071] The compounds of the invention may be prepared by the
following general method. IR, NMR, MS and elementary analysis have
confirmed the structures of the compounds. When melting points
(m.p.) are given, these are uncorrected.
Example 1
N-[1-((4-Chlorophenyl)-1H-Pyrrol-2-yl)methyleneamino]guanidine
[0072] 5 g (24.3 mmol) 1-(4-chlorophenyl)-pyrrol-2 carboxaldehyde
and 4.96 g (36.5 mmol) aminoguanidine bicarbonate was suspended in
500 ml acetonitrile. 120 ml acetic acid was added and the reaction
mixture was refluxed for 2 h. The solution was cooled and the
solvent was evaporated. The resulting crude product was dissolved
in ether and crystallised after four hours in the freezer. The
slightly yellow solid was recrystallised from acetonitrile/ethanol
(5:1) to give the pure product (1) as white crystals. Yield 3 g
(45%).
[0073] The novel compounds 2-50 were prepared in an analogous
manner:
Compounds 1-50
TABLE-US-00001 [0074] No. Name 1 N-{1-[(4-Chorophenyl)-1H-Pyrrol-2-
yl]methyleneamino}guanidine 2
N-[1-(5-propylamino-1-(2-butoxy-phenyl)-1H-pyrrol-2-yl)-
methyleneamino]-guanidine 3
N-{3-[1-(2-Isobutyryl-phenyl)-5-nitro-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 4
N-{1-[1-(3-(Cyanophenyl)-5-trifluoromethyl-1H-pyrrol-2-
yl]-methyleneamino}-guanidine 5
N-{3-[1-(3-Fluorophenyl)-5-methyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 6
N-[1-(4-Aminophenyl)-5-hydroxy-1H-pyrrol-2-
ylmethylideneamino]-guanidine 7
N-{3-[1-(4-Chlorophenyl)-5-phenethyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 8
N-{3-[1-(4-Propylaminophenyl)-5-trichloromethyl-1H-
pyrrol-3-yl]-propylideneamino}-guanidine 9
N-(5-tert-Butyl-1-phenyl-1H-pyrrol-2-ylmethylideneamino)- guanidine
10 N-[3-(5-Methoxy-1-phenyl-1H-pyrrol-3-yl)-
propylideneamino]-guanidine 11
N-[4-Pentyl-1-(2-trichloromethylphenyl)-1H-pyrrol-3-
ylmethylideneamino]-guanidine 12
N-(4-Cyano-1-o-tolyl-1H-pyrrol-3-ylmethylideneamino)- guanidine 13
N-{3-[4-Hydroxy-1-(3-trichloromethylphenyl)-1H-pyrrol-2-
yl]-propylideneamino}-guanidine 14
N-{3-[1-(3-tert-Butylphenyl)-5-isobutyryl-1H-pyrrol-2-
yl]-propylideneamino}-guanidine 15
N-(1-Biphenyl-4-yl-4-chloro-1H-pyrrol-2-ylmethylideneamino)-
guanidine 16 N-{3-[1-(4-Bromophenyl)-4-tert-butyl-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 17
N-(4-Butoxy-1-phenyl-1H-pyrrol-3-ylmethylideneamino)-guanidine 18
N-[3-(4-Methoxy-1-phenyl-1H-pyrrol-2-yl)-propylideneamino]-
guanidine 19 N-{3-[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 20
N-{3-[1-(2-Hydroxyphenyl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 21
N-[1-(3-Methoxyphenyl)-1H-pyrrol-2-ylmethylideneamino]- guanidine
22 N-[1-(3-Butylaminophenyl)-1H-pyrrol-3-ylmethylideneamino]-
guanidine 23
N-[1-(4-tert-Butylphenyl)-1H-pyrrol-3-ylmethylideneamino]-
guanidine 24 N-{3-[1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 25
N-(1-Phenyl-1H-pyrrol-3-ylmethylideneamino)-guanidine 26
N-[3-(1-Phenyl-1H-pyrrol-2-yl)-propylideneamino]- guanidine 29
N-[3-(4-Methyl-1-phenyl-1H-pyrrol-3-yl)-propylideneamino]-
guanidine 30 N-[1-(3-Nitro-4-propylaminophenyl)-1H-pyrrol-3-
ylmethylideneamino]-guanidine 31
N-{3-[1-(3-Butylamino-4-methylphenyl)-4-methyl-1H-pyrrol-2-
yl]-propylidene}-guanidine 32
N-{3-[5-Bromo-1-(4-bromophenyl)-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 33
N-[(5-Chloro-1-(4-isobutyrylphenyl)-4-pentyl-1H-pyrrol-2-
yl)methyleneamino]-guanidine 34
N-[3-(5-Propoxy-1-m-tolyl-1H-pyrrol-2-yl)-
propylideneamino]-guanidine 35
N-[4-Methyl-5-propylamino-1-(3-trichloromethylphenyl)-1H-
pyrrol-3-ylmethylideneamino]-guanidine 36
N-{3-[1-(3-Nitrobiphenyl-4-yl)-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 37
N-{2-[4-tert-Butyl-1-(4-methoxy-2-propylaminophenyl)-1H-
pyrrol-3-yl]-ethylideneamino}-guanidine 38
N-{3-[1-(2-Bromo-3-chlorophenyl)-1H-pyrrol-3-yl]-
propylideneamino}-guanidine 39
N-[4-Bromo-1-(2-butoxy-3-propoxyphenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 40
N-[5-Hydroxy-1-(2-hydroxyphenyl)-1H-pyrrol-3-
ylmethylideneamino]-guanidine 41
N-{3-[1-(2-tert-Butylphenyl)-4-chloro-5-methyl-1H-
pyrrol-2-yl]-propylideneamino}-guanidine 42
N-[5-Isobutyryl-1-(2,3,4-trimethoxyphenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 43
N-{3-[5-tert-Butyl-1-(2-tert-butyl-3,4-bis-
trichloromethylphenyl)-4-trichloromethyl-1H-pyrrol-2-yl]-
propylideneamino}-guanidine 44
N-{2-[1-(4-Pyrrol-1-ylphenyl)-1H-pyrrol-2-yl]-
ethylideneamino}-guanidine 45
N-[1-(4-Morpholin-4-yl-phenyl)-1H-pyrrol-2-
ylmethylideneamino]-guanidine 46
N-[1-4-Pyrrolidin-1-yl-phenyl)-1H-pyrrol-3-
ylmethylidenamino]-guanidine 47
N-((1-Phenyl-1H-pyrrol-2-yl)methyleneamino)guanidine 48
N-[(1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine 49 N-[(1-(3-cyanophenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine 50
N-[(1-(3,5-dichlorophenyl)-1H-pyrrol-2-
yl)methyleneamino]guanidine
Test 1. Affinity for the MC1-Receptor
[0075] The binding assay was carried out essentially as described
by Lunec et al, Melanoma Res 1992; 2; 5-12 using
I.sup.125-NDP-.alpha.MSH as ligand.
Test 2. Affinity for the MC3-Receptors, the MC4-Receptors and the
MC5-Receptors
[0076] The binding assays were carried out essentially as described
by Szardenings et al, J Biol Chem 1997; 272; 27943-27948 and
Schioth et al, FEBS Lett 1997; 410; 223-228 using
1125-NDP-.alpha.MSH as ligand.
Test 3. cAMP
[0077] The stimulation of cAMP was carried out essentially as
described by Schioth et al, Br J Pharmacol 1998; 124; 75-82,
however, the response is given relative to .alpha.-MSH.
TABLE-US-00002 TABLE 1a Affinity for MC-receptors Ki (.mu.M)
Compound MC1 MC3 MC4 MC5 1 0.42 15.6 5.1 17.5 48 1.20 0.07 7.8 50
0.70 12.84 3.60 7.52
TABLE-US-00003 TABLE 1b Influence on cAMP cAMP agonist/plateau
stim. .alpha.-MSH (%) Compound MC1 MC3 MC4 MC5 1 30 35 118 6 50
36
Example 2
In Vivo Effects on Food Intake
[0078] Compounds have been tested for their effects on food intake
and body weight in rats.
[0079] In order to investigate the agonistic effect, ie decrease in
food intake, of compounds, the nocturnal protocol was used.
[0080] Sprague-Dawley, male rats were used, which were cannulated
intracerebroventricularly. Stainless steel guide cannulae were
placed in the lateral ventricle and fixed in the skull. Animals
were acclimatized for a week before the experiments took place.
After the experiments were done, the rats were killed and placement
of the cannulae were checked.
Nocturnal Protocol:
[0081] Rats were cannulated as described above. They were used
without prior starvation, and compounds were administered at 5 pm
in a total volume of 5 ml. Doses of compound 2:4 used were 1, 4 and
10 nmoles. Food intake was measured at 3, 15 and 24 hours after
dosing, and body weight was recorded at 24 hours. For comparison,
the well known MC4 receptor agonist, Melanotan II (MTII) was used,
at a dose of 1 nmole.
Example 3
Anti Inflammatory Effects
Control
[0082] Female BALB/c mice (weight 20-22 g) were sensitized by
treatment of the shaved abdomen with 30 .mu.l of 0.5%
2,4-dinitrofluorobenzene (DNFB). After 4 days they were challenged
with 10 .mu.l of 0.3% DNFB to the paw. The unchallenged mice paws
served as a control. Twenty-four hours after the last challenge,
the difference in paws weight were determined as an indicator of
the inflammation (paw edema).
Alpha-MSH and Prednisolone Controls
[0083] Mice were treated as the control but were additionally
injected i.p. with .alpha.-MSH (0.5 mg/kg) or prednisolone (20
mg/kg) two hours before sensitization (day 0) and the same dose was
administered repeatedly after sensitization during four consecutive
days. The paw edema inhibition was measured as described above.
Study of New Compounds
[0084] Mice were treated as the control but were additionally
injected i.p. with various doses (0.05, 0.15 or 0.25, 0.375, 0.5
and 0.75 mg/kg) of each compounds two hours before sensitization
(day 0) and the same dose was administered repeatedly after
sensitization during four consecutive days. The paw edema
inhibition as described above.
[0085] Groups containing at least 10 mice each were used for all
experiments.
Example 4
[0086] The following formulations are representative for all of the
pharmacologically active compounds of the invention
Example of a Preparation Comprising a Capsule
TABLE-US-00004 [0087] Per capsule Active ingredient, as salt 5 mg
Lactose 250 mg Starch 120 mg Magnesium stearate 5 mg Total 380
mg
[0088] In case of higher amounts of active ingredient, the amount
of lactose used may be reduced.
Example of a Suitable Tablet Formulation.
TABLE-US-00005 [0089] Per tablet Active ingredient, as salt 5 mg
Potato starch 90 mg Colloidal Silica 10 mg Talc 20 mg Magnesium
stearate 2 mg 5% aqueous solution of gelatine 25 mg Total 152
mg
* * * * *