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WO2009074157A1 - Fully-modified phenyl pyrrole aminoguanidines - Google Patents

Fully-modified phenyl pyrrole aminoguanidines Download PDF

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Publication number
WO2009074157A1
WO2009074157A1 PCT/DK2008/050306 DK2008050306W WO2009074157A1 WO 2009074157 A1 WO2009074157 A1 WO 2009074157A1 DK 2008050306 W DK2008050306 W DK 2008050306W WO 2009074157 A1 WO2009074157 A1 WO 2009074157A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
compound according
hydrogen
amino
Prior art date
Application number
PCT/DK2008/050306
Other languages
French (fr)
Inventor
Thomas Engelbrecht Norkild Jonassen
Thomas Boesen
Original Assignee
Action Pharma A/S
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Publication date
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Publication of WO2009074157A1 publication Critical patent/WO2009074157A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to phenyl pyrrole aminoguanidines modified at the guanidine group.
  • the present invention further relates to the use of such modified phenyl pyrrole aminoguanidines for the treatment of diseases associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
  • a number of low molecular weight compounds are known, e.g., isoquinolines, spiropyridines and benzimidazoles, which show activity on the MC receptors. See, for example WO 99/55679, WO 99/64002 and WO 01/05401.
  • the compounds of the present invention are structurally different from the above-mentioned compounds and, consequently, constitute a new class of compounds that show activity to the MC receptors.
  • This hydroxyguanidine derivative has proven activity against xanthine oxidase/xanthine dehydrogenase enzymes.
  • the compounds disclosed in WO 03/013509 exhibit anti-inflammatory properties and binding affinity to the MC receptors.
  • the general structure of the compounds disclosed in WO 03/013509 is as follows:
  • X is (CH 2 ) n/ and n is 0, 1 or 2.
  • the compounds of WO 03/013509 are light-sensitive, i.e. light can induce a conversion from the trans isomeric form of the compounds to the cis isomeric form of the compounds. Trans-Cis conversion is well-known to be induced by light.
  • the compounds of the present invention differ from the compounds disclosed in WO 03/013509 inter alia in that the aminoguanidine group has been modified and/or in that the aminoguanidine substituent at the pyrrole ring has been modified into a more rigid structure allowing only minimal rotational freedom around the carbon atoms present in the aminoguanidine substituent.
  • the compounds of the invention possess a higher binding affinity for the MC-receptors compared to the compounds disclosed in WO 03/013509. Accordingly, one object of the present invention is to provide compounds which exhibit an increased binding affinity for one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509.
  • the compounds of the invention possess a higher efficacy with regard to stimulation of the adenylyl cyclase and production of cAMP via activation of one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509.
  • a second object of the present invention is to provide compounds which possess a higher efficacy with regard to stimulation of the adenylyl cyclase and production of cAMP via activation of one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509.
  • the compounds of the invention are more stable, such as e.g. more stable when exposed to light, compared to the compounds disclosed in WO 03/013509.
  • a third object of the present invention is to provide compounds which, compared to the compounds disclosed in WO 03/013509, are less light-sensitive (i.e. which are more stable).
  • the compounds of the invention possess a higher antiinflammatory activity compared to the compounds disclosed in WO 03/013509. Accordingly, another object of the present invention is to provide compounds which exhibit an increased anti-inflammatory activity compared to the compounds described in WO 03/013509.
  • the compounds of the invention possess a more significant effect regarding inhibition of food intake compared to the compounds disclosed in WO
  • a further object of the present invention is to provide compounds which exhibit a more significant effect with regard to inhibition of food intake compared to the compounds described in WO 03/013509.
  • the compounds of the invention posses a more significant anti-diabetic effect compared to the compounds disclosed in WO 03/013509. Accordingly, a further object of the present invention is to provide compounds which exhibit an increased anti-diabetic effect compared to the compounds described in WO 03/013509.
  • the present invention relates to a compound of the general formula (I):
  • Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of hydrogen, optionally substituted Ci- ⁇ -alkyI, optionally substituted C 3 . 6 -cycloalkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 . 6 -alkadienyl, optionally substituted C 2 . 6 - alkynyl, hydroxy, optionally substituted Ci- ⁇ -alkoxy, optionally substituted C 2 .
  • each R 9 , Ri 0 , Rn and R i2 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 - 6 -alkadienyl, optionally substituted C 2 - 6 -alkynyl, optionally substituted Ci -6 - alkoxycarbonyl, optionally substituted Ci- 6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- 6 - alkyl-aminocarbonyl and mono- and di(Ci- 6 -alkyl)amino-Ci-
  • R 9 , Ri 0 , Rn and R i2 are not hydrogen, or if R 9 and Ri 0 are both hydrogen then Rn and R i2 are not hydrogen, or if Rn and R i2 are both hydrogen then R 9 and Ri 0 are not hydrogen.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a dosage form comprising a pharmaceutical composition of the invention.
  • the present invention relates to a compound of the invention for use a medicament.
  • the present invention relates to a compound of the invention for the treatment or prevention of a disease selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, diabetes mellitus, diabetes mellitus type I, diabetes mellitus type II, obesity-induced diabetes mellitus, insulin-resistance, sexual dysfunction including dysfunction of male erection, eating disorders including anorexia, obesity, mental disorders, dysfunction of the endocrine system, drug-induced disorders of the blood and lymphoid system, allergy disorders, disorders of the cardiovascular system and pain.
  • inflammatory conditions e.g. acute or chronic inflammatory conditions
  • diabetes mellitus e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type I e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type II e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type II e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type II e.g. acute or chronic inflammatory conditions
  • the present invention also relates to a method of treating a mammal having a disease or disorder, or preventing a mammal from getting a disease or disorder, selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, diabetes mellitus, diabetes mellitus type I, diabetes mellitus type II, obesity- induced diabetes mellitus, insulin-resistance, sexual dysfunction including dysfunction of male erection, eating disorders including anorexia, obesity, mental disorders, dysfunction of the endocrine system, drug-induced disorders of the blood and lymphoid system, allergy disorders, disorders of the cardiovascular system and pain, said method comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
  • inflammatory conditions e.g. acute or chronic inflammatory conditions
  • diabetes mellitus e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type I e.g. acute or chronic inflammatory conditions
  • diabetes mellitus type II e.g. acute
  • Fig. 1 shows the synthetic route of a compound of the general formula (IV), wherein Q is nitrogen.
  • Fig. 2 shows the synthetic route of a compound of the general formula (IV), wherein Q is carbon.
  • Fig. 3 shows specific examples of preferred compounds of the invention.
  • Figs. 4-10 show the synthetic route for selected preferred compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • Ci_ 6 -alkyl is intended to mean a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, ⁇ -propyl, iso- propyl, ⁇ -butyl, /so-butyl, sec-butyl, ferf-butyl, ⁇ -pentyl, /so-pentyl, ⁇ eo-pentyl and ⁇ - hexyl, and the term "Ci. 4 -alkyl” is intended to cover a linear or branched hydrocarbon group having 1 to 4 carbon atoms, e.g. methyl, ethyl, ⁇ -propyl, /so-propyl, ⁇ -butyl, /so- butyl, sec-butyl and ferf-butyl.
  • Ci. 6 -alkyl Whenever the term "Ci. 6 -alkyl” is used herein, it should be understood that an interesting embodiment thereof is “Ci- 4 -alkyl". Most preferably, “Ci_ 6 -alkyl” (and “Ci- 4 -alkyl”) is methyl or ethyl, in particular methyl.
  • Cs- ⁇ -cycloalkyl is intended to mean a cyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term “five- or six-membered cycloalkyl group” refers to cyclopentyl and cyclohexyl.
  • C 2 - 6 -alkenyl and “C 4 - 6 -alkadienyl” are intended to cover linear or branched hydrocarbon groups having 2 to 6 and 4 to 6, carbon atoms, respectively, and comprising one and two unsaturated bonds, respectively.
  • alkenyl groups are vinyl, ally I, butenyl, pentenyl and hexenyl.
  • alkadienyl groups include butadienyl, pentadienyl and hexadienyl.
  • Preferred examples of alkenyl are vinyl, allyl and butenyl, especially allyl.
  • C 2 - 6 -alkynyl is intended to mean a linear or branched hydrocarbon group having 2 to 6 carbon atoms and containing one or more triple bonds.
  • Illustrative examples of C 2 - 6 -alkynyl groups include acetylene, propynyl, butynyl, as well as branched forms of these.
  • the position of unsaturation may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C 2 - 6 -alkynyl" is a di-yne or enedi-yne as is known to the person skilled in the art.
  • Ci- 6 -alkoxy is intended to mean Ci- ⁇ -alkyl-oxy, such as methoxy, ethoxy, ⁇ -propoxy, /so-propoxy, ⁇ -butoxy, /so-butoxy, sec-butoxy, ferf-butoxy, ⁇ -pentoxy, /so-pentoxy, ⁇ eo-pentoxy and ⁇ -hexoxy, and the term "Ci- 4 -alkoxy” is intended to mean Ci_ 4 -alkyl-oxy, e.g.
  • C 2 . 6 -alkenyl-oxy is intended to mean C 2 . 6 -alkenyl-oxy.
  • halogen includes fluoro, chloro, bromo, and iodo.
  • fluoro, chloro and bromo are preferred.
  • Chloro is the most preferred halogen.
  • alkyl alkenyl
  • alkadienyl alkynyl
  • alkynyl optionally substituted
  • the above-mentioned substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci -6 - alkoxy (i.e. Ci- 6 -alkyl-oxy), C 2 .
  • Ci- 6 -alkoxy particularly preferred examples include halogen- substituted alkyl groups, such as trihalo-Ci- 6 -alkyl, such as tribromomethyl, trichloromethyl or trifluoromethyl. In a particular interesting embodiment trihalo-Ci- 6 -alkyl is trifluoromethyl.
  • Ci- 6 -alkoxy is intended to mean that the alkoxy groups may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci- 6 -alkoxy (i.e.
  • Ci- 6 -alkyl-oxy Ci- 6 -alkyl-oxy), C 2 - 6 -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci- 6 -alkoxycarbonyl, Ci- 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, carbamoyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- 6 -alkyl-aminocarbonyl, mono- and di(Ci- 6 -alkyl)amino-Ci- 6 -alkyl-aminocarbonyl, cyano, guanidino, carbamido, Ci- 6 -alkyl-sulphonyl-amino, aryl-sulphon
  • substituents are those carrying one or two substituents selected from hydroxy, Ci- 6 -alkyl, Ci- 6 -alkoxy, C 2 - 6 -alkenyloxy, carboxy, halogen or Ci- 6 -alkylthio.
  • aryl is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, biphenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl, xanthenyl, among which phenyl, biphenyl and naphthyl are preferred examples.
  • the term “aryl” refers to phenyl.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl, phenyl pyrrolyl and N-phenyl pyrrolyl.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl, phenyl pyrrolyl and N-phenyl pyrrolyl, in particular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl, quinolyl, tetrazolyl, isoquinolyl, phenyl pyrrolyl and N-phenyl pyrrolyl.
  • the most preferred heteroaryl groups are pyrrolyl, indolyl, phenyl pyrolyl and N-phenyl pyrrol
  • heterocyclyl groups examples include imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahyd ropy ran, oxepane, tetrahydrothiophene, te
  • heterocyclyl groups are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine) and thiazinane.
  • aryl In connection with the terms “aryl”, “heteroaryl”, “cycloalkyl” and “heterocyclyl”, the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci- 6 -alkyl, Ci- ⁇ -alkoxy, C 2 - 6 -alkenyloxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci- 6 -alkoxycarbonyl, Ci- 6 -alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di(Ci- 6 -alkyl)amino; carbamoyl,
  • the above-mentioned substituents are selected from hydroxy, Ci- 6 -alkyl, Ci -6 - alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci -6 - alkylcarbonyl, formyl, amino, mono- and di(Ci- 6 -alkyl)amino; carbamoyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- ⁇ -alkyl-aminocarbonyl, Ci- ⁇ -alkylcarbonylamino, guanidino, carbamido, Ci- 6 -alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl- sulphonyl-amino, Ci- 6 -alkyl-suphonyl, Ci- 6 -alkyl-sulphinyl, Ci- 6 -alkyl-sul
  • substituents are Ci- 6 -alkyl, Ci_ 6 -alkoxy, amino, mono- and di(Ci- 6 -alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like representing substituents may be substituted with hydroxy, Ci- 6 -alkoxy, C 2-6 - alkenyloxy, amino, mono- and di(Ci- 6 -alkyl)amino, carboxy, Ci- ⁇ -alkylcarbonylamino, halogen, Ci- 6 -alkylthio, Ci- ⁇ -alkyl-sulphonyl-amino or guanidine.
  • salt thereof is intended to mean a pharmaceutically acceptable acid addition salt obtainable by treating the base form of a functional group, such as an amine, with appropriate acids such as inorganic acids, for example hydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric or hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanedioic, butanedioic, (Z)- 2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2- hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic acid, cycl
  • pharmaceutically acceptable when used in connection with the term “salt thereof” means that the salt does not cause any untoward effects in the patients to whom it is administered.
  • pharmaceutically acceptable when used in connection with the terms “carrier” and/or “excipient” means that the carrier and/or the excipient, at the dosages and with the concentrations employed, does not cause any untoward effects in the patients to whom it is administered.
  • any reference to "a” component e.g. in the context of a substituent, etc., is intended to refer to one or more of such components, unless stated otherwise or unless it is clear from the particular context that this is not the case.
  • the expression "a component selected from the group consisting of A, B and C” is intended to include all combinations of A, B and C, i.e. A; B; C; A+B; A+C; B+C and A+B+C.
  • terapéuticaally effective amount means a dosage or amount sufficient to produce a desired result.
  • the desired result may comprise an objective or subjective improvement in the recipient of the dosage or amount.
  • a prophylactic treatment is a treatment administered to a subject who does not display signs or symptoms of a disease, pathology, or medical disorder, or displays only early signs or symptoms of a disease, pathology, or disorder, such that treatment is administered for the purpose of diminishing, preventing, or decreasing the risk of developing the disease, pathology, or medical disorder.
  • a prophylactic treatment functions as a preventative treatment against a disease or disorder.
  • a “prophylactic activity” is an activity of an agent, such as a compound disclosed herein, or a composition thereof, that, when administered to a subject who does not display signs or symptoms of pathology, disease or disorder, or who displays only early signs or symptoms of pathology, disease, or disorder, diminishes, prevents, or decreases the risk of the subject developing a pathology, disease, or disorder.
  • terapéutica treatment means a treatment administered to a subject who displays symptoms or signs of pathology, disease, or disorder, in which treatment is administered to the subject for the purpose of diminishing or eliminating those signs or symptoms of pathology, disease, or disorder.
  • a “therapeutic activity” is an activity of an agent, such as a compound disclosed herein, or composition thereof, that eliminates or diminishes signs or symptoms of pathology, disease or disorder, when administered to a subject suffering from such signs or symptoms.
  • subject includes, but is not limited to, an organism; a mammal, including, e.g., a human being, non-human primate (e.g., baboon, orangutan, monkey), mouse, pig, cow, goat, cat, rabbit, rat, guinea pig, hamster, horse, monkey, sheep, or other non-human mammal; a non-mammal, including, e.g., a non-mammalian vertebrate, such as a bird (e.g., a chicken or duck) or a fish, and a non-mammalian invertebrate.
  • the subject is a human being.
  • the present invention relates to a compound of the general formula (I) shown above.
  • the aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ia) and (Ib) merely differ from each other by the site of attachment to the pyrrole ring.
  • the present invention relates to a compound of the general formula (Ia) or (Ib)
  • Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
  • each Ri, R 2 , R 3 , R 4 , R 5 , Re, R 7 and R 8 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 3 - 6 -cycloalkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 . 6 -alkadienyl, optionally substituted C 2 . 6 - alkynyl, hydroxy, optionally substituted Ci- 6 -alkoxy, optionally substituted C 2 .
  • each R 9 , Ri 0 , Rn and R i2 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 - 6 -alkadienyl, optionally substituted C 2 - 6 -alkynyl, optionally substituted Ci -6 - alkoxycarbonyl, optionally substituted Ci- 6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- 6 - alkyl-aminocarbonyl and mono- and di(Ci- 6 -alkyl)amino-Ci-
  • R 9 , Ri 0 , Rn and R i2 are not hydrogen, or if R 9 and Ri 0 are both hydrogen then Rn and R i2 are not hydrogen, or if Rn and R i2 are both hydrogen then R 9 and Ri 0 are not hydrogen.
  • the aminoguanidine substituent is attached to the pyrrole ring at position 2
  • the aminoguanidine substituent is attached to the pyrrole ring at position 3.
  • only compounds where the aminoguanidine substituent is attached to the pyrrole ring at position 2 is described with respect to preferred substituents, method for manufacturing, etc.
  • the compounds of the general formula (I) may, provided that at least one of Rg, Ri 0 , Rn and R i2 is hydrogen, exist in various tautomeric forms.
  • tautomeric forms thereof or “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Different tautomeric forms have the same molecular formula and are interchangeable forms involving the displacement of hydrogen atoms and electrons.
  • this atom may be a carbon atom or a nitrogen atom, i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group.
  • the molecule contains, in case Q is nitrogen, a single asymmetric carbon atom.
  • the molecule of invention may be either in its enantiomeric S-form, its enantiomeric R-form, or the molecule of the invention may be a racemic mixture.
  • the molecule contains, in case Q is carbon, two asymmetric carbon atoms.
  • the molecule of invention may be either in its SS-form, its RR-form, its SR-form, its RS- form, or any mixture thereof.
  • the compounds of the invention have basic properties and, consequently, they may be converted to their active acid addition salts by treatment with appropriate pharmaceutically acceptable acids.
  • acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids, such as acetic acid, propionic acid, hydroacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-butenedioic acid, 2- hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-l,2,3- propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid
  • each R 1 , R 2 , R 3 , R 4 , R 5 , Re, R 7 and R 8 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 . 6 - alkenyl, optionally substituted C 2 . 6 -alkynyl, hydroxy, optionally substituted Ci- 6 -alkoxy, optionally substituted C 2 .
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of hydrogen, optionally substituted CV 6 - alkyl, optionally substituted C 2 . 6 -alkenyl, hydroxy, optionally substituted CV 6 -alkoxy, amino, cyano, nitro and halogen, such as bromo, chloro and fluoro.
  • Specific examples of highly preferred (non-substituted) d- 6 -alkyl groups include C 1-4 -alkyl, such as methyl or ethyl, in particular methyl.
  • highly preferred substituted CV 6 -alkyl groups include substituted C 1-4 -alkyl, such as halogen-substituted C 1-4 -alkyl, e.g. trihalo- Ci- 4 -alkyl, in particular tribromomethyl, trichloromethyl and trifluoromethyl among which trichloromethyl and trifluoromethyl are particularly preferred.
  • Specific examples of highly preferred (non-substituted) C 2 . 6 -alkenyl groups include C 2 . 4 -alkenyl, such as vinyl, allyl and butenyl, in particular allyl.
  • Specific examples of highly preferred (non-substituted) CV 6 - alkoxy groups include Ci_ 4 -alkoxy, such as methoxy or ethoxy, in particular methoxy.
  • the invention relates to compounds of the general formula (I), wherein R 8 is hydrogen.
  • the compound of the invention has the structure shown in the general formula (Ic):
  • the invention relates to compounds of the general formula (I), wherein R 5 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (Id) :
  • the invention relates to compounds of the general formula (I), wherein R 4 , R 5 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (Ie):
  • the invention relates to compounds of the general formula (I), wherein R 4 , R 5 , R 7 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (If) :
  • the invention relates to compounds of the general formula (I), wherein R 3 , R 4 , R 5 , R 7 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (Ig) :
  • the invention relates to compounds of the general formula (I), wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (Ih) :
  • the attachment of the Ri and R 2 may be as follows: In one embodiment of the invention is Ri located in the 2-position and R 2 is located in the 3-position. In another embodiment of the invention is Ri located in the 2-position and R 2 is located in the 4- position. In yet another embodiment of the invention is Ri located in the 2-position and R 2 is located in the 5-position. In a further embodiment of the invention is Ri located in the 2- position and R 2 is located in the 6-position.
  • Ri is located in the 3-position and R 2 is located in the 4-position.
  • Ri located in the 3-position and R 2 is located in the 5- position.
  • Ri located in the 3-position and R 2 is located in the 6-position.
  • the invention relates to compounds of the general formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen.
  • the compound of the invention has the structure shown in the general formula (Ii) :
  • the invention relates to compounds of formula (Ii), wherein Rl is chloro located in the 4-position. In still a further embodiment, the invention relates to compounds of formula (Ii), wherein Rl is bromo. In still another embodiment, the invention relates to compounds of formula (Ii), wherein Rl is bromo located in the 2-position. In yet another embodiment, the invention relates to compounds of formula (Ii), wherein Rl is trihalo-Ci- 4 -alkyl, such as trifluoromethyl. In a further embodiment, the invention relates to compounds of formula (Ii), wherein Rl is trihalo-Ci- 4 -alkyl, such as trifluoromethyl, located in the 4-position.
  • substituents on the amino groups of the aminoguanidine substituent will be discussed in the following. It should be understood that all statements made in the following concerning preferred substituents is independent of the presence or absence of X, Y and Z (cf. formula (I)) and the actual values of i, j and k.
  • the substituents Rg, Ri 0 , Rn and R i2 may be individually selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 - 6 -alkadienyl, optionally substituted C 2 .
  • R 9 and Ri 0 may together form a five- or six- membered nitrogen-containing ring and/or Rn and R i2 may together form a five- or six- membered nitrogen-containing ring; or R 9 and Rn may together form a five- or six- membered nitrogen
  • R 9 , Ri 0 , Rn and R i2 are not hydrogen, or if R 9 and Ri 0 are both hydrogen then Rn and R i2 are not hydrogen, or if Rn and R i2 are both hydrogen then R 9 and Ri 0 are not hydrogen.
  • each R 9 , Ri 0 , Rn and R i2 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 . 6 -alkenyl, optionally substituted C 2 . 6 -alkynyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that at least three of R 9 , Ri 0 , Rn and R i2 are not hydrogen, or if R 9 and Ri 0 are both hydrogen then Rn and R i2 are not hydrogen, or if Rn and R i2 are both hydrogen then R 9 and Ri 0 are not hydrogen.
  • each R 9 , Ri 0 , Rn and R i2 is independently hydrogen or optionally substituted CV 6 -alkyl, preferably optionally substituted CV 4 -alkyl; with the proviso that at least three of R 9 , Ri 0 , Rn and R i2 are not hydrogen, or if R 9 and Ri 0 are both hydrogen then Rn and R i2 are not hydrogen, or if Rn and Ri 2 are both hydrogen then R 9 and Ri 0 are not hydrogen.
  • R 9 , Ri 0 , Rn and R i2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein each R 9 , Ri 0 , Rn and R i2 is optionally substituted Ci- 4 -alkyl.
  • each R 9 , Ri 0 , Rn and R i2 is independently methyl or ethyl. More preferably, R 9 , Rio, Rn and R i2 are methyl or ethyl, in particular methyl.
  • the compound of the invention may have the structures shown in the general formulae (Ik)-(Io):
  • R 9 is hydrogen and each Ri 0 , Rn and R 12 is independently hydrogen or optionally substituted Ci- 6 -alkyl, preferably optionally substituted Ci- 4 -alkyl; with the proviso that Ri 0 , Rn and R i2 are not hydrogen, or if Ri 0 is hydrogen then Rn and R i2 are not hydrogen.
  • R 9 is hydrogen and each Ri 0 , Rn and R i2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R 9 is hydrogen and Ri 0 , Rn and R i2 are optionally substituted Ci- 4 -alkyl.
  • each Ri 0 , Rn and R i2 is independently methyl or ethyl. More preferably, Ri 0 , Rn and R i2 are methyl or ethyl, in particular methyl.
  • the compound of the invention may have the structures shown in the general formulae (Ip) and (Ir) :
  • R 9 and Ri 0 are hydrogen and Rn and R i2 are different from hydrogen, such as optionally substituted Ci- 6 -alkyl, preferably optionally substituted Ci- 4 -alkyl. Therefore, in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R 9 and Ri 0 are hydrogen and Rn and R i2 are optionally substituted Ci- 4 -alkyl.
  • each Rn and R i2 is independently methyl or ethyl. More preferably, Rn and R i2 are methyl or ethyl, in particular methyl.
  • the compound of the invention may have the structures shown in the general formulae (Is) and (It) :
  • Rn is hydrogen and each R 9 , Rio and R i2 is independently hydrogen or optionally substituted Ci- 6 -alkyl, preferably optionally substituted Ci_ 4 -alkyl; with the proviso that R 9 , Ri 0 and R i2 are not hydrogen, or if Ri 2 is hydrogen then R 9 and Ri 0 are not hydrogen.
  • Rn is hydrogen and each R 9 , Ri 0 and R i2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein Rn is hydrogen and R 9 , Ri 0 and R i2 are optionally substituted Ci_ 4 -alkyl.
  • each R 9 , Ri 0 and R i2 is independently methyl or ethyl. More preferably, R 9 , Ri 0 and R i2 are methyl or ethyl, in particular methyl.
  • the compound of the invention may have the structures shown in the general formulae (Iu) and (Iv) :
  • Rn and R i2 are hydrogen and Rg and Ri 0 are different from hydrogen, such as optionally substituted Ci- 6 -alkyl, preferably optionally substituted Ci_ 4 -alkyl. Therefore, in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein Rn and R i2 are hydrogen and R 9 and Ri 0 are optionally substituted Ci -4 -alkyl.
  • each R 9 and Ri 0 is independently methyl or ethyl. More preferably, R 9 and Ri 0 are methyl or ethyl, in particular methyl.
  • the compound of the invention may have the structures shown in the general formulae (Iw) and (Ix) :
  • the X, Y and Z moieties will be discussed in the following. It should be understood that all previous statements made herein concerning preferred embodiments of Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Rg, Rio, Rn, and R i2 also apply to the following section.
  • the moieties X, Y and Z may be as follows: X is ⁇ ( ⁇ N s ⁇ and i is 0, 1 or 2;
  • Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
  • Z is t- -i and k is 0, 1, 2 or 3.
  • the compound of the invention has the structure shown in the general formula (II) :
  • Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs / R9 / Rio / Rn and R i2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formula (II).
  • the aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ha) and (lib), cf. below, merely differ from each other by the site of attachment to the pyrrole ring.
  • the present invention relates to a compound of the general formula (Ha) or (lib)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7, Rs / R 9 , R 10 , Rn and R 12 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 also apply to the compounds of the general formula (lie), i.e. in preferred embodiments of the invention, the compound of the general formula (He) has the structure shown in the general formulae (Hd)-(IIp) :
  • the compound of the invention has the structure shown in the general formula (III):
  • Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs/ R9/ Rio/ Rn and R i2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs/ R9/ Rio/ R-n/ R12 also apply to the compounds of the general formula (III).
  • aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ilia) and (HIb), cf. below, merely differ from each other by the site of attachment to the pyrrole ring.
  • the present invention relates to a compound of the general formula (Ilia) or (HIb)
  • Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs/ R9/ Rio/ Rn and R i2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formulae (Ilia) and (HIb).
  • the compound of the invention has the structure shown in the general formula (IIIc) :
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Ri 0 , Rn and R i2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Ri 0 , Rn, R i2 also apply to the compounds of the general formula (IIIc), i.e. in preferred embodiments of the invention, the compound of the general formula (IIIc) has the structure shown in the general formulae (HId)-(IIIp) :
  • the present invention relates to a compound of the general formula (IVa) or (IVb)
  • k is 0, 1, 2 or 3.
  • this atom may be a carbon atom or a nitrogen atom, i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group.
  • the molecule contains, in case Q is nitrogen, a single asymmetric carbon atom.
  • the molecule of invention may be in either its enantiomeric S-form, its enantiomeric R-form, or the molecule of the invention may be a racemic mixture.
  • the molecule contains, in case Q is carbon, two asymmetric carbon atoms.
  • the molecule of invention may be in either its SS-form, its RR-form, its SR-form, its RS-form, or any mixture thereof.
  • the optionally substituted six-membered cycloalkyl group has the following chemical structure:
  • each of Ri 3 , R 14 , Ri 5 , and Ri 6 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 3 . 6 -cycloalkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted C 4 .
  • each of Ri 3 , R 14 , R 15 , and Ri 6 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 . 6 -alkenyl, optionally substituted C 2 - 6 -alkynyl, hydroxy, optionally substituted Ci- 6 -alkoxy, optionally substituted C 2 - 6 -alkenyloxy, carboxy, optionally substituted Ci- 6 -alkoxycarbonyl, optionally substituted Ci- 6 -alkylcarbonyl, formyl, amino, mono- and di(Ci- 6 -alkyl)amino, carbamoyl, mono- and di(Ci- 6 -alkyl)aminocarbonyl, amino-Ci- ⁇ -alkyl-aminocarbonyl, mono- and di(Ci- 6 -alkyl)amino-Ci- 6 -alkyl-aminocarbonyl, Ci-
  • each of Ri 3 , R 14 , Ri 5 , and Ri 6 is independently selected from the group consisting of hydrogen, optionally substituted Ci- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, hydroxy, optionally substituted Ci- 6 -alkoxy, amino, cyano, nitro and halogen.
  • all of Ri 3 , R i4 , Ri 5 , and Ri 6 are hydrogen.
  • u represents, together with Q and the carbon atom covalently linked to Y, an optionally substituted five-membered cycloalkyl group as illustrated below:
  • R i3 , R i4 and R i5 are as defined above. Again, in a particular interesting embodiment of the invention all of R i3 , R i4 and R i5 are hydrogen.
  • Q is nitrogen (N), i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six- membered heterocyclyl group. Any of the heterocyclyl groups mentioned in connection with the definition of this term may be used for this purpose. However, in one embodiment of the invention u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted six-membered heterocyclyl group as illustrated below:
  • each of Ri 3 , R i4 , Ri 5 , and Ri 6 is as defined above. Also in this embodiment of the invention is it preferred that all of Ri 3 , R i4 , R i5 and Ri 6 are hydrogen.
  • u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five-membered heterocyclyl group as illustrated below:
  • R i3 , R i4 and R i5 are as defined above. In the most preferred embodiment of the invention, all of R i3 , R 14 and Ri 5 are hydrogen.
  • the compound of the general formula (IV) has the structure shown in the general formulae (IVf)-(IVr):
  • the compounds of the invention may be prepared by standard methods known to the skilled organic chemist.
  • a compound of the general formula (I) above may be prepared essentially as described in WO 03/013509. More particularly, a compound of the general formula (II)
  • Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs, R9, Rio, Rn and R i2 are as discussed above, may be prepared by reacting an aldehyde of the general formula A
  • a compound of the general formula A is reacted with an aminoguanidine derivative of the general formula B where the aminoguanidine derivative is in the form of an acid addition salt, such as the bicarbonate salt.
  • R 9 and Ri 0 are as discussed above.
  • the reaction is preferably performed in a polar aprotic solvent, such as ethanol.
  • Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs, R9, Rio, Rn and R i2 are as discussed above, may be prepared by reacting an aldehyde of the general formula F
  • the compounds of the general formula (III) may also be prepared by reacting the aldehyde F with thiosemicarbazide of the general formula C, followed by reaction with the amine E, as described above.
  • the aldehyde F is easily prepared from the starting aldehyde G
  • k, i, Q, u, Ri, R 2 , R3, R 4 , R 5 , Re, R7, Rs / R9 / Rio / Rn and R i2 are as discussed above, may be prepared as shown in Figs. 1 and 2.
  • an aldehyde of the general formula A is reacted with the amino acid ester H, where H may be in its S-form, R-form or a racemic mixture, in a suitable solvent (Step 1).
  • the amino acid ester H is typically an amino acid Ci- 6 -alkyl ester, i.e. R i7 is Ci -6 - alkyl, preferably methyl or ethyl.
  • Step 1 is carried out in the presence of a suitable reducing agent, such as sodium cyanoborohydride, sodium triacetoxy borohydride, sodium borohydride, or hydrogen in the presence of a suitable catalyst such as palladium or carbon, in a suitable organic solvent to yield an ester of the general formula J.
  • the obtained ester J may be reduced to its corresponding aldehyde K using a suitable reducing agent, such as lithium aluminium hydride in a suitable organic solvent, such as diethyl ether or THF.
  • a suitable reducing agent such as lithium aluminium hydride in a suitable organic solvent, such as diethyl ether or THF.
  • the aldehyde K is then converted to the chain-elongated aldehyde M, via the intermediate L, by the well-known Wittig reaction (Steps 3 and 4).
  • Step 3 Formation of the intermediate compound L is carried out in a suitable organic solvent, typically a protic solvent, such as dimethylsulfoxide, dimethylformamide, hexamethyl- phosphorotriamide, in the presence of a strong base, such as an alkoxide, e.g. sodium or potassium ferf-butoxide (Step 3).
  • a strong base such as an alkoxide, e.g. sodium or potassium ferf-butoxide
  • Step 4 an alkoxide, e.g. sodium or potassium ferf-butoxide
  • the compounds of the general formula (IV) may also be prepared by reacting the aldehyde N with thiosemicarbazide of the general formula C, followed by reaction with the amine E, as described above.
  • a halide, such as the bromide, of the general formula O is transformed into a Wittig reagent of the general formula P by standard methods by reaction with triphenyl phoshpine in a suitable solvent (Step 1).
  • the Wittig reagent P is reacted with a cyclic ketoester of the general formula Q, cf. Step 2 of Fig. 2, to yield the ester R.
  • the cyclic ketoester Q is typically a Ci- 6 -alkyl ester, i.e. Ri 8 is Ci- 6 -alkyl, preferably methyl or ethyl.
  • Step 3 is conveniently carried out using a suitable reducing agent, such as lithium aluminium hydride in a suitable organic solvent, such as diethyl ether or THF.
  • a suitable oxidising agent such as sulfur trioxide pyridine complex or oxalylchloride, dimethyl sulfoxide and triethyl amine (Swern oxidation) (Step 4).
  • compositions The compound of the invention is preferably administered in a composition including a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable means a carrier or excipient that does not cause any untoward effects in patients to whom it is administered.
  • Such pharmaceutically acceptable carriers and excipients are well known in the art (Remington's Pharmaceutical Sciences, 18th edition, A. R. Gennaro, Ed., Mack Publishing Company [1990]; Pharmaceutical Formulation Development of Peptides and Proteins, S. Frokjaer and L. Hovgaard, Eds., Taylor & Francis [2000]; and Handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press [2000]). The exact dose to be administered depends on the circumstances.
  • the dose should be capable of preventing or lessening the severity or spread of the condition or indication being treated. It will be apparent to those of skill in the art that an effective amount of the compound of the invention depends, inter alia, upon the disease, the dose, the administration schedule, whether the compound of the invention is administered alone or in conjunction with other therapeutic agents, the general health of the patient, and the like. Generally, and in particular if administered via the oral route, the compound of the invention should be administered in a dose of 0.1 to 100 mg body weight per kilo throughout the treatment period.
  • the pharmaceutical composition may be formulated in a variety of forms, including liquid, gel, lyophilised, powder, compressed solid, or any other suitable form.
  • the preferred form will depend upon the particular indication being treated and will be apparent to one of skill in the art.
  • the pharmaceutical composition may be administered orally, subcutaneously, intravenously, intracerebral ⁇ , intranasally, transdermal ⁇ , intraperitoneal ⁇ , intramuscularly, intrapulmonary, vaginally, rectally, intraocularly, or in any other acceptable manner, e.g. using PowderJect or ProLease technology.
  • the composition can be administered continuously by infusion, although bolus injection is acceptable, using techniques well known in the art, such as pumps or implantation. In some instances the composition may be directly applied as a solution or spray.
  • the preferred mode of administration will depend upon the particular indication being treated and will be apparent to one of skill in the art. However, the currently preferred mode of administration is via the oral route.
  • composition of the invention may be administered in conjunction with other therapeutic agents. These agents may be incorporated as part of the same pharmaceutical composition or may be administered separately from the composition of the invention, either concurrently or in accordance with any other acceptable treatment schedule.
  • the pharmaceutical composition may be in solid or liquid form, e.g. in the form of a capsule, tablet, suspension, emulsion or solution.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods.
  • Solid dosage forms for oral administration may include capsules, tablets, suppositories, powders and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances, e.g. lubricating agents such as magnesium stearate.
  • additional substances e.g. lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • the compound of the invention may be admixed with adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compound of the invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, oils (such as corn oil, peanut oil, cottonseed oil or sesame oil), tragacanth gum, and/or various buffers.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, buffers, fillers, etc.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, sweeteners, flavoring agents and perfuming agents.
  • 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.
  • the compounds of the present invention have been tested in the melanocortin system and have surprisingly been shown to be capable of binding to MC receptors as well as showing activity in functional assays.
  • the compounds of the present invention are either agonists or antagonists of a specific MC-receptor or of a number of MC-receptors, e.g. MCI, MC3, MC4 and/or MC5 receptors.
  • 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 MCI, MC2, MC3, MC4 and MC5, have been described.
  • MCI, MC2, MC3, MC4 and MC5 have been described.
  • the MC receptor's signalling is mainly mediated via cAMP, but other signal transduction pathways are also known. They are distinctly distributed in the body.
  • 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 as exemplified by the finding that selective MCl receptor agonists has marked anti-inflammatory action, but seems to lack the organ protective effect described for unspecific MC receptor agonists as ⁇ -MSH, where it has been suggested that additional MC3 and/or MC5 receptor stimulation are needed to get the organ protective effect. Another example is the central effects of melanocortin receptor stimulation where it is unclear whether both MC3 and MC4 receptor stimulation or only stimulation of one of the receptors are needed.
  • 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, (see, for example, Eberle: The melanotropins: Chemistry, physiology and mechanisms of action.
  • ⁇ -MSH immunomodulatory action of ⁇ -MSH includes both immunostimulatory and immunosuppressive effects.
  • cytokines such as IL-l ⁇ , IL-l ⁇ , IL-6 and TNF ⁇
  • IL-10 pro-inflammatory cytokine
  • 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, which may affect body weight, body fat mass and growth rate.
  • 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 ⁇ -MSH and ACTH(l-24) have been shown to markedly inhibit feeding (Poggioli et al., Peptides, 1986, 7, 843-848; Vergoni et al., Neuropeptides, 1986, 7, 153-158).
  • the MC5-receptor has recently been attributed a role in control of exocrine gland function 5 (van der Kraan, et al., Endocrinol. 1998, 139, 2348-2355; Chen et al., Cell. 1997, 91, 789-798).
  • 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 an MC-receptor blocker could inhibit the erectogenic effect of melanocortic peptides (Vergoni et al., Eur. J. Pharmacol., 1998, 362; 95-101).
  • the compounds of the present invention has valuable therapeutic properties, making them useful for the treatment of inflammatory conditions, e.g.
  • acute or chronic inflammatory conditions such as arthritis, including diseases associated with arthritis, osteoartritis, rheumatoid arthritis, spondylarthropathies (e.g. ankylosing spondilitis), reactive arthritis (including arthritis following rheumatic fever), Henoch-Schonlein purpura, and Reiter 's disease, connective tissue disorders such as systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis, mixed connetive tissue disease, sarcoidosis and primary Sjogrens syndrome including keratoconjunctivitis sicca, polymyalgia rheumatica, and other types of vasculitis, crystal deposition diseases (including gout), pyrophosphate arthropathy, acute calcific periarthritis; inflammatory bowel disease (including Chrons disease and ulcertive colitis), diverticular disease of the colon, and irritable bowel syndrome, pancreatitis,
  • Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of inflammation, an inflammatory condition or an inflammatory disease such as inflammation 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- ⁇ ).
  • IL-1 interleukin 1
  • IL-6 interleukin 6
  • TNF- ⁇ tumor necrosis factor a
  • 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.
  • upregulated refers to an increased activity or amount of the compound compared with that in a healthy individual.
  • 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.
  • down regulated refers to a decreased activity or amount of the compound compared with that in a healthy individual.
  • 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, ⁇ -radiation, ⁇ - or ⁇ - particles, sun burns, elevated temperature or mechanical injury.
  • 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.
  • 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.
  • inflammatory diseases of the skin including the dermis and epidermis
  • 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.
  • inflammatory diseases include all kinds of soft-tissue rheumatism including rheumatoid arthritis, bursitis, tenosynovitis or peritendonitis, enthesitis, nerve compression, periarthritis or capsulitis, muscle tension and muscle dysfunction.
  • inflammatory diseases include all kinds of arthtitis in children such as Juvenile Chronic arthritis including Still 's disease, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis.
  • 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.
  • gastritis including one of unknown origin, gastritis perniciosa (atrophic gastritis), ulcerous colitis (colitis ulcerosa), morbus Crohn (Chrons disease), systemic sclerosis, ulcus duodeni, coeliac disease, oesophagitis, ulcus ventriculi, acute and chronic gastritis, helicobacteer pylori infection, coeliac disease, gluten sensitive enteropathy, dermatitis herpitiformis, tropical sprue, Whipple 's diease, radiation enteritis, systemic amyloidosis, eosinophilic gastroenteritis, intestinal lympangiectasia, inflammatory bowel
  • 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.
  • 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.
  • a disease of the peripheral and/or central nervous system related to inflammation includes 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.
  • 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.
  • 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.
  • diseases of the eye and tear glands related to inflammation 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.
  • 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 ear related to inflammation, specific examples of which include polychondritis affecting the ear and external otitis.
  • 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.
  • 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.
  • diseases related to inflammation of the mouth, pharynx and salivary glands include Wegener's granulomatosis, mid-line granuloma, Sjogren's syndrome and polychondritis in these areas.
  • 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 and/or airways, such as e.g. acute or chronic or subchronic inflammation in the lung and/or airway.
  • diseases related to inflammation in the lung and/or airways such as e.g. acute or chronic or subchronic inflammation in the lung and/or airway.
  • idiopathic alveolitis primary pulmonary hypertension, bronchitis, chronic bronchitis, sarcoidosis, alveolitis in inflammatory systemic disease, pulmonary hypertension in inflammatory systemic disease, Wegener's granulomatosis, Good Pastures' syndrome, upper and lower airway diseases such as chronic obstructive pulmonary disease (COPD), exacerbations in COPD, allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, acute respiratory diseases and/or chronic and/or subchronic airway and lung diseases.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • diseases related to the inflammation of the heart 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.
  • 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.
  • diseases related to inflammation of the liver 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.
  • 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.
  • 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 acute pancreatitis, chronic pancreatitis.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to conditions with increased fasting levels of LDL-Cholesterol, conditions with combined increased fasting levels of LDL-Cholesterol and triglyceride, conditions with increased fasting levels of triglyceride and conditions with increased fasting levels of HDL- Cholesterol.
  • 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.
  • 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.
  • 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.
  • 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.
  • diseases related to the inflammation of the joints 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.
  • 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.
  • 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.
  • diseases related to the inflammation of blood vessels 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.
  • iNOS inducible nitric oxide synthesis
  • Inflammatory diseases also include all kind of inflammatory conditions causing backpain including infections, septic discitis, tuberculosis, malignancies (such as metastases, myeloma and others), spinal tumours, ancylosing spondylitis, acute disc prolapse, chronic disc diseaase/osteoarthritis, osteoporosis, and osteomalacia. It also includes Pagets disease, hyperparathyroidism, renal osteodystrophy, spondylolisthesis, spinal senosis congenital abnormalities and fibromyalgia.
  • 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, protozoae and fungus and include conditions such as AIDS, bacterial septicemia, systemic fungal infections, Rickettsial diseases, toxic shock syndrome, infectious mononucleosis, chlamydia thrachomatis, chlamydia psittaci, cytomegalovirus infection, Campylobacter, salmonella, influenza, poliomyelitis, toxoplasmosis, Lassa Fever, Yellow Fever, billharziose, colibacteria, enterococcus, preteus, klebsiella, pseudomonas, staphylococcus aureus, staphylococcus epidermidis, Candida albicans, tuberculos
  • 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, such as e.g. a chemical trauma involving one or more toxic substances and/or drugs.
  • 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, such as e.g. a chemical trauma involving one or more toxic substances and/or drugs.
  • drugs include tricyclic antidepressants, lithium salts, prenylamine, phenothizine derivatives, chemopreventive drugs including adriamycin.
  • physical traumas including electromagnetic radiation may cause damages.
  • Insulin resistance and Diabetes mellitus 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 insulin resistance, metabolic syndrome, diabetes mellitus including diabetes mellitus Type I, diabetes mellitus Type II, obesity-induced diabetes mellitus, obesity-induced diabetes mellitus Type II.
  • Diabetes mellitus Type II includes Type II diabetes mellitus where low grade inflammation in fatty tissue and muscles, plays a significant role for the development of impairment in the signal transduction of insulin and thereby the development of insulin resistance and eventually diabetes mellitus.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of insulin resistance, metabolic syndrome, diabetes mellitus including diabetes mellitus Type I, diabetes mellitus Type II, obesity- induced diabetes mellitus, obesity-induced diabetes mellitus Type II.
  • Eating disorders is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of inflammations related to eating disorders, such as e.g. anorexia and bulimia.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of eating disorders such as e.g. anorexia and bulimia.
  • 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 obesity and metabolic syndrome.
  • Obesity includes obesity where low grade inflammation in fatty tissue and muscles, plays a significant role for the development of the complications to obesity this includes the development of insulin resistance and eventually diabetes mellitus, e.g. diabetes mellitus type II, dyslipidemia, hypertension and aterosclerosis.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of obesity and/or metabolic syndrome.
  • 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 congestive heart failure where low grade inflammation including TNF- ⁇ production within the heart plays a significant role for the development of fibrosis and myocardial remodelling in the falling heart.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of congestive heart failure is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of congestive heart failure
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • drug-induced hypersensitivity including drug hypersensitivity
  • 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.
  • 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.
  • 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, reperfusion 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.
  • 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.
  • 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.
  • 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, atopic dermatitis, psoriasis and conditions related to malfunctions of the glands of the skin, e.g. sebacous glands and over or underproduction of sebum.
  • 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. Labels and tags
  • 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 (PET) 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.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • 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).
  • 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).
  • Compounds of formula (I) or the pharmacologically acceptable salts thereof may also be tagged with a toxic agent (i.e. doxorubicin, 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.
  • a toxic agent i.e. doxorubicin, ricin, diphtheria toxin or other
  • 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
  • the thus formed hybrid compound will direct cytotoxic cells to the malignant melanoma
  • 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.
  • 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.
  • 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.
  • Dimethylthiocarbamoyl chloride (161 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature. The solvent is removed in vacuo to give crude 4,4,S-trimethyl-isothiosemicarbazide hydroiodide, which is mixed with l-(4-chloro- phenyl)-pyrrole-2-carbaldehyde (206 mg, 1 mmol) in ethanol (5 ml) and heated at reflux.
  • Triethylamine (5 eq.) and subsequently SO 3 -pyridine complex (5 eqv.) are added and the reaction mixture is stirred at room temperature for 1 h.
  • the mixture is diluted with H 2 O and extracted with EtOAc.
  • the combined layers are washed with 1 N HCI and brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give crude l-[l-(4-chlorophenyl)-pyrrol-2- ylmethyl]-pyrrolidine-2-carbaldehyde.
  • Diethylthiocarbamoyl chloride (198 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature.
  • Diethylthiocarbamoyl chloride (198 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature.
  • MSH [ 125 I]-NDP-MSH
  • murine B16-F1 melanoma cells expressing MCl, but not other MC receptors are used for binding affinity studies against the murine MCl receptor (Siegrist et al.; 1988, J. Recept. Res., 8(l-4):323-43).
  • human MC3, MC4 and MC5 receptor affinities human recombinant CHO cells are used (Schioth et al. 1997, Neuropeptides 31 : 565-71,1997). Cells are suspended in HEPES buffer and by use of microwell plates radio-ligands, as well as test compound, in the concentration range of 10 10 to 10 '6 are added.

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Abstract

The invention relates to phenyl pyrrole aminoguanidines modified at the guanidine group of the general formula (I), including tautomeric and isomeric forms thereof, wherein, X is (II) and i is 0,1or 2, Y is (III) and j is 0 or 1; wherein Q is nitrogen (N) or carbon (C), and ∪ represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five-or six-membered heterocyclyl or cycloalkyl group; and Z is (IV) and k is 0,1,2 or 3. The invention further relates to the use of such modified phenyl pyrrole aminoguanidines for the treatment of diseases associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones. Such diseases include inflammatory diseases, metabolic syndrome, insulin-resistance, diabetes mellitus, and obesity.

Description

FULLY-MODIFIED PHENYL PYRROLE AMINOGUANIDINES
FIELD OF THE INVENTION
The present invention relates to phenyl pyrrole aminoguanidines modified at the guanidine group. The present invention further relates to the use of such modified phenyl pyrrole aminoguanidines for the treatment of diseases associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
BACKGROUND OF THE INVENTION 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, WO 99/21571.
Moreover, a number of low molecular weight compounds are known, e.g., isoquinolines, spiropyridines and benzimidazoles, which show activity on the MC receptors. See, for example WO 99/55679, WO 99/64002 and WO 01/05401. For further literature disclosing other compounds also acting on the MC receptors, reference is made to WO 00/74679, WO 00/58361, WO 02/18327, WO 02/12166, WO 01/55106, WO 01/55107, WO 01/55109, WO 02/11715 and WO 02/12178.
However, there is still a large need to provide low molecular weight compounds showing agonistic or antagonistic properties to the MC receptors. The compounds of the present invention are structurally different from the above-mentioned compounds and, consequently, constitute a new class of compounds that show activity to the MC receptors.
Prior art compounds, which have some structural relationship to the compounds of the present invention include the compounds described in WO 98/23267:
Figure imgf000003_0001
This hydroxyguanidine derivative has proven activity against xanthine oxidase/xanthine dehydrogenase enzymes.
Likewise, the compounds disclosed in WO 03/013509 exhibit anti-inflammatory properties and binding affinity to the MC receptors. The general structure of the compounds disclosed in WO 03/013509 is as follows:
Figure imgf000004_0001
where X is (CH2)n/ and n is 0, 1 or 2.
Though these compounds are able to stimulate MC receptors, they do not posses a high binding affinity to the MC-receptors compared to the native agonist, α-MSH. The binding affinity of the compounds of WO 03/013509 for the MC-receptors lies within the sub- micromolar to micromolar range compared to α-MSH, which possesses a binding affinity for the MC-receptors lying in the nanomolar range. Furthermore, the compounds of WO 03/013509 are light-sensitive, i.e. light can induce a conversion from the trans isomeric form of the compounds to the cis isomeric form of the compounds. Trans-Cis conversion is well-known to be induced by light. The compounds of the present invention differ from the compounds disclosed in WO 03/013509 inter alia in that the aminoguanidine group has been modified and/or in that the aminoguanidine substituent at the pyrrole ring has been modified into a more rigid structure allowing only minimal rotational freedom around the carbon atoms present in the aminoguanidine substituent.
In one embodiment, the compounds of the invention possess a higher binding affinity for the MC-receptors compared to the compounds disclosed in WO 03/013509. Accordingly, one object of the present invention is to provide compounds which exhibit an increased binding affinity for one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509.
In another embodiment, the compounds of the invention possess a higher efficacy with regard to stimulation of the adenylyl cyclase and production of cAMP via activation of one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509. Accordingly, a second object of the present invention is to provide compounds which possess a higher efficacy with regard to stimulation of the adenylyl cyclase and production of cAMP via activation of one or more of the MC-I, MC-2, MC-3, MC-4 and M-5 receptor(s) compared to the compounds described in WO 03/013509.
In yet another embodiment, the compounds of the invention are more stable, such as e.g. more stable when exposed to light, compared to the compounds disclosed in WO 03/013509. Thus, a third object of the present invention is to provide compounds which, compared to the compounds disclosed in WO 03/013509, are less light-sensitive (i.e. which are more stable).
In still another embodiment, the compounds of the invention possess a higher antiinflammatory activity compared to the compounds disclosed in WO 03/013509. Accordingly, another object of the present invention is to provide compounds which exhibit an increased anti-inflammatory activity compared to the compounds described in WO 03/013509.
In a further embodiment, the compounds of the invention possess a more significant effect regarding inhibition of food intake compared to the compounds disclosed in WO
03/013509. Accordingly, a further object of the present invention is to provide compounds which exhibit a more significant effect with regard to inhibition of food intake compared to the compounds described in WO 03/013509.
In still a further embodiment, the compounds of the invention posses a more significant anti-diabetic effect compared to the compounds disclosed in WO 03/013509. Accordingly, a further object of the present invention is to provide compounds which exhibit an increased anti-diabetic effect compared to the compounds described in WO 03/013509.
SUMMARY OF THE INVENTION
Thus, in a first aspect the present invention relates to a compound of the general formula (I):
Figure imgf000006_0001
including tautomeric and isomeric forms thereof, wherein
Figure imgf000006_0002
Figure imgf000006_0003
wherein Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
Figure imgf000006_0004
each R1, R2, R3, R4, R5, R6, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-β-alkyI, optionally substituted C3.6-cycloalkyl, optionally substituted C2-6-alkenyl, optionally substituted C4.6-alkadienyl, optionally substituted C2.6- alkynyl, hydroxy, optionally substituted Ci-β-alkoxy, optionally substituted C2.6-alkenyloxy, carboxy, optionally substituted Ci-β-alkoxycarbonyl, optionally substituted C^6- alkylcarbonyl, formyl, Ci-β-alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6- alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci_s-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen, where any nitrogen-bound Ci-6-alkyl is optionally substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine;
each R9, Ri0, Rn and Ri2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C4-6-alkadienyl, optionally substituted C2-6-alkynyl, optionally substituted Ci-6- alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6- alkyl-aminocarbonyl and mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl; or R9 and Rio may together form a five- or six-membered nitrogen-containing ring and/or Rn and Ri2 may together form a five- or six-membered nitrogen-containing ring; or R9 and Rn may together form a five- or six-membered nitrogen-containing ring;
or a pharmaceutically acceptable salt thereof;
with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
In a further aspect the present invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
In a still further aspect the present invention relates to a dosage form comprising a pharmaceutical composition of the invention. In yet another aspect the present invention relates to a compound of the invention for use a medicament.
In an even further aspect the present invention relates to a compound of the invention for the treatment or prevention of a disease selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, diabetes mellitus, diabetes mellitus type I, diabetes mellitus type II, obesity-induced diabetes mellitus, insulin-resistance, sexual dysfunction including dysfunction of male erection, eating disorders including anorexia, obesity, mental disorders, dysfunction of the endocrine system, drug-induced disorders of the blood and lymphoid system, allergy disorders, disorders of the cardiovascular system and pain.
Analogously, the present invention also relates to a method of treating a mammal having a disease or disorder, or preventing a mammal from getting a disease or disorder, selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, diabetes mellitus, diabetes mellitus type I, diabetes mellitus type II, obesity- induced diabetes mellitus, insulin-resistance, sexual dysfunction including dysfunction of male erection, eating disorders including anorexia, obesity, mental disorders, dysfunction of the endocrine system, drug-induced disorders of the blood and lymphoid system, allergy disorders, disorders of the cardiovascular system and pain, said method comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
Other aspects of the present invention will be apparent from the appended claims and the description below.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the synthetic route of a compound of the general formula (IV), wherein Q is nitrogen.
Fig. 2 shows the synthetic route of a compound of the general formula (IV), wherein Q is carbon.
Fig. 3 shows specific examples of preferred compounds of the invention.
Figs. 4-10 show the synthetic route for selected preferred compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION
Definitions
In the present context, the term "Ci_6-alkyl" is intended to mean a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, π-propyl, iso- propyl, π-butyl, /so-butyl, sec-butyl, ferf-butyl, π-pentyl, /so-pentyl, πeo-pentyl and π- hexyl, and the term "Ci.4-alkyl" is intended to cover a linear or branched hydrocarbon group having 1 to 4 carbon atoms, e.g. methyl, ethyl, π-propyl, /so-propyl, π-butyl, /so- butyl, sec-butyl and ferf-butyl.
Whenever the term "Ci.6-alkyl" is used herein, it should be understood that an interesting embodiment thereof is "Ci-4-alkyl". Most preferably, "Ci_6-alkyl" (and "Ci-4-alkyl") is methyl or ethyl, in particular methyl.
When used herein, the term "Cs-β-cycloalkyl" is intended to mean a cyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, the term "five- or six-membered cycloalkyl group" refers to cyclopentyl and cyclohexyl.
Similarly, the terms "C2-6-alkenyl" and "C4-6-alkadienyl", are intended to cover linear or branched hydrocarbon groups having 2 to 6 and 4 to 6, carbon atoms, respectively, and comprising one and two unsaturated bonds, respectively. Examples of alkenyl groups are vinyl, ally I, butenyl, pentenyl and hexenyl. Examples of alkadienyl groups include butadienyl, pentadienyl and hexadienyl. Preferred examples of alkenyl are vinyl, allyl and butenyl, especially allyl.
In the present context the term "C2-6-alkynyl" is intended to mean a linear or branched hydrocarbon group having 2 to 6 carbon atoms and containing one or more triple bonds. Illustrative examples of C2-6-alkynyl groups include acetylene, propynyl, butynyl, as well as branched forms of these. The position of unsaturation (the triple bond) may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C2-6-alkynyl" is a di-yne or enedi-yne as is known to the person skilled in the art.
When used herein the term "Ci-6-alkoxy" is intended to mean Ci-β-alkyl-oxy, such as methoxy, ethoxy, π-propoxy, /so-propoxy, π-butoxy, /so-butoxy, sec-butoxy, ferf-butoxy, π-pentoxy, /so-pentoxy, πeo-pentoxy and π-hexoxy, and the term "Ci-4-alkoxy" is intended to mean Ci_4-alkyl-oxy, e.g. methoxy, ethoxy, π-propoxy, /so-propoxy, π-butoxy, /so- butoxy, sec-butoxy and ferf-butoxy. Whenever the term "Ci_6-alkoxy" is used herein, it should be understood that a particularly interesting embodiment thereof is "Ci-4-alkoxy". Most preferably, "Ci-6-alkoxy" (and "Ci-4- alkoxy") is methoxy or ethoxy, in particular methoxy.
Likewise, the term "C2.6-alkenyl-oxy" is intended to mean C2.6-alkenyl-oxy.
Herein, the term "halogen" includes fluoro, chloro, bromo, and iodo. In particular, fluoro, chloro and bromo are preferred. Chloro is the most preferred halogen.
In the present context, i.e. in connection with the terms "alkyl", "alkenyl", "alkadienyl" and "alkynyl", the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6-alkoxy, C2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-6-alkoxycarbonyl, Ci-6-alkylcarbonyl, formyl, aryl, aryloxy- carbonyl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino, heteroaryloxy- carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, cyano, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl- sulphonyl-amino, Ci-6-alkanoyloxy, Ci-6-alkyl-sulphonyl, Ci-6-alkyl-sulphinyl, Ci-6- alkylsulphonyloxy, nitro, Ci-6-alkylthio and halogen, where any aryl and heteroaryl may be substituted as specifically described below for "optionally substituted aryl and heteroaryl", and any alkyl, alkoxy, and the like representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-6- alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine.
Preferably, the above-mentioned substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6- alkoxy (i.e. Ci-6-alkyl-oxy), C2.6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-6-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino, heteroaryloxy, heteroarylcarbonyl, amino, mono- and (Ji(Ci-6- alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl- aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbony- lamino, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, Ci-6-alkyl-sulphonyl, Ci-6-alkyl- sulphinyl, Ci-6-alkylthio and halogen, where any aryl and heteroaryl may be substituted as specifically described below for "optionally substituted aryl and heteroaryl". Especially preferred examples of such substituents are hydroxy, Ci-6-alkoxy, C2-β- alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino and guanidine, in particular halogen. Thus, particularly preferred "optionally substituted Ci-6-alkyl" groups include halogen- substituted alkyl groups, such as trihalo-Ci-6-alkyl, such as tribromomethyl, trichloromethyl or trifluoromethyl. In a particular interesting embodiment trihalo-Ci-6-alkyl is trifluoromethyl.
The term "optionally substituted Ci-6-alkoxy" is intended to mean that the alkoxy groups may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6-alkoxy (i.e. Ci-6-alkyl-oxy), C2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-6-alkoxycarbonyl, Ci-6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, cyano, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-6-alkanoyloxy, Ci-6-alkyl-sulphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylsulphonyloxy, nitro, Ci_6-alkylthio and halogen, where any aryl and heteroaryl may be substituted as specifically describe below for "optionally substituted aryl and heteroaryl".
Especially preferred examples of such substituents are those carrying one or two substituents selected from hydroxy, Ci-6-alkyl, Ci-6-alkoxy, C2-6-alkenyloxy, carboxy, halogen or Ci-6-alkylthio.
In the present context the term "aryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, biphenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl, xanthenyl, among which phenyl, biphenyl and naphthyl are preferred examples. In a particular preferred embodiment of the invention, the term "aryl" refers to phenyl.
The term "heteroaryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen ( = N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl, phenyl pyrrolyl and N-phenyl pyrrolyl.
Particularly interesting heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl, phenyl pyrrolyl and N-phenyl pyrrolyl, in particular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl, quinolyl, tetrazolyl, isoquinolyl, phenyl pyrrolyl and N-phenyl pyrrolyl. The most preferred heteroaryl groups are pyrrolyl, indolyl, phenyl pyrolyl and N-phenyl pyrrolyl.
In the present context, the term "heterocyclyl" is intended to mean a non-aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen ( = N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heterocyclyl groups are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahyd ropy ran, oxepane, tetrahydrothiophene, tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane, dioxepane, oxathiane and oxathiepane.
Preferred examples of heterocyclyl groups are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine) and thiazinane.
In connection with the terms "aryl", "heteroaryl", "cycloalkyl" and "heterocyclyl", the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci-6-alkyl, Ci-β-alkoxy, C2-6-alkenyloxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci-6-alkoxycarbonyl, Ci-6-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di(Ci-6-alkyl)amino; carbamoyl, mono- and di(Ci-6- alkyl)aminocarbonyl, amino-Ci-β-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6- alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyl- oxy, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-6- alkyl-suphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylsulphonyloxy, nitro, sulphanyl, amino, amino- sulfonyl, mono- and di(Ci-6-alkyl)amino-sulfonyl, dihalogen-Ci-4-alkyl, trihalogen-Ci-4-alkyl and halogen, where aryl and heteroaryl representing substituents may be substituted 1-3 times with Ci_4-alkyl, Ci_4-alkoxy, nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like representing substituents may be substituted with hydroxy, Ci_6-alkoxy, C2-β- alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino, or guanidine.
Preferably, the above-mentioned substituents are selected from hydroxy, Ci-6-alkyl, Ci-6- alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci-6- alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-β-alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl- sulphonyl-amino, Ci-6-alkyl-suphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- and di(Ci-6-alkyl)amino-sulfonyl or halogen, where any alkyl, alkoxy and the like representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-6- alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine.
Especially preferred examples of such substituents are Ci-6-alkyl, Ci_6-alkoxy, amino, mono- and di(Ci-6-alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6- alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-β-alkyl-sulphonyl-amino or guanidine.
The term "salt thereof" is intended to mean a pharmaceutically acceptable acid addition salt obtainable by treating the base form of a functional group, such as an amine, with appropriate acids such as inorganic acids, for example hydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric or hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanedioic, butanedioic, (Z)- 2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2- hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydoxybenzoic, 4-amino-2- hydroxybenzoic, and other acids known to the skilled practitioner.
The term "pharmaceutically acceptable" when used in connection with the term "salt thereof" means that the salt does not cause any untoward effects in the patients to whom it is administered. Likewise, the term "pharmaceutically acceptable" when used in connection with the terms "carrier" and/or "excipient" means that the carrier and/or the excipient, at the dosages and with the concentrations employed, does not cause any untoward effects in the patients to whom it is administered.
In the present description and claims, any reference to "a" component, e.g. in the context of a substituent, etc., is intended to refer to one or more of such components, unless stated otherwise or unless it is clear from the particular context that this is not the case. For example, the expression "a component selected from the group consisting of A, B and C" is intended to include all combinations of A, B and C, i.e. A; B; C; A+B; A+C; B+C and A+B+C.
The term "therapeutically effective amount" means a dosage or amount sufficient to produce a desired result. The desired result may comprise an objective or subjective improvement in the recipient of the dosage or amount.
A "prophylactic treatment" is a treatment administered to a subject who does not display signs or symptoms of a disease, pathology, or medical disorder, or displays only early signs or symptoms of a disease, pathology, or disorder, such that treatment is administered for the purpose of diminishing, preventing, or decreasing the risk of developing the disease, pathology, or medical disorder. A prophylactic treatment functions as a preventative treatment against a disease or disorder. A "prophylactic activity" is an activity of an agent, such as a compound disclosed herein, or a composition thereof, that, when administered to a subject who does not display signs or symptoms of pathology, disease or disorder, or who displays only early signs or symptoms of pathology, disease, or disorder, diminishes, prevents, or decreases the risk of the subject developing a pathology, disease, or disorder.
In the present context the term "therapeutic treatment", or simply "treatment", means a treatment administered to a subject who displays symptoms or signs of pathology, disease, or disorder, in which treatment is administered to the subject for the purpose of diminishing or eliminating those signs or symptoms of pathology, disease, or disorder. A "therapeutic activity" is an activity of an agent, such as a compound disclosed herein, or composition thereof, that eliminates or diminishes signs or symptoms of pathology, disease or disorder, when administered to a subject suffering from such signs or symptoms.
The term "subject" as used herein includes, but is not limited to, an organism; a mammal, including, e.g., a human being, non-human primate (e.g., baboon, orangutan, monkey), mouse, pig, cow, goat, cat, rabbit, rat, guinea pig, hamster, horse, monkey, sheep, or other non-human mammal; a non-mammal, including, e.g., a non-mammalian vertebrate, such as a bird (e.g., a chicken or duck) or a fish, and a non-mammalian invertebrate. In a preferred embodiment of the invention the subject is a human being.
The compound of the invention
As indicated above, the present invention relates to a compound of the general formula (I) shown above. As can be seen from formula (I), the aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ia) and (Ib) merely differ from each other by the site of attachment to the pyrrole ring.
Accordingly, in another aspect the present invention relates to a compound of the general formula (Ia) or (Ib)
Figure imgf000015_0001
including tautomeric and isomeric forms thereof, wherein
Figure imgf000016_0001
Figure imgf000016_0002
wherein Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
Figure imgf000016_0003
each Ri, R2, R3, R4, R5, Re, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C3-6-cycloalkyl, optionally substituted C2-6-alkenyl, optionally substituted C4.6-alkadienyl, optionally substituted C2.6- alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2.6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted CV6- alkylcarbonyl, formyl, Ci-6-alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci_6- alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci-6-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen, where any nitrogen-bound Ci-6-alkyl is optionally substituted with hydroxy, Ci_6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine;
each R9, Ri0, Rn and Ri2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C4-6-alkadienyl, optionally substituted C2-6-alkynyl, optionally substituted Ci-6- alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6- alkyl-aminocarbonyl and mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl; or R9 and Ri0 may together form a five- or six-membered nitrogen-containing ring and/or Rn and Ri2 may together form a five- or six-membered nitrogen-containing ring; or R9 and Rn may together form a five- or six-membered nitrogen-containing ring;
or a pharmaceutically acceptable salt thereof;
with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
As discussed above, in the compounds of the general formula (Ia) the aminoguanidine substituent is attached to the pyrrole ring at position 2, whereas in the compounds of the general formula (Ib) the aminoguanidine substituent is attached to the pyrrole ring at position 3. In the following description, only compounds where the aminoguanidine substituent is attached to the pyrrole ring at position 2 is described with respect to preferred substituents, method for manufacturing, etc. Although attachment of the aminoguanidine substituent to the pyrrole ring at position 2 is currently preferred, it should be understood, however, that all statements made below with respect to the compounds of the invention where the aminoguanidine substituent is attached to the pyrrole ring at position 2 also apply to the compounds of the invention where the aminoguanidine substituent is attached to the pyrrole ring at position 3. Furthermore, the compounds described herein are typically shown in their trans isomeric forms. It should be understood, however, that the compounds described herein may also be in their cis isomeric form. Thus, the configuration around a double bond in a molecule described herein may be either cis or trans, although the trans configuration is preferred. As will be understood by the skilled person the compounds of the general formula (I) may, provided that at least one of Rg, Ri0, Rn and Ri2 is hydrogen, exist in various tautomeric forms. In the present context the term "tautomeric forms thereof" or "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Different tautomeric forms have the same molecular formula and are interchangeable forms involving the displacement of hydrogen atoms and electrons. Thus, it will be understood that when a compound of the invention is illustrated by its chemical structure, all possible tautomeric forms of the specifically depicted molecule are also within the scope of the present invention.
Moreover, when j = l further isomers will be possible. With respect to Q, which forms part of the ring system present in the aminoguanidine substituent, this atom may be a carbon atom or a nitrogen atom, i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group. As will be understood, the molecule contains, in case Q is nitrogen, a single asymmetric carbon atom. Thus, in this embodiment of the invention the molecule of invention may be either in its enantiomeric S-form, its enantiomeric R-form, or the molecule of the invention may be a racemic mixture. Likewise, the molecule contains, in case Q is carbon, two asymmetric carbon atoms. Thus, in this embodiment of the invention the molecule of invention may be either in its SS-form, its RR-form, its SR-form, its RS- form, or any mixture thereof.
The compounds of the invention have basic properties and, consequently, they may be converted to their active acid addition salts by treatment with appropriate pharmaceutically acceptable acids. Examples of such acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids, such as acetic acid, propionic acid, hydroacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-butenedioic acid, 2- hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-l,2,3- propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydoxybenzoic acid, 4-amino- 2-hydroxybenzoic acid, and other acids known to the person skilled in the art.
The substituents R1, R2, R3, R4, R5, Re, R7 and R8
The substituents on the phenyl-pyrrole ring system will be discussed in the following. It should be understood that all statements made in the following concerning preferred substituents is independent of the presence or absence of A, B and C (cf. formula (I)) and the actual values of i, j and k.
The substituents Ri, R2, R3, R4, R5, Re, R7 and R8 may be individually selected from the group of substituents indicated above, cf. formula (I). However, in a preferred embodiment of the invention each R1, R2, R3, R4, R5, Re, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2.6- alkenyl, optionally substituted C2.6-alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2.6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, amino-Ci-6- alkyl-carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci-S-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-s-alkylthio and halogen.
In a more preferred embodiment of the invention each R1, R2, R3, R4, R5, R6, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted CV6- alkyl, optionally substituted C2.6-alkenyl, hydroxy, optionally substituted CV6-alkoxy, amino, cyano, nitro and halogen, such as bromo, chloro and fluoro. Specific examples of highly preferred (non-substituted) d-6-alkyl groups include C1-4-alkyl, such as methyl or ethyl, in particular methyl. Specific examples of highly preferred substituted CV6-alkyl groups include substituted C1-4-alkyl, such as halogen-substituted C1-4-alkyl, e.g. trihalo- Ci-4-alkyl, in particular tribromomethyl, trichloromethyl and trifluoromethyl among which trichloromethyl and trifluoromethyl are particularly preferred. Specific examples of highly preferred (non-substituted) C2.6-alkenyl groups include C2.4-alkenyl, such as vinyl, allyl and butenyl, in particular allyl. Specific examples of highly preferred (non-substituted) CV6- alkoxy groups include Ci_4-alkoxy, such as methoxy or ethoxy, in particular methoxy.
In an interesting embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R8 is hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ic):
Figure imgf000020_0001
(Ic)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, R9, Rio/ Rn, R12/ X/ Y and Z also apply to the compounds of the general formula (Ic).
In a further interesting embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R5 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Id) :
Figure imgf000020_0002
(Id)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, Re, R7, Rg, Rio, Rn, R12, X, Y and Z also apply to the compounds of the general formula (Id).
In a yet further embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R4, R5 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ie):
Figure imgf000021_0001
(Ie)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, Re, R7, R9, Rio, Rn, R12, X, Y and Z also apply to the compounds of the general formula (Ie).
In another embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R4, R5, R7 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (If) :
Figure imgf000021_0002
(If)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, Re, R9, Rio, Rn, R12, X, Y and Z also apply to the compounds of the general formula (If). In still another embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R3, R4, R5, R7 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ig) :
Figure imgf000022_0001
(ig)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, Re, R9, Rio, Rn, Ri2, X, Y and Z also apply to the compounds of the general formula (Ig).
In yet another embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R3, R4, R5, R6, R7 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ih) :
Figure imgf000022_0002
(Ih) It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, Rg, Rio, Rn, R12/ X/ Y and Z also apply to the compounds of the general formula (Ih).
Concerning the compounds described above in connection with the general formulae (Ia)- (Ih) it will be understood that the individual substituents may be attached to the ring systems at different positions. More particularly, and with reference to the general formula (Ih) above, the attachment of the Ri and R2 may be as follows: In one embodiment of the invention is Ri located in the 2-position and R2 is located in the 3-position. In another embodiment of the invention is Ri located in the 2-position and R2 is located in the 4- position. In yet another embodiment of the invention is Ri located in the 2-position and R2 is located in the 5-position. In a further embodiment of the invention is Ri located in the 2- position and R2 is located in the 6-position. In a still further embodiment of the invention is Ri is located in the 3-position and R2 is located in the 4-position. In an even further embodiment of the invention is Ri located in the 3-position and R2 is located in the 5- position. In yet another embodiment of the invention is Ri located in the 3-position and R2 is located in the 6-position.
In an even further embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R2, R3, R4, R5, R6, R7 and R8 are hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ii) :
Figure imgf000023_0001
(Ii)
It should be understood that all statements made herein concerning preferred embodiments of Ri, Rg, Ri0, Rn, Ri2, X, Y and Z also apply to the compounds of the general formula (Ii). In one embodiment of the invention is Ri located in the 2-position. In another embodiment of the invention is Ri located in the 3-position. In a third embodiment of the invention is R1 located in the 4-position. In a preferred embodiment, the invention relates to compounds of formula (Ii), wherein Rl is a halogen selected from the group of chloro and bromo. In another preferred embodiment, the invention relates to compounds of formula (Ii), wherein Rl is chloro. In yet a preferred embodiment, the invention relates to compounds of formula (Ii), wherein Rl is chloro located in the 4-position. In still a further embodiment, the invention relates to compounds of formula (Ii), wherein Rl is bromo. In still another embodiment, the invention relates to compounds of formula (Ii), wherein Rl is bromo located in the 2-position. In yet another embodiment, the invention relates to compounds of formula (Ii), wherein Rl is trihalo-Ci-4-alkyl, such as trifluoromethyl. In a further embodiment, the invention relates to compounds of formula (Ii), wherein Rl is trihalo-Ci-4-alkyl, such as trifluoromethyl, located in the 4-position.
In an even further interesting embodiment of the invention all of Ri, R2, R3, R4, R5, Re R7 and R8 are hydrogen, i.e. in an ever further embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R1, R2, R3, R4, R5, Re, R7 and R8 are all hydrogen. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (Ij) :
Figure imgf000024_0001
(Ij)
It should be understood that all statements made herein concerning preferred embodiments of R9, Ri0, Rn, Ri2, X, Y and Z also apply to the compounds of the general formula (Ij).
The substituents Rg, R10, Rn and R12
The substituents on the amino groups of the aminoguanidine substituent will be discussed in the following. It should be understood that all statements made in the following concerning preferred substituents is independent of the presence or absence of X, Y and Z (cf. formula (I)) and the actual values of i, j and k. As discussed previous, the substituents Rg, Ri0, Rn and Ri2 may be individually selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C4-6-alkadienyl, optionally substituted C2.6- alkynyl, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted CV6- alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-β-alkyl-aminocarbonyl and mono- and di(Ci-6- alkyQamino-Ci-β-alkyl-aminocarbonyl; or R9 and Ri0 may together form a five- or six- membered nitrogen-containing ring and/or Rn and Ri2 may together form a five- or six- membered nitrogen-containing ring; or R9 and Rn may together form a five- or six- membered nitrogen-containing ring;
with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
Preferably, each R9, Ri0, Rn and Ri2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2.6-alkenyl, optionally substituted C2.6-alkynyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen. More preferably, each R9, Ri0, Rn and Ri2 is independently hydrogen or optionally substituted CV6-alkyl, preferably optionally substituted CV4-alkyl; with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
In one embodiment of the invention all of R9, Ri0, Rn and Ri2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein each R9, Ri0, Rn and Ri2 is optionally substituted Ci-4-alkyl. Preferably, each R9, Ri0, Rn and Ri2 is independently methyl or ethyl. More preferably, R9, Rio, Rn and Ri2 are methyl or ethyl, in particular methyl. Thus, according to this embodiment of the invention, the compound of the invention may have the structures shown in the general formulae (Ik)-(Io):
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0001
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ X/ Y and Z also apply to the compounds of the general formulae (Ik)-(Io).
In another, and preferred, embodiment of the invention, R9 is hydrogen and each Ri0, Rn and R12 is independently hydrogen or optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl; with the proviso that Ri0, Rn and Ri2 are not hydrogen, or if Ri0 is hydrogen then Rn and Ri2 are not hydrogen.
In one embodiment of this particular aspect R9 is hydrogen and each Ri0, Rn and Ri2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R9 is hydrogen and Ri0, Rn and Ri2 are optionally substituted Ci-4-alkyl. Preferably, each Ri0, Rn and Ri2 is independently methyl or ethyl. More preferably, Ri0, Rn and Ri2 are methyl or ethyl, in particular methyl. Thus, according to this embodiment of the invention, the compound of the invention may have the structures shown in the general formulae (Ip) and (Ir) :
Figure imgf000028_0001
Figure imgf000028_0002
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ X/ Y and Z also apply to the compounds of the general formulae (Ip) and (Ir).
In another embodiment of this particular aspect R9 and Ri0 are hydrogen and Rn and Ri2 are different from hydrogen, such as optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl. Therefore, in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein R9 and Ri0 are hydrogen and Rn and Ri2 are optionally substituted Ci-4-alkyl. Preferably, each Rn and Ri2 is independently methyl or ethyl. More preferably, Rn and Ri2 are methyl or ethyl, in particular methyl. Thus, according to this embodiment of the invention, the compound of the invention may have the structures shown in the general formulae (Is) and (It) :
Figure imgf000029_0001
Figure imgf000029_0002
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ X/ Y and Z also apply to the compounds of the general formulae (Is) and (It).
In a similar, and also preferred, embodiment of the invention, Rn is hydrogen and each R9, Rio and Ri2 is independently hydrogen or optionally substituted Ci-6-alkyl, preferably optionally substituted Ci_4-alkyl; with the proviso that R9, Ri0 and Ri2 are not hydrogen, or if Ri2 is hydrogen then R9 and Ri0 are not hydrogen.
In one embodiment of this particular aspect Rn is hydrogen and each R9, Ri0 and Ri2 are different from hydrogen, i.e. in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein Rn is hydrogen and R9, Ri0 and Ri2 are optionally substituted Ci_4-alkyl. Preferably, each R9, Ri0 and Ri2 is independently methyl or ethyl. More preferably, R9, Ri0 and Ri2 are methyl or ethyl, in particular methyl. Thus, according to this embodiment of the invention, the compound of the invention may have the structures shown in the general formulae (Iu) and (Iv) :
Figure imgf000030_0001
Figure imgf000030_0002
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs, X, Y and Z also apply to the compounds of the general formulae (Iu) and (Iv).
In another embodiment of this particular aspect Rn and Ri2 are hydrogen and Rg and Ri0 are different from hydrogen, such as optionally substituted Ci-6-alkyl, preferably optionally substituted Ci_4-alkyl. Therefore, in one embodiment of the invention, the invention relates to compounds of the general formula (I), wherein Rn and Ri2 are hydrogen and R9 and Ri0 are optionally substituted Ci-4-alkyl. Preferably, each R9 and Ri0 is independently methyl or ethyl. More preferably, R9 and Ri0 are methyl or ethyl, in particular methyl. Thus, according to this embodiment of the invention, the compound of the invention may have the structures shown in the general formulae (Iw) and (Ix) :
Figure imgf000031_0001
Figure imgf000031_0002
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs, X, Y and Z also apply to the compounds of the general formulae (Iw) and (Ix).
The X, Y and Z moieties The X, Y and Z moieties will be discussed in the following. It should be understood that all previous statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, R6, R7, R8, Rg, Rio, Rn, and Ri2 also apply to the following section.
As discussed previously, the moieties X, Y and Z may be as follows: X is ^(^Ns^ and i is 0, 1 or 2;
Figure imgf000032_0001
wherein Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
Z is t- -i and k is 0, 1, 2 or 3.
The embodiment where Y and Z are absent (j=0 and k=0)
In one interesting embodiment of the invention, Y and Z are absent, i.e. j=0 and k=0. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (II) :
Figure imgf000032_0002
wherein i is 0, 1 or 2, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formula (II). The aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ha) and (lib), cf. below, merely differ from each other by the site of attachment to the pyrrole ring.
Accordingly, the present invention relates to a compound of the general formula (Ha) or (lib)
Figure imgf000033_0001
and
Figure imgf000033_0002
wherein i is 0, 1 or 2, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formulae (Ha) and (lib). In a preferred embodiment of the invention, X is absent, i.e. i = 0. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (lie):
Figure imgf000034_0001
(lie)
wherein R1, R2, R3, R4, R5, R6, R7, Rs/ R9, R10, Rn and R12 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 also apply to the compounds of the general formula (lie), i.e. in preferred embodiments of the invention, the compound of the general formula (He) has the structure shown in the general formulae (Hd)-(IIp) :
Figure imgf000034_0002
(Hd)
Figure imgf000035_0001
(lie)
Figure imgf000035_0002
(Mf)
Figure imgf000035_0003
(iig)
Figure imgf000036_0001
(Mh)
Figure imgf000036_0002
(Mi)
Figure imgf000036_0003
(Hj)
Figure imgf000037_0001
(Ilk)
Figure imgf000037_0002
(Hm)
Figure imgf000037_0003
(Hn)
Figure imgf000038_0001
(Ho)
Figure imgf000038_0002
(HP)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, and R8 also apply to the compounds of the general formulae (Hd)-(IIp).
The embodiment where X and Y are absent (i=0 and j=0)
In another interesting embodiment of the invention, X and Y are absent, i.e. i=0 and j = 0. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (III):
Figure imgf000039_0001
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ R-n/ R12 also apply to the compounds of the general formula (III).
The aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (Ilia) and (HIb), cf. below, merely differ from each other by the site of attachment to the pyrrole ring.
Accordingly, the present invention relates to a compound of the general formula (Ilia) or (HIb)
Figure imgf000039_0002
and
Figure imgf000040_0001
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formulae (Ilia) and (HIb).
In a preferred embodiment of the invention k= l. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (IIIc) :
Figure imgf000040_0002
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Ri0, Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of R1, R2, R3, R4, R5, R6, R7, R8, R9, Ri0, Rn, Ri2 also apply to the compounds of the general formula (IIIc), i.e. in preferred embodiments of the invention, the compound of the general formula (IIIc) has the structure shown in the general formulae (HId)-(IIIp) :
Figure imgf000041_0001
(MId)
Figure imgf000041_0002
Ie)
Figure imgf000042_0001
(MIf)
Figure imgf000042_0002
(ing)
Figure imgf000042_0003
(MIh)
Figure imgf000043_0001
(MIi)
Figure imgf000043_0002
(HIj)
Figure imgf000043_0003
(MIk)
Figure imgf000044_0001
(IMm)
Figure imgf000044_0002
(IMn)
Figure imgf000044_0003
Figure imgf000045_0001
(IMp)
It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, and R8 also apply to the compounds of the general formulae (HId)-(IIIp).
The embodiment where Y is present (j=l)
In still another interesting embodiment of the invention, Y is present, i.e. j = l. Thus, according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (IV):
Figure imgf000045_0002
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, R8/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, R6, R7, R8, Rg, Rio, Rn, Ri2 also apply to the compounds of the general formula (IV). The aminoguanidine substituent may be attached to the pyrrole ring at its position 2 or 3, i.e. the compounds of the general formula (IVa) and (IVb), cf. below, merely differ from each other by the site of attachment to the pyrrole ring.
Accordingly, the present invention relates to a compound of the general formula (IVa) or (IVb)
Figure imgf000046_0001
and
Figure imgf000046_0002
(IVb)
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rii/ R12 also apply to the compounds of the general formulae (IVa) and (IVb). As indicated above, i is 0, 1 or 2. In a preferred embodiment, i=0, i.e. according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (IVc) :
Figure imgf000047_0001
(IVc)
wherein k, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rn and R12 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of k, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 also apply to the compounds of the general formula (IVc).
As also indicated previously, k is 0, 1, 2 or 3. In a preferred embodiment, k=0, i.e. according to this embodiment of the invention, the compound of the invention has the structure shown in the general formula (IVd) :
Figure imgf000047_0002
wherein i, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of i, Q, Ri, R2, R3, R4, R5, Re, R7, Rβ/ R9/ Rio/ Rn and Ri2 also apply to the compounds of the general formula (IVd).
Based on the above discussion of compounds having the general formulae (IVc) and (IVd), it will be understood, that compounds which are particularly preferred according to this embodiment of the invention has the general formula (IVe):
Figure imgf000048_0001
(IVe)
wherein Q, Ri, R2, R3, R4, R5, R6, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above. It should be understood that all statements made herein concerning preferred embodiments of Q, Ri, R2, R3, R4, R5, R6, R7, R8, Rg, Rio, Rn and Ri2 also apply to the compounds of the general formula (IVe).
Concerning Q, which forms part of the ring system present in the aminoguanidine substituent, this atom may be a carbon atom or a nitrogen atom, i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group. As will be understood, the molecule contains, in case Q is nitrogen, a single asymmetric carbon atom. Thus, in this embodiment of the invention the molecule of invention may be in either its enantiomeric S-form, its enantiomeric R-form, or the molecule of the invention may be a racemic mixture. Likewise, the molecule contains, in case Q is carbon, two asymmetric carbon atoms. Thus, in this embodiment of the invention the molecule of invention may be in either its SS-form, its RR-form, its SR-form, its RS-form, or any mixture thereof.
In an interesting embodiment, Q is carbon (C). Accordingly, in an interesting embodiment of the invention the compounds disclosed and discussed herein (where Y is present, i.e. where j = l) contains a ring system wherein u together with Q and the carbon atom covalently linked to Q represents an optionally substituted five- or six-membered cycloalkyl group.
In one embodiment, the optionally substituted six-membered cycloalkyl group has the following chemical structure:
Figure imgf000049_0001
wherein each of Ri3, R14, Ri5, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C3.6-cycloalkyl, optionally substituted C2-6-alkenyl, optionally substituted C4.6-alkadienyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2-6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, formyl, Ci-6-alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6- alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci-S-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen, where any nitrogen-bound Ci_6-alkyl is optionally substituted with hydroxy, Ci_6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine.
Preferably, each of Ri3, R14, R15, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2.6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2-6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-β-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci_s-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen.
More preferably, each of Ri3, R14, Ri5, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, hydroxy, optionally substituted Ci-6-alkoxy, amino, cyano, nitro and halogen. In a particular interesting embodiment of the invention all of Ri3, Ri4, Ri5, and Ri6 are hydrogen.
In another embodiment of the invention u represents, together with Q and the carbon atom covalently linked to Y, an optionally substituted five-membered cycloalkyl group as illustrated below:
Figure imgf000050_0001
wherein each of Ri3, Ri4 and Ri5 is as defined above. Again, in a particular interesting embodiment of the invention all of Ri3, Ri4 and Ri5 are hydrogen.
In a preferred embodiment of the invention Q is nitrogen (N), i.e. u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six- membered heterocyclyl group. Any of the heterocyclyl groups mentioned in connection with the definition of this term may be used for this purpose. However, in one embodiment of the invention u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted six-membered heterocyclyl group as illustrated below:
Figure imgf000051_0001
wherein each of Ri3, Ri4, Ri5, and Ri6 is as defined above. Also in this embodiment of the invention is it preferred that all of Ri3, Ri4, Ri5 and Ri6 are hydrogen.
In an even more preferred embodiment of the invention, u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five-membered heterocyclyl group as illustrated below:
Figure imgf000051_0002
wherein each of Ri3, Ri4 and Ri5 are as defined above. In the most preferred embodiment of the invention, all of Ri3, R14 and Ri5 are hydrogen.
Based on the above disclosure, it will be understood that in preferred embodiments of this aspect of the invention, the compound of the general formula (IV) has the structure shown in the general formulae (IVf)-(IVr):
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
It should be understood that all statements made herein concerning preferred embodiments of i, k, R1, R2, R3, R4, R5, Re, R7, and R8 also apply to the compounds of the general formulae (IVf)-(IVr). In a highly preferred embodiment, i=k=0 in all of the above formulae (IVf)-(IVr). It is furthermore preferred that Q is nitrogen (N). In particular, it is preferred that u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl group, preferably an optionally substituted five-membered heterocyclyl group.
Methods of preparing the compounds of the invention
The compounds of the invention may be prepared by standard methods known to the skilled organic chemist. In general, a compound of the general formula (I) above may be prepared essentially as described in WO 03/013509. More particularly, a compound of the general formula (II)
Figure imgf000056_0001
wherein i is 0, 1 or 2, and Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, Rn and Ri2 are as discussed above, may be prepared by reacting an aldehyde of the general formula A
Figure imgf000056_0002
wherein i is 0, 1 or 2, and Ri, R2, R3, R4, R5, Re, R7 and R8 are as discussed above, with an aminoguanidine derivative of the general formula B
Figure imgf000056_0003
B wherein R9, Ri0, Rn and Ri2 are as discussed above, in a suitable organic solvent.
Preferably, a compound of the general formula A is reacted with an aminoguanidine derivative of the general formula B where the aminoguanidine derivative is in the form of an acid addition salt, such as the bicarbonate salt.
Alternatively, the compound of the general formula A is reacted with a thiosemicarbazide of the general formula C
Figure imgf000057_0001
wherein R9 and Ri0 are as discussed above. The reaction is preferably performed in a polar aprotic solvent, such as ethanol.
The resulting intermediate product of the general formula D
Figure imgf000057_0002
is subsequently reacted with an amine of the general formula E
Figure imgf000057_0003
E in a suitable solvent, e.g. a non-polar aprotic solvent, such as toluene, to obtain a compound of the general formula (II). The individual substituents have the same meaning as described above.
Similarly, a compound of the general formula (III)
Figure imgf000058_0001
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, Rn and Ri2 are as discussed above, may be prepared by reacting an aldehyde of the general formula F
Figure imgf000058_0002
with an aminoguanidine derivative of the general formula B (shown above) in a similar way as described above in connection with the preparation of compounds of the general formula (II). Evidently, the compounds of the general formula (III) may also be prepared by reacting the aldehyde F with thiosemicarbazide of the general formula C, followed by reaction with the amine E, as described above. The aldehyde F is easily prepared from the starting aldehyde G
Figure imgf000059_0001
by the well-known Wittig reaction.
The compounds of the general formula (IV)
Figure imgf000059_0002
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as discussed above, may be prepared as shown in Figs. 1 and 2.
More particularly, in case Q=N the compound of the general formula (IV) may be prepared as illustrated in Fig. 1.
Referring to Fig. 1, an aldehyde of the general formula A is reacted with the amino acid ester H, where H may be in its S-form, R-form or a racemic mixture, in a suitable solvent (Step 1). The amino acid ester H is typically an amino acid Ci-6-alkyl ester, i.e. Ri7 is Ci-6- alkyl, preferably methyl or ethyl. Step 1 is carried out in the presence of a suitable reducing agent, such as sodium cyanoborohydride, sodium triacetoxy borohydride, sodium borohydride, or hydrogen in the presence of a suitable catalyst such as palladium or carbon, in a suitable organic solvent to yield an ester of the general formula J.
In Step 2, the obtained ester J may be reduced to its corresponding aldehyde K using a suitable reducing agent, such as lithium aluminium hydride in a suitable organic solvent, such as diethyl ether or THF.
The aldehyde K is then converted to the chain-elongated aldehyde M, via the intermediate L, by the well-known Wittig reaction (Steps 3 and 4).
Formation of the intermediate compound L is carried out in a suitable organic solvent, typically a protic solvent, such as dimethylsulfoxide, dimethylformamide, hexamethyl- phosphorotriamide, in the presence of a strong base, such as an alkoxide, e.g. sodium or potassium ferf-butoxide (Step 3). The intermediate L is subsequently converted to the desired aldehyde M by acidic hydrolysis using standard methods (Step 4). As will be understood, Steps 3 and 4 may be repeated until the desired chain length (k) has been obtained. Thus, after repeated cycles of Steps 3 and 4, the aldehyde N is obtained.
The aldehyde N is then converted to the desired end-product (IV, Q=N) by reacting the aldehyde N with an aminoguanidine derivative of the below general formula B as described previously. Evidently, the compounds of the general formula (IV) may also be prepared by reacting the aldehyde N with thiosemicarbazide of the general formula C, followed by reaction with the amine E, as described above.
More particularly, in case Q=C the compound of the general formula (IV) may be prepared as illustrated in Fig. 2.
Referring to Fig. 2, a halide, such as the bromide, of the general formula O is transformed into a Wittig reagent of the general formula P by standard methods by reaction with triphenyl phoshpine in a suitable solvent (Step 1). In the well-known Wittig reaction, the Wittig reagent P is reacted with a cyclic ketoester of the general formula Q, cf. Step 2 of Fig. 2, to yield the ester R. The cyclic ketoester Q is typically a Ci-6-alkyl ester, i.e. Ri8 is Ci-6-alkyl, preferably methyl or ethyl.
The thus obtained ester R is transformed to its corresponding aldehyde T, via the alcohol intermediate S, using standard methods known to the person skilled in the art (Steps 3 and 4). Step 3 is conveniently carried out using a suitable reducing agent, such as lithium aluminium hydride in a suitable organic solvent, such as diethyl ether or THF. The alcohol intermediate S is subsequently oxidised to its corresponding aldehyde T by means of a suitable oxidising agent, such as sulfur trioxide pyridine complex or oxalylchloride, dimethyl sulfoxide and triethyl amine (Swern oxidation) (Step 4).
The obtained aldehyde T corresponds to the aldehyde K described above in the case where Q is nitrogen. Accordingly, Steps 5, 6 and 7 shown in Fig. 2 (where Q=C) may be conducted in a similar way as Steps 3, 4 and 5 (where Q=N) described above.
Pharmaceutical compositions The compound of the invention is preferably administered in a composition including a pharmaceutically acceptable carrier or excipient. The term "pharmaceutically acceptable" means a carrier or excipient that does not cause any untoward effects in patients to whom it is administered. Such pharmaceutically acceptable carriers and excipients are well known in the art (Remington's Pharmaceutical Sciences, 18th edition, A. R. Gennaro, Ed., Mack Publishing Company [1990]; Pharmaceutical Formulation Development of Peptides and Proteins, S. Frokjaer and L. Hovgaard, Eds., Taylor & Francis [2000]; and Handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press [2000]). The exact dose to be administered depends on the circumstances. Normally, the dose should be capable of preventing or lessening the severity or spread of the condition or indication being treated. It will be apparent to those of skill in the art that an effective amount of the compound of the invention depends, inter alia, upon the disease, the dose, the administration schedule, whether the compound of the invention is administered alone or in conjunction with other therapeutic agents, the general health of the patient, and the like. Generally, and in particular if administered via the oral route, the compound of the invention should be administered in a dose of 0.1 to 100 mg body weight per kilo throughout the treatment period.
The pharmaceutical composition may be formulated in a variety of forms, including liquid, gel, lyophilised, powder, compressed solid, or any other suitable form. The preferred form will depend upon the particular indication being treated and will be apparent to one of skill in the art.
The pharmaceutical composition may be administered orally, subcutaneously, intravenously, intracerebral^, intranasally, transdermal^, intraperitoneal^, intramuscularly, intrapulmonary, vaginally, rectally, intraocularly, or in any other acceptable manner, e.g. using PowderJect or ProLease technology. The composition can be administered continuously by infusion, although bolus injection is acceptable, using techniques well known in the art, such as pumps or implantation. In some instances the composition may be directly applied as a solution or spray. The preferred mode of administration will depend upon the particular indication being treated and will be apparent to one of skill in the art. However, the currently preferred mode of administration is via the oral route.
The pharmaceutical composition of the invention may be administered in conjunction with other therapeutic agents. These agents may be incorporated as part of the same pharmaceutical composition or may be administered separately from the composition of the invention, either concurrently or in accordance with any other acceptable treatment schedule.
Oral administration
For oral administration, the pharmaceutical composition may be in solid or liquid form, e.g. in the form of a capsule, tablet, suspension, emulsion or solution. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods.
Solid dosage forms for oral administration may include capsules, tablets, suppositories, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances, e.g. lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
The compound of the invention may be admixed with adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compound of the invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, oils (such as corn oil, peanut oil, cottonseed oil or sesame oil), tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, buffers, fillers, etc.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, sweeteners, flavoring agents and perfuming agents. 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.
Therapeutic use The compounds of the present invention have been tested in the melanocortin system and have surprisingly been shown to be capable of binding to MC receptors as well as showing activity in functional assays. The compounds of the present invention are either agonists or antagonists of a specific MC-receptor or of a number of MC-receptors, e.g. MCI, MC3, MC4 and/or MC5 receptors.
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 MCI, MC2, MC3, MC4 and MC5, have been described. The MC receptor's signalling is mainly mediated via cAMP, but other signal transduction pathways are also known. They are distinctly distributed in the body.
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 as exemplified by the finding that selective MCl receptor agonists has marked anti-inflammatory action, but seems to lack the organ protective effect described for unspecific MC receptor agonists as α-MSH, where it has been suggested that additional MC3 and/or MC5 receptor stimulation are needed to get the organ protective effect. Another example is the central effects of melanocortin receptor stimulation where it is unclear whether both MC3 and MC4 receptor stimulation or only stimulation of one of the receptors are needed.
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, (see, for example, Eberle: The melanotropins: Chemistry, physiology and mechanisms of action. Basel : Karger, Switzerland. 1988, ISBN 3-8055-4678-5; Gruber et al., Am. J. Physiol. 1989, 257, R681- R694; De Wildt et al., J. Cardiovascular Pharmacology. 1995, 25, 898-905) as well as inducing natriuresis (Tin et al., Hypertension. 1987, 10, 619-627).
Moreover, it is also well-known that the immunomodulatory action of α-MSH includes both immunostimulatory and immunosuppressive effects. Several studies have shown that α- MSH antagonises the effects of pro-inflammatory cytokines such as IL-lα, IL-lβ, IL-6 and TNFα, and induces the production of the anti-inflammatory cytokine, IL-10 (for review, see Catania & Upton, Endocr Rev. 1993 Oct; 14(5): 564-76).
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, 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 α-MSH and ACTH(l-24) have been shown to markedly inhibit feeding (Poggioli et al., Peptides, 1986, 7, 843-848; Vergoni et al., Neuropeptides, 1986, 7, 153-158).
The MC5-receptor has recently been attributed a role in control of exocrine gland function 5 (van der Kraan, et al., Endocrinol. 1998, 139, 2348-2355; Chen et al., Cell. 1997, 91, 789-798).
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 an MC-receptor blocker could inhibit the erectogenic effect of melanocortic peptides (Vergoni et al., Eur. J. Pharmacol., 1998, 362; 95-101). The compounds of the present invention has valuable therapeutic properties, making them useful for the treatment of inflammatory conditions, e.g. acute or chronic inflammatory conditions, such as arthritis, including diseases associated with arthritis, osteoartritis, rheumatoid arthritis, spondylarthropathies (e.g. ankylosing spondilitis), reactive arthritis (including arthritis following rheumatic fever), Henoch-Schonlein purpura, and Reiter 's disease, connective tissue disorders such as systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis, mixed connetive tissue disease, sarcoidosis and primary Sjogrens syndrome including keratoconjunctivitis sicca, polymyalgia rheumatica, and other types of vasculitis, crystal deposition diseases (including gout), pyrophosphate arthropathy, acute calcific periarthritis; inflammatory bowel disease (including Chrons disease and ulcertive colitis), diverticular disease of the colon, and irritable bowel syndrome, pancreatitis, inflammatory upper and lower airway diseases such as chronic obstructive pulmonary diseases (COPD), allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, allergic and non-allergic dermatitis, trauma and post operative stress syndromes, diabetes mellitus, insulin- resistance, metabolic syndrome, sexual dysfunction including dysfunction of male erection, eating disorders including anorexia, obesity, mental disorders, dysfunction of the endocrine system, drug-induced disorders of the blood and lymphoid system, allergy disorders, disorders of the cardiovascular system and pain.
In the following the conditions and diseases of which the compounds of the present invention are useful for treating, are described in details.
Inflammatory conditions
Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of inflammation, an inflammatory condition or an inflammatory disease such as inflammation 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-α).
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.
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 "down regulated" refers to a decreased activity or amount of the compound compared with that in a healthy individual.
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, γ-radiation, α- or β- 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.
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.
Moreover inflammatory diseases include all kinds of soft-tissue rheumatism including rheumatoid arthritis, bursitis, tenosynovitis or peritendonitis, enthesitis, nerve compression, periarthritis or capsulitis, muscle tension and muscle dysfunction. Furthermore, inflammatory diseases include all kinds of arthtitis in children such as Juvenile Chronic arthritis including Still 's disease, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis.
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 (Chrons disease), systemic sclerosis, ulcus duodeni, coeliac disease, oesophagitis, ulcus ventriculi, acute and chronic gastritis, helicobacteer pylori infection, coeliac disease, gluten sensitive enteropathy, dermatitis herpitiformis, tropical sprue, Whipple 's diease, radiation enteritis, systemic amyloidosis, eosinophilic gastroenteritis, intestinal lympangiectasia, inflammatory bowel disease, diverticular disease of the colon, and irritable bowel syndrome.
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.
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.
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. 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 ear related to inflammation, specific examples of which include polychondritis affecting the ear and external otitis.
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.
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.
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 and/or airways, such as e.g. acute or chronic or subchronic inflammation in the lung and/or airway. 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, Good Pastures' syndrome, upper and lower airway diseases such as chronic obstructive pulmonary disease (COPD), exacerbations in COPD, allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, acute respiratory diseases and/or chronic and/or subchronic airway and lung diseases.
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.
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.
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 acute pancreatitis, chronic pancreatitis.
Moreover, 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 conditions with increased fasting levels of LDL-Cholesterol, conditions with combined increased fasting levels of LDL-Cholesterol and triglyceride, conditions with increased fasting levels of triglyceride and conditions with increased fasting levels of HDL- Cholesterol.
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.
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.
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.
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.
Inflammatory diseases also include all kind of inflammatory conditions causing backpain including infections, septic discitis, tuberculosis, malignancies (such as metastases, myeloma and others), spinal tumours, ancylosing spondylitis, acute disc prolapse, chronic disc diseaase/osteoarthritis, osteoporosis, and osteomalacia. It also includes Pagets disease, hyperparathyroidism, renal osteodystrophy, spondylolisthesis, spinal senosis congenital abnormalities and fibromyalgia.
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, protozoae and fungus and include conditions such as AIDS, bacterial septicemia, systemic fungal infections, Rickettsial diseases, toxic shock syndrome, infectious mononucleosis, chlamydia thrachomatis, chlamydia psittaci, cytomegalovirus infection, Campylobacter, salmonella, influenza, poliomyelitis, toxoplasmosis, Lassa Fever, Yellow Fever, billharziose, colibacteria, enterococcus, preteus, klebsiella, pseudomonas, staphylococcus aureus, staphylococcus epidermidis, Candida albicans, tuberculosis, mumps, infectious mononucleosis, hepatitis and Coxackie virus.
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, such as e.g. a chemical trauma involving one or more toxic substances and/or drugs. Such drugs include tricyclic antidepressants, lithium salts, prenylamine, phenothizine derivatives, chemopreventive drugs including adriamycin. Also physical traumas including electromagnetic radiation may cause damages.
Insulin resistance and Diabetes mellitus 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 insulin resistance, metabolic syndrome, diabetes mellitus including diabetes mellitus Type I, diabetes mellitus Type II, obesity-induced diabetes mellitus, obesity-induced diabetes mellitus Type II. Diabetes mellitus Type II includes Type II diabetes mellitus where low grade inflammation in fatty tissue and muscles, plays a significant role for the development of impairment in the signal transduction of insulin and thereby the development of insulin resistance and eventually diabetes mellitus. Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of insulin resistance, metabolic syndrome, diabetes mellitus including diabetes mellitus Type I, diabetes mellitus Type II, obesity- induced diabetes mellitus, obesity-induced diabetes mellitus Type II.
Eating disorders 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 eating disorders, such as e.g. anorexia and bulimia. Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of eating disorders, such as e.g. anorexia and bulimia.
Obesity
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 obesity and metabolic syndrome. Obesity includes obesity where low grade inflammation in fatty tissue and muscles, plays a significant role for the development of the complications to obesity this includes the development of insulin resistance and eventually diabetes mellitus, e.g. diabetes mellitus type II, dyslipidemia, hypertension and aterosclerosis. Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of obesity and/or metabolic syndrome.
Congestive heart failure
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 congestive heart failure where low grade inflammation including TNF-α production within the heart plays a significant role for the development of fibrosis and myocardial remodelling in the falling heart. Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of congestive heart failure
Sexual dysfunction
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.
Mental disorders
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.
Dysfunction of the endocrine system
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.
Drug-induced disorders of the blood and lymphoid system
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.
Allergy disorders
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.
Disorders of the cardiovascular system
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, reperfusion 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.
Pain
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.
Other uses
Skin tanning
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.
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, atopic dermatitis, psoriasis and conditions related to malfunctions of the glands of the skin, e.g. sebacous glands and over or underproduction of sebum.
In vivo formation of second messenger elements
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. Labels and tags
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 (PET) 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.
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).
Compounds of formula (I) or the pharmacologically acceptable salts thereof may also be tagged with a toxic agent (i.e. doxorubicin, 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 MCl-receptor bearing malignant cells and inhibit the tumor growth.
Compounds of formula (I) or a pharmacologically acceptable salt thereof may be attached to the antibody chemically by covalent or non-covalent bond(s).
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.
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. Some of the compounds of the invention have an effect on xanthine oxidase in mammals, including humans. The invention is further illustrated by the following non-limiting examples.
EXPERIMENTAL
Example 1 - Synthesis of N-(l-[4-trifluoromethyl-phenyl]pyrτol-2-yl methylideneamino)- N',N',N"-trimethyl guanidine.
l-(4-trifluoromethyl-phenyl)-pyrrole-2-carbaldehyde (239 mg, 1 mmol) and 4,S-dimethyl- isothiosemicarbazide hydroiodide (247 mg, 1 mmol) are mixed in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of dimethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 4.
Example 2 - Synthesis of N-(l-[4-chlorophenyl]pyrrol-2-yl methylideneamino)- N',N',N",N"-tetramethyl guanidine.
Dimethylthiocarbamoyl chloride (161 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature. The solvent is removed in vacuo to give crude 4,4,S-trimethyl-isothiosemicarbazide hydroiodide, which is mixed with l-(4-chloro- phenyl)-pyrrole-2-carbaldehyde (206 mg, 1 mmol) in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of dimethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 5.
Example 3 - Synthesis of N-(l-[4-chlorophenyl]pyrrol-2-yl methylideneamino)-N',N'- diethyl-N",N"-dimethyl guanidine.
In analogy to Example 2, l-(4-chlorophenyl)-pyrrole-2-carbaldehyde (206 mg, 1 mmol) and crude 4,4,S-trimethyl-isothiosemicarbazide hydroiodide are mixed in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of diethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 6. Example 4 - Synthesis of N-(l-[4-chlorophenyl]pyrrol-2-yl methylideneamino)-N',N'- dimethyl guanidine.
l-(4-chlorophenyl)-pyrrole-2-carbaldehyde (206 mg, 1 mmol) and S-methylthiosemi- carbazide hydroiodide (233 mg, 1 mmol) are mixed in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of dimethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 7.
Example 5 - Synthesis of N-{3-(l-[4-chlorophenyl]pyrrol-2-yl)allylidene}amino-N',N'- diethyl guanidine.
3-[l-(4-chlorophenyl)-pyrrol-2-yl]-propenal (232 mg, 1 mmol) and S-methylthiosemi- carbazide hydroiodide (233 mg, 1 mmol) are mixed in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of diethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 8.
Example 6 - Synthesis of N-{l-[l-(4-chlorophenyl)-pyrrol-2-ylmethyl]-pyrrolidin-2- ylmethylene amino}-N',N',N"-triethyl guanidine.
l-(4-chlorophenyl)-pyrrole-2-carboxaldehyde (411 mg, 2 mmol) and pyrrolidin-2-yl- methanol (404 mg, 4 mmol) are dissolved in 2% AcOH in MeOH and NaCNBH3 (378 mg, 6 mmol) is added. The solution is stirred at room temperature for 18 hr. evaporated and purified by flash chromatography to give {l-[l-(4-Chloro-phenyl)-pyrrol-2-ylmethyl]- pyrrolidin-2-yl}-methanol. The alcohol (1 eqv.) is dissolved in DMSO: DCM (3: 1).
Triethylamine (5 eq.) and subsequently SO3-pyridine complex (5 eqv.) are added and the reaction mixture is stirred at room temperature for 1 h. The mixture is diluted with H2O and extracted with EtOAc. The combined layers are washed with 1 N HCI and brine, dried (Na2SO4), filtered and evaporated in vacuo to give crude l-[l-(4-chlorophenyl)-pyrrol-2- ylmethyl]-pyrrolidine-2-carbaldehyde.
Diethylthiocarbamoyl chloride (198 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature. The solvent is removed in vacuo to give crude 4,4- diethyl-S-methyl-isothiosemicarbazide hydroiodide, which is mixed with crude l-[l-(4- Chloro-phenyl)-pyrrol-2-ylmethyl]-pyrrolidine-2-carbaldehyde prepared as described above (289 mg, 1 mmol) in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of ethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 9.
Example 7 - Synthesis of N-{3-(l-[4-trifluoromethylphenyl]pyrrol-2-yl)allylidene}am ino-N',N',N",N"-tetraethyl guanidine
Diethylthiocarbamoyl chloride (198 mg, 1.3 mmol) and hydrazine monohydrate (65 mg, 1.3 mmol) are mixed in ethanol (3 ml). The mixture is stirred at room temperature until the acid chloride is consumed. Methyl iodide is added (185 mg, 1.3 mmol) and the reaction mixture is stirred at room temperature. The solvent is removed in vacuo to give crude 4,4- diethyl-S-methyl-isothiosemicarbazide hydroiodide, which is mixed with 3-[l-(4- trifluoromethylphenyl)-pyrrol-2-yl]-propenal (239 mg, 1 mmol) in ethanol (5 ml) and heated at reflux. When the aldehyde is consumed the solvent is removed. The residue is suspended in dry toluene (5 ml) and a solution of diethylamine (3 mmol) in dry toluene (1 ml) is added. The mixture is heated at reflux in a sealed vial until completion of the reaction. The solvent is removed and the solid residue is recrystallized to give the title product. The synthesis is illustrated in Fig. 10.
Example 8 - In vitro pharmacology and binding assays
Description of applied methods
Determination of binding affinities for MC receptors is performed by [125I]-[Nle4,D-Phe7]α-
MSH ([125I]-NDP-MSH) radio-ligand binding. In short, murine B16-F1 melanoma cells expressing MCl, but not other MC receptors, are used for binding affinity studies against the murine MCl receptor (Siegrist et al.; 1988, J. Recept. Res., 8(l-4):323-43). For human MC3, MC4 and MC5 receptor affinities human recombinant CHO cells are used (Schioth et al. 1997, Neuropeptides 31 : 565-71,1997). Cells are suspended in HEPES buffer and by use of microwell plates radio-ligands, as well as test compound, in the concentration range of 10 10 to 10'6 are added. After incubation at 37°C (22°C for the MCl receptor assay) separation of bound and free [125I]-NDP-MSH is performed by multiple washings with buffer. The results are expressed as a percent of control specific binding obtained in the presence of the test compounds. Mean values for each assay are presented in Table I below. The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) are determined by non-linear regression analysis of the competition curves using Hill equation curve fitting. The inhibition constants (KO are calculated from the Cheng Prusoff equation (K, = IC50/(l+(L/KD)), where L = concentration of radio-ligand in the assay, and KD = affinity of the radio-ligand for the receptor).
Table I Assay Ligand Cone. Non Specific Incubation
MC1 [125I]NDP-MSH °-05 nM NDP-MSH 90 min/22°C
(l μM)
MC3 (h) NDP-MSH 60 min/37°C
[125I]NDP-MSH 0.075 nM
(l μM)
MC4 ^ [125I]NDP-MSH °-05 nM NDP-MSH 120 min/37°C
(l μM)
MC5 ^ [125I]NDP-MSH °-05 nM NDP-MSH 60 min/37°C (l μM)
Figure imgf000079_0001

Claims

1. A compound of the general formula (I):
Figure imgf000080_0001
including tautomeric and isomeric forms thereof, wherein
Figure imgf000080_0002
Figure imgf000080_0003
wherein Q is nitrogen (N) or carbon (C), and u represents, together with Q and the carbon atom covalently linked to Q, an optionally substituted five- or six-membered heterocyclyl or cycloalkyl group;
Figure imgf000080_0004
each R1, R2, R3, R4, R5, Re, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-β-alkyI, optionally substituted C3-6-cycloalkyl, optionally substituted C2.6-alkenyl, optionally substituted C4.6-alkadienyl, optionally substituted C2.6- alkynyl, hydroxy, optionally substituted Ci-β-alkoxy, optionally substituted C2.6-alkenyloxy, carboxy, optionally substituted Ci-β-alkoxycarbonyl, optionally substituted C^6- alkylcarbonyl, formyl, Ci-6-alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6- alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci_s-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen, where any nitrogen-bound Ci_6-alkyl is optionally substituted with hydroxy, Ci_6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine;
each R9, Ri0, Rn and Ri2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C4-6-alkadienyl, optionally substituted C2-6-alkynyl, optionally substituted Ci-6- alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6- alkyl-aminocarbonyl and mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl; or R9 and Rio may together form a five- or six-membered nitrogen-containing ring and/or Rn and Ri2 may together form a five- or six-membered nitrogen-containing ring; or R9 and Rn may together form a five- or six-membered nitrogen-containing ring;
or a pharmaceutically acceptable salt thereof;
with the proviso that at least three of R9, Ri0, Rn and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
2. The compound according to claim 1, wherein each R1, R2, R3, R4, R5, R6, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6- alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2-6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, amino-Ci-β-alkyl-carbonylamino, mono- and di(Ci-6-alkyl)amino- Ci-6-alkyl-carbonylamino, cyano, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci-6- alkylsulphinyl, Ci-6-alkylsulphonyloxy, aminosulfonyl, mono- and di(Ci-6- alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen.
3. The compound according to claim 2, wherein each Ri, R2, R3, R4, R5, R6, R7 and R8 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6- alkyl, optionally substituted C2.6-alkenyl, hydroxy, optionally substituted Ci_6-alkoxy, amino, cyano, nitro and halogen.
4. The compound according to any of the preceding claims, wherein each R9, Ri0, Rn and Ri2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C2.6-alkenyl, optionally substituted C2.6-alkynyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that at least three of Rg, Rio, RH and Ri2 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
5. The compound according to claim 4, wherein each R9, Ri0, Rn and Ri2 is independently hydrogen or optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl; with the proviso that at least three of R9, Ri0, Rn and R12 are not hydrogen, or if R9 and Ri0 are both hydrogen then Rn and Ri2 are not hydrogen, or if Rn and Ri2 are both hydrogen then R9 and Ri0 are not hydrogen.
6. The compound according to claim 5, wherein R9, Ri0, Rn and Ri2 are optionally substituted Ci-4-alkyl.
7. The compound according to claim 6, wherein each R9, Ri0, Rn and R12 is independently methyl or ethyl.
8. The compound according to claim 7, wherein R9, Ri0, Rn and Ri2 are methyl.
9. The compound according to claim 8, wherein R9, Ri0, Rn and Ri2 are ethyl.
10. The compound according to claim 5, wherein R9 is hydrogen and each Ri0, Rn and Ri2 is independently hydrogen or optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl; with the proviso that Ri0, Rn and Ri2 are not hydrogen, or if Ri0 is hydrogen then Rn and Ri2 are not hydrogen.
5
11. The compound according to claim 10, wherein Ri0, Rn and Ri2 are optionally substituted Ci_4-alkyl.
12. The compound according to claim 11, wherein each Ri0, Rn and Ri2 is independently 10 methyl or ethyl.
13. The compound according to claim 12, wherein Ri0, Rn and Ri2 are methyl.
14. The compound according to claim 13, wherein Ri0, Rn and Ri2 are ethyl. 15
15. The compound according to claim 10, wherein R9 and Ri0 are hydrogen and Rn and Ri2 are optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl.
16. The compound according to claim 15, wherein Rn and Ri2 are optionally substituted 20 d-4-alkyl.
17. The compound according to claim 16 wherein each Rn and Ri2 is independently methyl or ethyl.
25 18. The compound according to claim 17, wherein Rn and Ri2 are methyl.
19. The compound according to claim 18, wherein Rn and Ri2 are ethyl.
20. The compound according to claim 5, wherein Rn is hydrogen and each R9, Ri0 and Ri2 30 is independently hydrogen or optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl; with the proviso that R9, Ri0 and Ri2 are not hydrogen, or if Ri2 is hydrogen then R9 and Ri0 are not hydrogen.
21. The compound according to claim 20, wherein R9, Ri0 and Ri2 are optionally substituted 35 Ci-4-alkyl.
22. The compound according to claim 21, wherein each R9, Ri0 and Ri2 is independently methyl or ethyl.
23. The compound according to claim 22, wherein R9, Ri0 and Ri2 are methyl.
24. The compound according to claim 23, wherein R9, Ri0 and Ri2 are ethyl.
5 25. The compound according to claim 20, wherein Rn and Ri2 are hydrogen and R9 and Ri0 are optionally substituted Ci-6-alkyl, preferably optionally substituted Ci-4-alkyl.
26. The compound according to claim 25, wherein R9 and Ri0 are optionally substituted Ci-4-alkyl.
10
27. The compound according to claim 26 wherein each R9 and Ri0 is independently methyl or ethyl.
28. The compound according to claim 27, wherein R9 and Ri0 are methyl. 15
29. The compound according to claim 28, wherein R9 and Ri0 are ethyl.
30. The compound according to any of the preceding claims, wherein R8 is hydrogen and Ri/ R2/ R.3/ R4, R5, R6 and R7 are as defined in any of claims 1-3.
20
31. The compound according to claim 30, wherein R5 and R8 are hydrogen and Ri, R2, R3, R4, R6 and R7 are as defined in any of claims 1-3.
32. The compound according to claim 31, wherein R4, R5 and R8 are hydrogen and Ri, R2, 25 R3, R6 and R7 are as defined in any of claims 1-3.
33. The compound according to claim 32, wherein R4, R5, R7 and R8 are hydrogen and Ri, R2, R3 and R6 are as defined in any of claims 1-3.
30 34. The compound according to claim 33, wherein R3, R4, R5, R7 and R8 are hydrogen and Ri, R2, and R6 are as defined in any of claims 1-3.
35. The compound according to claim 34, wherein R3, R4, R5, R6 R7 and R8 are hydrogen and Ri and R2 are as defined in any of claims 1-3.
35
36. The compound according to claim 34 or 35, wherein R1 is located in the 2-position and R2 is located in the 3-position.
37. The compound according to claim 34 or 35, wherein R1 is located in the 2-position and R2 is located in the 4-position.
38. The compound according to claim 34 or 35, wherein Ri is located in the 2-position and 5 R2 is located in the 5-position.
39. The compound according to claim 34 or 35, wherein Ri is located in the 2-position and R2 is located in the 6-position.
10 40. The compound according to claim 34 or 35, wherein Ri is located in the 3-position and R2 is located in the 4-position.
41. The compound according to claim 34 or 35, wherein Ri is located in the 3-position and R2 is located in the 5-position.
15
42. The compound according to claim 34 or 35, wherein Ri is located in the 3-position and R2 is located in the 6-position.
43. The compound according to claim 35, wherein R2, R3, R4, R5, R6 R7 and R8 are hydrogen 20 and Ri is as defined in any of claims 1-3.
44. The compound according to claim 43, wherein Ri is located in the 2-position.
45. The compound according to claim 43, wherein Ri is located in the 3-position. 25
46. The compound according to claim 43, wherein Ri is located in the 4-position.
47. The compound according to claim 43, wherein all of Ri, R2, R3, R4, R5, R6 R7 and R8 are hydrogen.
30
48. The compound according to any of the preceding claims, wherein j=0 and k=0.
49. The compound according to claim 48 of the general formula (II):
35
Figure imgf000086_0001
wherein i, R1, R2, R3, R4, R5, R6, R7, Rs/ R9, R10, Rn and R12 are as defined in any of claims 1-47.
50. The compound according to claim 49 of the general formula (Ha) :
Figure imgf000086_0002
wherein i, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined in any of claims 1-47.
51. The compound according to claim 49 of the general formula (lib):
Figure imgf000087_0001
wherein i, R1, R2, R3, R4, R5, R6, R7, Rs/ R9, R10, Rn and R12 are as defined in any of claims 1-47.
52. The compound according to any of claims 48-51, wherein i=0.
53. The compound according to claim 52 of the general formula (lie) :
Figure imgf000087_0002
(Hc) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined in any of claims 1- 47.
54. The compound according to any of claims 1-47, wherein i=0 and j=0.
55. The compound according to claim 54 of the general formula (III) :
Figure imgf000088_0001
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1-47.
56. The compound according to claim 55 of the general formula (Ilia) :
Figure imgf000088_0002
Ia)
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1-47.
57. The compound according to claim 55 of the general formula (HIb):
Figure imgf000089_0001
wherein k is 1, 2 or 3, and Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1-47.
58. The compound according to any of claims 44-57, wherein k= l.
59. The compound according to claim 58 of the general formula (IIIc) :
Figure imgf000089_0002
10
wherein R1, R2, R3, R4, R5, R6, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1- 47.
15 60. The compound according to any of claims 1-47, wherein j = l.
61. The compound according to claim 60 of the general formula (IV) :
Figure imgf000090_0001
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1-47.
62. The compound according to claim 60 or 61, wherein Q is carbon (C).
63. The compound according to claim 62, wherein u, together with Q and the carbon atom covalently linked to Q, represents an optionally substituted five- or six-membered cycloalkyl group.
64. The compound according to claim 63, wherein u, together with Q and the carbon atom covalently linked to Q, has the following chemical structure
Figure imgf000090_0002
wherein each of Ri3, Ri4, Ri5, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6-alkyl, optionally substituted C3.6-cycloalkyl, optionally substituted C2-6-alkenyl, optionally substituted C4.6-alkadienyl, optionally substituted C2.6-alkynyl, hydroxy, optionally substituted Ci-6-alkoxy, optionally substituted C2-6-alkenyloxy, carboxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci-6-alkylcarbonyl, formyl, Ci-6-alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-β-alkyl-aminocarbonyl, mono- and di(Ci-6- alkyQamino-Ci-β-alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, amino-Ci-6-alkyl- carbonylamino, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-carbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci_s-alkylsulphinyl, Ci-6-alkylsulphonyl- oxy, aminosulfonyl, mono- and di(Ci-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci-6-alkylthio and halogen, where any nitrogen-bound Ci_6-alkyl is optionally substituted with hydroxy, Ci_6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-β-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6-alkyl-sulphonyl-amino or guanidine.
65. The compound according to claim 64, wherein each of Ri3, R14, Ri5, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6- alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted CV6-alkoxy, optionally substituted C2-6-alkenyloxy, carboxy, optionally substituted CV6-alkoxycarbonyl, optionally substituted CV6-alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino, carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-δ-alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-β-alkylcarbonylamino, amino-Ci-β-alkyl-carbonylamino, mono- and di(Ci-6-alkyl)amino- Ci-6-alkyl-carbonylamino, cyano, carbamido, CV6-alkanoyloxy, Ci-6-alkylsulphonyl, Ci-6- alkylsulphinyl, Ci-6-alkylsulphonyloxy, aminosulfonyl, mono- and di(Ci_6- alkyl)aminosulfonyl, nitro, optionally substituted Ci_6-alkylthio and halogen.
66. The compound according to claim 65, wherein each of Ri3, Ri4, Ri5, and Ri6 is independently selected from the group consisting of hydrogen, optionally substituted Ci-6- alkyl, optionally substituted C2.6-alkenyl, hydroxy, optionally substituted Ci_6-alkoxy, amino, cyano, nitro and halogen.
67. The compound according to claim 66, wherein all of Ri3, Ri4, Ri5, and Ri6 are hydrogen.
68. The compound according to claim 63, wherein u, together with Q and the carbon atom covalently linked to Q, has the following chemical structure
Figure imgf000092_0001
wherein each of Ri3, R14 and Ri5 is as defined in any of claims 64-66.
69. The compound according to claim 68, wherein all of Ri3, R14 and Ri5 are hydrogen.
10 70. The compound according to claim 60 or 61, wherein Q is nitrogen (N).
71. The compound according to claim 70, wherein u, together with Q and the carbon atom covalently linked to Y, represents an optionally substituted five- or six-membered heterocyclyl group.
15
72. The compound according to claim 71, wherein u, together with Q and the carbon atom covalently linked to Q, has the following chemical structure
Figure imgf000092_0002
20 wherein each of Ri3, Ri4, Ri5, and Ri6 is as defined in any of claims 64-66.
73. The compound according to claim 72, wherein all of Ri3, Ri4, Ri5 and Ri6 are hydrogen.
25 74. The compound according to claim 71, wherein u, together with Q and the carbon atom covalently linked to Q, has the following chemical structure
Figure imgf000093_0001
wherein each of Ri3, R14 and Ri5 is as defined in any of claims 64-66.
5 75. The compound according to claim 74, wherein all of Ri3, Ri4 and Ri5 are hydrogen.
76. The compound according to any of claims 60-75, wherein i is 0 or 1.
77. The compound according to claim 76, wherein i=0.
10
78. The compound according to any of claims 60-77, wherein k is 0 or 1.
79. The compound according to claim 78, wherein k=0.
15 80. The compound according to any of claims 60-79 of the general formula (IVa) :
Figure imgf000093_0002
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of 20 claims 1-47.
81. The compound according to any of claims 60-79 of the general formula (IVb) :
Figure imgf000094_0001
(IVb)
wherein k, i, Q, u, Ri, R2, R3, R4, R5, Re, R7, Rs/ R9/ Rio/ Rn and Ri2 are as defined in any of claims 1-47.
82. A pharmaceutical composition comprising a compound as defined in any of claims 1-81 and a pharmaceutically acceptable carrier or excipient.
83. A dosage form comprising the pharmaceutical composition as defined in claim 82.
10
84. The dosage form according to claim 83, wherein said dosage form is a solid dosage form.
85. The solid dosage form according to claim 84, wherein said solid dosage form is in the 15 form of a tablet or capsule.
86. A compound as defined in any of claims 1-81 for use as a medicament.
87. A compound as defined in any of claims 1-81 for the treatment or prevention of a 20 disease or condition associated with the melanocortin receptor system.
88. A compound as defined in any of claims 1-81 for the treatment or prevention of an inflammatory disease.
25 89. A compound as defined in any of claims 1-81 for the treatment or prevention of metabolic syndrome.
90. A compound as defined in any of claims 1-81 for the treatment or prevention of insulin-resistance.
91. A compound as defined in any of claims 1-81 for the treatment or prevention of diabetes mellitus.
92. The compound according to claim 91, wherein the diabetes mellitus is selected from the group consisting of diabetes mellitus type I, diabetes mellitus type II and obesity- induced diabetes mellitus type II.
93. A compound as defined in any of claims 1-81 for the treatment or prevention of obesity.
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