Phenyl pyrrole aminoguanidine derivatives
Inventors
Boman, Arne • Jonassen, Thomas Engelbrecht Norkild • Lundstedt, Torbjorn
Assignees
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Publication Number
US-8058306-B2
Publication Date
2011-11-15
Expiration Date
Abstract
The present invention relates to phenyl pyrrole aminoguanidine derivatives of the general formula (I): (I) including tautomeric forms thereof, wherein n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. The present invention further relates to the use of such phenyl pyrrole aminoguanidine derivatives for the treatment of diseases associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
Core Innovation
The patent describes phenyl-pyrrole aminoguanidine derivatives as compounds of general formula (I), including tautomeric forms thereof, and pharmaceutically acceptable salts. The compounds include detailed substituent selections for R1 through R5 and R6 and R7, with preferred embodiments corresponding to general formulae (Ia), (Ib), and (II) to (VI), including cis/trans and tautomeric forms.
The compounds are framed in relation to melanocortin (MC) receptor-associated systems and are characterized through in vitro MC receptor binding findings using radio-ligand binding, including increased receptor binding affinity compared with reference compounds from WO 03/013509. Reported binding is expressed via Ki and IC50 values derived from competition curves and radio-ligand binding using [125I]-NDP-MSH.
The description also states in vivo testing context for anti-inflammatory outcomes, including LPS-induced TNF-b1 and IL-10 in rats, with dose-dependent reductions for selected compounds. The compounds and embodiments are presented as addressing MC receptor-associated diseases and disorders, including inflammatory conditions and disorders connected with the endocrine and mental systems, as well as pain and allergy-related conditions.
Claims Coverage
The partial content includes at least one independent claim and multiple dependent claims. Coverage includes compound definitions for general formula (I) with tautomeric forms and pharmaceutically acceptable salts, and a dependent treatment method claim for enumerated disease or disorder categories by administering a therapeutically effective amount of a compound of claim 1.
General formula phenyl-pyrrole aminoguanidine compounds with tautomeric forms
A compound of the general formula (I) including tautomeric forms thereof, wherein n is 1, 2 or 3, with substituents R1–R5 independently selected from a group of hydrogen, optionally substituted C1–6 alkyl/alkoxy/alkylcarbonyl/alkylsulphonylamino and other specified functional groups including guanidino, and with substituents R6 and R7 independently selected from a group including hydrogen, optionally substituted C1–6 alkyl/alkoxycarbonyl/alkylcarbonyl and aminocarbonyl/aminocarbonyl-related options, or R6 and R7 together forming a five- or six-membered nitrogen-containing ring, or a pharmaceutically acceptable salt thereof.
Rigid positional embodiments via defined substituent positions
A compound defined by general formula embodiments in which substituent patterns are fixed by positional placement on the ring system, including embodiments where R2 is in the 2-position and R3 is in the 3-position, and embodiments in which specific substituent selections are imposed, for example fixing R6 and R7 to hydrogen, or fixing R1 and R4 to hydrogen.
Therapeutic administration for enumerated disease or disorder categories
A method of treating a mammal having a disease or disorder selected from inflammatory conditions, diabetes mellitus, insulin-resistance, sexual dysfunction, eating disorders, 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 by administering a therapeutically effective amount of a compound as defined in claim 1.
Overall claim coverage centers on phenyl-pyrrole aminoguanidine derivatives defined by general formula (I) with tautomeric forms and broad substituent selections for n, R1–R5, and R6–R7, including pharmaceutically acceptable salts, and is narrowed in dependent claims by specific positional and fixed substituent constraints. Additional coverage includes a therapeutic method claim that administers compounds of claim 1 to treat enumerated disease or disorder categories.
Stated Advantages
Compounds show markedly increased receptor binding affinity versus WO 03/013509 reference compounds, as expressed by lower Ki and/or IC50 values.
Anti-inflammatory activity is described as dose-dependent in the context of LPS-induced TNF-b1 and IL-10 outcomes in rats.
Plasma pharmacokinetics and bioavailability are reported for example compounds (1-3), including terminal half-lives and oral bioavailability.
Documented Applications
Treatment of mammal diseases or disorders selected from inflammatory conditions, diabetes mellitus, insulin-resistance, sexual dysfunction, eating disorders, 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.
Therapeutic treatment of inflammation-related diseases across organs, including lung and airways inflammation such as idiopathic alveolitis, primary pulmonary hypertension, bronchitis, COPD, asthma, allergic rhinitis, and conjunctivitis.
Therapeutic treatment of heart inflammation such as pericarditis, myocarditis, and endocarditis.
Therapeutic treatment of liver inflammation such as hepatitis and biliary cirrhosis, and pancreatic inflammation such as pancreatitis.
Therapeutic treatment of kidney inflammation such as glomerulonephritis, IgA nephritis, pyelonephritis, and interstitial nephritis.
Therapeutic treatment of joint inflammation such as rheumatoid arthritis, psoriatic arthritis, and Bechterew's disease.
Therapeutic treatment of metabolic and inflammatory conditions including LDL/HDL and triglyceride abnormalities, insulin resistance, Type II diabetes, obesity, and metabolic syndrome.
Therapeutic treatment of infectious, traumatic, and injury-related inflammation and endocrine and other systemic disorders.
Therapeutic treatment of sexual and mental disorders including anxiety, depression, and psychoses.
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