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Melanocortin receptor ligandsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Quinolines (including Hydrogenated)Melanocortin receptor ligands description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060106059, Melanocortin receptor ligands. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a Continuation Application of Divisional application Ser. No. 10/856,983 filed May 28, 2004 which claims priority from application Ser. No. 10/121,874 filed Apr. 12, 2002 now U.S. Pat. No. 6,911,447 issued Jun. 28, 2005, which claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/286,610 filed Apr. 25, 2001. FIELD OF THE INVENTION [0002] The present invention relates to melanocortin (MC) receptor ligands that have a conformationally restricted ring element, which provides for enhanced activity. These ligands preferably exhibit selectivity for the MC-3 and/or MC-4 receptors relative to the other melanocortin receptors (in particular the MC-1 receptor) and are suitable for use in pharmaceutical compositions and in treatment methods. BACKGROUND OF THE INVENTION [0003] Melanocortin peptides (melanocortins) are natural peptide hormones in animals and man that bind to and stimulate MC receptors. Examples of melanocortins are .alpha.-MSH (melanocyte stimulating hormone), .beta.-MSH, .gamma.-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is mainly known for its ability to regulate peripheral pigmentation, whereas ACTH is known to induce steroidoneogenesis. The melanocortin peptides also mediate a number of other physiological effects. They are reported to affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, brain blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual activity, penile erection, blood glucose levels, intrauterine fetal growth, food motivated behavior, as well as other events related to parturition. [0004] Both the MC-4 and MC-3 receptors have been localized to the hypothalamus, a region of the brain believed to be involved in the modulation of feeding behavior. Compounds showing selectivity for the MC-3/MC-4 receptors have been shown to alter food intake following intracerebroventricular and peripheral injection in rodents. Specifically, agonists have been shown to reduce feeding, while antagonists have been shown to increase feeding. The role of the MC-4 and MC-3 receptors have been defined in the control of body weight regulation in mammals. It is believed that the MC-3 receptor influences feeding efficiency and the partitioning of fuel stores into fat, whereas the MC-4 receptor regulates food intake and possibly enery expenditure. Thus, these receptor subtypes appear to reduce body weight through distinct and complementary pathways. Therefore compounds that stimulate both the MC-3 and MC-4 receptors may have a greater weight loss effect than those that are selective for either the MC-3 or MC-4 receptor. [0005] Body weight disorders such as obesity, anorexia and cachexia are widely recognized as significant public health issues and there is a need for compounds and pharmaceutical compositions, which can treat these disorders. [0006] The Applicants have discovered a class of compounds that surprisingly have high affinity for the MC-4 and/or the MC-3 receptor subtypes, and that are typically selective for these MC receptors relative to the other melanocortin receptor subtypes, particularly the MC-1 subtype. SUMMARY OF THE INVENTION [0007] The present invention relates to a class of compounds that are ligands for MC-3 and/or MC-4 receptors and comprise a 5-8 atom ring, which conformationally restricts the orientation of the three pendant units. [0008] The compounds of the present invention include all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula: wherein A is a conformationally restricted ring system selected from the group consisting of: [0009] a) non-aromatic carbocyclic rings; [0010] b) aromatic carbocyclic rings; [0011] c) non-aromatic heterocyclic rings; [0012] d) aromatic heterocyclic rings; wherein said rings comprises from 5 to 8 atoms; [0013] W is a pendant unit having the formula: wherein R is selected from the group consisting of: [0014] a) non-aromatic carbocyclic rings; [0015] b) aromatic carbocyclic rings; [0016] c) non-aromatic heterocyclic rings; [0017] d) aromatic heterocyclic rings; said rings comprising from 3 to 12 atoms; [0018] J is selected from the group consisting of: [0019] i) --[C(R'').sub.d].sub.k--; wherein each R'' is independently hydrogen, C.sub.1-C.sub.12 linear or branched alkyl, -SUB, two R'' units can be taken together with an oxygen atom to form a carbonyl unit, two R'' units from any J units or an R'' unit and an R' unit from a T unit can be taken together to form a carbocyclic or heterocyclic fused ring, bicyclo ring, or spiroannulated ring comprising from 3 to 7 atoms; the index d has the value of 1 or 2; the index k has the value of 1 or 2; [0020] iii) --NR'--; wherein R' is hydrogen, C.sub.1-C.sub.6 linear or branched alkyl, or a SUB unit; [0021] iv) --O--; [0022] v) --S--; [0023] vi) --P(O)-- or --P(O).sub.2--; [0024] vii) and mixtures thereof. [0025] L is a suitable linking unit; [0026] B comprises a unit selected from the group consisting of: [0027] a) hydrogen; [0028] b) substituted or unsubstituted aromatic carbocyclic rings; [0029] c) substituted or unsubstituted aromatic heterocyclic rings; and [0030] d) mixtures thereof; [0031] Y is a pendant unit comprising at least one heteroatom; [0032] Z is a pendant unit, which comprises an aromatic ring or non-aromatic ring moiety. [0033] The present invention further relates to pharmaceutical compositions comprising the herein described MC3 and/or MC4 receptor ligands, said ligands having a high affinity and selectivity for the MC3 and/or MC4 receptor subtypes over the MC1 receptor subtype. [0034] These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (.degree. C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference. DETAILED DESCRIPTION OF THE INVENTION [0035] The present invention relates to receptor ligands. The melanocortin (MC) class of peptides mediates a wide range of physiological effects. Synthetic peptides and peptide mimetics, which modulate the interaction of natural MC ligands have varying degrees of selectivity and binding. The present invention is directed to ligands that are selective for the MC4 receptor, or that are selective for both the MC4 and MC3 receptor while minimizing the interaction at the MC1, MC2, and MC5 receptors. [0036] It has been surprisingly discovered that conformationally restricting the rotation along a key peptide linkage provides receptor ligands having increased selectivity and binding. Key to the present invention is the discovery that the conformationally restricted structure can comprise structural isosteres in several embodiments, inter alia, 5-member rings and 6-member rings as well as chemical bonds, which simply restrict the rotation of the normal peptide link. [0037] Although not wishing to be limited by theory, once the peptide or peptide mimetic rotation is fixed, the resulting appended moieties begin to differentiate between themselves as it relates to their physiological and biological functions. The appending units or moieties from the core ring structure are herein described as "W pendant units" or "units," "Y pendant units" or "units having a base moiety, a quaternary nitrogen moiety, or mixtures thereof;" and "Z pendant units." The units are so named to assist not only in differentiating their prospective functionality, but also as mnemonic devices to assist the formulator in conceptualizing the scope and embodiments described herein. Therefore, units conveniently described as units (W pendant units) may play one or more other roles in eliciting the desired physiological and biological response. The scope of the present invention is not limited by this need to differentiate the appendages for the sake of clearly defining the metes and bound of each group, unit, or moiety. [0038] As it relates to the term "amino acid", those of ordinary skill in the art will recognize this term to mean the naturally occurring constituent elements of peptides, enzymes, and the like, as well as non-naturally occurring variants. The following is a non-limiting list of common amino acids together with their abbreviation and single letter codes: alanine (Ala, A); arginine (Arg; R); asparagines (Asp; N); aspartic acid (Asp, D); cysteine (Cys, C); glutamic acid (Glu, Q); glutamine (Gln, E); glycine (Gly, G); histidine (His, H); isoleucine (Ile, I); leucine (Leu, L); lysine (Lys, K); methionin (Met, M); phenylalanine (Phe, F); proline (Pro, P); serine (Ser, S); threonine (Thr, T), tryptophan (Trp, W); tyrosine (Tyr, Y); valine (Val, V). Other non-naturally occurring amino acids includes p-Benzoyl-phenylalanine (Bpa); .beta.-(1-Naphthyl)-alanine (1-Nal); .alpha.-(2-naphthyl)-alanine (2-Nal); .beta.-cyclohexylalanine (Cha), 3,4-dichlorophenylalanine (3,4-Dcp); 4-fluorophenyl-alanine (4-Fpa); 4-nitrophenylalanine (4-Npa); 2-thienylalanine (Tha); 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (Tic); 3-benzothienylalanine (3-Bal); 4-cyanophenylalanine (4-Ypa); 4-iodophenylalanine (4-lpa); 4-bromophenylalanine (4-Rpa); 4,4'-biphenylalanine (Bip); ornithine (Orn); sarcosine (Sar); pentafluorophenylalanine (Pfp); and .beta.,.beta.-diphenylalanine (Dip). For the purposes of the present invention, the amino acids are in the L-form (levorotatory) unless otherwise indicated. For the common amino acids, the D-form is indicated by the lower case single letter abbreviation, for example, D-alanine is "a", D-threonine is "t". [0039] For the purposes of the present invention, when describing particular embodiments or examples, one or more units may be identified or highlighted with an asterisk, for example, R*, J*. This serves only to delineate one unit from another and to emphasize that the example focuses on changes or iterations in the particular unit. For example, each J unit whether J or J* can comprise the same elements, but for a particular example the focus is on the value of J units. [0040] Substituted Units, -SUB [0041] SUB units are units capable of replacing hydrogen atoms. The term "substituted" is used throughout the specification and for the purposes of the present invention the term "substituted" is defined as "replacement of a hydrogen atom, two hydrogen atoms, or three hydrogen atoms from a carbon atom to form a moiety, or the replacement of hydrogen atoms from adjacent carbon atoms to form a moiety." For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two-hydrogen atom replacement includes carbonyl, oximino, and the like. Three hydrogen replacements includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring", and 3-guanidinopropyl is a "substituted C.sub.3 alkyl unit." The term -SUB' is used to indicate a substitute for hydrogen is a unit which is capable of hydrogen bonding, inter alia, hydroxyl, carbonyl. [0042] The following are non-limiting examples of moieties, which can replace one or more hydrogen atoms on carbon to form -SUB units: [0043] i) --NHCOR.sup.30; [0044] ii) --COR.sup.30; [0045] iii) --COOR.sup.30; [0046] iv) --COCH.dbd.CH.sub.2; [0047] v) --C(.dbd.NH)NH.sub.2; [0048] vi) --NHC(.dbd.NH)NH.sub.2; [0049] vii) --N(R.sup.30).sub.2; [0050] viii) --NHC.sub.6H.sub.5; [0051] ix) .dbd.CHC.sub.6H.sub.5; [0052] x) --CON(R.sup.30).sub.2; [0053] xi) --CONHNH.sub.2; [0054] xii) --NHCN; [0055] xiii) --OCN; [0056] xiv) --CN; [0057] xv) F, Cl, Br, I, and mixtures thereof; [0058] xvi) .dbd.O; [0059] xvii) --OR.sup.30; [0060] xviii) --NHCHO; [0061] xix) --OH; [0062] xx) --NHN(R.sup.30).sub.2; [0063] xxi) .dbd.NR.sup.30; [0064] xxii) .dbd.NOR.sup.30; [0065] xxiii) --NHOR.sup.30; [0066] xxiv) --CNO; [0067] xxv) --NCS; [0068] xxvi) .dbd.C(R.sup.30).sub.2; [0069] xxvii) --SO.sub.3M; [0070] xxviii) --OSO.sub.3M; [0071] xxix) --SCN; [0072] xxx) --P(O)(OH)R.sup.30; [0073] xxxi) --P(O)(R.sup.30)R.sup.30; [0074] xxxii) --P(O)(OH).sub.2; [0075] xxxiii) --SO.sub.2NH.sub.2; [0076] xxxiv) --SO.sub.2R.sup.30; [0077] xxxv) --NO.sub.2; [0078] xxxvi) --CF.sub.3, --CCl.sub.3, --CBr.sub.3; [0079] xxxvii) and mixtures thereof; wherein R.sup.30 is hydrogen, C.sub.1-C.sub.20 linear or branched alkyl, C.sub.6-C.sub.20 aryl, C.sub.7-C.sub.20 alkylenearyl, and mixtures thereof; M is hydrogen, or a salt forming cation. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like. Non-limiting examples of an alkylenearyl unit include benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-phenylpropyl. As described further herein below, units defined herein as "substituted units capable of forming a hydrogen bond" are -SUB' units, examples of which include hydroxyl and carbonyl. [0080] For illustrative purposes, the following is a conformationally restricted ring having W, Y, and Z units attached thereto as well as an SUB substituted unit. In this example -SUB is an acetate (group (ii) wherein R.sup.30 is methyl): Continue reading about Melanocortin receptor ligands... 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