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  N-acylated lipophilic amino acid derivativesUSPTO Application #: 20080027038Title: N-acylated lipophilic amino acid derivatives Abstract: Compounds of structural formula (I) where A is a lipophilic group including an aliphatic bridging group, B is a lipophilic group, D is a group having at least one amino or substituted amino group and R is hydrogen, alkyl or cycloalkyl, and pharmaceutically acceptable salts and individual isomers thereof, which have growth hormone releasing activity in humans or animals. (end of abstract) Agent: Nixon & Vanderhye, PC - Arlington, VA, US Inventors: HIdenori Funamizu, Nobuo Ishiyama, Satoru Ikegami, Tadashi Okumo, Kiyoshi Inoguchi, Ping Huang, Gilda Loew USPTO Applicaton #: 20080027038 - Class: 514211070 (USPTO) Related 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 Contains Seven Members Including Nitrogen, Carbon And Chalcogen, Chalcogen Double Bonded Directly To A Ring Carbon Which Is Adjacent To The Ring Nitrogen, Polycyclo Ring System Which Contains The Seven-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, , The Patent Description & Claims data below is from USPTO Patent Application 20080027038. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention related to synthetic peptidomimetics having growth hormone releasing activity in humans or animals, and their use in humans for treating medical disorders resulting from a deficiency in growth hormone, or use in animals for increasing the rate and extent of growth, or for increasing the milk or wool production, or for treatment of ailments. BACKGROUND OF THE INVENTION [0002] Growth hormone, which is secreted from the pituitary, stimulate growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have following basic effects on the metabolic process of the body: 1) Increase the rate of protein synthesis in the cells of the body, 2) Decrease rate of carbohydrate utilization in the cells of the body; 3) Increase mobilization of the fatty acids and use of the fatty acids for the energy. [0003] Artificial manipulation of growth hormone levels has been demonstrated to have significant therapeutic utility. Human growth hormone supplementation has been shown to be an effective treatment for growth hormone deficiency and their related diseases states in humans, such as short statue (Robinson and Clark., Growth Hormone: Basic and Clinical Aspect, Isaksspn, Binder, Hall and Hokfelt eds., Amsterdam, p 109-127(1987). [0004] Apart from this application, studies have uncovered new and significant properties of growth hormone which lend further importance to the ability to control growth hormone levels. For example, recent clinical studies indicate that growth hormone supplementation may be useful in combating the maladies of aging in humans. Elevated growth hormone levels in animals also have been shown to result in increase lean mass muscle..One application of this latter observation could results in higher production of leaner meat products or larger and/or stronger animals. However, their clinical and/or animal application, as with recombinant growth hormone, has been limited due to their high cost and lack of oral efficiency (Low, L. C. K., Neuroendoclinology, 1991, 53 (Supp.1), 37-40: Thomer, M. O., Acta Pediatr 1993, 388 (Suppl),2-7). [0005] The release of growth hormone from pituitary organs is under tight control of a second protein, growth hormone releasing factor (GRF), which is also commonly known in the art as somatomedin, growth hormone releasing hormone (GHRH), growth releasing hormone (GRH) and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. As a result, the development of synthetic growth hormone releasing agents and the use of drugs acting through established neurotrasmitter systems in the brain to stimulate growth hormone releasing are being considered as alternative to highly expensive and lack of oral efficiency growth hormone replacement therapy for the restoration on normal serum growth hormone levels (Pharm. Rev., 46, 1-33(1994)). [0006] Even before the discovery of the endogenous releasing factor GHRH in 1982 (Guillemin, R. et al., Science, 1982, 218:585-587), Bowers and co-workers had reported on a series of peptides derived from Leu and Met enkephalins which specifically release growth hormone from pituitary(Bowers, C. Y. et al., Molecular Endoclinology. MacIntyne I (Ed.) Elsevier/North Holland Biomedical Press, Amsterdam 1977, 287-292). It was later discovered that these growth hormone releasing peptides (GHRPs) act directly on the pituitary through a different signal transduction pathway from that of GHRH. In combination with GHRH, GHRPs act synergistically at the pituitary to release growth hormone. A hypothalamic binding site for GHRPs, which may be partially responsible for their growth hormone releasing in vivo by releasing endogenous GHRH, has been identified (Codd, E. E. et al., Neuropharmacology, 1989, 28, 1139-1144; Howard, D. H. et al., Science,1996, 273, 974-976). Momany and Bowers employed molecular modeling techniques to discovered the growth hormone releasing hexapeptide GHRP-6, which is extremely potent and specific growth hormone secretagogue in human. More potent analogs of GHRP-6 have recently discovered and presently under clinical evaluation (Laron, A. Drugs, 1995, 50, 595-601). While GHRP-6 is a much more smaller peptide than either recombinant growth hormone or growth hormone releasing hormone, it still has low oral bioavailability in human (0.3%). However, GHRP-6 has demonstrated that relatively small molecule, with its possible advantage of lower cost and oral bioavailability, may be a viable alternative to subcutaneous treatment with recombinant growth hormone (DeVita, R. J. et al., Drugs of the Future, 1996, 21(3), 273-281). TABLE-US-00001 His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2 GHRP-6 Ala-His-D-.beta.-Nal-Ala-Trp-D-Phe-Lys-NH.sub.2 GHRP-1 D-Ala-D-.beta.-Nal-Ala-Trp-D-Phe-Lys-NH.sub.2 GHRP-2 (KP-102) His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH.sub.2 Hexarelin [0007] In recent years significant efforts have been taken to develop non-peptidyl analogs of this series of compounds. Such compounds, termed growth hormone secretagogues, should be orally bioavailable, induce production or release of growth hormone, and act as synergistically with growth hormone releasing hormone. Representative growth hormone secretagogues are disclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No.5,206,235 ; U.S. Pat. No. 5,248,841; U.S. Pat. No. 5,310,017; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,434,261; U.S. Pat. No. 5,552,385; U.S. Pat. No. 5,559,128; EP 144,230; EP 513,974; WO 94/07486; WO 94/08583; WO 94/11012; WO 94/13696; WO 95/03290; WO 95/09633; WO 95/12598; WO 95/13069; WO 95/14666; WO 95/16692; WO 95/16675; WO 95/17422; WO 95/17423; WO 95/34311; WO 96/02530; WO 96/05195; WO 96/13265; WO 96/15148; WO 96/22997; WO 96/24587; WO 96/35713; WO 96/38471; WO 97/00894; WO 96/24580; WO 97/06803; WO 97/07117; WO 97/11697; WO 97/15191; WO 97/22620; WO 97/23508; WO 97/24369 and Science,260,1640-1643(1993), the entire of all of which are herein incorporate by reference. [0008] U.S. Pat. No. 5,206,235 issued Apr. 27, 1993, describes a series of benzolactam compounds typified by the following structure. These compounds have demonstrated clinical activity in humans in raising the growth hormone secretory levels (B. J. Gertz., Journal of Clinical Endocrinology and Metabolism,77, 1393-1397(1993)). [0009] Second generation of growth hormone secretagogues is described in WO 94/13696, WO 96/15148. These compounds are typified by the following structure. [0010] A number of these compounds are reported to be safe and effective in promoting endogenous growth hormone release in humans, however, there remain problems with oral availability and specificity. SUMMARY OF THE INVENTION [0011] The instant invention is directed to certain novel amide compounds which have the ability to stimulate the release of natural or endogenous growth hormone. It is a still further object of this invention to provide more potent growth hormone secretagogues than those of the prior, especially "GHRP-6", "GHRP-1", "GHRP-2(KP-102)", "L-692,429", "L-692,585", "MK-0677" and "G07220". It is a further object to provide growth hormone secretagogues that are specific for growth hormone release and do not cause significant release of other hormones, especially; LH, FSH, TSH, ACTH, prolactin, vasopressin, oxytocin, insulin, and cortisol. The compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone production or in animals used for food, wool, and milk production where the stimulation of growth hormone will result in a large, more productive animals. Thus, it is an object of the present invention to described the compounds. It is a further object of this invention to described procedures for the preparation of such compounds and intermediates. A still further object is to describe the use of such compounds to increase the secretion of growth hormone in humans and animals. It is a still further object to provide compositions containing the compounds for the use of treating humans and animals so as to increase the levels of growth hormone secretions. These and other objects of the invention will be apparent from the following specification. The Strategy of Lead Finding and Lead Optimization [0012] It is the object of this invention to provide a novel class of non-peptidyl growth hormone secretagogues using an approach of computer-aided rational drug design and discovery. The computational strategy described below has produced 3D pharmacophores for 3D database search in the lead finding, and provided site-dependent quantitative structure activity relationship(QSAR) for fragment property refinement in the lead optimization, leading to the development of novel potent growth hormone secretagogues. The computational strategy has been implemented through three stages in the invention: [0013] (1) conceptual stage--generation and validation of 3D-pharmacophores [0014] (2) discovery stage--database search and compound modification [0015] (3) optimization stage--development of QSAR for refinement (1) Conceptual Stage--Pharmacophore Development [0016] The structural components of the growth hormone releasing peptides(GHRPs) and non-peptidyl derivatives are important for their growth hormone releasing potency. It is thus the crucial step in rational design to develop 3D pharmacophores, which represent the three dimensional arrangement of functional groups essential for activity, from a number of compounds with known activities, similar mechanism of action, and similar in vivo properties. The seven potent peptides selected for pharmacophore generation in the present invention include "GHRP-6", "[D-Lys.sup.6]GHRP-6", "KP102(GHRP-2)", and its four peptidyl analogs. Non-peptidyl analogs chosen for pharmacophore development include "L-692,429", "L-692,585", "MK-0677", and "L-164,080". In addition, one inactive peptide "[Val.sup.3]GHRP-6", and one inactive non-peptide "L-692,428" were used as control. Conformations of each of these compounds were generated using a strategy of repeated cycles of high (900.degree. K.) and low (300.degree. K.) temperature molecule dynamics combined with energy minimization of molecule structures. Details of this strategy are described by Chew, C. et al. (Mol. Pharm., 1991, 39, 502). The calculations were performed using Quanta/CHARMm 4.0 (Molecular Simulation, Inc. USA). The search for the form in which flexible molecules such as peptides bind to receptors is a challenging task because many low-energy conformations are accessible and they coexist in equilibrium. The complexity increases enormously when several diverse families of fairly flexible molecules are included and the goal is to identify the common geometric arrangements of moieties that are determinants of receptor recognition or activation because all low-energy conformations of each molecule should be included in analysis. A novel computer program, DistComp, was thus developed to perform systematic and automated comparisons of molecular conformations in different compounds for the determination of 3D pharmacophores (Huang, P. et al., J. Computer-Aided Molecular Design., 1997, 11, 21-28). DistComp provides a procedure for identifying common spatial arrangements of selected moieties in a given set of molecules. No prior assumption of an active conformation is necessary. There is also need for a rigid template. However, central to this procedure is the selection of sets of common functional moieties assumed to be important for recognition or activation. The validity of these candidate recognition or activation sites is then assessed by the program: for each hypothetical set of recognition or activation moieties selected, the program systematically determines whether any common 3D relationships among them exists in active analogs but are absent in inactive ones. Each set of proposed chemical moieties that satisfies this requirement, together with the common spatial arrangements identified,comprises candidate 3D pharmacophores. [0017] Using the program DistComp, a convergent model termed "Pharmacophore I" which is common to all seven peptides and two non-peptides("1-692,429", "L-692-585") was successfully developed. "Pharmacophore I " was subsequently validated using two new potent growth hormone secretagogues, "G-7220", "G-7134", developed at Genentech by that time with the results indicating that the two compounds fit well to the pharmacophore. Another convergent model,termed "Pharmacophore II" was developed when "MK-0677" and "L-164,080" were reported by Merck to be potent growth hormone secretagogues."Pharmacophore II" is common to all seven peptides and two non-peptides,"MK-0677" and "L-164,080". Pharmacophore I and II have some common features, but differ in two components. (2) Discovery Stage-Database Search and Compound Modification [0018] The successful development of the 3D pharmacophores provides a logical framework for the design and discovery of novel growth hormone secretagogues in the present invention. Using these 3D pharmacophores, 3D database search was performed of a number of databases including MDDR, Chapman & Hall Database of Organic Compounds, Maybridge, CAS30K, and NCI Database. Both 3D rigid and flexible search methods were used. While a rigid search does static comparison of the 3D structure stored in database of a compound with the pharmacophore, a flexible search takes into account molecular flexibility. Compounds obtained from database search were then screened and modified using structural and chemical intuition, with emphasis on scaffold novelty, conformational rigidity, minimum extra components, and chemical aspects such as excluding compounds that are polymeric, clathrate, molecular complex, metal complex, toxic, or peptides. Modification of compounds was performed mainly on compounds that have novel scaffolds. Subsequent computer modeling studies were then performed on compounds from the database search which had been either modified or obtained from a flexible search, in order to determine the extent to which they conformed either Pharmacophore I or II. Candidates which were found to be consistent with the pharmacophores and easy to synthesize were then selected for synthesis and pharmacological testing. Using these strategies, initial lead compounds in the present prevention have been successfully designed and discovered. (3) Optimization Stage--Development of QSAR for Refinement [0019] The goal in this stage was to enhance the activity of initial lead compounds from, typically, micromolar into the nanomolar range. While experimentalists focused on making various analogs of the leads for SAR studies, computational efforts focused on the development of site-dependent QSAR (Quantitative Structure Activity Relationship) procedure embodied in a suite program, for refinement of the lead compounds. The innovative approach is in addition to improving compounds by making them more consistent with the pharmacophores in terms of the three-dimensional arrangement/location of the functional groups. [0020] Preliminary investigation were performed that demonstrated no significant correlation between the overall molecular properties of growth hormone releasing peptides and their activity. Clearly, growth hormone secretion activity cannot be described simply by these molecular descriptors. A possible explanation for this is that the overall molecular descriptors can be significantly modulated by the molecular regions which are not important to the drug-receptor interaction. As we have already experienced in many cases, complex drug interactions cannot be simply described by overall descriptors of a molecule. Continue reading... Full patent description for N-acylated lipophilic amino acid derivatives Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this N-acylated lipophilic amino acid derivatives patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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