MXPA97002938A - Active compounds for cal receiver - Google Patents

Abstract

The present invention relates to compounds of the general formulas, a), b), c), which have the ability to modulate one or more activities of an inorganic ion receptor and the use of said compounds to treat diseases or disorders by activity Inorganic ion receptor modulator, preferably, the compound can limit or block the effect of extracellular Ca2 + on a calcium receptor

Description

«I ACTIVE COMPOUNDS FOR CALCIUM RECEPTOR FIELD OF THE INVENTION This invention relates to the design, development, composition and use of compounds capable of modulating one or more inorganic ion receptor activities.

BACKGROUND OF THE INVENTION "10 Certain cells in the grating respond not only to chemical signals, but also to ions such as extracellular calcium lobes (Ca2 + J.) Changes in extracellular Ca2 + concentration (referred to posten or men). -to in the present example "CCa2 + J") alter the answers # functional of these celui s. Such a specialized cell is the parathyroid cell, which secretes parathyroid hormone (PTH). PTH is the main endocrine factor that regulates the Ca2 + horneostasis in blood and fluids. extracellular. PTH, acting on bone and kidney cells, increases the level of Ca2 + in the blood. This increase in [Ca2 +] subsequently acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between ÜCa2 + 3 and the secretion of PTH forms the essential mechanism that binds + to the body's Ca2 + horneostasis. The extracellular Ca2 + ac + ua direc-tment in parathyroid cells to regulate the secretion of PTH. The existence of a parathyroid cell surface protein, which detects changes in CCa2 + I, has been confirmed. Brown et al., 366 Nature 574, 1993. In the cells of the parathyroid, it is + a protein acts as an i.eceptor for the extracellular Ca2 + + ("the calcium receptor"), and detects changes in CCa +] and for initiate a functional cellular response, the «3.0 secretion of PTH. Extracellular Ca2 + can exert effects on different, cell functions, mentioned in Neneth et al., 11 cell calciurn 319, 1990. The role of extracellular Ca + in parafoli cuJares cells (C cells) and cells of the cell. parathyroid is mentioned in Nerneth, 11 cell calc a 323, 1990. These cells have expressed to the Ca2 + receptor * if m Llar Brown et al., 366 Na-t ure 574, 1993; Mithal and others, 9 uppJ. 1 3. Bone and Mineral Res. S282, 1994; Rogers and others, 9 uppl, 1 3. Bonde and Mineral Res. S4099, 1994; Garrett et al., 9 Suppl. * 20 1 3. Bone and Mineral Res. S409, 1994. The role of Ca2 + ex racelula in bone osteoolasts is described by Zaidí, 10 Bioscience Reports 493, 1990. In addition, the keratmocytes, the yux + aglornerular cells, the tropoblasts , pancreatic beta cells and celuleis fats / adipose all respond to increases in extracellular calcium, which in turn reflects the acylation of the calcium receptors of these cells. The ability of several compounds to mimic extracellular Ca2 + 'm vitro is mentioned by Neineth and others, (Sperrnine and Sperrnidine) in "Calc? Urn - B? Nd? Ng Proteins m Health and Disease," 1987, Acadern c Press , Inc. pp. 33-35; Brown et al., (E.g., neonyein) 128 Endocrinology 3047, 1991; Chen et al., (D ltiazern and analogues, TA-3090) 5 J. Bone and Mineral Res. 581, 1990; and Zaidi et al. (v raparnil) 167 Biochem. B ophys. Res. Co rnun. 807, 1990. Nerneth et al., PCT / US93 / 01652, Number 0 International Publication WO 94/18959, and Nemeth et al., PCT / U 92/07175, International Publication Number WO 93/04373, describe various compounds that can Modulate the effect of an inorganic ion on a cell that has an inorganic ion receptor. 5 The references provided in the foregoing are not admitted co or prior art.

BRIEF DESCRIPTION OF THE INVENTION The present invention comprises compounds capable of modulating one or more activities of an inorganic ion receptor and methods for treating diseases or disorders by modulating inorganic ion receptor activity. Preferred compounds can mimic or block the effect of extracellular calcium R on a calcium receptor on a cell surface. The diseases or disorders that can be treated by modulating the activity of the inorganic ion receptor include one or more of the following types: i) those characterized by a horneostasis of abnormal inorganic ion, preferably calcium horneostasis; 2) those characterized by an abnormal amount of an extracellular or intracellular messenger whose production may be affected by the activity of the inorganic ion receptor, preferably the activity of the * calcium receptor; 3) that characterized by an abnormal effect (eg, a different effect on type or magnitude) of a * 410 intracellular or extracellular messenger which can itself be reduced by the activity of the inorganic ion receptor, preferably the activity of the calcium receptor, and 4) other diseases or disorders in which the modulation of the inorganic ion receptor activity , prefermente The activity of the calcium receptor exerts a beneficial effect, for example, in diseases or disorders in which the • # production of an extracellular intracellular messenger stimulated by receptor activity compensates for the abnormal amount of a different messenger. The examples of messengers Extracellular secretions whose secretion and / or effect can be affected by modulating the activity of the inorganic ion receptor include inorganic ions, hormones, neuret ansmi rans, growth factors, and quernokys. Examples of intracellular messengers include cAMP, cGMP, TP3, and diacyl glycerol. In this way, a compound of this invention preferably modulates the activity of the calcium receptor and is used in the treatment of diseases or disorders that may be effected by modulating one or more activities of a calcium receptor. Calcium receptor proteins make it possible for certain specialized cells to respond to changes in the concentration of extracellular Ca +. For example, extracellular Ca2 + inhibits the secretion of parathyroid hormone from parathyroid cells, inhibits bone resorption by osteocytes, and stimulates calcitonin secretion from C cells. In a preferred embodiment, the compound is used to treat a disease or disorder characterized by abnormal bone and mineral horneostasis, most preferably calcium horneostasis. The extracellular Ca2 + is under close control and controls several processes such as blood coagulation, the excitability of nerves and muscles and the proper formation of bones. Abnormal calcium honeostasis is characterized by one or more of the following activities. 1) an abnormal increase or decrease in serum calcium; 2) an abnormal increase or decrease in urinary calcium excretion; 3) an abnormal increase or decrease in calcium levels in the bone, for example, as calculated by bone mineral density measurements; 4) an abnormal absorption of dietary calcium; 5) an abnormal increase or decrease in production and / or release T? of messengers that affect serum calcium levels such as parathyroid hormone and calcitonin; and 6) an abnormal change in the response caused by messengers that affect calcium levels in the serum. The decrease or abnormal increase in these different aspects of the calcium pyreostasis is relative to that which occurs in the general population and is generally associated with a disease or disorder. Diseases and disorders characterized by abnormal calcium homeostasis may be due to different cellular defects, such as a defective activity of the calcium receptor, a defective number of calcium receptors or a defective intracellular protein activated by a calcium receptor. For example, in parat 11 * 01 des cells, the calcium receptor is coupled to the Gx protein, which in turn inhibits the production of cyclic AMP. The defects in Gi protein may affect its ability to inhibit the production of cyclic AMP. Thus, a first aspect of the invention includes an inorganic ion receptor modulator compound having the formula: STRUCTURE I CH3 wherein A i is either naphthyl or phenyl optionally substituted Linont with 0 or 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnetiienedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2CN, acetoxy, N (CH3) 2, phenyl, phenoxy, becil, benzyloxy, cr, cr ~ d? Net? Lbenc? Lo, NO2, CHO, CH3CIKOH), acetiio, ot iJendioxi; r2 is either na f tilo or femlo optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, lower alkoxy, lower thioalkyl, ethylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH-2CN, and acetoxy; q is 0, i, 2 or 3; and R is either H or lower alkyl; and pharmaceutical salts and complexes thereof. The compounds of this invention have a preferred stereochemistry. The CH3 shown in structure I is in a chiral center and provides a structure of a ~ (R) ~ rnetiio. When R is CH3, the R shown in structure I is also in a chiral center that provides a structure (R) ~ rnetium. In this way, when R is CH3, the compound of structure I has the stereoquip (ca, R). The activities of the inorganic ion receptor are 9 those procedures that are created as a result of the activation of the inorganic ion receptor. Such procedures include the production of molecules that can act as intracellular or extracellular messengers. The modulator compound of the inorganic ion receptor includes ionomeric, ionolitic, calimimic, and calcilytic. Lonopurnets are compounds that intertwine with an inorganic ion receptor and mimic (ie evoke or potentiate) the effects of an inorganic ion on an inorganic receptor. Preferred blernente, the compound affects one or more calcium receptor activities , the Calcimarrics are lonomi ethers that perform one or more calcium receptor activities and bind to a calcium receptor. Aonolithics are compounds that bind to an inorganic ion receptor and block (ie, inhibit or decrease) one or more activities caused by an inorganic ion in an inorganic ion receptor. Profepb Lemente, the compound affects one or more calcium receptor activities. Calcilytics are lonolithic that block one or more calcium receptor activities evoked by calcium extracellular and intertwine to a calcium receptor. The lonicos and ionolithics can be intertwined in the same receptor site, as the native inorganic ion ligand is interlaced or can be interlaced in a different site (eg, site aPostépco). For example, cl NPS R-467 crosslinking to a calcium receptor results in a calcium receptor activity and, thus, NPS R-467 is classified as a calcimimetic. However, NPS R-467 binds to the calcium receptor at a different site (ie, an alostepic site) than calcium extraduces. A measure of the effectiveness of a compound can be determined by calculating the ECso or ICso for that compound. The EC50 is the concentration of a compound that causes a maximum average imitation effect. The ECo is the concentration of compound that causes a maximum average blocking effect. The ECso and the IC50 for the compounds in a calcium receptor can be determined by evaluating one or more of the extracellular calcium activities in a calcium receptor. Examples of tests for measuring EC50 and IC50 are described in Nerneth et al., PCT / US93 / 01642, international publication number WO 94/18959, and Nerneth et al., PCT / US92 / 07175, international publication number WO 93/04373 , (both of these publications are incorporated herein by reference) and subsequently. Such tests include oocyte expression assays and the measurement of increases in the concentration of cellular calcium ion (rca2 +) i) due to the activity of the calcium receptor. Preferably, such tests measure the release or inhibition of a particular hormone associated with the activity of a calcium receptor. A preferred inorganic ion receptor modulator compound selectively selects the activity of the inorganic ion receptor in a particular cell. For example, selective selection of the activity of a calcium receptor is obtained by a compound that has a greater effect on a calcium receptor activity in one type of cell than in another cell or cell for a given concentration of compound. Preferably, the differential effect is 10 times or more according to whether it is alive or in vitro. Most preferably, the differential effect is measured in vivo and the concentration of compound is measured as the concentration of jgfc = plasma or the concentration of oxtracellular fluid and the measured effect is the production of extracellular messengers such as the plasma calcitonin, the parathyroid hormone or the plasma calcium. For example, in a preferred embodiment, the compound selectively identifies the secretion of PTH on the secretion of calcitonin. I preferred Blernente, the compound is either a calcitonin or a calcilitic having an ECso or ICso at a calcium receptor of less than or equal to 5 uM, and even very preferably less than or equal to 1 μM, ninolar, nanolar, 10 nanolar, or 1 nmolar using one of the tests described later. Most preferably, the test measures Ca2 + in HEK 293 cells transformed with nucleic acid expressing the calcium receptor of the human parati roldes and loaded with f? Ra-2. Low ECso's or ICso's are disadvantageous, since they allow to use low concentrations of compounds m alive or in vitro. The discovery of 2 R compounds with low ECso's and ICso's make possible the design and synthesis of additional compounds that have similar or improved potency, # effectiveness and / or selectivity. Another aspect of the present invention includes an inorganic ion receptor modulator compound having the formula: STRUCTURE II wherein Ar * 3 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each Independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, thioalkyl # inner, methylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, Of, ad? met? lbenc? lo, NO2, CHO, CH3CH (OH), (CH3) 2, ace ilo and ethylenedioxy. m is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, etiiendiox, Lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN and acetoxy; # Rs is either hydrogen femlo; R9 is either hydrogen or methyl; and Rio is either hydrogen, methyl or phenyl; or pharmaceutically acceptable salts and complexes of the same. Another aspect of the present invention includes an inorganic ion receptor modulator compound having the formula: STRUCTURE III 10 fifteen wherein Ar-5 is either naphthyl or fem Which is optionally substituted with 0 to 5 substituents each independently selected from the group consisting of inner alkyl, Halogen, lower alkoxy, lower thioalkyl, rnet, ylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, cf, "- d? Rnet?] Benzyl, NO2, CHO, CH3CI- KOH), acetyl, ethylenedioxy and -CH- = CH-phenol; Are is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of acetyl, inner alkyl, halogen, lower alkoxy, lower thioalkyl, rniperioxy, lower haioalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, carbornet oxy, OCH2C (0) C2He and acetoxy; R11 is hydrogen or methyl; and R12 is hydrogen or methyl. Another aspect of the present invention includes a pharmaceutical composition which constitutes an inorganic ion receptor modulator compound described herein and a physiologically acceptable vehicle. Urecomposition "Pharmacological" refers to a composition in a form suitable for administration to a mammal, preferably a human.Preferably, the pharmaceutical composition contains a sufficient amount of a calcium receptor modulator compound in a pharmaceutically suitable form for exert a therapeutic effect on a human. The considerations that are referred to in suitable forms of administration are known in the art and include toxic effects, solubility, route of administration and maintenance activity. For example, the compositions Pharmacological agents injected into the bloodstream must be soluble. The pharmaceutical compositions can also be formulated as pharmaceutically acceptable salts (e.g., acid addition salts) and complexes thereof. The preparation of R; Such salts may facilitate the pharmacological use of a compound by altering its physical characteristics without preventing it from exerting a physiological effect. Another aspect of the present invention includes a method for treating a patient by modulating the inorganic ion receptor activity using inorganic ion receptor modulator compounds described herein. The method includes administering to the patient a pharmaceutical composition containing a therapeutically effective amount of an inorganic ion receptor modulator compound. In a preferred embodiment, the disease or disorder is t a a a modulating the activity of the calcium receptor and admixing the patient with a therapeutically effective amount of a calcium receptor modulator compound. Inorganic ion receptor modulator compounds and compositions containing the compounds can be used to treat patients. A "patient" refers to a mammal in which the modulation of an inorganic ion receptor will have a beneficial effect. Patients in need of a treatment that includes the modulation of inorganic ion receptors can be identified using normal techniques known to those in the medical profession. Preferably, a patient is a human having a disease or disorder characterized by one or more of the following: (1) abnormal inorganic ion horneostasis, very Preferably abnormal calcium horneostasis; (2) an abnormal level of a messenger whose production or secretion is affected by the activity of the inorganic ion receptor, most preferably affected by the activity of the calcium receptor; and (3) an abnormal level or activity of a messenger whose function is affected by the activity of the inorganic ion receptor, most preferably affected by the activity of the calcium receptor. Diseases characterized by an abnormal calcium homeopathy include hyperparathyroidism, osteoporosis, and other disorders related to minerals and bones. similar (as described e.g., in standard medical textbooks, such as "I-larrison 'Principles of Internal! Medicine"). Such diseases are treated using calcium receptor modulator compounds that mimic or block one or ace of the effects of extracellular Ca2 + in a receptor calcium and, therefore, directly or indirectly affect the levels of proteins or other compounds in the patient's body. By "therapeutically effective amount" one tries to say an amount of a compound that alleviates to a certain point one or more symptoms of the disease or disorder in the patient; or return to the normal state either partially or completely one or more physiological or biochemical parameters associated with or cause of the disease or disorder. In a preferred embodiment, the patient has a OP: disease or disorder characterized by an abnormal level of one or more components regulated by calcium receptor and the compound is active in a rl receptor of a cell selected from the group consisting of ** parathyroid cell, bone osteoclast , juxtaglornerular renal cell, renal proximal tube cell, distal tube renal cell, central nervous cistern cell, peripheral nervous system cell, Henle's thick ascending loop cell and / or collecting duct, keratinocyte in the epidermis, cell parafollicular in the thyroid (C cell), intestinal cell, platelet, smooth muscle cell vasculai, cardiac atrial cell, gastrin secretory cell, glueagon secretory cell, renal kidney cell, mammary cell, beta cell, fat / adipose cell, immune cell, Gl tract cell, skin cell, adrenal cell, pituitary cell , hypothalaric cell and organ cell subformcal. Most preferably, the cells are selected from the group consisting of: parathyroid cell, central nervous system cell, peripheral nervous system cell, thick ascending tube of Henle's loop and / or duct Kidney collector, follicular cell in the thyroid (O cell, intestinal cell, TI tract cell, pituitary cell, hypothalarnic cell, subforn cal organ cell.) In a preferred embodiment, the compound is a calcinthyrnétic which acts in a calcium receptor cell of the parathyroid and reduces the level of parathyroid hormone in the patient's serum. Most preferably, the level is reduced to a sufficient degree to cause a decrease in plasma Ca2 +. Very preferably, the hormone level of the parat roldes is reduced to that present in a normal individual. In another preferred embodiment, the compound is a calcilytic which acts on a cell calcium receptor of the parathyroid and increases the hormone level of 1 A for the oids in the patient's serum. Very preferably, the level is increased to a degree sufficient to cause an increase in bone mineral density of a patient. Patients in need of such treatments can be identified by normal medical techniques, such as blood and urine tests. For example, detecting a protein deficiency whose production or secretion is affected by changes in inorganic ion concentrations, or detecting abnormal levels of inorganic hormones or hormones or hormones that effect the inorganic ion horneosta. Several examples are used through solitude. 0 These examples are not designed in any way to limit the invention. Other features and advantages of the invention will be apparent from the following figures, detailed description of the invention, examples and claims. A BRIEF DESCRIPTION OF THE DRAWINGS Figures la-1 r, show the chemical structures of different compounds. Figures 2-131 provide physical data for representative compounds described herein.

DESCRIPTION OF THE PREFERRED MODALITIES The present invention includes compounds capable of modulating one or more inorganic receptor activities, preferably the compound can mimic or block an effect of an extracellular ion in a cell having an inorganic ion receptor, most preferably the extracellular ion is ca +15 and the effect is on a cell that has a calcium receptor. Publications related to 1 ^ calcium, calcium receptor, and / or calcium receptor modulator compounds include the following: Brown et al., Nature 366. 574, 1993; Nerneth et al., PCTYUS93 / 016l 2, international publication number WO 94/18959; Nerneth et al., PCT US92 / 07175, international publication number WO 93/04373; Shobac and Chen, 3. Bone Mineral Res. J: 293 (1994); and Rac - > and others., FEBS Lett. 333: 132, (1993). These publications are not admitted as prior art for the claimed invention. 3 0 I. Calcium Receptors Calcium receptors are present on different types of cells and may have different activities in different cell types. The pharmacological effects of the following cells, in response to calcium, are consistent with the presence of a calcium receptor: parathyroid cell, bone osteoclast, juxtaglornerular renal cell, proximal tube renal cell, renal cell tube dista! central nervous system cell, peripheral nervous system cell, thick ascending Henle's loop tube and / or collecting duct, keratmocyte in the epidermis, parafollicular cell in the thyroid (cell C), intestinal cell, platelet, vascular smooth muscle cell, cell cardiac headset, cell gastpna secretor, glucagon secretory cell, kidney mesangial cell, mammary cell, beta cell, fat / adipose cell, immune cell, GT tract cell, skin cell, adrenal cell, pituitary cell, hypothalamic cell and cell of the organ your fornical. Additionally, the presence of calcium receptors in the paratn-oid cell, central nervous system cell, pep p nec nervous system cell, Henle's thick ascending loop cell and / or collecting duct in the kidney, parafollicular cell in the Thyroid (O cell, intestinal cell, tract cell 7 Gl, pituitary cell, hypothalaric cell, subformcal organ cell as confirmed by physical data.

The calcium receptor in these different types of cells may be different. It is also possible that a cell may have more than one type of calcium receptor. The comparison of the calcium receptor acivities and the sequences of ammounts of different cells indicate that there are life-types of calcium receptors. For example, calcium receptors can respond to a variety of cations and di- and trivalents. The parathyroid Ja calcium receptor responds to calcium and GF +, while the Osteoclasts respond to divalent cations such as calcium, but do not respond to Td3 +. In this way, the calcium receptor of the parathyroid is pharmacologically distinct from the calcium receptor in the osteoclast. On the other hand, the nucleic acid sequences that encode the calcium receptors present in parathyroid cells and C cells, indicate that these receptors have a rather similar amino acid structure. However, calcimetic compounds exhibit differential pharmacology and regulate different activities in parathyroid cells. and C cells. In this way, the pharmacological properties of calcium receptors can vary significantly depending on the type of cell or organ in which they are expressed, although calcium receptors may have similar or even identical structures. . 25 Calcium receptors, in general, have a low affinity for extracellular Ca2 + (\ <; á apparent generally greater than approximately O.dinM). Calcium receptors may include a free or bound supplier mechanism as defined by Cooper, Bloom and Roth, "The B ochei cal basis f Neuropharrnacology", Ch. 4, and thus are distinct from intracellular calcium receptors, v, gr ", calmodul i na and Las tropomnas. Calcium receptors respond to changes in levels of extracellular calcium. Exact changes depend on the particular receptor and the cell line that contains the receiver. For example, the m-vitro effect of calcium on c-1 calcium receptor in a parathyroid cell includes the following: 1. An increase in internal calcium. The increase is due to the entry of external calcium and / or to the mobilization of internal calcium. The characteristics of the increase in internal calcium include the following: a) A rapid increase (time to peak <5 seconds) and passenger at CCa2 + 3? which is refractory for the inhibition of La3 + of 1 μL or G + of 1 uMy and is deleted by the pretreatment with ileostomy (in the absence of extracellular Ca2 +); b) The increase is not inhibited by the dihydropyridines; c) The passenger increase is suppressed by- the OK pretreatment for 10 with lOrnM sodium fluoride; d) The passenger increase is decreased by the ") 7 # pretreatment with an activator of the protein qumase C (PKC), such as phorbol acetate ipstato (PMA), inozerein or (-) indolactarna V. The overall effect of the activator of the protein qumasa C and d L activator is to divert the concentration-response curve of calcium towards the skin without affecting the maximum response; and e) Pret ration with pertussis toxin (100 ng / in i during> 4 hours) does not affect this increase. 2.- A rapid increase (<30 seconds) in ia -formation Methyl toluene, 4, 5-triphosphate or diacgliotol "Pretreatment with pertussis toxin (100 ng / ml during> 4 hours) does not affect this increase; 3.- The inhibition of formation of AMP cy 11 co stimulated with dopamine and isoprot erenol. This effect is blocked by pretreatment with portussis toxin (100 ng / ml during> 4 hours); and 4"- The inhibition of PTH secretion. The pretreatment with pertussis toxin (100 ng / rnl> 4 hours) does not affect the inhibition of PTH secretion. Using techniques known in the art, the effect of calcium on other calcium receptors on different cells can be easily determined. Such effects may be similar in relation to the increase in internal calcium observed in the cells of the paralyroids. However, it is expected that the The effect differs in other respects, such as causing or inhibiting the release of a hormone other than the hormone of the parasite.

II-- Inorganic ion receptor modulator compounds Inorganic ion receptor modulator compounds modulate one or more activities of the inorganic ion receptor. The preferred calcium receptor modulator compounds are the calcitriomers and the calcilytics. The inorganic ion receptor modulator compounds can be identified #compacting compounds that are modeled just like a compound who has shown to have a particular activity (ie, a main compound). A preferred method for measuring the activity of the calcium receptor is to measure the changes in CCa2 + Hi. Changes in CCa2 +] can be measured using different techniques such as using HEC 293 cells transduced with nucleic acid that expresses the calcium receptor of the human parati roldes and loaded with fura-2; and measuring an increase in Cl- current in a Xenopus ooctito injected with nucleic acid encoding a calcium receptor. See (Nerneth and others, PCT / US93 / 01642, International Publication Number WO 94/1859.) For example, poly (a) * RNA can be obtained from cells expressing a calcium receptor, such as parathyroid cell, bone osteoelast, juxtaglomerular renal cell, renal cell of proximal tube, renal cell of 7K distal tube, central nervous system cell, peripheral nervous system cell, thick ascending tube F of Henle's loop and / or collecting duct, keratomyelitis in the epidermis, follicular cell in the thyroid (O cell) intestinal cell, plague, vascular smooth muscle cell, cardiac atrial cell, gastric secretory cell, glucagon secretory cell, renal kidney cell, mammary cell, beta cell, fat / adipose cell, immune cell , tract cell Gl, skin cell, adrenal cell, pituitary cell, hypothalaric cell and subformcal organ cell.Prefepbly, the nucleic acid co-comes from a cell parati roide, cell C or osteoclast. Most preferably, the nucleic acid encodes a calcium receptor and is present in a plasmid or vector. In preferred embodiments, the calcium receptor modulator compound is a calcirnarnetics that inhibits ia bone reabsorption in vivo by an esteoclast; inhibits bone reabsorption in vitro by an esteoclast; calcitonin secretion secretion m vit ro o m vivo of a C cell, inhibits the secretion of parathyroid hormone from a parathyroid cell in vitro and decreases the secretion of PTH m live; elevates calcitomin levels in vivo or blocks osteoclastic bone resorption m vitro and inhibits bone resorption i n v vo. In another preferred embodiment the calcium receptor modulator compound is a calcilytic that evokes the secretion of ? ? parathyroid hormone parathyroid cells m vitro and the mild level of parathyroid hormone in vivo.

F Preferably, the compound selectively identifies the activity of the inorganic ion receptor, most preferably the activity of the calcium receptor in a particular cell. By "selectively" it is meant that the compound exerts a greater effect on the activity of the inorganic ion receptor in a cell type than in ot or cell type for a given concentration of compound. In fact, the differential effect is LO locos or rnas. Preferably, the concentration refers to the concentration of blood plasma and the effect measured is the production of extracellular messengers such as plasma calcitomna, parathyroid hormone or plasma calcium. For example, in a preferred embodiment, the compound selectively identifies PTH secretion upon caicyonin secretion. In another preferred embodiment, the compound has an ECso or IC50 less than or equal to 5 μM in one or more, but not all cells chosen from the group consisting of: parathyroid cell, bone osteocyte, juxtaglornerular renal cell, renal cell of proxirnal tube, renal cell of distal tube, central nervous system cell, peripheral nervous system cell, Henle's thick ascending loop cell and / or collecting duct, nora kerata in the epidermis, parafollicular cell in the thyroid (cell C), intestinal cell , platelet, vascular smooth muscle cell, cardiac atrial cell, gastric secretory cell, glucagon secretory cell, renal kidney cell, mammary cell, beta cell, fat / adipose cell, immune cell, Gl tract cell, Lel cell, adrenal cell, cel pituitary thyla, cell hypotaiami ea and subformcai organ cell. Very preferably, the cells are chosen from the group consisting of: parathyroid cell, central nervous system cell, peripheral nervous system cell, HenLe's thick ascending loop cell v / or collecting duct in the kidney, c cell for follicular in the thyroid (cell C), intestinal cell, cell of the tract GT, pituitary cell, cell has potion and subfornical organ cell. The presence of a calcium receptor in this group of cells has been confirmed by physical data such as n-situ hybridization and antibody staining. Preferably, the modulator compounds of The ion receptor mimics or blocks the effects of an extracellular ion in a cell that has an inorganic receptor, such that the compounds achieve a therapeutic effect. Modular compounds of inorganic ion receptor may have different or different effects on cells having different types of inorganic ion receptor morphology (e.g., such as cells having normal inorganic ion receptors, a normal number of inorganic ion receptors and an abnormal inorganic ion receptor and a number abnormal of inorganic ion receptors). 9R Calcium receptor modulator compounds preferably mimic or block all effects of the extracellular f-ion in a cell having a calcium receptor. Nevertheless, the calcunimeticos do not need to possess all the biological activities of the extracellular Ca2 +. Sirní lannente, calciliticos do not need to block all activities caused by extracellular calcium. On the other hand, different cirrheinics and different calcilitics do not need to bind to the same site in the calcium receptor, as does extracellular Ca2 +, to exert its effects. Inorganic modulator compounds do not need perform the inorganic receptor activity at the same point or exactly in the same way as the natural ligand. For example, a calciminetic can effect the calcium receptor activity to a different point, a different duration, by binding to a different binding site or having a different affinity, compared to the broth acting on the calcium receptor. # A. Calcimimetics 1.- Compounds of structure I 20 Compounds of structure I capable of modulating calcium receptor activity have the following formula: Sjr in which i is either naphthyl or optionally substituted phenyl with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halothane, lower alkoxy, lower thioalkyl, methylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH , CONH2, CN, acetoxy, N (CH3) 2, femlo, phenoxy, benzyl, benzyloxy, OI, ODI-di-methyl-benzyl, NO, CHO, CH3CHI0H), acetyl, etiiendiox, preferably each substituent is independently selected from the group consisting of CH3, CH3O, CH3CH2O, rnetylenedioxy, Br, Cl, F, I, CF3, CHF2, CH2F, CF3O, CF3CH2O, CH3S, OH, CH2OH, CONH2, CN, N02, CH3dl2, pi-opyl, isopropyl, butyl, isobutyl, t-butyl and acetoxy, Most preferably i is either a naf-txlo or a phenyl with 1-5 substituent ß each selected independently of the A group consisting of isopropyl, CH3O, CH3S, CF3O, I, Cl, F, CF3 and CH3, preferably rnu and CF3O, I, Cl, F and OF3. r-2 is either naphthyl or femlo optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnet ilenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN and acetoxy, preferably each substituent is independently selected from the group consisting of CH3, CH3O, CH3CH2O, methylenedioxy, Br, Cl , F, I, CF3, CHF2, CH2F, CF3O, CF3CH2O, CH3S, OH, CH2OH, CONH2, CN, N02, CI-I3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl and acetoxy. Most preferably A1-2 is either a naphthyl or a phenol with 1-5 substituents each independently selected from the group consisting of isopropyl, CH 3 O, CH 3 S, CF 3 O, T, Cl, F, CF 3 and CH 3, most preferably CP3O, 1, Cl, F, CH3O and CF3., Q is 0, L, 2 or J; and R is either H or CH3; and pharmaceutically acceptable salts and complexes thereof. "Lower alkyl" refers to a hydrocarbon saturated having 1-4 carbons, preferably 1-3 carbon atoms, which may be straight or branched chain. "Lower alkoxy" refers to an "0-lower alkyl", in which "O" is an oxygen linked to a lower alkyl. "Lower alkyl" refers to "lower alkyl", wherein " S "is sulfur bonded to a lower alkyl" "Lower haloalkyl" refers to a lower alkyl substituted with at least one halogen.

Preferably, only the terminal carbon of the lower haloalkyl is substituted with a halogen and 1 to 3 halogens are present. Most preferably, the lower haloalkyl contains 1 carbon. Preferably, the halide definitions are either Cl or F. "Lower haloalkoxy" refers to "lower 0 haloalkyl", wherein "0" is an oxygen linked to a haloalkyl by a. to . Ari and Ar2 are both optionally substituted phenyls. In a preferred fashion, both are optionally substituted and the compound is formulated as follows: wherein R is hydrogen or methyl; rn and n are each independently 0, 1, 2, 3, 4 or 5; each X is independently selected from the group quo L5 consists of lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnet ílendi oxy, inverse haloalkyl, lower haloalkoxy, OH, CH 2 OH, CONH 2, CN, acetoxy, N (CH 3), phenoyl, phenoxy, benzyl, benzyloxy, a, c * r ~ d? met? ibenc? lo, NO2, CHO, CH3CI-KOH), acetyl and ethylenedioxy. Preferably every X is independently selected from the group consisting of CH3, CH3O, CH3CH2O, inethylenedioxy, Br, Cl, F, I, CF3, CHF2, CI-I2F, CF30, CF3 CH20, CH3, OH, CH2 OH, CONH2, CN, N02 , CH3 CH2, propyl, isopropyl, butyl, isobutyl, t -butyl and acetox. Most preferably, each X is selected independently from ? F group consisting of sopropyl, CH3O, OH3S, CF3O, I, Cl, F, CF3 and CH3, most preferably CF3O, I, 01, F, and CF3; each Z is independently selected from the group consisting of lower alkyl, halogen, lower aJco / i, lower thioalkyl, rnet ilenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN and ethoxy. Preferably each Z is independently selected from the group consisting of CI-I3, CH3O, CH3CH2O, rnetylenedioxy, Br, Cl, F, T, CF3, CHF, CH2 F, CF30, CF3 CH20, CH3, OH, CH2 OH, CONH2, CN, CH3CH2, propyl, isopropyl, butyl, isobuyl, t-butyl and acetoxy. Most preferably, each Z is selected LO independently of the group consisting of isopropyl, CH 3 O, CH 3, CF 3 O, CF 3, 1, Cl, F and CH 3 - In a further preferred embodiment, at least one of the Z substituents is in the meta position. Most preferably, the compound has the following formula: Wherein R is either hydrogen or methyl; rn is 0, l,?, 3, 4 or 5, preferably l 2; and each X is independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnetylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2,! = CN, acetoxy, (CH3) 2, phenyl, phenoxy, benzyl, benzyloxy, cf, cf-dirnethylbenzyl, NO2, CHO, CH3CH (OH), acetyl, and lendioxy, preferably each substituent is independently selected from the group consisting of CH3, CH3O, CH3CH2O, ethylenedioxy, Br, Ci, F, I, CF3, CHF2, CH2F, CF3O, CF3CH2O, CH3, OH, CH OH, CONH2, '-N, N02, CH3CH2, p 1' opyl, isopropyl, butyl, isobutyl, t-butyl and acetoxy, most preferably isopropyl, CH3O, CH3S, CF3O, CF3, I, CJ, F and OH3 the* wherein R is either hydrogen or methyl; Ri is either halogenic or hydrogen, preferably Ri is either F or hydrogen; R2 is either hydrogen, halogen, lower alkyl *, rnetiienedioxy, lower haloalkyl or lower haloalkoxy *, preferably R2 is either hydrogen CF3, CH3, OCF3 or F and R3 is either hydrogen, halogen or alkoxy, Preferably R3 is yasea Cl, F, hydrogen or rnetoxy, rnuy preferably methoxy. In alternative combinations, very preferred; at least two of Ri, R2 and R3 is halogen, I preferred B and R is hydrogen or CH3; R is hydrogen or CH3, R2 is either halo Lower alkyl or lower haloalkoxy, preferably OCF3 or CF3, and Ri and R3 is hydrogen; and R is CH3, R3 is halogen, preferably Cl, Ri is either halogen or hydrogen, preferably F or hydrogen, and R2 is either hydrogen, lower alkyl, lower haloalkyl or lower haloalkoxy, preferably, hydrogen CF3, CI-I3, OCF3 or F. b. r2 is naphthyl and q is 0 In another preferred embodiment, r-2 is naphthyl, q is 0 and wherein An is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, meth lenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONI-I2, CN, acetoxy, N (CH3Cl2 phenyl, phenoxy, benzyl, benzyloxy, α, -di-di-di-benzyl, NO2, CHO, CH3CH (OH), acetyl, ethylenedioxy, preferably each substituent is independently selected from the group consisting of CH3, CH30, CH3CH2O, rnetylenedioxy, Br, Cl, F, I, CF3, CHF2, CH2F, CF3O, CF3CH2O, CH3S, OH, CH2OH, CONH2 / CN, N02, CH3CH2, propyl, K-propyl, butyl, isobutyl, t-butyl and acetoxy. Most preferably i is already be a naphthyl or a femlo with 1-5 substituents each selected independently from the group consisting of i soprop, CH3O, CH3S, CF3, CF3O, I, Cl, F and CH3, most preferably in an optional substituted femLo The compound has the formula: wherein Xn represents the optional substituents for the optionally substituted femlo as described above (with the preferred substituents and number of theirs as described above). Even very preferably the compound has the fopnul a: wherein R is either CH3 or hydrogen, - R4 is either lower alkyl, halogen or alkoxy, preferably isopripyl, chloro or rnetoxy; and R Rs is either hydrogen, lower alkyl or halogen, preferably methyl, CH 3, Br or Cl. c. Ar2 is naphthyl and q is 2 In another preferred embodiment, Ari is a substituted f, Ar2 is naphthyl, q is 2 and the compound has 1? -Rornula: Wherein R is either hydrogen or CH3; n is O, 1, 2, 3, 4 or G, preferably 1 or 2; and each X is independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, eti lendi 0x1, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONI-I2, CN, acetoxy, (CH 3) 2, phenyl, phenoxy, benzyl, benzyloxy, C, O-dimethylbenzyl, NO 2, CHO, CH 3 CHC 0 H), acetyl, ethylenedioxy, preferably each substituent is independently selected from the group consisting of CH 3, CI -I3O, CH3CH2O, methylenedioxy, Br, Cl, F, I, CF3, CHF2, CH2F, CF3O, CF3CH2O, CH3, OH, CH2OH, CONH2, CN, NO2, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl and acetoxy, most preferably isopropyl, CH3O, CH3C *, CF3O, CF3, 1, Cl, F and CH3 - Very preferable, the compound has the formula wherein Re is either hydrogen, lower haloalkyl or lower haloalkoxy, preferably hydrogen, OCF3 or CF3; and R7 is either halogen or hydrogen, preferably chlorine or hydrogen. In other embodiments R, R & and R? they are as described above (with preferred substituents such as those described above), as long as when both R and Re are hydrogen, R7 is not Cl; and R is CH3, and Rs and R? -become was described above (with the preferred substitutes as described above). # 2. Compounds of structure II Compounds of structure II have the formula: Wherein Ar-3 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, inendiylenedioxy, lower haloalkyl, lower haloalkoxy , OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, cf, of -d? Met?] Benzio, NO2, CHO, CH3CHI0H), N (CH3) 2, acetyl, ethylenedioxy, preferably N (CH3) 2 / lower alkoxy or lower alkyl; Ar- is either naphthyl or phenyl optionally substituted with 0 to 5 substituyent each is selected # independently of the group consisting of lower alkyl, Halogen, lower alkoxy, lower thioalkyl, methyl lendi 0x1, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN and acetoxy, preferably lower alkoxy, most preferably rnetox 1, -Rβ is either hydrogen or fem, preferably hydrogen; R9 is either hydrogen or methyl and Rio is either hydrogen, methyl or phenyl, most preferably when Rio is methyl the quinal carbon to which this is attached is the crude esoteric (R). Preferably, the α-methyl in structure II is an (R) -oc-methyl group. 3. Compounds of structure III Compounds of structure 111 have the The formula: wherein Ars is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnet il end 10x1, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONI-I2, CM, acetoxy, benzyl, benzyloxy, ", cf-d? Methylbenz? Jo, NO2, CHO, CHsCHIOH), acetyl, ethylenedioxy and -CH-CH - eni Lo, preferably lower alkyl, phenoxy, - CH = CH - emio, dimethyl benzyl, rnetoxy, methanol or ethylene; 15 is either naphthyl or phen optionally substituted with 0 to 5 substitute is each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnediienedioxy, lower haloalkyl, lower haloalkoxy OH, CH2OH, CONH2, CN, carbornetoxy, OCi-fe C (0) C2 Hs and acetoxy, preferably methoxy, lower alkyl, femlo, halogen, CF3, CN, carbornetoxy or 0CH2C (0) C2H5; R11 is hydrogen or methyl, preferably when p is methyl, the carbon to which it is attached is a stereoimage omero ?! = • (R); and R 12 is hydrogen or methyl, preferably when R 12 O '. methyl carbon to which is attached a estoi 001 shallow (R) 4. Calcimimetic Activity The ability of the compounds to simulate Ca2 + activity in calcium receptors can be determined using techniques known in the art and described by Nerneth et al., PCT / US93 / 01642, International PubJ ication Number WO 94/13959 . For example, the caicimirnetics They possess one or more and preferably all of the following activities when tested in parathyroid cells in vitro: 1. The compound produces a rapid increase (time to reach the peak <5 seconds) and transient in the intracelular calcium concentration that is refractory to inhibition by L 3+ at 1 JJM or Gd3 + at 1 ja. The increase in CCa2 +]? it persists in the absence of extracellular Ca2 +, but it is suppressed by pretreatment with ithornicma (in the absence of extracellular Ca2 +); 20 2. The compound increases the increases in L "Ca2 + l produced by subrnaxirnas concentrations of extracellular Ca2 + 3. The increase in L" Ca2 +] i produced by extracellular Ca2 + is not inhibited by dihydropipdines; 4. The transient increase in ["Ca2 +]" caused by The compound is suppressed by pretreatment, for 10 minutes, with sodium fluoride at 10 nm; . The transient increase in L "Ca2 + 3? Caused by the compound decreases by p ratarine rat with a protein kinase C (PKC) activator, such as phorbol -miptate-acetate (PMA), rnezerema or (~) -? Ndoiac + am V. The total effect of the activator of pro te ma cmasa C is to modify the curve of concentration r-espuesta of the compound to the right without affecting the maximum response 6. The compound produces a rapid increase ('30 seconds) in the formation of 1, 4, 5- p phosphate or of mosatol and / or '10 diacylglycerol; 7. The compound inhibits the formation of cyclic AMP stimulated by dopa ma or isoproterenol; 8. The compound inhibits PTH secretion; 9. Pre-treatment with pertussis toxin (LOO) ng / rnl for 4 hours) blocks the inhibitory effect of F composed on the formation of cyclic AMP, but does not affect the increases in L "Ca2 + 3i, 1, 4, 5-inositol or diacylglycerol tpphosphate, nor decreases the secretion of PTH; 10. The compound produces increases in the current of Cl- in xnnopus oocytes injected with rRNA enriched with poly (A) + cells from bovine or human parat roids, but lacks effect on xenopus oocytes injected with water or liver rRNA; and 11. Also, using a calcium receptor cloned from a parathoid cell, the compound will produce a response in xenopus oocytes injected with the specific α-TDNe or rRNA that encode the receptor. Different calcium activities can be measured using available techniques. (See, Nerneth et al., PCT / US93 / 01642, International Publication Number WO 94/18959). Parallel definitions of compounds that simulate C2 + activity in other cells that respond to calcium, preferably in a calcium receptor, are evident from the examples given here and in Nemet h < * - • * • t. ai., PCT / US93 / 01642, International Publica + ion Nurnber WO 94/18959. Preferably, the compound, as determined by the bioassays described herein or by Nemeth et al, PCT / US93 / 01642, International Publication Number WO 94/18959, has one or more activities, but preferably all of the following: a transient increase in internal calcium, which lasted less than 30 seconds (I preferred blernente by mobilization of internal calcium); evokes a rapid increase in L "Ca2 + - ?, occurring within 30 seconds, evoking a sustained increase (greater than 30 seconds) in CCa2 + 3 (preferably causing an influx of external calcium), evoking an increase in 1, 4, 5-triphosphate levels of mositol or diacylglycerol, preferably within less than 60 seconds, and inhibits the formation of cyclic AMP stimulated by dopamine or isoproterenol.The transient increase in CCa2 + 3α is preferably suppressed by pret cell growth for ten minutes with sodium fluoride at 10 minutes, or the transient increase decreases by brief pro-tension (not ten years) of the cell with a protein activator or, preferably, phorbol - my pentate acetate (PMA), ezerein or (-) indolactárn V. c. Calcilytics The ability of a compound to block extracellular calcium activity in a calcium receptor # can be determined using normal techniques based on the present description. (See also Nerneth et al., PCT / US93 / 01642, International Publication Number Wo 94/18959). For example, compounds that block the effect of extracellular calcium, when used in relation to a parathyroid cell, possess one or more of the following 1 characteristics, preferably all of them, when tested in para-roic cells in vitro: 1. The compound blocks, either partially or completely, the ability of higher concentrations of extracellular Ca + to: 20 (a) increase CCa2 + 3 ?, (b) mobilize the intracellular Ca2 +, (c) increase the formation of 1,4,5- tp inositol phosphate, (d) decrease the formation of cyclic AMP stimulated by dopamine or isoproterenol, and (e) inhibit the secretion of PT ?; 2. The compound inhibits the increases in the Cl- current in snopus oocytes injected with RNAin enriched with poly (A) + parat iroid cells from bovine or human cells produced by extracellular C + or calcimetic compounds, but not in oocytes from 8nopus injected with water or mRNA from the liver; 3. Also, using a calcium receptor-cloned from a parathyroid cell, the compound will block # a response in xsnous oocytes injected with the cDNA, * 10 specific RNA or cRNA that encode the calcium receptor, produced by extracellular Ca + or a calcimetic compound. Parallel definitions of compounds that block Ca2 + activity in a cell that exhibits response to Calcium, preferably in a calcium receptor, are evident from the examples given here and in Nemeth et al., # PCT / US93 / 01642, International Publication Nurnber WO 94/10959.

III. TREATMENT OF DISEASES OR DISORDERS Diseases or disorders that can be treated by regulation of calcium receptor activity are known in the art. For example, diseases or disorders that can be treated by regulation of calcium receptor activity can be identified based on the functional responses of cells regulated by the activity of the calcium receptor. Functional responses of cells regulated by the calcium receptor, including I? PTH secretion by parata roldes cells, secretion of calcitomna by C cells and bone resorption by osteoclasts. These functional responses are associated with different diseases or disorders. For example, hyperparathyroidism results in elevated levels of PTH in the plasma. The decrease in plasma PTH levels # offers an effective way to treat the haperparat iro disrno.

Likewise, the increase in plasma levels of caletonin is associated with an inhibition of bone resorption. The inhibition of bone resorption is an effective treatment of osteoporosis. Thus, the regulation of calcium receptor activity can be used to treat diseases such as hyperparathyroidism and osteoporosis. Those compounds that regulate the activity of! Inorganic ion receptor, preferably calcium receptor activity, can be used to confer beneficial effects to patients suffering from various diseases or diseases. disorders. For example, osteoporosis is an age-related disorder that is characterized by loss of bone mass and an increased risk of bone fracture. Compounds that block osteoclastic bone resorption can be used, either directly (for example, a compound ?F; ionomimetic osteoclast co) or indirectly by increasing the levels of endogenous calciform (eg, a calcimimetic <C cells). Alternatively, a caicylate active in the calcium receptor of the cells of p * - iro ides will increase the circulating levels of parathyroid hormone, stimulating bone formation. These three approaches will have beneficial effects on patients suffering from ost eoporosis. In addition, it is known that dosing ba to intermittent with PTH has an anabolic effect on bone mass and proper bone remodeling. Thus, the compounds and # Dosage regimens that evoke transient increases on the parathyroid hormone (for example, intermittent dosing) with an ionolithic parati oid cell) can increase bone mass in patients suffering from ost eoporosis. Other diseases or disorders can be identified by identifying other cellular-functional responses, associated with a disease or disorder, which are regulated cock calcium receptor activity. The diseases or disorders that can be treated by reguLation of other inorganic ion receptors can be identified in an analogous way. The inorganic ion receptor regulatory compounds of the present invention can exert an effect on an inorganic ion receptor, having one or more cellular effects that ultimately produce a therapeutic effect. The calcium receptor regulatory compounds of the present The invention can exert an effect on the calcium receptor causing one or more cellular effects, ultimately producing a therapeutic effect. Different diseases can be treated by the present invention when labeling cells having a calcium receptor. For example, primary haperparathyroidism (HPT) is characterized by percalcemia and abnormal high levels of circulating PTH. A defect associated with the main HPT cap is a lower sensitivity of parathyroid cells to the negative feedback regulation by C 2+. # extracellular Thus, in the tissue of patients with primary HPT, the "fixed point" for extracellular Ca2 + changes to the right, so that higher-than-normal concentrations of extracellular Ca2 + are required to decrease PTH secretion. Furthermore, in primary HPT, even high extracellular Ca2 + concentrations frequently decrease PTH secretion only partially. In secondary HPT (urernic), a similar increase in the fi x point for extracellular C2 + is observed even when the degree to which Ca2 + suppresses PIH secretion is normal. Changes in PTH secretion are matched by changes in CCa2 + 3? = The fixed point for increases in CCa2 + 3? induced by extracellular Ca2 + changes to the right and the magnitude of these increases decreases. Patients suffering from secondary HPT may also suffer from renal osteodystrophy. The metabolic rate seems to be useful for the treatment of abnormal PTH secretion and osteodystrophy in these patients. Compounds that mimic the action of extracellular Ca2 + are beneficial in the long-term treatment of both primary and secondary HPT. These compounds provide the additional impetus that is required to suppress the secretion of PTH that the hypercalcernic condition alone can not alleviate and, therefore, help to improve the perealcemic condition. Compounds that are more effective than extracellular Ca2 + can overcome the manifest irrepressible component of PTH secretion that is particularly problematic in the # Primary form of primary HPT caused by adenoma of the parathyroid gland Alternatively or additionally, said compounds can decrease the synthesis of PTH, since it has been demonstrated that the prolonged hypereperience decreases the levels of preproPTH mRNA in adenornatosous tissue of bovine and human parathyroid. The prolonged hypercalcemia also decreases the proliferation of the pai-atyroid cells in vitro, so that calcitonins can effectively limit the parathyroid cell erplasia, characteristic of secondary HPT. Other cells apart from the cells of the 0 p ratiroldes may respond directly to physiological changes in the concentration of extracellular Ca2 +. For example, the secretion of calcitonin from the parafollicular cells of the thyroid (C cells) is regulated by changes in extracellular Ca2 + concentration. ? R Isolated osteoclasts respond to increases in extracellular C2 + concentration with corresponding increases in L "Ca2 + -3? That are due in part to the mobilization of intracellular Ca2 +, increases in CCa2 + 1? In osteoclasts. Associated with the inhibition of bone resorption The release of alkaline phosphatase from bone-forming osteoblasts is directly stimulated by calcium RN secretion from the juxtaglomerular cells of the kidney, just like PTH secretion, # is diminished by the higher concentrations of C 2+ extracellular. Excellular Ca2 + causes the mobilization of intracellular Ca2 + in these cells. Other cells of the kidney respond to calcium as follows; High Ca2 + inhibits the formation of 1,25 (0H) 2-vitamin D by cells of the proximal tubule, stimulates the production of calcium-binding r in the cells of the distal tubule and inhibits the tubular reabsorption of Ca2 + and M32 + V The action of the vasopressor on the thick ascending limb of the loop of Henle (MTAL), reduces the action of vasopressin in the cortical cells of the collecting duct and affects to vascular cells of smooth muscle in the blood vessels of the renal roundabout Calcium also promotes the differentiation of intestinal goblet cells, mammary cells and skin cells; inhibits the atrial secretion of the natp uretic peptide from the cardiac atria; decreases the accumulation of cAMP in platelets; alters the secretion of gastrin and glucagon; acts on vascular cells of smooth muscle to * modify the cellular secretion of vasoactive factors; and it affects the cells of the central nervous system and the peripheral nervous system. Thus, there are sufficient indications that C2 +, apart from its ubiquitous function as a signal cell, also functions as extracellular signal that regulates the responses of certain specialized cells. The compounds of this invention can be used in the treatment of diseases or disorders associated with JO interrupted responses to Ca2 + in these cells. Specific diseases and disorders that could be treated or prevented, based on the affected cells, also include those of the central nervous system, such as apoplectic seizures, stroke, brain trauma, La spinal cord, nerve cell damage induced by hypoxia as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases or Alzheirner's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression , anxiety, panic disorders, co-operative-obsessive disorder, post-traumatic stress disorder, schizophrenia, malignant neuroleptic syndrome and ourette syndrome; diseases that involve resorption of excess water by the kidney, such as syndrome of maternal ADH (S3ADH) secretion, cirrhosis, congestive heart failure and nephrosis; hypertension; prevention and / or reduction of renal toxicity from cationate antibiotics (eg, arynoglucoside antibiotics); disorders of intestinal motility, co or diarrhea and colon spasta co; ulcer diseases C? l; IT diseases with excessive calcium absorption such as sarcoidosis; and autoimmune diseases and rejection of organ transplantation. Even though the calcium receptor regulator compounds of the present invention will be used # typically in therapy for human patients, also can be used to treat similar or identical feeds in other warm-blooded animal species, such as other primates, farm animals such as pigs, cattle and poultry; and game animals and pets, such as horses, dogs and cats. 15 IV. ADMINISTRATION The different compounds described by the present invention can be used to treat different diseases or disorders by regulating the activity of the inorganic ion r-eceptor, preferably calcium receptor activity. The compounds of the invention can be formulated for various routes of administration, including systemic and topical or localized administration. The techniques and formulations can generally be found in Rernington's Pharrnaceutical Sciences, Mack Publishing Co., Easton, PA. The administration of ionomirnetics and lonolithics is discussed by Ne eth et al PCT / US93 / 01642, International Publication Number WO 04/18959. The appropriate dosage forms depend on part of the use or intake, for example oral, transderrnal or by injection. Said dosage forms should allow the compound to reach a target cell, whether the target cell is present in a mult cell host or on culture. For example, the compositions or compounds (archaeologists injected into the blood stream must be * soluble. Other factors are known in the art, and include considerations such as toxicity and dosage form that retard the action of the compound or composition. The compounds can also be formulated as pharmaceutically acceptable salts (for example, acid salts of addition) and complexes. The pharmaceutically acceptable salts are non-toxic salts at the concentration at which they are administered. The preparation of said salts can facilitate the pharmacological use by altering the physical character of the compound without preventing it from exerting its physiological effect.

Useful alterations in physical properties include lowering the melting point to facilitate administration by the transrucosal route and increase solubility to facilitate administration of higher concentrations of the drug. Pharmaceutically acceptable salts include acid addition salts with or those containing sulfate, hydrochloride, > ^^ malate, phosphate, sulfamate, acetate, c-time, lactate, tar-time, methanesulfonate, ethanesulfonate, benzenesulphonate, p-toluenesui fonate, cyclohexyl isulphanate and quate. (See for example, PCT / US92 / 03736, hereby incorporated by reference). Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, rhenic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, L acetic acid, tartaric acid, rumomachic acid, ethanesul fomic acid, acid. ethane? lf nico, benzenesulonic acid, P-tololuene fonic acid, cyclohexyl sulfamic acid and quinic acid. Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the base form of a compound is dissolved in an appropriate solvent, such as a aqueous solution or an aqueous solution-alcohol, containing the appropriate acid and then isolated by evaporation of the solution. In another example, a salt is prepared by reaction of the free base and the acid in an organic solvent. Vehicles or excipients can also be used to facilitate administration of the compound. Examples of vehicles and excipients include calcium carbonate, calcium phosphate, various sugars with lactose, glucose or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol and solvents.

TI-: physiologically compatible. The compositions or pharmaceutical composition can be administered by f different routes, including intravenous, intrapeptural, subcutaneous, intramuscular, oral, topical or transmucosal. For systemic administration, oral administration is preferred. Alternatively, administration by injection, for example, intravenous, intrapeptoneal and subcutaneous mRNA, can be used. For administration by injection, the compounds of the invention are formulated in liquid solutions, preferably in physiologically compatible pH side, such as the llank solution or the Rmger solution. In addition, the compounds can be formulated in solid form and redissolved or suded immediately before use. Freeze-dried forms can also be produced. Systemic administration can also be by transdermal or transdermal means, or the compounds can be administered orally. For transmucosal or transdermal administration, suitable penetrants for the barrier to be used are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transcutaneous administration, bile salts and derivatives of fusidic acid. In addition, detergents can be used to facilitate penetration. Transinucosal administration can be through nasal sprays, for example, or using suppositories. For oral administration K, the compounds can be formulated in conventional dosage forms for oral administration, co # capsules, tablets and liquid preparations. For topical administration, the compounds of the invention can be formulated in ointments, blisters, gels or creams, as is generally known in the art. The amounts of various compounds of this invention to be administered can be determined by standard procedures. In general, a therapeutically effective amount is between about 1 nmol and 3 umol of the # compound, preferably 0.1 nmol and 1 urnoi depending on your ECso or ICso and age and the patient's stature, as well as the disease or disorder associated with the patient. In general, it is an amount between about 0.1 and 50 mg / kg, preferably 0.01 and 20 mg / kg of the animal to be treated.

V. EXAMPLES Following are examples illustrating different aspects and inclusions of the present invention. These examples are not intended to limit the claimed invention.

EXAMPLE 1 Cloning of the calcium receptor in parathyroid from human to H Starting from a parathyroid gland adenoma from human This example describes the cloning of a calcium receptor in human parata from a human parathyroid gland adenoma using pBoPCaRl as a hibpization probe (See, Nerneth et al., PCT / US93 / 01642, International Publication Number WO 94/18959). The probe was used to identify nucleic acid encoding the calcium receptor in human parathyroid glands by cross-hybridization with reduced accuracy. Messenger RNA was prepared from an adenoma of a parathyroid gland of a human removed from a man Caucasian 39-year-old diagnosed with primary hyperparathyroidism. Northern blot analysis of this siRNA using pBoPCaRl as hybridization probe identified calcium receptor copies of almost 5 Kb and almost 4 Kb. A collection of cDNA was obtained from the rRNA. Double cDNA band greater than 3 Kbp was selected by size on an agarose gel and ligated into the lambda Zapll cloning vector. "^ 9 Five hundred thousand primary recombbinant phage were examined with the insertion of 5.2 Kbp cDNA of the pBoPCaRl as a hybridization probe.The insertion of pBoPCaR! Was marked by synthesis initiated randomly using C32P3-dCTP at a specific activity of 1 x 10 'cpin / μg. The library examination was carried out at a hybridization accuracy of 400 mM Na +, 50% forrnanide at a temperature of 38 ° C. The plate lift filters were hibbed at a probe concentration of 500,000 cprn / rnl for 20 hours. After hybridization, the filters were lxed in 1 x SSC at 40 ° C for 1 hour. The primary screen identified almost 250 positive clones identified by hybridization with pBoPCaRl. Seven of these clones were passed through secondary and tertiary screens to isolate clones mdi vidual is that hibpdaran with the probe pBoPCaRl. These seven clones were analyzed by means of restriction enzyme mapping and Southern blot analysis. Three of the clones contained cDNA insertions of almost 5 Kbp and appear to be normal long-term clones that LO corresponds to the 5 Kb rRNA. Two of the clones contain cDNA inserts of almost 4 Kbp and appear to be normal-length clones corresponding to the 4 Kb rRNA. The restriction enzyme rnapeo of the two inserts of different size indicates that they share regions of sequence similar at their 5 'ends, but diverge in the sequence of their 3' ends. DNA sequence analysis indicates that the smaller insert may result from alternative polyadenylation towards the 5 'end of the polyamide site used in the large insertion. Representative cDNA inserts for both size classes were subcloned into the blue SK marking of the vector plasmid. Linearization followed by viral transcription using T7 RNA polymerase produced copies of cRNA. Copies of cRNA were injected into xmo uß oocytes (150 ng / ul RNA; 50 nl / oocytes) for functional analysis. After incubation periods of 2 to 4 days, the oocytes were 9L tested for the presence of functional calcium receptors. Both types of clone gave rise to functional calcium receptors when they were evaluated by the stimulation of calcium-activated chloride currents after the addition of appropriate agonists of calcium receptors. Known calcium receptor agonists, including NPS R-467 and MPS R-568 (See, Nemeth et al., PCT / US93 / 01642, International Publication Number WO 94/18959), activated the receptor expressed in the oocytes to almost The same concentrations that are known to be effective for the r-eceptor-native cell for you roldes. Thus, both clones code for a functional calcium receptor in human parati roldes cells. The plasmids were prepared by sub-cloning each insertion group in blue-labeled, thereby producing pHuPCar 5.2 and pHuPCar 4.0. The nucleic acid sequence and the amino acid sequence of the insertions are shown in SEQ. ID; Nos. 1 and 2. Several differences were observed between the sequences of nucleic acid of the two cDNA inserts. The analysis of the sequences of the two cDNA insertions indicates the existence of at least two sequence variants that differ in the 3 'untranslated region and that can result from alternative polyadenylation. In addition, there is variation in 9R sequence at the 5 'end of the inserts. These distinct sequences correspond to untranslated regions and may have arisen due to alternative initiation and / or binding during transcription. Three other sequence variation sites are observed within the coding regions of cDNA clones pHuPCaR5.2 and pHuPCaR4.0 (see SEQ ID Nos. 1 and 2), demonstrating that these cDNA clones encode distinct proteins. The sequence analysis of the human CaR gene indicates that the additional 30 base pairs of the DNA in the ADMc? HuPCaR5.2 clone, when compared to the cDNA clone pHuPCaR 4.0, result from alternative binding of the mRNA. It is envisaged that the RNArn alternative linkage inserts another 10 amino acids into the CaR polypeptide encoded by the cDNA of pHuPCaR5"2 at a site between aa # 53B and aa # 537 in the polypeptide encoded by the ADMc? HuPCaR4.0. In addition, pHuPCaRí.O codes for glutamine (Oln) in aa # 925 and glycine (Tly) in position 990, while pl-luPCaR5.2 codes for argiruna (Arg) in both equivalent positions. The human CaR gene codes for Tln and Arg, respectively, in these positions. The difference between the pHuPCaR4.0 cDNA compared to human DNA seems to represent a real sequence polymorphism within the human population, whereas the only change of bases in pHuPCaR5"2 probably reflects a mutation that occurred during its cloning. Both cDNA molecules encode functional calcium receptors, as evidenced by the ability of oocytes 95 of xenous injected with cRNA prepared from these cDNA clones to respond to 10 M of extracellular calcium ^^ f as investigated by the CJ conductance - However, it is possible that these two iso forms of the receptor are functionally / or pharmacologically different.

EXAMPLE 2 Selection of stable recombinant cells expressing the calcium receptor Clonal cell lines expressing stably the two calcium receptors, in the human and in the bovine. CDNA molecules encoding calcium receptors were subcloned into two different expression vectors that exist in commerce; pMSG (obtained from Pharmacia) and Cep4B (obtained from Tnvitrogen),. He The first vector contains the selectable marker gene for xantma-guanine tosforpbosyl transferase (gpt), allowing stably transfected cells to overcome blockade of the biostatic pathway of the pupil imposed by the addition of 2 ug / rnl of arninoptepna and 25 ug / rnl of acid rni cofenolico. He The second vector encodes a gene that confers resistance to the hygr-ornicin antibiotic (used at 200 g / rnl). Molecules of ADMc pHuPCaR 5.2 and pHuPCaR 4.0 (SEO ID Nos. 1 and 2, respectively) were removed from the original blue-labeled plasmid with restriction enzymes Not I and Hmd III and ligated then directly in Ce? 4B digested with Not I + Hmd III or treated with the klenow fragment of the DNA pol-irnerase prior to ligamenting to the ex-blunt oar in SG-P digested with Srna T. The sub-portion pMSG containing the insert pHuPCaR 5.2 was transfected into üHQ cells as indicated above. The selection has resulted in 20 resistant clones that are being characterized. The Cep4B subclone containing the pHuPCaR 5.2 insert was transfected into ceJuJ s HEK 293, as described above. The selection with hygromnacin resulted in a common deposit of stable clones. Clones expressing the receptor isoform pHuPCaR 4.0 were prepared dol mode. Cells obtained from the cornun reservoir of HEK 293 cells selected with hygrornicma transfected with Ce? 4B containing the insert pHuPCaR 5.2 were placed on plates in Aklar squares coated with collagen which had been placed in individual wells of 12-well tissue culture plates. Two to six days later, the medium was removed and the cells were washed with balanced salt solution and 1 rnl pH buffer containing 1 jill of fura2-AM, 1 rnM of CaCl2 and 0-1% of BSA and ImM of CaCl2 - Measurements of Fluorescence on r-response to calcium receptor agonists was carried out at 37 ° C in a spectrofluopronetro using excitation and emission wavelengths of 340 and 510 nrn, respectively. For the calibration of the signal, Frnax was determined after the addition of icanum (40 uM) and ia Frnm Apparent 7R was determined by adding 0.3 M of EGTA, 2.5 M of Tris-HCl; at pH 10. Vigorous increases in CCa2t-3j. se - ^ 3 ^ ol- > They served in response to the addition of the following agonists of the calcium receptor: C + (10 nM), Mg2 + (20 thousand) and NPS R-467. Control cells expressing functional receptors of substance K did not respond to these calcitonin compounds. Other clonal isolates of HEK 293 cells transfected with the sequence? HuPCaR? .0 were obtained. These were tested for their response to calcimetics, as described above, except that the cells were tested while in suspension.

EXAMPLE 3 Use of parati olde cells loaded with Fura-2 to measure Calcium receptor activity This section describes procedures used to obtain paratiroi cells from calves and humans, and to use * parata roldes cells to measure calcium receptor activity. 20 Parat roids glands were obtained from freshly slaughtered calves (12 to 15 weeks of age) in a local cattle slaughterhouse and transported to the laboratory in pH * buffer of ice-cold paratroid cells (PCB) containing (M) : NaCl, 126; KC1, 4; MgCl2, 1; Na-HEPES, 20; pH IR 7.4; glucose, 5.6, and varying amounts of CaCl2, for example, 1.25 rnM. Human parathyroid glands were obtained from patients who underwent surgical removal of parathyroid tissues by hyperparathyroid but primary or urernic (UAE), and were treated more or less with bovine tissue. The glands were adjusted for their excess fat and connective tissue and were then comminuted with fine scissors in cubes of approximately 2 to 3 millimeters in size. The parasite cells were dissociated and prepared by administering collagenase and then purified by • 10 centrifugation in Percoll pH regulator, The resulting preparation of parathyroid cells essentially lacked erythrocytes, adipocytes and capillary tissue evaluated by phase contrast microscopy and Sudan B black staining. Dissociated and purified parat roldes cells appeared as small groups containing 5 to 20 cells. Cell viability, indicated by exclusion of trypan blue or ethidium bromide, was usually 95%. Although cells can be used for reliable experimental purposes at this point, responses must be determined Physiological changes (eg, suppression of PTH secretion and CCa2 * levels), at rest) after culturing the cells overnight. The main crop also has the advantage that the cells can be labeled with isotopes up to almost the isotopic equilibrium, which is necessary for 2R studies involving measurements of the metabolism of inositol phosphate. 03 After purification on PercoLL ingredients, the cells were washed several times in a J •: 1 mixture of Harn's F12 - DuJbecco's modified Eayle's medium (GTDCQ) supplemented with 50 ug / l of repticosin, 100 U / mJ of penicillin, 5 μg / ml of gentamioin and ITS +. ITS + is a pre-nested solution containing insulin, transfep-ina, selonium and bovine serum albumin (BSA) -lainoJenic acid (Co laborative Research, Bedford, MA). The cells were then shaken into plastic bottles (75 0 150 cm, »10 Falcon) and incubated overnight at 37 ° C in a humid atmosphere of 5% CO2. No serum was added to these c during the night, since their presence allows the cells to attach themselves to the plastic, suffer proliferation and dissipate. The cells cultured under the above conditions were easily removed from the bottles by decanting and show the same viability that cells fall prepared. Purified parathyroid cells were resuspended in 1.25 mM of CaCl2 ~ BSA-2% PCB containing 1 JM of fura-2-acetoxy-1-ester and incubated at 37 ° C for 20 minutes. minutes. The cells were then transformed into pellets, resuspended in the same pH regulator, but lacking the ester, and incubated for another 15 minutes at 37 ° C. The cells were subsequently washed twice with PCB containing 0.5 nM CaCl2 and 0.5% BSA and maintained at room temperature (almost 20 ° C). Immediately before use, the cells were diluted five times with 0.5 rnM of pre-warmed CaCl2 ~ PCB to obtain a final US concentration of 0.1%. the concentration of cells in the mixing vessel used for the fluorescence recording was 1-2 x 106 / rnl, The fluorescence of cells loaded with indicator was 37 ° C in a luopmeter specimen (Baorned lime).

Jnstrurnentation Group, Umversity of Pennsyl Vama, Philadelphia, PA) equipped with a mixing vessel holder with thermostat and magnetic stirrer 1 raising exempting and emission wavelengths of 340 and 510 nm, , 10 respectively. This fluorescence indicates the level of tosylic Ca2 * - ci. The fluorescence signals were calibrated using digitonin (50 jjg / rnl, final) to obtain rnaxirna fluorescence (F ax), and ETTA (10 mil, pH 8.3, final) to obtain minimum fluorescence (Fmin, and a constant of dissociation of 224 nM. The loss of dye depends on the temperature and occurs more frequently within the first 2 minutes after heating the cells in the mixing vessel. The loss of dye increases only very slowly from then on. To correct the calibration for the loss of dye, the cells were placed in the mixing vessel and shaken at 37 ° C for 2 to 3 minutes. The cell suspension was then removed, the cells were transformed into pellets and the supernatant was returned to a clean mixing container. The supernatant was treated then with digitonana and EGTA to estimate the dye loss, which is typically 10 to 15% of the total fluorescent signal dependent on Ca2 +. This value will remain from the Fmin,. apparent.

EXAMPLE 4 Use of HEK 293 / pHuPCaR4.0 cells loaded with Fura-2 to measure calcium receptor activity This section describes procedures used to test calcium receptor activity using cells HEK 293 / pHuPCaR4, .0 loaded with Fura-2. HEK 293 cells transfected with pHuPCaR .Q were loaded with Fura-2 by incubating the cells in C-agle media modified by Dulbecco whose pH was regulated with HEPES at 20 rnM containing almost 5 uM fluo-3 / AM for one hour at temperature atmosphere. Lae cells were then rinsed with Hank's balanced salt solution whose pH was regulated with HEPES at 20 rnM containing 1 mM CaCl2 and 1 rnM MgCl2. The compounds to be tested were then added to the cells and the fluorescence was determined (excitation and emission wavelengths of 340 and 510 n, respectively).

EXAMPLE 5 Measurement of the ability of compounds to regulate calcium receptor activity The ability of different compounds to regulate calcium receptor activity was tested by measuring increases in CCa2 +] i in HEK 293 cells with nucleic acid encoding for pHuPCaR4.0 using cells loaded with Fura-2 or using Fura-2 loaded parat i roi cells. The results of different experiments are summarized in Tables i.a, l.b.l, J.b "2, l.c. and 2. Tables 1.a, 1.b.l, 1.b.2 and i.c summarize the effects of the compounds, at different concentrations, on the activity of the calcium receptor probed with or described in Example 4. (ie, using HEK 293 cells, transfected with nucleic acid encoding pHuPCaR4.0, and loaded with fura-2). Table 2 summarizes the results of different experiments where the EC50 was calculated in cells from parata roldes or in HEK 293 / pHuPCaR4"0 cells, loaded with fura-2. -to cells were loaded with fura-2 and tested as described in Example 2 (for parathyroid cells des) or in Example 3 (for HEK 293 / pHuPCaR4.0 cells) " * TABLE 1.a. Calcimimetic compounds that produce a greater than 40% response at 3.3 ng / mL in HEK-2g3 cells, expressing the calcium receptor in humans% code activity at four compound concentrations (g / mL) 00 330 33 3.3 Reference Compounds 10 R-568 • "." 95 69 24 17P 101 86 54 17X 105 93 51 24X 126 109 124 109 24Y 119 120 127 102 17J 116 118 122 102 25A 122 120 114 92 17E 116 110 110 92 24Z 138 138 135 90: > H 14S 116 106 105 88 25E 132 129 122 85 17G 125 128 119 77 30 14T 126 125 117 77 17H 126 124 111 74 140 119 119 102 74 251 119 113 114 74 12J 131 130 113 68 Code of activity% to four compound concentrations (g / mL) 3300 330 3.3 121 115 111 93 68 25G 130 115 99 66 9R 108 101 64 12F 118 110 101 63 120 110 117 94 62 16V 114 10 102 58 250 126 115 96 57 25J 119 123 105 56 16L 146 138 98 56 12N 115 106 102 55 16T 97 88 55 25U 107 107 ~ 95 55 17P 101 86 54 16Q 110 88 53 23E 137 113 102 53 17C 113 120 99 52 25L 97 97 85 52 8Z 101 97 52 17X 105 93 51 13R 132 98 51 170 112 96 51! 23Q 122 114 98 51 16X 111 96 51 24V 127 98 71 50 130 115 94 50 7 17N '108 86 49 2IV 122 116 99 48 24 132 134 99 48 13U 108 79 47 ^ Code of activity% to four compound co n cent ra tions (n / rnL) 3300 330 33 3. 3 24P 140 138 110 46 17Y 109 94 79 46 11X 100 76 45 25H 115 107 89 45 22J 99 71 45 J & s- 9C 104 82 45 * 13 S 102 87 45 10Q 103 100 84 44 13 P 110 83 44 '"8K 98 81 44' 13N 114 88 43 ION 106 97 77 43 12H 114 115 94 43 25P 90 81 75 41 18A 111 88 40 14L 109 78 40 • # TABLE l.b.l. Calcimimetic compounds that produce a response greater than 40% at 33 ng / mL in HEK-2g3 cells, expressing the calcium receptor in the human-code Activity% at all compound concentrations (g / rnL) 69 24 R-568 95 10 17P 101 86 54 17X 105 93 51 39 12C 134 125 98 161 121 117 96 36 ro ro s? * Code of activity% to four compound concent rations (ng / mL) 3300 330 33 3.3 24G 109 94 75 22 151 111 93 75 24 0 23M 113 97 74 26 14Y - 109 73 17 17K 98 97 73 37 12E 117 121 73 23 17Z 99 73 37 16 '102 73 4 23K 106 107 72 24 .5 25X 96 94 72 22 13W 109 71 12 23P 125 99 70 22 18B 111 96 69 26 21Y 100 68 36 17W 92 67 13 ! 0 23A 103 67 24 23G 127 93 67 13 13M 92 66 15 21U 104 104 66 18 21R 100 66 15 10S / 10T 86 65 13 17R 98 65 13 .5 13X 102 65 13 4N 100 65 13 21E 94 64 4 15J 80 75 64 13 Code of activity% to four compound concentio en (/ rnl ") 3300 330 33 3.3 22Y 114 64 28 21G 88 63 18 24L 105 62 10 10V- 99 62 8 10 / 10X 98 61 9 17B 92 61 19 23Y 106 87 61 16 11Y 103 61 20 * TABLE l.b.2 Calcimimetic compounds that produce a response greater than 40% at 33 ng / mL in HEK-293 cells, expressing the calcium receptor in the human Activity X code to four concentrations (ng / mL) Reference compounds 10 R568 95 69 24 17P 101 86 54 17X 105 93 51 18C 99 87 € 0 18 23T 102 74 60 31 4V 93 59 3G 84 59 6 231 102 58 3 21 102 58 17 240 137 114 58 8 3ü 89 57 9A 82 56 6 12M 98 86 56 11 12B 130 110 56 4 Code of activity% to four compound concentrations ( nq / rnL) 3300 330 33 3.3 21P 92 56 13 8T 85 55 13 10L / 10M 99 55 4 241 109 84 55 11 14N 89 55 15 23R 104 86 54 13 23S 97 53 3 1T 133 112 53 3 1CW / 10X 81 53 4 13T 90 53 6 10 6R 94 52 7 201 87 52 12 24A 122 85 52 9 12D 128 109 52 5 6X 84 52 10 13T 99 74 52 14 21X 119 101 51 2 23J 102 61 51 29 15 10Z 96 51 5 16Z 88 51 9 23N 96 50 2 1SU 85 50 4 11D 96 50 4 23X 94 49 1 17A 88 49 7 20J 80 48 8 20 22X 86 48 10 23U 87 48 3 92 74 48 4 1SJ 92 76 47 31 25N 94 73 46 8 4P 81 46 8 2R Code of% of ac ti. vi four compound c in tra ciene (g / rn L) 3300 330 33 3.3 230 111 79 46 13 13Q 95 46 5 4G 83 46 12Y 80 46 10 12L 88 45 10 «& 23F 82 45 5 11 81 44 2 8H 88 44 7 25V 89 59 43 26 25W 95 69 42 8 10R 82 42 7 21N 124 98 42 4 as 73 42 7 8X 75 40 19 13E 123 94 40 2 CUñDRO l.c. Immune calci compounds that produce a response greater than 40% at 330 ng / mL in HEK-293 cells, expressing the calcium receptor in the human Code% activity to four compound concentrations (ng / ml-) 3300 330 33 3.3 ^ • Reference compounds R568 95 69 24 10 17P 101 86 54 17X 105 93 51 7X 85 3H 84 3L 81 28 160 129 81 21 2 8O / 8Q 124 80 14 0"t Code of% activity at quat or compound concentrations (ng / mL) 3300 330 33 3.3 14A 98 78 10 7 231, 107 77 37 9 ÍT 76 7 76 4H 77 37 8D • 75 5M 73 21 4U 72 10 24E 94 71 35 6 16M 130 68 11 4 4M 68 34 2S 67 29 17V 91 66 27 -1 • 2X 66 15 23D 91 66 35 13 4P 65 32 15 5B / 5C 65 20 3M 64 19 16K 78 62 36 8 • 5D 62 18 4D 61 13 24B 76 61 34 11 24H 81 60 32 13 5 60 16 20 2Y 59 10 5G 58 16 3V 56 14 2Q 56 4 14B 75 55 11 4 13Z 93 54 22 5 8A 54 24D 87 53 34 39? Co ndition of the activity% to four concentrations (ng / mL) 3300 330 33 3.3 ID 53 131 85 52 3 3B 52 15 8C 51 14H 112 49 7U 49 • 5E 48 7 10 3H 88 48 36 12 13Y 106 47 2 4 4J 47 8 141 80 45 11 4B 45 8 3D 45 4 3R 45 2 15 3A 41 7 14J 55 41 6 41 40 twenty • TABLE Calcimimetics of arylalkylamine of Figure 1 active in the calcium receptor of parathyroid cells in vitro (ECSO < 5 ufl) # Ü2 EXAMPLES 6 fi 17: 1U Synthesis of compounds The compounds described herein can be synthesized using standard techniques such as those described by Nerneth et al., PCT / US93 / 01642, International Publication Nurnber WO 94/18959. Examples that describe synthesis Representative of compounds described in the text are given below. The synthesis of the compounds 9R, 14U, and 1 7P was prepared by reductive aninacid of an aldehyde or an acetone which can be obtained commercially, with an amine. primary in the presence of ca noborder sodium idruro or sodium tpacetoxibohydride. Compounds 11Y, 12H, 12K,] 2M, J4S, 14T, 15L-0, 17E, I7G, 173, 24X, 24Y 25fi, 25E-25K, and 250 are prepared in the form im l r. It was found for the synthesis of these three compounds n vz (9R, 14U, and 16P) that sodium tpacethoxyborohydride produced the desired diastereoisornes with higher diasterooseloctivity than using sodium cyanoborohydride. The enriched mixtures were purified up to one individual diastererene by normal phase CLFIR or by recrystallization from organic solvents. Compounds Q3, 8U, 11X, 171, and 25Y were prepared from the condensation of a primary amine with an aldehyde or ketone in the presence of titanium (IV) isopropoxide. The resulting intermediate irins were then reduced in situ by the action of sodium cyanoborohi dpir, sodium borohydride or t pacetoxi borohi sodium druro. The intermediate enamel for the synthesis of compound 8U was catalytically reduced using palladium dihydroxide on carbon. The compounds 12U, 12V and 12Z were prepared by a condensation mediated by diisobutyl amide hydride or (OIBñL-H) of an amine with a nitrile. The resulting intermediate ion is reduced in situ by the action of sodium c -boroborohydride or * - borohydride. hate. The intermediate alkenes (compounds L2U and 12V) were reduced by hi catalytic digestion in EtOH using palladium on carbon. The compounds that were converted to their corresponding hydrochloride were thus obtained by treating the free base with ethereal HCl to produce white solids. The amines in this synthesis were purchased at > ? from Fildpch Chemical Co., Milwaul-'ee, UT, or Celgene Corp., (Jarren, NJ, or were synthetically prepared using standard techniques, etc. Other active chemicals were purchased from RJdpch ChericaJ Co.

EXAMPLE 6: Synthesis of the compound 25Y N ~ f 3-f 2- phenyDropyl) -l- (l -na tiDet lamina A mixture of 3- f-eni-1-propylamine (135 mg, 1 mrnol), The acetone (170 g, linmol), the titanium oxide (TV) (355 mg, 1.3 mol), was stirred at room temperature for 10 hours, and the reaction was treated. With 1M sodium cyanoborohydride (1 L) and stirring at room temperature for 16 hours, the reaction was diluted with ether and treated with water (0.1 mL), the reaction was centrifuged and the ether layer was removed and concentrated to a milky oil. parts of this material (10 μg) were purified by CLfiR (Phenornonex, 1.0 / 25 c, silica to G JJM) using a gradient of dichloromethane to 10% methanol in chloromethane containing 0.1% isopropy. This gave the product (free base) as an individual component by 0C / E1-MS 20 (Rt-- 10.48 irun) m / z (int. Re.) 289 (11 * -, ll), 274 ((53), 104 (5), 162 (5), 155 (J00), 141 (18), 115 (8), 91 (45),? 7 (5), ?! EXAMPLE 7 Synthesis of compound 83 N-f 3-fon? 1 prop 1) - I - (, 3 - 1 iprnet i j fen J) et i lamina. 3'-arninoaceto phenoa (2.7 g, 20 mmol) was dissolved in 4 mL of concentrated HCl, 4 g of ice and 8 mL of water. The solution was cooled to 0 ° C, and sodium nitrite (1.45 g, 21 rninol) dissolved in 3 to 5 inL of water was added for 5 minutes while maintaining the temperature below b ° C. Sodium thiorionatoxide (1.75 g, 25 mmol) was dissolved in 5 inL of water and cooled to 0 ° C.

This solution was added to the diazomo salt for 10 minutes while maintaining the temperature below 10 ° C. The reaction was stirred for a further hour while allowing the temperature to rise to room temperature. It was divided between ter and water.

The ether was separated and washed with sodium bicarbonate and sodium chloride and dried over sodium sulfate. The ether evaporated to give a yield of 74% thiornetilacetofenone. The raw material is dried by distillation at reduced pressure. 20 3-Fen? The propyl sheet (0.J3 g, 1 mmol), 3'-thiornetylaceto-inone (0.17 g, 1 mmol), and titanium (IV) dioxide (0.36 g, J.25 mrnol) were mixed together and dried. They let it rest for 4 hours. Ethanol (l mL) and sodium cyanoborohydride (0.063 g, inrnol) were added and the reaction was I stir during the night. The reaction was stimulated by the addition of 4 rnL of ter * and 200 μL of water. The mixture was submitted 06 A swirl action was made and rotated in a centrifuge to separate the solids. The ether layer was separated from the precipitate, and the solvent was removed in vacuo. The residue was redissolved in dichloroinothane and the compound was purified by preparative TLC on silica gel eluted with 3% methanol / dichloromethane to give the title compound as a pure oil: GC / FI-IISÍ Rt -? »64 rn n) rn / z (re. Nt.) 285 (11+, 18), 270 (90), 180 (17), 151 (100), J36 (32), 104 (I7); 9K54J, 77 (13), 10 EXAMPLE 8; Synthesis of compound 8U N-3- (2-metho-phenyl) -1-prop? J - (R) -3-metho-ot-met-11-benzyl-lane hydrochloride. 15 A mixture of (R) - (* -) - 3 -rnetoxy -cf-rnet l benzylamine (3.02 y, 20 nmol), 2-methox-c-n-nalnnal (3.24 g, 20 inmol), or isopropoxide of t titanium (IV) (8.53 g, 30 mmol, 1.5 Eq), stirred for 2 hours at room temperature and treated with 1 M sodium cyanoborohydride ethanol (20 rnL). The reaction The mixture was stirred overnight (J6 hours), diluted with diet ether J co and treated with water (1.44 mL, 00 mmol, 4 Eq.). After mixing for 1 hour, the reaction mixture was centrifuged and the ter layer was stirred and concentrated to an oil. This material was dissolved in glacial acetic acid, stirred with palladium hydroxide and hydrogen under hydrogen at 60 p.s.i. for 2 hours at room temperature. The catalyst was removed by filtration and the resulting solution was concentrated to a dense oil. This material was dissolved in dichloromethane and neutralized with 1 N NaOH. The dichloromethane solution was separated from the aqueous phase., dried over anhydrous potassium carbonate and concentrated to an oil. This material was dissolved in ether and treated with HCJ 1 ri in diethyl ether. CJ precipitate solution (white solid) was collected, treated with ethyl ether and dried in air. GC / E1-I1S fRt = 9.69 inin) of this material (free base) rnost r * o an individual component: m / z (mt ..) 299 (II », 21), 234 UQO), 164 ( 17), 150 (8), J35 (81), 121 (40), 102 (17), 9J (43), 7 7 (10).

EXAMPLE 9; L5 Synthesis of compound 9R Cl or h of (R) -N- (I - f 2- naft Uleii l) - f R) - 1 - (1 na tiJ) eta lamina A mixture of (R) - ( *) -1- (J -naf il) e ti lamina (i 0.0 y, 58 rnol), 2 '-acetone ft ona (9.4 g, 56 nmol), isopropoxide titanium (IV) f20.7 g, 73.0 mmol) and EtOH (abs.) (100 inL) was heated at 60 ° C for 3 hours. Then sodium cyanoborohydride (NaCNBH3) (3.67 g, 58.4 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. Ter (1 L) and H2O (10 mL) were added to the mixture of The reaction and the resulting precipitate were then removed by centioning. The supernatant was evaporated in vacuo and the crude product was recrystallized four times from hot hexane to yield 1.5 g of pure astereoeroero (98- *%). The free base was dissolved in hexane, filtered and ethereal HCl was then added to precipitate the product as a white solid (1.1 g, yield 6%), m.p .: softens at 200 to 240 ° C (dec.).

EXAMPLE 10; Synthesis of compound 11X 10 Chloride of N- (4-isopropylbenzl) - (R) -l- (l- to f-tii) e.? Larn? na A mixture of (R) - (* -) - 1- (J -n t i L) et? ia? n? a (1.06 g, 6.2 rnrnol), 4-? so? ro? lbenraldeh? do (0.92 g, 6.2 imnol), and titanium (IV) isopropoxide (2.2 g, 7.7 mmol) was heated at 100 ° C for 5 minutes and then stirred at temperature environment for 4 hours. Then sodium cyanoborohydride (NaCNJ3H3) C0.39 g, 6.2 mmol) was added followed by EtOH j mL). The reaction mixture was stirred at room temperature for 18 hours. Ether (00 ML) and I-I2O d mL) were added to the reaction mixture and the resulting product was removed. then by centrifugation. The supernatant is evaporated off in vacuo, the crude product is chromatographed on silica gel (column 50 rnrn x 30 crn) (elution with MeOH / CHCl 3 at 1%), and the chrome-rich material is then dissolved in hexane and dried. added ethereal HCl to precipitate * the product as a ? r-, white solid (0.67 g, 35% yield), m.p .; 257 to 259 ° C.

EXAMPLE 11; Synthesis of the compound 12U Clo hi drat or of N-3- (2 -metí lfe jl) -lp op? L- (P) -3-rnetox? -cy-inetiibenc i lamin A solution of 2-? Net? Lcmnarnon? The triethyl ester (1.43 g, 10 mmol) in dichloromethane (10 mL) was cooled to 0 ° C and treated dropwise (15 minutes) with di-butbutylidene-1-lium hydride (dichloromethane, 10 mL). The reaction was stirred at 0 ° C for 15 minutes and was added dropwise (15 minutes) with a 1-solution.

II of (R) - (+) - 3-rnetoxy-cr-rnet-ilbencylarnine (J .51 g, 10 rnmoJ) in dichloromethane (10 L). The reaction was stirred for 1 hour at 0 ° C and poured into an ethanol solution (100 mL) containing sodium cyanoborohydride (1 g, 16 rprnol). The reaction mixture was stirred for 48 hours at room temperature. The The reaction was diluted with ether and neutralized with 1 L NaOH. The ether rape was stirred, dried over anhydrous potassium carbonate and concentrated to an oil. This material is cured through silica using a gradient of di chloromethane to 5% methanol in dichloro-methane for produce the unsaturated intermediary, a single component by GC / EJ-MS (Rt = 10.06 rnin) rn / z (rm.mt,.) 281 ÜH-, 17), 266 (59), 176 (19), 146 ( 55), 135 (73), 131 (100), 91 (21), 77 (13). The intermediary msatui-ado on otanol is hydrogen R (H2 to 1 atr) in the presence of palladium or carbon for 16 hours at room temperature. The product of this reaction was converted to the hydrochloride sai by treatment with JM HCl in dietary Jico ether. GC / E1-I1S (Rt-0.31 min) of this material (free base) showed an individual component: in / z (re! Int.) 283 (M +, 21), 258 (100), 164 (12), 140 (3), 135 (85), 121 (12), 105 (49), 91 (23), 77 (21).

EXAMPLE 12: Synthesis of Compound 12V F N-3- Hydrochloride < 3 -met? Lfen? L) -I- rop? L- (R) -3-rnetox i - < y-.10 inetiibencí lamina The compound was prepared following the procedure described in Example 1, but using 2- rnetilcmnainonitplo. The MSaturated intermediate had an individual component by GC / E1 -MS (Rt-JO. 1 rnin) rn / z (Int.R.) 281 (11+, 57), 266 (85), 146 (98), 135 (88), 131 (100), J15 (43), 102 (26), 01 (43), 77 f 18). The reduction of This material and the formation of hydrochloride using the procedure described in Example 11 produced the product. GC / EI-MS (Rt - 9.18 inm) of this material (free base) showed a single component; rn / z (int. re.) 283 (M «-, 19), 268 (100), 164 (11), 148 (8), 135 (76), 121 (16), 105 (45), 91 ( 23), 71 (21).

EXAMPLE 13 Synthesis of compound 12Z N-3- (2-chloro fem 1) -1 - PI? PI! - (R) - i - (l-na ii) - eti l a na The compound was prepared following the procedures described in example 11, but using 2-chlorohydrocinarnom trilo and (R) - (* •) - L - (1 -nafti lo) et? La na na on a scale of 10 mmoles. Chromatography through silica Using a gradient of dichloromethane to 5% methanol in dichloromethane, the product was given as a single component by thin layer chromatography analysis (5% methanol in dichloromethane I. The hydrochloride was propagated by titration with 1 M HCl in diethyl ether. 1 ico 15 EXAMPLE 14 Synthesis of Compound 14U C orhydrate e (R) -M- (1-methoxyf iDeta j) - (R) -l-tine f 111) et ij arn j na 20 An inezda of ( R) - (+) - l - (1 -nt iDetila ina (Jl y, 6.2 inmoles) 4 '-rnetox lacetophenone (0.93 g, 6.2 rnrnoles), isopropoxide of titanium (IV) (2.2 g, 7.7 immoles), and E "* 01-1 (abs.) (1 inL), was heated at 60 ° C for 3 hours, then sodium cyanoborohydride (NaCNDHs) (0.39 g, 6.2 mmol) was added, and the reaction mixture was heated. The mixture was stirred at room temperature for 10 hours.Ether (200 mL) and HO (2 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation.The crude supernatant was evaporated or evaporated and the crude product was evaporated. chromatography on silica gel (column 25 mrn X 25 crn) (elution with MeOH / 1% CHC 3). A portion of this material is cured by high-performance liquid chromatography [Select osa! ] silica gel at 5 μh; 25 c x 10.0 rn (Phenornenex, Torrance, Cfl), 4 rnrn by immuto; det. of UV 275 nM 12% ethyl acetate-38% hexane (elution time 12.0 minutes)]. The diastereoinero purified by The chromatography of high-performance liquids was then dissolved in hexanes and ethereal HCl was added to precipitate the product as a white solid (20 mg), m.p. 209-210 ° C (dec.).

EXAMPLE 15 15 Synthesis of compound 17M Clorh dr to M- (3-chloro-4-rnet or benzyl) - (R) -1 - (ln t 11) eta l mine A mixture of (R) - («•) -1 - (1-naft? I) -et Ln ina (6.6 g, 39 rnrnoles), 3 '-chloro-4' -rnetoxybenzaldehyde (6.5 g, 39 rnrols), was heated at 80 ° C for 30 minutes and then allowed to stir at room temperature for 3 hours. After adding sodium cyanoborohydride (N CNDHs) (2.45 g, 39 rnrnoles) the reaction mixture was stirred at room temperature for 18 hours. Ether and H20 (2 rnL) were added to the reaction mixture and 95 the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was crushed on silica gel (column 50 rnrn for 30 a) (elution with CH2Cl2) - The chromatographed material was then dissolved in hexane (500 inL), decolor with filtered Nopt.RTM. (0.2 JJM), and then ethereal HCl was added to precipitate the co product or a white solid (10.2 g, 56% yield, mp 241-242 ° C (dec.) EXAMPLE 16 Synthesis of compound 17P 10 4 -Metox? -3-rnet? Jacetophenone C17P Precursor! A mixture of 4 '-ha droxi -3' -met Jaceto fenona (5.0 g, 33.3 rnmoles), yodomeme (5.7 g, 40.0 immoles), K2CO3 (granulated, anhydrous) (23.0 g, 167 immoles), and acetone (250 rnl) was refluxed for 3 hours. The reaction mixture is After cooling to room temperature, it was filtered to remove the inorganic salts and evaporated under vacuum. The crude product was dissolved in ether (100 ml) and washed with H2O (2 x 20 ml). The organic layer was dried (Na2 0") and evaporated to give 4.5 g, yield of 82.4%. The ketone was used in the following reaction without further purification.

(R) -N- (l- -Meto-3-met-3-phenyl-11-f-R) -l- (1-naphthyl) et? Larn? Na (Compound 17P) odor hydrate A mixture of () - (»-) -1- (1 -riafil) et? Iam? na (4.24 g, R 24.3 immoles), 4 '-rnetox? -3' -rnethyl acetone phenone (4.06 g, 24.8 nrnols), and isopropoxide titanium (IV) (8.8 g, JO., 9 rnrnols) , and EtOH (abs.) (IrnL) was heated at 100 ° C for 2 hours. Isopropanol (45 ml) was added and the reaction mixture was then cooled to 10 ° C in an ice bath. Then sodium NaHB (02CCH3) 3) (10.5 g, 49.5 mrnol) was added in portions over 15 minutes. The reaction mixture was then added at 70 ° C for 18 hours. The mixture was cooled to room temperature and emptied in ter (400 μl) "The suspension was centrifuged, the supernatant was collected and the pellet • < z? wash with ether (400 i). The combined organic washes IT evaporated under vacuum. The residue was dissolved in ether (400 rnl) and washed with NaOH at 1N (4 x 50 rnl) and H 2 O (2 x 50 inL). The organic layer was dried (Na2c-C), filtered and evaporated or evaporated. EtOH (abs.) Was added to the wet residue which was then dried uniformly in a rotary evaporator to provide a oil. The mixture was then c grated on silica gel (50 rnrn x 30 cin) [elution with (1% MeOH IPfl.CHCl al)%) to give 4.8 g of an oil]. The desired d-astereoinoro was then purified by high performance liquid chromatography [SUPELCOSIL ™ PLC-S? M, silica gel at 18 ul; 25 minutes; UV det 275 nM: 20% Et? P.c-00% hexane (elution time 9.5-11.0? mn) J. Injections (aliquots of 800 JJL) of the mixture (100 rng / rnl of solution in eluent) -65 ing of the desired isomer. Multiple injections of chromatographic material by CLAR gave 95 1.0 g, of purified material. The material cronagrated by CLfiR was dissolved in hexane (50 nmol) and the hydrochloride salt was precipitated with ethereal HCL. The salt was collected on filtered glass and washed with hexane to give 1.0 g of a white solid, m.p. 204-205 ° C.

EXAMPLE 17 Synthesis of compound 17X 3-chloro-4-met oxybenzaldehyde A mixture of 3-chloro-4-ha droxibenzaLdohido (25 y, 160 mrnoles), iodo-ethane (27.25 g, 192 rnrols), K2CO3 (granulated, anhydrous) (110.6 g, 800 min), and acetone (300 nl), was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. Ter-di-thiic acid (500 ml) was added and the mixture was filtered through paper to remove the inorganic solids. The filtered product is The mixture was poured under reduced pressure, dissolved in diethyl ether (800 ml), and washed with 0.1 N NaOH (3 <100 in. L), the organic layer was dried (Na.sub.2 O.sub.4) and evaporated or evaporated. for dr 24 °, 92% yield of crude product. This material was then purified by chromatography on silica gel (50 rnrn x 30 crn) (elution with hexane-EtOfic, 5r.l) to give 15.02 y, yield of 56% of a white solid: thin-film chroma togra (hexane -EtOfic, 5: 1) Rf- = 0.24; GC Rt- = 4.75 min; MS (El) rn / z J79Ü1 +), 172 (M + 2). Alcohol 1-rnet j - (3 '-chloro-4' -rnetoxybenzyl) 5 A mixture of 3-chloro-methoxy benzaldehyde (13 g, 76.5 mol), inethyl mercury chloride (52 g, 153 rnmoles), and THF ( 300 J) was refluxed for 3 hours. The reaction mixture was cooled to room temperature. NH4Cl (normal solution 6 rnl) was added dropwise followed by di ethyl ether (500 mL) and the mixture was filtered through a soft paper to remove the inorganic solids. The filtrate was evaporated under reduced pressure and the resulting solid was dissolved in diethyl ether (300 mL) and washed with water (4 x 25 mL). The organic layer was dried (Na2?) And evaporated under vacuum to give 11.3 F y, 80% yield of crude product. This material is then purified by chromatography on silica gel (50 rn x 30 cn) (elution with CH2Cl2) to give Ll.3 g, 63% yield of an oil; TLC (CH2CL2) Rf0.25; GC Rt) 5.30 rnin; MS (El) rn / z 186 (M +), 188 (M + 2). 3"-Chloro-4-rnetoxyacetophenone 15 A mixture of l-ethyl- (3'-chloro-4'-met oxybenzyl alcohol), pyrazinium chlorocrornate (7.0 g, 1 rnmoJes) (PCC) (13.15 G, 61.5 nrnol ), and CH2Cl3 (300 mL) was stirred at room temperature for 2 hours, diethyl ether (1000 mL) was added and the resulting mixture was placed on a column. 2 chromatographic silica gel (50 r n x 30 crn) (elution with diethyl ether) to give 7.3 g, yield of 97% crude solid product. The gas chromatography analysis of this rnost.ro material was 99% pure and was used in the next reaction without further purification. Coat chromatography thin (ter-diethyl) TLC Rf = 1.0; GC Rt = 5.3 rnin; MS (El) m / z 184 (M +), 184 (M + 2).

(R, m -N- (l -E11 -4 '-metox i -3' -coro phen 1) -1 - < 1 -na ft ai et11) a ina A mixture of 1'-chloro-4 '- etoxyacetophenone (5.3 g, 29 rnmoles), (R) - (+) - J - (1-naphthyl) et? lam? na (4.98 g, 29 immoles), and titanium (IV) sopropoxide (10.2 g, 36 immoles) ), and isopropanol (20 rnL) was heated at 100 ° C for 3 hours. Sodium tapacethoxy borohydride (NB (? 2CH3) 3; 12.29 g, 58 mmol) was added in portions over 10 minutes. The reaction mixture was heated to freeze for 30 minutes and then - :, e left "ngitar a • room temperature for 18 hours. The mixture is then vacuum in ethyl ether (500 rnL); H2O (2 inL) was added and the suspension was centrifuged to remove the fine precipitate of titanium salts. The supernatant was collected and the pellets were washed with ether (500 mL). The organic layers exchanged were dried (Na?) And evaporated under vacuum to give 6.81 g, 70% of production or crude. This material was then purified by chromatography on silica gel (50 mm x 30 crn) (elution with 3% MeOH-97% CH2Cl) to give 2.01 and an oil, then the oil was purified by re-talarization. . The labre base (1.98 g) was converted to its HCL salt with ethereal HCL. This salt was dissolved in hot isopropanol (65 rnL) and the solution was filtered through paper. The filtrate was evaporated or evaporated and the resulting solid was dissolved in isopropanol (30 rnL). After standing at room temperature for 10 hours 95 hours, the crystalline solid was collected, washed with cold isopropanol (20rnL), and dried to give 0.87 g, 40% (free base) of the diasterorne pure hydrochloride salt; GF 236-237 ¿c (dec); thin layer chromatography (MeOH-CH2Cl2 (99: D) Rf = 0.25; GC Rt = 11.06 rnin; FTIR (KBr pillary, crn) 3433, 2950, 2931, 2853, 2803, 2559, 2508, 2497, 1604 , 1595, 1504, 1461, 1444, 1268, 1260, 1067, 1021, 802, 721, 733; MS (El) m / z 339 (M), 341 (M + 2).

EXAMPLE 18 # Additional synthesis protocol PREPARATION OF 22 Z AND 23 ñ A stirred solution of sodium hydride (2173 g, 60% in oil, 54,325 mmol) in dimet ii forrnanide (100 nl) was treated dropwise with trie allophosphonoacetate (12.4 r "g, 55.65 mmol) and stirred 30 nm at room temperature and 30 ml at 100 ° C. The reaction was quenched by the addition of water and transferred to a separatory funnel using diethyl ether (500 ml). The ether solution was washed with saturated ammonium chloride (4 x 500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give M-tp riororomethoxy ethyl cinnamate as an oil; rn / z (reí.? nt.) "250 (M, 19), 232 (16), 215 (100), 187 (21), JOJ (28). The ethyl ester in methane! (J00 ml) was reduced under 4,218 Kg / cm of hydrogen using a catalytic amount (10% in 95 pesos) of hydroxide do pal adio. After reduction (2 hr room temperature) the reaction was filtered and concentrated to give ethyl trifluorine oxyhydrocinarnate as an oil; in / z (int. re), 262 (M, 16), 217 (7), 188 (100), 175 (28), 103 (31), 91 (18), 77 (23). The saturated ethyl ester was hydrolyzed in a solution of ethanol-sodium hydroxide at 10M (1: 1) for 16 hours at room temperature. After this time the solution was acidified and the product was extracted into diethyl ether. The ether solution was dried over sulfate # Anhydrous magnesium and concentrated to give 10-fluoride hydrochloride acid as a screed; rn / z fried, int.) 234 (M, 46), 18 (100), 174 (55), 103 (27), 91 (12), 77 (17). The acid was stirred in excess thionyl chloride for 4 hr at room temperature. Excess thionyl chloride was evaporated under reduced pressure (100 ° C) to give chloride of M-t pfluorornetroxyhydrocinarnil as an oil. The product was used without further modification. A solution of nitrideneflorornet oxyhydrocinarne chloride (9.0 g, 29 mol) in tetrahydrofuran was cooled to -78 ° C and treated dropwise with a solution (13 ml of 3 M in tetrahydrofuran). ) of methylrnagnesium bromide (39 rnrnoles). The reaction was stirred 4 hr at -78 ° 0.8 hr at room temperature and quenched with diluted HCL. The reaction mixture was extracted with dietary Jico ether. The ether is dried over anhydrous magnesium sulfate, filtered and 9R concentrated to an oil. The reduction of this material through silica using a gradient of hexane to acetone gave 4- (3-tr? Fluorornetrox phenol) -2-butone as an oil; m / z (int rej.) 232 (M, 58), 217 (7), 189 (59), 175 (31), 103 (28), 43 (100). A solution of 4- (3-tri-fluoromethoxy-phenol) -2-butanone (2.32 g, 10 mol), (R) -l- (3-meter x fem-Dethylane (1.51 g, 10 mol), and titanium asopropoxide (IV) (3.55 g, 12.5 mmol) were stirred for 4 h at room temperature, then the reaction mixture was treated with a solution (10 ml of 1 M) of ethanolic sodium cyanoborohydride (10 rnrnoles) and stirred. for 16 hr at room temperature. The reaction was diluted with diethyl ether (50 ml) and treated with water (0.72 i, 40 min). After mixing uniformly, the solution was centrifuged and the ether layer was decanted and concentrated to an oily solid. The solid was suspended in diethyl ether, filter to tr-birds of 0.45 uM of CR PTFE Rcrodisc and concentrate to give a clear oil. L chromotogra f the repeated preparative thin layer using 5% ethanol in chloroform gave the 2 diestereeros, (S, R) -N ~ (4 - (3-tr? Rl uorerntox and phenyl) -2-but? L) - -1 - (3-rnetox? Phen? L) et? Lam? na, 22Z (m / z (reí.? nt ") 367 (M, 3), 352 (20), 232 (4), 178 (47), 135 (100), 105 (14), 01 (10), 77 (11) and (R, R) -N- (4- (3- tp forornet roxi feni 1? -2-but? l) - 1 - (3 rnetoxi feral) etnarn? na 23fi; in / z (re.mt.) 367 (M, 3) 352 (19), 232 ( 7), 178 (43), 135 (100), 105 (19), 91 (10),, '7 (11).

F; PREPARATION OF 22X AND 22Y In a similar manner, a molar-equal amount of 4- (3-tpfluorornetoxyphen 1) -2-butanone, (R) -1- (1-n-phthyl) ethylene and 1"25 equivalents of titanium isopropoxide (IV) ) were mixed and the irnine intermediate reduced with ethanol cyanoborhydide. The treatment and the repetitive preparative thin layer or graph using 5% methanol in chloroform gives # (S, R) -N- (4- (3-trif luorornetoxa phenyl) -2-but? L) -i - (! -naf t l) ethylaniline, 22X; rn / z (m.m. ") 387 (11.3), 372 (15), L98 (15), 176 (12), 155 (100), 128 (8), 115 (6), 109 (4) , 103 (5), 71 (8) and (R, R) -N- (4- (3-tpfl uorornetroxa phenyl) -2-but i) -j- (L-naphthyl) -ethylamine, 22Y; rn / z (int. re.) 387 (M, 2), 372 (12), 198 (16), 176 (11), 155 (100), 128 (8), 115 (6), 109 ('. ), 103 (5), 77 1 (8). 4T PREPARATION In a similar manner, an equal molar amount of 4- (2-chlorophene-1) -2-butanone, prepared by the o-chlorobenzaldehyde, (R) -1 (3-rnet oxypheni 1) et? Lam? na and L.25 equivalents of titanium (IV) isopropoxide were mixed and the irnine intermediate was reduced with ethanolic sodium cyanoborhydide. The ointment layer treatment and croinot Repetitive preparative 9R using 5% methanol in chloroform gave (R, R) -N- (4- (2-chlorof-eml) -2-but-1) -1 -O. e oxy feniDeta lamina, 4T; n / z (r * eJ int.) 317 (M, 3), 302 116), 178 (62), 178 (62), J35 (J00), 125 (15), 105 (10), 91 ( 6), 77 (8).

PREPARATION OF 21Y In a similar manner, an equal molar amount of 4- (3- tri-fluotornetii fem) -2-but-anona, prepared from m-tpf JorornetiJbezaldehyde, (R) -1 - (3-methox? Phenyl) et i laminate and # 1.25 equivalents of titanium dioxide (TV) were mixed LO and the intermediary medium was reduced with ethanolic sodium cyanoborohydride. Treatment and repetitive preparative thin layer chromotography using 5% rnetanol in chloroform gave (R,) -N- C 4 - (3-1 pf 1 uorornet il fn il) - 2 buti 11 - 1 - (3 -rnetox if eni 1) - etHarnina, 21Y Crn / z (int. re.) 351 (M, 2), 336 (18), 215 (4), 202 (3), 178 (45), 135 (100), 105 (3), 91 (9), 71 (0) and (S, R) - N-C4- (3 - 1 IL fluororne orne i fern L) -2but? L 7-1- (3 me tox i feml) et i amine, 2 IX.

PREPARATION OF 25C AND 25D 20 In a similar way, an equal molar amount of 4- (3-1p fluorornethephenyl) -2-butanon, (R) -1- (1 -na f111) and 11-amine and 1.25 equivalents of isoproxide of titanium (IV) were mixed and the irnine intermediate was reduced with sodium cyanoborhydide 95 ethanolic. Treatment and repetitive gada layer chromatography using 5% methanol in chloroform gave (S, R) -N-C4 ~ f3-tr'iiluorornet? I?) -2 -but? L] -i- (J -naphthyl) - etiiarnine, 25C Cm / z (int. Re.) 371 (M, 3), 360 (16), 198 (15), 155 (100), 129 (8), J15 (5), 109 (3), 77 (2) 3 and (R, R) -N- - (3- trifluorornet? Lfenal) -2 ~ but? I] -l- (l-naft iDethylarnine, 25D: m / z ( mt.) 371 (M, 3), 356 (16), 198 (15), 155 (100), 129 (0), 115 (5), 109 (3), 77 (2).

PREPARATION OF 21D 0 In a similar manner, an equal molar amount of 4-phenyl-2-butanone (Aldrich Chemical Co.), (R) -l- (3-rmethoxyphenyl) ethylene, and 1.25 equivalent of isopropoxide do titanium (IV ) were mixed and the imine intermediate reduced with ethanolic sodium cyanoborhydide. The treatment and the 5 repetitive preparative thin layer crithotraphy using 5% methane in chloroform gave (R, R) -N- (- phena 1-2-but? L) -l- (3-rnetoxa femJ ) and ilarnine, 21D Cm / z (antiretro) 203 (M,), 268 (13), 178 (45), L35 (00), 105 (15), 91 (43), 77 (11)] and (S, R) - N- (4-pheny1-2-bu 111) -L- (3-rnetoxy-phena 1) e thiama na 21 E.

PREPARATION OF 21F In a similar manner, an equal molar amount of 4-fem-2-butanone (Aldrich Chemical Co.), (R) -l- (1--> naphthyl-Di-nate, and 1.25 molar equivalents of titanium (IV) isopropoxide were mixed and the irnine intermediate was reduced with cyanobo has ethanol zodiac.The treatment and the crotonotografia of repetitive preparative layer using 5% ethanol in chloroform gave (R, R) -n- (4-fem 1 -2 -but? i ) -i - (1 -na ftn) e ti lami a 21F; rn / z (real .mt) 303 (M, 6), 288 (14), 198 (22), 155 (100), (8), 115 (5), 91 (19), (77 (4).

PREPARATION OF 12Z A stirred solution of 2 -chlorohi drocinarnonitrile in dichloromethane (Aldpch Chemical Co., 1.66 g, Rnnols was cooled to -78 ° C and treated dropwise with diisobutyl-aluminum hydride (1.42 g, 10 rnmoles) .The reaction was stirred for one hour at room temperature. , cooled to -78 ° C and treated with a solution of 1 - (l -naftiDeta lamina (J..71 g, 10 rnrnols in dichlorornetane (25 rnl). The reaction was transferred to an ice bath and stirred for two hours. After this time, the reaction was emptied directly into a stirred solution of boric acid ethanol sodium boron (50 ml of 0.2 M, 10 rnrnoles). The mixture was stirred for 30 rnin. at temperature environment and the excess of sodium boride boride was extinguished by the addition of 10% HCl. The solution was then made basic by the addition of NaOH to ION and it was transferred to a separating enute by washing with diethyl ether (300 ml). The aqueous phase was removed and the remaining organic layer was washed with O: ?: NaOH at 1M (3-100) the organic layer was dried over anhydrous magnesium sulfate and concentrated to an oil. The croto-graze of this material through silicon gel using a gradient of chloroform to 10% methanol -chloro form gave 2.34 g. (72% yield) of (R) -N-C3 - (2-Chlorophene 1) propyl] - L - (1-naphthyl) etiiarnine, J2Z, as a clear oil; in / z (reJ. ant.) 323 (M +, 2), 308 (63), 288 (7), J96 (5), J84 (5), 155 (J00), 125 (24), 115 (8) , 103 (4), 91 (3), 77 (7).

PREPARATION OF 12B '# 10 In a similar case, the 4-? Net? L? Namonm t ril was treated with durumbutum hydride and the complex intermediary of alurninium-nnin was treated with (R) -1- (3 -metox? in? l) - ethylaniline. The intermediary is treated with sodium borohydride ethanol ico. The treatment and chromatography gave (R) ~ N-15 3- (4-rnet? I phene J) prop ~ 2-en? 1] - L- (3-rnetox a fena Deta lamina, 12 13, as a clear, colorless oil, m / z (int.r.) 281 (11- *, G), 626 (5), 176 (27) , 146 (75), 135 (63), 131 (100, LL5 (25), 105 (21), Ul (21),, 7 (21).

PREPARATION OF 12C In a similar way, the 2-nitronic acid was treated with aluminum diisobutyl chloride and the complex intermediate of aluminum-irin was treated with (R) -1- (3-nitethoxy) ) ethyl amine. The amine intermediate was treated with ethanolic sodium borohydride. Treatment and chromatography gave (R) ~ N- * C3- (2-ethyl phenyl) prop-2-enl3 -1- (3-methox? In? L) eta Lamin, 12 C, as a clear, colorless oil; rn / z (int. re.) 281 (M * -; 4), 626 (15), 176 (18), 145 (62), 135 (58), 131 (100), 115 (23), JOS ( 19), 91 (38), 77 (17).

PREPARATION OF 12D .aßs. In a similar way, the 2, 4, 6 -t prnet i Read narnonitp what was treated with daisobutj hydride lalurna nao and the intermediary The amino-imine complex was treated with (R) -i (3-rnetox-phenyl) etnainine. The irnina intermediary was treated with ethanolic sodium boride. Treatment and chromatography gave (R) -N-C3- (2, 4, 6-tr? Met? 1 phenyl) prop-2-ene 13-1- (3-methox? Phen?) - ethyl lamina, 12 D, as a clear, colorless oil; m / z (laugh. mt.) 309 (M <-, 8), 294 (25), 174 (82), 159 (100), 135 (52), 129 (129), 105 (21), 91 (17), 77 (14) PREPARATION OF 12E 20 In a similar way, the 4-isopropy Lea narnoni tra was treated with diisobutyl aluminum hydride and the complex intermediary of alurnimo-i ina was treated with (R) -1- (3-e -oxa feml) eti lamina. The intermediary irnina was treated with borhi druro de sodium ethanol ico. Rotation and chromatography gave (R) -N-9R ~ (2, 4-? Soprop? L phenyl) prop-2-ene-1- (3-methox? Phen? L) et i-amine, 12 E , as a clear colorless oil; rn / z (int. re.) 309 (M +, 9), 294 (7), 174 (98), 159 (22), 135 (80), 111 (100), 105 (30), 91 (37) , 77 (19).

PREPARATION OF 12F In a similar manner, 2,4-d? Rnet? Ic? Narnon? Tplo was treated with hydrous diisobutylurea and the complex intermediate of aluminum was treated with (R) -l- (3-? netoxif enyl) ethylamine. The amine intermediate was treated with borohydride Ethanol sodium. The treatment and chromatography gave (R) -M- C 3- (2, -dimethylphenal) prop-2 ~ in? L 3 -l- (3-methyl toxin phenethylamine, 12 F, as a clear oil colorless; rn / z (int. re.) 295 (M, 8), 249 (15), 174 (29), 150 (75), 145 (100), 135 (68), 117 (21), 105 ( 30), 91 (26), 77 (19) 15 PREPARATION OF 12G In a similar manner, the 3-? Net ilca narnone tplo was treated with aluminum dusobutii hydride and the complex intermediate of alurnmium-irnin was treated with (R) -1- (3-rnetox? Feni 1) eta Lamina. The irnine intermediary was treated with sodium ethanol borohydride. Treatment and chromatography gave (R) -N-C3- (4-rnet? Lfen? L) prop-2-eml3-l- (3-rnetoxy phenyl) and ilanoline, 12G, as a clear, colorless oil; m / z (int. re.) 281 (M «-, 5), 626 (9), 176 (24), TR1 146 (71), J35 (62), 131 (100), 115 (23), 105 (19), 91 (41), 77 (18) PREPARATION OF 25E In a similar manner, the cynarnamt was treated with diisobutylhydride and the complex intermediate of alurninium-inine was treated with (R) -i (3-rnethoxphenol) et? sheet . IE intermedia irnina was treated with ethanolic sodium borohydride. The treatment and chromatography gave (R) -M- (3-eny1) prop-2 ~ enii] -1- (-rnetoxyna1) et ij amine, 12%, as a clear, colorless oil; rn / z (int. re) 267 (M, 3), 252 (1), 176 U7), 135 0 (62), J17 (100), 105 (20), 91 (56), 77 (33) .

PREPARATION OF 25T In a similar manner, the L-N-N-nitrile of L5 was treated with diisobutyl hydride and the aluminum complex intermediate -irin with (R) -1 - (3-rnetox-fem) -ethalamin. The amana intermediary was treated with ethanolic sodium borohydride. The treatment and chromatography gave (R) -N- (3- (3-rnet? I fenal) prop -2-ena 1-1- (3-rnetox? Feni L) et? Lamina, 25G, 20 as an oil colorless clear; in / z (re., mt.) 281 ÍM », 5), 266 (18), 190 (12), 146 (78), 135 (82), 131 (100), 115 (21), 105 (21), 91 (62), 77 (19).

PREPARATION OF 5X 25 A stirred solution of sodium hydride (12.8 g, 75 rnnols) in dimethylforman t (L50rnl) was treated with a solution of diethylene glycine phosphonate (13.3 g, 75 mol) in dirnet and lophopranamide (50 l). The reaction was stirred for 30 min. at room temperature. After this time, the reaction was treated with 3-cJobenzene dheido (10.54 g, 75 rnrnoles) and stirred for one hour at room temperature and for 30 inin. at 50 ° C. The reaction was then quenched by the addition of water (200 i). The reaction mixture was transferred to a separatory funnel using ter dietii co (300 J) and the organic phase The resulting LO was washed with water (5 -300 mL) and brine. The organic layer was dried over anhydrous potassium carbonate and concentrated to give 3-cyclohexane? Tplo (11.06 g) as a solid. The solid was dissolved in tetrahydrofuran (50 ml) and treated with excess of diborane and stirred for 30 rnin. to 1 room temperature The reaction was drained over ice / 10% HCl. The aqueous acid phase was washed with diethyl ether (2-200 rnL). The aqueous phase was made basic by adding NaOH to LON and extracted with diethyl ether (200 i). The ether extract was dried over anhydrous potassium carbonate and concentrated to give 3- (3-chloro phenyl) propylamine as an oil (0.6 g, 3.54 mrnol). The 3- (3-chlorophenyl) propane sheet (0.60 g, 3.54 millimoles), 3'-rnetoxy acetophenone (0.53 g, 3.54 mrnoles) and 1.25 molar equivalents of titanium (IV) isopropoxide (1.26 g, 4.43 mol) are they were stirred for 4 hours at room temperature K and the irnine intermediate was treated with a sodium cyanoborohydride ethanol (5 rnl IM, 5 mmol). The reaction was stirred for 16 hours at room temperature, diluted with diethyl ether (50 mL) and water (0.32 mL, 17.7 mmol). After mixing uniformly, the solution was centrifuged and the ether layer was concentrated to a milky solid. This material was suspended in diethyl ether and filtered through 0.45 JJM of CR PTFE Acrodisc. The ether wash was concentrated to an oil. The croto-graph of this material (silica, crornotograf the preparative thin layer) using 3% ethanol - dichloromethane (containing isopropylamine 0.1% LO) gave N-C3- (3-chlorophen? L) propa 13-1- (3-rnetox? Phen? 1) -ethylarnma, 6X; rn / z (rel.int.) 303 (M +, 3), 288 (40), 196 (3), 164 (8), 135 (100), 125 (46), 103 (26), 91 (29) , 77 (29).

PREPARATION OF 6V 15 An equal molar amount of 3- (4-chlorophonyl) -propyl sheet (prepared in a manner similar to 4-chloro benzal, as before) '-netoxacete phenone and L.25 equivalents Molar lenses of titanium isopropoxide (IV) were mixed for 4 hrs at room temperature and the irnine intermediate was treated with sodium ethanoic cyanoborohydride (5 ml of 1M, 5 mole). The treatment and chromatography gave N-T3- (4-chlorophenyl) etamine, dV, as a -site m / z (int. Re.) 303 (M «-, B), 288 (91), J96), J64 (LO), J35 (100), 125 (61), 103 (21), 11 (18).

PREPARATION OF 20A In a similar manner, an equal molar amount of L- (l-rnetoxifoml) ethylamine, 4-t-butyiacete phenone and 1.25 molar equivalents of titanium (IV) opropoxide were mixed for 4 hrs at room temperature and the intermediary irnma was treated with sodium cyanoborhide sodium ethane (5 ml Je 1M, b immoles). The work-up and chromatography gave (R) -M-f l- (4-t-butylphenyl) et? L-l- (1-naphthyl) and Llama na, 20A, as an oil; rn / z (ant. laugh) 331 (M +, 12), 316 (29), 161 (70), 155 (100), 131 (14), 127 (13), 115 (10), 105 (6), 91 (10), 77 (7).

PREPARATION OF 25H AND 251 In a way Lnr, an equal molar quantity of (R) -L- (3-rnetox? Feml) et? lamin, rans-4-phena 1 -3-butan-2-one and 1.25 equavalent molars of titanium isopropoxide (TV) were mixed for 4 hrs at room temperature and the intermediary imana was treated with m-cyanoborhydrate or sodium ethanol (5 rnl of 1M, 5 immoles), The treatment and crotch or graph gave (R, R) -N- (2-rnet? L ~ 4 ~ fembut-3- eml) -J- (3-methoxyphenite Deta lamina, 25H , as? n oil rn / z (int. re.) 203 (M < -, 4), 258 (13), 178 (40), 135 (100), 105 (15), 91 (47), 77 (13) and (S, R) -N- (2-rnet? L-4-fenabut-3-emJ) -1- (3-ethoxifem) and the ina, 251, as an oil m / z (re. ant.) 283 (11 +, $), 258 (13), 170 (40), 135 (100), 105 (15), 91 (47), 77 (13) " PREPARATION OF 16L AND 16M In a similar manner, an equal molar amount of (R) -1- (3-rnetoxyphenyl) etamine, 3-ethoxyacetophenone and 1.25 molar equivalents of titanium isopropoxide (TV) is # mixed for 4 hrs at room temperature and the intermediate media was treated with sodium cyanoborhydride (5 nl of 1 M, 5 mol). The treatment and crust ogr f gave it (R, R) -N - C1- (4 ~? Netox? Feni 1) et lam? na, 16L, as an oil rn / z (m.mt.) 284 (Ml, 1), 270 (85), 150 (83), 135 (100), 120 (12), 105 (28), 91 ( 25), 77 (23) and (S, R) - J5 -N-C1-Í4- et oxy phenylDeta 1] -l- (3- rnetoxifem) ethylanana, 16M, as an oil rn / z (re. ) 284 (ML, 1), 270 (53), 150 198), J35 (100), 120 (11), 105 (33), 91 (25), 77 (23).

PREPARATION OF 5B / 5C 20 In a way, was 4 -c Loroaceto fenona used to prepare 3-rnet? 1 -3- (-chlorophenyl) c-naneditrile. The nitroplo was reduced catalytically (palladium hydroxide), acetic acid, 4.218 I g / cm2 of hydrogen for 2 hrs.) To generate metLl-3-9 (4-chlorophen? 1) prop? Larn? na An equal molar amount of the amine 3'-nitroethoxy enone and 1.25 molar equivalents of titanium (IV) ropoxide were mixed during hr at room temperature and the inthenethiapne imana was treated with a sodium cyanoborohydride ethanol co (5 mL of LM). , 5 mrnoles). The treatment and blotting yielded N- (3-rnet? L-3 - (4-chloropheniDropy L3-1 - (3-methox? F enyl) et? Lamina, 5B /% C as an oil rn / z ( int.) 317 (M +, 12), 135 (LOO), 121 (25), 103 (40), 91 (19), 77 (28).

# PREPARATION OF 4Z / 5A LO Similarly, 3-chloroacetofenone was used to prepare 3-rnetii -3- (3 ~ chlorophen 1) c arnoni tplo. The mixture was catalytically reduced (palladium hydroxide, acetic acid, 4,218 k / crn 2 hydrogen for 2 hours) to generate 3-15 rnet? I-3- (3-chloro-phena L) propane a na. An equal molar amount of amine, 3'-methoxyacetophenone and 1.25 molar equivalents of titanium (IV) isopropoxide were mixed for 4 hours at room temperature and the intermediate was inactivated with sodium cyanoborohydride ethanolac (5 ml of 1 M, 5 immoral). He treatment and crnotole raa gave N-C 3 -meta 1 - 3 - (3- c lorofemJ) ?? * o ?? l3-l- (3-rnetox? Feml) et Lamina, 4Z / 5A, as an ace ite; m / z (re., mt.) 283 (M +, 17), 268 (71), 164 (13), 135 100), 121 (21), 105 (27), 91 (26), 77 (14).

'PREPARATION OF 4Y In a similar manner, 2-chloroacetophenone was used to prepare 3-rnet? L -3-l-chloro-fem L) cynaronitone. The nitroplo was catalytically reduced (palladium hydroxide, here acetic, 4,218 kg per crn2 of hydrogen for 2 hours) to generate * 3-? Net? I ~ 3- (2-chlor * ofenal) propylarnin. An equal molar amount of the amine, 3'-β-nitroxycetophenone and 1.25 equivalent equivalents of titanium isopropoxide (IV) were mixed for 4 hours at The ambient temperature and the urea intermediate were treated with sodium ethanoic cyanoborohydride (5 ml of 1 M. 5 mmol). The treatment and chromatography gave N-C3-rnet? L-3- (2-chlorophenyl) pro? 3- l- (3-? Netox? Phenyl) et? Iamma, 4Y, as an oil rn / z (re., ant.) 283 (M +, 17) 268 (71), 154 (13), 135 (100), 121 (21), 105 (27), 91 (26), 77 (14).

PREPARATION OF 5T A solution of NPS R-568 (30.3 g 100 immoles) on dichloro-methane at -78 ° C was treated dropwise with < boron ribrornide (50 g, 300 immoles). The reaction was stirred for one hour at room temperature and emptied on ice. The hydrobromide was extracted from the aqueous phase with chlorine form. The soluble chloroform components were then washed (4 x 100) with IIC1 at 9 50%. In the chloroform bath, it was dried over anhydrous magnesium sulfate and concentrated to give hydrochloride of (R) -N ~ C3- (2-11! chlorophenyl) propyl -1- (-h? drox phenyl) et? lam? na as an odor. A solution of sodium hydride or (0.48 g, 20 rnrols) in dirne iiforrnarnide was treated with hydrochloride of (R) -I-1-C3- (2-chloropheniDpropyl 3-1- (3-ha droxyphenyl) et? Lamina ( 3.25 g, 10 rnnols) and the reaction was stirred for one hour at room temperature, the reaction was treated with iodoethane (1.71 g, 11 rnnols) and stirred for 16 hours at room temperature. through:, using 3% ethanol in chloroform gave (R) -N-C3- (2-chlorophen? 1) prop? l 3- 10 l - (3-ethoxy? phen? l) et? larn? na, 6T c?, p in oil rn / z (re. i nt.) 316 (M +, 1), 302 (100), 282 (11), 196 (5), 178 (7), 149 ( 74), 121 (34), 103 (25, 91 (28), 77 (29).

PREPARATION OF BR 15 NPS R-467 was used in a similar manner to prepare (R) -N- (3- fempropa 1) -1- (3-ethoxa phenyl) et? Larna na, 6R, as an oil; m / z (re., ant.J 283 (M +, LÚ), 268 (74), 178 'ID, 162 (8), 149 (100), 121 (30), 103 (16), 91 (86), 77 (29) .20 PREPARATION OF 3U An equal molar mixture of 3, 3-d? O fem Lpropí lamina (2.11 g, 10 immoles), and 1.25 equivalents of isopropoxide of 9R titanium (IV) (3.55 g, 12.5, rnrnoles were stirred for 4 hours at room temperature.) The reaction mixture was then treated with an LM solution of ethanolic sodium cyanoborohydride (12.5 ml, 12.5 min) and stirred for After 16 hours at room temperature, the reaction was diluted with diethyl ether (50 ml) and treated with water (0.72 ml, 40 mmol) After mixing, the mixture was centrifuged and the ether layer was concentrated and decontaminated. The oil was suspended in diethyl ether and filtered through 0.45 jaM of CR PTFE Acroda C. The filtered product of diethyl ether was concentrated to give N- (3, -di phenol? rop). ? .1) -1 - (L- afil) etiRanma, 3U, as a chlorine oil chlorine rn / z (rel.int.) 365 (M +, 17), 350 (19), 181 (23), 155 (100), 141 (25), 115 (11) , 91 (13), 77 (6).

PREPARATION OF 6F 15 In a long way, molar amounts i guaj s ié * L- (3-rnetoxy feniDet ilarnina (1.51 g, 10 rnrnoles), 2 '-acetone ftona (1.70 g, 10 immoles) and 1.25 equivalents of isopropoxado do titanio (IV) (3.55 g, 12.5 mmoles) treated the same as In the treatment, it gave N-Cl - (2 -naphthyl) et? l] -1-? 3-? nexaxa re i 1) - ethiiamma, 6F, as a clear, colorless oil; rn / z 'laugh ? nt ") 305 (M +, 1), 290 (35), 170 (49), 155 (100), 135 (55), 115 (8), 105 (10), 91 (9), 77 (10) . 4T PREPARATION In a similar manner, equal molar amounts of (R)) - 1-pheni le ti lamina, 1 '-aceton Tona and 1.25 equivalents of titanium (IV) isopropoxide were mixed and the resulting amine intermediate was reduced with sodium cyanoborohydride. ethanolic Tentatively and chromatographically, N-Cl-fl-naphthyl) et? L) -l-fomethylaniline, 46, as a clear oil, chlorine; rn / z (mt. re.) 275 (M +, 16), 260 (79), 155 (LOO), J27 (27), 105 (70), 77 (32).

PREPARATION OF 4H In a similar manner, equal molar quantities of 15 (R)) -l-phen? Let? Iarnma, 2'-acetonefona and 1.25 equivalents of io pro poxido titanium (IV) were mixed and the amine resulting was reduced with sodium cyanoborohydride ethanol ico. The treatment and chromatography gave N-C 1 -I - naphthyl) H 2 - phenylethyl a, 4H, with a clear oil, 20-chloro; rn / z (re. t.) 275 (M->, 1), 260 (51), 155 (100), 120 (36), 105 (55), 77 (15).

PREPARATION OF 6E In a similar manner, equal molar amounts of l- (3-rnetoxy-fondi-Detiiarnine, 1'-acetonaphthone and 1.25 equivalents of titanium (IV) isopropoxide were mixed and the resulting amine intermediate was reduced with ethanolic sodium cyanoborohydride. chromatography gave N ~ l- (1-naphthyl) et? l) - (3-nitroxyphene Dethylarnine, 6E, co or a clear oil, inc., in / z (re., nt ") 305 (M +, LO), 290 (30), L70 (43), 155 (100), 135 (69), 115 (9) 105 (15), 91 (14), 77 (18).

EXAMPLE 19 Pharmaceutical formulation. The preparation of a suitable pharmaceutical formulation for administering a calcimetic compound in a human patient is shown in Table 3.

TABLE 3 Ingredient rng / capsule g / lot representative of 5 il capsules NPS R-568 56.0 280.0 20 Pregela starch- 134.0 670.0 NF tincture inicrocps cellulose- 34.0 170.0 talin NF Silicon dioxide 1.0 5.0 colloidal K Total 225 rng 1125 g Other examples of NPS (R) -568 hydrochloride formulations and dosage forms include those suitable for sustained or extended release, using standard techniques. The proper dosage can also be carried out using normal techniques. For example, in a series of experiments, oral doses of 10-400 rnl of NPS (R) ~ 568 hydrochloride showed pharmacological activity in human subjects. Significant levels of the conjugate of 0-glucoromide of 17 0 a major rnetabolite of NPS (R) -5G8, was observed < > n Human plasma after oral administration of NPS hydrochloride (RJ-568) Thus, the glucoromide conjugate of 170 may be exerting some beneficial effect.Using normal techniques, close doses of appropriate doses for NPS (R) -560 can be determined. formulations and dosage forms for other compounds that are described here also can be determined by an expert in the technique based < * 9 | r in the teachings provided in the application. Other embodiments are within the following claims. Therefore, although they have been shown and As described in some embodiments, various modifications can be made without departing from the spirit and scope of the present invention.

LIST OF SEQUENCES 1 GENERAL INFORMATION: (i) APPLICANT NPS Pharnaceut t cal, INC., D) T OLE OF THE INVENTION: Active compounds for calcium r-eceptor. (Ül) SEQUENCE NUMBER: 2 (iv) CORRESPONDENCE DTRECTION: (A) RECIPIENT: Lyon & Lyon lü (B) STREET: First Interstate World Center, ui e 4700 633 West Pofth Street CITY: Los Angeles TADO: Cali form 15 (F) POSTAL CODE: 90017 (v) COMPUTER LEADABLE FORM: (A) TYPE OF MEDIUM: 3.5-inch disl-ette, 1.44 Mb of memory capacity 20 (B) COMPUTER: IBM PC compatible (OR OPERATING SYSTEM: PC-DOS / MS-DOS ( D) SOFTWARE :: Fast eq (vi) CURRENT DATA OF THE APPLICATION: (A) NUMBER OF APPLICATIONS: (B) PRESENTATION KEY: (OR CLASSIFICATION: (vile) PREVIOUS DATA OF THE SOLICITATION: Total of previous applications, including request described below: 2 30 (A) APPLICATION NUMBER: USA 08 / 353,704 (B) SUBMISSION DATE: December 8, 1994 (A) APPLICATION NUMBER: PCT / USA / / l 2117 (B) DATE OF SUBMISSION : October 21, 1994. 35 (vm) EMPLOYEE / AGENTF INFORMATION: (A) NAME: Heber, Sheldon 0. (B) REGISTRATION NUMBER: 38,179 (C) REFERENCE NUMBER / CASE: 215/304 (ix) TELECOMMUNICATIONS INFORMATION (A) TELEPHONE: (213) 489-1500 (B) TELEFAX: (213) 55-0440 (C) TELEX: 67-3510 (2) INFORMATION FOR IDENTIFICATION OF SEQUENCE NO .: 1¡ (I) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5006 base pairs 10 (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (II) TYPE OF MOLECULE: cDNA to rRNA (? ?) CHARACTERISTICS: (A) NAME / KEY: CDS (B) UBICACLON: 36 ... 3699 (D) OTHER INFORMATION: (xi) SEQUENCE DESCRIPTION: IDENTIFICATION OF SEQUENCE: 1: GCTGCTGTGG CCGGACCCGA AGGCGGGCGC CGGGAGCGCA 40 GCGAGCCAGA CGCGCCTCTC CAAGACCGTG ACCTTGGCAT 80 AGGGAGCGGG GCTGCGCGCA GTCCTGAGAT CAGACCAGAG 120 CTCATCCTCG TGGAGACCCA CGGCCGAGGG GCCGGAGCTG 160 CCTCTGTGCG AGGGAGCCCT GGCCGCGGCG CAGAAGGCAT 200 CACAGGAGGC CTCTGCATGA TGTGGCTTCC AAAGACTCAA 240 GGACCACCCA CATTACAAGT CTGGATTGAG GAAGGCAGAA 280 ATGGAGATTC AAACACCACG TCTTCTATTA TTTTATTAAT 320 CAATCTGTAG ACATGTGTCC CCACTGCAGG GAGTGAACTG 360 CTCCAAGGGA GAAACTTCTG GGAGCCTCCA AACTCCTAGC 400 TGTCTCATCC CTTGCCCTGG AGAGACGGCA GAACC 435 ATG GCA TTT TAT AGC TGC TGC TGG GTC CTC TTG GCA 471 Met Wing Phe Tyr Ser Cys Cys Tro Val Leu Leu Ala 1 5 * 10 CGA GCC CAA AAG AAG GGG GAC ATT ATC CTT GGG GGG 543 Arg Wing Gln Lys Lys Gly Asp He He Leu Gly Gly 25 30 35 CTC TTT CCT ATT CAT GGA GTA GCA GCT AAA GAT 579 Leu Phe Pro He His Phe Gly Val Wing Wing Lys Asp 40 45 CAA GAT CTC AAA TCA AGG CCG GAG TCT GTG GAA TGT 615 Gln ASD Leu Lys Ser Arg Pro Glu Ser Val Glu Cys 50 55 60 ATC AGG TAT AAT TTC CGT GGG TTT CGC TGG TTA CAG 651 Leu Gln GCT ATG ATA TTT GCC ATA GAG GAG ATA AG AGC 687 Ala Met lie Phe Ala He Glu Glu He Asn Ser Ser 75 80 CCA GCC CTT CTT CCC AAC 1U ACG CTG GGA TAC AGG 723 Pro Ala Leu Pro Asn Leu Thr Leu Gly Tyr Arg 85 90 95 ATA TTT GAC ACT TGC AAC ACC GTT CT AAG GCC TTG 759 lie Phe Asp Thr Cys Asn Thr Val Ser Lys Ala Leu 100 105 GAA GCC ACC CTG AGT TT GTT GCT CAA AAC AAA ATT 795 Glu Wing Thr Leu Ser Phe Val Wing Gln Asn Lys He 110 115 120 GAT TCT TTG AAC CTT GAT GAG TTC TGC AAC TGC TCA 831 Asp Ser Leu Asn Leu Asp Glu Phe Cys Asn Cys Ser 125 130 GAG CAC ATT CCC TCT ACG ATT GCT GTG GTG GGA GCA 867 Glu His lie Pro Ser Thr He Wing Val Val Gly Wing 135 140 ACT GGC TCA GGC GTC TCC ACG GCA GTG GCA AAT CTG 903 Thr Gly Ser Gly Val Ser Thr Ala Val Wing Asn Leu 145 150 155 CTG GGG CTC TTC TAC ATT CCC CAG GTC AGT TAT GCC 939 Leu Gly Leu Phe Tyr He Pro Gln Val Ser Tyr Wing 160 165 TCC TCC AGC AGA CTC CTC AGC AAC AAG AAT CAA TTC 975 Ser Ser Ser Arg Leu Leu Ser Asn Lys Asn Gln Phe 170 175 180 GAG CAC 1011 Glu His CAG GCC ACT GCC ATG GCA GAC ATC ATC GAG TAT TTC 1047 Gln Ala Thr Ala Met Wing Asp He He Glu Tyr Phe 195 200 CGC TGG AAC TGG GTG GGC ACA ATT GCA GCT GAT GAC 1083 Arg Trp Asn Tro Val Gly Thr He Ala Wing Asp ASD 205"210 215 GAC TAT GGG CGG CCG GGG ATT GAG AAA TTC CGA GAG 1119 Asp Tyr Gly Arg Pro Gly He Glu Lys Phe Arg Glu 220 225 1155 GAA CTC ATC TCC CAG TAC TCT GAT GAG GAA GAG ATC 1191 Glu Leu He Ser Gln Tyr Ser Asp Glu Glu Glu He 245 250 CAG CAT GTG GTA GTG ATT CAA AAT TCC ACG GCC 1227 Gln His Val Val Glu Val He Gln Asn Ser Thr Ala 255 260 AAA GTC ATC GTG GTT TTC TCC AGT GGC CCA GAT CTT 1263 Lys Val He Val Val Phe Ser Ser Gly Pro Asp Leu 265 270 275 GAG CCC CTC ATC AAG GAG ATT GTC CGG CGC AAT ATC 1299 Glu Pro Leu He Lys Glu He Val Arg Arg Asn He 280 285 ACG GGC AAG TC TGG CTG GCC AGC GAG GCC TGG GCC 1335 Thr Gly Lys He Trp Leu Wing Ser Glu Wing Trp Wing 290 295 300 AGC TCC TCC CTG ATC GCC ATG CCT CAG TAC TTC CAC 1371 Ser Ser Leu He Wing Met Pro Gln Tyr Phe His 305 310 GTG GTT GGC GGC ACC ATT GGA TTC GCT CTG AAG GCT 1407 Val Val Gly Gly Thr He Gly Phe Wing Leu Lys Wing 315 320 GGG CAG ATC CCA GGC TTC CGG GAA TTC CTG AAG AAG 1443 Gly Gln He Pro Gly Phe Arg Glu Phe Leu Lys Lys 325 330 335 GTC CAT CCC AGG AAG TCT GTC CAC AAT GGT TTT GCC 1479 Val His Pro Arg Lys Ser Val His Asn Gly Phe Wing 340 345 1515 CAA GAA GGT GCA AAA GGA CCT TTA CCT GTG GAC ACC 1551 Gln Glu Gly Ala Lys Gly Pro Leu Pro Val Asp Thr 365 370 TTT CTG AGA GGT CAC GAA GAA AGT GGC GAC AGG TTT 1587 Phe Leu Arg Gly His Glu Glu Ser Gly Asp Arg Phe 375 380 AGC AAC AGC TCG ACA GCC TTC CGA CCC CTC TGT ACA 1623 Ser Asn Ser Ser Thr Wing Phe Arg Pro Leu Cys Thr 385 390 395 GGG GAT GAC AAC ATC AGC AGT GTC GAG ACC CCT TAC 1659 Thr Pro Tyr ATA GAT TAC ACG CAT TTA CGG ATA TCC TAT AAT GTG 1695 He Asp Tyr Thr His Leu Arg He Ser Tyr Asn Val 410 415 420 TAC TTA GCA TTC TCC ATT GCC CAC GCC TTG CAA 1731 Tyr Leu Wing Val Tyr Ser Wing His Wing Ala Leu Gln 425 430 GAT ATA TAT ACC TGC TTA CCT GGG AGA GGG CTC TTC 1767 Asp He Tyr Thr Cys Leu Pro Gly Arg Gly Leu Phe 435 440 ACC AAT GGC TCC TGT GCA GAC ATC AAG AAA GTT GAG 1803 Thr Asn Gly Ser Cys Wing Asp He Lys Lys Val Glu 445 450 455 GCG TGG CAG GTC CTG AAG CAC CTA CGG CAT CTA AAC 1839 Wing Trp Gln Val Leu Lys His Leu Arg His Leu Asn 460 465 TTT AC AAC AAT ATG GGG GAG CAG GTG ACC TTT GAT 1875 Phe Thr Asn Asn Met Gly Glu Gln Val Thr Phe Asp 470 475 480 GAG TGT GGT GAC CTG GTG GGG AAC TAT TCC ATC ATC 1911 Glu Cys Gly Asp Leu Val Gly Asn Tyr Ser He He 485 490 AAC TGG CAC CTC TCC CCA GAG GAT GGC TCC ATC GTG 1947 Asn Trp His Leu Ser Pro Glu Asp Gly Ser He Val 495 500 TTT AAG GAA GTC GGG TAT. TAC AAC GTC TAT GCC AAG 1983 Phe Lys Glu Val Gly Tyr Tyr Asn Val Tyr Ala Lys 505 510 515 1.25 AAG GGA GAA AGA CTC ATC AAC GAG GAG AAA ATC 2019 Lys Gly Glu Arg Leu Phe He Asn Glu Glu Lys He # 520 525 CTG TGG AGT OVJV TTC TCC AGG GAG CCA CTC ACC TTT 2055 Leu Trp Ser Gly Phe Ser Arg Glu Pro Leu Thr Phe 530 535 540 GTG CTG TCT GTC CTC CAG GTG CCC TTC TCC AAC TGC 2091 Val Leu Ser Val Leu Gln Val Pro Phe Ser Asn Cys 545 550 AGC CGA GAC TGC CTG GCA GGG ACC AGG AAA GGG ATC 2127 Ser Arg ASD Cys Leu Wing Gly Thr Arg Lys Gly He 555 560 GTG 2163 Val GAG TGT CCT GAT GGG GAT TAT AGT GAT GAG ACÁ GAT 2199 Glu Cys Pro ASD Gly Glu Tyr Ser ASD Glu Thr Asp 580. 585 GCC AGT GCC TGT AAC AAG TGC CCA GAT GAC TTC TGG 2235 Wing Wing Wing Cys Asn Lys Cys Pro Asp Asp Phe Trp 590 595 600 TCC AAT GAG AAC CAC ACC TCC TGC ATT GCC AAG GAG 2271 Ser Asn Glu Asn His Thr Ser Cys He Wing Lys Glu 605 610 ATC GAG Tl CTG TCG TGG ACG GAG CCC TTT GGG ATC 2307 He Glu Phe Leu Ser Trp Thr Glu Pro Phe Gly He 615 620 GCA CTC ACC CTC TTT GCC GTG CTG GGC ATT TTC CTG 2343 Wing Leu Thr Leu Phe Wing Val Leu Gly He Phe Leu 625 630 635 AC GCC TTT GTG CTG GGT GTG TTT ATC AAG TTC CGC 2379 Thr Wing Phe Val Leu Gly Val Phe He Lys Phe Arg 640 645 AAC ACÁ CCC ATT GTC AAG GCC ACC AAC CGA GAG CTC 2415 Asn Thr Pro He Val Lys Wing Thr Asn Arg Glu Leu 650 655 660 TCC TTC CTC CTC CTC TTC TCC CTG CTC TGC TGC TTC 2451 Ser Tyr Leu Leu Leu Phe Leu Leu Cys Cys Phe 665 670 TCC AGC TCC CTG TTC TTC ATC GGG GAG CCC CAG GAC 2487 Ser Be Leu Phe Phe He Gly Glu Pro Gln Asp 675 680 ATC 2523 He AGC TTC GTG CTC TGC ATC TCA TGC ATC CTG GTG AAA 2559 Be Phe Val Leu Cys He Ser Cys He Leu Val Lys 700 * 705 ACC AAC CGT GTC CTC CTG GTG TTT GAG GCC AAG ATC 2595 Thr Asn Arg Val Leu Leu Val Phe Glu Wing Lys He 710 715 720 CCC ACC AGC TTC CAC CGC AAG TGG TGG GGG CTC AAC 2631 Pro Thr Ser Phe His Arg Lys Trp Trp Gly Leu Asn 725 730 TGC ACC TTC ATG 2667 Cvs Thr Phe Met CAG ATT GTC ATC TGT GTG ATC TGG CTC TAC ACC GCG 2703 Gln He Val He Cys Val He Trp Leu Tyr Thr Wing 745 750 755 CCC CCC TCA AGC TAC CGC AAC C AG GAG CTG GAG GAT 2739 Pro Pro Ser Tyr Arg Asn Gln Glu Leu Glu Asp 760 765 GAG ATC ATC TTC ATC ACG TGC CAC GAG GGC TCC CTC 2775 Glu He He Phe He Thr Cys His Glu Gly Ser Leu 770 775 780 ATG GCC CTG GGC TTC CTG ATC GGC TAC ACC TGC CTG 2811 Met Wing Leu Gly Phe Leu He Gly Tyr Thr Cys Leu 785 790 ^ p CTG GCT GCC ATC TGC TTC TTC TTT GCC TTC AAG TCC 2847 Leu Wing Wing Cys Phe Phe Phe Wing Phe Lys Ser 795 800 CGG AAG CTG CCG GAG AAC TTC AAT GAA GCC AAG TTC 2883 Arg Lys Leu Pro Glu Asn Phe Asn Glu Wing Lys Phe 805 810 815 ATC ACC TTC AGC ATG CTC ATC TTC TTC ATC GTC TGG 2919 He Thr Phe Ser Met Leu He Phe He Phe He Val Trp 820 825 ATC TCC TTC ATT CCA GCC TAT GCC AGC ACC TAT GGC 2955 He Ser Phe He Pro Wing Tyr Wing Ser Thr Tyr Gly 830 835 840 AAG TTT GTC TCT GCC GTA GAG GTG ATT GCC ATC CTG 2991 Lys Phe Val Ser Wing Val Glu Val He Wing He Leu 845 850 GCA GCC AGC GGC GCG TGC ATC TTC TTC 3027 Wing Wing Phe Gly Leu Leu Wing Cys He Phe Phe 855 860 AAC AAG ATC TAC ATC ATT CTC TTC AAG CCA TCC CGC 3063 Asn Lys He Tyr He He Leu Phe Lys Pro Ser Arg 865 870 875 AAC ACC ATC GAG GAG GTG CGT TGC AGC ACC GCA GCT 3099 Asn Thr He Glu Glu Val Arg Cys Ser Thr Wing Wing 880 885 CAC GCT TTC AAG GTG GCT GCC CGG GCC ACG CTG CGC 3135 His Wing Phe Lys Val Wing Wing Arg Wing Thr Leu Arg 890 895 900 CGC AGC AAC GTC TCC CGC AAG CGG TCC AGC AGC CTT 3171 Arg Ser Asn Val Ser Arg Lys Arg Ser Ser Leu 905 910 GGA GGC TCC ACG GGA CC ACC CCC TCC TCC TCC ATC 3207 Gly Gly Ser Thr Gly Ser Thr Pro Ser Ser Be He 915 920 AGC AGC AG AGA AGC GAA GAC AGA TTC CCA CGG 3243 Ser Ser Lys Ser Asn Ser Glu Asp Pro Phe Pro Arg 925 930 935 CC GAG AGG CAG AAG CAG CAG CAG CCG CTG GCC CTA 3279 Pro Glu Arg Gln Lys Gln Gln Gln Pro Leu Ala Leu 940 945 ACC CAG CAA GAG CAG CAG CAG CAG CCC CTG ACC CTC 3315 Thr Gln Gln Gln Gln Gln Gln Gln Pro Leu Thr Leu 950 955 960 CCA CAG CAG CAA CGA TCT CAG CAG CAG CCC AGA TGC 3351 Pro Gln Gln Gln Arg Ser Gln Gln Gln Pro Arg Cys 965 970 AAG CAG AAG GTC ATC TTT GGC AGC GGC ACG GTC ACC 3387 Lys Gln Lys Val He Phe Gly Ser Gly Thr Val Thr 975 980 TTC TCA CTG AGC TTT GAT GAG CCT CAG AAG AAC GCC 3423 Phe Ser Leu Ser Phe Asp Glu Pro Gln Lys Asn Wing 985 990 995 ATG GCC CAC AGG AAT TCT ACG CAC CAG AAC TCC CTG 3459 Met Wing His Arg Asn Ser Thr His Gln Asn Ser Leu 1000 1005 GAG GCC CAG AAA AGC GAT ACG CTG ACC CGA CAC 3495 Glu Ala Gln Lys Ser Ser Asp Thr Leu Thr Arg His 1010 1015 1020 CAG CCA TTA CTC CCG CTG CAG TGC GGG GAA ACG GAC 3531 Gln Pro Leu Leu Pro Leu Gln Cys Gly Glu Thr Asp 1025 1030 TTA GAT CTG ACC GTC CAG GAA ACA GGT CTG CAA GGA 3567 Leu Asp Leu Thr Val Gln Glu Thr Gly Leu Gln Gly 1035 '1040 CCT GTG GGT GGA GAC CAG CGG CCA GAG GTG GAG GAC 3603 Pro Val Gly Gly Asp Gln Arg Pro Glu Val Glu Asp 1045 1050 1055 CCT GAA GAG TTG TCC CCA GCA CTT GTA GTG TCC AGT 3639 Pro Glu Glu Leu Ser Pro Wing Leu Val Val Ser Ser 1060 1065 TCA CAG AGC TTT GTC ATC AGT GGT GGA GGC AGC ACT 3675 Ser Gln Ser Phe Val He Ser Gly Gly Gly Ser Thr 1070 1075 1080 GTT ACÁ GAA AAC GTA G TG AAT TCA TAAAATGGAA 3709 Val Thr Glu Asn Val Val Asn Ser 1085 GGAGAAGACT GGGCTAGGGA GAATGCAGAG AGGTTTCTTG 3749 GGGTCCCAGG GATGAGGAAT CGCCCCAGAC TCCTTTCCTC 3789 TGAGGAAGAA GGGATAATAG ACACATCAAA TGCCCCGAAT 3829 TTAGTCACAC CATCTTAAAT GACAGTGAAT TGACCCATGT 3869 TCCCTTTAAA ATTAAAAAAA AGAAGAGCCT TGTGTTTCTG 3909 TGGTTGCATT TGTCAAAGCA TTGAGATCTC CACGGTCAGA 3949 TTTGCTGTTC ACCCACATCT AATGTCTCTT CCTCTGTTCT 3989 ATCCCACCCA ACAGCTCAGA GATGAAACTA TGGCTTTAAA 4029 CTACCCTCCA GAGTGTGCAG ACTGATGGGA CATCAAATTT 4069 GCCACCACTA GAGCTGAGAG TCTGAAAGAC AGAATGTCAC 4109 CAGTCCTGCC CAATGCCTTG ACAACAGACT GAATTTTAAA 4149 TGTTCACAAC ATAAGGAGAA TGTATCTCCT CCTATTTATG 4189 AAAACCATAT GATATTTTGT CTCCTACCTG CTGCTGCTAT 4229 TATGTAACAT CCAGAAGGTT TGCACCCCTC CTATACCATA 4269 TGTCTGGTTC TGTCCAGGAC ATGATACTGA TGCCATGTTT 4309 AGATTCCAGG ATCACAAGAA TCACCTCAAA TTGTTAGGAA 4349 GGGACGGCAT AACCAATGA GCTGTATCTG TAATTAATAT 4389 TCG GCTTTATCC TTAGGAAAAT GCTTCTGTTG 4429 AATAGTCCA TGGACAATAT AAACTC-YYYY ATGTCAGTCT 4469 GGTTTATATA GGCAGTATT TTGAGCTCT ATTTCCCCAC 4509 'CCCACTATCC TCACTCCCAT AAGCTAAGCC TTATGTGAGC 4549 CC TTCAGGG ACTCAAGGGT CCAGAAGTCC CTCCCATCTC 4589 TACCCCAAAG AATTCCTGAA GCCAGATCCA CCCTATCCCT 4629 GTACAGAGTA AGTTCTCAAT TATTGGCCTG CTAATAGCTG 4669 CTAGGGTAGG AAAGCGTGGT TCCAAGAAAG ATCCACCCTC 4709 4749 C GCTATGTTCC CTCCAGCAGT GGTATTAATA GCCGGTCA CCCAGGCTCT GGAGCCAGAG AGACAGACCG 4789 GGGTTCAAGC CATGGCTTCG TCATTTGCAA GCTGAGTGAC 4829 ~ 4869 GTAGGCAGG GAACCTTAAC CTCTCTAAGC CACAGCTTCT T ATCTTTAA AATAAGGATA ATAATCATTC CTTCCCCTCA ... 4909 GAGCTCTTAT GTGGATTAAA CGAGATAATG TATATAAAGT 4949 A 4989 TTTAGCCT GGTACCTAGC ACACAATAAG CATTCAATAA -TATTAGTTA ATATTAT 5006 (2) INFORMATION FOR. SEC ID No: 2: (i) CHARACTERISTIC OF CONSEQUENCE (A) LENGTH 3809 paces of bases (B) TYPE OF NUCLEUS (C) TYPE OF INDIVIDUAL CHAIN (D) TOPOLOGY • linear (Ü) IPO "DÉ" MOLECULE cDNA a ARNai (ÍX) CHARACTERISTIC (A) NAME / KEY CDS (B) LOCATION 373. . 3606 (D) OTHER INFORMATION (Xi) descrpcion OF RESULT: SEQ ID No.: 2 AACAGGCAC CTGGCTGCAG CCAGGAAGGA CCGCACGCCC 40 TTTCGCGCAG GAGAGTGGAA GGAGGGAGCT GTTTGCCAGC 80 i ACCGAGGTCT TGCGGCACAG GCAACGCTTG ACCTGAGTCT 120 TGCAGAATGA AAGGCATCAC AGGAGGCCTC TGCATGATGT 160 i, # GGCTTCCAAA GACTCAAGGA CCACCCACAT TACAAGTCTG 200 GATTGAGGAA GGCAGAAATG GAGATTCAAA CACCACGTCT 240 TCTATTATTT TATTAATCAA TCTGTAGACA TGTGTCCCCA 280 CTGCAGGGAG TGAACTGCTC CAAGGGAGAA ACTTCTGGGA 320 GCCTCCAAAC TCCTAGCTGT CTCATCCCTT GCCCTGGAGA 360 GACGGCAGAA CC ATG GCA TTT TAT AGC TGC TGC TGG 396 Met Ala Phe Tyr Ser Cys Cys Trp May 1 * GTC CTC TTG GCA CTC ACC TGG CAC ACC TCT GCC TAC 432 Val Leu Leu Wing Leu Thr Trp His Thr Ser Wing Tyr 10 15 20 GGG CCA GAC CAG CGA GCC CAA AAG AAG GGG GAC ATT 468 Gly Pro Asp Gln Arg Wing Gln Lys Lys Gly Asp He 25 30 ATC CTT GGG GGG CTC TTT CCT ATT CAT. TTT GGA GTA 504 He Leu Gly Gly Leu Phe Pro He His Phe Gly Val 35 40 GCA GCT AAA GAT CAA GAT CTC AAA TCA AGG CCG GAG 540 Wing Wing Lys Asp Gln Asp Leu Lys Ser Arg Pro Glu 45 50 55 TCT GTG GAA TGT ATC AGG TAT AAT TTC CGT GGG TTT 576 Ser Val Glu Cys He Arg Tyr Asn Phe Arg Gly Phe 60 65 CGC TGG TTA CAG GCT ATG ATA TTT GCC ATA GAG GAG 612 Arg Trp Leu Gln Wing Met He Phe Wing He Glu Glu 70 75 80 ATA AAC AGC AGC CCA GCC CTT CTT CCC AAC TTG ACG 648 He Asn Ser Pro Pro Wing Leu Pro Asn Leu Thr 85 90 CTG GGA TAC AGG ATA TTT GAC ACT TGC AAC ACC GTT 684 Leu Gly Tyr Arg He Phe Asp Thr Cys Asn Thr Val 95 100 TCT AAG GCC TTG GAA GCC ACC CTG AGT TTT GTT GCT 720 Ser Lys Ala Leu Glu Ala Thr Leu Ser Phe Val Ala 105 110 115.1.3.1 CAA AAC AAA ATT GAT TCT TTG AAC CTT GAT GTC TTC 756 Gln Asn Lys He Asp Ser Leu Asn Leu Asp Glu Phe 120 125 TGC AAC TGC TCA GAG CAC ATT CCC TCT ACG ATT GCT 792 Cys Asn Cys Ser Glu His He Pro Ser Thr He Ala 130 135 • 140 GTG GTG GGA GCA ACT GGC TCA GGC GTC TCC ACG GCA 828 Val Val Gly Wing Thr Gly Ser Gly Val Ser Thr Wing 145 150 GTG GCA AAT CTG GGG CTC TTC TAC ATT CCC CAG 864 Val Wing Asn Leu Leu Gly Leu Phe Tyr He Pro Gln 155 160 GTC AGT TAT GCC TCC TCC AGC AGA CTC CTC AGC AAC 900 Val Ser Tyr Wing Ser Ser Arg Leu Leu Ser Asn 165 170 175 AAG AAT CAA TTC AAG TCT TTC CTC CGA ACC ATC CCC 936 Lys Asn Gln Phe Lys Ser Phe Leu Arg Thr He Pro 180 185 AAT GAT GAC CAC CAG GCC ACT GCC ATG GAC GAC ATC 972 Asn Asp Glu His Gln Wing Thr Wing Ala Wing Asp He 190 195 200 ATC GAG TAT TTC CGC TGG AAC TGG GTG GGC ACA ATT 1008 He Glu Tyr Phe Arg Trp Asn Trp Val Gly Thr He 205 210 GCA GCT GAT GAC TAC GGG CGG CCG GGG ATT GAG 1044 Wing Wing Asp Asp Tyr Gyr Arly Pro Gly He Glu 215 220 AAA TTC CGA GAG GAA GCT GAG GAA AGG GAT ATC TGC 1080 Lys Phe Arg Glu Glu Ala Glu Glu Arg Asp He Cys 225 230 235 ATC GAC TTC AGT GAA CTC ATC TCC CAG TAC TCT GAT 1116 He Asp Phe Ser Glu Leu He Ser Gln Tyr Ser Asp 240 245 GAG GAA GAG ATC CAG CAT G TG GTA GAG GTG ATT CAA 1152 Glu Glu Glu He Gln His Val Val Glu Val He Gln 250 255 260 AAT TCC ACG GCC AAA GTC ATC GTG GTT TTC TCC AGT 1188 Aen Ser Thr Ala Lys Val He Val Val Phe Ser Ser 265 270 GGC CCA GAT CTT GAG CCC CTC ATC AAG GAG ATT GTC 1224 Gly Pro Asp Leu Glu Pro Leu He Lys Glu He Val 275 280 CGG CGC AAT ATC ACG GGC AAG ATC TGG CTG GCC AGC 1260 Arg Arg Asn He Thr Gly Lys He Trp Leu Wing Ser 285 290 295 GAG GCC TGG GCC AGC TCC TCC CTG ATC GCC ATG CCT 1296 Glu Wing Trp Wing Ser Ser Leu He Wing Met Pro 300 305 CAG TAC TTC CTC GTG GTT GGC GGC ACC ATT GGA TTC 1332 Gln Tyr Phe His Val Val Gly Gly Thr He Gly Phe 310 315 320 GCT CTG AAG GCT GGG CAG ATC CCA GGC TTC CGG GAA 1368 Wing Leu Lys Wing Gly Gln He JPro Gly Phe Arg Glu 325 330 TTC CTG AAG AAG GTC CAT CCC AGG AAG TCT GTC CAC 1404 Phe Leu Lys Lys Val His Pro Arg Lys Ser Val His 335 340 AAT GGT TTT GCC AAG GAG TTT TGG GAA GAA ACA TTT 1440 Asn Gly Phe Ala Lys Glu Phe Trp Glu Glu Thr Phe 345 350 355 AAC TGC CAC CTC CAA GAA GGT GCA AAA GGA CCT TTA 1476 Asn Cys His Leu Gln Glu Gly Wing Lys Gly Pro Leu 360 365 CCT GTG GAC ACC TTT CTG AGA GGT CAC GAA GAA AGT 1512 Pro Val Asp Thr Phe Leu Arg Gly His Glu Glu Ser 370 '375 380 GGC GAC AGG TTT AGC AAC AGC TCG ACA GCC TTC CGA 1548 Gly Asp Arg Phe Ser Asn Ser Ser Thr Wing Phe Arg 385 390 CCC CTC TGT AC GGG GAT GAG AAC ATC AGC AGT GTC 1584 Pro Leu Cys Thr Gly Asp Glu Asn He Ser Ser Val 395 400 GAG ACC CCT TAC ATA GAT TAC ACG CAT TTA CGG ATA 1620 Glu Thr Pro Tyr He Asp Tyr Thr His Leu Arg He 405 410 415 TCC TAT AAT GTG TAC TTA GCA GTC TAC TCC ATT GCC 1656 Ser Tyr Asn Val Tyr Leu Wing Val Tyr Ser Wing 420 425 CAC GCC TTG CAA GAT ATA TAT ACC TGC TTA CCT GGG 1692 His Wing Leu Gln Asp He Tyr Thr Cys Leu Pro Gly 430 435 440 AGA GGG CTC TTC ACC AAT GGC TCC TGT GCA GAC ATC 1728 Arg Gly Leu Phe Thr Asn Gly Ser Cys Wing Asp He 445 450 AAG AAA GTT GAG GCG TGG CAG GTC CTG AAG CAC CTA 1764 Lys Lys Val Glu Wing Trp Gln Val Leu Lys His Leu 455 460 CGG CAT CTA AAC TTT ACA AAC AAT ATG GGG GAG CAG 1800 Arg His Leu Asn Phe Thr Asn Asn Met Gly Glu Gln 465 470 475 GTG ACC TTT GAT GAG TGT GGT GAC CTG GTG GGG AAC 1836 Val Thr Phe Asp Glu Cys Gly Asp Leu Val Gly Asn 480 485 TAT TCC ATC ATC AAC TGG CAC CTC TCC CCA GAG GAT 1872 Tyr Ser He He Asn Trp His Leu Ser Pro Glu Asp 490 495 500 GGC TCC ATC GTG TTT AAG GAA GTC GGG TAT TAC AAC 1908 Gly Ser He Val Phe Lys Glu Val Gly Tyr Tyr Asn 505 510 GTC TAT GCC AAG AAG GGA GAA AGA CTC TTC ATC AAC 1944 Val Tyr Ala Lys Lys Gly Glu Arg Leu Phe He Asn 515 520 GAG GAG AAA ATC CTG TGG AGT GGG TTC TCC AGG GAG 1980 Glu Glu Lys He Leu Trp Ser Gly Phe Ser Arg Glu 525 530 535 GTG CCC TTC TCC AAC TGC AGC CGA GAC T GC CTG GCA 2016 Val Pro Phe Ser Asn Cys Ser Arg Asp Cys Leu Wing 540 545 GGG ACC AGG AAA GGG ATC ATG GGG GAG CCC ACC 2052 Gly Thr Arg Lys Gly lie He Glu Gly Glu Pro Thr 550 555 560 TGC TGT TTT GAG TGT GTG GAG TGT CCT GAT GGG GAG 2088 Cys Cys Phe Glu Cys Val Glu Cys Pro Asp Gly Glu 565 570 TAT AGT GAT GAG HERE GAT GCC AGT GCC TGT AAC AAG 2124 Tyr Ser Asp Glu Thr Asp Ala Ser Ala Cys Asn Lys 575 580 TGC CCA GAT GAC TTC TGG TCC AAT GAG AAC CAC ACC 2160 Cys Pro Asp Asp Phe Trp Ser Asn Glu Asn His Thr 585 590 595 TCC TGC ATT GCC AAG GAG ATC GAG TTT CTG TCG TGG 2196 Ser Cys He Ala Lys Glu He Glu Phe Leu Ser Trp 600 605 ACG GAG CCC TTT GGG ATC GCA CTC ACC CTC TTT GCC 2232 Thr Glu Pro Phe Gly He Wing Leu Thr Leu Phe Wing 610 615 620 GTG CTG GGC ATT TTC CTG GCC TTT GTG CTG GGT 2268 Val Leu Gly He Phe Leu Thr Ala Phe Val Leu Gly 625 630 # GTG TTT ATC AAG TTC CGC AAC ACA CCC ATT GTC AAG 2304 Val Phe He Lys Phe Arg Asn Thr Pro He Val Lys 635"640 GCC ACC AAC CGA G AG CTC TCC TTC CTC TTC CTC CTC CTC TTC 2340 Thr Asn Arg Glu Leu Ser Tyr Leu Leu Leu Phe 645 650 655 TCC CTG CTC TGC TGC TTC TCC TCC TCC TTC CTTC 2376 Ser Leu Leu Cys Cys Phe Ser Ser Ser Leu Phe Phe 660 665 2412 2448 Gln Pro Wing Phe Gly He Ser Phe Val Leu Cys He 685 690 TCA TGC ATC CTG GTG AAA ACC AAC CGT GTC CTC CTG 2484 Ser Cys He Leu Val Lys Thr Asn Arg Val Leu Leu 695 700 GTG TTT GAG GCC AAG ATC CCC ACC AGC TTC CAC CGC 2520 Val Phe Glu Wing Lys He Pro Thr Ser Phe His Arg 705 710 715 AAG TGG TGG GGG CTC AAC CTG CAG TTC CTG CTG GTT 2556 Lys Trp Trp Gly Leu Asn Leu Gln Phe Leu Leu Val 720 725 # TTC CTC TGC ACC TTC ATG CAG ATT GTC ATC GTT 2592 Phe Leu Cys Thr Phe Met Gln He Val He Cys Val 730 735 740 ATC TGG CTC TAC ACC GCG CCC CCC TCA AGC TAC CGC 2628 He Trp Leu Tyr Thr Wing Pro Pro Ser Ser Tyr Arg 745 750 AAC CAG GAG CTG GAG GAT GAG ATC ATC TTC ATC ACG 2664 Asn Gln Glu Leu Glu Asp Glu He He Phe He Thr 755 760 TGC CAC GAG GGC TCC CTC ATG GCC CTG GGC TTC CTG 2700 Cys His Glu Gly Ser Leu Met Wing Leu Gly Phe Leu 765 770 775 ATC GGC TAC ACC TGC CTG CTG GCT GCC ATC TGC TTC 2736 He Gly Tyr Thr Cys Leu Leu Wing Wing Cys Phe 780 785 TTT GCC TTC AAG TCC CGG AAG CTG CCG GAG AAC 2772 Phe Phe Wing Phe Lys Ser Arg Lys Leu Pro Glu Asn 790 795 800 TTC AAT GAA GCC AAG TTC ATC ACC TTC AGC ATG CTC 2808 Phe Asn Glu Wing Lys Phe He Thr Phe Ser Met Leu 805 810 ATC TTC TC ATC GTC TGG ATC TCC TTC ATT CCA GCC 2844 He Phe Phe He Val Trp He Ser Phe He Pro Wing 815 820 TAT GCC AGC ACC TAT GGC AAG TTT GTC TCT GCC GTA 2880 Tyr Wing Ser Thr Tyr Gly Lys Phe Val Ser Wing Val 825 830 835 GAG GTG ATT GCC ATC CTG GCA GCC AGC TTT GGC TTG 2916 Phe Gly Leu2952 Tyr He He 860 CTC TTC AAG CCA TCC CGC AAC ACC ATC GAG GTG 2988 Leu Phe Lys Pro Ser Arg Asn Thr He Glu Glu Val 865 870 CGT TGC AGC ACC scA GCT CAC GCT TTC. AAG GTG GCT 3024 Arg Cys Ser Thr Ala Ala His Ala Phe Lys Val Ala 875 880 csc 3060 Arg TCC 3096 Lys Arg Ser Ser Be Leu Gly Gly Be Thr Gly Ser 900 905 ACC CCC TCC TCC TCC ATC AGC AGC AG AGC AAC AGC 3132 Thr Pro Ser Ser Ser Ser Ser Lys Ser Asn Ser 910 915 920 GAA GAC CCA TTC CCA CAG CCC GAG AGG CAG AAG CAG 3168 Glu Asp Pro Phe Pro Gln Pro Glu Arg Gln Lys Gln 925 930 CAG CAG CCG CTG GCC CTA ACC CAG CAA GAG CAG CAG 3204 Gln Gln Pro Leu Ala Leu Thr Gln Gln Gln Gln Gln 935 940 CAG CAG CCC CTG ACC CTC CCA CAG CAG CAA CGA TCT 3240 Gln Gln Pro Leu Thr Leu Pro Gln Gln Gln Arg Ser 945 950 955 GTC ATC TTT 3276 Val He Phe GGC AGC GGC ACG GTC ACC TTC TCA CTG AGT TTT GAT 3312 Gly Ser Gly Thr Val Thr Phe Ser Leu Ser Phe Asp 970 975 980 GAG CCT CAG AAG AAC GCC ATG GCC CAC GGG AAT TCT 3348 Glu Pro Gln Lys Asn Wing Met Wing His Gly Asn Ser 985 990 ACG CAC CAG AAC TCC CTG GAG GCC CAG AAA AGC AGC 3384 Thr His Gln Asn Ser Leu Glu Wing Gln Lys Ser Ser 995 1000 CTG 3420 Leu CAG 3456 Gin Cys Gly Glu Thr Asp Leu Asp Leu Thr Val Gln 1020 1025 GAA ACA GGT CTG CAA GGA CCT GTG GGT GGA GAC CAG 3492 Glu Thr Gly Leu Gln Gly Pro Val Gly Gly Asp Gln 1030 1035 -1040 CGG CCA GAG GTG GAG GAC CCT GAA GAG TTG TCC CCA 3528 Arg Pro Glu Val Glu Asp Pro Glu Glu Leu Ser Pro 1045 1050 GCA CTT GTA GTG TCC AGT TCA CAG AGC TTT GTC ATC 3564 Wing Leu Val Val Ser Ser Ser Gln Ser Phe Val H 1055 1060 AGT GGT GGA GGC AGC ACT GTT ACA GAA AAC GTA GTG 3600 Ser Gly Gly Gly Ser Thr Val Thr Glu Asn Val Val 1065 1070 1075 AAT TCA TAAAATGGAA GGAGAAGACT GGGCTAGGGA 3636 Asn Ser GAATGCAGAG AGGTTTCTTG GGGTCCCAGG GATGAGGAAT 3676 CGCCCCAGAC TCCTTTCCTC TGAGGAAGAA GGGATAATAG_3716_ACACATCAAA TGCCCCGAAT TTAGTCACAC CATCTTAAAT 3756 GACAGTGAAT TGACCCATGT TCCCTTTAAA AAAAAAAAAA 3796 AAAAAGCGGC CGC 3809

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - An inorganic ion receptor modulator compound having the formula: wherein ri is either naphthyl or phenyl optionally substituted by 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy lower thioalkyl, methylenedioxy, lower halogenalkyl, lower halogenoalkoxy, OH, CH2OH, CONH2, CN , acetoxy, N (CH 3) 2, phenyl, phenoxy, benzyl, benzyloxy, α, α-dirnethylbenzyl, NO 2, CHO, CH 3 CH (0H) ,. acetyl, ethylenedioxy; r * 2 is either naphthyl or phenyl optionally substituted by 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxyl, thioalkyl and lower -D-J, lower alkyl or haloalkoxy -lower, O and acetoxy., - q; and R is either H, lower alkyl; and pharmaceutically acceptable salts and complexes thereof; wherein said compound modulates one or more activities of inorganic ion receptors. /

2. The compound of claim 1, wherein said phenyl kidney, if present, has 1 to 5 substituents each independently selected from the group consisting of isopropyl, CH3O, CF3, CH3, S, CF3O, I, Cl , F, and CH3; said r 2 phenyl, if present, has 1 to 5 substituents each independently selected from the group consisting of isopropyl, CH 3 O, OH 3 S, CF 3 O, I, Cl, F, CF 3 and CH 3 • said compound is calcinarynitol; and said inorganic ion receptor activity is calcium receptor activity.

3. The compound of claim 2, said Ari phenyl having 1 to 5 substituyent.es is present and said 1-2 phenyl having 1 to 5 substituents is present.

4. A compound of claim 3, further characterized in that said phenyl is a rnetarnetoxy. phenyl

5. The compound of claim 2, further characterized in that q is 0 and said naphthyl Ar is preserite. The compound of claim 5, further characterized in that said phenyl Ari having 1 to 5 subs 'ti • t' u-y'en1t.es is present. ~ / '' \ x 1. - The compound of claim 2, further characterized in that q is 2, said Ari phenyl having - / 1 to substituents is present, and said Ar 2 naphthyl. The compound of claim 2, characterized in that said lipyl is present, has 1 to 5 substituents each independently selected from the group consisting of CF3O, I, Cl, F, and CF3; and said 1"2 phenyl, if present, has 1 to 5 substituents each independently selected from the group consisting of CF3O, I, Cl, F, CH3O and CF3 9. The compound of claim 3, further characterized in that said firi f-eniio has the 5 substituents each independently selected from the group consisting of CF3O, I, Cl, F, and CF3, and said r2 phenyl having 1 to 5 substitutes each independently selected from the group consisting of CF3O, I, Cl, F, CH3O, and CF3. 10, .- The cornpues-fo of the reividication c rac erizado also because said f * 2 femlo is a rnetarnetoxyphenyl. 11. The compound of the claim further characterized in that R is CH3 12. The compound of claim 3, further characterized in that R is CH3 13. The compound of the claim further characterized because R is CH3 14.- The compound of claim 7, further characterized in that R is CH 3 15. The compound of claim 11, further characterized in that said compound has the phopule: Hjco or pharmaceutically acceptable salts and complexes thereof. 16.- An inorganic ion receptor modulator compound that has the formula: wherein 1-3 is either naphthyl or optionally substituted by 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy lower alkyl, lower alkyl, lower halogenoalkyl, lower halogenoalkoxy, OH, CH2OH, CONI-I2, CONH2, CN, acetox, benzyl, loxi, dirnethylbenzene, NO2, CHO, CH3CI-KOH), N (CH3) 2, acetyl, ethylenedioxy; r is either a thiol or femlo optionally substituted by 0 to 5 substH utents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, thioal or lower, inethylmdioxy, lower halogenoalkyl, lower halogenoalkoxy, OH, CH2OH, COMH , CN, and acetox; Rs is either hydrogen or phenyl; Rg is either hydrogen or methyl; and Rio is either hydrogen, methyl or phenyl; or pharmaceutically acceptable salts and complexes thereof. 17. An inorganic ion receptor modulator compound having the formula. Wherein Ars is either naphthyl or phenyl optionally substituted by 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy thioalkyl Bottom, methylenedioxy, lower halogenalkyl, lower halogenoalkoxy, OH, CH2OH, CONH, CONH2, CN, ketoxy, benzyl, benzyloxy, a, a-dimethylbenzyl, NO2, CHO, CH3CH (0H), N (CH3) 2, acetyl, ethylenedioxy, -CH-CH-phenyl; Fsxßs either naphthyl or phenyl optionally substituted by 0 substituents each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, rnetylindioxy, lower halogenoalkyl lower halogenoalkoxy, OH, CH OH, COMH2, CN , carbornetoxy, 0CH2C (0) C2Hs and acetoxy; p is either Hydrogen or methyl; and R12 is either hydrogen or methyl. 18. A pharmaceutical composition comprising a compound of any of claims 1-17 and a pharmaceutically acceptable carrier. 19. The use of a therapeutically effective amount of a compound of any of claims 1-17, in the preparation of compositions for treating a disease, characterized by either, or both of: 1) abnormal calcium homeostasis and 2) a abnormal amount of an extracellular or intracellular messenger whose production can be affected by calcium receptor activity; in a human being and said compound is a magnetic cation. 20. The use of a compound of any of claims 1-17, according to claim 19, further characterized in that the compound used is a calcirnirnético .. 21.- The use of a compound of any of claims 1 to 17, in accordance with claim 19, further characterized in that said agent is a human being, and said disease is selected from the group consisting of primary and secondary hyperparathyroidism, and Paget's disease, osteoporotic malignant hypercalcemia, hypertension, and osteogenesis. ia renal.