CA2202879C - Calcium receptor-active compounds - Google Patents

Calcium receptor-active compounds Download PDF

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CA2202879C
CA2202879C CA002202879A CA2202879A CA2202879C CA 2202879 C CA2202879 C CA 2202879C CA 002202879 A CA002202879 A CA 002202879A CA 2202879 A CA2202879 A CA 2202879A CA 2202879 C CA2202879 C CA 2202879C
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compound
ethylamine
phenyl
complex
methyl
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CA2202879A1 (en
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Bradford C. Van Wagenen
Scott T. Moe
Manuel F. Balandrin
Eric G. Delmar
Edward F. Nemeth
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Shire NPS Pharmaceuticals Inc
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NPS Pharmaceuticals Inc
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Priority claimed from PCT/US1994/012117 external-priority patent/WO1995011221A1/en
Priority claimed from US08/353,784 external-priority patent/US6011068A/en
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Abstract

The present invention features compounds of general formulae a), b), c), abl e to modulate one or more activities of an inorganic ion receptor and methods for treating diseases or disorders by modulating inorganic ion receptor activity. Preferably, the compound can mimic or block the effect of extracellular Ca2+ on a calcium receptor.

Description

WO 96/12697 PCT/US9~/13704 DESCRIPTION
'" Calcium Receptor-Active Compounds Field of the Invention This invention relates to the design, development, composition and use of compounds able to modulate one or more inorganic ion receptor activities.
Backaround of the Invention _.

Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca2'). Changes in the concentration of extracellular Ca2' (referred to herein as " [Ca2'] ") alter the functional responses of these cells. One such - specialized cell is the parathyroid cell which secretes parathyroid hormone (PTH). PTH is the principal endocrine factor regulating Caz' homeostasis in the blood and extracellular fluids.

PTH, by acting on bone and kidney cells, increases the level of Ca2' in the blood. This increase in [Ca2']

then acts as a negative feedback signal, depressing PTH

secretion. The reciprocal relationship between [Ca2'] and PTH secretion forms the essential mechanism maintaining bodily Ca2' homeostasis.

Extracellular Caz' acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in [Ca2'] has been confirmed. Brown et al., 366 Nature 574, 1993. In parathyroid cells, this protein acts as a receptor for extracellular CaZ' ( "the calcium receptor" ) , and detects changes - in [Ca2'] and to initiate a functional cellular response, PTH secretion.

Extracellular Ca2' can exert effects on different cell functions, reviewed in Nemeth et a1. , 11 Cell Calcium 319, 1990. The role of extracellular Caz' in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth, 11 SUBSTITUTE SHEET (RULE 26) Cell Calcium 323 , 1990 . These cells have been shown to express similar Caz' receptor. Brown et al., 366 Nature .r~
574, 1993; Mithal et al., 9 Suppl. 1 J. Bone and Mineral Res. s282, 1994; Rogers et a1. , 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994; Garrett et al., 9 Suppl. 1 J.
Bone and Mineral Res. s409, 1994. The role of extra cellular Cap; on bone osteoclasts is discussed by Zaidi, 10 Bioscience Reports 493, 1990. In addition keratinocytes, juxtaglomerular cells, trophoblasts, pancreatic beta cells and fat/adipose cells all respond to increases in extra-cellular calcium which likely reflects activation of calcium receptors of these cells.
The ability of various compounds to mimic extra cellular Ca2' in vitro is discussed by Nemeth et al., (spermine and spermidine) in "Calcium-Binding Proteins in Health and Disease," 1987, Academic Press, Inc., pp. 33-35; Brown et al., (e. g., neomycin) 128 Endocrin-olOQV 3047, 1991; Chen et al., (diltiazem an~.its analog, TA-3090) 5 J. Bone and Mineral Res. 581, 1990; and Zaidi et al., (verapamil) 167 Biochem Biophys Res. Commun.
807, 1990. Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US92/07175, International Publication Number WO
93/04373, describe various compounds which can modulate the effect of an inorganic ion on a cell having an inorganic ion receptor.
The references provided in the background are not admitted to be prior art.
Summary of the Invention The present invention features compounds able to modulate 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 on a cell surface calcium receptor.
SUBSTITUTE Sf-~EET (RULE 26) Diseases or disorders which can be treated by modulating inorganic ion receptor activity include one or more of the following types: (1) those characterized by abnormal inorganic ion homeostasis, preferably calcium n homeostasis; (2) those characterized by an abnormal amount of an extracellular or intracellular messenger whose production can be affected by inorganic ion receptor activity, preferably calcium receptor activity; (3) those characterized by an abnormal effect (e. g., a different effect in kind or magnitude) of an intracellular or extra-cellular messenger which can itself be ameliorated by inorganic ion receptor activity, preferably calcium receptor activity; and (4) other diseases or disorders in which modulation of inorganic ion receptor activity, preferably calcium receptor activity will exert a bene-ficial effect, for example, in diseases or disorders where the production of an intracellular or extracellular messenger stimulated by receptor activity compensates for an abnormal amount of a different messenger. Examples of extracellular messengers whose secretion and/or effect can be affected by modulating inorganic ion receptor activity include inorganic ions, hormones, neurotransmitters, growth factors, and chemokines. Examples of intracellular messengers include cAMP, cGMP, IP3, and diacylglycerol.

Thus, a compound ,of this invention preferably modulates calcium receptor activity and is used in the treatment of diseases or disorders which can be affected by modulating one or more activities of a calcium receptor. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca2' concentration. For example, extracellular Ca2' inhibits the secretion of parathyroid hormone from para-thyroid cells, inhibits bone resorption by osteoclasts,-~and stimulates secretion of calcitonin from C-cells.

In a preferred embodiment, the compound is used to treat a disease or disorder characterized by abnormal bone and mineral homeostasis, more preferably calcium homeo-SUBSTITUTE SHEET (RULE 26) stasis. Extracellular Caz' is under tight homeostatic control and controls various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Abnormal calcium homeostasis is characterized r 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 excretion of calcium; (3) an abnormal increase or decrease in bone calcium levels, for example, as assessed by bone mineral density measurements; (4) an abnormal absorption of dietary calcium; (5) an abnormal increase or decrease in __s ~. _ the production and/or release of messengers which affect serum calcium levels such as parathyroid hormone and calcitonin; and (6) an abnormal change in the response elicited by messengers which affect serum calcium levels.
The abnormal increase or decrease in these different aspects of calcium homeostasis is relative to that occurring in the general population and is generally associated with a disease or disorder.
Diseases and disorders characterized by abnormal calcium homeostasis can be due to different cellular defects such as a defective calcium receptor activity, a defective number of calcium receptors, or a defective intracellular protein acted on by a calcium receptor. For example, in parathyroid cells, the calcium receptor is coupled to the Gi protein which in turn inhibits cyclic AMP
production. Defects in Gi protein can affect its ability to inhibit cyclic AMP production.
Thus, a first aspect the invention features an inorganic ion receptor modulating compound having the formula:
SUBSTITUTE SHEET (RULE 26) STRUCTURE I
H
H ~r t Sri ~ .
H
where Arl is either naphthyl or phenyl optionally sub-.
stituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, 5 halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONHz, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, cx,a-dimethylbenzyl, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy;
Ar2 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, and acetoxy;
q is 0, 1, 2, or 3; and R is either H, or lower alkyl;
and pharmaceutically salts and complexes thereof.
Compounds of this invention have preferred stereo-chemistry. The CH3 shown in Structure I is at a chiral center and provides an a-(R)-methyl structure. When R is CH3, the R shown in Structure I is also at chiral center which provides.an (R)-methyl structure. Thus, when R is CH3, the Structure I compound has (R, R) stereochemistry.
Inorganic ion receptor activities are those processes brought about as a result of inorganic ion receptor acti-vation. Such processes include the production of mole-cules which can act as intracellular or extracellular messengers.
SUBSTITUTE SHEET (RULE 26) Inorganic ion receptor-modulating compound include ionomimetics, ionolytics, calcimimetics, and calcilytics.
Ionomimetics are compounds which bind to an inorganic ion receptor and mimic (i.e., evoke or potentiate) the effects of an inorganic ion at an inorganic ion receptor. Prefer-ably, the compound affects one or more calcium receptor activities. Calcimimetics are ionomimetics which effects one or more calcium receptor activities and bind to a calcium receptor.
Ionolytics are compounds which bind to an, inorganic ion receptor and block (i.e., inhibit or diminish) one or more activities caused by an inorganic ion at an inorganic ion receptor. Preferably, the compound affects one or more calcium receptor activities. Calcilytics are iono-lytics which block one or more calcium receptor activities evoked by extracellular calcium and bind to a calcium receptor.
Ionomimetics and ionolytics may bind at the same receptor site as the native inorganic ion ligand binds or can bind at a different site (e.g., allosteric site). For example, NPS R-467 binding to a calcium receptor results in 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 (i.e., an allosteric site) than extracellular calcium.
A measure of a compounds effectiveness can be deter-mined by calculating the ECso or ICso for that compound.
The ECso is the concentration of a compound which causes a half maximal mimicking effect. The ICso is the concentra-tion of compound._which causes a half-maximal blocking effect . ECSO and ICso for compounds at a calcium receptor can be determined by assaying one or more of the activi-ties of extracellular calcium at a calcium receptor.
Examples of assays for measuring ECso, and ICso are ' described Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US92/0'7175, International Publication Number WO
SUBSTITUTE SHEET (RULE 26) . 79565-8 (S) 93/04373, and below. Such assays include oocyte expression assays and measuring increases in intra-cellular calcium ion concentraition ( [Cap'] ;) due to calcium receptor activity. Preferably, such assays measure the release or inhibition of a particular hormone associated with activity of a calcium receptor.
An inorganic ion receptor-modulating compound prefer-ably selectively targets inorganic ion receptor activity in a particular cell. For example, selective targeting of a calcium receptor activity is achieved by a compound exerting a greater effect on a calcium receptor activity in one cell type than at another cell type for a given concentration of compound. preferably, the differential effect is 10-fold or greater as measured in vivo or in vitro. More preferably, the differential effect is mea-sured in vivo and the compound concentration is measured as the plasma concentration or extracellular fluid con-centration and the measured effect is the production of extracellular messengers such as plasma calcitonin, a0 parathyroid hormone, or plasma calcium. For example, in a preferred embodiment, the compound selectively targets PTH secretion over calcitonin secretion.
Preferably, the compound is either a calcimimetic or calcilytic having an ECso or :LCso at a calcium receptor of less than or equal to 5 ~cM, and even more preferably less than or equal to 1 ~M, 100 nmolar, 10 nmolar, or 1 nmolar using one of the assays descr:.bed below. More preferably, the assay measures intracellular Ca'' in HEK 293 cells transformed with nucleic acid expressing the human para-thyroid calcium receptor and loaded with fura-2. Lower ECso' s or ICso' s are advantageous since they allow lower concentrations of compounds to be used in vivo or in vitro. The discovery of compounds with low ECso's and ICso's enables the design and synthesis of additional compounds having similar. or improved potency, effect-iveness, and/or selectivity.
Another aspect of the present invention features an inorganic ion receptor modulating compound having the formula:
STRUCTURE II
H
Ark N Ark P,~ Ri a ~K3 where Ar3 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONHz, CN, acetoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, NO2, CHO, CH3CH(OH) , N(CH3)2, acetyl, ethylene dioxy.
Ar4 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, and acetoxy;
RB is either hydrogen or phenyl;
R9 is either hydrogen or methyl; and Rlo is either hydrogen, methyl, or phenyl;
or pharmaceutically acceptable salts and complexes thereof .
Another aspect of the present invention features an "
inorganic ion receptor modulating compound having the formula:
SUBSTITUTE SHEET (RULE 26) ' , 79565-8 (S) STRUCTURE III
H
Ar'S N ~ E~6 Rt t Rt z where Ars is either naphthyl or prLenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONH2, CN, acetoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, N02, CHO, CH3CH(OH), acetyl, ethylene dioxy, -CH=CH-phenyl;
Ar6 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONHz, CN, carbomethoxy, OCH2C (O) CZHS and acetoxy;
Rll is hydrogen or methyl; and R12 is hydrogen or methyl.
In a particularly preferred aspect, the invention relates to a compound having the formula:
H
f~T'S N ~ AT6 Rl i -~i 2 wherein Ars is either naphthyl or ;phenyl, each optionally substituted with 1 to 5 substituen.ts each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONH2, CN, acetoxy, ' . 79565-8 (S) 9a benzyl, benzyloxy, ~,a-dimethylbenzyl, NOz, CHO, CH3CH(OH), acetyl, ethylene dioxy, and -CH=CH-phenyl;
Ar6 is phenyl substituted with 1 t:o 5 substituents each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONHa, CN, carbomethoxy, OCHzC (O) CzHs and OCHzC (0) OCZHS
and acetoxy, provided that at lea:at one substituent is OCHZC (O) OCaHS;
Rll is hydrogen or methyl; and Rlz is hydrogen or methyl;
provided that at least one of R11 and Rla is methyl; or a pharmaceutically acceptable salt or complex thereof.
In a further preferred aspect, the invention relates to a compound having the i:ormula:
H
sECitr.~. ~s r~:';: . . N Ar4 s~Er~f. y COFiRECTICN~ h~~ ~ ..
dour C~RI ~h:i~r,' wherein Ar3 is either naphthyl or phenyl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, met.hylene dioxy, lower haloalkyl, lower haloalkoxy, OH, C'.HzOH, CONHz, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO2, CHO, CH3CH(OH), 2 5 N ( CH3 ) a , acetyl , and ethyl ene di ox;r;
Ar4 is either naphthyl or phenyl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, i . . i1 , . n ~ I

. 79565-8 (S) 9b lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH20H, CONH2, CN, and acetoxy;
provided that:
if Ar4 is 3-methoxyphen~=1, then Ar3 is a substituted phenyl that is not a 2-methoxy, 3-methyl, 2-methyl, 4-methyl, 2,4-dimethyl, 2,4,6-trimethyl, or 4-isopropyl substituted phenyl; and if Ar4 is unsubstituted phenyl, then Ar3 is a substituted phenyl that is not 2-nitrophenyl, 4-nitrophenyl, or 4-dimethylaminophenyl;
Ra is either hydrogen or phenyl;
R9 is either hydrogen or methyl; and Rla is either hydrogen, methyl, or phenyl;
or a pharmaceutically acceptable ;salt or complex thereof.
Another aspect of the present invention features a pharmaceutical composition made up of an inorganic ion receptor-modulating compound described herein and a physiologically acceptable carrier. A "pharmacological composition" refers to a composition in a form suitable for administration into a mammal, preferably a human.
Preferably, the pharmaceutical composition contains a sufficient amount of a calcium receptor modulating compound in a proper pharmaceutical form to exert a therapeutic effect on a human. Pharmaceutical compo~.itions of the invention may be contained in a commercial package, optionally together with instructions for the use thereof as herein described.
Considerations concerning forms suitable for administration are known in the art and include toxic effects, solubility, route of administration, and maintaining WO 96/12697 PCTlUS9511370.~
activity. -For example, pharmacological- compositions injected into the blood stream should be soluble.
a Pharmaceutical compositions can also be formulated as pharmaceutically acceptable salts (e. g., acid addition 5 salts) and complexes thereof. The preparation of such salts can facilitate the pharmacological use of a compound by altering its physical characteristics without prevent ing it from exerting a physiological effect.
Another aspect the present invention features a 10 method for treating a patient by modulating inorganic ion receptor activity using inorganic ion receptor modulating compounds described herein. The method involves adminis tering to the patient a pharmaceutical composition con taining a therapeutically effective amount of an inorganic ion receptor-modulating compound. In a preferred embodi-ment, the disease or disorder is treated by modulating calcium receptor activity by administering to the patient a therapeutically effective amount of a calcium receptor-modulating compound.
Inorganic ion receptor-modulating compounds, and compositions containing the compounds, can be used to treat patients. A "patient" refers to a mammal in which modulation of an inorganic ion receptor will ::ave a bene-ficial effect. Patients in need of treatment involving modulation of inorganic ion receptors can be identified using standard techniques known to those in the medical profession.
Preferably, a patient is a human having a disease or disorder characterized by one more of the following: (1) abnormal inorganic ion homeostasis, more preferably abnormal calcium homeostasis; (2) an abnormal level of a messenger whose production or secretion is affected by inorganic ion receptor activity, more preferably affected by calcium receptor activity; and (3) an abnormal level or ' activity of a messenger whose function is affected by inorganic ion receptor activity, more preferably affected by calcium receptor activity.
SUBSTITUTE SHOE T (RULF 26) Diseases characterized by abnormal calcium homeo-stasis include hyperparathyroidism, osteoporosis and other bone and mineral-related disorders, and the like (as described, e.g., in standard medical text books, such as "Harrison's Principles of~ Internal Medicine"). Such diseases are treated using calcium receptor-modulating compounds which mimic or block one or more of the effects of extracellular Caz' on a calcium receptor and, thereby, directly or indirectly affect the levels of proteins or other compounds in the body of the patient.

By "therapeutically effective amount" is meant an amount of a compound which relieves to some extent one or more symptoms of the disease or disorder in the patient;

or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder.

In a preferred embodiment, the patient has a disease or disorder characterized by an abnormal level of one or more calcium receptor-regulated components and the com-pound is active on a calcium receptor of a cell selected from the group consisting of: parathyroid cell, bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, keratinocyte in the epidermis, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, cardiac atrial cell, gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell, mammary cell, beta cell, fat/adipose cell, immune cell, GI tract cell, skin cell, adrenal cell, pituitary cell, hypothalamic cell and cell of the subfornical organ.

More preferably, the cells are chosen from the group consisting of: parathyroid cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascending limb of Henle's loop and/or collecting duct in the kidney, parafollicular cell in the thyroid (C-cell), SUBSTITUTE SHEET (RULE 26) ' ~ ~ ~ 79565-8 (S) intestinal cell, GI tract cell, pituitary cell, hypothalamic cell and cell of the subformcal organ.
In a preferred embodiment, the compound is a calcimimetic acting on a parathyr~~id cell calcium receptor and reduces the level of parathyr~~id hormone in the serum of the patient. More preferably, th~= level is reduced to a degree sufficient to cause a decrease in plasma Ca2+. Most preferably, the parathyroid hormo=ze level is reduced to that present in a normal individual.
In another preferred embodiment, the compound is a calcilytic acting on a parathyroid cell calcium receptor and increases the level of parathyroid hormone in the serum of the patient. More preferably, the level is increased to a degree sufficient to cause an inc=cease in bone mineral density of a patient.
Patients in need of such treatments can be identified by standard medical tec=hniques, such as blood or urine analysis. For example, by detecting a deficiency of protein whose production or secretion is affected by changes in inorganic ion concentrations, or by detecting abnormal levels of inorganic ions or hormones which effect inorganic ion homeostasis.
In particularly preferred embodiments, the compounds of the invention are employed for:
~ inhibiting bone resorption in a patient;
~ treating a patient having a disease selected from the group consisting of hyperparat:hyroidism, a hypercalcemic disorder, osteoporosis and renal osteodystrophy;

i ii . 1 ~ 1 ' ~ ~ 79565-8 (S) 12a ~ treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis; and ~ decreasing parathyroid hormone level in a patient.
Various examples are used throughout the application. These examples are not intended in any way to limit the invention.
Other features and adva:ztages of the invention will be apparent from the followi:zg figures, detailed description of the invention, examples, and the claims.
Brief Description of the Drawings Figs. la-lr, show the chemical structures of different compounds.
Figs. 2-131 provided ph~~sical data for representative compounds herein df~scribed.

WO 96/12697 PCT/US95/1370a Description of the Preferred Embodiments The present invention features compounds able to modulate one or more inorganic ion receptor activities, preferably the compound can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca2* and the effect is on a cell having a calcium receptor.
Publications concerned with the calcium activity, calcium receptor and/or calcium receptor modulating compounds include the following: Brown et al., Nature 366: 574, 1993; Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959; Nemeth et al., PCT/US92/07175, International Publication Number WO
93/04373; Shoback and Chen, J. Bone Mineral Res. 9: 293 (1994); and Racke et al., FEBS Lett. 333: 132, (1993).
These publications are not admitted to be prior art to the claimed invention.
I. Calcium Receptors Calcium receptors are present on different cell types and can have different activities in different cell types.
The pharmacological effects of the following cells, in response to calcium, is consistent with the presence of a calcium receptor: parathyroid cell, bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascend-ing limb of Henle's loop and/or collecting duct, keratino-cyte in the epidermis, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, cardiac atrial cell, gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell, mammary cell, beta cell, fat/adipose cell, immune cell, GI tract cell, skin cell, adrenal cell, pituitary cell, hypothala-mic cell and cell of the subfornical organ. In addition, the presence of calcium receptors on parathyroid cell, central nervous system cell, peripheral nervous system SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTIUS95/1370.~
cell, cell of the thick ascending limb of Henle's loop and/or collecting duct in the kidney, parafollicular cell in the thyroid (C-cell), intestinal cell, GI tract cell, pituitary cell, hypothalamic cell and cell of the sub s fornical organ, has been confirmed by physical data.
The calcium receptor on these different cell types may be different. It is also possible that a cell can have more than one type of calcium receptor. Comparison of calcium receptor activities and amino acid sequences from different cells indicate that distinct calcium receptor-types exist. For example, calcium receptors can ~x , respond to a variety of di- and trivalent cations . The parathyroid calcium receptor responds to calcium and Gd3', while osteoclasts respond to divalent cations such as calcium, but do not respond to Gd3'. Thus, the parathyroid calcium receptor is pharmacologically distinct from the calcium receptor on the osteoclast.
On the other hand, the nucleic acid sequences encoding calcium receptors present in parathyroid cells and C-cells indicate that these receptors have a very similar amino acid structure. Nevertheless, calcimimetic compounds exhibit differential pharmacology and regulate different activities at parathyroid cells and C-cells.
Thus, pharmacological properties of calcium receptors may vary significantly depending upon the cell type or organ in which they are expressed even though the calcium receptors may have similar or even identical structures.
Calcium receptors, in general, have a low affinity for extracellular Ca2' (apparent Kd generally greater than about 0.5 mM). Calcium receptors may include a free or bound effector mechanism as defined by Cooper, Bloom and Roth, "The Biochemical Basis of Neuropharmacology", Ch. 4, ' and are thus distinct from intracellular calcium receptors, e.g., calmodulin and the troponins. ' Calcium receptors respond to changes in extracellular calcium levels. The exact changes depend on the particu-lar receptor and cell line containing the receptor. For SUBSTITUTE SHEET (RULE 26) example, the in vitro effect of calcium on the calcium receptor in a parathyroid cell includes the following:

1. An increase in internal calcium. The increase is due to the influx of external calcium and/or to 5 mobilization of internal calcium. Characteristics of the increase in internal calcium include the following:, (a) A rapid (time to peak < 5 seconds) and transient increase in [Caz']
that is refractor to i y inhibition by 1 ~M La3' or 1 ~.M Gd3* and is abolished by 10 pretreatment with ionomycin (in the absence of extracellular Ca2') - (b) The increase is not inhibited by dihydro-pyridines;

(c) The transient increase is abolished by pre-15 treatment for 10 minutes with 10 mM sodium fluoride;

(d) The transient increase is diminished by pretreatment with an activator of protein kinase C (PKC), such as phorbol myristate acetate (PMA), mezerein or (-)-indolactam V. The overall effect of the protein kinase C

activator is to shift the concentration-response curve of calcium to the right without affecting the maximal -.- response; and (e) Pretreatment with pertussis toxin (100 ng/ml for > 4 hours) does not affect the increase.

2.-- A rapid (< 30 seconds) increase in the formation of inositol-1,4,5-triphosphate or diacylglycerol. Pre-treatment with pertussis toxin (100 ng/ml for > 4 hours) does not affect this increase;

3. The inhibition of dopamine- and isoproterenol-stimulated cyclic AMP formation. This effect is blocked by pretreatment with pertussis toxin (100 ng/ml for > 4 i hours); and 4. The inhibition of PTH secretion. Pretreatment with pertussis toxin (100 ng/ml for > 4 hours) does not affect the inhibition in PTH secretion.

Using techniques known in the art, the effect of calcium on other calcium receptors in different cells can SUBSTITUTE SHEET (RULE 26) be readily determined. Such effects-may be -similar in regard to the increase in internal calcium observed in parathyroid cells. However, the effect is expected to differ in other aspects, such as causing or inhibiting the release of a hormone other~than parathyroid hormone.
II Inorganic Ion Receptor Modulating Compounds Inorganic ion receptor modulating compounds modulate one or more inorganic ion receptor activities. Preferred calcium receptor modulating-compounds-are calcimimetics and calcilytics. Inorganic ion receptor modulating com pounds can be identified by screening compounds which are modelled after a compound shown to have a particular activity (i.e., a lead compound).
A preferred method of measuring calcium receptor activity is to measure changes in [Ca2+]i. Changes in [Ca2']i can be measured using different techniques such by using HEK 293 cells transduced with nucleic acid express ing the human parathyroid calcium receptor and loaded with fura-2; and by measuring an increase in C1- current in a Xenopus oocyte injected with nucleic acid coding for a calcium receptor. (See Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959.) For example, poly(A)t mRNA can be obtained from cells express-ing a calcium receptor, such as a parathyroid cell, bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, keratinocyte in the epidermis, parafollicular cell in the thyroid (C-cell), intestinal cell, central nervous cell, peripheral nervous system cell, platelet, vascular smooth muscle'cell, cardiac atrial cell, gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell, mammary cell, beta cell, fat/adipose cell, immune cell, and GI
track cell. Preferably, the nucleic acid is from a parathyroid cell, C-cell, or osteoclast. More preferably, SUBSTITUTE SHEET (RULE 26) WO 96112697 . PCT/US95I13704 the nucleic acid encodes a calcium receptor and is present on a plasmid or vector.
In preferred embodiments the calcium receptor modulating compound is a calcimimetic which inhibits bone resorption in vivo by an osteoclast; inhibits bone resorp tion in vitro by an osteoclast; stimulates calcitonin secretion in vitro or in vivo from a c-cell; inhibits parathyroid hormone secretion from a parathyroid cell in vitro and decreases PTH secretion in vivo; elevates calcitonin levels in vivo; or blocks osteoclastic bone resorption in vitro and inhibits bone resorption in vivo.
_3. _ -In another preferred embodiment the calcium receptor modulating compound is a calcilytic which evokes the secre tion of parathyroid hormone from parathyroid cells in vitro and elevates the level of parathyroid hormone in vi vo . ' Preferably, the compound selectively targets inorganic ion receptor activity, more preferably calcium receptor activity, in a particular cell. By "selectively"
is meant that the compound exerts a greater effect on inorganic ion receptor activity in one cell type than at another cell type for a given concentration of compound.
Preferably, the differential effect is 10-fold or greater.
Preferably, the concentration refers to blood plasma concentration and the measured effect is the production of extracellular messengers such as plasma calcitonin, para-thyroid hormone or plasma calcium. For example, in a preferred embodiment, the compound selectively targets PTH
secretion over calcitonin secretion.
In another preferred embodiment, the compound has an ECso or ICso less than or equal to 5 uM at one or more, but not all cells chosen from the group consisting of: para-thyroid cell, bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, keratinocyte in the epi-SUBSTITUTE SHEET (RULE 26) dermis, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, cardiac atrial cell, gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell, mammary cell, beta cell, fat/adipose cell, immune cell, GI tract cell, skin cell, adrenal cell, pituitary cell, hypothalamic cell and cell of the subfornical organ. More preferably, the cells are chosen from the group consisting of parathyroid cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascending limb of Henle's loop and/or collecting duct in the kidney, parafollicular cell in the thyroid (C-cell), intestinal cell, GI tract cell, pituitary cell, hypothalamic cell and cell of the sub-fornical organ. The presence of a calcium receptor in this group of cells has been confirmed by physical data such as in situ hybridization and antibody staining.
Preferably, inorganic ion receptor modulating com-pounds mimic or block the effects of an extracellular ion on a cell having an inorganic ion receptor, such that the compounds achieve a therapeutic effect. Inorganic ion receptor modulating compounds may have the same, or dif-ferent, effects on cells having different types of inor-ganic ion receptor morphology (e. g., such as cells having normal inorganic ion receptors, a normal number of inor-ganic ion receptor, an abnormal inorganic ion receptor, and an abnormal number of inorganic ion receptors).
Calcium receptor modulating compounds preferably mimic or block all of the effects of extracellular ion in a cell having a calcium receptor. However, calcimimetics need not possess all the biological activities of extra cellular Ca2'. Similarly, calcilytics need not block all of the activities caused by extracellular calcium. Addi-tionally, different calcimimetics and different calci-lytics do not need to bind to the same site on the calcium receptor as does extracellular Cap' to exert their effects.
Inorganic modulating compounds need not effect inor ganic receptor activity to the same extent or in exactly SUBSTITUTE SHEET {RULE 26) WO 96/12697 PCT/US9~/13704 the same manner as the natural ligand. For example, a calcimimetic may effect calcium receptor activity to a different extent, to a different duration, by binding to a different binding site, or by having a different affin-ity, compared to calcium acting at a calcium receptor.
A. Calcimimetics 1. Structure I Compounds Structure I compounds able to modulate calcium receptor activity have the following formula:
H
~r Sri R ~f-~
where, Arl 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONHZ, CN, acetoxy,-N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, N02, CHO, CH3CH(OH), acetyl, ethylene dioxy, preferably each substituent is independently selected from the group consisting of, CH3, CH30, CH3CHz0, methylene dioxy, Br, C1, F, I, CF3, CHF2, CHZF, CF30, 2 0 CF3CHz0 , CH3S , OH , CHzOH, CONHZ , CN, NOz , CH3CH2 , propyl , isopropyl, butyl, isobutyl, t-butyl, and acetoxy. More preferably, Arl is either a naphthyl or a phenyl having 1-5 substituents each independently selected from the group consisting of isopropyl, CH30, CH3S, CF30, I, C1, F, CF3, and CH3, more preferably CF30, I, C1, F, and CF3;
Ar2 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, SUBSTITUTE SHEET (RULE 26) WO 96!12697 PCTIUS95113704 halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONHz, CN, and acetoxy,-preferably each substituent is independently selected from the group consisting of, CH3, CH30, CH3CH20, 5 methylene dioxy, Br, C1, ~F, I, CF3, CHF2, CHZF, CF30, ' CF3CH20, CH3S, OH, CHZOH, CONH2, CN, NO2, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy. More preferably, Arz is either a naphthyl or a phenyl having 1-5 substituents each independently selected from the group 10 consisting of isopropyl, CH30, CH3S, CF30, I, C1, F, CF3,, and CH3, more preferably CF30, I, Cl, F, CH30, and CF3.
q is 0, l, 2, or 3; and R is either H, or CH3;
and pharmaceutically salts and complexes thereof.
15 "Lower alkyl" refers to a saturated hydrocarbon having 1-4 carbons, preferably 1-3 carbon atoms, which may be straight chain or branched.
"Lower alkoxy" refers to "O-lower alkyl!'. Where "O"
is an oxygen joined to a lower alkyl.-20 "Lower thioalkyl" refers to "S-lower alkyl". Where "S" is a sulfur joined 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. More preferably, the lower haloalkyl contains 1 .carbon. Preferably, the halogen substitutions are either C1 or F.
"Lowerhaloalkoxy" refers to "O-lower haloalkyl".
Where "O" is an oxygen joined to a lower haloalkyl.
a. Arl and Ar2 are Both Optionally Substituted Phenyls In a preferred embodiment both Arl and Ar2 are optionally substituted phenyls and the compound has-following formula:
SUBSTITUTE SHEET (RULE 26) ~ n H ~ rti N

where R is hydrogen or methyl m and n are each independently 0, 1, 2, 3, 4, or 5;

each X is independently selected from the group con-sisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower halo-alkoxy, OH, CHzOH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, ~,c~-dimethylbenzyl, N02, CHO, CH3CH (OH) , acetyl, ethylene dioxy. Preferably each X
is independently selected from the group consisting of, CH3, CH30, CH3CH20, methylene dioxy, Br, C1, F, I, CF3, CHF2, CHZF, CF30, CF3CHz0, CH3S, OH, CHZOH, CONH2, CN, NO2, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy.

More preferably, each X is independently selected from the group consisting of isopropyl, CH30, CH3S, CF30, I, C1, F, CF3 , and CH3 , more pre f erably CF30 , I , C1, F , and CF3 ;

each Z is independently selected from the group con-sisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower halo-alkoxy, OH, CHzOH, CONHz, CN, and acetoxy. Preferably each Z is independently selected from the group consisting of, CH3, CH30, CH3CH20, methylene dioxy, Br, C1, F, I, CF3, CHFZ, CHZF, CF30, CF3CH20, CH3S, OH, CHZOH, CONH2, CN, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy.

More preferably, each Z is independently selected from the group consisting of, isopropyl, CH30, CH3S, CF30, CF3, I, Cl , F , and CH3 .

In a more preferred embodiment, at least one of the Z substituents is in the meta position. More preferably, the compound has the following formula:

SUBSTITUTE SHEET (RULE 26) ~n H
N
OCH,3 where R is either hydrogen or methyl;
m is 0, 1, 2, 3, 4, or 5, preferably 1 or 2;
and each X is independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower halo alkoxy, OH, CHzOH, CONH2, CN, acetoxy, N(CH3)z, phenyl, phenoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, N02, CHO, CH3CH(OH), acetyl, ethylene dioxy, preferably each substi-tuent is independently selected from the group consisting of, CH3, CH30, CH3CHz0, methylene dioxy, Br, C1, F, I, CF3, CHF2, CHZF, CF30, CF3CHz0, CH3S, OH, CHZOH, CONHz, CN, NO2, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy, more preferably, isopropyl, CH30, CH3S, CF30, CF3, I, C1, F, and CH3.
More preferably, the compound has the formula:
Rt H
N

where R is either hydrogen or methyl;
R1 is either halogen or hydrogen, preferably R1 is either F, or hydrogen;
SUBSTITUTE ShI~EET (RULE 26) RZ is either hydrogen, halogen, lower alkyl, lower haloalkyl, or lower haloalkoxy, preferably, RZ is either hydrogen, CF3, CH3, OCF3, or F, and R3 is either hydrogen, halogen, or alkoxy, preferably, R3 is either Cl, F, hydrogen, or methoxy, more preferably methoxy.
In alternative more preferred combinations; at least two of R1, R2, and R3 is halogen, preferably F and R is hydrogen or CH3; R is hydrogen or CH3, Rz is either lower haloalkyl, or lower haloalkoxy, preferably OCF3 or CF3, and Rl and R3 is hydrogen; and R is CH3, R3 is halogen, prefer ably C1, R1 is either halogen or hydrogen, preferably F or hydrogen, and RZ is either hydrogen, lower alkyl, lower haloalkyl, or lower haloalkoxy, preferably, hydrogen, CF3, CH3 , OCF3 , or F .
b. Arz is Naphthyl and q is 0 In another preferred embodiment, Arz is naphthyl, q is 0, and the compound has the formula:
H
~4r~ N
R
where Arl 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, cx,a-dimethylbenzyl, NOz, CHO, CH3CH(OH), acetyl, ethylene dioxy, preferably each substituent is independently selected from the group consisting of, CH3, CH30, CH3CHz0, SUBSTITUTE SWEET (RULE 26) methylene dioxy, Br, C1, F, I, CF3, CHF2, CHZF, CF30, CF3CHz0, CH3S, OH, CHZOH, CONHz, CN, NO2, CH3CHz, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy. More ' preferably, Ar, is either a naphthyl or a phenyl having 1-5 substituents each independently selected from the group ' consisting of isopropyl, CH30, CH3S, CF3, CF30 I, C1, F, and More preferably, Arl is an optional substituted phenyl where the compound has the formula:
N
R Ct-(3 where Xn represents the optional substituents for the optionally substituted phenyl as described above (with the preferred substituents and number of substituents as described above).
Even more preferably the compound has the formula:
I H I
M

R Gt-[3 '', where R is either CH3 or hydrogen;
R4 is either lower alkyl, halogen, or alkoxy, preferably isopropyl, chlorine, or methoxy; and RS is either hydrogen, lower alkyl, or halogen, preferably methyl, CH3, Br, or C1. -SUBSTITUTE SHEET (RULE 26) c. Ar2 is Naphthyl and q is 2 In another preferred embodiment, Arl is a substituted t phenyl, Arz is naphthyl, q is 2 and the compound has the formula:

H I
'~ N

where R is either hydrogen or CH3;
n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2; and each X is independently selected from the group consisting of, lower alkyl, halogen, lower alkox~~, lower 10 thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, acetoxy, N(CH3)z, phenyl, phenoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy, preferably each .,.. substituent is independently selected from the group 15 consisting of, CH3, CH30, CH3CH20, methylene dioxy, Br, C1, F, I, CF3, CHF2, CHZF, CF30, CF3CHz0, CH3S, OH, CHZOH, CONH2, CN, NO2, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy, more preferably, isopropyl, CH30, CH3S, CF30, CF3, I, C1, F, and CH3.
20 More preferably, the compound has the formula:

Rb a H
N
SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US95l1370.1 where R6 is either is either hydrogen, lower haloalkyl, or lower haloalkoxy, preferably hydrogen, OCF3 or CF3 ; and R., is either halogen or hydrogen, preferably chlorine or hydrogen. ' ' In other embodiments R, R6 and R., are as described above (with the preferred substituents as described above), provided that when both R and R6 are hydrogen, R, is not C1; and R is CH3, and R6 and R, is as described above l0 (with the preferred substituents as described above).
_2. Structure II Compounds Structure II compounds have the formula:
~9 ~r3 N ~4r~, P~ R10 O~
where Ar3 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONHz, CN, acetoxy, benzyl, benzyloxy, c~,a-dimethylbenzyl, NOZ, CHO, CH3CH(OH), N(CH3)2, acetyl, ethylene dioxy, preferably N(CH3)z, lower alkoxy, or lower alkyl;
Ar4 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, , and acetoxy, preferably lower alkoxy, more preferably methoxy;
R8 is either hydrogen or phenyl, preferably hydrogen;
SUBSTITUTE SHEET (RULE 26) R9 is either hydrogen or methyl; and Rlo is either hydrogen, methyl, or phenyl, more ' preferably when Rlo is methyl the chiral carbon it is attached to is the (R) stereoisomer.
Preferably, the a-methyl in Structure II is an (R)-a-methyl.
3. Structure III Compounds Structure III compounds have the formula:
H
~r~ hxl ~r~, X11 fit where 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, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHZOH, CONH2, CN, acetoxy, benzyl, benzyloxy, a,a-dimethylbenzyl, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy, -CH=CH-phenyl, prefer-ably, lower alkyl, phenoxy, -CH=CH-phenyl, dimethylbenzyl, methoxy, methylene, or ethylene;
Ars is either naphthyl or phenyl optionally substi tuted with 0 to 5 substituents each independently selected from the group consisting of, acetyl, lower alkyl, halo gen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CHzOH, CONHZ, CN, carbo methoxy, OCHZC (O) CzHs and acetoxy, preferably methoxy, lower alkyl, phenyl, halogen, CF3, CN, carbomethoxy or, OCHZC (O) CzHs;
' R1~ is hydrogen or methyl, preferably when Rll is methyl the carbon to which it is attached is an (R) stereoisomer; and SUBSTITUTE SH~ET (RULE 26) R1z is hydrogen or methyl, preferably when RlZ is methyl the carbon to which it is attached is an (R) stereoisomer.
_4. Calcimimetic Activ'ity ~
The ability of compounds to mimic the- activity of CaZ+
at calcium receptors can be determined using procedures known in the art and described by Nemeth et al., PCT/US93/
01642, International Publication Number WO 94/18959. For example, calcimimetics possess one or more and preferably all of the following activities when tested on parathyroid cells in vitro:
1. The compound causes a rapid (time to peak < 5 seconds) and transient increase in intracellular calcium concentration that is refractory to inhibition by 1 ~.M La3+ or 1 ~.M Gd3~. The increase in [Caz+] i persists in the absence of extracellular Ca2+, but is abolished by pre-treatment with ionomycin (in the absence of extracellular Ca2') ;
2 . The compound potentiates increases in [Ca2'] i elicited by submaximal concentrations of extracellular Ca2' 3 . The increase in (Ca2+] i elicited by extracellular Ca2+ is not inhibited by dihydropyridines;
4 . The transient increase in [Ca2+] i caused by the compound is abolished by pretreatment for 10 minutes with 10 mM sodium fluoride;
5. The transient increase in [Caz']i caused by the compound is diminished by pretreatment with an activator of protein kinase C (PKC), such as phorbol myristate acetate (PMA), mezerein or (--)-indolactam V.
The overall effect of the protein kinase C activator is to shift the concentration-response curve of the compound to, the right without affecting the maximal response;
6. The compound causes a rapid (< 30 seconds) increase in the formation of inositol-1,4,5-triphosphate and/or diacylglycerol;
SUBSTITUTE SHEET (RULE 26) WD 96/12697 PCTlUS95/13704 7. The compound inhibits dopamine- or isopro-terenol-stimulated cyclic AMP formation;

8. The compound inhibits PTH secretion;

9. Pretreatment with pertussis toxin (100 s 5 ng/ml for > 4 hours) blocks the inhibitory effect of the compound on cyclic AMP formation, but does not effect increases in [Ca2']i, inositol-1,4,5-triphosphate, or diacylglycerol, nor decreases in PTH secretion;

10. The compound elicits increases in C1-current in Xenopus oocytes inj ected with poly (A) +-enriched mRNA from bovine or human parathyroid cells, but is without effect in Xenopus oocytes injected with water, or liver mRNA; and 11. Similarly, using a cloned calcium receptor from a parathyroid cell, the compound will elicit a response in Xenopus oocytes injected with the specific cDNA or mRNA encoding the receptor.

Different calcium activities can be measured using available techniques. (See, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959.) Parallel definitions of compounds mimicking Caz" activity on other calcium responsive cell, preferably at a calcium receptor, are evident from the examples provided herein and Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959.

Preferably, the compound as measured by the bioassays described herein, or by Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, has one or more, more preferably all of the following activities:

evokes a transient increase in internal calcium, having a duration of less that 30 seconds (preferably by mobilizing ' internal calcium) ; evokes a rapid increase in [Caz']

i, occurring within thirty seconds; evokes a sustained increase (greater than thirty seconds) in [Ca2+]i (prefer-ably by causing an influx of external calcium); evokes an increase in inositol-1,4,5-triphosphate or diacylglycerol levels, preferably within less than 60 seconds; and SUBSTITUTE SHEET (RULE 26) inhibits dopamine- or isoproterenol-stimulated cyclic AMP
formation.
The transient increase in ICa2']i is preferably ' abolished by pretreatment of the cell for ten minutes with 5 10 mM sodium fluoride, or the transient increase is dimin-fished by brief pretreatment (not more than ten minutes) of the cell with an activator of protein kinase C, prefer-ably, phorbol myristate acetate (PMA), mezerein or (-) indolactam V.
10 C. Calcilytics The ability of a compound to block the activity of extracellular calcium at a calcium receptor can be deter-mined using standard techniques based on the present disclosure. (See, also Nemeth et al., PCT/US93/01642, 15 International Publication Number WO 94/18959.) For example, compounds which block the effect of extracellular calcium, when used in reference to a parathyroid cell, possess one or more, and preferably all of the following characteristics when tested on parathyroid cells in vitro:
20 1. The compound blocks, either partially or completely, the ability of increased concentrations of extracellular CaZ' to (a) increase [Caz'] i, (b) mobilize intracellular Ca2+, 25 (c) increase the formation of inositol-1,4,5-triphosphate, (d) decrease dopamine- or isoproterenol-stimulated cyclic AMP formation, and (e) inhibit PTH secretion;
30 2. The compound blocks increases in Cl- current in Xenopus oocytes inj ected with poly (A) +-mRNA f rom bovine or human parathyroid cells elicited by extracellular Ca~+ or calcimimetic compounds, but not in Xenopus oocytes , injected with water or liver mRNA;
3. Similarly, using a cloned calcium receptor from a parathyroid cell, the compound will block a response in SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTlUS95l13704 Xenopus oocytes injected with the specific cDNA, mRNA or cRNA encoding the calcium receptor, elicited by extracellular Ca2+ or a calcimimetic compound.
Parallel definitions of compounds blocking Ca2' activity on a calcium responsive cell, preferably at a calcium receptor, are evident from the examples provided herein and Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959.
III. TREATMENT OF DISEASES OR DISORDERS
Diseases or disorders which can be treated by modulating calcium receptor activity are known in the art.
For example, diseases or disorders which can be treated by modulating calcium receptor activity can be identified based on the functional responses of cells regulated by calcium receptor activity. Functional responses of cells regulated by calcium receptor are know in the art, includ-ing PTH secretion by parathyroid cells, calcitonin secretion by C-cells, and bone resorption by osteoclasts.
Such functional responses are associated with differ ent diseases or disorders. For example, hyperparathyroid ism results in elevated levels of PTH in the plasma.
Decreasing the plasma levels of PTH offers an effective means of treating hyperparathyroidism. Likewise, increas ing plasma levels of calcitonin is associated with an inhibition of bone resorption. Inhibiting bone resorption is an effective treatment for osteoporosis. Thus, modula-tion of calcium receptor activity can be used to treat diseases such as hyperparathyroidism, and osteoporosis.
Those compounds modulating inorganic ion receptor activity, preferably calcium receptor activity, can be used to confer beneficial effects to patients suffering from a variety of diseases or disorders. For example,,-.
osteoporosis is an age-related disorder characterized by loss of bone mass and increased risk of bone fracture.
Compounds can be used to block osteoclastic bone resorp-tion either directly (e. g., an osteoclast ionomimetic SUSSTITI~TE St+EET (RULE 26) compound) or indirectly by increasing endogenous calci-tonin levels (e. g., a C-cell calcimimetic). Alterna-tively, a calcilytic active on the parathyroid cell cal- ' cium receptor will increase circulating levels of para-thyroid hormone, stimulating bone formation. All three of these approaches will result in beneficial effects to patients suffering from osteoporosis.
In addition, it is known that intermittent low dosing with PTH results in an anabolic effect on bone mass and appropriate bone remodeling. Thus, compounds and dosing regimens evoking transient increases in parathyroid hor-mone (e. g., intermittent dosing with a parathyroid cell ionolytic) can increase bone mass in patients suffering from osteoporosis.
Additional diseases or disorders can be identified by identifying additional cellular functional responses, associated with a disease or disorder, which are regulated by calcium receptor activity. Diseases or disorder which can be treated by modulating other inorganic ion receptors can be identified in an analogous manner.
The inorganic ion receptor-modulating compounds of the present invention can exert an affect at an inorganic ion receptor causing one or more cellular effects ulti-mately producing a therapeutic effect. Calcium receptor-modulating compounds of the present invention can exert an effect on calcium receptor causing one or more cellular effects ultimately producing a therapeutic effect.
Different diseases can be treated by the present invention by targeting cells having a calcium receptor.
For example, primary hyperparathyroidism (HPT) is characterized by hypercalcemia and abnormal elevated levels of circulating PTH. A defect associated with the major type of HPT is a diminished sensitivity of para-thyroid cells to negative feedback regulation by extra- Y
cellular Ca2'. Thus, in tissue from patients with primary HPT, the "set-point" for extracellular Ca2+ is shifted to the right so that higher than normal concentrations of SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US9~I13704 extracellular Ca2' are required to depress PTH secretion.

Moreover, in primary HPT, even nigh concentrations of extracellular Ca2' often depress PTH secretion only partially. In secondary (uremic) HPT, a similar increase in the set-point for extracellular Ca2' is observed even though the degree to which Ca2+ suppresses PTH secretion is normal. The changes in PTH secretion are paralleled by changes in [Ca2'] i : the set-point for extracellular Ca2'-induced increases in [Ca2+] i is shifted to the right and the magnitude of such increases is reduced.

Patients suffering from secondary HPT may also have renal osteodystrophy. Calcimimetics appear to be useful for treating both abnormal PTH secretion and osteodys-trophy in such patients.

Compounds that mimic the action of extracellular Caz' are beneficial in the long-term management of both primary and secondary HPT. Such compounds provide the added impe-tus required to suppress PTH secretion which the hypercal-cemic condition alone cannot achieve and, thereby, help to relieve the hypercalcemic condition. Compounds with greater efficacy than extracellular Ca2' may overcome the apparent nonsuppressible component of PTH secretion which is particularly troublesome in the major form of primary HPT caused by adenoma of the parathyroid gland.

Alternatively or additionally, such compounds can depress synthesis of PTH, as prolonged hypercalcemia has been shown to depress the levels of preproPTH mRNA in bovine and human adenomatous parathyroid tissue. Prolonged hypercalcemia also depresses parathyroid cell prolifera-tion in vitro, so calcimimetics can also be effective in limiting the parathyroid cell hyperplasia characteristic of secondary HPT.

Cells other than parathyroid cells can respond directly to physiological changes in the concentration of extracellular Caz' . For example, calcitonin secretion from parafollicular cells in the thyroid (C-cells) is regulated by changes in the concentration of extracellular Ca2;.

SUBSTITI!TE SHEET (RULE 26) WO 96/12697 PCTIUS95/1370-l Isolated osteoclasts respond to increases in the concentration of extracellular Ca2' with corresponding increases in [CazT] _ that arise partly from the mobilization ' of intracellular Ca2" . Increases in [Caz'] i in osteoclasts are associated with the inhibition of bone resorption.
Release of alkaline phosphatase from bone-forming osteo blasts is directly stimulated by calcium.
Renin secretion from juxtaglomerular cells in the kidney, like PTH secretion, is depressed by increased concentrations of extracellular Ca2t. Extracellular Cap causes the mobilization of intracellular Ca2+ in these cells. Other kidney cells respond to calcium as follows:
elevated Ca2+ inhibits formation of 1,25(OH)z-vitamin D by proximal tubule cells, stimulates production of calcium-binding protein in distal tubule cells, and inhibits tubular reabsorptiorL of Caz' and Mg2' and the action of vasopressin on the thick ascending limb of Henle's loop (MTAL), reduces vasopressin action in the cortical collecting duct cells, and affects vascular smooth muscle cells in blood vessels of the renal glomerulus.
Calcium also promotes the differentiation of intestinal goblet cells, mammary cells, and skin cells;
inhibits atrial natriuretic peptide secretion from cardiac atria; reduces cAMP accumulation in platelets; alters gastrin and glucagon secretion; acts on vascular smooth muscle cells to modify cell secretion of vasoactive factors; and affects cells of the central nervous system and peripheral nervous system.
Thus, there are sufficient indications to suggest that Ca2', in addition to its ubiquitous role as an intracellular signal, also functions as an extracellular signal to regulate the responses of certain specialized -cells. Compounds of this invention can be used in the , treatment of diseases or disorders associated with disrupted Ca2~ responses in these cells.
Specific diseases and disorders which might be treated or prevented, based upon the affected cells, also SUBSTITUTE SHEET (RULE 26) include those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, neurodegenerative 5 diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depres-sion, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome;

10 diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis;

hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e. g., aminoglycoside anti-15 biotics); gut motility disorders such as diarrhea, and spastic colon; GI ulcer diseases; GI diseases with excessive calcium absorption such as sarcoidosis; and autoimmune diseases and organ transplant rejection.

while calcium receptor-modulating compounds of the 20 present invention will typically be used in therapy for human patients, they may also be used to treat similar or identical diseases in other warm-blooded animal species such as other primates, farm animals such as swine, cattle, and poultry; and sports animals and pets such as 25 horses, dogs and cats.

IV. Administration The different compounds described by the present invention can be used to treat different diseases or disorders by modulating inorganic ion receptor activity, 30 preferably calcium receptor activity. The compounds of the invention can be formulated for a variety of modes of L administration, including systemic and topical or local ized administration. Techniques and formulations gener-ally may be found in Reminaton's Pharmaceutical Sciences, 35 Mack Publishing Co., Easton, PA. Administration of iono-mimetics and ionolytics is discussed by Nemeth et al., SUBSTITUTE SHEET (RULE 26) ' ~ ~ ' 79565-8 (S) PCT/US93/01642, International Publication Number WO
94/18959.
Suitable dosage forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such dosage forms should allow the compound to reach a target cell whether the target cell is present in a -multicellular host or in culture. For example, .pharmacological compounds or compositions injected into the blood stream should be soluble. Other factors are known in the art, and in~=lude considerations such as toxicity and dosage form which retard the compound or composition from exerting its effect.
Compounds can also be :=ormulated as pharmaceutically acceptable salts (e. g., acic. addition salts) and complexes thereof. Pharmaceutically ~~cceptable salts are non-toxic .
salts at the concentration at which they are administered.
The preparation of such salts can facilitate the pharmaco-logical use by altering the physical characteristic of the compound without preventing it from exerting its physio-logical effect. Useful alterations in physical properties include lowering the melting point tc facilitate trans-mucosal administration and increasinc the solubility to facilitate administering higher concentrations of the drug.
Pharmaceutically acceptable salts include acid addi tion salts such as those cc>ntaining sulfate, hydrochlor ide, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methar.~esulf ovate, ethanesulfonate, benzenesulfonate, p-tolueneauifonate, cyclohexylsulfamate and quinate. (See e.g., WO 92/20642).
Pharmaceutically acceptable salts can be obtained from ' acids such as hydrochloric acid, malefic acid, sulfuric acid, phosphoric acid, sulf:amic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-tol.uenesulfonic acid, cyclohexylsulfamic acid, arid quinic acid.

WO 96112697 PCT/US9511370.1 Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound is dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution, containing the appro-priate acid and then isolated by evaporating the solution.

In another example, a salt is prepared by reacting the free base and acid in an organic solvent.

Carriers or excipients can also be used to facilitate administration of the compound. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. The compositions or pharmaceutical composition can be administered by different routes including intrave-nously, intraperitoneal, subcutaneous, and intramuscular, orally, topically, or transmucosally.

For systemic administration, oral administration is preferred. Alternatively, injection may be used, e.g., intramuscular, intravenous, intraperitoneal, and sub-cutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably in physio-logically compatible buffers such as Hank's solution or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means, or the compounds can be administered orally. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are '' used in the formulation. Such penetrants are, generally known in the art, and include, for example, for trans-s mucosal administration, bile salts and fusidic acid deriv-atives. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be through nasal sprays, for example, or using suppositories. For SUBSTITUTE SHEET (RULE 26) oral administration, the compounds can be formulated into conventional oral administration dosage forms such as capsules, tablets, and liquid preparations.
For topical administration, the compounds of the invention can be formulated into ointments, salves, 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.
Generally, a therapeutically effective amount is between about 1 nmole and 3 .mole of the compound, preferably 0.1 nmole and 1. .mole depending on its ECSO or ICso and on the age and size of the patient, and the disease or disorder associated with the patient. Generally, 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 Examples are provided below illustrating different aspects and embodiments of the present invention. These examples are not intended to limit the claimed invention.
Example 1 Cloning of Human Parathyroid Calcium Receptor From -a Human Parathyroid Gland Adenoma Tumor This example describes the cloning of a human para-thyroid calcium receptor from a human parathyroid gland adenoma tumor using pBoPCaRl as a hybridization probe (See, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959?. The probe was used to identify nucleic acid encoding human parathyroid gland calcium receptor by cross-hybridization at reduced stringency.
Messenger RNA was prepared from a human parathyroid gland adenoma tumor removed from a 39-year-old Caucasian , male diagnosed with primary hyperparathyroidism. Northern ' blot analysis of this mRNA using pBoPCaRl as a hybridiza tion probe identified calcium receptor transcripts of about 5 Kb and about 4 Kb. A cDNA library was constructed SUBSTITUTE SHEET (RULE 26) from the mRNA. Double-stranded cDNA larger than 3 Kbp were size-selected on an agarose gel and ligated into the cloning vector lambda ZapII. Five hundred thousand primary recombinant phage were screened with the 5.2 Kbp ' 5 cDNA insert of pBoPCaRl as a hybridization probe. The pBoPCaRl insert was labeled by random-primed synthesis using [32P] -dCTP to a specific activity of 1 x 109 cpm/~,g.
Library screening was performed at a hybridization stringency of 400 mM Na', 50 o formamide at a temperature of 38°C. Plaque lift filters were hybridized at a probe concentration of 500,000 cpm/ml for 20 hours. Following hybridization, filters were washed in 1 x SSC at 40°C for 1 hr.
The primary screen identified about 250 positive clones identified by hybridization to pBoPCaRl. Seven of these clones were taken through secondary and tertiary screens to isolate single clones that hybridized to the pBoPCaRl probe. These seven clones were analyzed by restriction enzyme mapping and Southern blot analysis.

Three of the clones contained cDNA inserts of about 5 Kbp and appear to be full-length clones corresponding to the 5 Kb mRNA. Two of the clones contain cDNA inserts of about 4 Kbp and appear to be full-length clones corresponding to the 4 Kb mRNA.

Restriction enzyme mapping of the two different sized inserts indicate that they share regions of sequence simi-larity in their 5' ends, but diverge in their 3' end sequences. DNA sequence analyses indicate that the smaller insert may result from alternative polyadenylation upstream of the polyadenylation site used in the larger insert.

Representative cDNA inserts for both size classes , ' were subcloned into the plasmid vector pBluescript SK.

Linearization followed by in vitro transcription using RNA polymerase produced cRNA transcripts. The cRNA

transcripts were injected into Xenopus oocytes (150 ng/~.l RNA; 50 nl/oocyte? for functional analysis. Following SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTlUS95/I370.~
incubation periods of 2-4 days, the oocytes were assayed for the presence of functional calcium receptors. Both clone types gave rise to functional calcium receptors as assessed by the stimulation of calcium-activated chloride 5 currents upon addition of~ appropriate calcium receptor .
agonists. Known calcium receptor agonists, including NPS
R-467 and NPS R-568 (see, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959), activated the oocyte-expressed receptor at about the same concen-l0 trations known to be effective for the native parathyroid cell receptor. Thus, both clones encode a functional, human parathyroid cell calcium receptor.
Plasmids were prepared by subcloning each size class of insert into pBluescript thereby producing pHuPCaR 5.2 15 and pHuCaR 4Ø The nucleic acid sequence, and amino acid sequence, of the inserts are shown in SEQ. ID. Nos. 1 and 2.
Several differences were observed between the nucleic acid sequences of the two cDNA inserts. Sequence analyses 20 of the two cDNA inserts indicate the existence of at least two sequence variants differing in t-he 3' untranslated region and which may result from alternative polyadenyla-tion. In addition, sequence variation exists at the 5' end of the inserts. These distinct sequences correspond 25 to untranslated regions and may have arisen due to alternative transcriptional initiation and/or splicing.
Three additional sites of sequence variation are observed within the coding regions of cDNA clones pHuPCaR5.2 and pHuPCaR4.0 (see SEQ. ID. NOs. 1 and 2) 30 demonstrating that these cDNA clones encode distinct proteins. Sequence analysis of the human CaR gene indicates that the additional 30 base pairs of DNA in cDNA
clone pHuPCaR5.2, as compared to the pHuPCaR 4.0 cDNA
clone, results from alternative mRNA splicing. The 35 alternative mRNA splicing is predicted to insert 10 additional amino acids into the CaR polypeptide encoded by the pHuPCaR5.2 cDNA at a site between as#536 and as#537 in SUBSTITUTE SHEET (RULE 26) polypeptide encoded by pHuPCaR4.0 cDNA. In addition, pHuPCaR4.0 encodes glutamine (Gln) at as#925 and glycine (Gly) at, position 990 whereas pHuPCaR5.2 encodes arg (Arg) at both equivalent positions. The human CaR gene encodes ' S for Gln and Arg, respectively, at these positions. The difference between the pHuPCaR4.0 cDNA compared to human DNA appears to represent a true sequence polymorphism within the human population while the single base change in pHuPCaR5.2 probably reflects a mutation which occurred during its cloning. Both cDNAs encode functional calcium receptors as demonstrated by the ability of Xenopus oocytes injected with cRNA prepared from these cDNA clones to respond to l0 mM extracellular calcium as ascertained by C1- conductance. However, it is possible that these two receptor isoforms are functionally and/or pharmaco-logically distinct.
Example 2: Selection of StableRecombinant Cells Expressing the Calcium Receptor Clonal cell lines that stably express the two human and the bovine calcium receptors have been isolated.
Calcium receptor cDNAs were subcloned in two different, commercially available expression vectors; pMSG (obtained from Pharmacia) and Cep4B (obtained from Invitrogen) . The first vector contains the selectable marker gene for xanthine-guanine phosphoribosyltransferase (gpt) allowing stably transfected cells to overcome the blockade of the purine biosynthetic pathway imposed by addition of 2 ~Cg/ml aminopterin and 25 ~.g/ml mycophenolic acid. The second vector encodes a gene conferring resistance to the anti-biotic hygromycin (used at 200 ~,g/ml).~ HuPCaR 5.2 and HuPCaR 4.0 cDNAs (SEQ. ID. NOs. 1 and 2, respectively) ~ were removed from the parent bluescript plasmid with Not I and Hind III restriction enzymes and then either ligated directly into Not I + Hind III digested Cep4B or treated with the klenow fragment of DNA polymerase prior to blunt end ligation into Sma I digested pMSG.
SUBSTITUTE SHEET (RULE 26) The pMSG subclone containing the HuPCaR 5.2 insert was transfected into CHO cells as discussed above.
Selection has resulted in 20 resistant clones which are being characterized. The Cep4B subclone containing the HuPCaR 5.2 insert was trarisfected into HEK 293 cells as described above. Selection with hygromycin resulted in a pool of stable clones. Clones expressing the HuPCaR 4.0 receptor isoform were prepared similarly.
Cells obtained from the pool of hygromycin selected HEK 293 cells transfected with Cep4B containing the HuPCaR
5.2 insert were plated on collagen coated Aklar squares which had been placed into individual wells of 12-well tissue culture plates. Two to six days later, medium was removed and the cells washed with balanced salt solution and 1 ml of buffer containing 1 ~.M fura2-AM, 1 mM CaClz and O.la BSA and 1 mM CaCl2. Measurements of fluorescence in response to calcium receptor agonists were performed at 37°C in a spectrofluorimeter using excitation and emission wavelengths of 340 and 510 nm, respectively. For signal calibration, Fmax was determined after addition of iono-mycin (40 ~.M) and the apparent Fmin- was determined by addition of 0.3 M EGTA, 2.5 M Tris-HCl; pH 10. Robust increases in [Caz+]i were observed in response to the addition of the following calcium receptor agonists: Ca2' (1.0 mM) . Mgz' (20 mM) and NPS R-467. Control cells expressing functional substance K receptors did not respond to these calcimimetic compounds.
Additional clonal isolates of HEK 293 cells trans fected with pHuPCaR4.0 sequence were obtained. These were tested for responsiveness to calcimimetics as described above except that the cells were tested while in suspension.
SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US95l13704 Example 3: Usincr Fura-2 Loaded Parathyroid cells To Measure to Calcium Receptor Activi This section describes procedures used to obtain parathyroid cells from calves and humans, and to use the ' 5 parathyroid cells to measure calcium receptor activity.

Parathyroid glands were obtained from freshly slaughtered calves (12-15 weeks old) at a local abattoir and transported to the laboratory in ice-cold parathyroid cell buffer (PCB) which contains (mM): NaCl, 126; KC1, 4;

MgClZ, 1; Na-HEPES, 20; pH 7.4; glucose, 5.6, and variable amounts of CaCl2, e.g., 1.25 mM. Human parathyroid glands, were obtained from patients undergoing surgical removal of parathyroid tissue for primary or uremic hyperparathyroid-ism (uremic HPT), and were treated similarly to bovine tissue.

Glands were trimmed of excess fat and connective tissue and then minced with fine scissors into cubes approximately 2-3 mm on a side. Dissociated parathyroid cells were prepared by collagenase digestion and then purified by centrifugation in Percoll buffer. The resultant parathyroid cell preparation was essentially .. devoid of red blood cells, adipocytes, and capillary tissue as assessed by phase contrast microscopy and Sudan black B staining. Dissociated and purified parathyroid cells were present as small clusters containing 5 to 20 cells. Cellular viability, as indexed by exclusion of trypan blue or ethidium bromide, was routinely 950.

Although cells can be used for experimental purposes at this point, physiological responses (e. g., suppressi-bility of PTH secretion and resting levels of [Ca2']i) should be determined after culturing the cells overnight.

Primary culture also has the advantage that cells can be ' labeled with isotopes to near isotopic equilibrium, as is necessary for studies involving measurements of inositol phosphate metabolism.

After purification on Percoll gradients, cells were washed several times in a 1:1 mixture of Ham's F12-SUBSTITUTE SHEET (RULE 26) WO 96112697 PCT/i1S95J13704 Dulbecco's modified Eagle's medium (GIBCO) supplemented with 50 Jcg/ml streptomycin, 100 U/ml penicillin, 5 ~.g/ml gentamicin and ITS. ITS' is a premixed solution con-taining insulin, transferrin, selenium, and bovine serum albumin (BSA)-linolenic acid (Collaborative Research, Bedford, MA). The cells were then transferred to plastic flasks (75 or 150 cm2; Falcon) and incubated overnight at 37°C in a humid atmosphere of 5% COz. No serum is added to these overnight cultures, since its presence allows the cells to attach to the plastic, undergo proliferation, and dedifferentiate. Cells cultured under the above condi-tions were readily removed from the flasks by decanting, and show the same viability as freshly prepared cells.
Purified parathyroid cells were resuspended in 1.25 mM CaCl2-2% BSA-PCB containing 1 ~M fura-2-acetoxymethyl ester and incubated at 37°C for 20 minutes. The cells were then pelleted, re suspended in the same buffer, but lacking the ester, and incubated a further 15 minutes at 37°C. The cells were subsequently washed twice with PCB
containing 0 .5 mM CaClz and 0 .5 o BSA and-maintained at room temperature (about 20°C). Immediately before use, the cells were diluted five-fold with prewarmed 0.5 mM CaCl2 PCB to obtain a final BSA concentration of 0.1%. The con centration of cells in the cuvette used for fluorescence recording was 1-2 x 106/m1.
The fluorescence of indicator-loaded cells was measured at 37°C in a spectrofluorimeter (Biomedical Instrumentation Group, University of Pennsylvania, Philadelphia, PA) equipped with a thermostated cuvette holder and magnetic stirrer using excitation and emission wavelengths of 340 and 510 nm, respectively. This fluorescence indicates the level of cytosolic Cap+.
Fluorescence signals were calibrated using digitonin (50 ~.g/ml , f final ) to obtain maximum f luorescence ( F~X) , and - 35 EGTA (10 mM, pH 8.3, final) to obtain minimal fluorescence (Fmin)~ and a dissociation constant of 224 nM. Leakage of dye is dependent on temperature and most occurs within the _ SUBSTITUTE S>-~EET (RULE 26) WO 96/12697 PCT/US9~I13704 first 2 minutes after warming the cells in the cuvette.
Dye leakage increases only very slowly thereafter. To correct the calibration for dye leakage, cells were placed in the cuvette and stirred at 37°C for 2-3 minutes. The ' S cell suspension was then removed, the cells pelleted, and the supernatant returned to a clean cuvette. The super natant was then treated with digitonin and EGTA to esti mate dye leakage, which is typically 10-15% of the total Ca2+-dependent fluorescent signal. This estimate was 10 subtracted from the apparent Fmin.
Example 4: Using Fura-2 Loaded HEK 293/pHuPCaR4.0 Cells To Measure to Calcium Receptor Activity This section describes procedures used to assay calcium receptor activity using fura-2 loaded HEK
15 293/pHuPCaR4.0 cells. HEK 293 cells transfected with pHuPCaR4.0 were loaded with fura-2 by incubating the cells in Dulbecco's modified Eagle's media buffered with 20 mM
HEPES containing about 5 ~.M fluo-3/AM for one hour at room temperature. Cell were then rinsed with Hank's balanced 20 salt solution buffered with 20 mM HEPES containing 1 mM
CaCl2 and 1 mM MgCl2. Compounds to be tested were then added to the cells and fluorescence was measured (excitation and emission wavelengths of 340 and 510 nm, respectively).
25 Example 5: Measurincr the Ability of Compounds to Modulate Calcium Receg,tor Activity The ability of different compounds to modulate cal-cium receptor activity was assayed by measuring increases in [Caz+]i in HEK 293 cells transfected with nucleic acid 30 encoding pHuPCaR4.0 using fura-2 loaded cells or using parathyroid cells loaded with using fura-2 loaded cells.
- Results of different experiments are summarized in Tables 1.a, 1.b.1, 1.b.2, 1.c., and 2. Tables 1.a, 1.b.1, 1.b.2, and 1.c summarizes the effects of compounds, at different 35 concentrations, on calcium receptor activity assayed as SUBSTITUTE SHEET (RULE 26) described in Example 4 (i.e., using HEK 293 cells trans-fected with nucleic acid encoding pHuPCaR4.0, which were loaded with fura-2).
Table 2, summarizes the results of different experi-ments where the EC~o was 'calculated either parathyroid , cells, or HEK 293/pHuPCaR4.0, loaded with fura-2. Cells were loaded with fura-2 and assayed as described in Example 2 (for parathyroid cells) or Example 3 (for HEK
293/pHuPCaR4.0 cells).
Table 1 a Calcimimetic comt~ounds crreater which produce than 40o rest~onse at 3 mL HEK-293 cells ressincs 3 ng/ in exp the human calcium receptor.

Compound o activity Code at four concentrations (ng/mL) 3300 330 33 3.3 Reference--compounds 125 128 119 77 , 14T , 1.40 25I . 119 113 114 74 SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTlUS95/13704 Compound a activity Code at four concentrations ' ( ng/mL ) 3300 330 33 3.3 12I '115 111 93 68 16L . 146 138 98 56 17P ~ 101 86 54 . 130 115 94 50 SUBSTITUTE SHEET (RULE 26) Compound o activity Code at four concentrations (ng/mL) 3300 330 33 3.3 24P 140 138 110 46 , lOQ 103 100 84 44 lON 106 97 77 43 25P 90 81 '-= 75 41 Table 1 b 1 Calcimimetic compounds cTreater which produce than 40% response at 33 /mL HEK-293 cells ressin na in exp the human calcium receptor Compound % activity Code at four concentrations (ng/mL) 3300 330 33 3.3 Reference compounds SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US9~/13704 Compound o activity Code at four concentrations ' (ng/mL) 3300 330 33 3.3 ' 17D ~ 108 91 38 lOF 96 84 27 :LO 13G 111 128 82 29 '?0 6T 123 129 78 15 23Fi 121 114 ~~,77 28 21C=4U 134 114 76 17 SUBSTITUTE SHEET (RULE 26) Compound a activity Code at four concentrations ~n3/mL) 3300 330 33 3.3 24J - ~ 103 75 31 ' lOP 102 74 8 1gg 111 96 69 26 lOS/lOT 86 65 13 SUBSTITUTE SHEET (RULE 26) WO 96112697 PC"T/US95113704 Compound o activity Code at four concentrations ( ng/mL ) 3300 330 33 3.3 ' 22Y ' 114 64 28 lOV 99 62 8 lOW/lOX 98 61 9 17B 92 61 . 19 Table 1. b.2 Calcimimetic compounds greater which produce than 40o response at 33 HEK-293 cells ~ressina nc~/mL in ext the human calcium receptor Compound Code % activityat four concentrations (ng/mL) ----3300 330 33 3.3 reference compounds f SUBSTITUTE SHEET (RULE 26) WO 96!12697 PCTlUS95l13704 Compound Code o activity at,four concentrations ,_ 3300 330 33 3.3 lOL/lOM 99 55 4 lOW/lOX 81 53 4 12D . 128 109 52 S

18T 99 ~ 74 52 14 22X 86 48 10 ' 4p 81 46 8 SUBSTITUTE SHEET (RULE
26) WO 96/12697 PCTlUS95/13704 Compound Code o activity at four concentrations (ng/mL) i 3300 330 33 3.3 lOR 82 42 7 Table 1.c. Calcimimetic compounds which produce greater than 40 a response at 330 nct/mL in HEK-293 cells expressing the human calcium receptor Compound Code o activity at four concentrations (ng/mL) 3300 330 33 3.3 reference compounds ' 25 3H 84 SUBSTfTUTE SHEET (RULE
26) Compound Code o activity at four concentrations (ng/mL) 3300 330 33 3.3 4H . 77 37 8D _.. 75 4p 65 32 3V ~ 56 14 2Q . 56 4 14B 75 55 11 4 ' SUBSTITUTE SHEET RULE 26) Compound Code a activity at four concentrations ( ng/mL ) 3300 330 33 3.3 13.I 85 52 3 1 10 4J 47 g 3R , 45 2 Arylalkylamine Calcimimetics from Figure 1 Active at the 20 Parathyroid Cell Calcium Receptor In Vitro (ECSO < 5 ~.M) Compound Code ECso Compound Code ECso (from Fig. 1) (~,M) (from Fig. 1) (~,M) NPS R-467 2.0 11X 0.83 ' NPS R-568 0.60 11Y 2.8 25 3U 0.64 12L 1.7 3V 1.8 12U 1.2 4A 1.4 12V 0.42 4B 2.0 12W 3.2 SUBSTITUTE SHEET (RULE 26) 4C 2.0 12Y 2.0 4D 4.4 12Z 0.11 4G 1.8 13Q ca. 0.8 4H >3.0 13R 0.25 ~

4J 2.2 13S <0.13 4M 2.1 13U 0.19 4N O,g 13X <0.75 4p 1.6 14L 0.26 4R/6V 4.2 14Q 0:47 4S 3.3 14U 0.13 4T/4U 1.6 14V 1.7 4V 2.5 14Y 0.38 4W 2.3 15G ca. 0.5 4Y 1.3 16Q 0.04 4Z/5A 4.4 16R 0.36 5B/5C 2.8 16T 0.04 5W/5Y 3.6 16V <0.13 6E 2.7 16W 0.59 6F(R,R-) 0.83 16X 0.10 6R 3.4 17M 0.15 6T 2.9 170 0.04 6X 2.5 17P 0.04 7W 3.2 17R 0.39 7X 1.1 17W 0.43 8D 2.5 17X 0.02 8J 0.78 20F <1.0 8K 1.3. 20I >1.0 8R 2.6 20J >3.0 8S 1.7 20R 2.4 , 8T 1.8 20S 4.2 8U p.44 21D 3.0 8X 0.76 21F 0.38 gZ 0.40 21G 1.1 SUBSTITUTE SHEET (RULE 26) 9C 0.60 210 0.26 9D 1.4 21P 0.43 9R 0.25 21Q 1.4 9S 4.8 21R 0.37 lOF 0.89 25C > 2 11D 1.8 25D 0.019 I

Examples 6-17: Synthesis of~Compounds The compounds described herein can be synthesized using standard techniques such as those described by Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959. Examples describing representative syntheses of compounds described in the text are provided below.

Synthesis of compounds 9R, 14U, and 17P were prepared by reductive amination of a commercially available aldehyde or ketone with a primary amine in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride.

Compounds 11Y, 12H, 12K, 12M, 14S, 14T, 16L-0, 17E, 17G, 17J, 24X, 24Y, 25A, 25E-25K, and 250 were prepared in a similar manner.

It was found for the syntheses of these three compounds (9R, 14U, and 16P) that sodium triacetoxyboro-hydride afforded the desired diastereoisomers with greater diastereoselectivity than using sodium cyanoborohydride.

The enriched mixtures were further purified to a single diastereomer by normal-phase HPLC or by recystallization from organic solvents.

Compounds 8J, 8U, 11X, 17M, and 25Y were prepared A
from the condensation of a primary amine with an aldehyde or ketone in the presence of titanium(IV) isopropoxide.

The resulting intermediate imines were then reduced in situ by the action of sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride. The intermediate enamine for the synthesis of compound 8U was SUBSTITUTE SHEET (RULE 26) catalytically reduced using or palladium dihydroxide on carbon.
Compounds 12U, 12V and 12Z were prepared by a diisobutylaluminum hydride (DIBAL-H) mediated condensation of an amine with a nitrile. The resulting intermediate imine is reduced in situ by the action of sodium cyano-borohydride or sodium borohydride. The intermediate alkenes (compounds 12U and 12V) were reduced by catalytic hydrogenation in EtOH using palladium on carbon.
Compounds which were converted to their corresponding hydrochloride were done so by treatment of the free base with ethereal HC1 to afford white solids.
The amines in these syntheses were purchased from Aldrich Chemical Co., Milwaukee, WI, or from Celgene Corp., Warren, NJ, or were prepared synthetically using standard techniques. All other reagent chemicals were purchased from Aldrich Chemical Co.
Example 6~ Synthesis of Compound 25Y
N- (3- (2-Phenyl)propyl) -1- (I-naphthyl) ethyl amine A mixture of 3-phenyl-1-propylamine (135 mg, 1 mmol), 1'-acetonaphthone (170 mg, 1 mmol), and titanium (IV) iso-propoxide (355 mg, 1.3 mmol) was stirred at room tempera-ture for 1 hour. The reaction was treated with 1 M
ethanolic sodium cyanoborohydride (1 mL) and stirred 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 removed and concen-trated to a milky oil. A small portion of this material (10 mg) was purified by HPLC (Phenomenex, 1.0 x 25 cm, 5 ~,M silica) using a gradient of dichloromethane to l00 methanol in dichloromethane containing O.lo isopropyl- ' amine. This afforded the product (free base) as a single component by GC/E1-MS (Rt= 10.48 min) m/z (rel. int.) 289 (M',11) , 274 (63) , 184 (5) , 162 (5) , 155 (100) , 141 (18) , 115 (8) , 91 (45) , 77 (5) .
SUBSTITUTE SHEET (RULE 26) Example 7: Synthesis of Compound 8J

N- (3 -phenylpropyl ) -1 - (3 - thiomethylphenyl ) ethyl amine hydrochloride 3'-Aminoacetophenone (2.7 g, 20 mmol) was dissolved in 4 mL of concentrated HC1~, 4 g of ice and 8 mL of water.

The solution was cooled to OC, and sodium nitrite (1.45 g, 21 mmol) dissolved in 3-5 mL of water was added over minutes while maintaining the temperature below 6C.

Sodium thiomethoxide (1.75 g, 25 mmol) was dissolved in mL of water and cooled to 0C. To this solution was added the diazonium salt over 10 minutes while maintaining the temperature below 10C. The reaction was stirred for an additional hour while allowing the temperature to rise to ambient. The reaction mixture was partitioned between ether and water . The ether layer was separated and washed with sodium bicarbonate and sodium chloride, and dried over sodium sulfate. The ether was evaporated to give a 74o yield of 3'-thiomethylacetophenone. The crude material was purified by distillation at reduced pressure.

3-Phenylpropylamine (0.13 g, 1 mmol), 3'-thiomethylacetophenone (0.17 g, 1 mmol), and titanium (IV) isopropoxide (0.36 g, 1.25 mmol) were mixed together and allowed to stand for 4 hours. Ethanol (1 mL) and sodium cyanoborohydride (0.063 g, l,mmol) were added and the reaction was stirred overnight. The reaction was worked up by the addition of 4 mL of ether and 200 ~.L of water.

The mixture was vortexed and then spun in a centrifuge to separate the solids. The ether layer was separated from the precipitate, and the solvent removed in vacuo. The oil was redissolved in dichloromethane and the compound purified by preparative TLC on silica gel eluted with 3%

methanol/dichloromethane to yield the title compound as a pure oil: GC/EI-MS (Rt=7. 64 min) m/z (rel. int. ) 285 (M', 18) , ' 270 (90) , 180 (17) , 151 (100) , 136 (32) , 104 (17) , 91 (54) , 77(13) .

SUBSTITUTE SHEET (RULE 26) WO 96112697 PCT/US95/1370.~
Example 8~ Synthesis of Compound SU
N-3 - (2 -me thoxyphenyl ) -1 -propyl - (R) -3 -me thoxy-a -methylbenzylamine hydrochloride A mixture of (R)-(+)-3-methoxy-a-methylbenzylamine 5 (3.02 g, 20 mmol), 2-methoxycinnamaldehyde (3.24 g, 20 mmol), and titanium (IV) isopropoxide (8.53 g, 30 mmol, 1.5 Eq.) was stirred 2 hours at room temperature and treated with 1 M (20 mL) ethanolic sodium cyanoboro hydride. The reaction was stirred overnight (16 hours), 10 diluted with diethylether, and treated with water (1.44 mL, 80 mmol, 4 Eq.). After mixing for 1 hour the reaction mixture was centrifuged and the ether layer removed and concentrated to an oil. This material was dissolved in glacial acetic acid, shaken with palladium hydroxide and 15 hydrogenated under 60 p.s.i. hydrogen for 2 hours at room temperature. The catalyst was removed by filtration and the resulting solution concentrated to a thick oil. This material was dissolved in dichloromethane and neutralized with 1 N NaOH. The dichloromethane solution was separated 20 from the aqueous phase, dried over anhydrous potassium carbonate and concentrated to an oil. This material was dissolved in ether and treated with 1 M HC1 in diethyl-ether. The resulting precipitate (white solid) was collected, washed with diethylether, and air dried.
25 GC/E1-MS (Rt - 9.69 min) of this material (free base) showed a single component: m/z (rel. int.) 299 (M+, 21), 284 (100), 164 (17), 150 (8), 135 (81), 121 (40), 102 (17) , 91 (43) , 77 (18) .
Example 9~ Synthesis of Compound 9R
30 . (R) -N- (Z- (2-naphthyl) ethyl) - (R) -1 - (1 -naphthyl) ethyl amine hydrochloride A mixture of (R) - (+) -1- (1-naphthyl) ethylamine (10 . 0 g, 58 mmol), 2'-acetonaphthone (9.4 g, 56 mmol), titanium (IV) isopropoxide (20.7 g, 73.0 mmol), and EtOH (abs.) 35 (100 mL) was heated to 60°C for 3 hours. Sodium cyana-borohydride (NaCNBH3) (3.67 g, 58.4 mmol) was then added.
SUBSTITUTE SHEET (RULE 26) The reaction mixture was stirred at room temperature far 18 hours . Ether ( 1 L) and Hz0 ( 10 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was recrystallized four times from hot hexane, to provide 1.5 g of pure (98+0) diastereomer. The free base was dissolved in hexane, filtered, and then ethereal HC1 was added to precipitate the product as a white solid (1.1 g, 6 % yield), m.p..
softens 200-240°C (dec.).
Example 10: Synthesis of Compound 11X
N- (4-Isopropylbenzyl) - (R) -1- (1-naphthyl) ethyl amine hydrochloride A mixture of (R) - (+) -1- (1-naphthyl) ethylamine (1. 06 g, 6.2 mmol), 4-isopropylbenzaldehyde (0.92 g, 6.2 mmol), and titanium (IV) isopropoxide (2.2 g, 7.7 mmol) was heated to 100°C for 5 min then allowed to _stir at room temperature for 4 hours. Sodium cyanoborohydride (NaCNBH3) (0.39 g, 6.2 mmol) was then added followed by EtOH (1 mL).
The reaction mixture was stirred at room temperature for 18 hours. Ether (100 mL) and H20 (1 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm X 30 cm column) (elution with to MeOH/
CHC13) . The chromatographed material was then dissolved in hexane and ethereal HC1 was added to precipitate the product as a white solid (0.67 g, 35 % yield), m.p.; 257 >. 259°C.
Example 11: Synthesis of Compound 12U
' N- 3 - (2 -me thylphenyl ) -1 -propyl - (R) -3 -me thoxy-a -' methylbenzylamine hydrochloride A solution of 2-methylcinnamonitrile (1.43 g, 10 mmol) in dichloromethane (10 mL) was cooled to 0°C and treated dropwise (15 minutes) with 1 M diisobutylaluminum SUBSTITUTE SHEET (RULE 26) hydride (10 mL, dichloromethane). The reaction was stirred at 0°C for 15 minutes and treated dropwise (15 minutes) with a 1 M solution of (R)-(+)-3-methoxy-a- ' methylbenzylamine (1.51 g, 10 mmol) in dichloromethane (10 mL). The reaction was stirred 1 hours at 0°C and poured into a solution of ethanol (100 mL) containing sodium cyanoborohydride (1 g, 16 mmol). The reaction mixture was stirred 48 hour at room temperature. The reaction was diluted with ether and neutralized with 1 N NaOH. The ether layer was removed, dried over anhydrous potassium, carbonate and concentrated to an oil. This material was chromatographed through silica using a gradient of dichloromethane to 5o methanol in dichloromethane to afford the unsaturated intermediate, a single component by GC/El-MS (Rt=10.06 min) m/z (rel. int. ) 281 (M+, 17) , 266 (59), 176 (19), 146 (65), 135 (73), 131 (100), 91 (21), 77 (13) .
The unsaturated intermediate in ethanol was hydrogenated (1 atm HZ) in the presence of palladium on carbon for 16 hours at room temperature. The product from this reaction was converted to the hydrochloride salt by treatment with 1 M HC1 in diethylether. GC/E1-MS (Rt -9.31 min) of this material (free base) showed a single component:--m/z (rel. int.) 283 (M+, 21), 268 (100), 164 (12) , 148 (8) , 135 (85) , 121 (12) , 105 (49) , 91 (23) , 77 (21) .
_Example 12~ Synthesis of Compound 12V
N- 3 - (3 -me thylphenyl ) -1 -propyl - (R) -3 -me thoxy-a -methylbenzylamine hydrochloride y The compound was prepared following the procedure described in Example 11, but using 2-methylcinnamonitrile.~
The unsaturated intermediate was a single component by .
GC/EI-MS (Rt = 10.21 min) m/z (rel. int.) 281 (M+, 57), 266 (86), 146 (98), 135 (88), 131 (100), 115 (43), 102 (26), 91 (43), 77 (18). Reduction of this material and hydro chloride formation using the procedure described Example SUBSTITUTE St+EET (RULE 26) 11 afforded the product. GC/EI-MS (Rt = 9.28 min) of this material (free base) showed a single component; m/z (rel.
int.) 283 (M+, 19), 268 (100), 164 (11), 148 (8), 135 (76) , 121 (16) , 105 (45) , 91 (23) , 77 (21) .
Examt~le 13: Synthesis of Compound 12Z
N-3- (2-chlorophenyl) -1-propyl- (R) -1- (1-naphthyl) ethylamine hydrochloride The compound was prepared following the procedures described in Example 11, but using 2-chlorohydrocinnamo nitrile and (R)-(+)-1-(1-naphthyl)ethylamine on a 10 mmol scale. Chromatography through silica using a gradient of dichloromethane to 5°s methanol in dichloromethane afforded the product as a single component by TLC analysis (5%
methanol in dichloromethane). The hydrochloride was prepared by treatment with 1 M HC1 in diethylether.
Example 14: Synthesis of Compound 14U
(R) -N- (1- (4-methoxyphenyl) ethyl) - (R) -1.- (1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (1.1 g, 6.2 mmol), 4'-methoxyacetophenone (0.93 g, 6.2 mmol), titanium (IV) isopropoxide (2.2 g, 7.7 mmol), and EtOH
(abs.) (1 mL) was heated to 60°C for 3 hours. Sodium cyanoborohydride (NaCNBH3) (0.39 g, 6.2 mmol) was then added, and the reaction mixture was stirred at room temperature for 18 hours. Ether (200 mL) and H20 (2 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (25 mm X 25 cm column) (elution with 1% MeOH/CHC13) . A portion of this material was HPLC chromatographed [Selectosil, 5 ~.M silica gel; 25 cm x 10.0 mm (Phenomenex, Torrance, CA), 4 mL per minute; UV det. 275 nM; 12% ethyl acetate-88a hexane (elution time 12.0 min)]. The HPLC purified diastereomer was then dissolved in hexanes and ethereal HC1 was added SUBSTITUTE SHEET (RULE 26) to precipitate the product as a white solid (20 mg) , m.p. .
209-210°C(dec.).
_Example 15- -Synthesis of Compound 17M
N- (3-chloro-4-methoxybenzyl) - (R) -1- (1-naphthyl) ethylamine hydrochloride A mixture of (R) - (+) -1- (1-naphthyl) ethylamine (6.6 g, 39 mmol), 3'-chloro-4'-methoxybenzaldehyde (6.6 g, 39 mmol) , and titanium (IV) isopropoxide (13 .8 g, 48.8 mmol) , and EtOH (abs.) (30 mL) was heated to 80°C for 30 minutes then allowed to stir at room temperature for 3 hours.
Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added. The reaction mixture was stirred at room temperature -for 18 hours. Ether (100 mL) and H20 (2 mL) were added to the reaction mixture and the resulting precipitate was- then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm X 30 cm column) (elution with CHZCIz). The chromatographed material was then dissolved in hexane (500 mL), decolor-ized with Norit° filtered (0.2 ~.M), and then ethereal HC1 was added to precipitate the product as a while solid (10.2 g, 56 % yield), m.p.. 241-242°C (dec.).
Example 16' Synthesis of Compound17P
4-Methoxy-3-methylacetophenone tl~P Precursor) A mixture of 4'-hydroxy-3'-methylacetophenone (5.0 g, 33.3 mmol), iodomethane (5.7 g, 40.0 mmol), K2C03 (granular, anhydrous) (23.0 g, 167 mmol), and acetone (250 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature, filtered to remove the inorganic salts, and evaporated under vacuum. The crude ' product was dissolved in ether (100 mL) and washed with H20 (2 x 20 mL) . The organic layer was dried (Na2S04) and evaporated-to yield 4.5 g, 82.4% yield. The ketone was used in the follouring reaction without further purification.
SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTlUS9511370.1 (R) -N- (1- (4-Methoxy-3-methylphenyl) ethyl) - (R) -1-(1-naphthyl)ethylamine hydrochloride [Compound 17P]

A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (4.24 g, 24.8 mmol), 4'-methoxy-3'-methylacetophenone (4.06 g, 5 24.8 mmol), and titanium ~(IV) isopropoxide(8.8 g, 30.9 mmol), and EtOH (abs.) (1 mL) was heated to 100C for 2 hours. Isopropanol (45 mL) was added and the reaction was then cooled to l0C in an ice bath. Sodium triacetoxy-borohydride (NaHB(OZCCH3)3) (10.5 g, 49.5 mmol) was then 10 added in portions over 15 minutes. The reaction mixture was then heated to 70C for 18 hours. The mixture was cooled to room temperature and poured into ether (400 mL).

The suspension was centrifuged, the supernatant was collected and the pellet was washed with ether (400 mL).

15 The combined organic washings were evaporated under vacuum. The residue was dissolved in ether (400 mL) and washed with 1 N NaOH (4 x 50 mL) and H20 (2 x 50 mL) .
The organic layer was dried (Na2S04), filtered and evaporated under vacuum. EtOH (abs.) was added to the wet residue 20 which was then dried thoroughly on a rotary evaporator to provide an oil. The mixture was then chromatographed on silica gel (50 mm x 30 cm) [elution with (1% MeOH:lo IPA:CHC13) to give 4.8 g of an oil] .

The desired diastereomer was further purified by HPLC

25 chromatography [SUPELCOSILT"" PLC-Si, 18 ~.M silica gel;

cm x 21.2 mm (Supelco, Inc., Bellefonte, PA), 7 mL per minute; W det. 275 nM: 20o EtOAc-80o hexane (elution time 9.5 - 11.0 min)]. Injections (800 ~,L aliquots) of the mixture (100 mg/mL solution in eluent) provided 65 mg of 30 the desired isomer. Multiple HPLC injections provided 1.0 g of purified material. The HPLC chromatographed material was dissolved in hexane (50 mL) and the hydrochloride salt was precipitated with ethereal HC1. The salt was collected on fritted glass and washed with hexane to 35 provide 1.0 g of a white solid, mp 204-205C.

SUBSTITUTE SHEET (RULE 26) Example 17' Synthesis of Compound 17X
3-Chloro-4-methoxybenzaldehyde s A mixture of 3-chloro-4-hydroxybenzaldehyde (25 g, 160 mmol) , iodomethane (27.25 g, 192 mmol) , KZC03 (granu lar, anhydrous) (110.6 g, 800 mmol), and acetone (300 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. Diethyl ether (500 mL) was added and the mixture was filtered through paper to remove the inorganic solids. The filtrate was evaporated under reduced pressure, dissolved in diethyl ether (800 mL), and washed with 0.1 N NaOH (3 x 100 mL). The organic layer was dried (NaZS04) and evaporated under vacuum to yield 24 g, 92o yield of crude product. This material was further purified by chromatography on silica gel (50 mm x 30 cm) (elution with hexane-EtOAc, 5:1) to give 15.02 g, 56%
yield of a white solid: TLC (hexane-EtOAc, 5:1) Rf=0.24; GC
Rt=4 .75 min; MS (EI) m/z 170 (M') , 172 (M+2) .
1-Methyl-(3'-chloro-4'-methoxybenzyl) alcohol A mixture of 3-chloro-4-methoxybenzaldehyde (13 g, 76.5 mmol), methylmagnesium chloride (52 g, 153 mmol), arid THF (300 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature. NH4C1 (satd.
soln., 6 mL) was added dropwise follo~nied by diethyl ether (500 mL) and the mixture was filtered through 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 (Na2S04) and evaporated under vacuum to yield 11.3 g, 80% yield of crude product. This material was further purified by chromatography on silica gel (50 mm x 30 cm) (elution with ' CHZC12) to yield 11.3 g~ 63°s yield of an oil; TLC (CHZCIz) Rf=0.25; GC Rt=5.30 min; MS (EI) m/z 186 (M') , 188 (M+2) .
SUBSTITUTE SHEET (RULE 26) 3'-Chloro-4'-methoxyacetophenone A mixture of 1-methyl-(3'-Chloro-4'-methoxybenzyl) alcohol (7.6 g, 41 mmol), pyridinium chlorochromate (PCC) (13 .16 g, 61.5 mmol) , and CHZC12 (300 mL) was allowed to stir at room temperature for 2 hours. Diethyl ether (1000 mL) was added and the resulting mixture was placed on a chromatography column of silica gel (50 mm x 30 cm) (elution with diethyl ether) to yield 7.3 g, 97o yield of crude solid product. GC analysis of this material showed it to be 99o pure and it was used in the following reac-tion without further purification. TLC (diethyl ether) Rf=1. 0; GC Rt=5.3 min; MS (EI) m/z 184 (M') , 184 (M+2) .
(R, R)-N- (1-Ethyl-4'-methoxy-3'-chlorophenyl) -1- (1-naph thyl a thyl ) amine A mixture of 3'-chloro-4'-methoxyacetophenone (5.3 g, 29 mmol) , (R) - (+) -1- (1-naphthyl) ethylamine (4.98 g, 29 mmol), titanium (IV) isopropoxide (10.2 g, 36 mmol), and isopropanol (20 mL) was heated to 100°C for 3 hours.
Sodium triacetoxyborohydride (NaB(OzCCH3)3; 12.29 g, 58 mmol) was added in portions over 10 minutes. The reaction mixture was heated to reflux for 30 minutes and was then allowed to stir at room temperature for 18 hours. The mixture was then poured into diethyl ether (500 mL) ; H20 (2 mL) was added and the suspension was centrifuged to remove the fine precipitate of titanium salts. The supernatant was collected and the pellet was washed with ether (500 mL) . The combined organic layers were dried (Na2S04) and evaporated under vacuum to yield 6.81 g, 70% of crude product.
This material was further purified by chromatography on silica gel (50 mm x 30 cm) (elution with 3o MeOH-97o CHZCIz) to give 2.01 g of an oil. The diastereomer was ' further purified by recrystallization. The free base (1.98 g) was converted to its HC1 salt with ethereal HC1.
This salt was dissolved in hot isopropanol (65 mL) and the solution was filtered through paper. The filtrate was SUBSTITUTE SHEET (RULE 26) PCT/US95/1370.1 evaporated under vacuum and the resulting solid dissolved r in isopropanol (30 mL). After standing at room tempera-ture for 18 hours, the crystalline solid was collected, washed with cold isopropanol (20 mL), and dried to yield 0.87 g, 400 (from free base) of the diastereomerically pure hydrochloride salt: mp 236-237;~C (dec); TLC (MeOH
CHzCl2 [99:1J ) Rf=0.25; GC Rt=11.06 min; FTIR (KBr pellet, cm-1) 3433, 2950, 2931, 2853, 2803, 2659, 2608, 2497, 1604, 1595, 1504, 1461, 1444, 1268, 1260, 1067, 1021, 802, 781, 733; MS (EI) m/z 339(M'), 341(M+2).
Example 18~ Additional Synthesis Protocol Preparation of 22Z and 23A
A stirred solution of sodium hydride (2.173 g, 60o in oil, 54.325 mmol) in dimethylformamide (100m1) was treated dropwise with triethyl phosphonoacetate (12.47 g, 55.65 mmol) and stirred 30 min at rt. After this time, a solution of m-trifluoromethoxy benzaldehyde (10.0 g, 52.6 mmol) in dimethylformamide (50 ml) was added dropwise and the solution stirred 30 min at rt and 30 min 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 mag-nesium sulfate, filtered and concentrated to afford ethyl m-trifluoromethoxycinnamate as an oil; m/z (rel. int.) 260 (M+, 19) , 232 (16) , 215 (100) , 187 (21) , 101 (28) .
The ethyl ester in ethanol (100 ml) was reduced under 60 p.s.i. hydrogen using a catalytic amount (loo by weight) palladium hydroxide. After reduction (2 hr, rt) the reaction was filtered and concentrated to afford ethyl m-trifluoromethoxyhydrocinnamate as an oil; m/z (rel. -int.) 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-10 M sodium hydroxide (1:1) for 16 hr at rt. After this time the solution was acidified anc3 the SUBSTITUTE SHEET (RULE 26) product extracted into diethyl ether. The ether solution was dried over anhydrous magnesium sulfate and concen-Y
trated to afford m-trifluoromethoxyhydrocinnamic acid as a solid; m/z (rel. int.) 234 (M+, 46), 188 (100), 174 ' 5 (65) , 103 (27) , 91 (12) , 77 (~17) .

The acid was stirred in excess thionyl chloride for 4 hr at rt. The excess thionyl chloride was evaporated at reduced pressure (100C) to afford m-trifluoromethoxy-hydrocinnamyl chloride as an oil. The product was used without further purification.

A solution of m-trifluoromethoxyhydrocinnamyl chloride (9.8 g, 39 mmol) in tetrahydrofuran was cooled to -78C and treated dropwise with a solution (13 ml of 3 M

in tetrahydrofuran) of methylmagnesium bromide (39 mmol).

The reaction was stirred 4 hr at -78C, 8 hr at rt, and quenched with dilute HC1. The reaction mixture was extracted with diethyl ether. The ether was dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. Chromatography of this material through silica using a gradient of hexane to acetone afforded 4-(3-trifluoromethoxyphenyl)-2-butanone as an oil; m/z (rel.

int.) 232 (M+, 68), 217 (7), 189 (59), 175 (31), 103 (28), 43 (100) .

A solution of 4- (3-trifluoromethoxyphenyl) -2-butanone (2.32 g, 10 mmol), (R)-1-(3-methoxyphenyl)ethylamine (1.51 g, 10 mmol), and titanium (IV) isopropoxide (3.55 g, 12.5 mmol) were stirred 4 hr at rt. The reaction mixture was then treated with a solution (10 ml of 1 M) of ethanolic sodium cyanoborohydride (10 mmol) and stirred 16 hr at rt.

The reaction was diluted with diethyl ether (50 ml) and h treated with water (0.72 ml, 40 mmol). After mixing ' thoroughly the solution was centrifuged and the ether._ -' layer decanted and concentrated to an oily~solid. The solid was suspended in diethyl ether, filtered through 0.45 uM CR PTFE Acrodisc and concentrated to give a clear oil. Repetitive preparative thin-layer chromatography using 5o methanol in chloroform afforded.. the two SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US9511370=t diasteriomers, (S,R)-N-[4-(3-trifluoromethoxyphenyl)-2- , butyl]-1-(3-methoxyphenyl)ethylamine, 22Z [m/z (rel. int.) y 367 (M+, 3) , 352 (20) , 232 (4) , 178 (47) , 135 (100) , 105 (14) , 91 (10) , 77 (11) ] and (R, R) -N- [4- (3-trifluoro 5 methoxyphenyl)-2-butyl]-1-~(3-methoxyphenyl)ethylamine, 23A; m/z (rel. int. ) 367 (M+, 3) , 352 (19) , 232 (7) , 178 (43) , 135 (100) , 105 (19) , 91 (10) , 77 (11) .
Preparation of 22X and 22Y
In a similar fashion an equal molar amount of 4-(3 10 trifluoromethoxyphenyl)-2-butanone, (R)-1-(1-naphthyl) _-~ ethylamine and 1.25 equivalents titanium (IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5o methanol in 15 chloroform afforded (S, R) -N- [4- (3-trifluoromethoxyphenyl) -2-butyl]-1-(1-naphthyl)ethylamine, 22X; m/z (rel. int.) 387 (M+, 3) , 372 (15) , 198 (15) , 176 (12) , 155 (100) , 128 (8), 115 (6), 109 (4), 103 (5), 77 (8) and (R,R)-N-[4-(3-trifluoromethoxyphenyl)-2-butyl]-1-(1-naphthyl)ethylamine, 20 22Y; m/'z (rel. int. ) 387 (M+,2) , 372 (12) , 198 (16) , 176 (11), 155 (100), 128 (8), 115 (6), 109 (4), 103 (5), 77 (8) .
Preparation of 4T
- In a similar fashion an equal molar amount of 4-(2 25 chlorophenyl)-2-butanone, prepared from o-chlorobezalde hyde, (R)-1(3-methoxyphenyl)ethylamine and 1.25 equiva lents titanium (IV) isopropoxide were mixed and the inter mediate imine reduced with ethanolic sodium cyanoboro hydride. Work-up and repetitive preparative thin-layer 30 chromatography using 5% methanol in chloroform afforded (R, R) -N- [4- (2-chlorophenyl) -2-butyl] -1- (3-methoxyphenyl) -ethylamine, 4T; m/z (rel. int.) 317 (M+,3), 302 (16), 178 (62), 178 (62), 135 (100), 125 (15), 105 (10), 91 (6), 77 (8) .
SUBSTITUTE SHEET (RULE 26) WO 96112697 PCTlUS95/13704 Preparation of 21Y
In a similar fashion an equal molar amount of 4-(3-trifluoromethylphenyl)-2-butanone, prepared from m-trifluoromethylbezaldehyde, (R)-1-(3-methoxyphenyl) ' 5 ethylamine and 1.25 equivalents titanium (IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5o methanol in chloroform afforded (R,R) -N- [4- (3-trifluoromethylphenyl) -2-butyl]-1-(3-methoxyphenyl)ethylamine, 21Y [m/z (rel.
int. ) 351 (M+, 2) , 336 (18) , 216 (4) , 202 (3) , 178 (45) , 135 (100) , 105 (13) , 91 (9) , 77 (8) ] and (S,R) -N- [4- (3-trifluoromethylphenyl)-2-butyl]-1-(3-methoxyphenyl) ethylamine, 21X.
Preparation of 25C and 25D
In a similar fashion an equal molar amount of 4-(3-trifluoromethylphenyl)-2-butanone, (R)-1-(1-naphthyl) ethylamine and 1.25 equivalents titanium (IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5o methanol in chloroform of forded ( S , R) -N- [4 - ( 3 -trif luoromethylphenyl ) -2-butyl]-1-(1-naphthyl)ethylamine, 25C [m/z (rel. int.) 371 (M', 3) , 356 (16) , 198 (15) , 155 (100) , 129 (8) , 115 (5) , 109 (3) , 77 (2) ] and (R, R) -N- [4- (3-trifluoro-methylphenyl)-2-butyl]-1-(1-naphthyl)ethylamine, 25D; m/z (rel. int.) 371 (M', 3), 356 (16), 198 (15), 155 (100), 129 (8) , 115 (5) , 109 (3) , 77 (2) .
Preparation of 21D
In a similar fashion an equal molar amount of 4 ' phenyl-2-butanone (Aldrich Chemical Co.), (R)-1-(3-meth oxyphenyl)ethylamine and 1.25 equivalents titanium (IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5a SUBSTITUTE SHEET (RULE 26) methanol in chloroform afforded (R,R)-N-(4-phenyl-2 butyl ) -1- ( 3 -methoxyphenyl ) ethylamine , 21D [m/ z ( rel . int . ) 283 (M+, 4) , 268 (13) , 178 (45) , 135 (100) , 105 (15) , 91 (43) , 77 (11) ] and (S,R) -N- (4-phenyl-2-butyl) -1- (3 methoxyphenyl)ethylamine, 21E.
Preparation of 21F
In a similar fashion an equal molar amount of 4-phenyl-2-butanone (Aldrich Chemical Co.), (R)-1-(1-naphthyl)ethylamine and 1.25 equivalents titanium (IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5%
methanol in chloroform afforded (R,R)-N-(4-phenyl-2-butyl)-1-(1-naphthyl)ethylamine, 21F; m/z (rel. int.) 303 (M', 6) , 288 (14) , 198 (22) , 155 (100) , 129 (8) , 115 (5) , 91 (19) , 77 (4) .
Preparationof 12Z
A stirred solution of 2-chlorohydrocinnamonitrile (Aldrich Chemical Co., 1.66 g, 10 mmol) in dichloromethane (100 ml) was cooled to -78°C and treated dropwise with diisobutylaluminum hydride (1.42 g, 10 mmol). The reac-tion was stirred 1 hr at rt, cooled to -78 °C and treated with a solution of 1-(1-naphthyl)ethylamine (1.71 g, 10 mmol) in dichloromethane (25 ml) . The reaction was trans-ferred to an ice bath and stirred 2 hr. After this time the reaction was poured directly into a stirred solution of ethanolic sodium borohydride (50 ml of 0.2 M, 10 mmol).
The mixture was stirred 30 min at rt and the excess sodium borohydride quenched by the addition of 10% HC1. The solution was then made basic by the addition of 10 N NaOH ' and transferred to a separatory funnel washing with diethyl ether (300 ml). The aqueous phase was removed and .
the remaining organic layer washed with 1 N NaOH (3 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to an oil. Chromatography of SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTlUS95113704 this material through silica gel using a gradient of chloroform to 10% methanol-chloroform afforded 2.348 (72%
yield) of (R) -N- [3- (2-chlorophenyl)propyl] -1- (1-naphthyl)ethylamine, 12Z, as a clear oil; m/z (rel. int.) ' 5 323 (M+, 2), 308 (63), 288 (7), 196 (5), 184 (5), 155 (100) , 125 (24) , 115 (8) , 103 (4) , 91 (3) , 77 (7) .
Preparation of 12B
In a similar fashion, 4-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3 --; _ methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(4-methylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12B, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 6), 266 (5), 176 (27), 146 (75), 135 (63), 131 (100), 115 (25), 105 (21), 91 (21) , 77 (21) .
Preparation of 12C
In a similar fashion, 2-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3 methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(2-methylphenyl)prop-2 enyl]-1-(3-methoxyphenyl)ethylamine, 12C, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 4), 266 (15), 176 (18) , 146 (62) , 135 (58) , 131 (100) , 115 (23) , 105 (19) , 91 (38) , 77 (17) .
Preparation of 12D
In a similar fashion, 2,4,6-trimethylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and SUBSTITUTE SHEET (RULE 26) chromatography yielded (R)-N-[3-(2,4,6-trimethylphenyl) prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12D, as a clear, colorless oil; m/z (rel. int.) 309 (M+,8), 294 (25) , 174 (82) , 159 (100) , 135 (52) , 129 (29) , 105 (21) , r 91 (17) , 77 (14) .
Preparation of 12E
In a similar fashion, 4-isopropylcinnamonitrile was treated with diisobutyl aluminum hydride and the inter-mediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded(R)-N-[3-(4-isopropylphenyl)prop-2-enylJ-1-(3-methoxyphenyl)ethylamine, 12E, as a clear, colorless oil; m/z (rel. int. ) 309 (M', 9) , 294 (7) , 174 (98), 159 (22), 135 (80), 117 (100), 105 (35), 91 (37), 77 (19) . .
Preparationof 12F
In a similar fashion, 2,4-dimethylcinnamonitrile was treated with diisobutyl aluminum hydride and the inter mediate aluminum-imine complex treated with, (R)-1-(3 methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(2,4-dimethylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12F, as a clear, colorless oil; m/z (rel. int.) 295 (M", 8), 294 (15), 174 (29) , 160 (75) , 145 (100) , 135 (68) , 117 (21) , 105 (30) , 91 (26) , 77 (19) .
Preparation of 12G
In a similar fashion, 3-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the inter mediate aluminum-imine complex treated with (R)-1-(3 methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(3-methylphenyl)prop-2 SUBSTITUTE SHEET (RULE 26) enyl]-1-(3-methoxyphenyl)ethylamine, 12G, as a clear, colorless oil; m/z (rel. int. ) 281 (M;, 5) , 266 (9) , 176 (24) , 146 (71) , 135 (62) , 131 (100) , 115 (23) , 105 (19) , 91 (41) , 77 (18) .
5 Preparation of 25E
In a similar fashion, cinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethyl-amine. The intermediate imine was treated with ethanolic 1.0 sodium borohydride. Work-up and chromatography yielded (R)-N-(3-phenylprop-2-enyl)-1-(3-methoxyphenyl)ethylamine, 25E, as a clear colorless oil; m/z (rel. int.) 267 (M', 3), 252 (14), 176 (17), 135 (62), 117 (100), 105 (28), 91 (56) , 77 (33) .
15 Preparation of 25G
In a similar fashion, a-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the inter-mediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was 20 treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-(2-methyl-3-phenylprop-2 enyl)-1-(3-methoxyphenyl)ethylamine, 25G, as a clear, colorless oil; m/z (rel. int.) 281 (M+,5), 266 (18), 190 (12) , 146 (78) , 135 (82) , 131 (100) , 115 (21) , 105 (21) , 25 91 (62) , 77 (19) .
Preparation of 6X
A stirred solution of sodium hydride (1.8 g, 75 mmol) in dimet~hylformamide (150 nil) was treated with a solution - of diethylcyanomethyl phosphonate (13.3 g, 75 mmol) in 30 dimethylformamide (50 ml). The reaction was stirred 30 min at rt. After this time the reaction was treated with 3-chlorobenzaldehyde (10.54 g, 75 mmol) and stirred 1 hr at rt and 30 min at 60°C. The reaction was then quenched by the addition of water (200 ml). The reaction mixture SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCT/US9511370.1 was transferred to a separatory funnel using diethyl ether (300 ml) and the resulting organic phase washed with water (5 x 300 ml) and brine. The organic layer was dried over anhydrous potassium carbonate and concentrated to yield 3-chlorocinnamonitrile (11.05 g) as a solid. The solid was dissolved in tetrahydrofuran (50 ml) and treated with excess diborane and stirred 30 min at rt. The reaction was poured over ice/10% HCl. The acidic aqueous phase was washed with diethyl ether (2 x 200 ml). The aqueous phase was made basic by the addition of 10 N NaOH and extracted with diethyl ether (200 ml). The ether extract was dried over anhydrous potassium carbonate and concentrated to afford 3-(3-chlorophenyl)propylamine as an oil (0.6 g, 3.54 mmol). The 3-(3-chlorophenyl)propylamine (0.60 g, 3.54 mmol), 3'-methoxyacetophenone (0.53 g, 3.54 mmol) and 1.25 molar equivalents titanium (IV) isopropoxide (1.26 g', 4.43 mmol) were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). The reaction was stirred 16 hr at rt, diluted with diethyl ether (50 ml) and treated with water (0.32 ml, 17.7 mmol). After mixing thoroughly the solution was centrifuged and the ether layer concentrated to a milky solid. This material was suspended in diethyl ether and filtered through a 0.45 ~.M CR PTFE Acrodisc.
The ether wash was concentrated to an oil. Chromatography of this material (silica, preparative thin-layer chromata-graphy) using 3% methanol-dichloromethane (containing 0.1%
isopropylamine) afforded N-[3-(3-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine, 6X; m/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
An equal molar amount of 3-(4-chlorophenyl) -propylamine (prepared in a similar fashion from 4-chlorobenzaldehyde as above) 3'-methoxyacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were SUBSTITUTE SHEET (RULE 26) mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1M, 5 mmol).
Work-up and chromatography afforded N-[3-(4-chlorophenyl) propyl]-1-(3-methoxyphenyl)ethylamine, 6V, as an oil; m/z (rel. int. ) 303 (M+, 8) , 288 ~(91) , 196 (4) , 164 (10) , 135 (100) , 125 (61) , 103 (21) , 91 (21) , 77 (18) .
Preparation of 20A
In a similar fashion, an equal molar amount of 1-(1 methoxyphenyl)ethylamine, 4-t-butylacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethan-olic sodium cyanoborohydride (5 ml of 1M, 5 mmol). Work-up and chromatography afforded (R)-N-[1-(4-t-butylphenyl) ethyl] -1- (1-naphthyl) ethyl amine, 20A, as an oil; m/z (rel.
int.) 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 25I
In a-similar fashion, an equal molar amount of (R)-1 (3-methoxyphenyl)ethylamine, trans-4-phenyl-3-butene-2-one and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded (R,R)-N-(2-methyl-4-phenybut-3-enyl)-1-(3-methoxyphenyl)ethylamine, 25H, as an oil; m/z (rel. int.) 283 (M+, 4), 268 (13), 178 (40) , 135 (100) , 105 (15) , 91 (47) , 77 (13) and (S, R) -N-(2-methyl-4-phenybut-3-enyl)-1-(3-methoxyphenyl) ethylamine, 25I, as an oil; m/z (rel. int.) 283 (M+,4), 268 (13), 178 (40), 135 (100), 105 (15), 91 (47), 77 (13).
Preparation of 16L and 16M
In a similar fashion, an equal molar amount of (R) -1-(3-methoxyphenyl)ethylamine, 3-methoxyacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with SUBSTITUTE SHEET (RULE 26) an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol ) . Work-up and chromatography of forded ( R, R) -N- [ 1- ( 4 -methoxyphenyl)ethyl]-1-(3-methoxyphenyl)ethylamine, 16L, as an oil; m/z (rel. int.) 284 (M-1, 1), 270 (85), 150 (83), 135 (100), 120 (12), 105 (28), 91 (25), 77 (23) and r (S,R) -N- [1- (4-methoxyphenyl) ethyl] -1- (3-methoxyphenyl) ethylamine, 16M, as an oil; m/z (rel. int.) 284 (M-1, 1), 270 (53), 150 (98), 135 (100), 120 (11), 105 (33), 91 (25) , 77 (23) .
_Pret~aration of 5B/5C
In a similar fashion, 4-chloroacetophenone was used to prepare 3-methyl-3-(4-chlorophenyl)cinnamonitrile. The nitrite was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(4-chlorophenyl)propylamine. An equal molar amount of the amine, 3'-methoxyacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded N-(3-methyl-3-(4-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 5B/5C
as an oil; m/z (rel. int.) 317 (M+, 12), 302 (74), 210 (2) , 182 (4) , 164 (12) , 135 (100) , 121 (25) , 103 (40) , 91 (19) , 77 (28) .
Preparation of 4Z/5A
In a similar fashion, 3-chloroacetophenone was used to prepare 3-methyl-3-(3-chlorophenyl)cinnamonitrile. The nitrite was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(3-chlorophenyl)propylamine. An equal molar amount of the amine, 3'-methoxyacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded N-[3-methyl-3-(3-chlorophenyl) SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTIUS9511370=1 propyl]-1-(3-methoxyphenyl)ethylamine, 4Z/5A, as an oil;
m/z (rel. int.) 283 (M+, 17), 268 (71), 164 (13), 135 (100) , 121 (21) , 105 (27) , 91 (26) , 77 (14) .
Preparation of 4Y
In a similar fashion, 2-chloroacetophenone was used to prepare 3-methyl-3-(2-chlorophenyl)cinnamonitrile. The nitrile was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(2-chlorophenyl)propylamine. An equal molar amount of the amine, 3'-methoxyacetophenone and 1.25 molar equivalents titanium (IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride ( 5 ml of 1 M, 5 mmol ) . Work-up and chromatography afforded N-[3-methyl-3-(2-chloro-phenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 4Y, as an oil; m/z (rel. int. ) 283 (M', 17) 268 (71) , 164 (13) , 135 (100) , 121 (21) , 105 (27) , 91 (26) , 77 (14) .--~
Preparation of 6T
A solution of NPS R-568 (30.3 g 100 mmol) in dichloromethane at -78°C was treated dropwise with boron tribromide (50 g, 200 mmol). The reaction was stirred 1 hr at rt and poured over ice. The hydrobromide was extracted from the aqueous phase with chloroform. The chloroform solubles were then washed (4 x 100 ml) with 50%
HC1. The chloroform wash was dried over anhydrous magnesium sulfate and concentrated to afford (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydro-chloride as a solid. A solution of sodium hydride (0.48 " g, 20 mmol) in dimethylformamide was treated with (R)-N
I3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride (3.25 g, l0 mmol) and the reaction stirred 1 hr at rt. The reaction was treated with iodoethane (1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and chromatography through silica using 3% methanol in chloroform afforded (R) -N- [3- (2-chlorophenyl)propyl] -1- (3-SUBSTITUTE SHEET (RULE 28) ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.) 316 (M+,1), 302 (100), 282 (11), 196 (5), 178 (7), 149 (74) , 121 (34) , 103 (25) , 91 (28) , 77 (29) .
Preparation of 6R
NPS R-467 was used in a similar fashion to prepare (R)-N-(3-phenylpropyl)-1-(3-ethoxyphenyl)ethylamine, 6R, as an oil; m/z (rel. int.) 283 (M+,10), 268 (74), 178 (11), 162 (8), 149 (100), 121 (30), 103 (16), 91 (86), 77 (29) .
Preparation of 3U
An equal molar mixture of 3,3-diphenylpropylamine (2.11 g, 10 mmol), 1'-acetonaphthone (1.70 g, 10 mmol) and 1.25 equivalents of titanium (IV) isopropoxide (3.55 g, 12.5 mmol) were stirred 4 hr at rt. The reaction mixture was then treated with a 1 M solution of ethanolic sodium cyanoborohydride (12.5 m1,,12.5 mmol) and stirred 16 hr at rt. The reaction was diluted with diethyl ether (50 ml) and treated with water (0.72 ml, 40 mmol). After mixing thoroughly the mixture was centrifuged, and the ether layer decanted and concentrated to a milky oil. The oil was suspended in diethyl ether and filtered through a 0.45 ~.M
CR PTFE Acrodisc. The diethyl ether filtrate was concen-trated to afford N-(3,3-diphenylpropyl)-1-(1-naphthyl) ethylamine, 3U, as a clear, colorless oil; m/z (rel. int.) 365 (M+, 17), 350 (19), 181 (23), 155 (100), 141 (25), 115 (11) , 91 (13) , 77 (6) .
Prewaration of 6F
In a similar fashion equal molar amounts 1-(3-methoxyphenyl)ethylamine (1.51 g, 10 mmol), 2'-acetonaph- ' thone (1.70 g, 10 mmol) and 1.25 equivalents of titanium -(IV) isopropoxide (3.55 g, 12.5 mmol) were treated as above. Work-up yielded N- [1- (2-naphthyl) ethyl) -1- (3-methoxyphenyl)ethylamine, 6F, as a clear, colorless oil;
SUBSTITUTE SHEET (RULE 26) m/z (rel. int.) 305 (M+,1), 290 (35), 170 (49), 155 (100), 135 (55) , 115 (8) , 105 (10) , 91 (9) , 77 (10) .
Preparation of 4G
' In a similar fashion equal molar amounts of (R))-1 phenylethylamine " 1'-acetonaphthone and 1.25 equivalents of titanium (IV) isopropoxide were mixed and the resulting intermediate imine was reduced with ethanolic sodium cyanoborohydride, work-up and chromatography yielded N
[1-(1-naphthyl)ethyl)-1-phenylethylamine, 4G, as a clear, colorless oil; m/z (rel. int.) 275 (M+,16), 260 (79), 155 (100) , 127 (27) , 105 (70) , 77 (32) .
Preparation of 4H
In a similar fashion equal molar amounts of (R) -1 phenylethylamine, 2'-acetonaphthone and 1.25 equivalents of-titanium (IV) isopropoxide were mixed and the resulting intermediate imine was reduced with ethanolic sodium cyanoborohydride. Work-up and chromatography yielded N
[1-(2-naphthyl)ethyl]-1-phenylethylamine, 4H, as a clear, colorless oil; m/z (rel. int. ) 275 (M+, 1) , 260 (61) , 155 (100), 120 (36), 105 (55), 77 (15).
_ Preparation of 6E
In a similar fashion equal molar amounts of 1-(3-methoxyphenyl)ethylamine, 1'-acetonaphthone and 1.25 equivalents of titanium (IV) isopropoxide were mixed and the resulting intermediate imine was reduced with ethan olic sodium cyanoborohydride. Work-up and chromatography yielded N-1-(1-naphthyl)ethyl-1-(3-methoxyphenyl)ethyl amine, 6E, as a clear, colorless oil; m/z (rel. int.) 305 (M+,10), 290 (30), 170 (43), 155 (100), 135 (69), 115 (9), 105 (15), 91 (14), 77 (18).
SUBSTITUTE SHEET (RULE 26) Example 19- Pharmaceutical Formulation Preparation of a pharmaceutical formulation suitable for administering a calcimimetic into a human patient is shown in Table 3.
r Ingredient mg/capsule g/representative batch of 5,000 capsules NPS R-568 56.0- 280.0 Pregelatinized 134.0 670.0 Starch NF

Microcrystalline 34.0 170.0 Cellulose NF

Colloidal Silicon 1.0 5.0 Dioxide Total 225 mg 1125 g Other examples of NPS (R)-568 hydrochloride formulations and dosage forms include those suitable for sustained or extended release, using standard techniques.
Proper dosing can also be carried out using standard techniques-. For example,-in one set of experiments, 10 400 mg oral doses of NPS (R)-568 hydrochloride showed pharmacological activity in human subjects. Significant levels of the O-glucuronide conjugate of 17Q, a principal metabolite of NPS (R)-568, was observed in human plasma following oral administration of NPS (R)-568 hydro-chloride. Thus, the glucuronide conjugate of 17Q may be exerting some beneficial effect.
Using standard techniques other suitable dosage -ranges for NPS (R)-568 can be determined.
Suitable dosage ranges, formulations, and dosage forms for other compounds described herein can also be determined by one skilled in art based on the teachings provided in the application.
SUBSTITUTE SHEET (RULE 26) Other embodiments are within the following claims.
Thus, while several embodiments have been shown and de scribed,. various modifications may be made, without departing from the spirit and scope of the present inven tion.
SUBSTITUTE SHEET (RULE 26) WO 96/12697 PCTIUS95/1370.1 SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: NPS Pharmaceuticals, Inc.
(ii) TITLE OF INVENTION: CALCIUM RECEPTOR-ACTIVE ' COMPOUNDS
(iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Lyon & Lyon (B) STREET: First Interstate World Center, Suite 4700 633 West Fifth Street (C) CITY: Los Angeles (D) STATE: California (E) COUNTRY: USA
(F) ZIP: 90017 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: 3.5" Diskette, 1.44 Mb storage (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE : FastSeq (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(vii) PRIOR APPLICATION DATA:
Prior applications total, including application described below: 2 (A) APPLICATION NUMBER: U.S. 08/353,784 (B) FILING DATE: 8 December; 1994 (A) APPLICATION NUMBER: PCT/US/94/12117 (B) FILING DATE: 21 October, 1994 (viii) ATTORNEY/AGENT INFORMATION:
SUBSTITUTE SHEET (RULE 26) (A) NAME: Heber, Sheldon O.
(B) REGISTRATION NUMBER: 38,179 (C) REFERENCE/DOCKET NUMBER: 215/304 (ix) TELECOMMUNICATION INFORMATION:
k (A) TELEPHONE: (213) 489-1600 (B) TELEFAX: (213) 955-0440 (C) TELEX: 67-3510 (2) INFORMATION FOR SEQ ID N_O: 1:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5006 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA to mRNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 436..3699 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:

Met Ala Phe Tyr Ser Cys Cys Trp Val Leu Leu Ala SUBSTITUTE SHEET (RULE 26) Leu Thr Trp His Thr Ser Ala Tyr Gly Pro Asp Gln Arg Ala Gln Lys Lys Gly Asp Ile Ile Leu Gly Gly 25 30 ' 35 Leu Phe Pro Ile His Phe Gly Val Ala Ala Lys Asp Gln Asp Leu Lys Ser Arg Pro Glu Ser Val Glu Cys Ile Arg Tyr Asn Phe Arg Gly Phe Arg Trp Leu Gln Ala Met Ile Phe Ala Ile Glu Glu Ile Asn Ser Ser Pro Ala Leu Leu Pro Asn Leu Thr Leu Gly Tyr Arg 85 90 95.~.

Ile Phe Asp Thr Cys Asn Thr Val Ser Lys Ala Leu Glu Ala Thr Leu Ser Phe Val Ala Gln Asn Lys Ile Asp Ser Leu Asn Leu Asp Glu Phe Cys Asn Cys Ser Glu His Ile Pro Ser Thr Ile Ala Val Val Gly Ala Thr Gly Ser Gly Val Ser Thr Ala Val Ala Asn Le u Leu Gly Leu Phe Tyr Ile Pro Gln Val Ser Tyr Ala Ser Ser Ser Arg Leu Leu Ser Asn Lys Asn Gln Phe SUBSTITUTE SHEET (RULE 26) _ AAG TCT TTC CTC CGA ACC ATC CCC AAT GAT GAG CAC 1011 Lys Ser Phe Leu Arg Thr Ile Pro Asn Asp Glu His Gln Ala Thr Ala Met Ala Asp Ile Ile Glu Tyr Phe ' 195 ' 200 ArgTrp Asn Trp Val Gly Thr Ile Ala Ala Asp Asp AspTyr Gly Arg Pro Gly Ile Glu Lys Phe Arg Glu GluAla Glu Glu Arg Asp Ile Cys Ile Asp Phe Ser GluLeu Ile Ser Gln Tyr Ser Asp Glu Glu Glu Ile GlnHis Val Val Glu Val Ile Gln Asn Ser Thr Ala LysVal Ile Val Val Phe Ser Ser Gly Pro Asp Leu GluPro Leu Ile Lys Glu Ile Val Arg Arg Asn Ile ThrGly Lys Ile Trp Leu Ala Ser Glu Ala Trp Ala SerSer Ser Leu Ile Ala Met Pro Gln Tyr Phe His Val Val Gly Gly Thr Ile Gly Phe Ala Leu Lys Ala GGG CAG ATC CCA GGC TTC CGG GAA TTC CTG AAG AAG 1443_ Gly Gln Ile Pro Gly Phe Arg Glu Phe Leu Lys Lys Val His Pro Arg Lys Ser Val His Asn Gly Phe Ala SUBSTITUTE SHEET (RULE 26) TGG ACA
TTT
AAC

Lys Glu Phe Glu Glu Thr Phe Cys His Leu ' Trp Asn 350 . 355 360 GCA

Gln Glu Gly Lys Gly Pro Leu ProVal Asp Thr Ala 365 ~ 370 ' Phe Leu Arg Gly His Glu Glu Ser GlyAsp Arg Phe Ser Asn Ser Ser Thr Ala Phe Arg ProLeu Cys Thr Gly Asp Glu Asn Ile Ser Ser Val GluThr Pro Tyr Ile Asp Tyr Thr His Leu Arg Ile SerTyr Asn Val Tyr Leu Ala Val Tyr Ser Ile Ala HisAla Leu Gln Asp Ile Tyr Thr Cys Leu Pro Gly ArgGly Leu Phe Thr Asn Gly Ser Cys Ala Asp Ile LysLys Val Glu Ala Trp Gln Val Leu Lys His Leu ArgHis Leu Asn AAC

Phe Thr Asn Asn Met Gly Glu Gln ValThr Phe Asp GAG TGT GGT GAC CTG GTG GGG AAC TATTCC ATC ATC 1911 _ Glu Cys Gly Asp Leu Val Gly Asn TyrSer Ile Ile TCC TCC
CCA
GAG

Asn Trp His Leu Asp Gly Val ' Ser Ser Pro Ile Glu GTC GGG TAT
TAC AAC GTC
TAT GCC AAG

Phe Lys Glu Val Gly Tyr Tyr Asn Val Tyr Ala Lys SUBSTITUTE SHEET (RULE 26) Lys Gly Glu Arg Leu Phe Ile Asn Glu Glu LysIle _ 520 525 Leu Trp Ser Gly Phe Ser Arg Glu Pro Leu ThrPhe ' 530 535 540 Val Leu Ser Val Leu Gln Val Pro Phe Ser AsnCys Ser Arg Asp Cys Leu Ala Gly Thr Arg Lys GlyIle Ile Glu Gly Glu Pro Thr Cys Cys Phe Glu CysVal Glu Cys Pro Asp Gly Glu Tyr Ser Asp Glu ThrAsp 580. 585 Ala Ser Ala Cys Asn Lys Cys Pro Asp Asp PheTrp Ser Asn Glu Asn His Thr Ser Cys Ile Ala LysGlu Ile Glu Phe Leu Ser Trp Thr Glu Pro Phe GlyIle Ala Leu Thr Leu Phe Ala Val Leu Gly Ile PheLeu Thr Ala Phe Val Leu Gly Val Phe Ile Lys PheArg Asn Thr Pro Ile Val Lys Ala Thr Asn Arg GluLeu " 650 655 660 TCC TAC CTC CTC CTC T'I'CTCC CTG CTC TGC TGCTTC 2451 Ser Tyr Leu Leu Leu Phe Ser Leu Leu Cys CysPhe Ser Ser Ser Leu Phe Phe Ile Gly Glu Pro Gln Asp SUBSTITUTE SHEET (RULE 26) WO 96112697 PCT/US95/1370.1 ACG CGC
CTG
CGC

Trp Cys Gln Pro Phe Gly Ile ' Thr Arg Ala Leu Arg ATC

Ser Phe Val Leu Cys IleSer Cys Ile Leu Val Lys 700 ~ 705 Thr Asn Arg Val Leu LeuVal Phe Glu Ala Lys Ile Pro Thr Ser Phe His ArgLys Trp Trp Gly Leu Asn Leu Gln Phe Leu Leu ValPhe Leu Cys Thr Phe Met Gln Ile Val Ile Cys ValIle Trp Leu Tyr Thr Ala Pro Pro Ser Ser Tyr ArgAsn Gln Glu Leu Glu Asp 760 ~ 765 Glu Ile Ile Phe Ile ThrCys His Glu Gly Ser Leu Met Ala Leu Gly Phe LeuIle Gly Tyr Thr Cys Leu Leu Ala Ala Ile Cys PhePhe Phe Ala Phe Lys Ser Arg Lys Leu Pro Glu AsnPhe Asn Glu Ala Lys Phe TTC

Ile Thr Ser Met LeuIle Phe Phe Ile Val Trp Phe TTC TAT TAT
GCC

Ile Ser Ile Pro Ala Ser Thr Gly Phe Tyr Tyr Ala TTT GAG ATC
GTC GTG CTG
TCT ATT

Lys Ser Val Ile Ala Phe Ala Glu Ile Val Val Leu SUBSTITUTESHEET (RULE 26) Ala Ala Ser Phe Gly Leu Leu Ala Cys Ile Phe Phe Asn Lys Ile Tyr Ile Ile Leu Phe Lys Pro Ser Arg '" 865 870 ' 875 Asn Thr Ile Glu Glu Val Arg Cys Ser Thr Ala Ala His Ala Phe Lys Val Ala Ala Arg Ala Thr Leu Arg -_ - Arg Ser Asn Val Ser Arg Lys Arg Ser Ser Ser Leu Gly Gly Ser Thr Gly Ser '1'hr Pro Ser Ser Ser 11e Ser Ser Lys Ser Asn Ser Glu Asp Pro Phe Pro Arg Pro Glu Arg Gln Lys Gln Gln Gln Pro Leu Ala Leu Thr Gln Gln Glu Gln Gln Gln Gln Pro Leu Thr Leu Pro Gln Gln Gln Arg Ser Gln Gln Gln Pro Arg Cys Lys Gln Lys Val Ile Phe Gly Ser Gly Thr Val Thr Phe Ser Leu Ser Phe Asp Glu Pro Gln Lys Asn Ala Met Ala His Arg Asn Ser Thr His Gln Asn Ser Leu Glu Ala Gln Lys Ser Ser Asp Thr Leu Thr Arg His SUBSTITUTE SHEET (RULE 26) TTA

Gln Pro Leu Pro Leu Gln Cys Gly Glu Thr Asp ' Leu CTG

Leu Asp Thr Val Gln Glu Thr Gly Leu Gln Gly Leu 1035 ' 1040 GGT

Pro Val Gly Asp Gln Arg Pro Glu Val Glu Asp Gly GAG

Pro Glu Leu Ser Pro Ala Leu Val Val Ser Ser Glu AGC

Ser Gln Phe Val Ile Ser Gly Gly Gly Ser Thr Ser GAA

Val Thr Asn Val Val Asn Ser Glu TCCCTTTAAA ATTAP~A.A.~ AGAAGAGCCT TGTGTTTCTG . 3 9 U 9 AAAACCATAT GATATTTTGT CTCCTACCTG CTGCTGCTAT 4229 _ TGTCTGGTTC TGTCCAGGAC AT.GATACTGA TGCCATGTTT 4309 SUBSTITUTE SHEET (RULE 26) (2) INFORMATION FOR SEQ ID NO: 2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3809 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single - (D) TOPOLOGY: linear (ii) MOLECULE.TYPE: cDNA to mRNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 373..3606 > (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:

SUBSTfTUTE SHEET (RULE 26) WO 96112697 PCT/US95/I3?O.l AGC TGC TGC TG

Met Ala Phe Tyr Se r Cys Cys Trp Val Leu Leu Ala Leu Thr Trp His Thr Ser Ala Tyr . 15 20 Gly Pro Asp Gln Arg Ala Gln Lys Lys Gly Asp Ile ATC CTT GGG GGG CTC TTT CCT ATT CAT.TTT GGA GTA 504 Ile Leu Gly Gly Leu Phe Pro Ile His Phe Gly Val Ala Ala Lys Asp Gln Asp Leu Lys Ser Arg Pro Glu Ser Val Glu Cys Ile Arg Tyr Asn Phe Arg Gly Phe Arg Trp Leu Gln Ala Met Ile Phe Ala Ile Glu Glu Ile Asn Ser Ser Pro Ala Leu Leu Pro Asn Leu Thr CTG GGA TAC AGG ATA TTT GAC ACT TGC AAC ACC GTT 684 _ Leu Gly Tyr Arg Ile Phe Asp Thr Cys Asn Thr Val g5 100 Ser Lys Ala Leu Glu Ala Thr Leu Ser Phe Val Ala SUBSTITUTE SHEET (RULE 26) Gln Asn Lys Ile Asp Ser Leu Asn Leu Asp Glu Phe _ TGC AAC TGC TCA GAG CAC ATT CCC TCT ACG ATT GCT 792 Cys Asn Cys Ser Glu His Ile Pro Ser Thr Ile Ala 13 0 13 5 ' 14 0 Val Val Gly Ala Thr Gly Ser Gly Val Ser Thr Ala Val Ala Asn Leu Leu Gly Leu Phe Tyr Ile Pro Gln Val Ser Tyr Ala Ser Ser Ser Arg Leu Leu Ser Asn Lys Asn Gln Phe Lys Ser Phe Leu Arg Thr Ile Pro Asn Asp Glu His Gln Ala Thr Ala Met Ala Asp Ile Ile Glu Tyr Phe Arg Trp Asn Trp Val Gly Thr Ile GCA GCT GAT GAC GAC TAT GGG CGG CCG GGG ATT GAG. 1044 Ala Ala Asp Asp Asp Tyr Gly Arg Pro Gly Ile Glu Lys Phe Arg Glu Glu Ala Glu Glu Arg Asp Ile Cys Ile Asp Phe Ser Glu Leu Ile Ser Gln Tyr Ser Asp Glu Glu Glu Ile Gln His Val Val Glu Val Ile Gln . AAT TCC ACG GCC AAA GTC ATC GTG GTT TTC TCC AGT 1188 Asn Ser Thr Ala Lys Val Ile Val Val Phe Ser Ser Gly Pro Asp Leu Glu Pro Leu Ile Lys Glu Ile Val SUBSTITUTE SHEET (RULE 26) WO 96112697 PCT/US9511370:1 ATC ACG CTG AGC ' GGC AAG
ATC

Arg Arg Asn Ile Thr Gly Trp Ala Lys Ile Leu Ser GCC

Glu Ala Trp Ala Ser Ser Ser Leu Ile Met Pro Ala 300 ~ 305 "

ATT

Gln Tyr Phe His Val Val Gly Gly Thr Ile Gly Phe Ala Leu Lys Ala Gly Gln Ile Pro Gly Phe Arg Glu Phe Leu Lys Lys Val His Pro Arg Lys Ser Val His Asn Gly Phe Ala Lys Glu Phe Trp Glu Glu Thr Phe Asn Cys His Leu Gln Glu Gly Ala Lys Gly Pro Leu Pro Val Asp Thr Phe Leu Arg Gly His Glu Glu Ser Gly Asp Arg Phe Ser Asn Ser Ser Thr Ala Phe Arg Pro Leu Cys Thr Gly Asp Glu Asn Ile Ser Ser Val CGG

Glu Thr Pro Tyr Ile Asp Tyr Thr His Leu Ile Arg GTG TAC ATT
TTA

Ser Tyr Asn Ala Val Tyr Ser Ala Val Tyr Ile Leu CAA GAT CCT
ATA TAT
ACC TGC

His Ala Leu Tyr Thr Leu Gly Gln Asp Cys Pro Ile TTC ACC GAC
AAT GGC ATC
TCC TGT

Arg Gly Leu Ala Phe Thr Asp Asn Gly Ile Ser Cys SUBSTITUTE SHEET (RULE 26~

Lys Lys Val Glu Ala Trp Gln Val Leu Lys His Leu Arg His Leu Asn Phe Thr Asn Asn Met Gly Glu Gln 465 470 ' 475 Val Thr Phe Asp Glu Cys Gly Asp Leu Val Gly Asn Tyr Ser Ile Ile Asn Trp His Leu Ser Pro Glu Asp Gly Ser Ile Val Phe Lys Glu Val Gly Tyr Tyr Asn Val Tyr Ala Lys Lys Gly Glu Arg Leu Phe Ile Asn Glu Glu Lys Ile Leu Trp Ser Gly Phe Ser Arg Glu Val Pro Phe Ser Asn Cys Ser Arg Asp Cys Leu Ala Gly Thr Arg Lys Gly Ile Ile Glu Gly Glu Pro Thr Cys Cys Phe Glu Cys Val Glu Cys Pro Asp Gly Glu Tyr Ser Asp Glu Thr Asp Ala Ser Ala Cys Asn Lys Cys Pro Asp Asp Phe Trp Ser Asn Glu Asn His Thr -585 590 595 .

Ser Cys Ile Ala Lys Glu Ile Glu Phe Leu Ser Trp a - 600 605 Thr Glu Pro Phe Gly Ile Ala Leu Thr Leu Phe Ala SUBSTITUTE SHEET (RULE 26) GGT

Val Leu Gly Ile Phe Leu Thr Ala Phe Val Leu ' Gly GTG TTT ATC AAG TTC CGC AAC ACA CCC ATT GTC 2304 _ AAG

Val Phe Ile Lys Phe Arg Asn Thr Pro Ile ValLys 635 '640 Ala Thr Asn Arg Glu Leu Ser Tyr Leu Leu LeuPhe Ser Leu Leu Cys Cys Phe Ser Ser Ser Leu PhePhe _x Ile Gly Glu Pro Gln Asp Trp Thr Cys Arg LeuArg Gln Pro Ala Phe Gly Ile Ser Phe Val Leu CysIle Ser Cys Ile Leu Val Lys Thr Asn Arg Val LeuLeu Val Phe Glu Ala Lys Ile Pro Thr Ser Phe HisArg Lys Trp Trp Gly Leu Asn Leu Gln Phe Leu LeuVal Phe Leu Cys Thr Phe Met Gln Ile Val Ile CysVal Ile Trp Leu Tyr Thr Ala Pro Pro Ser Ser TyrArg TTC

Asn Gln Glu Leu Glu Asp Glu Ile Ile IleThr Phe GGC TTC

Cys His Glu Gly Ser Leu Met Ala Leu Leu Gly Phe ATC TGC TTC

Ile Gly Tyr Thr Cys Leu Leu Ala Ala Ile Cys Phe SUBSTITUTE SHEET (RULE 26) Phe Phe Ala Phe Lys Ser Arg Lys Leu Pro Glu Asn _ 790 795 800 Phe Asn Glu Ala Lys Phe Ile Thr Phe Ser Met Leu ' 805 ' 810 Ile Phe Phe Ile Val Trp Ile Ser Phe Ile Pro Ala Tyr Ala Ser Thr Tyr Gly Lys Phe Val Ser Ala Val Glu Val Ile Ala Ile Leu Ala Ala Ser Phe Gly Leu Leu Ala Cys Ile Phe Phe Asn Lys Ile Tyr Ile Ile 850 . 855 860 Leu Phe Lys Pro Ser Arg Asn Thr Ile Glu Glu Val CGT TGC AGC ACC GCA GCT CAC GCT TTC.AAG GTG GCT 3024 Arg Cys Ser Thr Ala Ala His Ala Phe Lys Val Ala Ala Arg Ala Thr Leu Arg Arg Ser Asn Val Ser Arg Lys Arg Ser Ser Ser Leu Gly Gly Ser Thr Gly Ser Thr Pro Ser Ser Ser Ile Ser Ser Lys Ser Asn Ser Glu Asp Pro Phe Pro Gln Pro Glu Arg Gln Lys Gln Gln Gln Pro Leu Ala Leu Thr Gln Gln Glu Gln Gln Gln Gln Pro Leu Thr Leu Pro Gln Gln Gln Arg Ser SUBSTITUTE SHEET RULE 26) AAG

Gln Gln Gln Pro Arg Cys Lys Gln Val Ile Phe Lys CTG

Gly Ser Gly Thr Val Thr Phe Ser Ser Phe Asp Leu 970 975 ~ 980 CAC

Glu Pro Gln Lys Asn Ala Met Ala Gly Asn Ser His CAG

Thr His Gln Asn Ser Leu Glu Ala Lys Ser Ser Gln g95 1000 TTA

Asp Thr Leu Thr Arg His Gln Pro Leu Pro Leu Leu CTG

Gln Cys Gly Glu Thr Asp Leu Asp Thr Val Gln Leu GGT

Glu Thr Gly Leu Gln Gly Pro Val Gly Asp Gln Gly GAG

Arg Pro Glu Val Glu Asp Pro Glu Leu Ser Pro Glu AGC

Ala Leu Val Val Ser Ser Ser Gln Phe Val Ile Ser GAA

Ser Gly Gly Gly Ser Thr Val Thr Asn Val Val Glu GGGCTAGGGA

Asn Ser GGGTCCCAGG
GATGAGGAAT

TGAGGAAGAA
GGGATAATAG

TTAGTCACAC
CATCTTAAAT

TCCCTTTAAA

SUBSTITUTE SHEET (RULE 26)

Claims (40)

CLAIMS:
1. A compound having the formula:
wherein Ar5 is either naphthyl or phenyl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, .alpha.,.alpha.-dimethylbenzyl, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy, and -CH=CH-phenyl;
Ar6 is phenyl substituted with 1 to 5 substituents each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, carbomethoxy, OCH2C (O) C2H5 and OCH2C(O)OC2H5 and acetoxy, provided that at least one substituent is OCH2C(O)OC2H5;
R11 is hydrogen or methyl; and R12 is hydrogen or methyl;
provided that at least one of R11 and R12 is methyl; or a pharmaceutically acceptable salt or complex thereof.
2. The compound, salt or complex of claim 1, wherein Ar6 is a substituted phenyl comprising a OCH2C(O)OC2H5 substituent in a meta position.
3. A compound selected from the group consisting of:

((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)-ethylamine);
((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)-ethylamine);
((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)-ethylamine);
((R, R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);
((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)-ethylamine);
((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);
((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)-ethylamine);
(N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)-phenyl)ethylamine);
((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine);
((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)-ethylamine);
(N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)-phenyl)ethylamine);
((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)-ethylamine);
((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)-ethylamine);

(((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);
(((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)-ethylamine); and pharmaceutically acceptable salts and complexes thereof.
4. The compound ((R,R)-N-(4-(3-(trifluoromethyl)-phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
5. The compound ((R)-N-(3-(3-(trifluoromethyl)-phenyl)propyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
6. The compound (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
7. The compound (((R,R)-N-(4-(3-trifluoromethyl)-phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
8. The compound ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
9. The compound ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
10. The compound ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.
11. ~The compound((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
12. ~The compound(N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
13. ~The compound((R)-N-((3-(trifluoromethoxy)phenyl)-methyl)-1-(1-naphthyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
14. ~The compound((R)-N-(3-(3-(trifluoromethoxy)phenyl)-propyl)-1-(1-naphthyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
15. ~The compound((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
16. ~The compound((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
17. ~The compound((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
18. ~The compound((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
19. ~The compound(((S,R)-N-(4-(3-trifluoromethyl)-phenyl)-2-butyl)-1-(1-naphthyl)ethylamine)or a pharmaceutically acceptable salt or complex thereof.
20. ~A pharmaceutical composition comprising the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, and a pharmaceutically acceptable carrier.
21. ~A pharmaceutical composition comprising a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for inhibiting bone resorption in a patient.
22. ~A pharmaceutical composition comprising a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for treating a patient having a disease selected from the group consisting of hyperparathyroidism, a hypercalcemic disorder, osteoporosis and renal osteodystrophy.
23. ~The pharmaceutical composition of claim 22, wherein the disease is hyperparathyroidism.
24. ~The pharmaceutical composition of claim 22, wherein the disease is a hypercalcemic disorder.
25. ~The pharmaceutical composition of claim 22, wherein the disease is osteoporosis.
26. ~The pharmaceutical composition of claim 22, wherein the disease is renal osteodystrophy.
27. ~A pharmaceutical composition comprising a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis.

106~
28. ~A pharmaceutical composition comprising a therapeutically effective amount cf the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for decreasing parathyroid hormone level in a patient.
29. ~A commercial package comprising the pharmaceutical composition of claim 21, 22, 23, 24, 25, 26, 27 or 28 and instructions for the use thereof.
30. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 in the manufacture of a medicament for inhibiting bone resorption in a patient.
31. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 in the manufacture of a medicament for treating hyperparathyroidism, a hypercalcemic disorder, osteoporosis or renal osteodystrophy in a patient.
32. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 in the manufacture of a medicament for treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis.
33. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 in the manufacture of a medicament for decreasing parathyroid hormone level in a patient.
34. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for inhibiting bone resorption in a patient.
35. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for treating hyperparathyroidism, a hypercalcemic disorder, osteoporosis or renal osteodystrophy in a patient.
36. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 for treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis.
37. ~Use of a therapeutically effective amount of the compound, salt or complex of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17; 18 or 19 for decreasing parathyroid hormone level in a patient.
38. ~A compound having the formula:
wherein Ar3 is either naphthyl or phenyl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO2, CHO, CH3CH(OH), N(CH3)2, acetyl, and ethylene dioxy;

Ar4 is either naphthyl or phenyl, each optionally substituted with 1 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, and acetoxy;

provided that:

if Ar4 is 3-methoxyphenyl, then Ar3 is a substituted phenyl that is not a 2-methoxy, 3-methyl, 2-methyl, 4-methyl, 2,4-dimethyl, 2,4,6-trimethyl, or 4-isopropyl substituted phenyl; and if Ar4 is unsubstituted phenyl, then Ar3 is a substituted phenyl that is not 2-nitrophenyl, 4-nitrophenyl, or 4-dimethylaminophenyl;

R8 is either hydrogen or phenyl;

R9 is either hydrogen or methyl; and R10 is either hydrogen, methyl, or phenyl;

or a pharmaceutically acceptable salt or complex thereof.
39. The compound, salt or complex of claim 38, wherein Ar3 is either naphthyl optionally substituted with 1 to 5 substituents or phenyl optionally substituted with 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO2, CHO, CH3CH (OH), N(CH3)2, acetyl, and ethylene dioxy.
40. A pharmaceutical composition comprising the compound of claim 38 or 39, and a pharmaceutically acceptable carrier.
CA002202879A 1994-10-21 1995-10-23 Calcium receptor-active compounds Expired - Lifetime CA2202879C (en)

Applications Claiming Priority (5)

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PCT/US1994/012117 WO1995011221A1 (en) 1991-08-23 1994-10-21 Calcium receptor-active arylalkyl amines
WOPCT/US94/12117 1994-10-21
US08/353,784 US6011068A (en) 1991-08-23 1994-12-08 Calcium receptor-active molecules
US08/353,784 1994-12-08
PCT/US1995/013704 WO1996012697A2 (en) 1994-10-21 1995-10-23 Calcium receptor-active compounds

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