ZA200500782B

ZA200500782B - Calcium receptor modulating compound and use thereof

Info

Publication number: ZA200500782B
Application number: ZA200500782A
Authority: ZA
Inventors: Yasuma Tsuneo; Mori Akira; Kawase Masahiro; Kimura Hiroyuki; Masato Yoshida; Albert Charles Gyorkos; Pratt Scott Alan; Corrette Christopher Peter
Original assignee: Takeda Pharmaceutical
Priority date: 2002-08-26
Filing date: 2003-08-21
Publication date: 2007-10-31
Also published as: CN1771231A; CN1771231B

Description

DESCRIPTION

CALC IUM RECEPTOR MODULATING C OMPOUND AND USE THER EOF

BACKGROUND OF THE INVENTION

Fieald of the Invention

The= present invention relates to heterocyclic compounds having calcium-se nsing receptor (Cask, hereinafter simply referred to &s Ca receptor) modualating (agonist. ic or antagonistic) activity, pharmaceutical composit ions containing them amd intermediate compounds useful f or synthesizing them.

Bac kground Art

Cal cium ion (hereinafter s imply referred to &s Ca) plays an. essential role to maintain and modulate functions of vario us cells such as endocrin.e and exocrine cells , etc., in additzion to nerve and muscle. For this reasor, the blood Ca level is strictly maintained in a narrow range.

Parathyr oid hormone (PTH) plays a central role in maintain ing this blood Ca level. Therefore, secretmon of

PTH from parathyroid gland responds sharply to charge in the blood Ca level and is must be modulated accordzing to this. In fact, when the blood Ca level is changed, the blood PT"H level is rapidly changed in response to this.

The possibility of a mechanism by which the extracellular

Ca concentration is sensed by parathyro-id gland cells arad the informationn transmitted into cells h.as been pointed out early by Browrn et al. In 1993, they succeeded in tlme cloning and characterization of a Cea&a-sensing receptor (CaSR; hereinafter, simply referred to a= Ca receptor) froem bovine parathyroid (Nature, 366, 575-580 (1993)).

The Ca receptor is composed of a large terminal extracellular xegion spanning 600 amino acids at the N - terminal, having seven transmembrane spamnning domains lik.e other G protein coupled receptors, and an intracellular region consisting of 200 or less amino acids at the caboxy 1

C-terminal.

It is considered that, when the extracellular C a concentration is increased, phosphol _ipase (PL) -C is activated, leading tc increase 1n the intracellular Ca concentration and inhibition of PTH secretion due te increase in inositol triphosphate (IP3). Since when a high value of the extracellular Ca concentrat ion is maintained the intracellul ar Ca concentration is th ereafter increased continuously, it is considered that infl ux of Ca from the outside of a «ell is also promoted. PL-A, and D are activated due to increase in extracellula.r Ca, but there is a possibility that these are via protein kinase (PK)-C and the like which are activated at the same time via Ca receptor. “The Ca receptor also inhi bits adenylyl cycl_ase via Gi protein or via arachidonic acid production due to activation of PL-A; and decreases intracellular cyclic AMP (Bone, 20, 303-309 (199%97)).

Ca receptor mRNA is expressed in many tissues, and the expression amount is high, in parat hyroid gland, thyr-oid gland C cell, medulla and cortex thic k ascending limb (MTAL and CTAL) of kidney wuriniferous tt ubule, intramedullary collecting tubule (IMCD) and encephalic subfornical o=xrgan (SFO) and mippocampus (Bone, 20, 303-309 (1997)). In addition, ex pression is recognized ir many tissues such as encephalic hypothalamus, cerebellum &=nd olfactory nucleus, regions other than TAL of renal urimiferous tubule, lung, stomach, pamcreas, intestine and skin. Since the Ca receptor 1s present in various tissuies, its physiological function has yet to be fully unders tood. However, itz is expected that the Ca receptor modwlating (agonistic or antagonistic) drug would provide for- a novel treatments of various disesase states which include the following: 1. Drugs for Treating Bone Diseases

Since the anabolic activity is manifested by intermittent administration of PTH, Ca receptor modula ting drugs which are considered to be able to regulate secre tion of PTH are promising as a drug for treating osteoporo sis.

In additiorm, Ca receptor modulat ing drugs which are selectable for thyroid gland C cell may be also effective for toreating osteoporosis by stimulation of calczitonin secretzion. Whether the same Ca receptor as tkat of parathyroid gland is present in osteoblast, osteoclast and bone «ell or not is disputable . However, some Ca-ssensing mecharmism is assuredly present therein and, ther—efore, drugs which directly act on them can be expected as a drug for tr-eating bone diseases. 22. Kidney-Acting Drugs

Handling of water and mineral in kidney is no t only based on the results of function as a target organ for hormomes, such as PTH, vitamima D etc., but also -the Ca receptor in kidney is presumed to function in a respo=nse to the Ca concentration and the magnesium ion concentration in the extracellular fluid (Kidney Int, 50, 2128-2139 (1.99¢)).

Further, it is also considered that Ca receptor modu lating drugs may modulate the blood amount in kidney, the amount of glomerulus filtration, renin secretion and activat ion of vitamin D in addition to control of influx and efflux of water and mineral. 3 . Central Nervous System and Endocrine-Acting Drugs

Ca receptor is present im almost all areas i.n the centra 1 nervous system, and is remarkably expresse=d, in particular, in the hippocampus, cerebellum and subfo_rnical organ (Brain Res, 744. 47-56 (1997)). Although the destails of the function are still unclear, the term of C&= receptor expression after birth in thes hippocampus is consistent with the term of acquisitiora of LTP (Long MWightening

Phenomenon) (Develop Brain Ress, 100, 13-21 (19 97)) and, 5 therefore, the relationship with memory and learni ng can be presumed. Therefore, Ca receptor modulating dr ugs which are high in brain-blood barriers permeability and selective for the central nerve system m-ay be utilized for- treating

Alzheimer’s disease. In additmdon, since dry mou th occurs in hypercalcemic patient, Ca receptor modulating drugs may control them. The presence of Ca receptor in mouse pituitary gland cells which se<creteACTH has been reported (Mol Endocrinol, 10, 555-565 (1996) ). It is also considered that Ca receptor modulating drugs can =e applied to Sheehann’s syndrome and hypopituitar—ism or hyperpituiltarismn. 4. Digestive System-Acting Drugs

It is considered that a Ca receptor is presemt in the

Auerbach nerve plexus of the dogestive tract and controls intestinal tract motion. Constipation is known in hypercalcemic patients and stimulation of digestdve tract motion is known in hypocalcemic patients in clinic al tests.

The existence of a Ca receptor in the gastrin secreting cell (G cell) of the stomach kas been reported (J. Clin

Invest, 99, 2328-2333 (1997) ), and intestinal tract absorption , constipation, di-arrhea, defecation and secretion of acid in the stomach may be controlled by drugs which act <n a Ca receptor in thes digestive tract. Fuarther, it has been found that a Ca rec eptor is present in human colon cancesr cell strains and it controls c-myc expression and proliferation (Biochem Bioph—ys Res Commum, 232, 80-83 (1997)), this is better consistemmt with the fact tha.t the

Ca uptake and sideration of «olon and rectum ca&ncers exhibit the negative correlat-don and, therefore , Ca receptor regulating drugs can be expected also as a drug for preventing and treating such ccancers.

Various heterocyclic compouneds have been disclos-ed in the prior art. For example, WO 01/53266 discloses a compound of the formula: 0

R

VY

RR Lo where in R, R! and R? are indeperadently H, hydroxyl, etc.

This compound has a phosphoinosi tide 3-kinase inhib¥ tory activity and is useful for treating coronary obstruction, etc. Indi an J. Chem., Sect. BE (1993), 32B(5), 586-9 discloses tlae synthesis of a compouwand of the formula:

R

Me

N— 7 No —

N

HN H

0 R wherein R is hydrogen, chl orine, methyl or methoxy.

However, no utility is disclo sed. U.S. Patent 4,746,656 (JP 63-33380 A) discloses a compound of the formul a:

R Ry

EAN

Ny COOR, 0=_I_ wherein R; is aryl or heterocyclic group, Rz is ar yl, etc.,

R; amd R4 are independently H, alkyl, etc. This compound is a Ca channel blocker.

EP 2717142 discloses a compound of the formula:

R

N—y R, 4 — oR,

Rg R, wherein R is hydrogen, alkyl, etc., Ri; is hydrogen, nitro, cyano, etc., Rp is phenyl, cycl.calkyl, etc., R3 is hydrogen,

acyl etc., and Rg 1s carboxyl, carbamoyl, etc. This compound is also a Ca channel blocker.

However, a heterocyclic compournd having Ca receptom modulating activity is not found in t he prior art.

OBJECTS OF T HE INVENTION

One object of the present inv ention is to provide compounds ha ving Ca receptor modulating activity includingr novel compounds.

Another object of the present imevention is to provide pharmaceutical compositions containing the compounds of the present invention.

These olbjects as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.

SUMMARY OF THE INVENTION

The present inventors have intesnsively investigated compounds hawing Ca receptor modulat ing activity. As a result, it has been found that compounds represented by formula (I) as shown hereinafter have Ca receptor modulating activity useful for medicine and, among them, compounds represented by the formul as (II), (ITI) and (IIIa) as shown hereinafter are novel compounds.

According to the present inventiora, there is provided:

1. A compound of the formula (II): ra R' y

R

: x! 2 N~ Ar 3

R whereirm ring A is an optionally substituted 5- to 7- memberexd ring;

OQ is CC, CR’ (wherein R® is Hi, an optionally substituted hydrocarbon group, an optional ly substituted hy droxyl group, an optionally substituted amino group, an optionally substituted thicl group, cyan< group, a halogen atom, an optiona lly substituted heterocyclic group, or a group of the formula: -%'-%2° (wherein -=!'- is -CO-, -CS- , -SO- or -

SO,—, amd Zz? is an optionally substituted hydrocarbon group, an opti onally substituted heterrocyclic group, ara optionally substituted hydroxyl group, or an optionally substituted amino gzroup)), or N; x! is CR! (wherein rR! is H, an optionally substituted hydrocazxbon group, an optionall y substituted hyd roxyl group, an opt-ionally substituted amino group, an optionally substitwited thiol group, cyano group, a haloge=n atom, an optional ly substituted heterocxsclic group, or a group of the foromula: -2'-z° (wherein —z'- and 2? are as defined above) ), CRIR? (wherein R! is as defined above, amd R? is H, or an opotionally substituted hy drocarbon group), N, or NR'3

(wherein R!'® is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an cpticnally substituted amino group, an optionally substituted heterocyclic group, or a group of thes formula: -21-2% (wherein -2'- and 7% are as defined above));

R® is H, an optionally substituted hydrocarbon «group, an ptionally substituted hydroxyl group, an optionally =substituted amino group, an optionally su bstituted heterocyclic group, or a group of the formula: -z1-z°2 (wherein -z'- and z? are as defined above); w is C, CR? (wherein R® is H, an optionally sulbstituted

Fydrocarbon group, an optionally substituted hydro=yl group, =n optionally substituted amino group, an optionally substituted thiol group, c¢yano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -2!-7Z%2 (wherein -z!- and 2? are as defined a. bove)), or N;

A_r is an optionally substituted cyclic group;

R? and RY? are the same or different and are H, an optionally substituted hydrocarbon group, an optionally s-ubstituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyan o group, a halogen atom, an optionally substituted hete rocyclic group, or a group of the formula: -2'-2%2 (wherein -2Z'- and 72 are as defined above) ; and RY and R¥? are the same or dif ferent and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -2''-2z? (wherein -% _ is -CS-, -SO- or -S02—, and 22 is as defined above); om R® and R', or R' and R!? may be combined to form an oxo =group, methylene g roup or a ring; or RY and R! may be combimed to form a ring _; and - -— - is a single bond or a doub le bond; provided that (1) when ring A is a 6-membered ring and Q is C or CR’, x? is C-2'-22, c(-2'-2?)R?® or N-2'-7Z? and both R’ an d R' are not H, or R? and R!® are not comboined to form an o=xo group, or RY and RY are not combined to form a 5-membered ring, (2) when ring A is a 6-membered ring and Q is N, x! is C- 71-22, c(-2'-2?)R?® or N-2'-22, and R® and R! are not combined to form an oxo group, (3) when ring A is a 5-membered ring and Q is C or Cr’, x! is Cc-z'-22, C(-2'-2%)R? or N-2z'-2%2, and 7° is an optionally substituted amino group, and (4) when ring A is a 5-membered ring and Q is N, at least one of R? and R'® is CHR!®R!® (wher-ein at least one o-f R!® and

RY are the same or different and are H, an opotionally substituted hydrocarbon group, an optionally sukostituted hydroxyl group, ary optionally substitwmited amino group, an optionally substittuted thiol group, a halogen atom, an optionally substittuted heterocyclic g.roup, or a Jgroup of the formula:-%'-22 (wherein -2Z'- and Zz? are as defired above) ) and the other 1s other than an optional ly substituted phenyl group; or a salt thereof; 2. A compourid of the formula (III):

Rr RY ly =A aD

N~ Ar

RR wherein R! is H, an optionally subsstituted hydrocari>on group, an optionally substituted kydroxyl group, an optionally subst ® tuted thiol group, an optional ly substituted amino group, cyano Jgroup, a halogen atom, an optionally substituted heterocyclic gr-oup, or a group of the formula: -2'-z% (wherein -2z'- is -C0-, -CS-, -S0- or - 50,-, and 7Z? is an optionally substitut ed hydrocarbon gro up, an optionally substzituted heterocyclic group, an optional ly substituted hydrox—yl group, or an optionally substitut ed amino group):

R® is H, an optiorally substituted hy drocarbon group, an optionally substituted hydroxyl group, an optional ly substituted amino group, an opti.onally substitute=d heterocyclic group, or a group of the formula: -z1_ gy?

(wherein -2z%*- and 2? are as defined above);

Y is Cc, CR? (wherein R* is H, am optionally subs tituted hydrocarbon group, an optionally substituted hydroxy 1 group, an optionallly substituted amino group, an opt.ionally substituted thiol group, cyano group, a halogen atom, an optionally s=substituted heterocyclic group, or a gr-oup of the formula : -2'-2z? (wherein -2'- and 2z° are as defined above)) or N ;

R® is H, an optionally substituted hydrocarbon gro=up, an optionally substituted hydroxyl group, an optXonally substituted amino group, an optiormally substituted thiol group, cyarao group, a halogen atom, an opti onally substituted heterocyclic group, or a group of the formula: -z'-2? (where=in -Z'- and Zz? are as de-fined above);

Ar is an opt donally substituted cycl ic group:

R® and RY are the same or different and are H, an optionally substituted hydrocarbon group, an opti onally substituted hydroxyl group, an optionally substituted. amino group, an op-tionally substituted thz=iol group, cyano group, a halogen a.tom, an optionally suabstituted hetero cyclic group, or a group of the formula: —z2'-22 (wherein -Z '- and 72 are as de=fined above), or R° and R'® may be combimed to form an oxo group, methylene group © r a ring; x? is a bond., oxygen atom, an optionally oxidized =ulfur atom, N, NR?" (wherein R’ is H, an optionally subst=ituted hydrocarb on group, an optionally substituted hydroxy 1 group, an optioenally substituted amino group, an opt_dicnally substitut ed heterocyclic group, or a group of the fozxrmula - z''-2% (wh.erein -2''- is -CS-, -SO- or -S0,-, and Z® is as defined a.bove)), or an optionally substituted bivalent Ci: hydrocarbeon group; and - —- —-— is &= single bond or a doubl e bond; provided -that at least one of R?> and R'® is CHR'YR!® (wherein

RY? and ®R!'®° are the same or different and are H, an optionallsy substituted hydrocarloon group, an optionally substitute=d hydroxyl group, an op tionally substituted amino group, an. optionally substituted thiol group, a Imnalogen atom, an optionally substituted heterocyclic group,- or a group of the formula:-2z'-2z° (wherein -z2!'- and 2° =@=re as defined alkoove)) and the other is other than an opti_onally substituted phenyl group; or a salt thereof; 3. The compound according to the above 1 or 2, wherein R= is (1) an optionally substituted hetero-cyclic group, or (2) a group of the formula: -2'-2? (wherein -z!- is -CO-, -CS-, ~-S0- or -S0;—, and 2? is an opti onally substitute=d hydrocarbon group, an optionally subst ituted heterocycl ic group, an optionally substituted hy droxyl group, or an optionally substituted amino group); 4. The compound according to the above 3, wher—ein gz?! is -CO- arad 2° is an optionally substituted hydroxyl group or an optionally substituted amiro group; 5. The compound according to the above 2, wherein Rr’ is H, a Cp -¢ alkyl group or a Cs-14 aralkyl group; 6. The compound according to the above 2, wherein R® is H, a Ci.¢ alkyl group, a Ci-¢ alkylthic group or a Ci-s alkoxy group which may be substittuted with hydroxyl group; 7. The compound accordincg to the above 1 or 2, wherein R? and R' are the same or different and are a Cig alkyl growp or R? and RY are comBoined each other to form a ring: 8. The compound according to the above 2, wherein rR? is a group of the formula: -z'-2=2 (wherein -z'- is -CO-, - cS-, -S0- or -S0,-, and 72 is an optionally substituted hydrocarbo n group, an optionally substituted heterocyclic group, an optionally substitute d hydroxyl group, or an optionally substituted amino group): R® is H; Ar 1s an optionally substituted aromatic ring group; x3 is CR!MR?!? (wherein RZ! and R'? are the same or different and are H, an optionally substituted hydrocarloon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cya no group, : a halogen atom, an optionally substituted heterocyclic group, or a group of the formula : -z'-2? (wherein -2z'- and 72 are as defined above), or R!'' and R'? may be combined to form an ox © group, methylene grouip or a ring); and R® and

R}® are the same or different amd a Cis alkyl group, or R® and R'® may be combined to form & ring; 9. T"he compound according to the above 8, wherein Rr! is an optioesnally substituted carbamoyl group; 10. The compound accordincg to the above 9, wherein R! is a group of the formula: —~CONRR?® (CR?*'R??R?%) (wherein R*’ is

H or an optionally substituted hydrocarbon group, and rR,

R?*2, and R?? are the same or diff erent and are an optionally substituted hydrocarbon group ors an optionally subsstituted heterocycli ¢ group, or R?® and R=! may be combined to form a ring): 11. A compound of the formula (IIIa):

R2 R' oy

EEE Ye (11a)

N Ar

RY R3 wherein R*® is (1) an optionall y substituted heterocyclic group, or (=2) a group of the forrmula: -z'3-7?% (where in -z'2- is -CO-, -C S-, -SO- or -S0,-, arad 2°® is (i) an optionally substituted heterocyclic group , (ii) -NR?0%(CR?!=R??2R%3e) (wherein (&) R?®® is H or aan optionally subsstituted hydrocarbon group; and R?® is an optionally substituted heterocyclicz group which may be fused with an optionally substituted benzene ring, or aan optionally subs tituted phenyl group which may be f used with an opt ionally substit uted aromatic heterocyclic ring and ERR*? and R*? are the samme or different and are an optional ly substituted hydroca rbon group or an optieonally substitute=d heterocyclic group o r R??? and R?*®* may be combined to form a ring, or (b)

R%%® is H or an optionally substituted hydr-ocarbon group; and R?'® , R??% and R?*® are the same or differ ent and are an optiona_lly substituted Cj-g aliphatic hydreocarbon group, providecd that the sum total of the number o f carbon atoms is 7 or= more), (iii) -NR?°®R *?2 (wherein R%*’® is as defined above a.nd R?®? is an optionally substituted Ceo aryl-Cz-s alkyl, Ce-10 aryloxy-C,.4 alkyl , Ce-10 arylamino -Cz-4 alkyl, Cy- 14 aralkylamino-C,-4 alkyl, h eterocyclic ring-C;-4 alkyl or heterocyclic group), (iv) a substituted 5- to 7-membered cyclic amino group, or (v) -OR?'® (wherein R**® is (a) an optional ly substituted Co- 14 aralkyl group, (b) an optional ly substituted Cs;.; alicyclic hydrocar=bon group, (c) an optionally substituted Cy.=4 aliphatic hydr ocarbon group, or (d) aan optionally substitu ted heterocyclic group):

R?® is H , an optionally substituted hydrocar-bon group, "an optional ly substituted hydroxyl group, =n optionally substitu ted amino group, an optionally— substituted heterocyclic group, or a group of the formula: 71-72 (wherein. -2z'- is -CO-, -CS-, -50- or -S0,-, and Zz? is an optional ly substituted hydrocarbon group, an optionally substitu ted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group)’

Y is Cc, CR? (wherein R*? is H, an. optionally substituted hydrocarbon group, an optionally su bstituted hydroxyl g roup, an optionallly substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally =ubstituted heterocyclic group, or a group of the formula : -2Z!'-2° (wherein -2'- and 2° are as defzned above)) or NE;

R® is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optiorially substituted thiol group, cyaro group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formaala: 71-22 (wherein -2'- and 22? are as de fined above);

Ar is an opt ionally substituted cycl ic group;

R® and RY are the same or different and are H, an optionally substituted hydrocarbon group, an opticna.lly substituted ihydroxyl group, an optionally substituted amino group, an op tionally substituted thiol group, cyano gro up, a halogen atom, an optionally substituted heterocyc lic group, or a group of the formula: —z21-2? (wherein -Zz'- and 72 are as de fined above), or R? and R!® may be combined to form an oxo group, methylene group © r a ring; x3 is a bond, oxygen atom, an optionally oxidized sul fur atom, N, NR’ (wherein R’' is H, an optionally substitu-—ted hydrescarbon group, an optionally substituted hydroxyl group, an optionally substitut ed amino group, an optionally subs®ituted heterocyclic group, or a group ox the formula - z''-7 2 (wherein -2z''- is — CS-, -SO- or -SO,-, and 2? is as defirmed above)), or an op-tionally substituted bivalent Ci-2 hydrocarbon group; and ~- —- — is a single bond or a double bond; provi.ded that at least one of R’> and R*® is CHRYMR'® (wherein

R® =nd R!'®* are the same or different amd are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl groups, an optionally sulostituted amino groups, an optionally sub stituted thiol group, a halogen atom, an optionally subst-ituted heterocycli ¢ group, or a group of the formula: -zt—72? (wherein -2'~ a@nd 2% are as defin ed above)) and the other is other than an optionally subst ituted phenyl group; =or a salt thereof; 12. The compound ‘according to the abowe 11, wherein

R'® iss a group of the formula: -CONR?°?(CR?'PR*ZPR**®) (wherein

R2%? j= as defined above ard at least one of R*®, R?*?®, and

R?°® | s an optionally substituted heterocyclic group which may b e fused with an optieonally substituted benzene ring, or arm optionally substituted phenyl group which may be fused with an optionally s ubstituted aromatic heterocyclic ring) = 1.3. The compound acc ording to the above 11, wherein

R™ is (1) an optionally substitiated 5- to 7-membe=red aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (2) a group of the formula: -co—z%¢ (wherein 22° is (i) an optionally substituted 5- to 7- membered aromatic or non-aromatic he-terocyclic group hav ing 1-4 hetero atoms selected from nitr ogen atom, oxygen atom and sulfur at om, (ii) -NR2?°°(CR?!°R?2°R=3¢)} (wherein (a) R?%® is

H or an optionally substituted hydr occarbon group selec ted from C;.3 saturated aliphatic hye=drocarbon group, Crs unsaturated aliphatic hydrocarbon group, Ci; saturated alicyclic hydrocarbon group, Cj3-7 unsaturated alicyclic hydrocarbon group, Cs-ig partly satura ted and fused bicyclic hydrocarbon gxoup, C;.; saturated or unsaturated alicycli_c-

C,-g saturated or unsaturated aliphatic hydrocarben group,

Cy-19 partly saturated and fused bicyclic hydrocarbon-Cji4 alkyl group, Cg-19 partly saturated and fused bicycl ic hydrocarbon-C, _4 alkenyl group, Cg10 aryl group and Co. aralkyl groups and R?® is 1) an optionally substituted 5- to 7-membered aromatic or non-aromatzic heterocyclic gro up having 1-4 hetero atoms selected from nitrogen atom, oxyg en atom and sulfur atom, which may be fumsed with an optional ly substituted besnzene ring, or 2) an optionally substitut ed

Ce-1p aryl group which may be fused with an optional ly substituted 5— to 7-membered aromatic heterocyclic rimg having 1-4 hetero atoms selected from nit rogen atom, oxygen atom and sulfur atoru; and R?**® and R?*® are the same Or different and are am optionally substi tuted hydrocarbon group selected from C;-3 saturated alip-hatic hydrocarbon group, Cjy.g unsaturat-ed aliphatic hydrocarbon group, Cs-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarborm group, Cg-10 part ly saturated and fused bicyclic hydzrocarbon group, Cs saturated or unsaturated alicycl ic-Ci-g saturated or unsaturated aliphatic hydrocarbora group, Cg-10 partly saturated and fused bicyclic hydro carbon-Ci-4 alkyl group, Cs-19 partly saturated and fused b-cyclic hydrocarbon-C,., alkenyl group,

C¢-10 aryl group and Cy-i4 aralkyl group or an optionally substituted 5- to J-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atoom, or R?%¢ and R2%3¢ may be combined to form a C;.; carbon ring, or (b) R?%© is H or an opt-ionally substituted hydrocarbon group selected from Cig saturated aliphatic h—ydrocarbon group,

C,_g unsaturated aliphatic hydrocarbon group, C37 saturated alicyclic hydrocarborm group, Ci; unsaturated alicyclic hydrocarbon group, Cs-mo partly saturated a nd fused bicyclic hydrocarbon group, Cs-— saturated or unsat urated alicyclic-

C;-3 saturated or unsa_turated aliphatic h-ydrocarbon group,

Ce-10 partly saturated and fused bicyclic hydrocarbon~Ci_y4

Claims

\ CLAIMS

1. A compound of the formula (IIIa): R3 R'® EAA (IT1a N Ar 2 2 where in R*? is (1) an optionally substituted 5- to 7-membered arom atic or non-a romatic heterocyclic group having 1-4 hetero atoms selec ted from nitrogen atom, oxygen atom and sulfu r atom, or (2) a group of the formula: -C0-2Z°¢ (wherein 2°¢ i.s (i) an optionally substituted 5-~ to 7-membered aromatic or non-a romatic heterocyclic group having 1-4 hetero atoms selec ted from nitrogen atom, oxygen atom and sulfur atom, (ii) ~NR?°°(CR®°R*’°R**¢) (wherein (a) R*®° is H or an optionally substituted hydr-ocarbon gr oup selected from C,.g saturated aliphatic hydr-ocarbon gr oup, C,.g unsaturated aliphatic hydrocarbon gro up, Cj; sa turated alicyclic hydrocarbon group, Cs. unsaturated al icyclic hydrocarbon group, Cs-10 partly satura ted and fu sed bicyclic hydrocarbon group, C3; saturated or un saturated alicyclic-Ci-g saturated or unsaturated al iphatic hydrocarbon group, Cs-1p partly satura ted and fu sed bicyclic hydrocarbon-C;-, alkyl group, Cg.10 partly sa turated and fused bicyclic hydrocarbon-C;_4 alkenyl Amended Sheet 30°" Octoloer 2007 group, Ce-10 aryl group and Cs14 aralkyl group; and R=! is

1) an optionally substituted 5- to 7-membered arormatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen &tom, oxygen atom and sulfur atom, which may be fus ed with an optiorially substituted benzene ring, ox 2) an optiorially substituted Cg..p aryl group which may be fused witch an optionally substituted 5- to 7T-membered arormatic heterocyclic ring having 1-4 het ero atoms selected from nitrogen attom, oxygen atom and sulfur atom; and R?**~ and R?’® are the same or different and are an optilorially substituted hydreccarbon group selected from Ci-g saturated &liphatic hydrocarbon group, Cz-g unsaturated aliphatic hydrocarbon group, Cm.7 saturated alicsyclic hydrocarbora group, Cs-; unsaturated alicyclic hydrocarbon group, Co—10 partly saturated and fused bic=yclic hydrocarbor group, Cig saturated or unsaturated alicyclic-C,.g saturated or unsaturated aliphatic hydrocarbora group, Cg-10 partly saturated and fused bicyclic hydrocarbon-Ci.4 alkyl. group, Cys-10 partly saturated and fused bicyclic hydrocarbon-C,_, alkenyl group, Ce10 aryl group and Cy.1 4 aralkyl group or an optionally substituted 5- to 7-membered aromatic or non- aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, Amended.

Sheet 30" October 2007 or R%¥¢ and RZ? may be combined to form a C3, carbon r ing, or (b) R* is H or an optionally substituted hydrocarbon group selected f rom Ci.g saturated al iphatic hydrocarbon group, C,;.3 unsat urated aliphatic hydrocarbon group, C37 saturated alicyc lic hydrocarbon growp, C3.7 unsaturated alicyclic hydroc arbon group, Cs-10 partly saturated -and fused bicyclic hydrocarbon group, C37 saturated or unsaturated ali cyclic-Ci_g saturated or unsaturated aliphatic hydroc arbon group, Ceo partly saturated -and fused bicyclic h ydrocarbon-C;.; alkyl group, Cs-;0 par—tly saturated and fused bicyclic hydrescarbon-C,.4, alkemyl group, Cg-10 aryl group and Cy.i4 aral kyl group; and R=1C, R**® and R®* are the same or dif ferent and are an optionally subst dtuted C;.s aliphatic. hydrocarbon gro—up, provided that the sum total of th- number of carbon atoms 1s 7 or more),

(iii) -NR?°°R?*¢ (whe rein R?*°® is as defined above and R** is an optionally substituted Cg10 ar—vyl-C;4 alkyl, C-o¢19 aryloxy-Cs_4 alkyl, Ce-10 arylamino-Cyoy alkyl, C 9.14 aralkylamino-Cs_q4 alkyl, 5- to 7-mernbered heterocyclic ring (having 1-4 hetero atoms selected from nitrocgen atom, oxygen atom and sulfur atom)-C; -4 alkyl or 5- to 7- membered heteroc yclic group having 1-4 hetero atoms selected from nZdtrogen atom, oxygen atom and sul=fur atom), Amended She et 30% October 2007

( iv) a substituted 5- to 7 -membered cyclic amino group, Or ( v) -OR%*¢ (wherein R** is (a) an optionally subst ituted Cs-..4 aralkyl gro up, {b) an optionally substituted C35 alicyclic hydrocarbon g roup, (c) an optionally substituted Cs.24 aliphatic mhydrocarbon group, Or (d) an optionally substituted 5- to 7-membere=d aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms s elected from nitrogen atom, oxygen atom and sulfur atom; w herein said substituents for R'?, 2%, R?%¢, R?'¢, R?%*€, R%¥, R ?*° and R?*® are 1 to 2 substituents selected from the group c onsisting of 1) Ci-¢ alkyl, 2) Cy. alkenvyl, 3) Cz-6 alkynyl, 4) Ci.7 cycloalkyl, 5) Cg-1ec aryl which may be substituted with 1 to 3 substituents selected from the group consisting of Cig alkyl, amino, N-(C;_¢ alkwyl)amino, N,N-di-(C;_¢ a lkyl)amino, amidino, carbamoyl, N-(C;.; alkyl)carbamoyl, NI,N-di-(C;¢ alkyl)carpbamoyl, sulfamowyl, N-{(Ci_.¢ alkyl)sulfamxnoyl, N,N- di- (Ci. alkyl)sulfamoyl, carboxyl, C,.7 alkoxycarbonyl, hydroxyl, C;-¢ alkoxy, mercapto, C;.¢ alkylthi.o, sulfo, cyano, azido, halogen, nitro, nitroso, phosphono, Cig Amended Sheet 30'" Ocztober 2007 alkoxy phosphoryl, di-(C,.¢ alkoxvy)phosphoryl and C;-¢ alkyl substi tuted with phosphono, Ci_¢ alkoxyphosphory 1 and di- (Ci-¢ &|Alkoxy)phosphoryl (hereinafter the group of 5) is referr ed to as group “C”), 6) aro matic heterocyclic group selected from (a) aromatic 5- or 6-membered heterocyclic group having 1—4 hetero atoms selected from nitrogen at om, oxygen atom a nd sulfur atom, {(b) fused bicyclic heterocyclic group formed by conden sation of an aromatic 5- or 6-membered het _erocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur at om with benzene r-ing or an aromat ic 5- or 6-membered heterocyclic group ha ving 1 to 3 hete=ro atoms selected from mitrogen atom, ox ygen atom and sulfur atom and (cc) fused tricyclic het=erocyclic group formed by condensation off [1] an aromatic 5- or 6- member ed heterocyclic group having 1-3 hete=ro atoms select ed from nitrogen atom, oxygen atom and sul fur atom,

[2] benzene ring, and [3] an aromatic 5- or &-membered hetero cyclic group having 1-3 hetero atoms sele cted from nitrog en atom, oxygen atom and sulfur atom ox benzene ring, 7) het erocyclic-oxy group formed by combining ea. ch of the above aromatic heterocyclic groups (a), (b) and (cc) with OXY gr oup, 8) ncen-aromatic 4- or 7-membered heterocycl_ ic group Amen ded Sheet 30 Oct=ober 2007 having 1 to 3 hetero atoms selectesd from nitrogen atom, oxygen at om and sulfur atom, 9) Cy.1; «aralkyl which may be subsstituted with 1 to 3 substituents selected from the group “CC”,

10) amino group, 11) N-moonre-substituted amino s elected from N- (C16 alkyl)amimo, N-(Cs_6¢ alke nyl)amino, N- (3-9 cycloalky l)amino group and N-(Cg-30 aryl)amino which may be substituted with 1 to 3 substituents selected from t=he group “C” , 12) amino substituted with two substituents selected fr-om Ci-¢ alkyl, C,.¢ alkenyl, Cs; cycloalkenyl and Ce ar-yl which maw be substituted with 1 to 3 substituerats selected from the group “C7,

13) amidirmo, 14) acyl selected from C;.g alkano yl, Ci. alkenoyl, Cs, cycloalkyl -carbonyl, Ciz-7 cycloa_lkenyl-carbonyl, Ce-10 aryl-carbonyl which may be substituted with 1 to 3 substituents selected from the group “cr, a nd heterocycldlic-carbonyl formed by bin ding of an aromatic or non-arcmatic 5- or 6-memberecd heterocyclic group havi ng 1-3 hetero atoms selected from nitr ogen atom, oxygen at. om and sulfur atom with carbonyl, 15) carbamoyl,

16) mono-ssubstituted carbamoyl group selected from N-(C 4

Amended Sheet 30" October 20 ¢7 alkyl) cark=amoyl, N-{Cs_¢ alkenyl) carbamoyl, N-(C3-7 cycloalkyl )carbamoyl and N= (Cg-.1g aryl)carbamoyl wh ich may be substituted with 1 to 3 subst ituents selected f rom the group “C”,

17) carbamoyl substituted with two substituents sselected from Cy .¢ alkyl, Ci.¢ alkenyl, Cs. cycloalkyl and Cgs-i0 aryl which may= be substituted with 1 to 3 substzituents selected f£ rom the group “C”,

18) sulfamuoyl,

19) N-mon o-substituted sulfamoyl selected from N-(Ci-6 alkyl)sulf amovl, N-(Cs_¢ alkenyl)sulfamoyl, N-(C3-7 cycloalkyl )sulfamoyl and N-(Cg.10 aryl)sulfamoyl wh ich may be substituted with 1 to 3 substituents selected f rom the group “C”,

20) sulfamoyl substituted with two substituents selected from Cj;-s alkyl, Ci. alkenyl, C37 cycloalkyl a nd Ce-1p aryl whickh may be substituted with 1 to 3 subst-ituents selected f rom the group “C”,

21) carboxyl, 22) Ci-¢ al koxy-carbonyl, 23) hydrox vl, 24) Ci -¢ al koxy, 25) Co.1p alkenyloxy, 26) Ci3-7 cy cloalkyloxy, 27) Cs-10 &Aryloxy which may be substituted with 1 to 3 amended Sheet 30 Octolkser 2007 substituents selected from the group “C’7, 28) Cy-:4 aral kyloxy which may be substi tuted with 1 to 3 substituents selected from the group “C’'7, 29) mercapto, 30) Ci-g alkylthio,

31) Cy.:4 aralkylthio which may be stbstidtuted with 1 zo 3 substituents selected from the group “C7, 32) Ce-10 aryl thio which may be substittuted with 1 to 3 substituents selected from the group “C’7,

33) Ci. alkylsulfinyl, 34) Cq.14 aral kylsulfinyl which may be substituted with 1 to 3 substituents selected from the group “C7, 35) Cg-10 aryl sulfinyl which may be substituted with 1 to 3 substituents selected from the group “CC”,

36) Ci-5 alkylsulfonyl, 38) Cq-14 aral kylsulfonyl which may be substituted with 1 to 3 substituents selected from the group “C”, 39) Ce-10 arylsulfonyl which may be subs tituted with 1 to 3 substituents selected from the group “CC”,

40) sulfo, 41) cyano, 42) azido, 43) halogen, 44) nitro,

45) nitroso,

Amended Sheett 30°" October 2007

46) phosphono, 47) C:.¢ alkoxy-phcsphoryl 48) di-C;-¢ alkoxy -plosphoryl, 49) Cig alkyd substituted with phosphono, Ci—¢ alkoxyphosphoryl or di-{(C;.¢ alkoxy)ph osphoryl 50) C..s alkyl sulostituted with 1 to 4 halogen atoms 51) Ci-¢ alkoxy swumbstituted with 1 to 4 halogen atoms and 52) Ci-¢ alkylenedioxy (hereinafter the group of above 1) t o 52) is referred t o as group “B”); R® is H, a Ci-¢ alkys]l group or a Ci.14 aralkyl group; R® is H, a Ci.¢ alk yl group, a C..¢ alkylthio group or a Ci—g¢ alkoxy group which may be substituted with hydroxyl group; Ar 1s (1) a C¢-1e« aryl group, (2) a 5- to 7-membere d aromatic or non-&=romatic heterocycli ¢ group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom an d sulfur atom, or (3) a C;3.7 saturated or unsaturate d alicyclic hydroca rbon group, each of which may be substituted with 1 to 3 substituents selected from the group “B”; one of R® and R!? is a hydrogen atom or C;-g alkyl group which may be subst ituted with 1 to 3 substituents selected from the group “B” and the other is (1) a hydrocarbon group selected from C;.g saturated aliphatic hydrocarbon group,

C;.g unsaturated al _iphatic hydrocarbon group, Cs-7 saturated Amended Sh eet 30" October 20077 alicyclic hydrocarbon g roup, Ci; unsaturated alicyclic h=ydrocarbon group, Ce-19 partly saturated and fusecd bicyclic hsydrocarbon group, Cj3-; saturated or unsaturated alicyclic-

Cx .s saturated or unsatur ated aliphatic hydrocarloon group, Cog partly saturated arxd fused bicyclic hydro<carbon-Cig alkyl group, Csi partly saturated and fused bicyclic hwdrocarbon-C,.; alkenyl group, Ce-19 aryl group and Ci-1a axalkyl group, each of wh ich may be substituted with 1 to 3 stibstituents selected from the group “B” or (2) & 5- to 7- meembered aromatic or non- aromatic heterocyclic group having 1—4 hetero atoms selected from nitrogen atom, oxygen atom arid sulfur atom, which may be substituted wit h 1 to 3 suibstituents selected froxn the group “B”, or R= and R?° may be combined to form a Cs. carbon rirg, provided that at least one of R® and R!? is C,.5 alkyl group which may be substituted with 1 to 3 substituents selected from the group “B” and tne other is other than a phenyl group which may be substituted with 1 to 3 sulkstituents selected from the group “B”; or a salt thereof.

2. N-(l-ethyl-1-(4—methylphenyl)propyl)-7, 77- dimethyl-5-phenyl-4,5,6, 7—tetrahydropyrazolo[1l, 5- a} pyrimidine-3-carboxamide or a salt thereof, N— (1-ethyl-1-(4-methylpheryl)propyl)-5-(2-fluoropkenyl)- 7 ,~ 7-dimethyl-4,5,6, 7-tetrahydropyrazolo[l, 5-alpyrdmidine-3- carboxamide or a salt thexxeof, amended Sheet 30" October 2007

N-(l-ethy l-1-(4-methylphenyl)prop=yl)-2,7,7-trimethy}k -5- phenyl-4, 5,6, 7-tetrahydropyrazolo=[1,5-alpyrimidine-3- carboxamide or a salt thereof, N-(l-ethy 1l-1-(4-ethylphenyl)propy-1)-2,7,7-trimethyl—>5~ phenyl-4, 5,6, 7-tetrahydropyrazolo-{1l,5-alpyrimidine-33- carboxamide or a salt thereof, N-(l-ethy 1-1-(4-methylphenyl)prop-yl)-5-(2-fluoropheryl)- 2,7,7-trimethyl-4,5,6, 7-tetrahydr opyrazolol[l, 5- alpyrimid ine-3-carboxamide or a s alt thereof,

N-(l-ethy 1-1-(4-ethylphenyl)propy 1) -5-(2-fluoropheny1l) - 2,7,7-trimethyl-4,5,6,7-tetrahydr opyrazolo[l, 5- alpyrimid ine-3-carboxamide or a s alt thereof, 5-(2-chlo rophenyl)-N-(l-ethyl-1-{( 4-methylphenyl)promyl)- 2,7,7-trimethyl-4,5,6, 7-tetrahydr cpyrazolo[1i, 5-

alpyrimidine-3-carboxamide or a s alt thereof, N-(1-(4-(dimethylamino)phenyl)-1- ethylpropyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5 ,6,7- tetrahydropyrazolo[l,5-alpyrimidi ne-3-carboxamide or a salt thereof,

N-(1l,1l-diethylbutyl)-5-(2-fluorop henyl)-2,7,7-trimetthyl- 4,5,6,7-tetrahydropyrazolo(l,5-a] pyrimidine-3-carbosxamide or a salt thereof,

N-(l-ethyl-1l-phenylpropyl)-5-(2-f luocrophenyl)-2,7,7— trimethyl—4,5,6, 7-tetrahydropyraz-olo[l,5-alpyrimidine-3-

carboxamide or a salt thereof,

Amencded Sheet 30" Octokser 2007

3-(5-(l-ethyl-1-(4 -methylphenyl)propyl)-1, 3,4 -oxadiazol-2- vyl)-2,7,7-trimethy1-5-phenyl-4,5,6,7- tetrahydropyrazolo[l,5~-alpyrimidine or a salt thereof, 3-(5-(l-ethyl~1-(4 -methylphenyl)propyl)-1,3,4 -thiadiazol-2- yl)-2,7,7-trimethyl1~5-phenyl-4,5,6,7- tetrahydropyrazolo 1, 5-alpyrimidine or a salt thereof, 3-((4-(benzyloxy)—2,2-diethyl-1-pyrrolidinyl) carbonyl)-7,7- dimethyl-5-phenyl—4,5, 6, 7-tetrahydropyrazolo[ 1,5- alpyrimidine or a salt thereof, 3-((2,2-diethyl-4—methoxy-1l-pyrrolidinyl)carb onyl)-7,7- dimethyl-5-phenyl—4,5,6,7-tetrahydropyrazolo[ 1,5- aljpyrimidine or a salt thereof, or 3-((2,2-diethyl-4—fluoroc-l-pyrrolidinyl)carbo nyl)-7,7- dimethyl-5-phenyl—4,5,6, 7-tetrahydropyrazclof{ 1,5- alpyrimidine or a salt thereof.

3. The compound according to claim 2 , which is an optically active compound.

14. A pharmaceutical composition which comprises the compound according to claim 1.

5. A composition for modulating cal cium receptor which comprises a compound of claim 1.

6. The composition according to claim 5, which is a calcium receptor antagonist.

7. The composition according to claim 5, which is an agent for preventing or treating diseases caused by Amended Sheet 30%" October 2007 abnormality of calcium concentrattion in a living b ody or a calcium receptzor.

8. The composition accordi ng to claim 5, whi ch is an agent for prewenting or treating bone diseases.

9. The composition accordi ng to claim 5, whi ch is an agent for prewenting or treating osteoporosis or fr acture.

10. Use of the compound of the formula (I) ox a salt thereof or a prodrug thereof according to clairn 1 for producing a camlcium receptor modu lator.

11. Use of the compound of the formula (I) ox a salt thereof or a prodrug thereof a ccording to claim 1 for producing a composition for pre venting or treating bone diseases. Amende=d Sheet 30% Octolbwer 2007