AU763615B2

AU763615B2 - Use of a NK-1 receptor antagonist for treating or preventing abnormal bone resorption

Info

Publication number: AU763615B2
Application number: AU50599/99A
Authority: AU
Inventors: Richard John Hargreaves; Nadia Melanie Rupniak
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1998-08-04
Filing date: 1999-07-30
Publication date: 2003-07-31
Anticipated expiration: 2019-07-30
Also published as: WO2000007598A1; JP2002522389A; EP1102590A1; CA2339146A1; GB9816897D0; AU5059999A

Description

WO 00/07598 PCT/GB99/02509 -1- USE OF A NK-1 RECEPTOR ANTAGONIST FOR TREATING OR PREVENTING ABNORMAL BONE RESORPTION This invention relates to the treatment or prevention of abnormal bone resorption by the administration of a NK-1 receptor antagonist, optionally in combination with one or more active agents from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones.

The term "abnormal bone resorption", as used herein means a degree of bone resorption that exceeds the degree of bone formation, either locally, or in the skeleton as a whole. "Abnormal bone resorption" can also be associated with the formation of bone having an abnormal structure.

A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, peridontal disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy.

The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic patients usually experience bone resorption in excess of bone formation, causing chronic bone loss. Because osteoporosis, as well as other disorders associated with ongoing bone loss, are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.

Multinucleated cells called osteoclasts are responsible for a process known as bone resorption. In osteoporosis, the bone resorption rate exceeds the bone formation rate, causing net bone loss. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of generalized or localized bone WO 00/07598 PCT/GB99/02509 -2disorders caused by or associated with abnormal bone resorption. See H.

Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated by reference herein in its entirety.

At present, a great amount of preclinical and clinical data exists for the potent bisphosphonate compound alendronate. Evidence suggests that other amino-bisphosphonates such as risedronate, ibandronate and zoledronate, have many properties in common with alendronate, including both high bone specificity and potency as inhibitors of osteoclastic bone resorption. An older non-amino-bisphosphonate compound, etidronate, also inhibits bone resorption. However, unlike the more potent bisphosphonates, etidronate impairs mineralization at doses used clinically, and may give rise to osteomalacia, a condition resulting in an undesirable decrease in bone mineralization and bone strength. See Boyce, B. Fogelman, Ralston, S. et al. (1984) Lancet 1(8381), pp. 821- 824 (1984), and Gibbs, C. Aaron, J. Peacock, M. (1986) Br. Med. J.

292, pp. 1227-1229 (1986), both of which are incorporated by reference herein in their entirety.

Peak bone mass in women is achieved at around 30-35 years of age.

Bone mass is then relatively stable until the perimenopausal period (usually the late fifth decade of life). The rate of bone loss accelerates markedly during the early post menopausal period to a rate of 3-4% annually, especially at sites with a high component of trabecular bone.

After 8-10 years of menopausal life, the bone loss rate slowly stabilizes at about 1% annually.

The average woman has a greater than 40% chance of developing at least one osteoporotic fracture during her lifetime. Osteoporotic fractures, especially of the hip, occur in 16% of all women reaching 80 years of age, and are associated with a marked reduction in the quality of life and high cost of treatment. The total costs and morbidity associated with all WO 00/07598 PCT/GB99/02509 -3osteoporotic fractures are certain to substantially exceed those of hip fracture alone, although precise estimates are not available.

Apart from bisphosphonates such as alendronate, other generally recognised therapies for prevention of osteoporosis are estrogen replacement therapy, raloxifene, a selective estrogen receptor modulator, and calcitonin. Along with preventing of bone loss associated with reduced endogenous estrogen production, administration of estrogen can help reduce post menopausal symptoms such as vasomotor instability, vaginal atrophy, and increased incidence of cardiovascular problems, possibly associated with a deterioriation in the lipid profile. However, at the doses of estrogen commonly employed for bone loss prevention, some women continue to lose bone during treatment. Furthermore, estrogen treatment is also associated with some serious risks, including endometrial carcinoma, symptomatic gall bladder disease, deep vein thrombosis and an increased incidence of breast cancer. Although some of these risks can be lowered by addition of progestins to the therapeutic regimen, a large proportion of women will not accept long-term estrogen treatment mainly because of breakthrough bleeding and safety concerns.

It would be desirable to have an agent other than a bisphosphonate, that prevents osteoporosis without the risks and side effects associated with estrogen.

Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. To date, the role of substance P in abnormal bone resorption, and the use of NK-1 receptor antagonists to treat or prevent abnormal bone resorption, has not been elucidated.

We have now found that NK-1 receptor antagonists are effective in the treatment of abnormal bone resorption, as evidenced by their effect on bone density in vivo in an animal model of inflammatory joint disease.

4 Furthermore, a combination of a NK-1 receptor antagonist with a bisphosphonate may provide enhanced inhibition of bone resorption over that provided by the bisphosphonate alone. They may also allow for a reduced dosage or frequency of dosing with the bisphosphonate which would be particularly advantageous when side-effects are a liability with high dosage or chronic administration regimens.

There is disclosed herein the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

There is further disclosed herein a method for the treatment or prevention of abnormal bone resorption, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.

There is also disclosed herein a pharmaceutical composition for the treatment or prevention of abnormal bone resorption comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.

In addition to monotherapy, the NK-1 receptor antagonist may be administered in combination with one or more active agents selected from, but not limited to, the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones.

There is further disclosed herein the use of a NK-1 receptor antagonist and one or more active agents selected from, but not limited to, the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, for Sthe manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

There is yet further disclosed herein a method for the treatment or prevention of abnormal bone resorption, which method comprises administration to a patient in need of such treatment a therapeutically effective amount of a NK-1 receptor antagonist and one or more active agents selected from, but not limited to, the group consisting of bisphosphonates, estrogen and androgen receptor modulators and peptide hormones, such that together they give effective relief.

There is also disclosed herein a pharmaceutical composition comprising a NK-1 S 30 receptor antagonist and one or more active agents selected from, but not limited to, the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, together with at least one pharmaceutically acceptable carrier or excipient.

It will be appreciated that the NK-1 receptor antagonist and the additional active agent(s) may be present as a combined preparation for simultaneous, separate or [R:\LIBXX]04068.doc:aak sequential use for the treatment or prevention of abnormal bone resorption. Such combined preparations may be, for example, in the form of a twin pack.

There is further disclosed herein a product comprising a NK-1 receptor antagonist and one or more active agents selected from, but not limited to, the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of abnormal bone resorption.

The methods and compositions of the present invention are useful for both treating and preventing abnormal bone resorption and conditions associated therewith.

According to the disclosure, when used in combination therapy, the NK-1 receptor antagonist is administered in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen receptor modulators, and peptide hormones.

When used in combination therapy, the NK-1 receptor antagonist is preferably administered in combination with a bisphosphonate.

Conditions associated with abnormal bone resorption include both generalized and localized bone loss. The term "generalized bone loss" means bone loss at multiple skeletal sites or throughout the skeletal system. The term "localized bone loss" means bone loss at one or more specific, defined skeletal sites.

According to a first embodiment the present invention provides use of a NK-1 Sreceptor antagonist of formula R 3 X R 4

R

2

RS

R

(I)

or a pharmaceutically acceptable salt thereof, wherein: R' is selected from the group consisting of: C i6alkyl, substituted with one or more of the substituents selected from: S* a) heterocycle, wherein the heterocycle is selected from the group consisting of: S* benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, [R:\LIBXX]04068.doc:aak pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:

C

1 6 alkyl, unsubstituted or substituted with halo, -CF 3

-OCH

3 or phenyl, (11) C 1 6 alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl,

-(CH

2 )m-NR 9

R

10 wherein m is 0, 1 or 2, and R 9 and R1 0 are independently selected from: hydrogen, (11) C I 6 alkyl, ~(111) hydroxy C I 6 alkyl, and phenyl, (xi) -NR 9

COR'

0 wherein R 9 and R 10 are as defined above, and (xii) -CONR 9

R'

0 wherein R 9 and R 10 are as defined above, R 2and R 3 are independently selected from the group consisting of: 0 hydrogen; C I 6 alkyl;

C

2 6 alkenyl, and phenyl; X is R 4i [R:\LIBXX]04068.doc:aak

R

5 is phenyl, unsubstituted or substituted with halo; R R 7 and R 8 are independently selected from the group consisting of: hydrogen, Ci-6alkyl, halo, and

-CF

3 Y is and Z is hydrogen or CI.

4 alkyl; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

According to a second embodiment the present invention provides use of a NK-1 receptor antagonist of formula (II):

A

1

Y

N 3

I

.R6/ A3 15i (II) wherein: A' is fluorine or CF 3

A

2 is fluorine or CF 3

A

3 is fluorine or hydrogen; 20 R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a Ci- 4 alkyl group, and optionally substituted by a group of the formula ZNR 7

R

8 where Z is Ci-6alkylene or C3-6cycloalkylene; S* R 7 is hydrogen, C14alkyl, C3-7cycloalkyl or C3-7cycloalkylC-4alkyl, or C24alkyl 25 substituted by Cl-4alkoxy or hydroxyl; [R:\LIBXX]04068.doc:aak

R

8 is hydrogen, Cl4alkyl, C3- 7 cycloalkyl or C3.7cycloalkyiC 1 4 alkyi, or C24alkyl substituted by one or two substituents selected from Cl4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and

S;

or R 7 R and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where R is Cl4alkyl optionally substituted by hydroxy or CI.

4 alkoxy; or R 7

R

8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a Ci- 4 alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is Ci.

4 alkyl, R 6 is substituted at least by a group of formula ZNR 7

R

8 as defined above; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

According to a third embodiment the present invention provides use of a NK-1 Sreceptor antagonist of formula (III):

R.

9

R

2R6 R N

R

2 and R 3 are independently selected from the group consisting of: hydrogen, CC0. Cl~ 6 alkyl,

C

2 6 alkenyl, and (2)C -alyl (3

R

13 akeyl and [R:\LIBXX]04068.doc:aak phenyl; R 6, R 7 and R 8 are independently selected from the group consisting ofhydrogen, C 1 6 alkyl, fluoro, chloro, bromo, iodo, and

-CF

3 R 1 2 and R" 3 are independently selected from the group consisting of: fluoro, chloro, bromo, and iodo; A is unsubstituted i.

6 alkyI; B is selected from the group consisting of:

H

N-N

N S x N-N

H

N-N

H

X

H

N-N

H

N-N

N 0 x

H

N-N

N-N"'

X/N,S/ x 0 0 0

N-N"

No

H

N

N'S

x

N

1 x

H

N 0

N'

x x

NS

H~

H

N S P isO0 or 1; [R:\LIBXX]04068.doc:aak 6d X is selected from: -PO(OH)cY e M+ is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 9 2M+, -PO(0-) 2

D

2 wherein D 2 is a pharmaceutically acceptable divalent countenion,

-CH(R

4 )-PO(OH)EY wherein R 4 is hydrogen or CI.

3 alkyl,

-CH(R

4 2 2M+,

-CH(R

4 2 o.

-CO-CH

2

CH

2 -C0 2

*M,

-CH(CH

3 )-O-CO-R 5 wherein R 5 isselected from the group consisting of:

+M

(ii)

O

(iii) C02M CO V (iv) C0jM Y C0 2

NH

3 KC02-M+ O. -0 C2M C0 2

_M

0 M (vii) ,and Y is Z is hydrogen or C 1 6 alkyl; 20 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

According to a fourth embodiment the present invention provides use of a NK-1 .receptor antagonist as defined in the -first, second or third embodiments in combination [1:\DAYLIB\LLBH]02553.doc:sxc 6e with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

According to a fifth embodiment the present invention provides use of a NK-1 receptor antagonist as defined in the first, second or third embodiments and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

According to a sixth embodiment the present invention provides a pharmaceutical 1o composition comprising a NK-1 receptor antagonist as defined in the first, second or third embodiments and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, together with at least one pharmaceutically acceptable carrier or excipient.

According to a seventh embodiment the present invention provides a product comprising a NK-1 receptor antagonist as defined in the first, second or third embodiments and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of abnormal bone resorption.

According to an eighth embodiment the present invention provides a method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of NK- 1 receptor antagonist of formula as defined in the first embodiment.

"-According to a ninth embodiment the present invention provides a method for the 25 treatment or prevention of abnormal bone resorption said method comprising :"administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula (II) as defined in the second embodiment.

According to a tenth embodiment the present invention provides a method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), as defined in the third embodiment.

According to an eleventh embodiment the present invention provides a method for the treatment or prevention of abnormal bone resorption said method comprising gadministration to a patient in need of such treatment a therapeutically effective amount of a:.et a NK-1 receptor antagonist, as defined in the first, second or third embodiments in .0i [I:\DAYLIB\LIBH]02553.doc:sxc 6f combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones.

According to a twelfth embodiment the present invention provides a method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a NK-1 receptor antagonist, as defined in the first, second or third embodiments and one or more active agents selected from the group consisting ofbisphosphonates, estrogen and androgen receptor modulators, and peptide hormones.

According to a thirteenth embodiment the present invention provides use of a NK-1 1o receptor antagonist of formula as defined in the first embodiment, when used for the treatment or prevention of abnormal bone resorption.

According to a fourteenth embodiment the present invention provides a NK-1 receptor antagonist of formula (II) as defined in the second embodiment, when used for the treatment or prevention of abnormal bone resorption.

According to a fifteenth embodiment the present invention provides use of a NK-1 receptor antagonist of formula (III) as defined in the third embodiment when used for the treatment or prevention of abnormal bone resorption.

According to a sixteenth embodiment the present invention provides use of a NK-1 receptor antagonist, as defined in the first, second or third embodiments in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, when used for the treatment or prevention of abnormal bone resorption.

According to a seventeenth embodiment the present invention provides a NK-1 •.receptor antagonist, as defined in the first, second or third embodiments and one or more 25 active agents selected from the group consisting of bisphosphonates, estrogen and •o0• androgen receptor modulators, and peptide hormones, when used for the treatment or prevention of abnormal bone resorption.

Generalized bone loss is usually associated with osteoporosis. Osteoporosis is most common in post-menopausal women, wherein estrogen production has diminished.

However, osteoporosis can also be glucocorticoid-induced and has been observed in males due to age and reduced androgen production. Osteoporosis can be induced by *...disease, e.g. rheumatoid arthritis; by secondary causes, glucocorticoid therapy; or by no identifiable cause, i.e. idiopathic osteoporosis, possibly of inherited origin. In the present invention, preferred methods include the treatment or prevention of abnormal 35 bone resorption in osteoporotic humans.

[I:\DAYL1B\L1BHj02553.doc:sxc 6g Localized bone loss has been associated with periodontal disease and periprosthetic osteolysis where bone resorption has occurred in proximity to a dental or orthopaedic prosthetic implant.

Generalized or localized bone loss can occur from disuse, often a problem for those confined to a bed or a wheelchair, those who have an immobilized limb set in a cast or held in traction, or those who suffer permanently disabling strokes.

The methods and compositions of the present disclosure are useful for treating and/or preventing the following conditions or disease states: osteoporosis, including postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, and idiopathic osteoporosis; Paget's disease; abnormally increased bone turnover; hypercalcemia of malignancy; osteogensis imperfecta; periodontal disease; periprosthetic osteolysis; and abnormal bone resorption associated with immunosuppressive therapy.

The term "pharmaceutically effective amount", as used herein, means that amount of the NK-1 receptor antagonist and (where present) [1:\DAYLIB\LIBHj02553.doc:sxc WO 00/07598 PCT/GB99/02509 -7the additional active agent(s), that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen. A preferred pharmaceutically effective amount of the NK-1 receptor antagonist and (where present) the additional active agent(s) is a bone resorption inhibiting amount.

The term "bone resorption inhibiting", as used herein, means preventing bone resorption by the direct or indirect alteration of osteoclast formation or activity. Inhibition of bone resorption refers to prevention of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity.

It will be appreciated that the NK-1 receptor antagonist and any additional active agent(s) should be continuously administered, according to the dosing schedule chosen, until the desired therapeutic effect is achieved, i.e. up to the time that the clinical or medical effect sought for the disease or condition being treated is observed by the clinician or researcher. For methods of treatment of the present invention, the NK-1 receptor antagonist and any additional active agent(s) should be continuously administered until the desired change in bone resorption rate, bone mass, or bone structure is observed. In such instances, achieving an increase in bone mass or a replacement of abnormal bone structure with normal bone structure are the desired objectives. For methods of prevention of the present invention, the NK-1 receptor antagonist and any additional active agent(s) should be continuously administered for as long as necessary to prevent the undesired condition.

In such instances, maintenance of existing bone mass is often the objective. Non-limiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can range from about 2 weeks to the remaining lifespan of the human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably WO 00/07598 PCT/GB99/02509 -8from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.

The term "mammal" as used herein include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.

The compositions of the present invention are especially useful for the treatment or prevention of abnormal bone resorption where the use of a bisphosphonate or estrogen replacement therapy is generally prescribed.

By the use of a NK-1 receptor antagonist, optionally in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones in accordance with the present invention, it is now also possible to treat or prevent abnormal bone resorption in patients for whom conventional therapy might not be wholly successful or where patient compliance with existing therapeutic regimens is problematic.

NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, WO 00/07598 -9- 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/21702, 97/22597, 97/24350, 97/30055, 97/38692, PCT/GB99/02509 95/07886, 95/07908, 95/17382, 95/18124, 95/23798, 95/26338, 96/06094, 96/07649, 96/29304, 96/29317, 97/01553, 97/01554, 97/19084, 97/19942, 97/49710, 98/01450, 98/13369, 98/49170, 98/54187, 99/00368 and 99/24423; and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, 2 302 689, 2 309 458 and 2 321 058.

Particularly preferred NK-1 receptor antagonists are those described in European Patent Specification No. 0 577 394, especially compounds of formula x

R

4

(I)

R- N R

R

or a pharmaceutically acceptable salt thereof, wherein:

R

1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, WO 00/07598 PCT/GB99/02509 pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Ci-6alkyl, unsubstituted or substituted with halo, -CF 3

-OCH

3 or phenyl, (ii) Cl-6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl,

-(CH

2 )m-NR 9

R

1 0 wherein m is 0, 1 or 2, and R 9 and Ro 1 areindependently selected from: hydrogen, (II) CI-6alkyl, (III) hydroxyCl-6alkyl, and (IV) phenyl, (xi) -NR 9

COR'

1 wherein R 9 and R' 1 are as defined above, and (xii) -CONR 9 R'O, wherein R 9 and RI' are as defined above,

R

2 and R 3 are independently selected from the group consisting of: hydrogen; Ci-ealkyl WO 00/07598 PCT/GB99/02509 C2-6alkenyl, and phenyl; X is

R

4 is R 7 z R8

R

5 is phenyl, unsubstituted or substituted with halo;

R

6

R

7 and R 8 are independently selected from the group consisting of: hydrogen, CI-6alkyl, halo, and

-CF

3 Y is and Z is hydrogen or C1-4alkyl; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula are: 1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)phenyl-morpholine; 1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)phenyl-morpholine; 4-(3-(5-oxo- 1H,4H-1,2,4-triazolo)methyl)-2(S)-(3 bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.

Further preferred NK-1 receptor antagonists are those described in International (PCT) Patent Specification No. WO 95/18124, especially compounds of formula (ID) and pharmaceutically acceptable salts thereof.

WO 00/07598 PCT/GB99/02509 -12-

A

1

YI

O O A 2 KN A R A 3

(II)

wherein:

A

1 is fluorine or CF 3

A

2 is fluorine or CF 3

A

3 is fluorine or hydrogen;

R

6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR 7 R where Z is Cl.1alkylene or C3.6cycloalkylene;

R

7 is hydrogen, C1- 4 alkyl, C3.7cycloalkyl or C3-7cycloalkylC1.4alkyl, or C2- 4 alkyl substituted by CI-4alkoxy or hydroxyl;

R

8 is hydrogen, C.- 4 alkyl, C3a7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2- 4 alkyl substituted by one or two substituents selected from C1.4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7

R

8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1- 4 alkyl optionally substituted by hydroxy or C1.4alkoxy; or R 7

R

8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; WO 00/07598 PCT/GB99/02509 -13or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C1-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is C1-4alkyl, R 6 is susbstituted at least by a group of formula ZNR 7

R

8 as defined above.

Particularly preferred compounds of formula (II) include: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-l,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-l,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine; and pharmaceutically acceptable salts thereof.

Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 95/23798, especially compounds of formula (III): R X 7 Z Z R

(III)

I R (0)P

A

(O)p A S 12 B R 3 or a pharmaceutically acceptable salt thereof, wherein:

R

2 and R 3 are independently selected from the group consisting of: hydrogen, Ci- 6 alkyl,

C

2 -6alkenyl, and WO 00/07598 PCT/GB99/02509 -14phenyl;

R

6

R

7 and R 8 are independently selected from the group consisting of: hydrogen, Ci-6alkyl, fluoro, chloro, bromo, iodo, and

-CF

3

R

11

R

12 and R 13 are independently selected from the group consisting of: fluoro, chloro, bromo, and iodo; A is unsubstituted 1-6alkyl; B is selected from the group consisting of: N-N X H X N- ,X H X\ H N-N N-N N-N N o o SN 0 N N X

H

X

N-N H X N-N N-N N-N N S N S X ,X I N N 0 S X H N X N-N N N-N

N

N N

N

N X X WO 00/07598 WO 0007598PCT/GB99/02509 15 x

N

H

N

x N 0 x

H

N

N 0 x

N

S

H

1

N

S"

p is 0ocr 1; X is selected from: -PO(OH)0- wherein M' is a pharmaceutically acceptable monovalent counterion,

-PO(O-)

2 *2M+, -PO(0-) 2

D

2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R4)-PO(OH)0- wherein R4 is hydrogen or CI3alkyl, Wi -CO-CH 2

CH

2 -C0 2 0

-CH(CH

3 )-O-CO-R5, wherein R 5 is selected from the group consisting of: WO 00/07598 WO 0007598PCT/GB99/02509 16

H

2

M-

(ii) OH (iii) (iv)

(M

(vi) (vii) 0 C02M+ 0N~ C0 2 M 0 Y C0 2

NH

3 0

CO,-

and Y is Z is hydrogen or C1l6alkyl; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula (III) include: ,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine N-oxide; WO 00/07598 PCT/GB99/02509 17 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4- (ethoxycarbonyloxy- 1-ethyl)-5-oxo-1H- 1,2,4triazolo)methyl)morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H- 1,2,4triazolo)methyl)morpholine; ,5-bis(trifiuoromethyl)phenyl )ethoxy)-3-(S)-(4fluorophenyl)-4-(3-( 1-monophosphoryl-5-oxo-1H- 1,2,4triazolo)methyl)morpholine; ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S fiuorophenyl)-4-(3-(2-monophosphoryl-5-oxo- 1H-1 ,2 ,4triazolo)methyl)morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-( fluorophenyl)-4-(3-(5-oxyphosphoryl- 1H- 1,2,4triazolo)methyl)morpholine; ,5-bis(trifluoromethyl)phenyl )ethoxy)-3-(S)-(4fluorophenyl)-4-(3-( 1-monophosphoryl-5-oxo-4H- 1,2,4triazolo)methyl )morpholine; and pharmaceutically acceptable salts thereof.

Further preferred NK-1 receptor antagonists are those described in International Patent Specification No. WO 97/49710, especially compounds of formula (IV) R I Rk 0-

(IV)

H1 wherein WO 00/07598 PCT/GB99/02509 18 RI represents hydrogen, hydroxy, Cl-6alkyl, C2-6alkenyl, C3.7cycloalkyl, C3-7CYCloalkylC l.4alkyl, C 1 6alkoxy, fluoroC 1-6alkoxy, C l-6alkoxyC l.4alkyl, CI-6alkoxyCl- 4 alkoxy, fluoroC l.6alkoxyC 1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCl- 4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, SO 2 Ra, OSO 2 Ra, NRaCOR14, CORa, CO 2 Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1v4alkyl or fluoroCl.4alkyl;

R

2 represents hydrogen, halogen, Cp-6alkyl or C1.6alkoxy; or RI and R 2 may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from C1a 4 alkyl, CF3, =0 or=S

R

3 represents hydrogen, halogen, C 1-6alkyl, fluoroC l6alkyl, C 1-6alkoxy, fluoroC 1-alkoxy, C3-7cycloalkyl, C3-7cycloalkylCla4alkyl, cyano, SRa, SORa, SO 2 Ra, NRaRb, NRaCORI4, CORa, C0 2 Ra, CONRaRb or C14alkyl substituted by cyano, C0 2 Ra or CONRaRb where Ra and Rb are as previously defined; R4 represents hydrogen, halogen, C1v6alkyl, C1-6alkoxy, CF 3

OCF

3 N0 2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2.6alkenyl, C2.6alkynyl or C1v 4 alkyl substituted by Ci-4alkoxy, where Ra and Rb are as previously defined; and the broken line represents an optional double bond; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula (IV) include: (3R ,5R,68)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl- 1-oxa-7aza-spiro decane; (3R ,5R,6S)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-6-phenyl-1-oxa-7-azaspiro ,6S)-7-benzyl [2-methoxy-5-(trifluoromethoxy)phenyl] -6-phenyl- 1oxa-7-aza-spiro[4.5ldecane; (3R, 51?,6S)-3-(2-methoxy-5-trifluorornethoxyphenyl)-6-phenyl- 1-oxa- 7 -aza- 19 spiro decane; (3R,SR ,6S)-3 ,6-bis(phenyl )-l1-oxa-7-aza-spiro [4.51 decane; (3R ,5R,6S)-7-benzyl-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1..

oxa-7-aza-spiro[4.51 decane; *,5R*,6S*)..3.(2..methoxyphenyl).6phenyl-..oxa.7.

(phenylmethoxycarbonyl)aza-spiro [4.51 decane; (3R,5R,6S)-3-(2-methoxyphenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5] decane; (3S, 5R,6S)-3-(2-cyclopropoxy-5-(tifluoromethoxy)phenyl)-6-phenyl- 1-oxa- 7-aza-spiro[4.51 decane; (3R, 5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl] -6-phenyl-1-oxa- 7-aza-spiro [4.51 decane; (3S, 5R,6S [2-cyclopropoxy-5-(trifluoromethyl)pheny] -6-phen~yl-1 -oxa-7aza-spiro decane; and pharmaceutically acceptable salts thereof.

Another class of NK-1 receptor antagonists of use in the present disclosure is that described in European Patent Specification No.

0 436 334, i.e. compounds of formula

RI

I R3

V)

R (1 16

R

or a pharmaceutically acceptable salt thereof, wherein Y is WCHO. wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH 2 may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said WCHO. may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH 2 may optionally be substituted with R 7 WO 00/07598 PCT/GB99/02509 Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CH2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 )m may optionally be substituted with

R

8

R

1 is hydrogen or Cl-salkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;

R

2 is a radical selected from hydrogen, C 1 -6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl C2-6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-6 alkyl, C1-6alkoxy, trifluoromethyl, amino, Cli6alkylamino, Cli-alkyl-O-CO, CI.6alkyl-O-CO- C1-6alkyl, Cl-6alkyl-CO-O, CI-6alkyl-CO-Ci-6alkyl-O-, Cl-6alkyl-CO,

C.I

6 alkyl-CO-C1-6alkyl-, di-CI.-alkylamino, -CONH-Cl-6alkyl, C l-alkyl-CO-NH-CI-6alkyl, -NHCOH and -NHCO-Cl.6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;

R

5 is hydrogen, phenyl or Cli6alkyl; or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the

CH

2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;

R

3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 WO 00/07598 PCT/GB99/02509 -21carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-acycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, CI-6alkyl, C-.6alkoxy, trifluoromethyl, amino, Ci.-alkylamino, -CO-NH- C1.6alkyl, C1-6alkyl-CO-NH-CI-6alkyl, -NHCOH and -NHCO-Ci-6alkyl;

R

4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Cl-6alkylamino, di-Ci.-alkylamino, Ci-6alkoxy, C-.6alkyl-O-CO, C1-6alkyl-O-CO-C1-6alkyl, C-6alkyl-CO-O, C1-6alkyl-CO-C.-6alkyl-O-, C1.6alkyl-CO-, C-.6alkyl-CO-CI.6alkyl, and the radicals set forth in the definition of R 2

R

6 is -NHCOR 9

-NHCH

2

R

9 S0 2

R

8 or one of the radicals set forth in any of the definitions of R 2

R

4 and R 7

R

8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2

R

4 and R 7

R

9 is Cl-6alkyl, hydrogen, phenyl or phenylCl-6alkyl; with the proviso that when m is 0, R 8 is absent, when R 4

R

6

R

7 or

R

8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R 5 and when R 4 and R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and Cl-6alkyl, or R 4 and R 7 together with the carbon to which they are attached, for a C3-6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.

A particularly preferred compound of formula is (2S,3S)-cis-3-(2methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.

-22- Another class of NK-1 receptor antagonists of use in the present disclosure is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (VI): R R 0

R

CH--R

1 (vI)

R

3

R

4 or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;

R

I is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;

R

2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;

R

3 is optionally 2-substituted phenyl;

R

4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond.

A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)- 7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.

0 591 040, i.e. compounds of formula (VII): R

Q

Ar-T-CO-N-CH 2

-C-CH

2

-CH

2 -Am A (VII) Ar' wherein -23- Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a Cl-4alkoxymethylene group or a C1-salkylene group; Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or d fluorine, trifluoromethyl, C1-4alkoxy, Ci-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group; R represents hydrogen, C-4alkyl, o-C1-4alkoxyC1-4alkyl, or o-C 2 -4alkanoyloxyC2-4alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4butylene group; Am* represents the radical 213 in which X 1

X

2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and 20 A- represents a pharmaceutically acceptable anion.

A particularly preferred compound of formula (VII) is (3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl] ethyl] -4phenyl-l-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.

0 532 456, i.e. compounds of formula (VIII): -24-

R

j R -N 4

(VIII)

.R-Xi or a pharmaceutically acceptable salt thereof, wherein

R

1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an a-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;

R

2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;

R

3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;

R

4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;

X

2 represents alkylene, carbonyl or a bond; and

X

3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy.

20 A particularly preferred compound of formula (VIII) is 4S*)-2benzyl-l-(3,5-dimethylbenzoyl)-N-( 4 -quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.

0 443 132, i.e. compounds of formula (IX) $*eo WO 00/07598 PCT/GB99/02509

CH,

R

4

R

1 -Y-A-N CONHCHCON (IX) or a pharmaceutically acceptable salt thereof, wherein

R

1 is aryl, or a group of the formula: z X is CH or N; and Z is O or N-R 5 in which R 5 is hydrogen or lower alkyl;

R

2 is hydroxy or lower alkoxy;

R

3 is hydrogen or optionally substituted lower alkyl;

R

4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.

A particularly preferred compound of formula (IX) is the compound of formula (IXa)

HO

I I (IXa)

N-

H

3

C

or a pharmaceutically acceptable salt thereof.

-26- Another class of NK-1 receptor antagonists of use in the present disclosure is that described in International Patent Specification No. WO 92/17449, i.e. compounds of the formula (X) H

R

r..z v

R

or a pharmaceutically acceptable salt thereof, wherein

R

1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3s.cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci-ioalkyl optionally substituted with from one to three fluoro groups, Ci-loalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-loalkyl-S-, Ci-ioalkyl-S(O)-, Ci-ioalkyl-S02-, phenyl, phenoxy, C1-loalkyl-SO 2

NH-,

Ci-loalkyl-SO2NH-Ci-ioakyl-, Ci-ioalkylamino-diC1i.oalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Cl-6alkylamino, Cl-6dialkylamino, HC(O)NH- and Ci-loalkyl-C(O)NH-; and 20 R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-1oalkyl optionally substituted with from one to three fluoro groups and Ci-ioalkoxy optionally substituted with from one to three fluoro groups.

A particularly preferred compound of formula is (2S,3S)-3-(2methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.

-27- Another class of NK-1 receptor antagonists of use in the present disclosure is that described in International Patent Specification No.

WO 95/08549, i.e. compounds of formula (XI)

R

2

(CH

2 )x

H

N R 3 H R 4

(XI)

or a pharmaceutically acceptable salt thereof, wherein

R

1 is a C1.4alkoxy group;

R

2 is 6

N

N-N

R

3 is a hydrogen or halogen atom;

R

4 and R 5 may each independently represent a hydrogen or halogen atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group; R6 is a hydrogen atom, a Ci-4alkyl, (CH2)mcyclopropyl, S(O)nC-4alkyl, phenyl, NR 7

R

8

CH

2

C(O)CF

3 or trifluoromethyl group;

R

7 and R 8 may each independently represent a hydrogen atom, or a Cl4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1.

Particularly preferred compounds of formula (XI) are 20 tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.

28 Another class of tachykinin antagonists of use in the present disclosure is that described in International Patent Specificat ion No.

WO 95/14017, i.e. compounds of formula (XII) R8 R4 1 1 R-(CH )R 3 NHi R

(OH

2 1 1 (XII) or a pharmaceutically acceptable salt thereof, wherein mn is zero, 1, 2 or 3; n is zero or 1;o is zero, Ilor 2; p is zero or 1; R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl; which R groups may be substituted with one or two halo, CI.3alkoxy, trifluoromethyl, C 14alkyl, phenyl-C 1.3alkoxy, or C 1-4alkanoyl groups; RI is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, 15 piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(CI- 4 alkyl)-, phenyl-(Ci~alkoxy)-, quinolinyl-(Cl 4 alkyl)-, isoquinolinyl-(Cl~alkyl)-, reduced quniolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Cl-4alkyl)-, benzoyl-(C 1-3alkyl)-, C 1.4alkyl, or -NH-CH 2 any one of which RI groups may be substituted with halo, C14alkyl, C14alkoxy, trifluoromethyl, amino, Ci-4alkylamino, di(CI-4alkyl)amino, or C2-4alkanoylamino; or any one of which RI groups may be substituted with phenyl, 25 piperazinyl, C3-SCYCloalkyl, benzyl, C 14alkyl, piperidinyl, pyridinyl, .9.9 99 S 9.9.

9.

*9 *9

S

9 *990 9.

99 9

S

99 .9 9. 9 9 .99 99 99 S 9 9 9.

S 9 @999 @9 9 99

S.

WO 00/07598 PCT/GB99/02509 29 pyrimidinyl, C 2 6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C I 4 alkoxycarbonyl; any one of which groups may be substituted with halo, CI-4alkyl, C1.

4 alkoxy, trifluoromethyl, amino, C1.4alkylamino, di(CI-4alkyl)amino, or C2 4 alkanoylamino; or RI is amino, a leaving group, hydrogen, Cl-4alkylamino, or di(C 1-4alkylbamino;

R

5 is pyridyl, anilino-(C 1-3alkyl or anilinocarbonyl;

R

2 is hydrogen, C 1.4alkyl, C 1-4alkylsulfonyl, carboxy-(C 1-3alkyl)-, Cl.

3 alkoxycarbonyl-(CI-3alkyl)-, or -CO-R 6

R

6 is hydrogen, C1- 4 alkyl, CI-3haloalkyl, phenyl, C1iaalkoxy, Cl-3hydroxyalkyl, amino, CI-4alkylamino, di(Cli 4 alkyl)amino, or -(CH2)q-R 7 q is zero to 3;

R

7 is carboxy, Cl-4alkoxycarbonyl, Cl4alkylcarbonyloxy, amino, Cl.4alkylamino, di(Cli 4 alkyl)amino, C1.6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrroli dinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C 1-4alkyl)-, quinolinyl-(Cl-4alkyl)-, isoquinolinyl-(Ca-4alkyl)-, reduced quinolinyl- (Cl-4alkyl)-, reduced isoquinolinyl-(C1.4alkyl)-, benzoyl-C l3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C 1-4alkoxy, C 14alkyl, amino, C l4alkylamino, di(C 1-4alkyl)amino, or C2-4akanoylamino; or any one of which R 7 groups may be substituted with phenyl, piperazinyl, C 3 8CYCloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C26alkanoyl, or Cl-4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C 1 4 alkoxy, C1- 4 alkyl, Cl.4alkylamino, di(CI- 4 alkyl)amino, or C2- 4 alkanoylamino;

R

8 is hydrogen or C1p6alkyl;

R

3 is phenyl, phenyl-(C-6alkyl)-, C3.8cycloalkyl, C 5 .scycloalkenyl, Ci-8alkyl, naphthyl, C2-8alkenyl, or hydrogen; WO 00/07598 PCT/GB99/02509 any one or which groups except hydrogen may be substituted with one or two halo, C1.3alkoxy, C1-3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and

R

4 is hydrogen or C1.-alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(CI-6alkyl)-, C3-scycloalkyl, Cs.5cycloalkenyl, or naphthyl.

A particularly preferred compound of formula (XII) is methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1yl)piperidin-l-yl)acetylamino] propane; or a pharmaceutically acceptable salt thereof.

The bisphosphonates of use in the present invention correspond to the chemical formula (XIII)

PO

3 H2

A-C-X

PO

3

H

2

(XIII)

wherein A and X are independently selected from the group consisting of H, OH, halogen, NH 2 SH, phenyl, C 1 -Cao alkyl, Ca-C 30 cycloalkyl, C 1

-C

3 0 substituted alkyl, Ca-C30 substituted cycloalkyl, C 1 -Clo alkyl or C 3

-C

1 o cycloalkyl mono- or di- substituted NH 2

C

1

-C

1 o alkoxy, Ci-Clo alkyl or

C

3 -Clo cycloalkyl substituted thio, phenyl substituted thio, C 1 -Cio alkyl or

C

3

-C

10 cycloalkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl.

In the foregoing chemical formula (XIII), the alkyl groups can be straight or branched. The C 1 -C30 substituted alkyl and C 3

-C

3 0 substituted cycloalkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, WO 00/07598 PCT/GB99/02509 -31furanyl, pyrrolidinyl, imidazonyl, NH 2

C

1 -Clo alkyl or C 3

-C

10 cycloalkyl mono- or di- substituted NH 2 OH, SH, and Ci-Co alkoxy.

In the foregoing chemical formula (XIII), A can include X and X can include A such that the two moieties can form part of the same cyclic structure.

The foregoing chemical formula (XIII) is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and/or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Preferred compounds of formula (XIII) are those in which A is selected from the group consisting of H, OH, and halogen, X is selected from the group consisting of C 1

-C

3 0 alkyl, C3-C 30 cycloalkyl, C 1 substituted alkyl, C 3

-C

30 substituted cycloalkyl, halogen, Ci-Clo alkyl or

C

3 -Co 1 cycloalkyl substituted thio, and phenyl substituted thio.

Particularly preferred compounds of formula (XIII) are those in which A is selected from the group consisting of H, OH, and Cl, and X is selected from the group consisting of C 1

-C

3 0 alkyl, C 3

-C

3 0 cycloalkyl, C 1

-C

30 substituted alkyl, C 3

-C

3 0 substituted cycloalkyl, C1, and chlorophenylthio.

Most preferred is when A is OH and X is 4-aminobutyl, i.e.

alendronate.

Non-limiting examples of bisphosphonates useful herein include the following: Alendronic acid, 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid.

Alendronate (also known as alendronate sodium or monosodium trihydrate), 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium trihydrate.

Alendronic acid and alendronate are described in U.S. Patents 4,922,007, to Kieczykowski et al., issued May 1, 1990, and 5,019,651, to Kieczykowski, issued May 28, 1991, both of which are incorporated by reference herein in their entirety.

WO 00/07598 PCT/GB99/02509 -32- Cycloheptylaminomethylene-l,l-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), as described in U.S. Patent 4,970,335, to Isomura et al., issued November 13, 1990, which is incorporated by reference herein in its entirety.

1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are incorporated by reference herein in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid (EB-1053).

1-hydroxyethane-l,l-diphosphonic acid (etidronic acid).

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-l,1bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim (ibandronate), is described in U.S. Patent No. 4,927,814, issued May 22, 1990, which is incorporated by reference herein in its entirety.

6-amino- -hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

3-(dimethylamino)-l-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate).

3-amino-l-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).

[2-(2-pyridinyl)ethylidene]-l,l-bisphosphonic acid (piridronate) is described in U.S. Patent No. 4,761,406, which is incorporated by reference in its entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid (risedronate).

(4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) as described in U.S. Patent 4,876,248, to Breliere et al., October 24, 1989, which is incorporated by reference herein in its entirety.

WO 00/07598 PCT/GB99/02509 -33- 1-hydroxy-2-(1H-imidazol- 1-yl)ethylidene-1,1-bisphosphonic acid (zoledronate).

Preferred are bisphosphonates selected from the group consisting of alendronate, cimadronate, clodronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

More preferred is alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

Most preferred is alendronate monosodium trihydrate.

Estrogen receptor modulators are known for use in hormone replacement therapy and for their anti-bone resorption benefits.

Nonlimiting examples of estrogen receptor modulators useful herein include estrogen, progestins, estradiol, raloxifene, and tamoxifene, and their pharmaceutically acceptable salts, and mixtures thereof.

Further examples of estrogen receptor modulators include clometherone, delmadinone, droloxifene, idoxifene, nafoxidine, nitromifene, ormeloxifene (centchroman), toremifene, trioxifene, BE-25327, CP-336156 and ([2-(4-hydroxyphenyl)-6-hydroxynaphthalen- 1yll -piperidinyl)ethoxy]phenyl]methane, and their pharmaceutically acceptable salts, and mixtures thereof.

Non-limiting examples of an androgen receptor modulators include danazol, 5a-dihydrotestosterone, testosterone, nandrolane decanoate, methyltestosterone, methanadrostenolone, stanozolol, fluoxymesterone, oxymetholone, oxandrolone, oxymethol, norethandrolone, ethylestranol, 4-androsten-19-al-3,17-dione, 19-nortestosterone, norethandrone, norethisterone, dehydroepiandrosterone, epiandrosterone sulfate, androstenedione and androstenediol, testosterone propionate, testosterone cytpionate, and testosterone enanthate.

A peptide hormone useful herein is calcitonin, which is approved for use for treating osteoporosis. Both human and salmon calcitonin are useful herein.

WO 00/07598 PCT/GB99/02509 -34- The preferred compounds of formulae (II) and (III) will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula: O0 1 2 N i

R

Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either when the substituent is an alkyl methyl) group or when the substituent is a hydroxyalkyl hydroxymethyl) group.

The preferred compounds of formula (IV) will have the stereochemistry of the 5- and 6-positions as shown below Where the optional double bond shown in formula (IV) is absent, the particularly preferred compounds will have the stereochemistry of the 3-position as shown below 0 N

H

Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straightchained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

WO 00/07598 PCT/GB99/02509 Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.

Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.

Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.

A particular aryl-C.(;alkyl, e.g. phenyl-Ci-,alkyl, group is benzyl.

Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.

WO 00/07598 PCT/GB99/02509 -36- The compounds of use in this invention may have one or more chiral centers and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric forms and mixtures thereof being included within the scope of this invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention. Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Pharmaceutically acceptable salts and derivatives of the bisphosphonates are also useful herein. Nonlimiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-Cl-C3o-alkyl-substituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

Nonlimiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.

It should be noted that the terms "bisphosphonate" and "bisphosphonates", as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials. The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those or ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, WO 00/07598 PCT/GB99/02509 -37unless indicated otherwise herein. For example, the phrase "about 70 mg of a bone resorption inhibiting bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basis" means that the amount of the bisphosphonate compound selected is calculated based on 70 mg of alendronic acid.

As stated above, the NK-1 receptor antagonist and the bisphosphonate may be formulated in a single pharmaceutical composition or alternatively in individual pharmaceutical compositions for simultaneous, separate or sequential use in accordance with the present invention.

Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal patches or by buccal cavity absorption wafers. Oral dosage forms are particularly preferred tablets, capsules, pills or wafers).

For preparing solid compositions such as tablets, the principal active ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like; for oral administration in liquid form, elixirs and syrups, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated. Suitable binders can include starch, gelatin, natural sugars such a glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in WO 00/07598 PCT/GB99/02509 -38these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

A particularly preferred tablet formulation for alendronate monosodium trihydrate is that described in U.S. Patent No. 5,358,941, to Bechard et al, issued October 25, 1994, which is incorporated by reference herein in its entirety. The compounds used in the present method can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide, and the like.

In the preparation of solid oral dosage forms, a solid preformulation composition containing a homogeneous mixture of one or more compounds of the present invention or a non-toxic pharmaceutically acceptable salt thereof, is conveniently prepared. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

WO 00/07598 PCT/GB99/02509 -39- The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).

Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans TweenTM 20, 40, 60, 80 or and other sorbitans Span

T

20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and surface-active agent, and preferably between 0.1 and It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and Lipiphysan

TM

The active ingredient may be either dissolved in a premixed emulsion composition or alternatively it may be dissolved in an oil soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and The fat emulsion will preferably comprise fat droplets between 0.1 WO 00/07598 PCT/GB99/02509 and 1.Om, particularly 0.1 and 0.5gum, and have a pH in the range of to Particularly preferred emulsion compositions are those prepared by mixing a NK-1 receptor antagonist selected from the compounds of formulae (III), (VII), (VIII), (XI) and (XII) with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.

Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.

The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist and a bisphosphonate, which process comprises bringing a NK-1 receptor antagonist and a bisphosphonate, into association with a pharmaceutically acceptable carrier or excipient.

When administered in combination, either as a single or as separate pharmaceutical composition(s), the NK-1 receptor antagonist and WO 00/07598 PCT/GB99/02509 -41 bisphosphonate, are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the NK-1 receptor antagonist and the bisphosphonate will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.

A suitable dosage level for the NK-1 receptor antagonist about 0.05 to 1500mg per day, preferably about 0.25 to 1500mg per day, and especially about 0.25 to 500mg per day. Preferred oral dosages in humans may include 10mg, 30mg, 100mg and 300mg of the NK-1 receptor antagonist per dose. The compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 1 or 2 times daily.

A suitable dosage level for the bisphosphonate is between 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day.

Preferred oral dosages in humans may range from daily total dosages of about 2.5-20 mg/day over the effective treatment period, and a preferred prophylactic amount is 2.5, 5, or 10 mg/day.

Alendronate may be administered in a single daily dose or in a divided dose. It is desirable for the dosage to be given in the absence of food, preferably from about 30 minutes to 2 hours prior to a meal, such as breakfast, to permit adequate absorption.

A suitable dosage level for the estrogen or androgen receptor modulator is between about 0.1 and 100 mg/day, and preferably between about 0.1 and 10 mg/day, depending on the potency of the agent.

It will be appreciated that the amount of the NK-1 receptor antagonist and (where present) the additional active agent(s) required for use in the treatment or prevention of abnormal bone resorption will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, WO 00/07598 PCT/GB99/02509 -42and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.

The compounds of formulae (III), (VII), (VIII), (XI) and (XII) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 97/49710, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95/14017, respectively.

Particularly preferred NK-1 receptor antagonists of the formulae (III), (VII), (VIII), (XI) and (XII) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (ICoo) of less than 100nM.

Even more preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists with an NK-1 receptor affinity (ICo) of less than favourably less than 2nM and preferably less than InM.

Especially preferred NK-1 receptor antagonists of use in the present invention are orally active, long acting, NK-1 receptor antagonists, identified using a combination of the following assays: ASSAY 1: NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J.

Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 1 2 'I-Tyr 8 -substance P nM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 51l dimethylsulphoxide, WO 00/07598 PCT/GB99/02509 -43- DMSO) with 5x104 CHO cells. Ligand binding is performed in 0.25ml of Tris-HC1, pH7.5, containing 5mM MnC12, 150mM NaC1, 0.02% bovine serum albumin (Sigma), 50g/ml chymostatin (Peninsula), 0.lnM phenylmethylsulphonyl fluoride, 24g/ml pepstatin, 24g/ml leupeptin and 2.8tg/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (lpM) and represents <10% of total binding.

ASSAY 2: Gerbil Foot-Tapping Long acting NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by central infusion of NK-1 receptor agonists such as GR73632 based on the method of Rupniak Williams, Eur. J. Pharmacol., 1994, 265, 179.

Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of approximately 5ml/kg i.v. Alternatively, test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. A selective NK-1 receptor agonist GR73632 (d Ala[L-Pro 9 ,Me-Leu] 0 -substance is infused directly into the cerebral ventricles 3pmol in 5i1 depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (approximately x 20cm x 20cm). The duration of hind foot tapping is then recorded continuously for approximately 5 minutes.

WO 00/07598 PCT/GB99/02509 -44- Duration of action may be determined by comparing the effect of the test compound on foot tapping when administered five minutes or 1 hour before NK-1 agonist challenge, against the effect when the test compound is administered 24 hours before the NK-1 agonist challenge.

ASSAY 3: Ferret Emesis Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (10mg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.

ASSAY 4: Ovariectomized Rat Long acting NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit abnormal bone resorption induced by ovariectomy in six-month old rats, as described in Wronski et al. Endocrinology 123:681-686 (1988). Since estrogen deficiency is the main risk factor for post-menopausal osteoporosis in people, abnormal bone resorption in the OVX rat model is extremely relevant to the human condition.

Ovariectomy (OVX) is completed by dorsal or ventral approach; sham-surgery is completed in age/sex-matched rats. Test compounds are administered orally, subcutaneously, or intraperitoneally to OVX rats WO 00/07598 PCT/GB99/02509 beginning the day after surgery. All rats are killed at four weeks post-surgery.

Bone loss accompanied by accelerated bone resorption and formation in OVX rats is detectable by techniques that are routinely applied in humans. These include measurement of: 1) bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) in bone regions that contain varying amounts of cortical and trabecular bone (central femur [cortical] and distal femur [trabecular]); 2) urinary deoxypyridiniline crosslinks (uDPD), a biochemical marker of bone turnover; and 3) bone turnover via quantitation of in vivo fluorochrome labelled bone forming surfaces (mineralizing surface; MS/BS) on histologic sections in cancellous bone of the proximal tibia.

BMD significantly above, uDPD significantly below, and MS/BS significantly below that seen in OVX rats after four weeks treatment, are regarded as coordinated signs of test compound efficacy in preventing abnormal bone resorption associated with acute estrogen deficiency.

A typical experimental design using the OVX rat assay in an active pre-clinical development program has six groups: a) Sham-operation b) Ovariectomy (OVX) c) OVX+Low Dose NK-1 Antagonist d) OVX+Medium Dose NK-1 Antagonist e) OVX+High Dose NK-1 Antagonist f) OVX+.OO3mpk daily alendronate Alendronate, a known inhibitor of abnormal bone resorption, and a drug already approved for the prevention/treatment of osteoporosis, is used as a positive control.

A suitable selection cascade for NKi antagonists of use according to the present invention is as follows: WO 00/07598 PCT/GB99/02509 -46- Determine affinity for human NKI receptor in radioligand binding studies (Assay select compounds with IC 5 0 o 10nM, preferably ICno 2nM, especially ICoo 5 InM.

(ii) Determine ability of compounds to inhibit foot tapping in gerbils induced by central injection of an NKi agonist (Assay select compounds that inhibit foot tapping with ID5o 3mg/kg and preferably ID 5 o Img/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID5o 30mg/kg and preferably ID 5 so 10mg/kg p.o. 1 hour prior to challenge.

(iii) Determine duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NKi agonist challenge; select compounds showing 25-fold loss of potency compared with IDo5 determined in step (ii) above with the proviso that ID 5 o 10mg/kg and preferably 5mg/kg i.v. after 24 hour pre-treatment.

(iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay select compounds with IDoo 3mg/kg and preferably IDoo I1mg/kg p.o.

Determine ability of orally-administered compounds to inhibit abnormal bone resorption induced by ovariectomy in adult female rats (Assay select compounds with ID90 (3mg/kg and preferably (Img/kg Particularly preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK- 1 receptor binding criteria of step which, in addition, have 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.

One example of a NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)- WO 00/07598 PCT/GB99/02509 -47ethoxy)-3-(S)-(4-fluorophenyl)-4-( 3 -(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: IC 5 o=0. InM gerbil foot-tapping (5 mins.): ID 5 o=0.36mg/kg i.v.

gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.

ferret emesis: ID9o<3mg/kg p.o.

Another example of a NK-1 receptor antagonist of use in the present invention is the compound 1,2,3triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is described in International Patent Specification No. WO 95/18124. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: ICo=0.25nM gerbil foot-tapping (5 mins.): IDo=0.12mg/kg i.v.

gerbil foot-tapping (24 hrs.): IDso=0.17mg/kg i.v.

The following examples illustrate pharmaceutical compositions according to the invention.

These formulations may be prepared with separate active ingredients or with a combination of active ingredients in one composition.

In such combined preparations, the ratio of the NK-1 receptor antagonist and the anorectic agent will depend upon the choice of active ingredients.

WO 00/07598 PCT/GB99/02509 -48- EXAMPLE 1 Amount (mg) per tablet NK-1 receptor antagonist 50.0 100.0 300.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 189.5 139.5 139.5 Magnesium Stearate 0.5 0.5 The active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.

EXAMPLE 2 Bisphosphonate containing tablets are prepared using standard mixing and formation techniques as described in U.S. Patent No.

5,358,941, to Bechard et al., issued October 25, 1994, which is incorporated by reference herein in its entirety.

Tablets containing about 35 mg of alendronate, on an alendronic acid active basis, are prepared using the following relative weights of ingredients.

Ingredient Per Tablet Per 4000 Tablets Alendronate Monosodium Trihydrate 45.68 mg 182.72 g Anhydrous Lactose, NF 71.32 mg 285.28 g Microcrystalline Cellulose, NF 80.0 mg 320.0 g Magnesium Stearate, NF 1.0 mg 4.0 g Croscarmellose Sodium, NF 2.0 mg 8.0 g WO 00/07598 PCT/GB99/02509 49 Tablets comprising other relative weights of alendronate, on an alendronic acid active basis may also be prepared: about 8.75, 17.5, and 140 mg per tablet. Also, tablets containing other bisphosphonates at appropriate active levels are similarly prepared: cimadronate, clodronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, and pharmaceutically acceptable salts thereof.

Also, tablets containing combinations of bisphosphonates are similarly prepared.

EXAMPLE 3 Amount (mg) per tablet NK-1 Receptor Antagonist 50.0 100.0 300.0 Alendronate Monosodium 45.0 45.0 45.0 Trihydrate Microcrystalline Cellulose 80.0 80.0 80.0 Modified Food Corn Starch 80.0 80.0 80.0 Lactose 144.5 194.5 144.5 Magnesium Stearate 0.5 0.5 The active ingredients cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist and 45mg of alendronate monosodium trihydrate per tablet.

Claims

1. Use of a NK-1 receptor antagonist of formula 3 4 R N R X R 1 1 R or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Cl-6alkyl, unsubstituted or substituted with halo, -CF 3 -OCH 3 or phenyl, WO 00/07598 PCT/GB99/02509 51 (ii) C1. 6 alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x -(CH2)m-NR 9 R 1 0 wherein mi is 0, 1 or 2, and R 9 and R' 0 areindependently selected from: hydrogen, (II) CI-6alkyl, (III) hydroxyCl.6alkyl, and (IV) phenyl, (xi) NR9CORI 0 wherein R 9 and RIO are as defined above, and (xii) -CONR 9 R 1 0 wherein R 9 and R' 0 are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; Ci- 6 alkyl C 2 -6alkenyl, and phenyl; X is R 4 1s R 5 is phenyl, unsubstituted or substituted with halo;, R 6 R1 and R 8 are independently selected from the group consisting of: hydrogen, WO 00/07598 PCT/GB99/02509 52 C1.6alkyl, halo, and -CF 3 Y is and Z is hydrogen or Ci4alkyl; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.

2. Use as claimed in Claim 1 wherein said compound of formula is selected from: 1,2,4-triazolo)methyl)-2(S)-(3 ,5-bis(trifluoromethyl)benzyloxy)-3(S)- phenyl-morpholine; 1,2 ,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)- phenyl-morpholine;

4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof. 3. Use of a NK-1 receptor antagonist of formula (II): A 1 0 0" 2 WO 00/07598 PCT/GB99/02509 -53- wherein: A 1 is fluorine or CF3; A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR 7 R 8 where Z is C.-6alkylene or C3-6cycloalkylene; R 7 is hydrogen, C1-4alkyl, Cs.7cycloalkyl or C3.7cycloalkylC1- 4 alkyl, or C24alkyl substituted by C1-4alkoxy or hydroxyl; R 8 is hydrogen, C1.4alkyl, C3s7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by one or two substituents selected from CI-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0)2 or a second nitrogen atom which will be part of a NH or NRC moiety where RC is C1.4alkyl optionally substituted by hydroxy or C1-4alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C1- 4 alkyl group optionally substituted by a hydroxyl group; with the proviso that ifY is C1. 4 alkyl, R 6 is susbstituted at least by a group of formula ZNR 7 R 8 as defined above; or a pharmaceutically acceptable salt thereof; 54 for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption. 4. Use as claimed in Claim 3 wherein said compound of formula (11) is selected from: ,-bis(trifluoromethyl)pheny1 )ethoxy)-4-(5-(dimethylamjfl 0 methyl-l,2,3-triazol.4.yl)methy13(S)-phenylmorphoVn methyl-i ,-rao--lmehl3()(-lorpey~opoie ,S-bis(trifluoromethyl)phenyl)2hydroetho) 3 4 fluorophenyl l, 2 4 -triazol-3-yl)methylmorpholine; or a pharmaceutically acceptable salt thereof. Use of a NK-1 receptor antagonist of formula (111):. R 3 0 yR7 8 z R (III) (O)p 13~ R1 wherein: R2 and R3 are independently selected from the group consisting of: hydrogen, C1..6alkyl, (3 C2..6alkenyl, and phenyl; R6, R 7 and R8 are independently selected from the group consisting of: hydrogen, 23 Ci-6alkyl, fluoro, WO 00/07598 PCT/GB99/02509 55 chioro, bromo, iodo, and -CF 3 R 12 and R1 3 are independently selected from the group consisting of: fluoro, chioro, bromo, and iodo; A is unsubstituted l.6alkyl; B is selected from the group consisting of: HH vNo. N-N N0 IN 0N 0 X H x H N-N 4x -S N- x x N-N N x N- H H N-N N 0, x N-N N N x N x x N 0 H N x H 1 N N 0 x N H H N p isO0 or 1; WO 00/07598 PCT/GB99/02509 56 X is selected from: -PO(OH)O- wherein M' is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 *2MI, -PO(0-) 2 *D 2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R4)-PO(OH)O- wherein R 4 is hydrogen or CI- 3 alkyl, -CH(R4)-PO(O-) 2 2MI, -CH(R4)-PO(O-) 2 2* -CO-CH 2 CH 2 -C0 2 M -CH(CH 3 )-O-CO-R5, wherein R 5 is selected from the group consisting of: 57 (iii)0 0'M OV) CO 2 M 0 CO;M+ 2- CO 2 -Y NH 3 CO,- M+ (Vi) 0 CO, M+ Co., M+ CO~; M+ (vii) and Y is :Z is hydrogen or C1-Galkyl; or a Pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption. 58

6. Use as claimed in Claim 5 wherein said compound of formula (III) is selected from: 5-bis(trifluoromethyl)belZyloxy)- 3 -(S)-phenyl-4-(3-(5-oxo- 1H, 4H-1 4-triazolo)methyl)morpholifle N-oxide; 5-bis(trifluoromethyl)belzyloxy)-3-(S)-phenl-l 4 (ethoxycarbonyloxy- 1-ethyl)-5-oxo- 1H- 1,2,4- triazolo)methyl)morpholifle; fluorophenyl)-4- (3-(4-monophosphoryl- 5-oxo- lH-1,2,4- triazolo)methyl)morpholine; 5.bis(trfuoromethyl)phenyl)ethoxy)-3-(S)-(4---- fluorophenyl)4-(3-(-monophosphoryl 5-oxo-lH- 1,2,4- triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)4-(3-(2-monophosphoryl-5-oxo- 1H- 1,2,4- tr,.azolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4- fluorophenyl)-4- (3-(5.oxyp hosphoryl- 1H- 1,2,4- triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophe-nyl)-4- (3-(1-monophosphoryl-5-oxo-4H- 1,2,4- triazolo)methyl)morpholine; :or a pharmaceutically acceptable salt thereof.

7. Use of a NK-1 receptor antagonist as defined in any one of Claims I. to 6 in combination with one or more active agents selected from V, the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, for the manufacture of a mjedicament for the treatment or prevention of abnormal bone resorption. 59 S. Use as claimed in Claim 7 wherein said bisphosphonate is a compound of formula (XIII): P0 3 H1 2 P0 3 H 2 (XIII) wherein A and X are independently selected from the group consisting of H, OH, halogen, Nz, SH, phenyl, C 1 -Cao alkyl, C.I-C30 cycloalkyl, C 1 -C 3 o substituted alkyl, C 3 -C30 substituted cycloalkyl, Ci-Cio alkyl or C 3 -Clo cycloalkyl. mono- or di- substituted NH 2 CI-Cio alkoxy, Cl-Oj.o alkyl or C3-Clo cycloalkyl. substituted thio, phenyl. substituted thio, Ci-Ojo alkyl or C3-ClO cycloalkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl- Use as claimed in Claim 8 wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof. Use as claimed in Claim 9 wherein said bisphosphonate is alendronate monosodium trihydrate. 25

11. Use as claimed in Claim 7 wherein said estrogen receptor modulator is selected from the group consisting of estrogen, progestins, .0 00. 60 estradiol, raloxifene, tamoxifene, clometherofle, delinadinofle, droloxifene, idoxifene, nafoxidine, nitromifene, ormeloxifene, toremifene, trioxifene, 327, CP-336 166 and ([-4hdoyhnl-6h~xnphhln1 yl] 2 -(l-piperidil)ethoxy]phefl]l)metharie and their pharmaceutically acceptable salts, and mixtures thereof.

12. Use as claimed in Claim 7 wherein said androgen receptor modulator is selected from the group consisting of danazol, testosterone, nandrolane decanoate, methyltestosterofle, methanadrostelolofle, stanozolol, fluoxymesterofle, oxymetholone, oxandrolone, oxymethol, norethandrolofle, ethylestranol, 4-androsten-1 9 -al- 3

17-dione,

19-nortestosterofle, norethandrone, norethisterone, dehydroepiandrosteronle, epiandrosterofle sulfate, androstenediofle and androstenediol, te stosterone propionate, testosterone cytpionate, and testosterone enanthate- 13. Use a6 claimed in Claim 7 wherein said peptide hormone is calcitonin. 14. Use of a NK-1 receptor antagonist as defined in any one of Claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption. A pharmaceutical composition comprising a NK-1 receptor antagonist as defined in any one of Claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, together with at 30 least one pharmaceutically acceptable carrier or excipient. 61 16. A product comprising a NK-1 receptor antagonist as defined in any one of Claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of abnormal bone resorption. 17. The product as claimed in Claim 16 wherein the condition associated with abnormal bone resorption is selected from the group consisting of generalized bone loss, localized bone loss, and the creation of bone having an abnormal structure. 18. The product as claimed in Claim 17 wherein the condition associated with abnormal bone resorption is selected from the group consisting of the following conditions or disease states: osteoporosis, post-menopausal osteoporosis, glucocorticoid- induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, Paget's disease, abnormally increased bone turnover, hypercalcemia of malignancy, osteogensis imperfecta, periodontal disease, periprosthetic osteolysis, and abnormal bone resorption associated with immunosuppressive therapy. 19. A method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a NK-1 receptor antagonist of formula as defined in claim 1. A method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula (II) as defined in claim 3.

21. A method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), as defined in claim

22. A method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a NK-1 receptor antagonist, as defined in any one of claims 1 to 6 in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones.

23. A method for the treatment or prevention of abnormal bone resorption said method comprising administration to a patient in need of such treatment a therapeutically effective amount of a NK-1 receptor antagonist, as defined in any one of claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen S" and androgen receptor modulators, and peptide hormones. [I:\DAYLIB\LIBH]02553.doc:sxc 62

24. A NK-1 receptor antagonist of formula as defined in claim 1, when used for the treatment or prevention of abnormal bone resorption. A NK-1 receptor antagonist of formula (II) as defined in claim 3, when used for the treatment or prevention of abnormal bone resorption.

26. A NK-1 receptor antagonist of formula (III) as defined in claim 5 when used for the treatment or prevention of abnormal bone resorption.

27. A NK-1 receptor antagonist, as defined in any one of claims 1 to 6 in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, o0 when used for the treatment or prevention of abnormal bone resorption.

28. A NK-1 receptor antagonist, as defined in any one of claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, when used for the treatment or prevention of abnormal bone resorption.

29. The use of any one of claims 1 to 14 or 24 to 28 wherein the condition associated with abnormal bone resorption is selected from the group consisting of generalized bone loss, localized bone loss, and the creation of bone having an abnormal structure. The use as claimed in claim 29 wherein the condition associated with abnormal bone resorption is selected from the group consisting of the following conditions or disease states: osteoporosis, post-menopausal osteoporosis, glucocorticoid- induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, Paget's disease, abnormally increased bone turnover, hypercalcemia of malignancy, osteogensis imperfecta, periodontal disease, periprosthetic osteolysis, and abnormal bone resorption associated with immunosuppressive therapy.

31. The method of any one of claims 19 to 23 wherein the condition associated with abnormal bone resorption is selected from the group consisting of generalized bone loss, localized bone loss, and the creation of bone having an abnormal structure.

32. The method of claim 31 wherein the condition associated with abnormal bone resorption is selected from the group consisting of the following conditions or disease states: osteoporosis, post-menopausal osteoporosis, glucocorticoid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, Paget's disease, abnormally increased bone turnover, hypercalcemia of malignancy, osteogensis imperfecta, periodontal disease, periprosthetic osteolysis, and abnormal bone resorption 35 associated with immunosuppressive therapy. S. [I:\DAYL1B\LBH02553.doc:sxc 63

33. A pharmaceutical composition comprising a NK-1 receptor antagonist as defined in any one of Claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, together with at least one pharmaceutically acceptable carrier or excipient substantially as hereinbefore described with reference to Example 3.

34. A process for preparing a pharmaceutical composition comprising a NK-1 receptor antagonist as defined in any one of Claims 1 to 6 and one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, together with at least one pharmaceutically acceptable carrier or excipient substantially as hereinbefore described with reference to Example 3. A pharmaceutical composition when prepared by the process of claim 34. Dated 22 May, 2003 Merck Sharp Dohme Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [I:\DAYIB\LIBH]02553.doc:sxc S. [I:\DAYLIB\LIBH]02553.doc:sxc