EP1102590A1 - Use of a nk-1 receptor antagonist for treating or preventing abnormal bone resorption - Google Patents

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

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Publication number
EP1102590A1
EP1102590A1 EP99934993A EP99934993A EP1102590A1 EP 1102590 A1 EP1102590 A1 EP 1102590A1 EP 99934993 A EP99934993 A EP 99934993A EP 99934993 A EP99934993 A EP 99934993A EP 1102590 A1 EP1102590 A1 EP 1102590A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
alkyl
group
substituted
trifluoromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99934993A
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German (de)
French (fr)
Inventor
Richard John Hargreaves
Nadia Melanie Rupniak
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Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
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Publication of EP1102590A1 publication Critical patent/EP1102590A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • abnormal bone resorption 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 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.
  • X is -O-
  • R 6 , R 7 and R 8 are independently selected from the group consisting of:
  • R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Ci- ⁇ alkylamino, di-C ⁇ -6alkylamino, Ci- ⁇ alkoxy, Ci- ⁇ alkyl-O-CO, Ci- ⁇ alkyl-O-CO-Ci-ealkyl, Ci- ⁇ alkyl-CO-O, Ci- ⁇ alkyl-CO-Ci-ealkyl-O-, Ci- ⁇ alkyl-CO-, C ⁇ -6alkyl-CO-C ⁇ -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 ;
  • suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
  • 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.
  • 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 these 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.
  • compositions with a surface- active agent will conveniently comprise between 0.05 and 5% surface -active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion will preferably comprise fat droplets between 0.1 and l.O ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0.
  • 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 lOmg, 30mg, lOOmg 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.
  • the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (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.
  • 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.
  • test compounds may be administered orally or by subcutaneous or intraperitoneal routes.
  • a skin incision is then made in the mi ⁇ hne of the scalp to expose the skull.
  • a selective NK-1 receptor agonist e.g. GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]-substance P-(7-l l)
  • GR73632 d Ala[L-Pro 9 ,Me-Leu 10 ]-substance P-(7-l l)
  • 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 deoxypyrichniline 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 bone mineral density
  • DXA dual energy x-ray absorptiometry
  • uDPD urinary deoxypyrichniline crosslinks
  • MS/BS in vivo fluorochrome labelled bone forming surfaces
  • Tablets containing about 35 mg of alendronate, on an alendronic acid active basis, are prepared using the following relative weights of ingredients.

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  • Life Sciences & Earth Sciences (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to the use of an NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption, optionally in combination with one or more active agents selected from the group consisting of bisphosphonates, estrogen and androgen receptor modulators, and peptide hormones, and to methods of using the same, and to compositions and products containing the same.

Description

USE OF ANK-1 RECEPTOR ANTAGONIST FOR TREATING OR PREVENTINGABNORMAL 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 disorders 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. F., Fogelman, I., Ralston, S. et al. (1984) Lancet 1(8381), pp. 821- 824 (1984), and Gibbs, C. J., Aaron, J. E.; 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 osteoporotic 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. 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 adminstration regimens.
The present invention accordingly provides the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption. The present invention also provides 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.
In a further aspect of the present invention, there is provided 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.
The present invention therefore further provides 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 the manufacture of a medicament for the treatment or prevention of abnormal bone resorption. The present invention also provides 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.
In a further aspect of the present invention, there is provided a pharmaceutical composition 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, 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 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.
In a further or alternative aspect of the present invention, there is therefore provided 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 a particular aspect of the present invention, 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.
Generalized boss 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, e.g., 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 bone resorption in osteoporotic humans. 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 invention are useful for treating and/or preventing the following conditions or disease states: osteoporosis, including post-menopausal 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) the 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 from 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, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, 97/22597, 97/24350, 97/30055, 97/38692, 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 (I):
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of:
(1) Ci-βalkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) imidazolyl, (C) isoxazolyl,
(D) isothiazolyl,
(E) oxadiazolyl,
(F) pyrazinyl, (G) pyrazolyl,
(H) pyridyl,
(I) pyrrolyl,
(J) tetrazolyl,
(K) thiadiazolyl,
(L) triazolyl, and
(M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-βalkyl, unsubstituted or substituted with halo, -CF3,
-OCH3, or phenyl,
(ii) Ci-βalkoxy,
(iii) oxo,
(iv) thioxo,
(v) cyano,
(vii) phenyl,
(viii) hydroxy,
(ix) trifluoromethyl ,
(x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and R9 and R10 areindependently selected from:
(I) hydrogen,
(II) Ci-βalkyl,
(III) hydroxyCi-βalkyl, and
(IV) phenyl,
(xi) -NR9COR10, wherein R9 and R10 are as defined above, and
(xii) -CONR9R10, wherein R9 and R10 are as defined above, R2 and R3 are independently selected from the group consisting of: (1) hydrogen;
(2) Ci-βalkyl (3) C2-6alkenyl, and (5) phenyl;
X is -O-
R is
R5 is phenyl, unsubstituted or substituted with halo;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) Ci-ealkyl, (3) halo, and
(4) -CF3;
Y is -0-; and
Z is hydrogen or Cι- alkyl; and pharmaceutically acceptable salts thereof. Particularly preferred compounds of formula (I) are:
4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)- phenyl-morpholine;
4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)- phenyl-morpholine; 4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)-2(S)-(3,5- bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(5-oxo-lH,4H-l,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 (II) and pharmaceutically acceptable salts thereof:
(II) wherein:
A1 is fluorine or CF3;
A2 is fluorine or CF3; A3 is fluorine or hydrogen;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =0, =S or a Cι- alkyl group, and optionally substituted by a group of the formula ZNR7R8 where
Z is Ci-βalkylene or C3-6cycloalkylene; R7 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylCι- alkyl, or
C2- alkyl substituted by Cι- alkoxy or hydroxyl;
R8 is hydrogen, Cι- alkyl, C3-7cycloalkyl or C3-7cycloalkylCι- alkyl, or C2- alkyl substituted by one or two substituents selected from Cι- alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 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(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is Cι- alkyl optionally substituted by hydroxy or Cι- alkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R7 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 Cι- alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is Cι- alkyl, R6 is susbstituted at least by a group of formula ZNR7R8 as defined above.
Particularly preferred compounds of formula (II) include: 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-l,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(l-(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)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4- fluorophenyl)-4-(l,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):
or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) Ci-ealkyl,
(3) C2-6alkenyl, and (4) phenyl; R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) Ci-ealkyl, (3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) -CF3; Rn, R12 and R13 are independently selected from the group consisting of:
(1) fluoro,
(2) chloro,
(3) bromo, and
(4) iodo; A is unsubstituted l-βalkyl;
B is selected from the group consisting of:
p is 0 or 1;
X is selected from:
(a) -PO(OH)0" • M+, wherein M+ is a pharmaceutically acceptable monovalent counterion,
(b) -PO(0-)2 • 2M+,
(c) -PO(0")2 • D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion,
(d) -CH(R4)-PO(OH)O" • M+, wherein R4 is hydrogen or Cι-3alkyl, (e) -CH(R4)-PO(0-)2 • 2M+,
(f) -CH(R4)-PO(0-)2 • D +,
(i) -CO-CH2CH2-C02- • M+,
(j) -CH(CH3)-0-CO-R5, wherein R5 is selected from the group consisting of:
(i) .NE + M"
X
(iii) <X C02 " M
Y is -0-;
Z is hydrogen or Ci-βalkyl; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (III) include: (1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo- lH,4H-l,2,4-triazolo)methyl)morpholine N-oxide; (2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4- (ethoxycarbonyloxy-l-ethyl)-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(3) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(4) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-( l-monophosphoryl-5-oxo- IH- 1,2,4- triazolo)methyl)morpholine; (5) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(6) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-lH-l,2,4- triazolo)methyl)morpholine;
(7) 2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-( l-monophosphoryl-5-oxo-4H- 1,2,4- triazolo)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):
wherein R1 represents hydrogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι- alkyl, Ci-βalkoxy, fluoroCi-βalkoxy, C ι-6alkoxy C ι- alkyl, Ci-βalkoxyC i- alkoxy , fluoroC ι-6alkoxyC ι-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCi- alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaR , SRa, SORa, S02Ra, OS02Ra, NRaCOR14, CORa, C02Ra or CONRaRb where Ra and Rb each independently represent hydrogen, Cι- alkyl or fluoroCι- alkyl;
R2 represents hydrogen, halogen, d-βalkyl or Ci-βalkoxy; or R1 and R2 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 Cι- alkyl, CF3, =0 or =S;
R3 represents hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl, Cι-6alkoxy, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, cyano, SRa, SORa, S02Ra, NRaRb, NRaCOR*4, CORa, C02Ra, CONRaR or Cι-4alkyl substituted by cyano, Cθ2Ra or CONRaRb where Ra and Rb are as previously defined;
R4 represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, N02, CN, SRa, SORa, S02Ra, C02Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or Cι- alkyl substituted by Cι- alkoxy, 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: (3E,5JR,6S)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- aza-spiro[4.5]decane;
(3-R,5 ,6S)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-6-phenyl-l-oxa-7-aza- spiro[4.5]decane;
(3i?,5β,6S)-7-benzyl-3-[2-methoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l- oxa-7-aza-spiro[4.5]decane;
(3i?,5Λ,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-l-oxa-7-aza- spiro[4.5]decane;
(3i?,5-R,6S)-3,6-bis(phenyl)-l-oxa-7-aza-spiro[4.5]decane;
(3R,5i?,6S')-7-benzyl-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-l- oxa-7-aza-spiro[4.5]decane; (±)-(3i?*,5 *,65*)-3-(2-methoxyphenyl)-6-phenyl-l-oxa-7-
(phenylmethoxycarbonyl)aza-spiro[4.5]decane;
(3i?,5i?,6S)-3-(2-methoxyphenyl)-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(3S,5-R,6S)-3-(2-cyclopropoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-
7-aza-spiro [4.5] decane; (3i?,5R.,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-
7-aza-spiro[4.5]decane;
(3S,5 ?,6S)-3-[2-cyclopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-l-oxa-7- aza-spiro [4.5] decane; and pharmaceutically acceptable salts thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (V):
R '
or a pharmaceutically acceptable salt thereof, wherein
Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH2)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R7; 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 (CH2)m may optionally be substituted with R8;
R1 is hydrogen or Ci-salkyl optionally substituted with hydroxy, Cι- alkoxy or fluoro;
R2 is a radical selected from hydrogen, Cι-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH2 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, d-βalkoxy, trifluoromethyl, amino, Cι-6alkylamino, Ci-βalkyl-O-CO, Ci-βalkyl-O-CO- Ci-ealkyl, Cι-6alkyl-CO-0, Cι-6alkyl-CO-Ci-6alkyl-0-, Cι-6alkyl-CO, Ci-ealkyl-CO-Ci-ealkyl-, di-Ci-ealkylamino, -CONH-C1-6alkyl, Ci-ealkyl-CO-NH-Ci-ealkyl, -NHCOH and -NHCO-Cι.6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or Ci-βalkyl; or R2 and R5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 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 carbon atoms wherein one of the (CH2) 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 C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, Ci-βalkyl, Ci-βalkoxy, trifluoromethyl, amino, Ci-βalkylamino, -CO-NH- Ci-βalkyl, Ci-βalkyl-CO-NH-Ci-βalkyl, -NHCOH and -NHCO-Ci-βalkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Ci-βalkylamino, di-Cι-6alkylamino, Ci-βalkoxy, Ci-βalkyl-O-CO, Ci-βalkyl-O-CO-Ci-ealkyl, Ci-βalkyl-CO-O, Ci-βalkyl-CO-Ci-ealkyl-O-, Ci-βalkyl-CO-, Cι-6alkyl-CO-Cι-6alkyl, and the radicals set forth in the definition of R2; R6 is -NHCOR9, -NHCH2R9, S02R8 or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R9 is Ci-βalkyl, hydrogen, phenyl or phenylCi-βalkyl; with the proviso that (a) when m is 0, R8 is absent, (b) when R4, R6, R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached ,a ring with R5, and (c) when R4 and R7 are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and Ci-βalkyl, or R4 and R7, 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 (V) is (2S,3S)-cis-3-(2- methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (VI):
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;
R1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyl oxycarbonyl, benzyloxy carbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl; R4 is OH or fluorine when R5 is H; or R4 and R5 are OH ; or R4 and R5 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.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No. 0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-N-CH2 -C -CH2 -CH2 -Am + , A ' (VII)
Ar ' wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a Cι- alkoxymethylene group or a Ci-salkylene group; Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, Cι- alkoxy, Cι- alkyl 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, Cι- alkyl, ω-Cι- alkoxyCι- alkyl, or ω-C2- alkanoyloxyC2- alkyl;
Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4- butylene group; Am+ represents the radical
in which Xi, X2 and X3, 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 A- represents a pharmaceutically acceptable anion.
A particularly preferred compound of formula (VII) is (+) l-[2-[3-
(3,4-dichlorophenyl)-l-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4- phenyl-l-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII): or a pharmaceutically acceptable salt thereof, wherein
R1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an α-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R4 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; X2 represents alkylene, carbonyl or a bond; and X3 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 α-position) hydroxy. A particularly preferred compound of formula (VIII) is (2R", 4S*)-2- benzyl-l-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No. 0 443 132, i.e. compounds of formula (IX)
or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, or a group of the formula:
X is CH or N; and
Z is O or N-R5, in which R5 is hydrogen or lower alkyl; R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl; R4 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)
or a pharmaceutically acceptable salt thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 92/17449, i.e. compounds of the formula (X)
or a pharmaceutically acceptable salt thereof, wherein
R1 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 C3-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Cι-ιoalkyl optionally substituted with from one to three fluoro groups, Ci-ioalkoxy optionally substituted with from one to three fluoro groups, amino, Cι-ιoalkyl-S-, Cι-ιoalkyl-S(O)-, Cι-ιoalkyl-Sθ2-, phenyl, phenoxy, Cι-ιoalkyl-Sθ2NH-,
Cι-ιoalkyl-S02NH-Cι-ιoakyl-, Ci-ioalkylamino-diCi-ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci-βalkylamino, Ci-βdialkylamino, HC(0)NH- and Cn0alkyl-C(O)NH-; and R2 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, Ci-ioalkyl 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 (X) is (2S,3S)-3-(2- methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 95/08549, i.e. compounds of formula (XI)
or a pharmaceutically acceptable salt thereof, wherein R1 is a Cι- alkoxy group; R2 is
R3 is a hydrogen or halogen atom; R4 and R5 may each independently represent a hydrogen or halogen atom, or a Cι- alkyl, Cι- alkoxy or trifluoromethyl group;
R6 is a hydrogen atom, a Cι- alkyl, (CH2)mcyclopropyl, - S(0)nCι- alkyl, phenyl, NR7R8, CH2C(0)CF3 or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a Cι- alkyl 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 (2-methoxy-5- tetrazol-l-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2- methoxy-5-(5-trifluoromethyl-tetrazol-l-yl)-benzyl]-([2S,35]-2-phenyl- piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof. Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO 95/14017, i.e. compounds of formula (XII)
R8 R4
I I
R— (CH — C-CtL— N— (CH,) — R3
NH Rz
(CO)
or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3; n is zero or 1; o is zero, 1 or 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, Cι-3alkoxy, trifluoromethyl, Cι-4alkyl, phenyl-Ci-3alkoxy, or Cι-4alkanoyl groups; R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cι-4alkyl)-, phenyl-(Cι-4alkoxy)-, quinolinyl-(Cι-4alkyl)-, isoquinolinyl-(C1- alkyl)-, reduced quniolinyl-(Cι-4alkyl)-, reduced isoquinolinyl-(Cι-4alkyl)-! benzoyl-(Cι.3alkyl)-, Cι_4alkyl, or -NH-CH2-R5; any one of which R1 groups may be substituted with halo, Cι-4alkyl, Cι-4alkoxy, trifluoromethyl, amino, Cι.4alkylamino, di(Cι-4alkyl)amino, or C2-4alkanoylamino; or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, C -6alkanoylamino, pyrrolidinyl, C2_6alkanoyl, or C ι- alkoxy carbonyl ; any one of which groups may be substituted with halo, Cι-4alkyl, Cι- alkoxy, trifluoromethyl, amino, Cι-4alkylamino, di(Cι-4alkyl)amino, or C2-4alkanoylamino; or R1 is amino, a leaving group, hydrogen, Cι-4alkylamino, or di(Cι-4alkyl)amino;
R5 is pyridyl, anilino-(Ci-3alkyl)-, or anilinocarbonyl;
R2 is hydrogen, Cι-4alkyl, Cι- alkylsulfonyl, carboxy-(Cι_3alkyl)-, Cι-3alkoxycarbonyl-(C1-3alkyl)-, or -CO-R6;
R6 is hydrogen, Cι-4alkyl, Cι-3haloalkyl, phenyl, Cι-3hydroxyalkyl, amino, Cι-4alkylamino, di(Cι-4alkyl)amino, or -(CH2)q-R7; q is zero to 3;
R7 is carboxy, Ci-4alkoxycarbonyl, Cι-4alkylcarbonyloxy, amino, Cι-4alkylamino, di(Ci-4alkyl)amino, Ci-ealkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Cι- alkyl)-, quinolinyl-(Cι-4alkyl)-, isoquinolinyl-(Cι-4alkyl)-, reduced quinolinyl- (Cι-4alkyl)-, reduced isoquinolinyl-(Cι-4alkyl)-, benzoyl-Cι-3alkyl; any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, Cι-4alkoxy, Ci-4alkyl, amino, Cι-4alkylamino, di(Cι- alkyl)amino, or C2-4alkanoylamino; or any one of which R7 groups may be substituted with phenyl, piperazinyl, C3-scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2-6alkanoyl, or Cι- alkoxy carbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Cι_ alkoxy, Cι_ alkyl, Cι-4alkylamino, di(Cι- alkyl)amino, or C2-4alkanoylamino;
R8 is hydrogen or Ci-βalkyl; R3 is phenyl, phenyl-(Ci-6alkyl)-, C3-8cycloalkyl, Cs-scycloalkenyl,
Ci-βalkyl, naphthyl, C2-salkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, Ci-3alkoxy, Ci-3alkylthio, nitro, trifluoromethyl, or Ci-3alkyl groups; and
R4 is hydrogen or Cι-3alkyl; with the proviso that if R1 is hydrogen or halo, R3 is phenyl, phenyl-(Cι-6alkyl)-, C3-scycloalkyl, Cδ-scycloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2- methoxybenzyl)acetylamino]-3-(lH-indol-3-yl)-2-[N-(2-(4-piperidin-l- yl)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)
P03H2
A-C-X
P03H2 (XIII) wherein
A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3-C30 cycloalkyl, C1-C30 substituted alkyl, C3-C30 substituted cycloalkyl, C1-C10 alkyl or C3-C10 cycloalkyl mono- or di- substituted NH2, C1-C10 alkoxy, C1-C10 alkyl or
C3-C10 cycloalkyl substituted thio, phenyl substituted thio, C1-C10 alkyl or C3-Cio cycloalkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl.
In the foregoing chemical formula (XIII), the alkyl groups can be straight or branched. The C1-C30 substituted alkyl and C3-C30 substituted cycloalkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, Ci-Cio alkyl or C3-C10 cycloalkyl mono- or di- substituted NH2, OH, SH, and C1-C10 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 C1-C30 alkyl, C3-C30 cycloalkyl, C1-C30 substituted alkyl, C3-C30 substituted cycloalkyl, halogen, C1-C10 alkyl or C3-C10 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 C1-C30 alkyl, C3-C30 cycloalkyl, C1-C30 substituted alkyl, C3-C30 substituted cycloalkyl, Cl, 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-l,l-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. 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. l,l-dichloromethylene-l,l-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. l-hydroxy-3-(l-pyrrolidinyl)-propylidene-l,l-bisphosphonic acid (EB-1053). l-hydroxyethane-l,l-diphosphonic acid (etidronic acid). l-hydroxy-3-(N-methyl-N-pentylamino)propylidene-l,l- bisphosphonic 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-l-hydroxyhexylidene-l,l-bisphosphonic acid (neridronate).
3-(dimethylamino)-l-hydroxypropylidene-l,l-bisphosphonic acid (olpadronate). 3-amino-l-hydroxypropylidene-l,l-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. l-hydroxy-2-(3-pyridinyl)-ethylidene-l,l-bisphosphonic acid
(risedronate).
(4-chlorophenyl)thiomethane-l,l-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. l-hydroxy-2-(lH-imidazol-l-yl)ethyhdene-l, 1-bisphosphonic acid (zoledronate).
Preferred are bisphosphonates selected from the group consisting of alendronate, cimadronate, clodronate, etidronate, ibandronate, risedronate, piridronate, paniidronate, 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-l- yl][4-[2-(l-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, norethandiOne, norethisterone, dehydroepiandrosterone, epiandrosterone sulfate, androstenedione and androstenediol, testosterone propionate, testosterone cytpionate, and testosterone enanthate.
A peptide hormone useful herein is calcitonin, w iich is approved for use for treating osteoporosis. Both human and salmon calcitonin are useful herein. The preferred compounds of formulae (I), (II) and (III) will have the 2- and 3-substituents on the morphohne ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula:
Where the benzyloxy moiety is α-substituted, the preferred stereochemistry of the α-carbon is either (R) when the substituent is an alkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl (e.g. hydiOxymethyl) group.
The preferred compounds of formula (IV) will have the stereochemistry of the 5- and 6-positions as shown below (5-(R), 6-(S ). 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 (3-(i?)):
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 straight- chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. 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 cyclop r o yl and cyclohexyl. Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-C,.6alkyl, e.g. phenyl-Ci-calkyl, 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. 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 crystaUine 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. Nonhmiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-Cι-C3o-alkyl-substituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. Nonhmiting 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, unless 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 (e.g. 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, e.g., 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 these 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, polyhydroxylpropyl- methacrylamide, 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. 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 (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface- active agent will conveniently comprise between 0.05 and 5% surface -active agent, and preferably between 0.1 and 2.5%. 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 Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre- mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. 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 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.Oμm, particularly 0.1 and 0.5μm, and have a pH in the range of 5.5 to 8.0.
Particularly preferred emulsion compositions are those prepared by mixing a NK-1 receptor antagonist selected from the compounds of formulae (I), (ID, (HI), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) with Intralipid™ 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 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 lOmg, 30mg, lOOmg 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, and 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 (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (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 (I), (IT), (HI), <JV), (V), (VI), (VII), (VIII), (IX), (X), (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 (ICόo) of less than lOOnM.
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 (ICso) of less than lOnM, 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 3xl05 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. 125I-Tyr8-substance P (0. InM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5xl04 CHO cells. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCls, 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50μg/ml chymostatin (Peninsula), O. lnM phenylmethylsulphonyl fluoride, 2μg/ml pepstatin, 2μg/ml leupeptin and 2.8μg/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 (lμM) 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 miάhne of the scalp to expose the skull. A selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro9,Me-Leu10]-substance P-(7-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5μl i.e. v., 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 25cm x 20cm x 20cm). The duration of hind foot tapping is then recorded continuously for approximately 5 minutes. Duration of action may be determined by comparing the effect of the test compound on foot tapping when administered five minutes (i.v.) or 1 hour (p.o.) 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 lOOg of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/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: Ovar ectomized 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 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 deoxypyrichniline 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+.003mpk 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: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with IC50 < lOnM, preferably ICπo < 2nM, especially IC50 < InM.
(ii) Determine ability of compounds to inhibit foot tapping in gerbils induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with ID50 < 3mg/kg i.v., and preferably ID50 < lmg/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID50 < 30mg/kg p.o., and preferably ID50 < lOmg/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 ID50 determined in step (ii) above with the proviso that IDso < lOmg/kg i.v., 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 3); select compounds with IDoo < 3mg/kg p.o., and preferably IDoo < lmg/kg p.o.
(v) Determine ability of orally- administered compounds to inhibit abnormal bone resorption induced by ovariectomy in adult female rats (Assay 4); select compounds with ID90 (3mg kg p.o., and preferably ID90 (lmg/kg p.o.). 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 (i) 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)-(l-(R)-(3,5-bis(triQuoromethyl)phenyl)- ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo- lH,4H-l,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: ICso=0. InM gerbil foot-tapping (5 mins.): i.v. gerbil foot-tapping (24 hrs.): i.v. ferret emesis: IDoo<3mg/kg p.o.
Another example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(R)-(3,5- bis(trifluoiOmethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- 1,2,3- triazol-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: IC5o=0.25nM gerbil foot-tapping (5 mins.): i.v. gerbil foot-tapping (24 hrs.): ID50X).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. EXAMPLE 1
Amount (mg) per tablet
NK- 1 receptor antagonist 50.0 100.0 300.0
Macrocrystalline 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 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, lOOmg 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
Microcrystalhne 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 Tablets comprising other relative weights of alendronate, on an alendronic acid active basis may also be prepared: e.g., about 8.75, 17.5, 70, and 140 mg per tablet. Also, tablets containing other bisphosphonates at appropriate active levels are similarly prepared: e.g., 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 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, lOOmg and 300mg of the NK-1 receptor antagonist and 45mg of alendronate monosodium trihydrate per tablet.

Claims

CLAIMS:
1. Use of a NK-1 receptor antagonist of formula (I):
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of:
(1) Ci-βalkyl, substituted with one or more of the substituents selected from: (a) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) imidazolyl,
(C) isoxazolyl, (D) isothiazolyl,
(E) oxadiazolyl,
(F) pyrazinyl,
(G) pyrazolyl, (H) pyridyl, (I) pyrrolyl,
(J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-βalkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl, (ii) Cι-6alkoxy,
(iii) oxo,
(iv) thioxo,
(v) cyano,
(vi) -SCH3,
(vii) phenyl,
(viii) hydroxy,
(ix) trifluoromethyl,
(x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and RQ and R10 areindependently selected from:
(I) hydrogen,
(II) Ci-ealkyl,
(III) hydroxyCι-6alkyl, and
(IV) phenyl,
(xi) -NR9COR10, wherein R9 and R10 are as defined above, and
(xii) -CONR9R10, wherein R9 and R10 are as defined above, R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) Ci-ealkyl
(3) C2-6alkenyl, and (5) phenyl;
X is -0-; R4 is
R5 is phenyl, unsubstituted or substituted with halo; R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) Ci-ealkyl,
(3) halo, and
(4) -CF3; Y is -0-; and Z is hydrogen or Cι_4alkyl; 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
(I) is selected from:
4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)- phenyl-morpholine;
4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)- phenyl-morpholine;
4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)-2(S)-(3,5- bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
3. Use of a NK-1 receptor antagonist of formula (II):
(ID wherein:
A1 is fluorine or CF3; A2 is fluorine or CF3; A3 is fluorine or hydrogen; R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or
3 nitrogen atoms optionally substituted by =0, =S or a Cι- alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is Ci-βalkylene or C3-6cycloalkylene;
R7 is hydrogen, Cι-4alkyl, C3-7cycloalkyl or C3-7cycloalkylCι- alkyl, or C2- alkyl substituted by Cι- alkoxy or hydroxyl;
R8 is hydrogen, Cι- alkyl, C3-7cycloalkyl or C3-7cycloalkylCι- alkyl, or C2-4alkyl substituted by one or two substituents selected from Cι-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 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(O) or S(0)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is Cι-4alkyl optionally substituted by hydroxy or Cι-4alkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R7 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 Cι-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is Cι-4alkyl, R6 is susbstituted at least by a group of formula ZNR7R8 as defined above; or a pharmaceutically acceptable salt thereof; 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 (II) is selected from:
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-l,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(l-(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)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4- fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine; or a pharmaceutically acceptable salt thereof.
5. Use of a NK-1 receptor antagonist of formula (III):
wherein:
R2 and R3 are independently selected from the group consisting of: (1) hydrogen, (2) Ci-ealkyl,
(3) C2-6alkenyl, and
(4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) Ci-ealkyl,
(3) fluoro, (4) chloro,
(5) bromo,
(6) iodo, and
(7) -CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) fluoro,
(2) chloro,
(3) bromo, and
(4) iodo;
A is unsubstituted ] L-ealkyl;
B is selected from the group consisting of:
p is 0 or 1; X is selected from:
(a) -PO(OH)0" • M+, wherein M+ is a pharmaceutically acceptable monovalent counterion,
(b) -PO(0")2 • 2M\ (c) -PO(0")2 • D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion,
(d) -CH(R )-PO(OH)0" • M+, wherein R4 is hydrogen or C1-3alkyl,
(e) -CH(R4)-PO(0")2 • 2M+,
(f) -CH(R4)-PO(0-)2 • D ÷, (i) -CO-CH2CH2-C02- • M÷,
(j) -CH(CH3)-0-CO-R5, wherein R5 is selected from the group consisting of:
(i) ,NH„ M"
X'
H2 M"
(ii) .X
0 'OH
(iii) o" ^C02 " M+
Y is -0-;
Z is hydrogen or Ci-βalkyl; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.
6. Use as claimed in Claim 5 wherein said compound of formula
(III) is selected from: (1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo- lH,4H-l,2,4-triazolo)methyl)morpholine N-oxide;
(2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4- (ethoxycarbonyloxy-l-ethyl)-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(3) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(4) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
(5) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine; (6) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-lH-l,2,4- triazolo)methyl)morpholine; (7) 2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo-4H-l,2,4- triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
7. Use of a NK-1 receptor antagonist of formula (IV):
wherein R1 represents hydrogen, hydroxy, Ci-βalkyl, C -6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι- alkyl, Ci-βalkoxy, fluoroCι-6alkoxy, Cι_6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fluoroCι-6alkoxyCι- alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι_ alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, S02Ra, OS02Ra, NRaCOR14, CORa, C02Ra or CONRaRb where Ra and Rb each independently represent hydrogen, Cι-4alkyl or fluoroCι- alkyl;
R2 represents hydrogen, halogen, Ci-εalkyl or Ci-βalkoxy; or R1 and R2 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 C1- alkyl, CF3, =0 or =S;
R3 represents hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl, Cι-6alkoxy, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι- alkyl, cyano, SRa, SORa, S02Ra, NRaRb, NRaCOR* , CORa, C02Ra, CONRaRb or Cι.4alkyl substituted by cyano, C02Ra or CONRaRb where Ra and Rb are as previously defined;
R4 represents hydrogen, halogen, Ci-βalkyl, Ci-εalkoxy, CF3, OCF3, N0 , CN, SRa, SORa, S02Ra, C02Ra, CONRaRb, C2.6alkenyl, C2-6alkynyl or Cι- alkyl substituted by Cι- alkoxy, where Ra and Rb are as previously defined; and the broken line represents an optional double bond; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.
8. Use as claimed in Claim 7 wherein said compound of formula (IV) is selected from:
(3i?,5R,6.S)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- aza-spiro[4.5]decane; (3i?,5Λ,6S)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-6-phenyl-l-oxa-7-aza- spiro [4.5] decane;
(3i?,5i?,6S,)-7-benzyl-3-[2-methoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l- oxa-7-aza-spiro[4.5]decane; (3 ,5JR,6S')-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-l-oxa-7-aza- spiro[4.5]decane;
(3R, 5R ,6S)-3 ,6-bis(phenyl)-l-oxa-7-aza-spiro [4.5] decane;
(3i?,57?,6S)-7-benzyl-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-l- oxa-7-aza-spiro[4.5]decane; (±)-(3JR*,5R.*,6S,*)-3-(2-methoxyphenyl)-6-phenyl-l-oxa-7-
(phenylmethoxycarbonyl)aza-spiro[4.5]decane;
(3R,5Λ,6S)-3-(2-methoxyphenyl)-6-phenyl-l-oxa-7-aza-spiro[4.5] decane;
(3S',5JR,6S)-3-(2-cyclopropoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-
7-aza-spiro[4.5] decane; (37?,5-I?,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-
7-aza-spiro[4.5]decane;
(3S',5i?,6S)-3-[2-cyclopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-l-oxa-7- aza-spiro [4.5] decane; or a pharmaceutically acceptable salt thereof.
9. Use of a NK-1 receptor antagonist of formulae (V), (VI), (VII),
(VIII), (IX), (X), (XI) or (XII) as defined herein, for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.
10. Use of a NK-1 receptor antagonist as defined in any one of
Claims 1 to 9 in combination 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.
11. Use as claimed in Claim 10 wherein said bisphosphonate is a compound of formula (XIII):
P03H2
A-C-X
P03H2 (XIII) wherein
A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3-C30 cycloalkyl, C1-C30 substituted alkyl, C3-C30 substituted cycloalkyl, Ci-Cio alkyl or C3-C10 cycloalkyl mono- or di- substituted NH2, C1-C10 alkoxy, C1-C10 alkyl or
C3-Cio cycloalkyl substituted thio, phenyl substituted thio, C1-C10 alkyl or C3-C10 cycloalkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl.
12. Use as claimed in Claim 11 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.
13. Use as claimed in Claim 21 wherein said bisphosphonate is alendronate monosodium trihydrate.
14. Use as claimed in Claim 10 wherein said estrogen receptor modulator is selected from the group consisting of estrogen, progestins, estradiol, raloxifene, tamoxifene, clometherone, delmadinone, droloxifene, idoxifene, nafoxidine, nitromifene, ormeloxifene, toremifene, trioxifene, BE-25327, CP-336156 and ([2-(4-hydroxyphenyl)-6-hydroxynaphthalen-l- yl][4-[2-(l-piperidinyl)ethoxy]phenyl])methane and their pharmaceutically acceptable salts, and mixtures thereof.
15. Use as claimed in Claim 10 wherein said androgen receptor modulator is selected from the group consisting of 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.
16. Use as claimed in Claim 10 wherein said peptide hormone is calcitonin.
17. Use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of abnormal bone resorption.
18. 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.
19. 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.
20. Use of a NK-1 receptor antagonist 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.
21. 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 the group consisting of bisphosphonates, estrogen and androgen receptor modulators and peptide hormones, such that together they give effective relief.
22. A pharmaceutical composition comprising a NK- 1 receptor antagonist 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.
23. A product comprising a NK-1 receptor antagonist 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.
24. A use, method, composition or product as claimed in any one of Claims 1 to 23 wherein the condition associated with abnormal bone resorption is selected from the group consisting of generalized bone loss, locahzed bone loss, and the creation of bone having an abnormal structure.
25. A use, method, composition or product as claimed in Claim 24 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 mahgnancy, osteogensis imperfecta, periodontal disease, periprosthetic osteolysis, and abnormal bone resorption associated with immunosuppressive therapy.
EP99934993A 1998-08-04 1999-07-30 Use of a nk-1 receptor antagonist for treating or preventing abnormal bone resorption Withdrawn EP1102590A1 (en)

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