Calcium receptor-active compounds

• US 6,211,244 B1
• Filed: 10/23/1995
• Issued: 04/03/2001
• Est. Priority Date: 10/21/1994
• Status: Expired due to Term

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Inventors: Nemeth, Edward F., Balandrin, Manuel F., Van Wagenen, Bradford C., Moe, Scott T., DelMar, Eric G.
• Primary Examiner(s): Geist, Gary
• Assistant Examiner(s): PADMANABHAN, SREENIVASAN
• Application Number:
  US08/546,998
• Time in Patent Office: 1,989 Days
• Field of Search: 564/374, 564/182, 564/271, 514/649, 536/23.5
• US Class Current: 514/649
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/20 for decreasing, blocking or antagonising the activity of PTH
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 211/27 having amino groups linked to the six-membered aromatic ring by saturated carbon chains
• CPC Class Codes: C07C 211/28 having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains
• CPC Class Codes: C07C 211/30 the six-membered aromatic ring being part of a condensed ring system formed by two rings
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 217/62 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 225/16 and containing six-membered aromatic rings
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/32 : having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 2800/04 : Endocrine or metabolic disorders
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/6872 : Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

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

Claims

1. A compound having the formula:

wherein Ar₅ is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy, benzyl, benzyloxy, α

,α

-dimethylbenzyl, NO₂, CHO, CH₃CH(OH), acetyl, ethylene dioxy, and —

CH═

CH-phenyl;

Ar₆ is phenyl substituted with 1 to 5 substituents each independently selected from the group consisting of acetyl, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, carbomethoxy, OCH₂C(O)C₂H₅ and OCH₂C(O)OC₂H₅ and acetoxy, provided that at least one substituent is OCH₂C(O)OC₂H₅;

R₁₁ is hydrogen or methyl; and

R₁₂ is hydrogen or methyl;

provided that at least one of R₁₁ and R₁₂ is methyl;

or a pharmaceutically acceptable salt or complex thereof.

2. The compound of claim 1, wherein Ar₆ is a substituted phenyl comprising a OCH₂C(O)OC₂H₅ substituent in a meta position.

30. A method of treating a patient having a disease selected from the group consisting of hyperparathyroidism, Paget'"'"'s disease, a hypercalcemic disorder, osteoporosis, hypertension, and renal osteodystrophy, comprising the step of administering to said patient an effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 1314, 15, 16, 17, 18 or 19 or 20.

31. The method of claim 30, wherein said disease is hyperparathyroidism.

32. The method of claim 30, wherein said disease is Paget'"'"'s disease.

33. The method of claim 30, wherein said disease is osteoporosis.

34. The method of claim 30, wherein said disease is hypertension.

35. The method of claim 30, wherein said disease is renal osteodystrophy.

44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 20 and a pharmaceutically acceptable carrier.

45. A method of treating a patient having a disease or disorder characterized by abnormal bone and mineral homeostasis comprising the step of administering to said patient a therapeutically effective amount of the compound of any of claims 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

3. A compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine);

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyohenyl)methyl)-1(2-(trifluoromethyl)phenyl)ethylamine);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)proyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine);

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine;

or a pharmaceutically acceptable salt or complex thereof.

4. The compound of claim 3, wherein said compound is 21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

5. The compound of claim 3, wherein said compound is 22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

6. The compound of claim 3, wherein said compound is 24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

7. The compound of claim 3, wherein said compound is 25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

10. The compound of claim 3, wherein said compound is 21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

11. The compound of claim 3, wherein said compound is

((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

12. The compound of claim 3, wherein said compound is 21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

13. The compound of claim 3, wherein said compound is 23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

14. The compound of claim 3, wherein said compound is 24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

15. The compound of claim 3, wherein said compound is 23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

16. The compound of claim 3, wherein said compound is 24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

17. The compound of claim 3, wherein said compound is 24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

18. The compound of claim 3, wherein said compound is 24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine)) or a pharmaceutically acceptable salt or complex thereof.

19. The compound of claim 3, wherein said compound is 24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

20. The compound of claim 3, wherein said compound is 25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

8. A method of inhibiting bone resorption in a patient comprising the step of administering to said patient a therapeutically effective amount of a compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine);

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylamine);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine);

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine;

or a pharmaceutically acceptable salt or complex thereof.

9. A compound having the formula:

wherein Ar₃ is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO₂, CHO, CH₃CH(OH), N(CH₃)₂, acetyl, and ethylene dioxy;

Ar₄ is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, and acetoxy;

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

if Ar₄ is unsubstituted phenyl, then Ar₃ is a substituted phenyl that is not 2-nitrophenyl, 4-nitrophenyl, or 4-dimethylaminophenyl;

R₈ is either hydrogen or phenyl;

R₉ is either hydrogen or methyl; and

R₁₀ is either hydrogen, methyl, or phenyl;

or a pharmaceutically acceptable salt or complex thereof.

46. The compound of claim 9, wherein Ar₃ is either naphthyl optionally substituted with 0-5 substituents or phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy, benzyl, benzyloxy, dimethylbenzyl, NO₂, CHO, CH₃CH(OH), N(CH₃)₂, acetyl, and ethylene dioxy.

21. A method of decreasing parathyroid hormone level in a patent to achieve a beneficial effect comprising the step of administering to said patient an effective amount of a compound selected from the group consisting of:

21S ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine);

21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine);

21U ((R)-N-(3-(2-chlorophenyl)propyl)-1(3-isobutoxyphenyl)ethylamine);

21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine);

23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine);

23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine;

24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylamine);

24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine;

24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine;

24V (N-((3-methyl-4-methoxyphenyl)methyl)-1(3-(ethylacetoxy)phenyl)ethylamine);

24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine);

24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine;

25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine); and

25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine);

25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

22. The method of claim 21, wherein said compound is 21S (R)-N-(3-(2-chlorophenyl)propyl)-1-(3-propoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

23. The method of claim 21, wherein said compound is 21T ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isopropoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

24. The method of claim 21, wherein said compound is 21U ((R)-N-(3-(2-chlorophenyl)propyl)-1-(3-isobutoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

25. The method of claim 21, wherein said compound is 21Y ((R,R)-N-(4-(3-(trifluoromethyl)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

26. The method of claim 21, wherein said compound is 22J ((R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

27. The method of claim 21, wherein said compound is 23A ((R)-N-(4-(3-(trifluoromethoxy)phenyl)-2-butyl)-1-(3-methoxyphenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

28. The method of claim 21, wherein said compound is 23E ((R)-N-((3-(trifluoromethoxy)phenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

29. The method of claim 21, wherein said compound is 24B (N-((3-methyl-4-methoxyphenyl)methyl)-1-(2-(trifluoromethyl)phenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

36. The method of claim 21, wherein said compound is 24J ((R)-N-(3-(3-(trifluoromethoxy)phenyl)propyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

37. The method of claim 21, wherein said compound is 24M ((R)-N-(3-(3,5-difluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

38. The method of claim 21, wherein said compound is 24V (N-((3-methyl-4-methoxyphenyl)methyl)-1-(3-(ethylacetoxy)phenyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

39. The method of claim 21, wherein said compound is 24X ((R)-N-((3-bromo-4-methoxyphenyl)methyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

40. The method of claim 21, wherein said compound is 24Y ((R)-N-((3-chloro-4-ethoxyphenyl)methyl)-1-(1-naphthyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.

41. The method of claim 21, wherein said compound is 25C ((S,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

42. The method of claim 21, wherein said compound is 25D ((R,R)-N-(4-(3-trifluoromethyl)phenyl)-2-butyl)-1-(1-naphthyl)ethylamine) or a pharmaceutically acceptable salt or complex thereof.

43. The method of claim 21, wherein said compound is 25E ((R)-N-(3-phenylprop-2-en-1-yl)-1-(3-methoxyphenyl)ethylamine or a pharmaceutically acceptable salt or complex thereof.