Heterocyclic Compounds and Methods For Their Use

a technology of heterocyclic compounds and at2 receptors, applied in the field of compounds, can solve the problems of neuropathic pain, inflammatory pain, and other types of pain that are difficult to treat, and achieve the effect of treating or preventing a cell proliferative disorder

Inactive Publication Date: 2015-01-08
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In still another aspect of the invention there is provided a method of treating or preventing a cell proliferative disorder in a subject comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Problems solved by technology

In addition, current therapies of neuropathic pain, inflammatory pain, impaired nerve conduction velocity and other types of pain that are difficult to treat, have serious side effects, for example, cognitive changes, sedation, nausea and in the case of narcotic drugs, tolerance and dependence.
However, uncontrolled cell proliferation and angiogenesis can lead to tumors and other proliferative disorders.
While there are some effective chemotherapies available for tumors, many result in unpleasant side effects and / or have high toxicity for normal cells.
Osteoporosis is a significant problem in older populations, especially in post-menopausal women.
However, the control of bone formation and bone resorption is complex and further therapies for improving bone mass are required and AT2 receptor antagonists have been shown to increase bone mass [Izu et al., 2009].

Method used

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  • Heterocyclic Compounds and Methods For Their Use
  • Heterocyclic Compounds and Methods For Their Use
  • Heterocyclic Compounds and Methods For Their Use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Compound 4 (S)-1-(2,2-diphenylacetyl)-4-phenylpiperazine-2-carboxylic acid

[0171]1. Procedure for the Preparation of 4b

[0172]To a stirred solution of compound 4a (100 mg, 0.41 mmol) and PhB(OH)2 (75 mg, 0.61 mmol) in DCM (2 mL) was added Cu(OAc)2 (22 mg, 0.12 mmol) at RT and the mixture was stirred overnight, TLC (MeOH:DCM=1:10) showed most of starting material was consumed. The reaction was repeated on a larger batch of compound 4a (1.0 g, 4.1 mmol) and the reaction mixtures were combined and washed with cold water (20 mL) then brine (10 mL×2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (EA:PE=1:50) to give 4b (450 mg, 31%) as a colorless oil. LC-MS (Agilent): Rt 3.35 min; m / z calculated for C17H24N2O4 [M+H]+ 321.2, [M+Na]+343.2. found [M+H]+321.1, [M+Na]+343.1.

[0173]2. Procedure for the Preparation of 4c

[0174]To a stirred solution of 4b (0.45 g, 1.4 mmol) in DCM (5 mL) was added CF3COOH (0.96 g, 8.4 mmol) at RT and the mixture ...

example 2

Compound 5 (S)-4-benzyl-1-(2,2-diphenylacetyl)piperazine-2-carboxylic acid

[0179]1. Procedure for the Preparation of Compound 5a

[0180]To a solution of 4a (0.5 g, 2.0 mmol) in DMF (10 mL) at 0° C. was added DIPEA (317.4 mg, 2.45 mmol) and benzyl bromide (359.1 mg, 2.1 mmol) and the mixture was stirred at RT for 40 min, TLC (PE:EA=4:1) showed that the starting material was consumed. Water (30 mL) was added and the mixture was extracted with EA (30 mL). The organic extract was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 5a (650 mg, 97%) as a yellow oil. LC-MS (Agilent): Rt 3.28 min; m / z calculated for C18H26N2O4 [M+H]+ 335.1. found [M+H]+ 355.1.

[0181]2. Procedure for the Preparation of Compound 5b

[0182]To a solution of 5a (650 mg, 1.95 mmol) in DCM (8 mL) was added TFA (1.34 g, 11.7 mmol) and the mixture was stirred at RT overnight, TLC (PE:EA=4:1) showed that the starting material was consumed. The solvent was removed in vacuo, water (15 mL) and Et2O (15 mL) ...

example 3

Compound 6 (S)-4-(1,5-diphenyl-1H-pyrazol-3-yl)-1-(2,2-diphenylacetyl)-piperazine-2-carboxylic acid

[0187]1. Procedure for the Preparation of 6b

[0188]A mixture of the 4a (2.00 g, 13.8 mmol) and 6a (9.34 g, 41.6 mmol) (prepared according to the procedure in Tetrahedron, 2010, 66, 2843) in toluene (40 mL) was heated at 130° C. in a sealed tube for 3 hours, TLC (DCM:MeOH=20:1) showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by Al2O3 column (PE:EA=10:1 to 4:1) to give 6b (600 mg, 16%) as a thick yellow oil. LC-MS (Agilent): Rt 3.27 min; m / z calculated for C21H28N2O5S [M+H]+ 421.2, [M+Na]+443.2. found [M+H]+421.2, [M+Na]+443.2.

[0189]2. Procedure for the Preparation of Compound 6c

[0190]A mixture of 6b (600 mg, 1.42 mmol), DABCO (192 mg, 1.71 mmol) and PhNHNH2 (185 mg, 1.71 mmol) in t-BuOH (30 mL) was heated at reflux overnight, TLC (PE:EtOAc=2:1) showed most of the starting material was consumed. The mixture was cooled to RT and conc...

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Abstract

The present invention relates to heterocyclic compounds useful for antagonizing angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to piperazine and diazepine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.

Description

FIELDS OF THE INVENTION[0001]The present invention relates generally to compounds that are useful in antagonizing the angiotensin II type 2 (AT2) receptor. More particularly, the invention relates to heterocyclic compounds of formula (I) and their use as AT2 receptor antagonists. Pharmaceutical compositions comprising the compounds and their use in modulating the AT2 receptor and therapies that require modulation of the AT2 receptor are described.BACKGROUND OF THE INVENTION[0002]Although the AT2 receptor has been known since the 1980s, much less is known about its biological function than the angiotensin II type 1 (AT1) receptor, which has been studied for its functional effects on vasoconstriction, aldosterone release and cardiovascular growth [Wexler et al., 1996]. However, more recently the AT2 receptor has been implicated in the differentiation and regeneration of neuronal tissue [Steckelings et al., 2005; Chakrabarty et al., 2008], cell proliferation and angiogenesis [Clere et ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D295/185C07D231/12
CPCC07D231/12C07D295/185C07D241/04C07D243/08C07D403/04C07D413/04C07D413/06A61P19/08A61P19/10A61P25/00A61P25/02A61P25/04A61P35/00
Inventor MCCARTHY, THOMAS DAVIDNAYLOR, ALAN
Owner NOVARTIS AG
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