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Formamide derivatives useful as adrenoceptor

A halogen, compound technology, applied in the field of β2 agonists, can solve the problem of not showing pharmacological profile, etc., to achieve the effect of excellent potency

Inactive Publication Date: 2007-03-21
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, none of the above-mentioned carboxamide derivatives exhibits a pharmacological profile that would make them useful drugs for the treatment of β2-mediated diseases and / or conditions such as allergic and non-allergic airway diseases; in particular via the inhalation route

Method used

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  • Formamide derivatives useful as adrenoceptor
  • Formamide derivatives useful as adrenoceptor
  • Formamide derivatives useful as adrenoceptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0810] Example 1: N-benzyl-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-methyl Propyl}phenyl)acetamide

[0811]

[0812]Preparation 15 (24 mg, 40 micromol), formic acid (0.5 mL), tetrahydrofuran (5 mL) and water (0.5 mL) were heated to 90° C. for 18 hours. Further aliquots of formic acid (0.5 mL) and tetrahydrofuran (5 mL) were added and heating continued for a further 18 hours. Solvent was removed and chromatographed (0-10% methanol in dichloromethane + 0.3% ammonia). The product was dissolved in methanol (x3) and evaporated (10 mg).

[0813] 1 HNMR (CD 3 OD, 400MHz) δ: 1.05-1.09 (6H, m), 2.69-2.78 (2H, m), 2.78-2.83 (1H, m), 2.87-2.93 (1H, m), 3.53 (2H, s), 4.35 (2H,s), 4.65(1H,dd), 6.82-6.86(1H,m), 6.99(1H,dd), 7.03-7.06(1H,m), 7.13-7.28(7H,m), 8.08(d ), 8.28(s), 8.55(s), 8.61(s); MS(APCI) m / z 476[M+H] + ; HRMS C 28 h 33 N 3 o 4 476.2544[M+H] + found 476.2533.

Embodiment 2

[0814] Example 2: N-(3,4-dimethylbenzyl)-2-(3-{2-[(2R)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxy Ethylamino]-2-methylpropyl}phenyl)acetamide:

[0815]

[0816] The preparation was carried out using the amide from preparation 16 and the method described for Example 1 .

[0817] 1 HNMR (CD 3 OD, 400MHz) δ: 1.05-1.08 (6H, m), 2.18 (3H, s), 2.19 (3H, s), 2.67-2.94 (4H, m), 3.52 (2H, s), 4.27 (2H, s ), 4.62(1H,dd), 4.65(1H,dd), 6.81-7.06(6H,m), 7.12-7.24(3H,m), 8.07(d), 8.27(s), 8.55(s), 8.61 (s).

[0818] MS(APCI)M / Z 504[M+H] + ; HRMS C 30 h 37 N 3 o 4 504.2857[M+H] + FOUND504.2842.

Embodiment 3

[0819] Example 3: N-[4-(dimethylamino)benzyl]-2-{3-[(2R)-2-({(2R)-2-[3-(formylamino)-4- hydroxyphenyl]-2-hydroxyethyl}amino)propyl]phenyl}acetamide

[0820]

[0821] A mixture of the product from Preparation 27 (131 mg, 0.21 mmol) and triethylamine trihydrofluoric acid (16 μL, 0.10 mmol) in THF (2 mL) was stirred at room temperature for 3 days. The mixture was then concentrated in vacuo, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1) to yield 36% Yield The title compound as a brown foam, 18 mg.

[0822] 1 H NMR (400MHz, CD 3 Cl 3 )δ: 1.07 (3H, m), 2.57 (1H, dd), 2.67-2.76 (2H, m), 2.85-2.99 (2H, m), 2.87 (6H, s), 3.47 (1H, m), 4.23 (2H,s), 4.68(1H,dd), 6.67-6.71(2H,m), 6.77-6.79(2H,d), 6.90(1H,m), 6.97-7.70(m,6H), 7.97(d ), 8.27(s), 8.35(s); LRMS APCI m / z 619[M+H] -

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Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

technical field [0001] The present invention relates to beta2 agonists of the following general formula: [0002] [0003] where R 1 , R 2 , n and Q 1 has the meanings stated hereinafter, and the invention relates to processes for the preparation of such derivatives, compositions comprising such derivatives and uses of such derivatives. Background technique [0004] Adrenergic receptors are members of the large superfamily of G-protein coupled receptors. The adrenergic receptor subfamily itself is divided into α and β subfamilies, of which the β subfamily is composed of at least three receptor subtypes: β1, β2, and β3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. β2-adrenergic (β2) receptors are predominantly expressed in smooth muscle cells (e.g., vascular, bronchial, uterine, or intestinal smooth muscle), whereas β3-adrenergic receptors are predominantly expressed in adipose tissue (thus β3 agonists c...

Claims

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Application Information

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IPC IPC(8): C07C233/43C07C217/60A61K31/135
Inventor A·D·布朗M·E·宾纳格P·A·格洛索普K·詹姆斯C·A·L·莱恩R·A·卢思韦特D·A·普赖斯
Owner PFIZER INC
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