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Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders

a technology of pyrrolopyridazine and compounds, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of poor prognosis, high src activity, and loss of signal transduction normally exerted by the array of kinase enzymes in malignant cells,

Inactive Publication Date: 2005-07-21
SALVATI MARK +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Greatly increased Src activity is also associated with metastasis (>90%) and poor prognosis.
In summary, the tight regulation of signal transduction normally exerted by the array of kinase enzymes is often lost in malignant cells.

Method used

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  • Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders
  • Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders
  • Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 3-Cyano-4-(cyclohexylamino)-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (1E)

[0225]

A. Preparation of 3-Methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (1A)

[0226] To a solution of ethyl isocyanoacetate (38.1 mL, 0.34 mol) and DBU (50.8 mL, 0.34 mol) in THF (400 mL) at 50° C. was added a solution of acetaldehyde (9.5 mL, 0.17 mol) in THF (100 mL) over 25 min. The reaction mixture was stirred at 55° C. for 17 h, cooled to 25° C. and acetic acid (20 mL) was slowly added. The resulting mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (800 mL) and washed with HCl (1 N, 3×300 mL). The combined aqueous washes were extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with NaHCO3 (sat. aq., 3×200 mL), water (100 mL) and brine (100 mL) and then concentrated in vacuo to afford a dark brown oil. Elution of this oil through a silica pad using ethyl acetate / hexanes (1:1) and the conc...

example 2

Preparation of 3-Cyano-5-methyl-4-phenoxypyrrolo [1,2-b]pyridazine-6-carboxylic acid ethyl ester

[0231]

[0232] To a solution of compound 1D (18 mg, 0.068 mmol) in acetonitrile (0.5 mL) at room temperature were added Et3N (21 uL, 0.205 mmol) and phenol (7 mg, 0.075 mmol). The reaction mixture was stirred for 24 h and then poured onto dichloromethane (10 mL) and NaHCO3 (sat. aq., 10 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (3×5 mL), and the combined organic extracts were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to afford compound 2 (15 mg, 68%) as a yellow solid. HPLC: 100% at 4.35 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL / min, monitoring at 220 nm). MS (ES): m / z 340.0 [M+NH4]+.

example 3

Preparation of 6-(Methoxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile (3C)

[0233]

A. Preparation of 3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (3A)

[0234] To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 mL) were added K2CO3 (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25° C. The reaction mixture was stirred for 12 h and then diluted with dichloromethane (15 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4 and concentrated and the resulting residue was triturated with methanol to afford 31 mg (76% yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL / min, monitoring at 220 nm). MS (ES): m / z 413.12 [M+H]+.

[0235] Compound 3A can also be prepared as follows: To a solution ...

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Abstract

Disclosed are pyrrolopyridazine compounds, methods of preparing such compounds, and their use for the treatment of proliferative, inflammatory, and other disorders.

Description

RELATED APPLICATIONS [0001] This application is a divisional of Ser. No. 10 / 396,197 filed on Mar. 25, 2003 which claims priority benefit under Title 35 § 119(e) of U.S. provisional Application Nos. 60 / 368,249, filed Mar. 28, 2002, and 60 / 402,118, filed Aug. 8, 2002, the contents of which are herein incorporated by reference.FIELD OF THE INVENTION [0002] The present invention relates to pyrrolopyridazine compounds, methods of preparing such compounds, and their use for the treatment of proliferative and other disorders. BACKGROUND OF THE INVENTION [0003] Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate. Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins have intracellular domains that function as protein kinases and it is through this function that they effect signaling. The interaction of growth facto...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5025A61K45/06C07D487/04
CPCA61K31/5025A61K45/06C07D487/04A61P29/00A61P35/00A61P5/00A61P5/26A61P5/28Y02A50/30A61K2300/00
Inventor SALVATI, MARKBARBOSA, STEPHANIECHEN, ZHONGHUNT, JOHN
Owner SALVATI MARK
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