Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9637497-B2
Application number	US-201615256916-A
Country	US
Kind code	B2
Filing date	Sep 6, 2016
Priority date	May 22, 2003
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (I),

wherein
R is

X is —NH—;
R 1 is methyl;
R 2 is —NHCH 3 ;
A is —CH 2 —C(CH 3 ) 2 — or —C(CH 3 ) 2 —CH 2 —;
or a pharmaceutically acceptable salt thereof, comprising:
st.9) reacting 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one with diethyl oxalate in the presence of sodium hydride so as to obtain a compound of formula (XI)

st.10) reacting the compound of formula (XI) with a hydrazine derivative of formula CH 3 —NHNH 2 (III), in the presence of acetic acid so as to obtain a compound of formula (XIIa)

st.11) reacting the compound of formula (XIIa) with dimethylformamide-di-tert-butylacetale so as to obtain a compound of formula (XIIIa)

st.12) reacting the compound of formula (XIIIa) with a guanidine derivative of formula R′—NH—C(═NH)NH 2 (VI), so as to obtain a compound of formula (Ia)

wherein R′ is hydrogen or R, and R 2 ′ is ethoxy; and reacting the compound of formula (Ia) according to one of the following sequences of steps:

Sequence A) when R′ is R:
st.24) converting the compound of formula (Ia) into a compound of formula (I), by treatment with an amine of formula R″—NH 2 (XXII), wherein R″ is methyl;

Sequence B) when R′ is R:
st.25) first converting the compound of formula (Ia) into a compound of formula (Ia′), through acidic or basic ester hydrolysis

st.26) then converting the compound of formula (Ia′) into a compound of formula (I), through reaction with an amine of formula R″—NH 2 (XXII), wherein R″ is methyl, under basic conditions and in the presence of a suitable condensing agent

Sequence C) when R′ is hydrogen:
st.25) converting the compound of formula (Ia) into a compound of formula (Ia″), through acidic or basic ester hydrolysis

st.26) converting the compound of formula (Ia″) into a compound of formula (Ia′″) through reaction with an amine of formula R″—NH 2 (XXII), wherein R″ is methyl, under basic conditions and in the presence of a suitable condensing agent

st.29) converting the compound of formula (Ia′″) into a compound of formula (I), by first converting the amino group to iodine with iso-amylnitrite and diiodomethane or cesium iodide, in the presence of iodine and CuI, and by subsequently reacting the iododerivative with an arylamine of formula R′—NH 2 (XXVII), wherein R′ is R, in the presence of palladium acetate and (2,2′-bis(diphenylphosphino))-1,1′-binaphthalene (BINAP)

Sequence D) when R′ is hydrogen:
st.29) converting the compound of formula (Ia), wherein R′ is hydrogen, into a compound of formula (Ia), wherein R′ is R, by first converting the amino group to iodine with iso-amylnitrite and diiodomethane or cesium iodide, in the presence of iodine and CuI, and subsequently reacting the iododerivative with an arylamine of formula R′—NH 2 (XXVII), wherein R′ is R, in the presence of palladium acetate and (2,2′-bis(diphenylphosphino))-1,1′-binaphthalene (BINAP), to obtain the compound of formula (Ia) wherein R′ is R

then proceeding with st.25) and st.26) of Sequence B) to obtain a compound of formula (I).

2. The process of claim 1 , wherein the sequence of steps is Sequence B, wherein st.25) is carried out through basic ester hydrolysis by using potassium hydroxide and st.26) is carried out by using EDC as condensing agent.

3. The process of claim 1 , wherein the sequence of steps is Sequence C, wherein st.25) is carried out through basic ester hydrolysis by using potassium hydroxide, st.26) is carried out by using EDC as condensing agent and st.29) is carried out by using cesium iodide.

4. The process of claim 1 , wherein the sequence of steps is Sequence D, wherein st.29) is carried out by using cesium iodide.

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Traquandi Gabriella
• Brasca Maria Gabriella
• D'Alessio Roberto
• Polucci Paolo
• Roletto Fulvia
• Vulpetti Anna
• Pevarello Paolo
• Panzeri Achille
• Quartieri Francesca
• Ferguson Ron
• Vianello Paola
• Fancelli Daniele

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title