US 8,026,261 B2Granted

Fluorinated derivatives of deferiprone

AssigneeApotex Technologies Inc.

InventorsTim Fat Tam, Regis Leung-Toung, Yingsheng Wang, Yanqing Zhao

Life of this patent

Estimating the term…

Abstract

The present invention relates to novel derivatives of deferiprone. In particular, the present invention relates to fluorinated derivatives of deferiprone or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, processes for the manufacture thereof and their use in the treatment of neurodegenerative diseases caused by the presence of free iron or iron accumulation in neural tissues and in diseases wherein excess iron must be removed or redistributed.

Claims49

Dependent claims

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(a) a compound of formula (II):
(b) a compound of formula (III):
(c) a compound of formula (IIIC):
and
(d) a compound of formula (IV):
wherein in formula I:
Y is O or NR1,
R1 is selected from the group consisting of:
hydrogen, C1-C6 alkyl, cyclopropylmethyl, allyl and cyclopropyl:
R2 is selected from the group consisting of:
hydrogen, C1-C6 alkyl, CHF2, CH2CF3, CF3CHOH and R5CHOH,
R5 is selected from the group consisting of:
hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is selected from the group consisting of:
methyl, hydrogen, CF3CHOH, C1-C6 alkyl, CH2CF3, and CH(OCH3)CF3;
and
R4 is selected from the group consisting of:
CHF2, methyl, hydrogen, C1-C6 alkyl, CH2CF3, and CF3CHOH;
provided that
(a) when the compound of formula (I) is a compound of formula (II), then
Y is NR1, wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and R5CHOH wherein R5 is selected from the group consisting of hydrogen, C1-C3 alkyl and trifluoromethyl;
R3 is selected from the group consisting of methyl, hydrogen and CF3CHOH;
and
R4 is CHF2;
and
(b) when the compound of formula (I) is a compound of formula (III), then:
Y is NR1, wherein R1 is defined as above;
R2 is selected from the group consisting of CHF2, CH2CF3, and CF3CHOH;
and
R3 and R4 are each selected from the group consisting of methyl and hydrogen;
and
(c) when the compound of formula (I) is a compound of formula (IIIC), then;
Y is NR1 and R1 is defined as above;
R2 is selected from the group consisting of hydrogen and C1-C6 alkyl, with the proviso that when R4 is hydrogen, R2 is not hydrogen;
R3 is CF3CHOH;
and
R4 is selected from the group consisting of hydrogen and methyl;
and
(d) when the compound of formula (I) is a compound of formula (IV) then:
Y is O;
R2 is CF3CHOH;
R3 is selected from the group consisting of methyl and hydrogen;
and
R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
or
Y is O;
R2 is hydrogen;
R3 is hydrogen;
and
R4 is difluoromethyl;
or;
Y is NR1, wherein R is defined as above;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and R5CHOH, wherein R5 is selected from the group consisting of hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is hydrogen, methyl, C1-C6 alkyl;
and
R4 is CH2CF3, and CF3CHOH;
or
Y is NR1, wherein R1 is defined as above;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and R5CHOH, wherein R5 is selected from the group consisting of hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is CH2CF3, CH(OCH3)CF3;
and
R4 is hydrogen, methyl, C1-C6 alkyl.

61 more elements

A method for the preparation of a compound of formula (II)

wherein:
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, R5CHOH wherein R5 is hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is hydrogen;
and
wherein the method comprises the following processes:
Process (A) which comprises the following steps:
(a) oxidation of a compound (1) with an oxidating agent selected from the group consisting of 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO), potassium bromate, sodium hypochlorite and sulfur trioxide pyridine complex to give compound (2);
(b) reacting compound (2) from step (a) with diethylaminosulfur trifluoride (DAST) to give compound (3);
(c) reacting compound (3) with an amine of the formula R1NH2 wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (4) wherein R1 is defined as in R1NH2;
and
(d) hydrogenation of compound (4) with palladium on charcoal to give compound of formula (IIA) wherein the compound of formula (IIA) is a compound of formula (II) when R2 and R3 are each hydrogen, with the proviso that when R1 in compound (4) is allyl, boron tribromide is used instead of catalytic hydrogenation, or
Process (B) which comprises the following steps:
(e) debenzylation of compound (3) from Process (A), step (b), with BBr2 to give compound (5);
(f) reacting compound (5) with an aliphatic aldehyde R5CHO wherein R5 is selected from the group consisting of hydrogen and C1-C6 alkyl to give compound (6) wherein R5 is as defined above;
(g) reacting compound (6) with benzyl bromide and sodium hydroxide to give compound (7) wherein R5 is as defined above;
(h) reacting compound (7) with an amine of the formula R1NH2, wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (8) wherein R1 is as defined in R1NH2;
and
(i) hydrogenation of compound (8) with palladium on charcoal to give a compound of formula (IIB) with the proviso that R1 is not allyl;
a compound of formula (IIB) is a compound of formula (II) when R2 is R5CHOH, or
Process (C) which comprises the following steps:
(j) reacting compound (7) from Process (B), step (g), with thionyl chloride to give the chloride (9) wherein R5 is defined as above;
(k) reduction of compound (9), prepared from step i) in situ, without isolation, with zinc in hydrochloric acid to give compound (10);
(l) reacting compound (10) from step (k) with an amine of the formula R1NH2 wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (11) wherein R1 is as defined in R1NH2;
and
(m) hydrogenation of compound (11) from step (l) with palladium on charcoal to give a compound of formula (IIC) with the proviso that R1 is not allyl;
a compound of formula (IIC) is the same as a compound of formula (II) when R2 is CH2R5, or
Process (D) which comprises the following steps:
(n) reacting a compound (8) from Process (B) wherein R5 is hydrogen with triethylamine and methanesulfonyl chloride to give compound (8A);
and
(o) hydrogenation of compound (8A) with palladium on charcoal to give a compound of formula (IIC) wherein R5 is hydrogen, with the proviso that R1 is not allyl;
a compound of formula (IIC) is the same as a compound of formula (II) when R2 is CH2R5, or
Process (E) which comprises the following steps:
reacting a compound of formula (IIA) with CF3CH(O—C1-C4 linear alkyl)OH in the presence of potassium carbonate at a temperature of about 100° C. to about 130° C. to give a compound of formula (IIB) wherein R3 is hydrogen, and R2 is R5CHOH wherein R5 is trifluoromethyl.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/078,079Filed 27 Mar 2008 · us provisional application
Priority: 28 Mar 2007
Published: US 2008/0242706 A12 Oct 2008
Granted: 27 Sep 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 309/40
With oxygen atoms directly attached to ring carbon atoms: oxygen atoms attached in positions 3 and 4, e.g. maltol
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs

Family

Application60/907,290Us provisional application · filed 28 Mar 2007
US 2008/0242706 A1Pre-grant publication · published 2 Oct 2008
US 8,026,261 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(a) a compound of formula (II):
(b) a compound of formula (III):
(c) a compound of formula (IIIC):
and
(d) a compound of formula (IV):
wherein in formula I:
Y is O or NR1,
R1 is selected from the group consisting of:
hydrogen, C1-C6 alkyl, cyclopropylmethyl, allyl and cyclopropyl:
R2 is selected from the group consisting of:
hydrogen, C1-C6 alkyl, CHF2, CH2CF3, CF3CHOH and R5CHOH,
R5 is selected from the group consisting of:
hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is selected from the group consisting of:
methyl, hydrogen, CF3CHOH, C1-C6 alkyl, CH2CF3, and CH(OCH3)CF3;
and
R4 is selected from the group consisting of:
CHF2, methyl, hydrogen, C1-C6 alkyl, CH2CF3, and CF3CHOH;
provided that
(a) when the compound of formula (I) is a compound of formula (II), then
Y is NR1, wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and R5CHOH wherein R5 is selected from the group consisting of hydrogen, C1-C3 alkyl and trifluoromethyl;
R3 is selected from the group consisting of methyl, hydrogen and CF3CHOH;
and
R4 is CHF2;
and
(b) when the compound of formula (I) is a compound of formula (III), then:
Y is NR1, wherein R1 is defined as above;
R2 is selected from the group consisting of CHF2, CH2CF3, and CF3CHOH;
and
R3 and R4 are each selected from the group consisting of methyl and hydrogen;
and
(c) when the compound of formula (I) is a compound of formula (IIIC), then;
Y is NR1 and R1 is defined as above;
R2 is selected from the group consisting of hydrogen and C1-C6 alkyl, with the proviso that when R4 is hydrogen, R2 is not hydrogen;
R3 is CF3CHOH;
and
R4 is selected from the group consisting of hydrogen and methyl;
and
(d) when the compound of formula (I) is a compound of formula (IV) then:
Y is O;
R2 is CF3CHOH;
R3 is selected from the group consisting of methyl and hydrogen;
and
R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
or
Y is O;
R2 is hydrogen;
R3 is hydrogen;
and
R4 is difluoromethyl;
or;
Y is NR1, wherein R is defined as above;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and R5CHOH, wherein R5 is selected from the group consisting of hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is hydrogen, methyl, C1-C6 alkyl;
and
R4 is CH2CF3, and CF3CHOH;
or
Y is NR1, wherein R1 is defined as above;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, and R5CHOH, wherein R5 is selected from the group consisting of hydrogen, C1-C6 alkyl and trifluoromethyl;
R3 is CH2CF3, CH(OCH3)CF3;
and
R4 is hydrogen, methyl, C1-C6 alkyl.

61 more elements

Facts

Application

12/078,079Filed 27 Mar 2008 · us provisional application

Priority

28 Mar 2007

Published

US 2008/0242706 A12 Oct 2008

Granted

27 Sep 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 309/40
With oxygen atoms directly attached to ring carbon atoms: oxygen atoms attached in positions 3 and 4, e.g. maltol
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs