Process for preparing certain phenyl urea compounds

Details Process for preparing certain phenyl urea compounds Process for preparing certain phenyl urea compounds

2001-02-27

2002-04-16

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C558S411000, C564S048000, C564S049000, C564S050000, C564S052000, C564S053000, C564S055000

Reexamination Certificate

active

06372933

ABSTRACT:

SCOPE OF THE INVENTION
This invention relates to a process for making certain phenyl urea compounds. The end-product phenyl urea compounds are useful in treating IL-8, GRO&agr;, GROG&bgr;, GRO&ggr; and NAP-2 mediated diseases.
BACKGROUND OF THE INVENTION
Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1a, IL-1b or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al,
J. Clin. Invest
. 84, 1045 (1989); J. Schroder et al,
J. Immunol
. 139, 3474 (1987) and
J. Immunol
. 144, 2223 (1990); Strieter, et al,
Science
243, 1467 (1989) and
J. Biol. Chem
. 264, 10621 (1989); Cassatella et al,
J. Immunol
. 148, 3216 (1992).
There is a need for treatment in this field, for compounds which are capable of binding to the IL-8 &agr; or &bgr; receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding. Such compounds have been disclosed in published patent applications exemplified by the likes of PCT/US96/13632) published Aug. 21, 1997 as WIPO No. WO97/29743.
Specifically this invention provides a method for synthesising N-[2-hydroxy-4-cyanophenyl]-N′-[2-bromophenyl]urea, a compound disclosed in PCT application serial number PCT/US96/13632, published Aug. 21, 1997 an WIPO No. WO97/29743 and related compounds.
SUMMARY OF THE INVENTION
In a first aspect this invention covers a process for making a compound of Formula
wherein
X is oxygen;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less.
R1 is independently selected from hydrogen; halogen; nitro; cyano; C
1-10
alkyl; halosubstituted C
1-10
alkyl; C
2-10
alkenyl; C
1-10
alkoxy; halosubstituted C
1-10
alkoxy; azide; S(O)
t
R
4
; (CR
8
R
8
)q S(O)
t
R
4
; hydroxy; hydroxy substituted C
1-4
alkyl; aryl; aryl C
1-4
alkyl; aryl C
2-10
alkenyl; aryloxy; aryl C
1-4
alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C
2-10
alkenyl; heteroaryl C
1-4
alkyloxy; heterocyclic, heterocyclic C
1-4
alkyl; heterocyclicC
1-4
alkyloxy; heterocyclicC
2-10
alkenyl; (CR
8
R
8
)q NR
4
R
5
; (CR
8
R
8
)q C(O)NR
4
R
5
; C
2-10
alkenyl C(O)NR
4
R
5
; (CR
8
R
8
)q C(O)NR
4
R
10
; S(O)
3
H; S(O)
3
R
8
; (CR
8
R
8
)q C(O)R
11
; C
1-10
alkenyl C(O)R
11
: C
2-10
alkenyl C(O)OR
11
; (CR
8
R
8
)q C(O)OR
11
; (CR
8
R
8
)q OC(O)R
11
; (CR
8
R
8
)qNR
4
C(O)R
11
; (CR
8
R
8
)q C(NR
4
)NR
4
R
5
; (CR
8
R
8
)q NR
4
C(NR
5
)R
11
, (CR
8
R
8
)q S(O)
2
NR
4
R
5
, or two R
1
moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
t is 0 or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R
5
are independently, optionally substituted C
1-4
alkyl, optionally substituted aryl, optionally substituted aryl C
1-4
alkyl, optional v substituted heteroaryl, optionally substituted heteroaryl C
1-4
alkyl, heterocyclic, heterocyclic C
1-4
alkyl, or R
4
and R
5
together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N or S;
Y is R
1
;
q is 0 or an integer having a value of 1 to 10;
m is an integer having a value of 1 to 3;
R
6
and R
7
are independently hydrogen or a C
1-4
alkyl group, or R
6
and R
7
together with the nitrogen to which they are attached form a 5 to 7 member ring which ring, may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
R
8
is hydrogen or C
1-4
alkyl;
R
10
is C
1-10
alkyl C(O)
2
R
8
;
R
11
is hydrogen, optionally substituted C
1-4
alkyl, optionally substituted aryl, optionally substituted aryl C
1-4
alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC
1-4
alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC
1-4
alkyl,
R
12
is hydrogen, C
1-10
alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R
13
is suitably C
1-4
alkyl, aryl, aryl C
1-4
alkyl heteroaryl, heteroarylC
1-4
alkyl, heterocyclic, or heterocyclicC
1-4
alkyl;
R
b
is NR
6
R
7
, alkyl, aryl, aryl C
1-4
alkyl, aryl C
2-4
alkenyl, heteroaryl, heteroaryl C
1-4
alkyl, heteroarylC
2-4
alkenyl, heterocyclic, heterocyclic C
1-4
alkyl, heterocyclic C
2-4
alkenyl, or camphor, all of which groups may be optionally substituted;
wherein said process comprises reacting a compound of Formula (A)
where R
1
is the same as defined in Formula I with a nucleophile illustrated by the amine of Formula (B)
where Y is the same as defined above in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) to form the urea of Formula (I).
In a second aspect, this invention relates to a process for making a compound of Formula (I) as described above wherein the process comprises treating a benzoxazolinone of Formula (D)
with a halogen in the presence of an acid to form a compound of Formula (C);
then treating Formula C with CuCN to form a compound of Formula (A1), and
reacting Formula A1 with a nucleophile illustrated by Formula (B)
where Y is the same as defined in Formula I in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) and form the compound of Formula (I) where R is OH and R
1
is CN.
The preferred compounds which can be synthesised by these methods and using these inter mediates are those where R
1
is halogen, cyano, nitro, CF
3
, C(O)NR
4
R
5
, alkenyl C(O)NR
4
R
5
, C(O) R
4
R
10
, alkenyl C(O)OR
12
, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR
4
R
5
, and preferably one of R
4
or R
5
is phenyl. A preferred ring substitution for R
1
is in the 4-position of the phenyl ring.
Preferably R
1
is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR
4
R
5
.
Y is preferably a halogen, C
1-4
alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR
4
R
5
. thioC
1-4
alkyl, thioaryl halosubstituted alkoxy, optionally substituted C
1-4
alkyl, or hydroxy alkyl, Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2′-position or 2′-, 31-position. 25 While Y may be substituted in any of the 5 ring positions, preferably when R is OH, or SH, Y is preferably mono-substituted in the 2′-position or 3′-position, with the 4′-preferably being unsubstituted. If the ring is disubstituted, when R is OH or SH substituents are preferably in the 2′ or 3′ position of a monocyclic ring. While both R
1
and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.
Preferred compounds include:
N-[2-hydroxy-4-cyanophenyl]-N′-[2-bromophenyl] urea
N-[2-hydroxy-4-cyanophenyl]-N′-[2,3-dichlorophenyl] urea
N-(2-hydroxy-4-cyanophenyl)-N′-(2-(4-pyridylmethyloxy)phenyl)urea, and
N-(2-hydroxy-4-cyanophenyl)-N′-(2-chlorophenyl)urea.
SPECIFIC EMBODIMENTS OF THE INVENTION
Reaction Scheme 1 details in graphical form the process and representative intermediates which are the subject of this invention.
The benzoxazolinone starting material is commercially available (formula 1-1). See for example Aldrich. It is halogenated (formula 1-2) by mixing it with a solution of an organic acid and a the alkali metal salt of that acid in a molar amount about equal to that of the benzoxazolinone and treating that mixture o

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