Title of Invention

"PROCESSES FOR THE PREPARATION OF ISOTHIAZOLE DERIVATIVES"

Abstract A process for the preparation of a compound of Formula I or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; wherein R1, R2 and R3 are herein as described as in specification and claims.
Full Text BACKGROUND OF THE INVENTION
This invention relates to processes for preparing isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. It is known that polypeptide growth factors, such as vascular endothelial growth factor (VEGF), which has a high affinity for the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly to vasculogenesis" and angiogenesis. The present invention provides a process for preparing compounds that are capable of binding to or modulating the KDR/FLK-1 receptor. The compounds may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
This invention also relates to processes for preparing intermediates that may be converted to the aforementioned isothiazole derivatives and to the intermediates prepared. , Processes for preparing isothiazole derivatives and their intermediates have been disclosed in International Patent Publication WO 99/62890, published December 9, 1999, and United States Patent Nos. 6,235,764; 6,380,214; and 6,548,526, issuing on May 22, 2001, April 30, 2002 and April 15i 2003, respectively. Processes for preparing 3-alkoxyisothiazole derivatives as herbicides have been disclosed in United States Patent No. 4,059,433, issuing' on November. 22, 1977. Processes for preparing 5-amino-3-hydroxy{alkoxy,-amino-)isothiazoles have been disclosed in Chemische Berichte (1964), 97(11), 3106-17
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the Formula I
(Formula Removed)
or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; wherein
R1 is H, C1-C10 alky!, C2-C10 alkenyl, C2-C10 alkynyl, -C(O)(C1-C10 alkyl), -(CH2),(C6-C10 aryl), -(CH2),(4-10 membered heterocyclic), -C(O)(CH2)t(C6-C10 aryl), or -C(O)(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)-.with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic, group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=O) moiety; and the foregoing R1
groups, except H, are optionally substituted by 1 to 3 R4 groups;
R2 is selected from the list of substituents provided in the definition of R1,
-SO2(CH2)t(C6-C10 aryl), -SO2(CH2)t(4-10 membered heterocyclic), and -OR5, t Is an integer
ranging from.O to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4
groups;
or R1 and R2 may be taken together with the nitrogen to which each is attached to
form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered
heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2
heteroatoms selected from O, S and -N(R6)- in addition to the nitrogen to which R1 and R2 are
attached, said -N(R6)- is optionally =N- or -N= where R1 and R2 are taken together as said
heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or
2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6
group of said -N(R6)-, are optionally substituted by 1 to 3 R4 groups;
R3 is H, CrC10 alkyl, C2-C10 alkenyl, C2-Ci0 alkynyl, -(CH2),(C6-C10 aryl), or -(CH2),(4-
10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally
includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and
heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a G5-C8 saturated cyclic
group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=O) moiety; the -(CH2)r moieties of
the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an
integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4
groups;
each R4 is independently selected from halo, C^-Cn alkyl, C2-C10 alkenyl, C2-C10
alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azidoi -OR5, -NR6C(O)OR5, -NR6SO2R5,
-S02NR5R6, -NR6C(0)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7 wherein j is an integer ranging from
0 to 2, -NR5(CR6R7),OR6, -(CH2),(C6-C10 aryl), -SO2(CH2),(C6-C10 aryl), -S(CH2), -O(CH2),(C6-C10 aryl), -(CH2),(4-10 membered heterocyclic), and -(CR6R7)mOR6, wherein m is
an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or
2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S
atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic
R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-
10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties
are optionally substituted by an oxo (=O) moiety; and the alkyl, aryl and heterocyclic moieties
of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently
selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5, -SO2NR5R6,
-NR6C(0)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6 wherein m is an integer from 1 to 5, -OR5
and the substituents listed in the definition of R5;
each R5 is independently selected from H, CrC10 alkyl, -{CH2)t(C6-Cio aryl), and
-(CH2)t(4-10 membered heterocyclic), wherein t Is an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that
two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said
aryl and heterocyclic R5 groups are optionally fused to a C6-do aryl group, a Cs-Ca saturated
cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R5 subsituents,
except H, are optionally substituted by 1 to 3 substituents independently selected from nitro,
trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7. -C(O)NR6R7, -NR6R7, hydroxy, d-C6
alkyl, and Ci-C6 alkoxy; and
each R6 and R7 is independently H or d-Ce alkyl;
comprising reacting a compound of the Formula II
wherein R8 is H, 0,-do alkyl, -C(O)(d-C10 alkyl). -C(O)(C6-do aryl),
-C(O)(4-10 membered heterocyclic), -(CH2)t(C6-C10 aryl), -(CH2)t(4-10 membered
heterocyclic), -C(O)O(CrC10 alkyl); -C(O)O(C6-C10 , aryl), -C(O)O(4-10 membered
heterocyclic) wherein t is an integer from 0 to 5; said aryl and heterocyclic R8 groups are
optionally fused to a C6-C10 aryl group; and the foregoing aryl and heterocyclic R8 groups are
optionally substituted with 1-2 substituents independently selected from halogen,
trifluoromethyl, d-C6 alkoxy, d-C6 alkyl, and nitro groups; and R1, R2, R3, R4, R5, R6 and R7
are as defined above for the compound of the Formula I, with an ammonia source in a solvent
to give a compound of the Formula I. The reaction is preferably performed at a temperature
between about -50°C and about 150°C and pressures between about atmospheric pressure
and about 200 psi, more preferably at a temperature of about 50°C to about 70°C at about
to about 40 psi, and still more preferably at about 30°C to about 50°C and at about 45 to
about 80 psi. The ammonia source is preferably anhydrous ammonia, but the source of
ammonia is not critical to the success of the invention. Other non-limiting sources of
ammonia include ammonium hydroxide, liquid ammonia, ammonium chloride, sodamide, and
formamide.
The reaction is preferably conducted in the presence of a solvent, such as CrC4
alcohols (e.g., methanol, ethanol, propanol, 2-propanol), dipolar aprotic solvents (e.g.,
dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidinone), ethers
•(e.g., tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether, dioxane. 2-
methyltetrahydrofuran), water or mixtures of at least two thereof. Tetrahydrofuran and
methanol or mixtures thereof are especially preferred.
i
An embodiment of the present invention refers to those processes and compounds
where R2 is H and R1 is C^C^ alkyl optionally substituted by 1 or 2 substituents
independently selected from -NR5R6. -NR5(CR8R7),OR6 and -(CH2),(4-10 membered
heterocyclic) where t is an integer from 0 to 5. In another embodiment R1 is selected from
propyl, butyl, pentyl and hexyl, and may be optionally substituted with dimethylamino, hydroxy,
pyrrolidinyl, morpholino, and ethyl-(2-hydroxy-ethyl)-amino, and R2 is H.
In another embodiment R2 is H and R1 is -(CH2)t(4-10 membered heterocyclic)
wherein t is an integer from 0 to 5, said heterocyclic group is optionally fused to a C6-C-io aryl
group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group and the R1
group, including any fused portions of said R1 group, may be substituted by 1 or 2
substituents independently selected from C^-C^ alkyl, hydroxy and hydroxymethyl.
In yet another embodiment R2 is H and the 4-10 membered heterocyclic moiety of the
R1 group, when the t variable of the R1 group ranges from 2-5, may be any one of morpholino,
pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl, and 2,5-diaza-bicyclo[2.2.1]hept-2-yl and the R1
group is optionally substituted with hydroxy, hydroxymethyl and methyl.
, An embodiment of the present invention refers to those processes and compounds
wherein R3 is -(CH2)t(C6-C10 aryl) wherein t is an integer from 1 to 3 and the R3 group is
optionally substituted with 1 to 4 R4 groups. In another embodiment R3 is benzyl optionally
substituted by 1 to 4 halo substituents.
In a preferred embodiment, the present invention refers to those processes and
compounds wherein R2 is H, R1 is -(CH2)4-1-pyrrolidine, R3 is 2,6-difluoro-4-bromobenzyl, and
R8 is methyl. Preferably, in this embodiment the compound of Formula II is reacted with
anhydrous ammonia in methanol at 50°C to 70°C at 10 to 40 psi. Still more preferably, in this
embodiment the compound of Formula II is reacted with anhydr'ous ammonia in methanol and
tetrahydrofuran at 30°C to 50°C at 45 to 80 psi.
Another embodiment of the present invention refers to those processes wherein the
compound of Formula I is selected from the group consisting of 3-(4-Bromo-2,6-difluorobenzyloxy)-
5-[3-(4-pyrrolidin-1 -yl-buty!)-ureido}-isothiazole-4-carboxylic acid amide;
5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-
ureido)-isothiazole-4-carboxylic acid amide;
3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-4-[4-(2-hydroxy-ethyI)-piperazin-1-yl]-butyl}-
ureido)-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole'
4-carboxylic acid amide;
3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-
carboxylic acid amide;
hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]
ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyI-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-
ureido)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido}-
isothiazole-4-carboxyIic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl]-butyl]-
ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-
ureido}- isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4rcarboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2l6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido}-isothiazole-4-
carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-f3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-
isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-5-piperidin-1-yl-pentyl)-
ureido]-isothiazole-4-carboxylic acid amide;
-6-
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-
ureido)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-y!)-hexyl)-ureido}-
isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,3l6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-
ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl-propyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzy!oxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-
isothiazole-4-carboxylic acid amide;
5-[3-(4-Pyrrdlidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-
4-carboxylic acid amide;
5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazo!e-4-carboxylic acid amide;
3-(4-Chloro-2,6-difIuoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
2-yl)-propyl]-ureido}-isothiazole-4-carboxyiic acid amide;
3-(4-Chloro-2,3,6-trifIuoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifIuoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid amide;
5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyI-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2>3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide; 5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyI-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(3-Hydroxy-5-isopropropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(3-lsopropylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-{3-[4-(4-Methyl-pipera2in-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyI}-ureido)-3-(2l3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difIuoro-benzyloxy)-5-[3-{4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid amide;
5-{3-{4-tEthyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid amide;
3-(4-Chloro-(2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxmethyl-piperidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2.3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-
isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido}-isothiazole-
4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethy!amino-propyI)-ureido]-isothiazole-
4-carboxylic acid amide;
3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid amide;
3-(4-Chloro-2,3,6-difluoro-benzyioxy)-5-(3-{3-[ethylr(2-hydroxy-ethyl)-amino]-propyl}-
ureido)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-
ureido)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Methylamino-propyl)-ureido]-3-{2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-
4-carboxylic acid amide;
S-IS-fS-Amino-propyO-S-methyl-ureidoJ-S^.S.e-trifluoro^-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(4-Diethylamino-butyl)-ureido]-3-(2,3.6-trifluoro-4-methyl-ben2yloxy)-isothiazole-
4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothia2ole-
4-carboxylic acid amide;
3-(3-Chloro-216-diflu6ro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-
isothiazole-4-carboxylic acid amide;
5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,'6-difluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid amide;
and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of said
compounds.
In an especially preferred embodiment, the present invention refers to those
processes wherein the compound of Formula I is 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-
pyrrolidin-1-yl-butyl]-ureido}-isothiazole-4-carboxylic acid amide and the pharmaceutically
acceptable salts, prodrugs, hydrates and solvates thereof.
The present invention also relates to a process for the preparation of a compound of
(Figure Removed) or a pharmaceutically acceptable salt thereof; wherein
R1, R2, R3, R4, R5. R6, R7, and R8 are as defined above for Formula I; comprising (1)
reacting a compound of Formula IV
CO2R8
wherein R3, R4, R5, R6, R7 and R8 are as defined above for Formula II with a source of
carbpnyl, with or without an added base, and then adding a compound of Formula III
HNR1R2 III
wherein R1 and R2 are as defined above for Formula II, in a solvent to give a
compound of the Formula II or (2) reacting a compound of Formula III with a source of
carbonyl, with or without an added base; and then adding a compound of Formula IV in a
solvent to give a compound of the Formula II.
-9-
The source of carbonyl may be any suitable carbonyl source known to those skilled in
the art. In one embodiment the source of carbonyl is represented by the Formula
R'OCOX'
wherein R' is a Ci-C4 alkyl or C6-C10 aryl, and X1 is a leaving group such as a chloro group.
Alternatively, other non-limiting examples of suitable carbonyl sources include 1,1'-
carbonyldiimidazole, di-tert-butyl-dicarbonate in the presence of 4-dimethylaminopyridine and
phosgene or its equivalents such as diphosgene or triphosgene.
The reaction may be carried out at a temperature of between about -78°C to about
100"C, and preferably between about 15°C and about 25°C.
The reaction may utilize any suitable base known to those skilled in the art. Nonlimiting
examples of a suitable base include tertiary amines (e.g. triethylamine.
diisopropylethylamine, pyridine, 4-dimethylaminopyridine), alkali metal carbonates, and alkali
metal hydrogen carbonates.
The reaction may occur in any suitable solvent known to those skilled in the art.
Preferably, the reaction is carried out in the presence of a halogenated hydrocarbon solvent
such as dichloromethane or chloroform; an ether such as tetrahydrofuran. diisopropyl ether,
methyl-tert-butyl ether, and 2-methyltetrahydrofuran; a dipolar aprotic solvent such as
dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone, and dimethylacetamide, and
mixtures thereof.
In a preferred embodiment the compound of Formula IV is treated with triphosgene
and triethylamine in dichloromethane at a temperature of between about -78°C to about 20CC,
then a compound of Formula III is added, preferably a compound of Formula III wherein R1 is
H and R2 is -(CH2)4-1-pyrrolidino, to give a compound of Formula II.
In a more preferred embodiment, the present invention refers to those processes
wherein the compound of Formula II is 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-
1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester.
In a more preferred embodiment the compound of Formula III wherein R1 is H and R2
is -(CH2)4-1-pyrrolidine is treated with 1,1'-carbonyldiimidazole in tetrahydrofuran at a
temperature of about -10°C to about 10°C to produce a product that is added to a compound
of Formula IV in dimethylsulfoxide and potassium carbonate at a temperature of about 15°C
to about 25°C, to give a compound of the Formula II, which is preferably 3-(4-Bromo-2,6-
difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl
ester.
Another embodiment of the present invention refers to those processes wherein the
compound of Formula II is selected from the group consisting of 3-(4-Bromo-2,6-difluorobenzyloxy)-
5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylic acid methyl ester;
5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-
ureido)-isothiazo!e-4-carboxylic acid methyl ester;
3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-
ureido)-isothiazole-4-carboxylic acid methyl ester;
3-(2,5-DifIuoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester;
3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-
carboxylic acid methyl ester;
hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)
ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chioro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid methyl ester;
3-(4-Chloro-2.6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-{4-Chloro-2,6-difluoro-benzyloxy)-5-{3-H1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyldxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-
ureido)-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chlpro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3J4-dihydroxy-pyrrolidin-1-yl]-butyljureido}-
isothiazo!e-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-
ureido}- isothiazole-4-carboxylic acid methyl ester;
3-(2,5-Difluoro-4-methyl-benzyloxy)T5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-dif!uoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
t
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido}-isothiazole-'
carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-
isothiazole-4-carboxylic acid methyl ester;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-5-piperidin-1-yl-pentyl)-
ureido]-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-
ureido)-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl)-hexyl)-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-be nzyloxy)-5-{3-[3-(4-methyl-piperazin-1 -yl-pro py l]-ure ido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-
isothiazole-4'-carboxylic acid methyl ester;
5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-
4-carboxylic acid methyl ester;
5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diazabicycIo[2.2.1Jhept-2-
yl)-propyl]-ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-{3-(5-methyl-2,5-d!aza-bicyclo[2.2.1]hept-.
2-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid methyl'ester;
3-(4-Chloro-2,3,6-trifIuoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2I3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,316-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3l6-trifluoro-4-methyl-benzyloxy)-
isothiazofe-4-carboxylic acid methyl ester;
5-[3-(3-Hydroxy-5-isopropropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-(3-lsopropylamino-propyl)-ure.ido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-{3-[4-(4-Methyl-piperazin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-(3-{4-t4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido.)-3-(2,3,6-trifluoro-4-methyIbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,6-difIuoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-
carboxylic acid methyl ester;
5-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-(2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxmethyl-piperidin-1-yl)-butyl]-
ureido}-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifiuoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1 -yl-pentyl)-ureido]-
isothiazole-4-carboxylic acid methyl ester;
3-(4-Bromo-2,6-difIuoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-
isothiazole-4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido}-isothiazole-
4-carboxylic acid methyl ester; .
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester; •
3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifIuoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-difluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-
ureido)-isothiazole-4-carboxylic acid methyl ester;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-
ureido)-isothiazole-4-carboxylic acid methyl ester;
5-[3-(3-Methylamino-propyl)-ureido]-3-(2.3,6-trifluoro-4-methyl-ben2yloxy)-isothia2Ole-
4-carboxylic acid methyl ester;
5-[3-(3-Amino-propyl)-3-methyl-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
5-[3-{4-Diethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-
4-carboxylic acid methyl ester;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-
4-carboxylic acid methyl ester;
3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-
isothiazole-4-carboxylic acid methyl ester;
5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,6-difluoro-4-methylbenzyloxy)-
isothiazole-4-carboxylic acid methyl ester;
and pharmaceutically acceptable salts thereof.
The present invention also relates to a process for the preparation of a compound of
Formula IV
R3
or a pharmaceutically acceptable salt thereof; wherein R3, R4, R5, R6, R7, and R8 are as
defined above;
comprising reacting a compound of the Formula V
in
R3, R4, R5, R6, R7 and R8 are as defined above; R9 is CrC10 alkyl, C6-C10 aryl, 4-10
membered heterocyclic, said aryl and heterocyclic R9 groups are optionally fused to a C6-C10
aryl group; and the foregoing aryl and heterocyclic R9 groups are optionally substituted
independently with 1-2 substituents independently selected from halogen, trifluoromethyl, Cr
C6 alkoxy, C-|-C6 alkyl, and nitro groups; and
nis 0,1, or 2;
with .an ammonia source in a solvent to give a compound of the Formula IV. The
reaction is preferably performed at a temperature between about -50°C to about 150°C and
pressures between about atmospheric pressure and about 200 psi, more preferably at a
temperature of about 20°C to about 60°C at about atmospheric pressure to about 50 psi, and
still more preferably at a temperature of about 40°C to about 50°C and at about 45-55 psi.
The ammonia source is preferably anhydrous ammonia, but the source of ammonia is not
critical to the success of the invention. Other non-limiting sources of ammonia include
ammonium hydroxide and liquid ammonia.
The reaction is preferably conducted in the presence of a solvent, such as water, C^
C4 alcohols (e.g., methanol, ethanol, propanol, isopropanol), ethers (e.g., tetrahydrofuran,
diisopropyl ether, methyl-tert-butyl ether, dioxane, 2-methyltetrahydrofuran), and dipolar
aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone, and
dimethylacetamide).
An embodiment of the present invention refers to those processes wherein the
compound of Formula V is reacted with an ammonia source in a solvent to give a compound
of Formula IV and wherein R3 is -(CH2)t(C6-Cio aryl) wherein t is an integer from 1 to 3 and the
R3 group is optionally substituted with 1 to 4 R4 groups. In another embodiment R3 is benzyl
optionally substituted by 1 to 4 halo substituents.
In a preferred embodiment, the present invention refers to those processes wherein
the compound of Formula V is reacted with an ammonia source in a solvent to give a
compound of Formula IV wherein R3 is 2,6-difluoro-4-bromobenzyl, R8 is methyl, R9 is methyl;
and n is 2. Preferably in this embodiment the compound of Formula V is reacted with
anhydrous ammonia in methanol or dimethylsulfoxide at 20°C to 60"C at atmospheric
pressure to 50 psi. Still more preferably, in this embodiment the compound of Formula V is
reacted with anhydrous ammonia in tetrahydrofuran, and preferably at about 40°C to about
50°C at 45 to 55 psi.
In an especially preferred embodiment, the present invention refers to those
processes wherein the compound of Formula. IV is 5-Amino-3-(4-br6mo-2,6-difluorobenzyloxy)-
isothiazole-4-carboxylic acid rriethyl ester.
The present invention also relates to a process for the preparation of a compound of
Formula V
S(0)nR9
or a pharmaceutically acceptable salt thereof; wherein
R3, R4, R5, R6., R7, R8, and R9 are as defined above; and
n is 0, 1 , or 2;
comprising reacting a compound of the Formula VII
HO CO2R8
wherein n, R8, and R9 are as defined above, with a compound of Formula VI
R3X VI
wherein R3 is as defined above and X is a halogen such as chlorine, bromine or
iodine; hydroxyl; Ci-C4 alkyl sulfonate ester; aryl sulfonate ester such as tosylate, nosylate,
besylate or brosylate; or an imidate such as trichloromethyl imidate in the presence of an
acid, a base, or Mitsunobu reagents R'3P and R"OC(O)N=NC(O)OR" wherein each R1 and R"
is independently CrC4 alkyl or C6-C10 aryl, and wherein said R' and R" alkyl and aryl groups
are optionally substituted with 1 to 3 R10 groups;
R10 is CrC10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl,
trifluoromethoxy, -OR5, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R8, -NR6C(O)RS, -C(O)NR5R6,
-NR5R6, -S(O)jR7 wherein j is an integer ranging from 0 to 2, -NR5(CR6R7),OR6, -(CH2),(C6-C10
aryl), -SO2(CH2)t(C6-C10 aryl), -S{CH2MC6-C10 aryl), -O(CH2),(C6-C10 aryl), -(CH2),(4-10
membered heterocyclic), and -(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an
integer from 0 to 5; said CrC™ alkyl group optionally contains 1 or 2 hetero moieties selected
from O, S and -N(R6)- with the proviso that two O atoms, two S atoms, or an O and S atom
are not attached directly to each other; said -(CH2)f(C6-Cio aryl), -SO2(CH2)t(C6-C10 aryl),
-S(CH2)t(C6-Cio aryl), -O{CH2)t(C6-C10 aryl), and -(CH2)t(4-10 membered heterocyclic) groups
are optionally fused to a C6-C-io aryl group, a C5-Ca saturated cyclic group, or a 4-10
membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties are
optionally substituted by an oxo (=O) moiety; and the alkyl, aryl and heterocyclic moieties of
the foregoing R10 groups are optionally substituted by 1 to 3 substituents independently
selected from nitro, trifluoromethyl, trifluoromethoxy, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5,
-C(0)NR5R6, -NR5R6, -(CR6R7)mOR6 wherein m is an integer from 1 to 5, -OR5 and the
substituents listed in the definition of R5 where R5, R6, and R7 are as defined above with the
proviso that R5, R6, and R7 cannot be H, in a solvent, to give a compound of the Formula V.
When X is a halogen or a sulfonate ester, a base is typically used. Non-limiting examples of a
suitable base include alkali metal carbonates, alkali metal hydroxide, alkaline earth metal
carbonate, alkaline earth metal hydroxide, alkali metal CrC4 alkoxide, alkali metal hydride,
and tertiary amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo-
[5.4.0]undec-7-ene ("DBU") and 1 ,5-Diazabicyclo-[4.3.0]non-5-ene ("DBN"). When X is' an
imidate, acids are typically used. Non-limiting examples include mineral acids such as
hydrochloric acid and sulfuric acid, Bronsted acids such as triflic acid, or Lewis acids such as
Trimethylsilyl trifluoromethane-sulfonate, transition metal chlorides (e.g., SnCI4, TiCI4), BF3
etherate, and ianthanide triflate (e.g., Sc(OTf)3 and Ln(OTf>3). When X is hydroxyl, Mitsunobu
reagents R'3P and R"OC(O)OR° are preferably used. Preferred reagents are wherein R' is
CrC4 alkyl or C-\-C4 aryl and R" is CrC4 alkyl or CrC4 aryl. More preferred reagents are
wherein R' is phenyl and R" is ethyl or isopropyl.
The reaction may be carried out at a temperature of between about -20°C to about
100°C, and preferably at between about 15°C to about 35°C.
The reaction is also preferably carried out in the presence of a solvent. Preferably,
when X is a halogen, sulfonate, or hydroxyl the solvent is a halogenated hydrocarbon solvent
such as dichloromethane or chloroform, an ether, such as tetrahydrofuran. diisopropyl ether,
methyl-tert-butyl ether, dioxane, or 2-methyltetrahydrofuran, or a dipolar aprotic solvent, such
as dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone, or dimethylacetamide.
Preferably, when X is an imidate, the solvent is a polar solvent such as nitromethane,
acetonitrile, or 2,2,2-trifluoroethanol or a halogenated hydrocarbon solvent such as
dichloromethane or chloroform.
A preferred embodiment of the present invention refers to those processes wherein
the compound of Formula VII is reacted with a compound of Formula VI in which X is an aryl
sulfonate ester in a dipolar aprotic solvent with an alkali metal carbonate base to give a
compound of the Formula V. It is especially preferred when R3 is 2,6-difluoro-4-bromobenzyl;
X is p-toluene sulfonate ester; Ra is methyl; R9 is methyl; n is 2; the alkali metal carbonate
base is potassium carbonate; and the solvent is dimethylsulfoxide. This preferred process
may be performed at about 15°C to about 35°C.
In an especially preferred embodiment, the present invention refers to those
processes wherein the compound of Formula V is 3-(4-Bromo-2,6-difluoro-benzy!oxy)-5-
methanesulfonyl-isothiazole-4-carboxylic acid methyl ester.
The invention also relates to compounds of Formulae lla, IVa or Va that are useful in
the preparation of the isothiazole derivatives of Formula I, which are in turn useful for binding
or modulating KDR/FLK-1 receptors.
or a pharmaceutically acceptable salt thereof; wherein
(Figure Removed)R1 is H, d-C10 alky!, C2-Cia atkenyl, C2-C10 alkynyl, -C(O)(d-Ci0 alkyl), -(CH2),(C6-C10
aryl), -(CH2)»(4-10 membered heterocyctic), -C(O)(CH2)t(C6-C10 aryl), or -C(O)(CH2)t(4-10
membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally
includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and
heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-Cfl saturated cyclic
group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=O) moiety; and the foregoing R1
groups, except H, are optionally substituted by 1 to 3 R4 groups;
R2 is selected from the list of substituents provided in the definition of R1,
-SO2(CH2)t(C6-C10 aryl), -SO2(CH2)t{4-10 membered heterocyclic), and -OR5, t is an integer
ranging from 0 to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4
groups;
or R1 and R2 may be taken together with the nitrogen to which each is attached to
form a 4-10 membered saturated monocyclic or pblycyclic ring or a 5-10 membered
heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2
heteroatoms selected from O, S and -N(R6)- in addition to the nitrogen to which R1 and R2 are
attached, said -N(R8)- is optionally =N- or -N= where R1 and R2 are taken together as said
heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or
2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6
group of said -N(R6)-, are optionally substituted by 1 to 3 R4 groups;
R3 is H, d-d alkyl, CZ-C10 alkenyl, C2-do alkynyl, -{CH2),(C6-do aryl), or -{CH2)t(4-
10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally
includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and
heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic
group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=O) moiety; the -(CH2)t- moieties of
the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an
integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4
groups;
each R4 is independently selected from halo, CrC10 alkyl, d-do alkenyl, C2-C10
alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5, -NR6C -SO2NR5R6, -NR6C(O)R5,.-C(O)NR5R6, -NR5R6, -S(O)jR7 wherein j is an integer ranging from
0 to 2, -NRS(CR6R7),OR6, -(CH2MC6-C10 aryl), -SO2 -O(CH2)t(C6-do aryl), -(CHz)t(4-10 membered heterocyclic), and -(CR6R7)mOR6, wherein m is
an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or
2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S
atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic
R4 groups are optionally fused to a C6-Ci0 aryl group, a C5-C8 saturated cyclic group, or a 4-
10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties
are optionally substituted by an oxo (=O) moiety; and the alkyl, aryl and heterocyclic moieties
of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently
selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5, -SO2NR5R6,
-NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6 wherein m is an integer from 1 to 5, -OR5
and the substituents listed in the definition of R5;
each R5 is independently selected from H, C-i-Cio alkyl, -(CH2)t(C6-Cio aryl), and
-(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that
two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said
aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a CS-C8 saturated
cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R5 subsituents,
except H, are optionally substituted by 1 to 3 substituents independently selected from nitro,
trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy. CrC0
alkyl, and C,-Ce alkoxy;
each R6 and R7 is independently H or CrCe alkyl; and
Ra is H, CrC10 alkyl, -CfOXd-do alkyl), -C(O)(C6-C10 aryl), ,C(O)(4-10
membered heterocyclic), -(CH2)t(C6-Cio aryl), -(CH2),(4-10 membered heterocyclic), -
C(O)O(d-C10 alkyl); -C(O)O(C6-C10 aryl), -C(O)O(4-10 membered heterocyclic), wherein t is
an integer from 0 to 5; said aryl and heterocyclic R8 groups are optionally fused to a C6-C10
aryl group; and the foregoing aryl and heterocyclic R8 groups are optionally substituted with
2 substituents independently selected from halogen, trifluoromethyl, d-Ce alkoxy, CrC6 alkyl,
and nitro groups with the proviso that R8 is not ethyl when simultaneously R1 is H, R2 is
pyrrolidin-1-yl-butyl and R3 is CrC3 alkyl.
An embodiment of the present invention refers to the compounds of Formula lla
where R2 is H and R1 is CrCi0 alkyl optionally substituted by 1 or 2 substituents
independently selected from.-NR5R6, -NR5(CR6R7)tOR6 and -(CH2)t(4-10 membered
heterocyclic) where t is an integer from 0 to 5. In another embodiment R1 is selected from
propyl, butyl, pentyl and hexyl, and may be optionally substituted with dimethylamino, hydroxy,
pyrrolidinyl, morpholino, and ethyl-(2-hydroxy-ethyl)-amino, and R2 is H.
In another embodiment the present invention refers to the compounds of Formula lla
where R2 is H and R1 is -(CH2)t(4-10 membered heterocyclic) wherein t is an integer from 0 to
5, said heterocyclic group is optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic
group, or a 4-10 membered heterocyclic group and the R1 group, including any fused portions
of said R1 group, may be substituted by 1 or 2 substituents independently selected from C-i-C4
alkyl, hydroxy and hydroxymethyl. In this embodiment, preferably the 4-10 membered
heterocyclic of R1 is selected from one of morpholino, pyrrolidinyl, imidazolyl, piperazinyl,
piperidinyl, and 2,5-diaza-bicycloI2.2.1]hept-2-yl and the R1 group is optionally substituted with
hydroxy, hydroxymethyl and methyl, and the t variable of the R1 group ranges from 2-5.
An embodiment of the present invention refers to the compounds of Formula I la
wherein R3 is -(CH2MC6-C10 aryl) wherein t is an integer from 1 to 3 and the R3 group is
optionally substituted with 1 to 4 R4 groups. In this embodiment, preferably R3 is benzyl
optionally substituted by 1 to 4 halo substituents.
In a preferred embodiment, the present invention refers to compounds of Formula tla
wherein R2 is H, R1 is -(CH2)4-1-pyrrolidine, R3 is 2,6-difluoro-4-bromobenzyl, and Ra is
methyl.
Another embodiment of the present invention refers to the compounds of Formula IVa
or a pharmaceutically acceptable salt thereof; wherein
R3 is H, C^do alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)t{C6-Cio aryl), or -(CH2)t(4-
.10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally
includes 1 or 2 hetero moieties selected from O, S and -N{R6)- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and
heterocyclic R3 groups are optionally fused to a C6-Ci0 aryl group, a C5-CB saturated cyclic
group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=0) moiety; the -(CH2)r moieties of
the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an
integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4.
groups;
each R4 is independently selected from halo, C,-C10 alkyl, C2-C10 alkenyt, C2-C10
alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5, -NR6C{O)OR5, -NR6SO2R5,
-S02NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7 wherein j is an integer ranging from
0 to 2, -NR5(CR6R7)tOR6, -(CH2),(C6-C10 aryl), -SO2(CH2),(C6-C10 aryl), -S(CH2)t(C6-C10 aryl),
-O(CH2)[(Ce-C10 aryi), -(CH2)t(4-10 membered heterocyclic), and -(CR6R7)mOR6, wherein m is
an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or
2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S
atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic
R4 groups are optionally fused to a C6-Cio aryl group, a C5-C8 saturated cyclic group, or a 4-
10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties
are optionally substituted by an oxo (=O) moiety; and the alkyl, aryl and heterocyclic moieties
of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently
selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5. -SO2NR5R6,
-NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6 wherein m is an integer from 1 to 5, -OR5
and the substituents listed in the definition of R5;
each R5 is independently selected from H, C-i-Cio alkyl, -(CH2)i(C6-C10 aryl), and
-(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that
two 0 atoms, two S atoms, or an O and S atom are not attached directly to each other; said
aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-Ca saturated
cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R5 subsituents,
except H, are optionally substituted by 1 to 3 substituents independently selected from nitro,
'trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy, CrC8
alkyl, and CrC6 alkoxy;
each R6 and R7 is independently H or CrC6 alkyl; and
R8 is H. d-C10 alkyl, -C(O)(CrC10 alkyl), -C(O)(C6-C10 aryl), -C(O)(4-10
membered heterocyclic), -(CH2)t(C6-C10 aryl), -(CH2)t(4-10 membered heterocyclic), -
C(O)O(C1-C10 alkyl); -C(O)O(C6-C10 aryl), -C(O)O(4-10 membered heterocyclic), wherein t is
an integer from 0 to 5; said aryl and heterocyclic R8 groups are optionally fused to a C6-C10
aryl group; and the foregoing aryl and heterocyclic R8 groups are optionally substituted with
2 substituents independently selected from halogen, trifluoromethyl, C^Ce alkoxy, CrC6 alkyl,
and nitro groups with the proviso that Ra is not ethyl when R3 is CrC3 alkyl.
In a preferred compound of Formula IVa, R3 is -(CH2)t(C6-C1o aryl), wherein t is an
integer from 1 to 3 and R3 is optionally substituted by 1 to 4 R4 groups, and more preferred R3
is benzyl substituted by 1 to 4 halo substituents.
In a preferred embodiment, the present invention refers to compounds of Formula IVa
wherein R3 is 2,6-difluoro-4-brornobenzyl) and R8 is methyl.
Another embodiment of the present invention refers to the compounds of Formula Va
C02R8
or a pharmaceutically acceptable salt thereof; wherein
-21-
R3 is CrC:o alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)t(C6-C10 aryl), or -(CH2)i(4-10
membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally
includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and
heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-CB saturated cyclic
group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing
heterocyclic moieties are optionally substituted by an oxo (=O) moiety; the -(CH2)t- moieties of
the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an
integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4
groups;
each R4 is independently selected from halo, CVCio alkyl, C2-Cio alkenyl, C2-Cio
alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5, -NR6C(O)OR5, -NR6SO2R5,
-S02NR5R6, -NR6C(0)R5, -C(O)NR5R6, -NRSR6, -S(O)jR7 wherein j is an integer ranging from
0 to 2, -NR5(CR6R7),OR6. -(CH2)t(C6-C10 aryl), -SO2(CH2),(C6-C10 aryl), -S(CH2)l(C6-C10 aryl),
-O(CH2)t(C6-C10 aryl), -(CH2),(4-10 membered heterocyclic), and -(CR6R7)mOR6, wherein m is
an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or
2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S
atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic
R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-
10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties
are optionally substituted by an oxo (=O) moiety; and the alkyl, aryl and heterocyclic moieties
of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently
selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5, -SO2NRSR6,
-NRBC(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6.wherein m is an integer from 1 to 5, -OR5
and the substituents listed in the definition of R5;
each R5 is independently selected from H, Ci-Cio alkyl. -(CH2),(C6-C10 aryl), and
-(CH2}t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that
two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said
aryl and heterocyclic R5 groups are optionally fused to a C6-Cio aryl group, a C5-C8 saturated
cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R5 subsituents,
except H, are optionally substituted by 1 to 3 substituents independently selected from nitro,
trifluoromethyl, trifluoromethoxy, azido, -NR6C(0)R7, -C(O)NR6R7, -NR6R7, hydroxy, C,-C6
alkyl, and CrC6 alkoxy;
each R6 and R7 is independently H or CrC6 alkyl;
R8 is H, CrC10 alkyl, -C{O)(CrC10 alkyl), -C(O)(C6-C10 aryl),
-C(O){4-10 membered heterocyclic), -(CH2)t(C6-C10 aryl), -(CH2)t(4-10 membered
heterocyclic), -C(O)0(CrC10 alkyl); -C{0)O(C6-C10 aryl}, -C(O)O(4-10 membered
heterocyclic), wherein t is an integer from 0 to 5; said aryl and heterocyclic R8 groups are
optionally fused to a C6-C10 aryl group; and the foregoing aryl and heterocyclic R8 groups are
optionally substituted with 1-2 substituents independently selected from halogen,
trifluoromethyl, C-|-C6 alkoxy, CrC6 alkyl, and nitro groups;
R9 is C-pC.,0 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, the aryl and heterocyclic
R9 groups are optionally fused to a C6-Cio aryl group; and the foregoing aryl and heterocyclic
R9 groups are optionally substituted independently with 1-2 substituents independently
selected from halogen, trifluoromethyl, C^Ce alkoxy, Ci-C6 alkyl, and nitro groups; and
n is 1 or 2.
In a preferred compound of Formula Va, R3 is -(CH2)i{C6-C10 aryl), wherein t is an
integer from 1 to 3 and the R3 group is optionally substituted by 1 to 4 R4 groups, and more
preferably R3 is benzyl optionally substituted by 1 to 4 halo substituents, still more preferably
R8 and R9 are methyl.
In a still more preferred embodiment, the present invention refers to compounds of
Formula Va wherein n is 2, R3 is 2,6-diffuoro-4-bromobenzyl, Re is methyl, and R9 is methyl.
In an embodiment, the compound of the Formula I, as defined previously, Is prepared
by reacting the compound of Formula lla with an ammonia source in a solvent.
In another embodiment, the compound of the Formula II, as defined previously, is
prepared by reacting a compound of the Formula IVa with a source of carbonyl with or without
an added base, and then adding a compound of Formula III, as previously defined, in a
solvent or alternatively, reacting a compound of Formula III with a source of carbonyl with or
without an added base, and then adding a compound of Formula IVa in a solvent to give a
compound of the Formula II.
In yet another embodiment; the compound of trie Formula IV, as defined previously,
is prepared by reacting a compound of Formula Va with an ammonia source in a solvent.
In this invention, the term "halo," unless otherwise indicated, includes fluoro, chloro,
bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term "alkyl," as used herein, unless otherwise indicated, includes saturated
monovalent hydrocarbon radicals having straight, cyclic-or branched moieties/ It is
understood that for cyclic moieties at least three carbon atoms are required in said alkyl
group.
The term "alkenyl," as used herein, unless otherwise indicated, includes monovalent
hydrocarbon radicals having at least one carbon-carbon double bond and also having
straight, cyclic or branched moieties as provided above in the definition of "alkyl."
The term "alkynyl," as used herein, unless otherwise indicated, includes monovalenl
hydrocarbon radicals having at least one carbon-carbon triple bond and also having straight,
cyclic or branched moieties as provided above in the definition of "alkyl."
The term "alkoxy," as used herein, unless otherwise indicated, includes O-alkyl
groups wherein "alkyl" is as defined above.
The term "aryl," as used herein, unless otherwise indicated, includes an organic
radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or
naphthyl.
The term "heteroaryl," as used herein, unless otherwise indicated, includes an
organic, radical derived by removal of one hydrogen atom from a carbon atom in the ring of a
heteroaromatic hydrocarbon, containing one or more heteroatoms independently selected
from O, S, and N. Heteroaryl groups must have at least 5 atoms in their ring system and are
optionally substituted independently with 0-2 halogen, trifluoromethyl, C^-Ce alkoxy, C^-Ce
alkyl, or nitro groups.
The term "4-10 membered heterocyclic," as used herein, unless otherwise indicated,
includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms
each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its
ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their
ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An
example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered
heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,
homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1.2,3,6-
tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2'H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-
dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-
azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic
groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyi, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and
furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be Cattached
or N-attached where such is possible. For instance, a group derived from pyrrole
may be pyrrol-1 -yl (N-attached) or pyrrol-3-yl (C-attached).
The term "saturated cyclic group" as used herein, unless otherwise indicated,
includes non-aromatic, fully saturated cyclic moieties wherein alkyl is as defined above.
The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise
indicated, includes salts of acidic or basic groups which may be present in the compounds of
the invention. The compounds of the invention that are basic in nature are capable of forming
a wide variety of salts with various inorganic and organic acids. The acids that may be used
to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the
invention are those that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable an ions, such as the hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,
t
citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the invention that are acidic in nature are capable of forming
base salts with various pharmacologically acceptable cations. Examples of such salts include
the alkali metal or alkaline earth metal salts and particularly the sodium and potassium salts.
The term "solvate," as used herein includes a compound of the invention or a salt
thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound
by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, -and/or
acceptable for topical administration to humans.
The term "hydrate," as used herein refers to a compound of the invention or a salt
thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces.
Certain compounds of the present invention may have asymmetric centers and
therefore appear in different enantiomeric forms. This invention relates to the use of all
optical isomers and stereoisomers' of the compounds of the invention and mixtures thereof.
The compounds of the invention may also appear as tautomers. This invention relates to the
use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled compounds, and the
pharmaceutically acceptable salts thereof, which are identical to those recited in Formulas I,
II, lla, IV, IVa, V and Va but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be incorporated into compounds of
the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and
chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170,35S, 18F, and 36CI, respectively. Compounds
of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope -of this invention. Certain isotopically-labelled
compounds of the present invention, for example those into which radioactive isotopes such
as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of
preparation and detectability. Further, substitution with heavier isotopes such as deuterium,
i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of Formula I of this
invention and prodrugs thereof can generally be prepared by carrying out the procedures
disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a
readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Compounds of Formula I having free amino, amido, hydroxy or carboxylic groups can
be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or
a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently
joined through an amide or ester bond to a free amino. hydroxy or carboxylic acid group of
compounds of Formula I. The amino acid residues include but are not limited to the 20
naturally occurring amino acids commonly designated by three letter symbols and also
includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,
beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and
methionine sulfone.
Additional types of prodrugs are also encompassed. For instance, free carboxyl
groups can be derivatized as amides or alkyl esters. The amide and ester moieties may
incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
Free hydroxy groups may be derivatized using groups including but not limited to
hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B.H. Stewart,
t
Advanced Drug Delivery Reviews (1996) 19,115. Carbamate prodrugs of hydroxy and amino
groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups.
Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the
acyl group may be an alkyl ester, optionally substituted with groups including but not limited to
ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid
ester as described above, are also encompassed. Prodrugs of this type are described in R.P.
Robinson et al., J. Medicinal Chemistry (1996) 39, 10.
Each of the patents, patent applications, published International applications, and
scientific publications referred to in this patent application is incorporated herein by reference
in its entirety.

PETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are useful as agents for binding or modulating
KDR/FLK-1 receptors and are thus useful in the treatment of hyperproliferative diseases, such
as cancers in mammals.
The process of the present invention in its first aspect concerns preparing the
isothiazole derivatives of Formula I. Compounds of the Formula I may be prepared according
to the following reaction scheme and discussion. Unless otherwise indicated, R1, R2, R3, R4,
R5, R6, R7, RB, R9 and R10 in the reaction scheme and discussion that follow are as defined
With reference to Scheme 1 above, the compound of Formula I may be prepared by
treating a malonate diester (XIII) with base and carbon disulfide (reaction a), followed by
treatment with an alkylating agent to provide an (alkyl)sulfanyl-ethenethiol anion (XI) (reaction
b). Amination of the (alkyl)sulfanyl-ethenethiol anion via an electrophilic aminating agent
yields the 5-(alkyl)sulfanyl isothiazole (VIII) (reaction c). Oxidation of the isothiazole (VIII)
with an oxidizing agent in a suitable solvent yields either the 5-(alkyl)sulfonyl isothiazole when
n=2; or 5-(alkyl)sulfinyl isothiazole when n=1 (VII) (reaction d). Alternatively, the isothiazole,
VIII, may be protected with a suitable protecting group (PG) to give a compound of general
Formula X (reaction e), which may then be treated with an oxidizing agent in a suitable
solvent to prepare compounds of general Formula IX (reaction f). Compounds of general
-27-
formula IX may then be deprotected to give compounds of 5-(alkyl)sulfonyl (or sulfinyl)
isothiazole. VII. This mechanism is illustrated in Scheme 2 below.
Referring back to Scheme 1, the 5-(alkyl)sulfonyl/sulfinyl isothiazole VII is treated with
a compound of general formula R3X (VI), typically under basic conditions, to yield an
isothiazole (V) now having alkoxy functionality at position three (3) of the isothiazole (reaction
h). This reaction is particularly and unexpectedly advantageous when compound VI is a
tosylate and the conditions include a base in a dipolar aprotic solvent. The reaction under
these conditions proceeds in unusually high O:N selectivity where alkylation takes place on
the hydroxyl group instead of the nitrogen atom of the isothiazole ring. Under the appropriate
conditions O:N selectivity approximates a ratio of 35:1 O:N selectivity.
Alkylations of a variety of substituted 3-hydroxyisothiazoles have been reported in the
literature. Mixtures of O- and N-alkylated products were observed in all cases, with a wide
variety of electrophiles (alkyl halides, alkyl sulfates, diazomethane), solvents (water, acetone,
DMSO, DMF, MeCN, DME) and bases (NaOH, K2CO3, Li2CO3l Ag2CO3) being used. For
example, a thorough study on the alkylation of 3-hydroxyisothiazole is reported in
Tetrahedron, 1970; (26), 2497-2506:
HO
76% yield. 1.1:1 O:N Acta Chem. Scand ser. B 1976, (30). 781-785
68% O (N isomer not isolated) J. Med. Chem. 1997. 40(4). 520-527
The alkylation step (reaction h) in the process of the present invention proceeds with
very high O:N selectivity, namely, approximately 35:1 for the. conditions described in the
experimental procedure of Example seven (7) discussed below, which is much higher than
the selectivity ratios published in the references cited herein.
Referring again to Scheme 1, the alkoxylated isothiazole (V) is treated with a source
of ammonia in a suitable solvent converting the sulfonyl/sulfinyl moiety at position five (5) of
the isothiazole to a primary amine (IV) (reaction i). A compound of general Formula IV may
be combined with a secondary amine and a carbonyl source, with or without an added base,
in a suitable solvent to give the compound of general Formula II, replacing the primary amine
with ureido functionality at position five (5) on the isothiazole. A second treatment with an
ammonia source converts the alkyl ester to an amide providing the compound of general
(Figure Removed)The starting materials employed in Scheme I are readily commercially available or
readily prepared using methods well known in the art.
In each of the reactions discussed or illustrated in the Schemes, pressure is not
critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5
atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is
preferred as a matter of convenience.
The examples and preparations provided below further illustrate and exemplify the
compounds of the present invention, methods of preparing such compounds, and the
methods of the present invention. It is to be understood that the scope of the present
invention is not limited in any way by the scope of the following examples and preparations.
In the following examples molecules with a single chiral center, unless otherwise noted, exist
as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise
noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may
be obtained by methods known to those skilled in the art.
The present invention is illustrated by the following Examples. It will be understood,
however, that the invention is not limited by the specific details of the following Examples.
A reaction vessel was charged with acetonitrile (240 ml, 6 volumes) followed by 1 ,8-
diazabicyclo-[5.4.0]undec-7-ene (2.1 equivalents, 96. 8g). The mixture was cooled to 5"C
under nitrogen atmosphere. Dimethyl malonate (1.0 equiv, 40.0 g) was added over 10-15
minutes. The mixture was held for 30-45 minutes at 5°C, Carbon disulfide (1.0 equiv, 23.1 g)
was added over 10-15 minutes, and then the mixture was held for 60-70 minutes at 5°C.
Dimethyl sulfate (1.05 equiv, 40.1 g) was added over 10-15 minutes, arid then the mixture
was held at 5°C for 16 hours. The mixture containing 2,2-Bis-methoxycarbonyl-1-
methylsulfanyl-ethenethiol anion was finally warmed to 25°C over 3d minutes, and held at
25°C for 1-2 hours.
A separate reaction vessel was charged with water (280 ml, 7 volumes) and sodium
hydrogencarbonate (1 .5 equiv, 38.2 g). The water/ sodium hydrogencarbonate mixture was
cooled to 5°C under nitrogen atmosphere. Hydroxylamine-O-sulfonic acid (1.2 equiv, 41.1 g)
was added over 5 minutes, and the mixture was stirred 15-30 minutes. The 2,2-Bismethoxycarbonyl-
1-methylsulfanyl-ethenethiol anion/acetonitrile solution from Example 1 was
added over 60-70 minutes. The mixture was warmed to 25°C over 1 hour, then held for 16
hours at 25°C. Most of the acetonitrile was removed by vacuum distillation (1 30 Torr, 50°C).
The residue was cooled to room temperature, acidified to pH -1 by addition of 37%
hydrochloric acid (32 mL). The solids were granulated for 16 hours at 25°C. The slurry was
filtered, and the filter cake was washed 3 x 100 mL with water, once with 200 mL 1:3 ethyl
acetate:hexanes (v/v), and once with 100 mL 1:3 ethyl acetate:hexanes (v/v). The wet cake
(50.5 g) was dried in a vacuum oven for 16 hours to give 3-Hydroxy-5-methylsulfanylisothiazole-
4-carboxylic acid methyl ester, providing 45.4 grams (73% yield). 1H NMR:
(DMSO-dg) 6 11.92 (s, 1H); 3.74 (s, 3H); 2.53 (s, 3H). MS: (API-ES.pos) 206 (M+H)+, base.
EXAMPLE 3
Preparation of 3-Methoxycarbonyloxy-5-methylsulfanyl-isothiazole-4-carboxylic
acid methyl ester
triethylamine \\ _ ^
HC> CO2Me methyl chloroform ate / \ ,CO2Me
MeO
CH3CN
0-25°C
3-Hydroxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester (1.00 equiv,
10.0 g) and dichloromethane (100 mL, 10 volumes) were charged to a flask and held at 25°C
under nitrogen atmosphere. Triethylamine (1.0 equiv, 6.78 mL, 4.88 g) was added. An
orange solution formed, which was cooled to 0°C. Methyl chloroformate (1 .0 equiv, 3.74 mL,
4.56 g) was added over 3 minutes. The mixture stirred at 25°C for 2 hours, then was washed
with water (50 mL, 5 volumes) then brine (50 mL, 5 volumes).. The solvent was displaced with
acetonitrile (100 mL, 10 volumes) to give a tan slurry containing 3-Methoxycarbonyloxy-5-
methylsulfanyl-isothiazole-4-carboxylic acid methyl ester.
EXAMPLE 4
Preparation of 5-Methanesulfonyl-3-methoxvcarbonyloxy-isothiazole-4-
carboxylic acid methyl ester
The 3-Methoxycarbonyloxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl
ester slurry was cooled to 0°C, and urea hydrogen peroxide addition compound (2.8 equiv,
12.8 g) was added. Trifluoroacetic acid anhydride (2.8 equiv, 19.2 mL, 28.4 g) was added
dropwise over 20 .minutes. The mixture stirred at 0°C for 45 minutes, and quenched with
sodium hydrogen sulfite (2.0 equiv, 10.0 g) in water (90 mL, 9 volumes) and stirred at 25°C.
Most of the acetonitrile was removed under vacuum, then the aqueous residue was extracted
once with 100 ml and once again with 50 mL dichloromethane to provide 5-Methanesulfonyl-
3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester.
The 5-Methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl
ester /dichloromethane extracts were combined, then displaced with methanol (150 mL, 15
volumes). A solution of 98% sulfuric acid (50 mL, 5 volumes) in water (100 mL. 10 volumes)
was added and the mixture was heated at 65"C for 6 hours. The foamy slurry became a clear
solution with some insoluble white solids over time. The mixture was cooled to 25"C and
stirred for 16 hours. Most of the methanol was removed under vacuum. The aqueous
residue was extracted once with 100 mL dichloromethane, then twice with 50 mL
dichloromethane. The combined dichloromethane extracts were dried over anhydrous
magnesium sulfate and filtered. The dichloromethane was displaced with hexanes (100 mL,
10 volumes) and stirred at 25°C until solids formed. The solids were filtered, and the filter
cake was rinsed with hexane and dried^ to give 9.27 g of 3-Hydroxy-5-methanesulfonylisothiazole-
4-carboxylic acid methyl ester (80% yield). 1H NMR (DMSO-d6): 5 13.07 (s, 1H);
lamine p
0-25°C
In a flask under nitrogen (4-Bromo-2,6-difluoro-phenyl)-methanol (1.10 equiv, 19.1 g)
was taken up in dichloromethane (185 mL, 10 volumes) and p-toluenesulfonic anhydride (1.1
equiv, 28.9 g) was added. The mixture was cooled to 0°C and triethylamine (1.2 equiv, 13.0
mL, 9.47 g) was added dropwise over 20 minutes. The mixture was warmed to 25°C and
stirred for one hour. The mixture was then washed once with 185 mL 1N hydrochloric acid,
then once with 92.5 ml 1N hydrochloric acid. The organic layer, containing toluene-4-sulfonic
acid 4-bromo-2,6-dif!uoro-benzyl ester, was concentrated to about 55-60 ml.
EXAMPLE 7
Preparation of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-methanesulfonylisothiazole-
4-carboxylic acid methyl ester
HO C02Me
1) DMSO. K2CO3
2) Br
,CO2Me
S02Me
In a separate vessel, 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid
methyl ester (1.00 equiv, 18.5 g) was taken up in dimethyls.ulfoxide (185 mL, 10 volumes) and
potassium carbonate (1.0 equiv, 10.8 g) was added. The toluene-4-sulfonic acid 4-bromo-
2,6-difluoro-benzyl ester/dichloromethane solution from Example 6 was added to the 3-
Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl /potassium
carbonate/dimethylsulfoxide slurry dropwise over 1 hour. The mixture was stirred at 25"C for
16.5 hours. Dichloromethane (185 mL, 10 volumes) then water {185 mL, 10 volumes) were
added and the layers were separated. The organic layer was dried over magnesium sulfate
and filtered. The dichloromethane was removed under vacuum to leave an orange paste.
The orange paste was diluted with 10 volumes of 1:1 EtOAc:Hexanes (v/v) and slurried at
25"C for 16 hours. The mixture was filtered and the filter cake washed with 55-60 mL of 1:1
EtOAc:Hexanes (v/v) and dried to give 24.22 g of 3-(4-Bromo-2,6rdifluoro-benzyloxy)-5-
methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (70% yield). 1H NMR: (DMSO-d6)
6 7.57 (m, 2H); 5.46 (s, 2H); 3.80 (s, 3H); 3.57 205/207 (1,5-difluoro-3-bromotropylium ion), base.
EXAMPLE 8
Preparation of 5-Amino-3-(4-bro'mo-2,6-difluoro-benzyloxy)-isothiazole-4-
carboxylic acid methyl ester
O CO2Me
1)NH3| ,THF,45psi.500C
2) 60:40 CH3CN/H2O (v/v), 70°C
L autoclave 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-methanesulfonyl-isothiazole-
4-carboxylic acid methyl ester (1.00 equiv, 28.0 g) was taken up in tetrahydrofuran (840 ml,
30 volumes). The vessel was evacuated, heated to 50°C, then placed under 45 psi of
anhydrous ammonia gas. The mixture was stirred at 600 rpm for 3 days, then 1000 rpm for
an additional 21 hours. The mixture was cooled to 25°C, purged with nitrogen, then the
tetrahydrofuran was removed on a rotovap. A 60:40 acetonitrile/water (v/v) solution (240ml,
10 volumes with respect to theoretical product mass) was added to the residue. The slurry
was heated to 70°C for 1 hour then stirred at 25°C overnight. The slurry was filtered and the
filter cake rinsed with 60:40 acetonitrile/water (v/v) (40 mL). The solids were dried under
vacuum to give 21.55 g of 5-Amino-3-(4-bromo-2,6-difluoro-benzyloxy)-isothiazole-4-
carboxylic acid methyl ester (90% yield). 1H NMR (DMSO-d6) 5 7.87 (s, 2H); 7.52 (m, 2H);
5.26 (s, 2H); 3.60 (s, 3H). MS: (API-ES pos) 379/381 (M+H)+; 205/207 (1,5-difluoro-3-
bromotropylium ion), base.
In a flask under nitrogen, 4-Pyrro!idi!>1-yl-butylamine (1.3 equiv, 10.1 g) was taken
up in tetrahydrofuran (105 mL, 5 volumes). The mixture was cooled to 0°C and 1,1'-
carbonyldiimidazole (1.3 equiv, 11.6 g) was added. The mixture stirred at 0°C for 20 minutes,
then warmed to 20°C over 10 minutes and held at 20°C for 30 minutes.
Dimethylsulfoxide (105 ml, 5 volumes) was added to the imidazole-1-carboxylic acid
(4-pyrrolidin-1-yl-butyl)-amide /tetrahydrofuran mixture, the tetrahydrofuran was removed by
distillation under vacuum. The mixture was cooled to 20°C then 5-Amino-3-(4-bromo-2,6-
difluoro-benzyloxy)-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 21.0 g) was added,
followed by potassium carbonate (2.0 equiv, 15.2 g). The mixture stirred at20°C for 21.5
hours. Ethyl acetate (210 mL, 10 volumes) then water (210 mL, 10 volumes) were added.
The slurry was stirred at 20°C for 3-4 hours. The solids were filtered and the filter cake was
rinsed with ethyl acetate (63.0 ml, 3 volumes). The solids were dried in a vacuum oven for
17 hours to give 27.36 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-ylbutyl)-
ureido]-isothiazole-4-carboxylic acid methyl ester (90% yield). 1H NMR: (DMSO-d6) 6
10.38 (s, 1H); 8.11 (m, 1H); 7.54 (m, 2H); 5.30 (s, 2H); 3.70 (s, 3H); 3.12 (m, 2H); 2.48 (m,
6H); 1.63 (m, 4H); 1.44 (m, 4H). MS (API-ES pos): 547/549 (M+H)+. base.
In a 1 Liter autoclave 3-{4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-
ureido]-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 27.0 g) was slurried in
methanol (270 mL, 10 volumes) and tetrahydrofuran (270 mL, 10 volumes). The mixture was
cooled to 0°C and stirred at 600 rpm. Anhydrous ammonia gas was charged carefully,
keeping the temperature below 10°C. Once a steady pressure of around 10 psi was
maintained, the mixture was heated to 40°C. The pressure increased to about 45 psi. The
pressure was adjusted to 50 psi and stirred at 600 rpm and 40°C for 90 hours. The stir rate
was then adjusted to 1000 rpm and stirred for an additional 24 hours. The ammonia was
removed by vacuum, and the mixture was cooled to 20°C and transferred out of the reactor.
The mixture was filtered to remove insoluble solids (non-product related). The filtrate was
diluted with 2-propanol (270 mL, 10 volumes), and the tetrahydrofuran and methanol were
distilled atmospherically. Additional 2-propanol (135 m'L, 5 volumes) were added, then the
mixture was distilled to approximately 250mL total volume. The slurry was cooled to 20°C
and stirred 18 hours. The solids were filtered and then dried under vacuum to give 19.9
grams of 3-(4-Bromo-2,6-diflubro-benzyioxy)-5-{3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-
4-carboxylic acid amide (76% yield). 1H NMR (DMSO-d6): 6 10.98 (s, 1H); 8.18 (m, 1H); 7.55
(m, 3H); 6.80 (s, 1H); 5.41 (s, 2H); 3.08 (m, 2H); 2.47 (m, 6H); 1.62 (m, 4H); 1.42 (m, 4H).
MS (API-ES pos) 532/534 (M+Hf. base.







We Claim:
1. A process for the preparation of a compound of Formula I
(Formula Removed)
or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; wherein
R1 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -C(O)(C1-C10 alkyl), -(CH2)t(C6-C10 aryl), -(CH2)t(4-10 membered heterocyclic), -C(OXCH2)t(C6-C10 aryl), or -C(O)(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)-with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly toreach other, said aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (=O) moiety;
and the foregoing R1 groups, except H, are optionally substituted by 1 to 3 R4 groups;
R2 is selected from the list of substituents provided in the definition of R1, -SO2(CH2)t(C6-C10 aryl), -SO2(CH2),(4-10 membered heterocyclic), and -OR5, t is an integer ranging from 0 to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4 groups;
or R1 and R2 may be taken together with the nitrogen to which each is attached to form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2

heteroatoms selected from O, S and -NOR.6)- in addition to the nitrogen to which R1 and R2 are attached, said -NCR6)- is optionally =N- or -N= where R1 and R2 are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6 group of said -N(R6)-, are optionally substituted by: to 3 R4 groups;
R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)t(C6-C10 aryl), or -(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other, said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (=O) moiety; the -(CH2)r moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -ORs, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7 wherein j is an integer ranging from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-10 aryl), -SO2(CH2)t(C6-C10 aryl), -S(CH2)t(C6-C10 aryl), -O(CH2)t(C6-C10 aryl), -(CH2)t(4-10 membered heterocyclic), and -(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and -N(R6)- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10


membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (=0) moiety; and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy,
wherein m is an integer from 1 to 5, -OR5 and the substituents listed in the definition
of R5;
each R5 is independently selected from H, C1-C10 alkyl, -(CH2)t(C6-C10 aryl),
and -(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said
alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and -N(R6)-
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R5 groups are optionally fused to a
C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic
group;
and the foregoing R5 subsituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromefayl, trifluoromethoxy, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy, and each R6 and R7 is independently H or C1-C6 alkyl;
comprising reacting a compound of Formula II
(Formula Removed)
wherein R8 is H, C1-C10 alkyl, -C(O)(C1-C10 alkyl), -C(O)(C6-C10 aryl), -C(O)(4-10 membered heterocyclic), -(CH2)t(C6-10 aryl), -(CH2)t(4-10 membered heterocyclic), -C(O)O(C1-C10 alkyl); -C(O)O(C6-C10 aryl), -C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said aryl and heterocyclic R8 groups

are optionally fused to a C6-C10 aryl group; and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups; and R1, R2, R3, R4, R5, R6 and R7 are as defined above for the compound of Formula I, with an ammonia source in a solvent to give a compound of the Formula I.
2. The process as claimed in claim 1, wherein the compound of Formula I is selected from the group consisting of:
3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-l-yl-butyl)-ureido}-isothiazole-4-carboxylic acid amide;
5- {3-[3-(4-Methyl-piperazin-l-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxyiic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylic acid amide;
3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-l-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-4-[4-(2-hydroxy-ethyl)-piperazm yl]-butyl}-ureido))-isothiazole-4-carboxylic acid amide;
3-{2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isc-thiazole-4-carboxylic acid amide;
3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isoproylamino-pentyl)-ureido3-isothiazole-4-carboxylic acid amide;
hydrochloride salt of 3-{4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-l-yl-butyl)-ureido}-isotbiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-{4-pyrrolidin-l-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-l-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5- {3-[-(l -methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic add amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-butyl}-ureido)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6diflouro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,dihydroxy-pyrrolidin-1-yl]-butyl]-ureido}-isothiazole-4-carboxylic add amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}- isothiazole-4-carboxylic add amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6difluoro-benzyloxy)-5-[3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic add amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5- {3-[4-(3-hydroxy-pyrrlidin-l -yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-{4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido)-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5- {3-[4-{3-hydroxy-5-piperidin-l -yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5- {3-[4-(2-hydroxythethyl-piperidin-1 -yl)-butyl]-ureido}-isotbiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylic acid amide;
3-(4-(Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-l-yl)-hexyl)-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-l-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-l-yl-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pynolidin-l-yl-
pentyl)-ureido]-isothiazole-4-carboxylic acid amide; 5-[3-(4-Pyrrolidin-l-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-
isothiazole-4-carboxylic acid amide;
5-[3-(3-Hydroxy-5-pyrrolidin-l-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-
diazabicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[2-(l-methyl-pyrrolidm-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3s6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isotbiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-l-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,3,6-trifluro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Hydroxy-5-isopropropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Isopropylamino-propyl)-ureido]-3-(2,336-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-{3-[4-(4-Methyl-piperazin4-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-(3-{4-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Pyrrolidin-l-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isotbiazole-4-carboxylic acid amide;
5-[3-(4-Hydroxy-5-piperidin-l-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-l-yl-butyl)-ureido]-isotbiazole-4-carboxylic acid amide;
5-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isotbiazole-4-carboxylic acid amide;
3-(4-Chloro-(2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxmethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido3-isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,6-difluoro-benzyloxy)-5- {3-[3-(4-methyl-piperazin-l -yl)-propyl]-ureido}-isothiazole-4-carboxylic acid amide;

3-(2,6-Difluoro-4-methyl--benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolindin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-l-yl-butyl)-ureido]-isotbiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-difluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-
amino]-propyl}-tireido)-isotbiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[ethyl-(hydroxy-ethyl)-
amino]-propyl}-ureido)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Methylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Amino-propyl)-3-methyl-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(4-Diethylamino-butyl)-ureido]-3-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy-5-[3-(3-pyrrolidin-l-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;

and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of said compounds.

Documents:

1088-DELNP-2007-Abstract-(07-06-2011).pdf

1088-delnp-2007-abstract.pdf

1088-DELNP-2007-Asignment-(21-05-2009).pdf

1088-DELNP-2007-Claims-(07-06-2011).pdf

1088-delnp-2007-claims.pdf

1088-DELNP-2007-Correspondence Others-(07-06-2011).pdf

1088-DELNP-2007-Correspondence Others-(10-06-2011).pdf

1088-DELNP-2007-Correspondence-Others (23-11-2009).pdf

1088-DELNP-2007-Correspondence-Others-(21-05-2009).pdf

1088-DELNP-2007-Correspondence-Others-1.pdf

1088-DELNP-2007-Correspondence-Others.pdf

1088-DELNP-2007-Description (Complete)-(07-06-2011).pdf

1088-delnp-2007-description (complete).pdf

1088-DELNP-2007-Form-1-(07-06-2011).pdf

1088-DELNP-2007-Form-1.pdf

1088-delnp-2007-form-18.pdf

1088-delnp-2007-form-2.pdf

1088-DELNP-2007-Form-3-(07-06-2011).pdf

1088-delnp-2007-form-3.pdf

1088-DELNP-2007-Form-5-(07-06-2011).pdf

1088-delnp-2007-form-5.pdf

1088-DELNP-2007-GPA (23-11-2009).pdf

1088-DELNP-2007-GPA-(07-06-2011).pdf

1088-DELNP-2007-GPA-(21-05-2009).pdf

1088-delnp-2007-GPA.pdf

1088-delnp-2007-pct-210.pdf

1088-DELNP-2007-Petition-137-(07-06-2011).pdf

1088-DELNP-2007Claims-(10-06-2011).pdf

abstract.jpg


Patent Number 250834
Indian Patent Application Number 1088/DELNP/2007
PG Journal Number 05/2012
Publication Date 03-Feb-2012
Grant Date 31-Jan-2012
Date of Filing 09-Feb-2007
Name of Patentee PFIZER INC.,
Applicant Address 235 EAST 42nd STREET, NEW YORK NEW YORK, 10017-5755 USA
Inventors:
# Inventor's Name Inventor's Address
1 DAVID B. DAMON 247 CAPSTAN AVENUE, MYSTIC, CONNECTICUT 06355, USA.
2 BRAIN P. JONES 152 ALTON BRADFORD RD., BRADFORD, RHODE ISLAND 02808, USA.
PCT International Classification Number A61K 31/425
PCT International Application Number PCT/US2005/027398
PCT International Filing date 2005-08-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/604,542 2004-08-26 U.S.A.