U.S. patent application number 14/227212 was filed with the patent office on 2014-07-17 for protease inhibitors.
This patent application is currently assigned to ORION CORPORATION. The applicant listed for this patent is Orion Corporation. Invention is credited to Chakshusmathi GHADIYARAM, Rajeev GOSWAMI, Muralidhara RAMACHANDRA, Ramesh SISTLA, Ramesh VELUDANDI, Anil Kumar VUPPALA.
Application Number | 20140200225 14/227212 |
Document ID | / |
Family ID | 42357464 |
Filed Date | 2014-07-17 |
United States Patent
Application |
20140200225 |
Kind Code |
A1 |
GOSWAMI; Rajeev ; et
al. |
July 17, 2014 |
PROTEASE INHIBITORS
Abstract
A compound of formula (I) wherein R.sub.1 to R.sub.15, P.sub.1,
P.sub.2, A, B and Q are as defined in the claims and
pharmaceutically acceptable salts and esters thereof, are
disclosed. The compounds of formula (I) possess utility as
matriptase inhibitors and are useful in the treatment of matriptase
dependent conditions, particularly cancer.
Inventors: |
GOSWAMI; Rajeev; (Dehradun,
IN) ; VUPPALA; Anil Kumar; (Warangal, IN) ;
VELUDANDI; Ramesh; (Warangal, IN) ; SISTLA;
Ramesh; (Bangalore, IN) ; GHADIYARAM;
Chakshusmathi; (Bangalore, IN) ; RAMACHANDRA;
Muralidhara; (Bangalore, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orion Corporation |
Espoo |
|
FI |
|
|
Assignee: |
ORION CORPORATION
Espoo
FI
|
Family ID: |
42357464 |
Appl. No.: |
14/227212 |
Filed: |
March 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13321078 |
Jan 31, 2012 |
8722930 |
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PCT/FI2010/000031 |
May 18, 2010 |
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14227212 |
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Current U.S.
Class: |
514/253.11 ;
514/318; 514/330; 514/349; 514/350; 514/352; 514/603; 514/637;
544/365; 546/194; 546/231; 546/297; 546/298; 546/312; 562/67;
564/86 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 401/06 20130101; C07C 259/18 20130101; C07C 235/62 20130101;
A61P 35/04 20180101; C07D 217/06 20130101; C07D 213/82 20130101;
C07D 213/73 20130101; C07C 311/47 20130101; C07C 311/21 20130101;
C07D 211/58 20130101; C07D 295/104 20130101; C07C 309/51 20130101;
C07D 213/68 20130101; C07C 257/18 20130101; C07D 211/26 20130101;
C07D 213/61 20130101; C07D 213/75 20130101; C07D 213/76 20130101;
A61P 35/00 20180101; C07D 213/78 20130101; C07D 215/08
20130101 |
Class at
Publication: |
514/253.11 ;
514/318; 514/330; 514/349; 514/350; 514/352; 514/603; 514/637;
544/365; 546/194; 546/231; 546/297; 546/298; 546/312; 562/67;
564/86 |
International
Class: |
C07C 311/47 20060101
C07C311/47; C07C 309/51 20060101 C07C309/51; C07D 213/68 20060101
C07D213/68; C07D 213/76 20060101 C07D213/76; C07D 295/104 20060101
C07D295/104; C07D 213/82 20060101 C07D213/82 |
Foreign Application Data
Date |
Code |
Application Number |
May 18, 2009 |
IN |
758/KOL/2009 |
Claims
1. A compound of formula (I) ##STR00021## wherein P.sub.1 is a
bond, and P.sub.2 is --CH.sub.2; A is CH; B is CH or N; R.sub.1 is
--NH--SO.sub.2-- ZR.sub.9R.sub.13,
--NR.sub.4--CO--ZR.sub.9R.sub.13, --CO--NR.sub.7R.sub.8,
--CO--O--ZR.sub.9R.sub.13,
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13, or a group of formula
(II) ##STR00022## wherein the ring portion in formula (II) is a
5-12 membered saturated, partially saturated, or aromatic ring,
wherein said ring is monocyclic or bicyclic, and which contains 0,
1, 2, or 3 heteroatoms selected from N, O, S, or combinations
thereof; R.sub.3 is --C(NR.sub.17)NH.sub.2 or amino C.sub.1-7
alkyl; R.sub.10, R.sub.14, and R.sub.15 are independently hydrogen,
halogen, hydroxy, C.sub.1-7 alkyl, halogen C.sub.1-7 alkyl, or
--C(NR.sub.17)NH.sub.2; Q is hydrogen or halogen; R.sub.4 is
hydrogen or C.sub.1-7 alkyl; Z is a 5-12 membered saturated,
partially saturated, or aromatic ring, wherein said ring is
monocyclic or bicyclic, and which contains 0, 1, 2, or 3
heteroatoms selected from N, O, S, or combinations thereof; R.sub.9
and R.sub.13 are independently hydrogen, halogen, hydroxy, carboxy,
C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, hydroxy C.sub.1-7 alkyl,
C.sub.1-7 alkoxycarbonyl, R.sup.ANH.sub.2, or --COR.sup.BNH.sub.2;
R.sup.A, R.sup.B, and R.sup.X are independently a bond or C.sub.1-7
alkyl; R.sub.7 and R.sub.8 are independently hydrogen, amino
C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, or C.sub.1-7 alkyl, with
a proviso that R.sub.7 and R.sub.8 are not simultaneously hydrogen;
R.sub.2 is C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, carboxy
C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl C.sub.1-7 alkyl,
C.sub.1-7 alkylamino, carboxy C.sub.1-7 alkylamino,
R.sup.DC(NR.sub.17)NH.sub.2, or a group of formula (III)
##STR00023## y=0-2; R.sup.D is a bond or C.sub.1-7 alkyl; G is CH
or N; R.sub.11 is hydrogen, halogen, amino, carboxy, amino
C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl, halogen C.sub.1-7
alkoxy, --C(NR.sub.17)NH.sub.2, --NHCOR.sup.GNH.sub.2,
R.sup.JHCOOR.sup.U, or --CONR.sub.19R.sub.20, R.sup.G is C.sub.1-7
alkyl; R.sup.J is a bond or C.sub.1-7 alkyl; R.sup.U is hydrogen or
C.sub.1-7 alkyl; R.sub.12 and R.sub.16 are independently hydrogen,
halogen or C.sub.1-7 alkyl; or R.sub.12 and R.sub.16 form, together
with the carbon atoms to which they are attached, a 5 or 6 membered
saturated, partially saturated, or aromatic ring, which contains 0,
1, 2, or 3 heteroatoms selected from N, O, S, or combinations
thereof, wherein said ring is substituted or unsubstituted;
R.sub.17 is hydrogen, --OH, C.sub.1-7 alkoxy, --O(CO)OR.sub.18, or
--(CO)OR.sub.18; R.sub.18 is C.sub.1-7 alkyl; R.sub.19 and R.sub.20
are independently hydrogen, C.sub.1-7 alkyl, or C.sub.1-7 alkoxy;
or a pharmaceutically acceptable salt or ester thereof.
2. The compound according to claim 1, wherein B is CH.
3. The compound according to claim 1, wherein R.sub.3 is
--C(NR.sub.17)NH.sub.2 and R.sub.10, R.sub.14, and R.sub.15 are
hydrogen.
4. The compound according to claim 1, wherein R.sub.2 is a group of
formula (III), wherein G is CH, y is 0-1, R.sub.11 is
--C(NR.sub.17)NH.sub.2 or amino C.sub.1-7 alkyl, and R.sub.12 and
R.sub.16 are hydrogen.
5. (canceled)
6. (canceled)
7. The compound according to claim 1, wherein R.sub.1 is a group of
formula (II).
8. The compound according to claim 7, wherein the ring portion of
formula (II) is a 6 or 10 membered saturated, partially saturated,
or aromatic ring.
9. The compound according to claim 8, wherein the ring portion of
formula (II) is piperidinyl, piperazinyl, nonahydro-quinolinyl, or
3,4-dihydro-1H-quinolinyl.
10. The compound according to claim 1, wherein R.sub.1 is
--NR.sub.4--CO--ZR.sub.9R.sub.13, --CO--O--ZR.sub.9R.sub.13, or
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13.
11. The compound according to claim 10, wherein Z is a 6 or 10
membered saturated, partially saturated, or aromatic ring.
12. The compound according to claim 11, wherein Z is cyclohexyl,
piperidinyl, phenyl, naphthyl, or quinolinyl.
13. The compound according to claim 12, wherein Z is cyclohexyl or
piperidinyl, R.sub.4 is hydrogen, R.sup.X is a bond, R.sub.9 is
R.sup.ANH.sub.2, and R.sub.13 is hydrogen.
14. A pharmaceutical composition comprising a compound of claim 1
together with a pharmaceutically acceptable carrier.
15. A method for the treatment of a matriptase dependent condition,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1.
16. A method for the treatment of cancer, comprising administering
to a subject in need thereof a therapeutically effective amount of
a compound of claim 1.
Description
TECHNICAL FIELD
[0001] The present invention relates to therapeutically active
compounds and pharmaceutically acceptable salts and esters thereof
useful in the treatment of conditions involving matriptase
activity, particularly cancer.
BACKGROUND OF THE INVENTION
[0002] Cancer drug discovery has traditionally focused on targeting
DNA synthesis and cell division, resulting in drugs such as
antimetabolites and DNA alkylating agents. Although these drugs
show efficacy, their lack of selectivity for tumor cells over
normal cells can lead to severe side effects. The recent
recognition that certain genes are associated with cancer has
resulted in several rational and targeted drugs for cancer therapy.
However, many of the available targeted cancer treatments inhibit
only a specific aspect of cancer progression such as proliferation,
angiogenesis or metastasis. This limits their utility and
necessitates their use in combination with traditional
chemotherapeutic agents. Examples of such targeted cancer drugs
include erlotinib (Tarceva.RTM.) and bevacizumab (Avastin.RTM.).
Erlotinib inhibits cell proliferation, while bevacizumab is an
anti-angiogenesis drug. These drugs target kinases or proteins
involved in kinase signaling pathways. Recent findings indicate
that matriptase, a transmembrane serine protease, plays a role in
triggering the formation of tumor cells. Unlike kinases, the
localization of matriptase on the cell surface makes it more
accessible to a potential inhibitor. Matriptase is over-expressed
(up to several hundredfold) in all phases of cancer in multiple
cancer types and has also been shown to play a role in invasion and
metastasis. Therefore, a matriptase inhibitor could comprise a
potential first-in-class drug with a broad spectrum of anti-tumor
activity including anti-proliferative and anti-invasive
activities.
[0003] Matriptase is a multi-domain 80-kDa type II transmembrane
serine protease and belongs to the Si trypsin-like family.
Matriptase is involved in matrix remodeling/degradation, regulation
of cell growth and survival, cell motility, cell morphogenesis, and
activation of other membrane bound proteins. It is also called the
membrane-type serine protease-1 (MT-SP1), the tumor-associated
differentially expressed gene-15 (TAGD-15), or epithin in mouse.
Matriptase is overexpressed in a vast array of human tumors of
epithelial origin including prostate, ovarian, uterine, colon,
epithelial-type mesothelioma, cervical and head and neck squamous
cell carcinoma. Epidemiological studies have revealed that
increased expression of matriptase relative to HAI-1 correlates
with the grade of the tumor and results in poor prognosis in breast
and ovarian cancer.
[0004] The role of matriptase has been well established in pathways
involved in cancer even though the exact function of human
matriptase has not been elucidated. Matriptase enhances tumor cell
proliferation through phosphatidylinositol 3-Kinase signaling and
invasion through the HGF/cMet and uPAR activation. Glycosylation of
matriptase by UDP-GlcNAc alpha-mannoside
beta1-6-N-acetylglucosaminyltransferase (GnT-V) plays a key role in
metastasis by increasing the stability of degradation-resistant
active form of the enzyme. Furthermore, matriptase activates other
proteases such as receptor-bound urokinase-type plasminogen
activator (uPA). Overexpression of uPA or its receptor (uPAR) is a
feature of malignancy and plays a critical role in angiogenesis,
tumor invasion and metastasis. Down-regulation of matriptase
inhibits tumor invasion through suppression of uPAR activation.
[0005] Several other "trypsin like serine proteases" such as uPA,
trypsin, plasmin, hepsin and kallikrein play a critical role in
cancer affecting various pathways leading to angiogenesis, invasion
and metastasis. Urokinase-type plasminogen activator (uPA) plays a
major role in extracellular proteolytic events associated with
tumor cell growth, migration and angiogenesis. Many cancer cells
secrete pro-uPA and its receptor uPAR. Binding of pro-uPA to uPAR
leads to its activation, with subsequent generation of plasmin by
the uPA-catalyzed hydrolysis of extracellular plasminogen. The
increased production of plasmin leads to degradation of
extracellular matrix both by plasmin itself and by other proteases
that are activated by plasmin. The surface location of bound uPA
provides directionality to the degradation of matrix, thereby
assisting the directional migration of cancer cells. uPA in complex
with uPAR also affects other biological processes including
signaling pathways that influence cell proliferation. Hepsin is
another type II transmembrane serine protease (TTSP) expressed on
the surface of epithelial cells. It has been implicated in ovarian
cancer and prostate cancer, where several gene expression studies
have identified it as one of the most highly induced genes. Hepsin
over-expression was associated with basement membrane disruption
and was shown to be connected the HGF/c-Met pathway and uPA pathway
connecting hepsin to the pathways leading to basement membrane
disruption and tumor progression.
[0006] Therefore, inhibitors of matriptase and other related serine
proteases could be of significant therapeutic value because of the
following reasons: [0007] potential to be used as a `mono-therapy`
due to wide expression and activity of matriptase and other
proteases in both early and late stages of cancer [0008] superior
safety profile due to localization of matriptase, uPA and hepsin at
the cell membrane which avoids the need of cellular entry of the
drug [0009] superior efficacy profile due to tumor-specific
expression [0010] potential for reducing morbidity due to a larger
therapeutic window that results from fewer therapy-related side
effects typically associated with cytotoxic agents
[0011] Matriptase inhibitors have been described earlier e.g. in
Enyedy, I. et al., J. Med. Chem., 2001, 44, 1349-1355; and in
international patent publications WO 01/97794, WO 2004/058688, WO
2004/101507, WO 2008/085608, WO 2008/107176, WO 2008/097673, WO
2008097676 and WO 2008/107176. Other benzamidine compounds have
been described earlier e.g. in Phillips, G. et al., J. Med. Chem.,
1999, 42, 1749-1756; Phillips, G. et al., J. Med. Chem., 1998, 41,
3557-3562; and EP 0 813 525.
SUMMARY OF THE INVENTION
[0012] It has been found that compounds of formula (I) are serine
protease inhibitors. In particular, it has been found that the
compounds of formula (I) are potent and selective matriptase
inhibitors. The compounds of the invention are able to inhibit
invasion and metastasis of various tumor cells and inhibit tumor
growth. Compounds of the invention provide also good safety, and
are therefore particularly useful in the treatment of cancer.
[0013] The compounds of the present invention have a structure
represented by formula (I)
##STR00001##
[0014] wherein
[0015] P.sub.1 and P.sub.2 are, independently a bond or C.sub.1-3
alkyl;
[0016] A is CH or N;
[0017] B is CH or N;
[0018] R.sub.1 is hydrogen, amino, --NH--SO.sub.2--
ZR.sub.9R.sub.13, --NR.sub.4--CO--ZR.sub.9R.sub.13,
--CO--NR.sub.7R.sub.8, --CO--O--ZR.sub.9R.sub.13,
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13 or a group of formula
##STR00002##
[0019] wherein the ring portion in formula (II) is a 5-12 membered
saturated, partially saturated or aromatic ring which may be
monocyclic or bicyclic, and which may contain 1-3 further
heteroatoms selected from N, O, S or combinations thereof;
[0020] R.sub.3 is --C(NR.sub.17)NH.sub.2, or in case A is CH,
R.sub.3 can also be amino C.sub.1-7 alkyl;
[0021] R.sub.10, R.sub.14 and R.sub.15 are independently hydrogen,
halogen, hydroxy, C.sub.1-7 alkyl, halogen C.sub.1-7 alkyl or
--C(NR.sub.17)NH.sub.2;
[0022] Q is hydrogen or halogen, with a proviso that R.sub.1 and Q
are not simultaneously hydrogen;
[0023] R.sub.4 is hydrogen or C.sub.1-7 alkyl;
[0024] Z is a 5-12 membered saturated, partially saturated or
aromatic ring which may be monocyclic or bicyclic, and which may
contain 1-3 heteroatoms selected from N, O, S or combinations
thereof;
[0025] R.sub.9 and R.sub.13 are, independently, hydrogen, halogen,
hydroxy, carboxy, C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, hydroxy
C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl, R.sup.ANH.sub.2 or
--COR.sup.BNH.sub.2;
[0026] R.sup.A, R.sup.B and R.sup.X are, independently, a bond or
C.sub.1-7 alkyl;
[0027] R.sub.7 and R.sub.8 are, independently, hydrogen, amino
C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, or in case A is CH,
R.sub.7 and R.sub.8, independently, can also be C.sub.1-7
alkyl,
[0028] with a proviso that R.sub.7 and R.sub.8 are not
simultaneously hydrogen;
[0029] R.sub.2 is C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, carboxy
C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl C.sub.1-7 alkyl,
C.sub.1-7 alkylamino, carboxy C.sub.1-7 alkylamino,
R.sup.DC(NR.sub.17)NH.sub.2, or a group of formula (III)
##STR00003##
[0030] y=0-2; R.sup.D is a bond or C.sub.1-7 alkyl; G is CH or N;
R.sub.11 is hydrogen, halogen, amino, carboxy, amino C.sub.1-7
alkyl, C.sub.1-7 alkoxycarbonyl, halogen C.sub.1-7 alkoxy,
--C(NR.sub.17)NH.sub.2, --NHCOR.sup.GNH.sub.2, R.sup.JNHCOOR.sup.U
or --CONR.sub.19R.sub.20;
[0031] R.sup.G is C.sub.1-7 alkyl; R.sup.J is a bond or C.sub.1-7
alkyl; R.sup.U is hydrogen or C.sub.1-7 alkyl;
[0032] R.sub.12 and R.sub.16 are, independently, hydrogen, halogen
or C.sub.1-7 alkyl; or R.sub.12 and R.sub.16 form, together with
the carbon atoms to which they are attached, a 5 or 6 membered
saturated, partially saturated or aromatic ring which may contain
1-3 heteroatoms selected from N, O, S or combinations thereof,
which ring can be substituted;
[0033] R.sub.17 is hydrogen, --OH, C.sub.1-7 alkoxy,
--O(CO)OR.sub.18 or --(CO)OR.sub.18;
[0034] R.sub.18 is C.sub.1-7 alkyl;
[0035] R.sub.19 and R.sub.20 are, independently, hydrogen,
C.sub.1-7 alkyl or C.sub.1-7 alkoxy;
[0036] or a pharmaceutically acceptable salt or ester thereof.
[0037] In one class of preferred compounds are compounds of formula
(I), wherein A is CH and B is CH. A subclass of these preferred
compounds are compounds wherein R.sub.3 is --C(NR.sub.17)NH.sub.2
and R.sub.10, R.sub.14 and R.sub.15 are hydrogen. In one class of
preferred compounds are compounds wherein R.sub.2 is a group of
formula (III) wherein G is CH, y is 0-1, R.sub.11 is
--C(NR.sub.17)NH.sub.2 or amino C.sub.1-7 alkyl, R.sub.12 and
R.sub.16 are hydrogen. In still another class of preferred
compounds are compounds of formula (I), wherein P.sub.1 and P.sub.2
is a bond. In still another class of preferred compounds are
compounds of formula (I), wherein P.sub.1 is a bond and P.sub.2 is
--CH.sub.2--.
[0038] In one class of preferred compounds are compounds of formula
(I), wherein R.sub.1 is a group of formula (II). In another class
of preferred compounds are compounds of formula (I), wherein the
ring portion of formula (II) is a 6 or 10 membered saturated,
partially saturated or aromatic ring, which may be monocyclic or
bicyclic, and which may contain one further heteroatom N. Examples
of particularly preferred compounds are those, wherein the ring
portion of formula (II) is piperidinyl, piperazinyl,
nonahydro-quinolinyl or 3,4-dihydro-1H-quinolinyl. In another class
of preferred compounds are compounds of formula (I), wherein
R.sub.1 is --NR.sub.4--CO--ZR.sub.9R.sub.13,
--CO--O--ZR.sub.9R.sub.13, or
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13. Z is suitably a 6 or 10
membered saturated, partially saturated or aromatic ring, which may
be monocyclic or bicyclic, and which may contain 1 or 2 N atoms.
Examples of particularly preferred compounds are those, wherein Z
is cyclohexyl, piperidinyl, phenyl, naphthyl or quinolinyl. In a
subclass of preferred compounds are compounds, wherein Z is
cyclohexyl or piperidinyl, R.sub.4 is hydrogen, Rx is a bond,
R.sub.9 is R.sup.ANH.sub.2 and R.sub.13 is hydrogen.
[0039] In another class of preferred compounds are compounds of
formula (I), wherein A is N and B is CH.
[0040] The present invention also provides a pharmaceutical
composition comprising a compound of formula (I) together with a
pharmaceutically acceptable carrier.
[0041] The present invention provides further a method for the
treatment of a matriptase dependent condition, comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of formula (I).
[0042] The present invention provides a compound of formula (I) for
use in the treatment of a matriptase dependent condition.
[0043] The present invention provides further a method for the
treatment of cancer, comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of formula
(I).
[0044] The present invention provides a compound of formula (I) for
use in the treatment of cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The compounds of the invention can be prepared according to
the following Schemes. It should be noted that any appropriate
leaving groups, e.g. N-protecting groups, such as t-butoxycarbonyl
(t-BOC) group, can be used in well known manner during the
syntheses in order to improve the selectivity of the reaction
steps.
[0046] Compounds of formula (I), wherein R.sub.1 is
--NH--SO.sub.2-- ZR.sub.9R.sub.13, R.sub.3 is
--C(NR.sub.17)NH.sub.2, R.sub.2 is a group of formula (III) and
R.sub.11 is --C(NR.sub.17)NH.sub.2 can be prepared according to the
Scheme 1 or Scheme 2 by sulfonylating the amino group of the
compound of formula (IV) with suitable sulfonylchloride
Cl--SO.sub.2--ZR.sub.9R.sub.13 using a base such as sodium hydride,
TEA, DIPEA or combinations thereof along with solvents such DMF,
THF and the like at temperatures ranging from about 0.degree. C. to
80.degree. C. The reaction affords the sulfonamide of formula
(V).
##STR00004##
##STR00005##
[0047] Compound of formula (V) is converted to the corresponding
imidate (VI') or hydroxyamidine (VI) derivative as explained
below.
[0048] Using the method of Scheme 1, the nitrile group of the
compound (V) is reacted with hydroxylamine hydrochloride with a
suitable base such as TEA or DIPEA in solvent such as DMF, THF and
the like at temperatures ranging from about 20.degree. C. to
100.degree. C. to afford the hydroxyamidine compound (VI). This
compound is either first acetylated using acetic anhydride in
solvents such as acetic acid at RT and then reduced using a
reducing agent such as Zn, Pd/C and the like in solvents such as
methanol, ethanol or acetic acid at temperatures ranging from about
20.degree. C. to 50.degree. C. to afford the corresponding amidine
compound (VIII). Alternatively the hydroxyamidine (VI) is directly
reduced with a reducing agent such as Pd/C in solvents such as
methanol or acetic acid at a temperature ranging from about
40.degree. C. to 70.degree. C. to afford the corresponding amidine
compound (VIII).
[0049] Subsequent to the above step, deprotection of the product
from any protecting groups such as t-BOC, where applicable, is
carried out with appropriate reagents such as HCl-TFA or the like
to afford the required final compounds.
[0050] Using the method of Scheme 2, the nitrile group of the
compound of formula (V) is allowed to react with alcoholic HCl for
approximately 15 to 48 h at a temperature ranging from about
0.degree. C. to about RT to afford the corresponding imidate ester
(VI'). This compound is then subjected to reaction with alcoholic
ammonia to get the corresponding amidine compound (VIII).
[0051] Compounds of formula (I), wherein R.sub.1 is
CO--NR.sub.7R.sub.8, and R.sub.2 is a group of formula (III) and
R.sub.11 is --C(NR.sub.17)NH.sub.2, can be prepared according to
the Scheme 3 by coupling the carboxylic group of compound (IX) with
amine HNR.sub.7R.sub.8. The reaction is carried out in the presence
of suitable coupling reagents, such as PyBOP, EDC.HCl or HOBt and
the like, and a base such as DIPEA, TEA and the like in a solvent
of such as THF, DMF and the like under inert atmosphere at a
temperature ranging from about 0.degree. C. to 40.degree. C. The
reaction affords the desired amide compound of formula (X).
Starting from compound (X) and following the last steps of Scheme 1
or 2 affords the final product.
##STR00006##
[0052] Compounds of formula (I), wherein R.sub.1 is
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13, R.sub.2 is a group of
formula (III) and R.sub.11 is --C(NR.sub.17)NH.sub.2, can be
prepared according to the Scheme 4 such as to obtain first a
compound of formula (XI) and following then the last steps of
Scheme 1 or 2 to obtain the final product.
##STR00007##
[0053] Compounds of formula (I), wherein R.sub.1 is
CO--O--ZR.sub.9R.sub.13, and R.sub.2 is a group of formula (III)
and R.sub.11 is --C(NR.sub.17)NH.sub.2, can be prepared according
to the Scheme 5 such as to obtain first a compound of formula
(XXXII) and following then the last steps of Scheme 1 or 2 to
obtain the final product.
##STR00008##
[0054] Compounds of formula (I), wherein R.sub.1 is
NH--CO--ZR.sub.9R.sub.13, and R.sub.2 is a group of formula (III)
and R.sub.11 is --C(NR.sub.17)NH.sub.2, can be prepared according
to the Scheme 6 such as to obtain first a compound of formula
(XXXI) and following then the last steps of Scheme 1 or 2 to obtain
the final product.
##STR00009##
[0055] Compounds of formula (I), wherein R.sub.1 is a group of
formula (II), and R.sub.2 is a group of formula (III) and R.sub.11
is --C(NR.sub.17)NH.sub.2, can be prepared according to the Scheme
7 such as to obtain first a compound of formula (XII) and following
then the last steps of Scheme 1 or 2 to obtain the final
product.
##STR00010##
[0056] Compounds of formula (I), wherein R.sub.1 is a group of
formula (II), R.sub.2 is a group of formula (III), and R.sub.9 or
R.sub.13 is --COR.sup.BNH.sub.2 group linked to a nitrogen atom of
the ring portion of formula (II), can be prepared according to the
Scheme 8 such as to obtain first a compound of formula (XV) by a
acid coupling reaction and following then the last steps of Scheme
1 or 2 to obtain the final product. L is an acid labile protection
group such as a t-BOC group.
##STR00011##
[0057] Similarly, compounds of formula (I), wherein R.sub.1 is
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13, R.sub.2 is a group of
formula (III), and R.sub.9 or R.sub.13 is --COR.sup.BNH.sub.2 group
linked to a nitrogen atom of the ring portion Z, may also be
prepared by reacting compound of formula (IX) with a compound of
formula HNR.sub.4--R.sup.X--Z-L, wherein L is an acid labile
protection group, such as a t-BOC group, attached to the nitrogen
atom of the ring portion Z. After deprotection, the amino moiety of
the Z ring is coupled with HOOCR.sup.BNH.sub.2 by acid coupling
reaction to obtain first a compound of formula (XVI)
##STR00012##
and following then the last steps of Scheme 1 or 2 to obtain the
final product.
[0058] Compounds of formula (I), wherein R.sub.1 is a group of
formula (II), R.sub.2 is a group of formula (III), and R.sub.9 or
R.sub.13 is carboxy C.sub.1-7 alkyl or R.sup.ANH.sub.2 group linked
to a nitrogen atom of the ring portion of formula (II), may be
prepared according to the Scheme 9 such as to obtain first a
compound of formula (XVII) by an alkylhalide reaction and following
then the last steps of Scheme 1 or 2 to obtain the final
product.
##STR00013##
[0059] Similarly, compounds of formula (I), wherein R.sub.1 is
--CO--NR.sub.4--R.sup.X--ZR.sub.9R.sub.13, R.sub.2 is a group of
formula (III), and R.sub.9 or R.sub.13 is carboxy C.sub.1-7 alkyl
or R.sup.ANH.sub.2 group linked to a nitrogen atom of the ring
portion Z, can be prepared by coupling the amino moiety of the Z
ring with a suitable alkylhalide, e.g. XR.sup.ANH.sub.2, wherein X
is halogen, to obtain a compound of formula (XVIII)
##STR00014##
and following then the last steps of Scheme 1 or 2 to obtain the
final product.
[0060] Compounds of formula (I), wherein R.sub.2 is C.sub.1-7
alkyl, amino C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, C.sub.1-7
alkoxycarbonyl C.sub.1-7 alkyl, C.sub.1-7 alkylamino, carboxy
C.sub.1-7 alkylamino, or R.sup.DC(NR.sub.17)NH.sub.2, may be
prepared starting from a compound of formula (XIX),
##STR00015##
wherein R.sub.2 is C.sub.1-7 alkyl, amino C.sub.1-7 alkyl, carboxy
C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl C.sub.1-7 alkyl,
C.sub.1-7 alkylamino, carboxy C.sub.1-7 alkylamino, or
R.sup.DC(NR.sub.17)NH.sub.2, and Y is --NH.sub.2, or --COOH, and
following the general procedures of any of Schemes 1 to 9 to obtain
the final product.
[0061] Compounds of formula (I); wherein R.sub.2 is a group of
formula (III) and R.sub.11 is hydrogen, halogen, amino, carboxy,
amino C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl, halogen C.sub.1-7
alkoxy, --NHCOR.sup.GNH.sub.2, R.sup.JNHCOOR.sup.U or
--CONR.sub.19R.sub.20 may be prepared starting from a compound of
formula (XX),
##STR00016##
[0062] wherein T is hydrogen, halogen, amino, carboxy, amino
C.sub.1-7 alkyl, C.sub.1-7 alkoxy-carbonyl, halogen C.sub.1-7
alkoxy, --NHCOR.sup.GNH.sub.2, R.sup.JNHCOOR.sup.U or
--CONR.sub.19R.sub.20, and Y is --NH.sub.2, or --COOH, and
following the general procedures of any of Schemes 1 to 9 to obtain
the final product.
[0063] Compounds of formula (I), wherein R.sub.3 is amino C.sub.1-7
alkyl or both R.sub.3 and R.sub.11 are amino C.sub.1-7 alkyl, can
be prepared by treating the nitrile compound of formula (V), (X),
(XI), (XII), (XV), (XVI), (XVII), (XVIII) or (XX) with Raney nickel
and NH.sub.3-methanol on hydrogen gas pressure.
[0064] Compounds of formula (IV) which may be used as intermediates
can be prepared according to Scheme 10 in a reaction between halide
and alcohol. A halide (or alcohol) of formula (XXI), wherein
M.sub.1 and M.sub.2 is halogen or a hydroxyl group, is treated with
an alcohol (or halide) of formula (XXII), wherein L.sub.1 is
halogen or a hydroxyl group, in the presence of a base such as
potassium carbonate, sodium hydride, cesium carbonate and the like
in suitable solvent, such as DMF, THF and the like, at temperatures
ranging from about 0.degree. C. to 45.degree. C. to obtain a halide
(or alcohol) compound of formula (XXIII).
[0065] The halide (or alcohol) compound of formula (XXIII) is
reacted with an alcohol (or halide) compound of formula (XXIV),
wherein T.sub.1 is halogen or a hydroxyl group, in the presence of
a base and suitable solvent at temperatures ranging from about
40.degree. C. to 85.degree. C. to obtain the nitro compound of
formula (XXV). Reduction of the nitro group can be carried out
using a reducing agent such as zinc or palladium/carbon under
hydrogen pressure along with solvents such as acetic
acid/methanol/ethanol at temperatures ranging from about 0.degree.
C. to 80.degree. C.
##STR00017##
[0066] Compounds (IX) which may be used as intermediates can be
prepared in a similar manner using a reaction between halide and
alcohol according to Scheme 11, wherein M.sub.1, M.sub.2, L.sub.1
and T.sub.1 mean halogen or a hydroxyl group. Hydrolysis of ester
group of the compound of formula (XXVIII) can be carried out using
a base such as lithium hydroxide, sodium hydroxide and the like in
solvent such as THF-water mixture at temperatures ranging from
about 0.degree. C. to 25.degree. C.
##STR00018##
[0067] Compounds of formula (XIX) which may be used as
intermediates can be prepared using a reaction between halide and
alcohol according to Scheme 12, wherein M.sub.2 and L.sub.1 mean
halogen or a hydroxyl group, Y.sub.1 means --NO.sub.2, --NH.sub.2,
--COOEt or --COOH group, R.sub.2 is C.sub.1-7 alkyl, amino
C.sub.1-7 alkyl, carboxy C.sub.1-7 alkyl, C.sub.1-7 alkoxycarbonyl
C.sub.1-7 alkyl, C.sub.1-7 alkylamino, carboxy C.sub.1-7
alkylamino, R.sup.DC(NR.sub.17)NH.sub.2, and Y means --NH.sub.2 or
--COOH group.
##STR00019##
[0068] Compounds of formula (I) wherein R.sub.10, R.sub.14 and/or
R.sub.15 is halogen, halogen C.sub.1-7 alkyl or
--C(NR.sub.17)NH.sub.2 can be prepared according to the above
Schemes starting from compound (XXII) that contain 1 to 3 further
nitrile, halogen and/or halogen C.sub.1-7 alkyl substituents in the
ring portion.
[0069] Pharmaceutically acceptable salts, e.g. acid addition salts
with both organic and inorganic acids are well known in the field
of pharmaceuticals. Non-limiting examples of these salts include
chlorides, bromides, sulfates, nitrates, phosphates, sulfonates,
formates, tartrates, maleates, citrates, benzoates, salicylates and
ascorbates. Pharmaceutically acceptable esters, when applicable,
may be prepared by known methods using pharmaceutically acceptable
acids that are conventional in the field of pharmaceuticals and
that retain the pharmacological properties of the free form.
Non-limiting examples of these esters include esters of aliphatic
or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and
carbonate esters, are also within the scope of the invention.
[0070] The terms employed herein have the following meanings:
[0071] The term "halo" or "halogen", as employed herein as such or
as part of another group, refers to chlorine, bromine, fluorine or
iodine.
[0072] The term "C.sub.1-7 alkyl", as employed herein as such or as
part of another group, refers to a straight, branched or cyclized,
saturated or unsaturated, chain radical having 1 to 7 carbon atoms.
Representative examples of C.sub.1-7 alkyl include, but are not
limited to, methyl, ethyl, ethenyl, n-propyl, isopropyl, propenyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, n-hexyl, cyclopentyl, cyclohexyl and the like.
"C.sub.1-3 alkyl" is an embodiment of "C.sub.1-7 alkyl" having 1 to
3 carbon atoms.
[0073] The term "C.sub.2-7 alkenyl", as employed herein as such or
as part of another group, refers to a straight, branched or
cyclized chain radical having 2 to 7 carbon atoms, and containing
one or several double bonds.
[0074] The term "hydroxy", as employed herein as such or as part of
another group, refers to an OH group. The term "cyano", as employed
herein as such or as part of another group, refers to a CN group.
The term "amino", as employed herein as such or as part of another
group, refers to a NH.sub.2 group. The term "carboxy", as employed
herein as such or as part of another group, refers to COOH group.
The term "carbonyl", as employed herein as such or as part of
another group, refers to a carbon atom double-bonded to an oxygen
atom (C.dbd.O).
[0075] The term "C.sub.1-7 alkoxy", as employed herein as such or
as part of another group, refers to C.sub.1-7 alkyl, as defined
herein, appended to the parent molecular moiety through an oxygen
atom. Representative examples of C.sub.1-7 alkoxy include, but are
not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, and the like.
[0076] The term "hydroxyl C.sub.1-7 alkyl", as employed herein,
refers to at least one hydroxy group, as defined herein, appended
to the parent molecular moiety through a C.sub.1-7 alkyl group, as
defined herein. Representative examples of hydroxyl C.sub.1-7 alkyl
include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl,
1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl,
1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl, and the
like.
[0077] The term "halo C.sub.1-7 alkyl", as employed herein, refers
to at least one halogen, as defined herein, appended to the parent
molecular moiety through a C.sub.1-7 alkyl group, as defined
herein. Representative examples of halo C.sub.1-7 alkyl include,
but are not limited to, fluoromethyl, difluoromethyl,
trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the like.
[0078] The term "cyano C.sub.1-7 alkyl", as employed herein, refers
to a cyano group, as defined herein, appended to the parent
molecular moiety through a C.sub.1-7 alkyl group, as defined
herein. Representative examples of cyano C.sub.1-7 alkyl include,
but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl,
2-cyanopropyl, and the like.
[0079] The term "carboxy C.sub.1-7 alkyl", as employed herein as
such or as part of another group, refers to a carboxy group, as
defined herein, appended to the parent molecular moiety through a
C.sub.1-7 alkyl group, as defined herein.
[0080] The term "halogen C.sub.1-7 alkoxy", as employed herein,
refers to at least one halogen, as defined herein, appended to the
parent molecular moiety through a C.sub.1-7 alkoxy group, as
defined herein.
[0081] The term "C.sub.1-7 alkoxycarbonyl", as employed herein as
such or as part of another group, refers to a C.sub.1-7 alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein.
[0082] The term "aminocarbonyl", as employed herein as such or as
part of another group, refers to an amino group, as defined herein,
appended to the parent molecular moiety through a carbonyl group,
as defined herein.
[0083] The term "amino C.sub.1-7 alkyl", as employed herein, refers
to at least one amino group, as defined herein, appended to the
parent molecular moiety through a C.sub.1-7 alkyl group, as defined
herein. Representative examples of amino C.sub.1-7 alkyl include,
but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl,
2,2-diaminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl,
1-methyl-1-aminoethyl, and the like.
[0084] The term "C.sub.1-7 alkylamino", as employed herein as such
or as part of another group, refers to at least one C.sub.1-7 alkyl
group, as defined herein, appended to the parent molecular moiety
through an amino group, as defined herein. Representative examples
of C.sub.1-7 alkylamino include, but are not limited to
methylamino, ethylamino, propylamino, butylamino, dimethylamino,
diethylamino, N-ethyl-N-methylamino, and the like.
[0085] The term "carboxy C.sub.1-7 alkylamino", as employed herein
as such or as part of another group, refers to at least one carboxy
group, as defined herein, appended to the parent molecular moiety
through an C.sub.1-7 alkylamino group, as defined herein
[0086] The term "C.sub.1-7 alkoxy C.sub.1-7 alkyl", as employed
herein, refers to at least one C.sub.1-7 alkoxy group, as defined
herein, appended to the parent molecular moiety through an
C.sub.1-7 alkyl group, as defined herein.
[0087] The term "C.sub.1-7 alkoxycarbonyl C.sub.1-7 alkyl", as
employed herein, refers to at least one C.sub.1-7 alkoxycarbonyl
group, as defined herein, appended to the parent molecular moiety
through an C.sub.1-7 alkyl group, as defined herein.
[0088] The term "substituted" as used herein in connection with
various residues refers to halogen substituents, such as fluorine,
chlorine, bromine, iodine, or C.sub.1-7 alkyl, halo C.sub.1-7
alkyl, hydroxy, amino, C.sub.1-7 alkoxy, C.sub.2-7 acyl C.sub.1-7
alkylamino, amino C.sub.1-7 alkyl, nitro, cyano, or thiol
substituents.
[0089] The "substituted" groups may contain 1 to 3, preferably 1 or
2, most preferably 1 of the above mentioned substituents.
[0090] The definition of formula (I) above is inclusive of all the
possible stereoisomers of the compounds, including geometric
isomers, e.g. Z and E isomers (cis and trans isomers), and optical
isomers, e.g. diastereomers and enantiomers, and all prodrug
esters, e.g. phosphate esters and carbonate esters, and isotopes.
Furthermore, the invention includes in its scope both the
individual isomers and any mixtures thereof, e.g. racemic mixtures.
The individual isomers may be obtained using the corresponding
isomeric forms of the starting material or they may be separated
after the preparation of the end compound according to conventional
separation methods. For the separation of optical isomers, e.g.
enantiomers, from the mixture thereof the conventional resolution
methods, e.g. fractional crystallisation, may be used.
[0091] Compounds of the invention may be administered to a patient
in therapeutically effective amounts which range usually from about
0.1 to about 1000 mg per day depending on the age, weight, ethnic
group, condition of the patient, condition to be treated,
administration route and the protease inhibitor used. The compounds
of the invention can be formulated into dosage forms using the
principles known in the art. The compound can be given to a patient
as such or in combination with suitable pharmaceutical excipients
in the form of tablets, granules, capsules, suppositories,
emulsions, suspensions or solutions. Choosing suitable ingredients
for the composition is a routine for those of ordinary skill in the
art. Suitable carriers, solvents, gel forming ingredients,
dispersion forming ingredients, antioxidants, colours, sweeteners,
wetting compounds and other ingredients normally used in this field
of technology may be also used. The compositions containing the
active compound can be given enterally or parenterally, the oral
route being the preferred way. The contents of the active compound
in the composition is from about 0.5 to 100%, preferably from about
0.5 to about 20%, per weight of the total composition.
[0092] The present invention will be explained in more detail by
the following experiments and examples. The experiments and
examples are meant only for illustrating purposes and do not limit
the scope of the invention defined in claims.
Experiments
1. Inhibition of Matriptase and Other Proteases
[0093] Methods
[0094] Purified recombinant matriptase was used in a
fluorescence-based screening assay using Gln-Ala-Arg peptide as a
substrate. In this assay the cleavage of AMC from
Boc-Gln-Ala-Arg-7-amido-4 methylcoumarin hydrochloride
(Boc-Gln-Ala-Arg-AMC) (Sigma, USA) was monitored by measuring the
increase in fluorescence intensity of AMC released upon proteolytic
cleavage at 480 nm (.lamda.ex=360 nm). Similarly, enzymatic assays
in fluorimetric or colorimetric format for uPA, Factor Xa,
thrombin, plasmin and trypsin (Sigma, USA) were established using
substrates pyroGlu-Gly-Arg-pNA.HCl, Boc-Gln-Ala-Arg-AMC,
CH.sub.3OCO-D-CHA-Gly-Arg-PNA.AcoH, Pyro Glu-Phe-Lys-pNA.HCl and
Boc-Gln-Ala-Arg-AMC, respectively.
[0095] Results
[0096] Enzymatic activity and selectivity of selected compounds of
the invention on different proteases is presented in Table 1. The
compounds of the invention were found to be potent and selective
matriptase inhibitors.
TABLE-US-00001 TABLE 1 Inhibition of matriptase and other proteases
Selectivity Screening (% Inhibition at 5 .mu.M) Matriptase uPA
Factor Xa Thrombin Plasmin Trypsin Inhibition Inhibition Inhibition
Inhibition Inhibition Inhibition Compound IC.sub.50 (.mu.M) (%) (%)
(%) (%) (%) Example 13 0.02 13 84 28 33 92 Example 27 0.017 14 83
41 33 61 Example 58 0.035 7 73 70 42 46 Example 57 0.029 10 94 57
50 74 Example 31 0.088 5 94 61 40 85 Example 43 0.016 7 76 45 33 63
Example 42 0.010 11 93 36 30 ND Example 47 0.038 -1 71 3 18 36
Example 45 0.048 6 47 -12 21 35 Example 77 0.005 11 96 76 22 69
Example 65 0.0168 4 63 27 5 23 Example 66 0.0161 3 43 21 5 26
Example 51 0.379 23 52 41 25 53 Example 69 0.0189 9 81 26 22 37
Example 74 0.0132 11 86 33 10 28 Example 35 0.31270 10 69 67 69 84
Example 37 0.47943 13 67 74 65 84 Example 84 0.06343 5 5 36 10 37
Example 103 0.002 25 92 44 58 92 Example 108 0.004 23 81 49 61 76
Example 111 0.029 17 74 44 46 63 Example 119 0.007 14 97 47 30
77
2. Cytotoxicity and Inhibition of Migration and Invasion
[0097] Methods
[0098] Cytotoxicity of the compounds was tested in cell lines or
primary cells using Calcein AM assay. This assay measures cell
viability by quantitation of cleaved fluorescent product of a cell
permeable substrate that is retained in the cytoplasm of cells with
uncompromised cytoplasmic membrane integrity. The cells were seeded
into 96-well plate and allowed to adhere for a day followed by
addition of compound at several different concentrations. After
four days of incubation with the compound, media was removed from
the cells followed by addition of PBS and addition of Calcein AM
reagent at 1 .mu.M final concentration. The cells were then allowed
to incubate at 37.degree. C. for half an hour followed by reading
on the fluorimeter. Percent viability was calculated based on
fluorescence value obtained at 485/520 nm with cut off at 495 nm.
In the cytotoxicty assays, none of the compounds tested showed any
effect up to 10 .mu.M when tested on the prostate cancer cell lines
DU145 and LnCap.
[0099] Migration assays were performed to determine the effect of
matriptase inhibitors on cell motility. Cells were seeded with 10
.mu.M test compound into transwell chambers and allowed to migrate
for 24 hours using a combination of 10% FBS and 5 .mu.g/ml
fibronectin as chemoattractant.
[0100] Cell invasion assays were done for quantitating the degree
to which invasive cells penetrate a barrier essentially as in
migration assay but with the use of matrigel consisting of basement
membrane components in the transwell inserts and incubating for 48
hours. The barrier used was matrigel. This was followed by fixing
and staining of the transwell insert with 0.5% crystal violet in
25% methanol in order to visualize cells migrated.
[0101] Soft agar colony formation assays were performed to measure
the long-term survival and anchorage-independent growth capacity of
tumor cells. DU145 cells were seeded in 0.7% nutrient agar with the
test compound on an underlay of 1.4% nutrient agar in a six well
plate. On the day following cell seeding, liquid cell culture
medium containing the compound was added to the well to prevent the
agar from drying out and was changed regularly till the completion
of the experiment. The cells were allowed to form colonies for a
period of about three weeks following which the colonies were
stained with 0.005% solution of crystal violet in 25% methanol. The
colonies were counted under a dissecting microscope.
[0102] Results
[0103] Effects of selected compounds on cytotoxicity, migration and
invasion of DU145 cells are presented in Table 2.
TABLE-US-00002 TABLE 2 Effect of selected compounds on DU145 cells
Inhibition of Inhibition of Matriptase Cell survival at migration
at invasion at Compound IC.sub.50 (.mu.M) 10 .mu.M (%) 10 .mu.M (%)
10 .mu.M (%) Example 27 0.017 100 88 79 Example 58 0.035 100 63 91
Example 47 0.038 100 39 63 Example 65 0.016 96 7 88 Example 66
0.016 87 88 95 Example 51 0.122 93 -4 61 Example 74 0.013 95 18 45
Example 35 0.312 78 18 75 Example 84 0.063 100 80 92 Example 87
0.158 113 47 88
EC.sub.50 values for inhibition of soft agar colony formation of
DU145 cells by selected compounds are presented in Table 3.
TABLE-US-00003 TABLE 3 EC.sub.50 values for inhibition of soft agar
colony formation of DU145 cells Compound EC.sub.50 (.mu.M) Example
13 0.5 Example 58 0.1 Example 27 0.2 Example 51 0.7 Example 47
0.9
3. Efficacy in In-Vivo Tumor Models
[0104] Methods
[0105] In order to determine the in vivo efficacy, xenograft models
were established by injecting 5.times.10.sup.6 DU145 cells with
matrigel or 5.times.10.sup.6 PC3 cells without matrigel
subcutaneously. Once the tumors reached palpable size (.about.80
mm3), compound of Example 27 was administered in a vehicle
comprising of 2% ethanol, 10% hydroxyl cyclodextrin in 0.9% saline.
The compound of Example 27 was dosed subcutaneously to animals with
DU145 tumors at 1.5, 5 and 15 mg/kg for 15 days. In the PC3
xenograft study, compound of Example 27 was administered at 0.5,
1.5, 5.0 and 15.0 mg/kg daily.
[0106] Results
[0107] In DU145 xenograft study the compound of Example 27 caused a
significant reduction in tumor volume as shown in Table 4.
TABLE-US-00004 TABLE 4 Tumor growth inhibition in DU145 model upon
treatment with the compound of Example 27 (for 15 days) Compound
Tumor growth inhibition of Example 27 (%) 1.5 mg/kg 61.2 5 mg/kg
84.5 15 mg/kg 75
[0108] In the PC3 xenograft study, the compound of Example 27
caused significant and dose-dependent inhibition of tumor growth as
shown in Table 5.
TABLE-US-00005 TABLE 5 Tumor growth inhibition in PC3 model upon
treatment with the compound of Example 27 (for 21 days) Compound
Tumor growth inhibition of Example 27 (%) 0.5 mg/kg 14 1.5 mg/kg 44
5 mg/kg 65 15 mg/kg 62
4. Maximum Tolerated Dose (MTD)
[0109] An MTD study was performed for the compound of Example 27.
The objective of the study was to establish the maximum dose that
does not induce drug related lethality and/or body weight loss of
more than 20% of baseline weight during the study period of 14
days. The compound was administered at 1, 3, 10 and 30 mg/kg once
daily in male athymic mice via subcutaneous route in 5 mice each.
Dosing at the tested doses did not show any mortality. Body weight
reduction was less than 2% and no gross changes in clinical signs
were seen indicating doses up to 30 mg/kg are well tolerated.
[0110] The preparation of the compounds of the invention is
illustrated by the following Examples.
EXAMPLES
[0111] LCMS data has been recorded in +ve mode unless otherwise
mentioned.
Example 1
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridin-
e
a) 2,6-Bis(4-cyanophenoxy)-3-nitro pyridine
[0112] Potassium carbonate (2.09 g, 15.1 mmol) was added to a
stirred solution of 2,6-Dichloro-3-nitro pyridine (1.0 g, 5.3
mmol), dissolved in 10 ml of DMF, at a temperature of 5.degree. C.
The flask was stirred for 10 min at the same temperature. 4-Cyano
phenol (1.26 g, 10.6 mmol), dissolved in 5 ml of DMF was added
dropwise to the reaction mixture over a period of 10 min and the
flask was heated to 80.degree. C. for 10-12 h. The reaction mixture
was poured into ice-cold water and the product was extracted with
250 ml of ethyl acetate. Ethyl acetate layer was washed with water
and brine solution. The organic layer was dried over anhydrous
sodium sulphate and concentrated under reduced pressure to afford
1.35 g of the required 2,6-Bis(4-cyanophenoxy)-3-nitro pyridine
which was used in the next step without further purification.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.06 (1H, d), 7.32 (4H, dd),
7.82 (4H, t), 8.74 (1H, d).
b) 3-Amino-2,6-bis(4-cyanophenoxy)pyridine
[0113] 10% Pd/carbon (0.24 g) was added under hydrogen atmosphere
(balloon pressure) to a stirred solution of
2,6-Bis(4-Cyanophenoxy)-3-nitro pyridine (1.20 g, 3.35 mmol) in 20
ml of methanol:ethyl acetate (1:1) at ambient temperature and the
reaction mixture was stirred for 1 h. The reaction mixture was
filtered through celite, washed with 20 ml of ethyl acetate and
concentrated under reduced pressure. Water was added to the
residual mixture and it was extracted with ethyl acetate. Ethyl
acetate layer was washed with water followed by brine. The organic
layer was dried over sodium sulphate to afford 0.95 g of the title
product which was used for the next step without further
purification. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.32 (2H, brs),
6.82 (1H, d), 7.15 (1H, d), 7.22 (2H, d), 7.34 (2H, d), 7.80 (4H,
m).
c)
2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
[0114] 4-Fluoro benzene sulfonyl chloride (0.15 g, 0.77 mmol),
dissolved in 2 ml of tetrahydrofuran (THF), was added to a stirred
solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.77
mmol), triethylamine (0.155 g, 1.54 mmol) and
N,N-diisopropylethylamine (0.1 g, 0.77 mmol), in 10 ml of THF, in
an inert atmosphere and stirred at RT for 12 h. The reaction
mixture was concentrated and dissolved in 100 ml of ethyl acetate,
washed with 1N HCl followed by saturated brine solution and dried
over anhydrous sodium sulphate. The organic phase was concentrated
and the crude product was purified by column chromatography to
afford 0.3 g of the required compound. .sup.1H NMR (DMSO-d.sub.6):
.delta. 6.94 (1H, d), 7.12 (2H, m), 7.25 (1H, d), 7.35 (4H, d),
7.56 (4H, m), 7.80 (4H, m), 8.04 (4H, m).
d)
2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido-
)-pyridine
[0115]
2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
0.3 g (0.61 mmol) was added to 70 ml of ethanol (saturated with HCl
gas at -25.degree. C.) and the reaction mixture was kept in a tight
vessel at room temperature overnight. The reaction mixture was
concentrated under reduced pressure to afford 0.46 g of the crude
product which was taken for the next step without purification.
Percentage purity: 51.1%, (M+1)=578.1+1.
e)
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyri-
dine
[0116] 0.46 g (0.79 mmol) of
2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluoro-benzene-sulphonamido)-
-pyridine was added to 70 ml of ammoniated ethanol (ethanol
saturated with NH.sub.3 gas at -50.degree. C.). The reaction
mixture was kept in tight vessel (sealed tube) at room temperature
for 48 hrs. The reaction mixture was cooled in dry ice and
concentrated under reduced pressure to afford a crude product which
was purified by reverse-phase preparative HPLC to afford 0.15 g of
the required product. Percentage purity (HPLC): 98.16%, (LCMS):
95.66%. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.9 (1H, d), 7.0 (2H,
d), 7.3 (4H, m), 7.8 (6H, m), 9.25 (7H, m), 10.3 (1H, s).
Example 2
2,6-Bis(4-carbamimidoylphenoxy)-3-(2-naphthylsulphonamido)-pyridine
[0117] Intermediates (a) and (b) are the same as in Example 1.
c)
2,6-Bis-(4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine
[0118] 2-Naphthyl sulfonyl chloride (0.17 g, 0.76 mmol) was added
to a stirred solution of 3-amino-2,6-bis(4-cyanophenoxy)pyridine
(0.25 g, 0.76 mmol) along with other reagents as mentioned in
Example 1(c) to afford 0.27 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 5.38 (1H, brs), 6.82 (1H, d), 7.12 (1H, d),
7.22 (2H, d), 7.35 (2H, dd), 7.44 (1H, d), 7.80 (7H, m), 7.95 (2H,
m), 8.15 (2H, d), 8.56 (1H, s).
d)
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonamido-
)-pyridine
[0119] N,N-Diisopropylethylamine (DIPEA) 0.36 ml (2.08 mmol)
followed by 144 mg (2.08 mmol) of hydroxylamine hydrochloride was
added to a stirred solution of
2,6-bis-(4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine 0.27
g (0.52 mmol) in 10 ml of ethanol and the flask was heated at
100.degree. C. for 8 h. The reaction mixture was concentrated under
reduced pressure to afford 0.35 g (57.5%) of the product which was
used for the next step without further purification.
M.sup.+=584.1+1 (actual mass: 584.1).
e)
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulpho-
n-amido)-pyridine
[0120] Acetic anhydride (0.12 ml, 1.25 mmol) was added dropwise to
a solution of
2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonamido)--
pyridine (0.35 g, 0.59 mmol) in 5 ml of acetic acid at room
temperature. The reaction mixture was stirred at room temperature
for 2 h. The reaction mixture was concentrated under reduced
pressure to afford 0.3 g (51.0%) of the crude product which was
used for the next step without further purification. M.sup.+=LCMS
(+ve mode) 668.1+1.
f)
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine
[0121] 10% Pd/C (0.1 g) was added under an atmosphere of nitrogen
gas to
2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(4-fluorobenzene-sul-
phonamido)-pyridine 0.3 g (0.44 mmol) dissolved in 50 ml methanol.
30 mg of 10% Pd/C was added under nitrogen atmosphere and the
reaction mixture was stirred under hydrogen pressure (balloon) at
room temperature for 3 h. The reaction mixture was passed through
celite, washed with methanol and concentrated under reduced
pressure. The concentrate was purified using reverse-phase
preparative HPLC column to afford 0.06 g. of the required product.
Percentage purity (HPLC): 85.01%, (LCMS): 82.7 3%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.75 (2H, d), 6.9 (1H, d), 7.3 (2H, d), 7.5
(2H, d), 7.65 (2H, m), 7.8 (3H, d), 8.0 (4H, m), 8.35 (1H, s), 9.03
(4H, d), 9.2 (4H, s), 10.2 (1H, s).
Example 3
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
[0122] Intermediates (a) and (b) are the same as in Example 1.
c)
2,6-Bis-(4-cyanophenoxy)-3-(8-quinoline-sulphonamido)-pyridine
[0123] 8-Quinoline sulfonyl chloride (0.172 g, 0.76 mmol) was added
to a stirred solution of 3-amino-2,6-bis(4-cyanophenoxy)pyridine
(0.25 g, 0.76 mmol). Using other reagents and reaction conditions
as mentioned in Example 1(c) afforded 0.4 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.92 (1H, d), 7.11
(1H, d), 7.18 (2H, d), 7.25 (1H, d), 7.51 (2H, d), 7.56 (1H, dd),
7.66 (1H, t), 7.74 (2H, d), 7.80 (2H, m), 7.98 (1H, d), 8.20 (2H,
m), 8.38 (1H, d).
d)
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamid-
o)-pyridine
[0124]
2,6-Bis-(4-cyanophenoxy)-3-(8-quinoline-sulphonamido)-pyridine 0.4
g (0.77 mmol), DIPEA 0.53 ml (3.08 mmol) and 214 mg (3.08 mmol) of
hydroxylamine hydrochloride were used to synthesize
2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamido)-
-pyridine using the procedure of Example 2(d) to afford 0.4 g of
the required product. Percentage purity: 94.4%, (M+1)=585.1+1.
e)
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulph-
onamido)-pyridine
[0125]
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphon-
amido)-pyridine 0.4 g (0.68 mmol) was acetylated with 0.14 g (1.36
mmol) of acetic anhydride using the procedure of Example 2(e) to
afford 0.4 g of the required product. Percentage purity: 38.6%,
(M+1)=669.1+1.
f)
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
[0126]
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-s-
ulphonamido)-pyridine 0.4 g (0.59 mmol) was reduced using the
procedure of Example 2(f) to afford 0.2 g of required product.
Percentage purity (HPLC): 95.88%, (LCMS): 97.3%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.5 (2H, d), 6.85 (1H, d), 7.25 (2H, d),
7.55 (3H, m), 7.7 (1H, m), 7.8 (2H, d), 8.0 (1H, d), 8.25 (2H, t),
8.4 (1H, d), 8.98 (1H, d), 9.1 (4H, d), 9.2 (4H, d), 9.65 (1H,
brs).
Example 4
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)-py-
ridine
[0127] Intermediates (a) and (b) are the same as in Example 1.
c)
N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulfonam-
ide
[0128] 3,5-difluorobenzene sulfonyl chloride (0.5 g, 2.35 mmol) was
added to a stirred solution of
3-amino-2,6-bis(4-cyanophenoxy)pyridine (0.77 g, 2.35 mmol) using
the reagents and reaction conditions described in Example 1(c) to
afford 0.9 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 6.82 (1H, d), 6.95 (1H, d), 7.11 (2H, d), 7.24 (3H, m),
7.34 (2H, d), 7.80 (7H, m).
d)
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-su-
lphonamido)-pyridine
[0129]
N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulf-
onamide 0.9 g (1.78 mmol), DIPEA 1.24 ml (7.12 mmol) and 0.494 g
(7.12 mmol) of hydroxylamine hydrochloride were used as described
in Example 2(d) to afford 0.8 g of the required product. Percentage
purity: 62.1%, (M+1)=570.0+1.
e)
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benz-
ene-sulphonamido)-pyridine
[0130]
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzen-
e-sulphon-amido)-pyridine, 0.8 g (1.40 mmol), was acetylated with
0.29 g (3.1 mmol) of acetic anhydride using the procedure of
Example 2(e) to afford 0.8 g of the required product. Percentage
purity: 47.3%. (M+1)=654.1+1.
f)
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)-
-pyridine
[0131]
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro--
benzene-sulphonamido)-pyridine, 0.8 g (1.22 mmol), was reduced
using the procedure of Example 2(f) to afford 0.2 g of required
product. Percentage purity (HPLC): 88.35%, (LCMS): 93.37%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 6.6 (3H, m), 6.9 (1H, d), 7.05 (2H, d),
7.35 (2H, d), 7.5 (3H, m), 7.8 (2H, m), 7.9 (1H, d), 9.1 (3H, s),
9.25 (3H, s), 10.5 (1H, s).
Example 5
2-(1-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-4-y-
l)-ethylamine
a) 2,6-Bis(4-Cyanophenoxy)-nicotinic acid ethyl ester
[0132] Potassium carbonate 1.58 g (11.5 mmol) was added to a
stirred solution of 2,6-dichloro-nicotinic acid ethyl ester 1.0 g
(4.6 mmol) in 5 ml of DMF and stirred for 10 min.
4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of
DMF, was added dropwise to the stirred DMF solution and the flask
was stirred at 80.degree. C. for 4 h. The reaction mixture was
poured into ice-cold water and the result was partitioned using
ethyl acetate. The organic phase was washed with 1M of
Na.sub.2CO.sub.3 and saturated brine solution, dried over sodium
sulphate and concentrated. The oily residue was purified by column
chromatography using hexane-ethyl acetate (10:2) to afford 1.6 g of
the required product. Percentage purity: 84.8%, (M+1)=385.1.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.36 (3H, t), 4.22 (2H, q),
6.78 (1H, d), 7.06 (4H, d), 7.58 (4H, d), 8.21 (1H, d).
b) 2,6-Bis(4-cyanophenoxy)-nicotinic acid
[0133] 0.2 g (8.4 mmol) of lithium hydroxide was added to a stirred
solution of 2,6-bis(4-cyanophenoxy)-nicotinic acid ethyl ester, 1.6
g (4.15 mmol), in a mixture of 5 ml of water and 2.5 ml of THF
(2:1) at 5.degree. C. and the contents were stirred for 3 h at RT.
The reaction mixture was washed with diethylether. 6 N HCl was
added to aqueous layer with stirring until the solution attained a
pH of 2. The white precipitate obtained was collected, washed with
water and dried under reduced pressure to afford 1.1 g of the
required product. Percentage purity (LCMS): 83.2%, (M+1)=357.0+1.
.sup.1H NMR (DMSO-d.sub.6): .delta. 6.98 (1H, d), 7.26 (4H, d),
7.80 (4H, d), 13.22 (1H, brs).
c)
(2-{1-[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-piperidin-4-yl}-e-
thyl)-carbamic acid tert-butyl ester
[0134] A solution of 2,6-Bis(4-cyanophenoxy)-nicotinic acid, 0.335
g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred
suspension of 0.489 g (0.94 mmol) of
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(PyBop) in 5 ml of DMF and followed by N,N-diisopropylethylamine
0.242 g (1.88 mmol) while the temperature was maintained below
5.degree. C. during the addition. The mixture was stirred for 10
min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The
mixture was stirred overnight at RT. The solvent was concentrated
under reduced pressure and the residue was dissolved in a mixture
of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted
to 2-3 with 6 N HCl and the phases were separated. The aqueous
phase was extracted with ethyl acetate. The combined organic phase
was washed with 10% solution of potassium hydrogen sulphate
followed by saturated sodium bicarbonate solutiona and saturated
brine solution, and dried over sodium sulphate and concentrated.
The crude oily residue was purified by column chromatography using
hexane-ethyl acetate (10:2) to afford 0.4 g of the required
product. Percentage purity: 36.3%, (M+1)=567.2. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m),
2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (1H, t), 6.95 (1H,
d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).
d)
2-(1-{2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-pipe-
ridin-4-yl)-ethylamine
[0135] Using
(2-{1-[2,6-bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-piperidin-4-yl}-eth-
yl)-carbamic acid tert-butyl ester (0.4 g, 0.7 mmol) and following
the procedure of Example 1(d) afforded 0.4 g of the required
product. Percentage purity (LCMS): 30.7%. (M+1)=559.2.
e)
2-(1-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin--
4-yl)-ethylamine
[0136] Using
(2-(1-{2,6-bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-piper-
idin-4-yl)-ethylamine (0.4 g, 0.71 mmol) and following the
procedure of Example 1(e) 0.05 g of the required product was
obtained. Percentage purity (HPLC): 93.52%, (LCMS): 96.46%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.5 (2H, m), 1.65 (2H, m,), 1.85 (2H,
m), 2.8 (3H, m), 3.1 (1H, m), 3.7 (2H, m), 4.5 (1H, d), 6.9 (1H,
d), 7.2 (1H, s), 7.4 (4H, t), 7.9 (5H, brs), 8.05 (1H, brs), 9.3
(6H, s).
Example 6
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide
[0137] Intermediates (a) and (b) are the same as in Example 5.
c)
(4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}-cyclohexyl)-ca-
rbamic acid tert-butyl ester
[0138] Following the procedure of Example 5(c)
2,6-bis(4-cyanophenoxy)-nicotinic acid 0.335 g (0.94 mmol) and
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.94
mmol) were used to afford 0.35 g of the required product.
Percentage purity (LCMS): 86.8%, (M+1)=553.6 (with BOC). .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.38 (9H, s), 1.82 (4H,
m), 3.18 (1H, m), 3.64 (1H, m), 6.74 (1H, d), 6.95 (1H, d,), 7.28
(4H, dd), 7.82 (4H, dd), 8.08 (1H, d), 8.21 (1H, d).
d)
4-({2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-amino)-
-cyclohexylamine
[0139]
(4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}-cyclohexyl-
)carbamic acid tert-butyl ester (0.35 g, 0.63 mmol) was used and
the procedure of Example 1(d) was followed to afford 0.3 g of the
required product. Percentage purity (LCMS): 40.2%, (M+1)=545.2.
e)
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide
[0140]
4-({2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-am-
ino)-cyclohexylamine (0.3 g, 0.55 mmol) was used the procedure of
Example 1(e) was followed to afford 0.05 g of the required product.
Percentage purity (HPLC): 97.07%, (LCMS): 81.64%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.95 (4H, m), 3.0 (1H, m), 3.7
(1H, m), 6.9 (1H, d), 7.0 (2H, d,), 7.3 (4H, m), 7.8 (6H, m), 9.25
(7H, m), 10.3 (1H, s).
Example 7
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-propyl-a-
mine
[0141] Intermediates (a) and (b) are the same as in Example 5.
c)
(3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propyl)-carb-
amic acid tert-butyl ester
[0142] Following the procedure of Example 5(c)
2,6-bis(4-Cyanophenoxy)-nicotinic acid 0.335 g (0.94 mmol) and
(3-amino-propyl)-carbamic acid tert-butyl ester (0.163 g, 0.94
mmol) were used to afford 0.3 g of the required product. Percentage
purity (LCMS): 78.7%, (M+1)=513.5+1.
d)
3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-
-propylamine
[0143]
(3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propyl)--
carbamic acid tert-butyl ester (0.3 g, 0.58 mmol) was used
following the procedure of Example 1(d) to afford 0.3 g of the
required product. Percentage purity (LCMS): 38.6%, (M+1)=505.2.
e)
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-propy-
lamine
[0144]
3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3-carbonyl]-am-
ino}-propylamine (0.3 g, 0.59 mmol) was used following the
procedure of Example 1(e) to afford 0.12 g of the required product.
Percentage purity (HPLC): 92.98%, (LCMS): 97.61%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.8 (2H, m), 2.85 (2H, m), 3.45 (2H, m),
6.9 (1H, d), 7.0 (1H, s), 7.2 (1H, d), 7.3 (4H, m), 7.85 (6H, d),
8.3 (1H, d), 8.55 (1H, brs), 9.3 (7H, brs).
Example 8
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}propionic
acid
[0145] Intermediates (a) and (b) are the same as in Example 5.
c)
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionicacid
ethyl ester
[0146] Following the procedure of Example 5(c)
2,6-bis(4-Cyanophenoxy)-nicotinic acid 0.5 g (1.42 mmol) and
3-amino-propionic acid ethyl ester (0.166 g, 1.42 mmol) were used
to afford 0.5 g of the required product. Percentage purity (LCMS):
30.7%, (M+1)=456.1.
d)
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic
acid
[0147]
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic
acid ethyl ester (0.5 g, 1.09 mmol) was deesterified using the
procedure of Example 5(b) to afford 0.35 g of the required product.
Percentage purity (LCMS): 71.6%, (M+1)=428.4.
e)
3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl]amino}-p-
ropionic acid
[0148]
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic
acid (0.35 g, 0.81 mmol) was used and the procedure of Example 1(d)
was followed to afford 0.3 g of the required product. Percentage
purity (LCMS): 38.6%, (M+1)=520.1+2.
f)
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]amino}propioni-
c acid
[0149]
3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl]amin-
o}-propionic acid (0.3 g, 0.57 mmol) was used and the procedure of
Example 1(e) was followed to afford 0.15 g of the required product.
Percentage purity (HPLC): 95.73%, (LCMS): 97.10%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 2.3 (1H, m), 3.5 (1H, m), 6.9 (1H, d), 7.04
(1H, s), 7.22 (1H, s), 7.4 (3H, m), 7.88 (2H, d), 8.36 (1H, d),
8.52 (1H, m), 9.3 (4H, d).
Example 9
3-{4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin-1-y-
l}-3-oxo-propylamine
[0150] Intermediates (a) and (b) are the same as in Example 5.
c)
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-1-carboxyli-
c acid tert-butyl ester
[0151] Following the procedure of Example 5(c)
2,6-bis(4-cyanophenoxy)-nicotinic acid 1.25 g (3.5 mmol) and
piperazine-1-carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol)
were used to afford 1.2 g of the required product. Percentage
purity (LCMS): 95.6%, (M+1)=525.2 (with BOC). .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.40 (9H, s), 3.30 (2H, m), 3.42 (4H, m),
3.61 (2H, m), 6.98 (1H, d), 7.35 (4H, m), 7.82 (4H, dd), 8.02 (2H,
d).
d) 4-[2,6-Bis-(4-cyanophenoxy)pyridine-3-carbonyl]piperazine
[0152]
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-1-carbo-
xylic acid tert-butyl ester 1.2 g (2.28 mmol) was dissolved in 5 ml
of DCM at 5.degree. C. under inert atmosphere. 0.7 ml of TFA was
added over a 10 min period, while the temperature was maintained at
5.degree. C. Stirring was continued for 1 h at RT and reaction
progress was monitored by TLC. The reaction mixture was
concentrated under reduced pressure and the residual crude product
was purified by column chromatography using chloroform:
ethylacetate (8:2) as eluant to afford 0.9 g of the required
product. Percentage purity (LCMS): 88.2%, (M+1): 425.1. .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.15 (2H, m), 3.22 (2H, m), 3.64 (2H, m),
3.85 (2H, m), 7.00 (1H, d), 7.34 (4H, t), 7.82 (4H, t), 8.08 (1H,
d), 9.02 (1H, brs).
e)
(3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-1-yl}-3-o-
xo propyl)carbamic acid tert-butyl ester
[0153] A solution of 3-tert-butoxycarbonylamino-propionic acid,
0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred
suspension of 0.72 g (3.76 mmol) of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)
and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF
at RT. That was followed by the addition of
N,N-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the
temperature was maintained below 5.degree. C. The mixture was
stirred for 10 min and a solution of
4-[2,6-Bis-(4-cyanophenoxy)pyridine-3-carbonyl]piperazine (0.4 g,
0.94 mmol) in DMF (10 ml) was added followed by stirring overnight
at RT. The reaction mixture was concentrated under reduced pressure
and partitioned between water (150 ml) and ethyl acetate (150 ml)
after the pH was adjusted to 2-3 with 6 N HCl. The organic phase
was washed with 1M Na.sub.2CO.sub.3 and saturated brine solution,
dried over sodium sulphate and concentrated. The crude oily residue
was purified by column chromatography using hexane-ethyl acetate
(10:2) to afford 0.45 g of the required product. Percentage purity
(LCMS): 10.3%. (M+1)=596.2 (with BOC).
f)
3-(4-{2,6-bis-(4-ethoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-piper-
azin-1-yl)-3-oxopropylamine
[0154]
(3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-1-yl}-
-3-oxo propyl)carbamic acid tert-butyl ester (0.45 g, 0.75 mmol)
was used and the procedure of Example 1(d) was followed to afford
0.3 g of the required product. Percentage purity (LCMS): 32.8%,
(M+1)=496.1.
g)
3-{4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin--
1-yl}-3-oxo-propylamine
[0155]
3-(4-{2,6-bis-(4-ethoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-p-
iperazin-1-yl)-3-oxopropylamine (0.3 g, 0.60 mmol) was used and the
procedure of Example 1(e) was followed to afford 0.12 g of the
required product. Percentage purity (HPLC): 73.56%, (LCMS): 97.21%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.8 (2H, m), 2.8 (2H, m), 3.4
(3H, m), 6.9 (1H, d), 7.04 (1H, s), 7.20 (1H, s), 7.4 (5H, m), 7.88
(7H, m), 8.32 (1H, d), 8.54 (1H, brs), 9.34 (6H, s).
Example 10
3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}-piperi-
dinyl)-3-oxopropylamine
[0156] Intermediates (a) and (b) are the same as in Example 5.
c)
4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-1-car-
boxylic acid tert-butyl ester
[0157] Following the procedure of Example 5(c)
2,6-bis(4-cyanophenoxy)-nicotinic acid 1.5 g (4.20 mmol) and
4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 4.20
mmol) were used to afford 1.7 g of the required product. Percentage
purity (LCMS): 74.6%, (M+1)=539.2 (with BOC).
d) 2,6-Bis-(4-cyanophenoxy)-N-piperidine-4-yl nicotinamide
[0158] Following the procedure of Example 9(d)
4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-1-carbo-
xylic acid tert-butyl ester (1.7 g, 3.15 mmol) were used to afford
1.3 g of the required product. Percentage purity (LCMS): 97.9%,
(M+1)=439.1+1.
e)
[3-(4-{[2,6-bis-(4-cyanophenoxy)pyridine-3-carbonyl]amino}piperidine-1--
yl)-3-oxopropyl]carbamic acid tert-butyl ester
[0159] 3-tert-Butoxycarbonylamino-propionic acid (0.177 g, 0.91
mmol) and 2,6-bis-(4-cyanophenoxy)-N-piperidine-4-yl nicotinamide
(0.4 g, 0.91 mmol) and other reagents as described in Example 9(e)
were used to afford 0.45 g of the required product. Percentage
purity (LCMS): 82.8%, (M+1)=610.1+1.
f)
{3-[4-({2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3-carbony-
l}-amino)-piperidin-1-yl]-3-oxopropyl}-carbamic acid tert-butyl
ester
[0160]
[3-(4-{[2,6-bis-(4-cyanophenoxy)pyridine-3-carbonyl]amino}piperidin-
e-1-yl)-3-oxopropyl]carbamic acid tert-butyl ester (0.45 g, 0.73
mmol), hydroxylamine hydrochloride (0.202 g, 2.92 mmol) and DIPEA
(0.377 g, 2.92 mmol) were used and the procedure of Example 2(d)
was followed to afford 0.4 g of the required product. Percentage
purity (LCMS): 68.6%, (M+1)=676.3.
g)
{3-[4-({2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-pyridine-3-c-
arbonyl}amino)-piperidin-1-yl]-3-oxopropyl}-carbamic acid
tert-butyl ester
[0161]
{3-[4-({2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3-car-
bonyl}-amino)-piperidin-1-yl]-3-oxopropyl}-carbamic acid tert-butyl
ester 0.4 g (0.59 mmol) was acetylated with 0.123 g (1.2 mmol) of
acetic anhydride. The procedure of Example 2(e) was followed to
afford 0.45 g of the required product. Percentage purity (LCMS):
40.0%, (M+1)=660.2+1 (de-boc).
h)
[3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}-pi-
peridinyl)-3-oxopropyl]carbamic acid tert-butyl ester
[0162]
{3-[4-({2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-pyridine-
-3-carbonyl}amino)-piperidin-1-yl]-3-oxopropyl}-carbamic acid
tert-butyl ester 0.45 g (0.59 mmol) was reduced by using the
procedure of Example 2(f) to afford 0.2 g of the required product.
Percentage purity (LCMS): 58.5%. (M+1)=644.3+1.
i)
3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}-pip-
eridinyl)-3-oxopropylamine
[0163] The Boc group was removed from
[3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-pip-
eridinyl)-3-oxopropyl]carbamic acid tert-butyl ester 0.2 g (0.31
mmol) using the procedure of Example 9(d) to afford 0.055 g of the
required product. Percentage purity (HPLC): 95.77%, (LCMS): 88.95%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (3H, m), 1.9 (2H, m), 2.6
(1H, m), 3.0 (2H, m), 3.2 (1H, m), 3.7 (2H, d), 4.2 (2H, d), 6.9
(1H, d), 7.05 (1H, s), 7.2 (1H, s), 7.4 (3H, m), 7.9 (5H, s), 8.3
(2H, dd), 9.35 (6H, d).
Example 11
N-[1-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)-nic-
otinamide
[0164] Intermediates (a) to (d) are the same as in Example 10.
e)
[3-(4-{[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-1-
-yl)propyl]carbamic acid tert-butyl ester
[0165] 0.117 g (0.85 mmol) of K.sub.2CO.sub.3 and
N,N-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g
(0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester,
dissolved in 5 ml of DMF, were added to a stirred solution of 0.373
g (0.85 mmol) of 2,6-bis-(4-cyanophenoxy)-N-piperidine-4-yl
nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at
20.degree. C. Reaction mixture was allowed to attain RT and heated
to 45.degree. C. for 2 h. The reaction mixture was concentrated
under reduced pressure to remove the solvent. The residue was
partitioned between water (150 ml) and ethyl acetate (150 ml). The
organic phase was washed with 1M Na.sub.2CO.sub.3 and saturated
brine solution, and dried over sodium sulphate. The solution was
concentrated and the oily residue was purified by column
chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g
of the required product. Percentage purity (LCMS): 72.5%,
(M+1)=596.2+1.
f)
3-(4-[{2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl}amino-
]-piperidin-1-yl) propylamine
[0166]
[3-(4-{[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidi-
ne-1-yl) propyl]carbamic acid tert-butyl ester (0.45 g, 0.75 mmol)
was used and the procedure of Example 1(d) was followed to afford
0.3 g of the required product. Percentage purity (LCMS): 55.6%,
(M+1)=496.2+1.
g)
N-[1-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)--
nicotinamide
[0167]
3-(4-[{2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl}a-
mino]-piperidin-1-yl) propylamine (0.3 g, 0.60 mmol) was used by
following the procedure of Example 1(e) to afford 0.12 g of the
required product. Percentage purity (HPLC): 92.11%, (LCMS): 90.51%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.8 (2H, m), 2.0 (5H, m), 2.9
(2H, m), 3.15 (4H, m), 4.0 (2H, m), 6.9 (1H, d), 7.35 (3H, d), 7.85
(3H, m), 8.0 (3H, brs), 8.2 (1H, d), 8.5 (1H, d), 9.3 (7H, d), 10.1
(1H, brs).
Example 12
(2-{1-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidin-4--
yl}-ethylamine
a) 2,6-bis(4-Cyanophenoxy)-isonicotinic acid ethyl ester
[0168] Potassium carbonate 3.17 g (23.0 mmol) was added to
2,6-dichloro-isonicotinic acid ethyl ester 1.0 g (4.6 mmol),
dissolved in 5 ml of DMF, and stirred for 10 min. This was followed
by the dropwise addition of 4-hydroxy-benzonitirle 1.64 g (13.8
mmol), dissolved in 5 ml of DMF, followed by stirring at
100.degree. C. for 3 h. The reaction mixture was poured into
ice-cold water and extracted with ethyl acetate. The organic phase
was washed with 1M Na.sub.2CO.sub.3 and saturated brine solution,
dried over sodium sulphate and concentrated. The crude oily residue
was purified by column chromatography using hexane-ethyl acetate
(10:2) to afford 0.4 g of the required product. Percentage purity
(LCMS): 87.4%. (M+1)=385.1+1. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.42 (3H, t), 4.44 (2H, q), 7.16 (4H, d), 7.27 (2H, d), 7.64 (4H,
d).
b) 2,6-bis(4-Cyanophenoxy)-isonicotinic acid
[0169] 0.4 g (1.03 mmol) of 2,6-bis(4-Cyanophenoxy)-isonicotinic
acid ethyl ester was hydrolysed by using the procedure of Example
5(b) to afford 0.3 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 7.22 (2H, s), 7.38 (4H, d), 7.82 (4H,
d).
c)
(2-{1-[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-yl}et-
hyl)-carbamic acid tert-butyl esters
[0170] 2,6-bis(4-Cyanophenoxy)-isonicotinic acid (0.3 g, 0.84 mmol)
and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.191
g, 0.84 mmol) were coupled using the procedure of Example 5(c) to
afford 0.4 g.of the required product. Percentage purity (LCMS):
79.0%, (M+1)=567.2 (with BOC). .sup.1H NMR (DMSO-d.sub.6): .delta.
1.15 (2H, m), 1.38 (9H, s), 1.62 (2H, m), 1.75 (1H, m), 2.74 (1H,
m), 2.88 (3H, m), 3.55 (1H, m), 4.42 (1H, m), 6.80 (1H, m), 6.89
(2H, s), 7.35 (4H, d), 7.84 (4H, d).
d)
(2-{1-[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbony-
l]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
[0171]
(2-{1-[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-y-
l}ethyl)-carbamic acid tert-butyl esters (0.4 g, 0.70 mmol),
hydroxylamine hydrochloride (0.194 g, 2.8 mmol) and DIPEA (0.36 g,
2.8 mmol) were used and the procedure of Example 2(d) was followed
to afford 0.3 g of the required product. Percentage purity (LCMS):
59.2%, (M+1)=633.3+1.
e)
(2-{1-[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-c-
arbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
[0172]
(2-{1-[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-car-
bonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.3 g
(0.473 mmol) was acetylated with 0.095 g (0.95 mmol) of acetic
anhydride using the procedure of Example 2(e) to afford 0.3 g of
the required product. Percentage purity (LCMS): 56.2%,
(M+1)=717.3+1.
f)
(2-{1-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidin-
e-4-yl}ethyl)carbamic acid tert-butyl esters
[0173]
(2-{1-[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-
-4-carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
0.3 g (0.41 mmol) was reduced using the procedure of Example 2(f)
to afford 0.17 g of required product. Percentage purity (LCMS):
59.3%, (M+1)=601.3.
g)
2-{1-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidine-
-4-yl}ethylamine
[0174] The Boc group was removed from
(2-{1-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidine--
4-yl}ethyl)carbamic acid tert-butyl esters 0.17 g (0.31 mmol) using
the procedure of Example 9(d) to afford 50 mg of the required
product. Percentage purity (HPLC): 95.99%, (LCMS): 98.52%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.1 (2H, m), 1.5 (2H, m), 1.6 (2H, m),
1.75 (1H, m), 2.7 (1H, m), 2.85 (2H, m), 3.05 (1H, m), 3.55 (1H,
m), 4.4 (1H, m), 6.9 (1H, s), 7.4 (4H, d), 7.75 (3H, brs), 7.85
(4H, d), 9.3 (8H, s).
Example 13
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamide
[0175] Intermediates (a) and (b) are the same as in Example 12.
c)
(4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-cyclohexyl)-c-
arbamic acid tert-butyl esters
[0176] 2,6-bis(4-Cyanophenoxy)-isonicotinic acid (0.428 g, 1.2
mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester
(0.282 g, 1.32 mmol) were coupled using the procedure of Example
5(c) to afford 0.51 g of the required product. Percentage purity
(LCMS -ve mode): (M-1)=553.2. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.25 (4H, m), 1.40 (9H, s), 1.84 (4H, m), 2.74 (1H, s), 2.80 (1H,
m), 3.22 (2H, m), 3.72 (1H, m), 6.78 (1H, d), 7.28 (1H, s), 7.35
(3H, d), 7.85 (4H, d), 7.95 (1H, s), 8.60 (1H, brs).
d)
(4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]-
-amino}cyclohexyl)carbamic acid tert-butyl esters
[0177]
(4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-cyclohexy-
l)-carbamic acid tert-butyl esters (0.276 g, 0.70 mmol),
hydroxylamine hydrochloride (0.208 g, 3.0 mmol) and DIPEA (0.387 g,
3.0 mmol) were used and the procedure of Example 2(d) was followed
to afford 0.7 g of the required product. Percentage purity (LCMS):
47.3%, (M+1)=619.2.
e)
(4-{[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-car-
bonyl]-amino}cyclohexyl)carbamic acid tert-butyl esters
[0178]
(4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbo-
nyl]-amino}cyclohexyl)carbamic acid tert-butyl esters 0.6 g (0.96
mmol) was acetylated with 0.2 g (2.0 mmol) of acetic anhydride
using the procedure of Example 2(e) to afford 0.65 g of the
required product. Percentage purity (LCMS): 59.4%,
(M+1)=703.2+1.
f)
(4-{[2,6-Bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}cyclo-h-
exyl)-carbamic acid tert-butyl esters
[0179]
(4-{[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
-carbonyl]-amino}cyclohexyl)carbamic acid tert-butyl esters 0.65 g
(0.92 mmol) was reduced by using the procedure of Example 2(f) to
afford 0.56 g of required product. Percentage purity (LCMS): 60.2%,
(M+1)=587.2+1.
g)
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamid-
e
[0180] The Boc group was removed from
(4-{[2,6-bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}cyclohexy-
l)-carbamic acid tert-butyl esters 0.55 g (0.93 mmol) using the
procedure of Example 9(d) to afford 0.26 mg of the required
product. Percentage purity (HPLC): 94.36%, (LCMS): 96.21%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.4 (3H, m), 2.0 (4H, m), 3.0 (2H, m),
3.75 (1H, m), 7.26 (2H, s), 7.4 (3H, d), 7.86 (3H, d), 8.0 (3H,
brs), 8.72 (1H, m), 9.30 (6H, d).
Example 14
N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxy-carbamimidoyl)-phenoxy]-isonico-
tinamide
[0181] Intermediates (a) to (d) are the same as in Example 13.
e)
N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxycarbamimidoyl)phenoxy]-isonic-
otinamide
[0182] The Boc group was removed from
(4-{[2,6-Bis-(4-(N-hydroxy-carbarnimidoyl)-phenoxy)-pyridine-4-carbonyl]--
amino}cyclohexyl)carbamic acid tert-butyl esters 0.25 g (0.41 mmol)
using the procedure of Example 9(d) to afford 0.115 g of the
required product. The crude product was purified by reverse-phase
preparative HPLC to afford 0.115 g of the required product.
Percentage purity (HPLC): 97.73%, (LCMS): 94.78%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.75
(1H, m), 7.20 (2H, s), 7.36 (4H, d), 7.76 (4H, d), 7.9 (3H, brs),
8.5 (2H, m), 8.68 (1H, d). 11.0 (2H, s).
Example 15
N-[1-(4-aminobutyryl)piperidin-4-yl]-2,6-bis[4-carbamimidoylphenoxy]-isoni-
cotinamide
[0183] Intermediates (a) and (b) are the same as in Example 12.
c)
4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-piperidine-1-c-
arboxylic acid tert-butyl ester
[0184] 2,6-bis(4-Cyanophenoxy)-isonicotinic acid (0.220 g, 0.61
mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester
(0.142 g, 0.71 mmol) were coupled using the procedure of Example
5(c) to afford 0.295 g of the required product. Percentage purity
(LCMS): 59.4%, (M+1)=439.2+1 (with BOC). .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.40 (9H, s), 1.81 (4H, m), 2.86 (4H, m),
3.82 (1H, m), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.64 (1H,
d).
d) 2,6-Bis(4-cyanophenoxy)-N-piperidin-4-yl-isonicotinamide
[0185] The Boc group was removed from
4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-piperidine-1-car-
boxylic acid tert-butyl ester 0.29 g (0.53 mmol) using the
procedure of Example 9(d) to afford 0.2 g of the required product.
Percentage purity (LCMS): 88.3%, (M+1)=439.2+1. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.62 (2H, m), 2.00 (3H, m), 3.02 (2H, m),
4.05 (2H, m), 7.30 (6H, m), 7.85 (4H, d), 8.32 (2H, brs), 8.88 (1H,
d).
e)
[3-(4-{[2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}piperidin-1--
yl)-propyl]carbamic acid tert-butyl ester
[0186] 2,6-Bis(4-cyanophenoxy)-N-piperidin-4-yl-isonicotinamide
0.16 g (0.364 mmol), (3-bromo-propyl)-carbamic acid tert-butyl
ester 0.12 g (0.50 mmol) and potassium carbonate 0.175 g (1.26
mmol) were used and the procedure of Example 11(e) was followed to
afford 0.175 g of the required product. Percentage purity (LCMS):
80.4%, (M+1)=596.2+1. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (9H,
s), 1.88 (9H, m), 2.95 (4H, m), 3.85 (2H, m), 6.86 (2H, brs), 7.26
(2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.15 (2H, brs), 9.02 (1H,
brs).
f)
[3-(4-{[2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbony-
l]-amino}-piperidin-1-yl)-propyl]carbamic acid tert-butyl ester
[0187]
[3-(4-{[2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}piperidi-
n-1-yl)-propyl]carbamic acid tert-butyl ester (0.17 g, 0.28 mmol),
hydroxylamine hydrochloride (87.5 mg, 1.26 mmol) and DIPEA (162.8
mg, 1.26 mmol) were used and the procedure Example 2(d) was
followed to afford 0.13 g of the required product. Percentage
purity (LCMS): 42.4%, (M+1)=662.3+1.
g)
[3-(4-{[2,6-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-c-
arbonyl]amino}-piperidin-1-yl)-propyl]carbamic acid tert-butyl
ester
[0188]
[3-(4-{[2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-car-
bonyl]-amino}-piperidin-1-yl)-propyl]carbamic acid tert-butyl ester
0.13 g (0.19 mmol) was acetylated using 45 mg (0.4 mmol) of acetic
anhydride following the procedure of Example 2(e) to afford 0.12 g
of the required product. Percentage purity (LCMS): 66.9%,
(M+1)=746.3+1.
h)
[3-(4-{[2,6-Bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}-pip-
eridin-1-yl)propyl]carbamic acid tert-butyl ester
[0189]
[3-(4-{[2,6-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-
-4-carbonyl]amino}-piperidin-1-yl)-propyl]carbamic acid tert-butyl
ester 0.13 g (0.17 mmol) was reduced using the procedure of Example
2(f) to afford 0.115 g of the required product. Percentage purity
(LCMS): 81.1%, (M+1)=630.3+1.
i) N-[1-(4-aminobutyryl)piperidin-4-yl]-2,6-bis-[4-carbamimidoyl
phenoxy]-isonicotinamide
[0190] The Boc group was removed from
[3-(4-{[2,6-bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}-piper-
idin-1-yl)propyl]carbamic acid tert-butyl ester 0.115 g (0.18 mmol)
using the procedure of Example 9(d) to afford 28 mg of the required
product. Percentage purity (HPLC): 97.58%, (LCMS): 96.9%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.8 (2H, m), 2.0 (5H, m), 2.9 (2H, m),
3.15 (4H, m), 3.55 (1H, m), 4.1 (1H, m), 7.3 (2H, s), 7.4 (4H, d),
7.85 (6H, m), 8.9 (1H, d), 9.3 (6H, s), 10.05 (1H, brs).
Example 16
4-{4-[4-(2-aminoethyl)piperidine-1-carbonyl]-6-isopropoxypyridine-2-yloxy}-
-benzamidine
a) 2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester
[0191] 2,6-Dihydroxyisonicatonic acid (2.0 g, 12.9 mmol) was
dissolved in 20 ml of propane-2-ol at 0.degree. C. 2 ml of
concentrated sulfuric acid was added to the stirred solution of
dihydroxy acid at 0.degree. C. over a period of 10 min and then the
contents of the flask were refluxed overnight at 100.degree. C. The
solvent was removed under reduced pressure and the crude residual
mixture was dissolved in 250 ml of ethylacetate and washed with
water. The organic phase was dried over anhydrous sodium sulphate,
concentrated under reduced pressure and subjected to column
chromatography, using chloroform:ethylacetate (8:2) as eluant to
afford 0.5 g of required product. .sup.1H NMR (CDCl.sub.3): .delta.
1.2 (6H, d), 1.35 (6H, d), 4.8 (1H, m), 5.25 (1H, m), 6.85 (1H, s),
6.95 (1H, s), 10.52 (1H, brs).
b) 2-(4-Cyano-phenoxy)-6-isopropoxy-isonicotinic acid isopropyl
ester
[0192] 2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester
(0.5 g, 2.09 mmol) and 0.577 g (4.18 mmol) potassium carbonate was
dissolved in 5 ml of dry DMF. 0.25 g (2.09 mmol) of
4-fluorobenzonitrile, dissolved in 5 ml of DMF, was added to the
stirred solution of hydroxynicotinate over a period of 15 min and
then the contents of the reaction flask were stirred overnight at
100.degree. C. Reaction mixture was concentrated and the residue
was dissolved in 100 ml of ethylacetate and washed with water.
Ethyl acetate layer was dried over anhydrous sodium sulphate and
concentrated under reduced pressure to afford 0.3 g of required
product which was used for the next step without further
purification. .sup.1H NMR (CDCl.sub.3): .delta. 1.2 (6H, d), 1.35
(6H, d), 4.8 (1H, m), 5.25 (1H, m), 7.2 (3H, m), 7.7 (3H, m).
c) 2-(4-cyanophenoxy)-6-isopropoxy isonicotinic acid
[0193] 2-(4-cyanophenoxy)-6-isopropoxy isonicotinic acid isopropyl
ester (0.3 g, 0.88 mmol) was deesterified using the procedure of
Example 5(b) to afford 0.20 g of the required product. Percentage
purity (LCMS): 96.71%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (6H,
d), 4.8 (1H, m), 6.85 (1H, s), 6.9 (1H, s), 7.4 (2H, d), 7.98 (2H,
m), 14.0 (1H, brs).
d)
(2-{1-[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperidin-4-
-yl}ethyl)-carbamic acid tert-butyl ester
[0194] 2-(4-cyanophenoxy)-6-isopropoxy isonicotinic acid (0.20 g,
0.67 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl
ester (0.16 g, 0.7 mmol) were coupled using the procedure of
Example 5(c) to afford 0.12 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.12 (2H, m), 1.15 (6H, d), 1.4 (9H, s),
1.6 (2H, m), 1.75 (1H, m), 2.7 (1H, m), 2.98 (3H, m), 3.5 (1H, m),
4.45 (1H, m), 4.8 (1H, m), 6.48 (1H, s), 6.58 (1H, s), 6.8 (1H,
brs), 7.38 (2H, d), 7.9 (2H, d).
e)
4-{4-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-6-isopropoxy-pyridin-2-y-
loxy}-benzimidic acid ethyl ester
[0195]
(2-{1-[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperid-
in-4-yl}ethyl)-carbamic acid tert-butyl ester (0.12 g, 0.23 mmol)
was used and the procedure of Example 1(d) was followed to afford
0.11 g of the required product. Percentage purity (LCMS):
51.13%.
f)
4-{4-[4-(2-amino-ethyl)piperidine-1-carbonyl]-6-isopropoxy-pyridine-2-y-
loxy}-benzamidine
[0196]
4-{4-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-6-isopropoxy-pyridin-
-2-yloxy}-benzimidic acid ethyl ester (0.11 g, 0.24 mmol) was used
and the procedure of Example 1(e) was followed to afford 50 mg of
the required product. Percentage purity (HPLC): 99.46%, (LCMS):
97.7%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15 (6H, s), 1.5 (2H,
m), 1.6 (2H, m), 1.75 (1H, m), 2.7 (1H, m), 2.85 (2H, m), 3.0 (1H,
m), 3.2 (2H, s), 4.45 (1H, m), 4.85 (1H, m), 6.5 (1H, s), 6.6 (1H,
s), 7.4 (2H, d), 7.75 (3H, brs), 7.9 (2H, d), 9.25 (2H, m), 9.35
(2H, s).
Example 17
4-[5-[4-(2-aminoethyl)-piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phenox-
y)-pyridine-2-yloxy]benzamidine
a) 2-Chloro-6-(4-cyanophenoxy)nicotinic acid ethyl ester
[0197] 96.7 mg (0.7 mmol) of potassium carbonate was added to a
stirred solution of 2,6-dichloro nicotinic acid ethyl ester 0.15 g
(0.7 mmol) in 10 ml of N,N-dimethyl-formamide (DMF) cooled to
5.degree. C. This was followed by dropwise addition (over a period
of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of
DMF. The reaction mixture was allowed to stir at RT for 2 h,
concentrated under reduced pressure and the residue was dissolved
in 100 ml of ethylacetate. The organic layer was washed with water
and dried over anhydrous sodium sulphate and concentrated under
reduced pressure. The crude product was purified by column
chromatography using hexane:ethylacetate (8:2) as eluants to afford
0.13 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d),
7.96 (2H, d).
b) 6-(4-cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)nicotinic acid
ethyl ester
[0198] Potassium carbonate (60 mg, 0.43 mmol) was added to a
stirred and cooled (0.degree. C.) solution of
2-chloro-6-(4-cyanophenoxy)nicotinic acid ethyl ester 0.13 g (0.43
mmol) in 10 ml DMF and stirred for 10 min at the same temperature.
This was followed by the addition of 76.5 mg (0.43 mmol) of
4-trifluoromethoxy phenol, dissolved in 2 ml of DMF, over a period
of 10 min. After the addition was completed, the contents were
allowed to stir at RT. This was followed by heating for 3 h at
80.degree. C. The reaction mixture was concentrated under reduced
pressure, poured into ice-cold water and dissolved in 50 ml of
ethyl acetate. Organic layer was then washed with brine solution
followed by water and the crude product was purified by column
chromatography using hexane:ethyl acetate (8:2) to afford 0.18 g of
the required product. Percentage purity: LCMS eve mode):
20.12%.
c) 6-(4-Cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)nicotinic
acid
[0199] 6-(4-cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)nicotinic
acid ethyl ester (0.18 g, 0.40 mmol) was deesterified by using the
procedure of Example 5(b) to afford 0.15 g of the required product.
Percentage purity: LCMS eve mode): 41.96%.
d)
(2-{1-[6-(4-cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)pyridine-3-carbo-
nyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
[0200] 6-(4-Cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)nicotinic
acid (0.15 g, 0.36 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.082 g, 0.36 mmol) were coupled using the
procedure of Example 5(c) to afford 0.15 g of the required product.
Percentage purity (LCMS): 43.23%.
e)
4-[5-[4-(2-Aminoethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phen-
oxy)pyridine-2-yloxy]benzimidic acid ethyl ester
[0201]
(2-{1-[6-(4-cyanophenoxy)-2-(4-trifluoromethoxyphenoxy)pyridine-3-c-
arbonyl]-piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.15
g, 0.24 mmol) was used and the procedure of Example 1(d) was
followed to afford 0.20 g of the required product. Percentage
purity: LCMS (+ve mode): 35.2%.
f)
4-[5-[4-(2-aminoethyl)-piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phe-
noxy)-pyridine-2-yloxy]benzamidine
[0202]
4-[5-[4-(2-Aminoethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy--
phenoxy)-pyridine-2-yloxy]benzimidic acid ethyl ester (0.20 g, 0.34
mmol) was used and the procedure of Example 1(e) was followed to
afford 0.1 g of the required product. Percentage purity (HPLC):
89.68%, (LCMS): 74.9%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.05
(1H, m), 1.25 (1H, m), 1.65 (5H, m), 2.8 (4H, m), 3.2 (1H, m), 4.5
(1H, m), 6.85 (1H, d), 7.25 (2H, s), 7.35 (4H, m), 7.85 (4H, m),
7.9 (1H, m), 9.2 (2H, s), 9.3 (2H, s).
Example 18
4-[5-[4-(2-amino-ethyl)piperidine-1-carbonyl]-6-(4-fluoro-phenoxy)pyridine-
-2-yloxy]-benzamidine
[0203] Intermediate (a) is the same as in Example 17.
b) 6-(4-Cyanophenoxy)-2-(4-fluorophenoxy)nicotinic acid ethyl
ester
[0204] 2-Chloro-6-(4-cyanophenoxy)nicotinic acid ethyl ester (0.25
g, 0.81 mmol) and 4-fluorophenol (0.09 g, 0.81 mmol) were coupled
using the procedure of Example 17(b) to afford 0.23 g of the
required product. Percentage purity (LCMS): 61.86%.
c) 6-(4-cyanophenoxy)-2-(4-fluorophenoxy)nicotinic acid
[0205] 6-(4-Cyanophenoxy)-2-(4-fluorophenoxy)nicotinic acid ethyl
ester (0.23 g, 0.60 mmol) was deesterified using the procedure of
Example 5(b) to afford 0.2 g of the required product. Percentage
purity: LCMS (-ve mode): 57.29%.
d)
(2-{1-[6-(4-cyanophenoxy)-2-(4-fluorophenoxy)pyridine-3-carbonyl]piperi-
din-4-yl}ethyl)carbamic acid tert-butyl ester
[0206] 6-(4-cyanophenoxy)-2-(4-fluorophenoxy)nicotinic acid (0.2 g,
0.57 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl
ester (0.13 g, 0.57 mmol) were coupled using the procedure of
Example 5(c) to afford 0.25 g of the required product. Percentage
purity: LCMS (-ve mode): 67.5%.
e)
4-[5-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-6-(4-fluoro-phenoxy)-pyr-
idin-2-yloxy]-benzimidic acid ethyl ester
[0207]
(2-{1-[6-(4-cyanophenoxy)-2-(4-fluorophenoxy)pyridine-3-carbonyl]pi-
peridin-4-yl}ethyl)carbamic acid tert-butyl ester (0.25 g, 0.44
mmol) was used and the procedure of Example 1(d) was followed to
afford 0.28 g of the required product. Percentage purity (LCMS):
51.02%.
f)
4-[5-[4-(2-aminoethyl)piperidine-1-carbonyl]-6-(4-fluorophenoxy)pyridin-
e-2-yloxy]benzamidine
[0208]
4-[5-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-6-(4-fluoro-phenoxy)-
-pyridin-2-yloxy]-benzimidic acid ethyl ester (0.28 g, 0.55 mmol)
was used and the procedure of Example 1(e) was followed to afford
0.12 g of the required product. Percentage purity (HPLC): 95.03%,
(LCMS): 90.18%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.05 (2H, m),
1.25 (1H, s), 1.5 (2H, m), 1.65 (2H, m), 1.75 (1H, m), 2.8 (2H, m),
3.05 (3H, m), 3.65 (1H, d), 4.5 (1H, d), 6.8 (1H, s), 7.18 (2H, d),
7.36 (2H, d), 7.68 (2H, brs), 7.82 (1H, d), 7.94 (1H, m), 8.98 (1H,
s), 9.30 (1H, s).
Example 19
4-[3-[4-(2-aminoethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy
phenoxy)pyridin-2-yloxy]benzamidine
a) 2-Chloro-6-(4-trifluoromethoxyphenoxy)nicotinic acid ethyl
ester
[0209] 2,6-dichloronicotinic acid ethyl ester (0.22 g, 0.1 mmol)
and 4-trifluoromethoxy-phenol (0.178 g, 0.1 mmol) were coupled
using the procedure of Example 17(a) to afford 0.3 g of the
required product. Percentage purity (LCMS): 64.0%.
b) 2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)nicotinic acid
ethyl ester
[0210] 2-Chloro-6-(4-trifluoromethoxyphenoxy)nicotinic acid ethyl
ester (0.3 g, 0.83 mmol) and 4-cyanophenol (98.8 mg, 0.83 mmol)
were coupled using the procedure of Example 17(b) to afford 0.23 g
of the required product. Percentage purity (LCMS): 82.35%.
c) 2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)nicotinic
acid
[0211] 2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)nicotinic
acid ethyl ester (0.23 g, 0.51 mmol) was deesterified using the
procedure of Example 5(b) to afford 0.2 g of the required product.
Percentage purity: LCMS (-ve mode): 66.14%.
d)
(2-{1-[2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3-carbo-
nyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
[0212] 2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)nicotinic
acid (0.2 g, 0.48 mmol) and (2-Piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.11 g, 0.48 mmol) were coupled using the
procedure of Example 5(c) to afford 0.21 g of the required product.
Percentage purity (LCMS): 68.11%.
e)
4-[3-[4-(2-Amino-ethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phe-
noxy)-pyridine-2-yloxy]benzimidic acid ethyl ester
[0213]
(2-{1-[2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3-c-
arbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.2 g,
0.319 mmol) was used and the procedure of Example 1(d) was followed
to afford 0.25 g of the required product. Percentage purity (LCMS):
52.44%.
f)
4-[3-[4-(2-Amino-ethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phe-
noxy)-pyridine-2-yloxy]benzamidine
[0214]
4-[3-[4-(2-Amino-ethyl)piperidine-1-carbonyl]-6-(4-trifluoromethoxy-
-phenoxy)-pyridine-2-yloxyl]benzimidic acid ethyl ester (0.25 g,
0.43 mmol) was used and the procedure of Example 1(e) was followed
to afford 0.050 g of the required product. Percentage purity
(HPLC): 94.13%, (LCMS): 91.76%. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.5 (2H, m), 1.65 (2H, m), 1.75 (1H, m), 2.3 (1H, m), 2.8 (4H, m),
3.1 (2H, m), 3.65 (1H, d), 4.5 (1H, d), 6.88 (1H, s), 7.26 (2H, m),
7.36 (3H, m), 7.82 (2H, d), 7.94 (2H, brs), 9.14 (2H, s), 9.34 (2H,
s).
Example 20
4-[5-[4-(2-amino-ethyl)piperidine-1-carbonyl]-3-fluoro-6-(3-trifluorometho-
xy phenoxy)-pyridine-2-yloxy]benzamidine
a) 2-chloro-6-(4-cyanophenoxy)-5-fluoro nicotinic acid ethyl
ester
[0215] 2,6-Dichloro-5-fluoro-nicotinic acid ethyl ester (3.5 g,
15.0 mmol) and 4-cyano-phenol (1.78 g, 15.0 mmol) were coupled
using the procedure of Example 17(a) to afford 2.4 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35 (3H, t),
4.4 (2H, q), 7.58 (2H, d), 8.0 (2H, d), 8.4 (1H, d).
b)
6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)nicotinic
acid ethyl ester
[0216] 2-chloro-6-(4-cyanophenoxy)-5-fluoro nicotinic acid ethyl
ester (2.4 g, 7.49 mmol) and 3-trifluoromethoxyphenol (1.33 g, 7.49
mmol) were coupled using the procedure of Example 17(b) to afford
1.8 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.35 (3H, t), 4.4 (2H, q), 7.22 (2H, d), 7.3 (3H, d), 7.34 (1H, m),
7.54 (2H, d), 8.38 (1H, d).
c)
6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)nicotinic
acid
[0217]
6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)nicotinic
acid ethyl ester (1.8 g, 2.79 mmol) was deesterified using the
procedure of Example 5(b) to afford 1.3 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.22 (2H, d), 7.3 (4H, m), 7.74
(2H, d), 8.34 (1H, d), 13.2 (1H, brs).
d)
(2-{1-[6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)pyridin-
e-3-carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl
ester
[0218]
6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)nicotinic
acid (1.3 g, 2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.684 g, 3.0 mmol) were coupled using the
procedure of Example 5(c) to afford 1.1 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (2H, m), 1.4 (9H, d), 1.5
(2H, m), 1.6 (2H, m), 2.2 (1H, m), 2.35 (1H, m), 3.0 (3H, m), 3.7
(1H, m), 4.45 (1H, m), 6.78 (1H, m), 7.18 (1H, m), 7.26 (2H, m),
7.32 (1H, s), 7.46 (1H, m), 7.76 (1H, m), 7.86 (1H, s), 8.1 (1H,
m).
e)
4-[5-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-fluoro-6-(3-trifluoromet-
hoxy phenoxy)pyridine-2-yloxy]benzimidic acid ethyl ester
[0219]
(2-{1-[6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy)pyr-
idine-3-carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl
ester (1.1 g, 1.70 mmol) was used and the procedure of Example 1(d)
was followed to afford 1.0 g of the required product. Percentage
purity (LCMS): 11.21%.
f)
4-[5-[4-(2-Aminoethyl)piperidine-1-carbonyl-3-fluoro-6-(3-trifluorometh-
oxy phenoxy)pyridine-2-yloxy]benzamidine
[0220]
4-[3-[4-(2-Amino-ethyl)piperidine-1-carbonyl]-6-(3-trifluoromethoxy-
-phenoxy)-pyridine-2-yloxyl]benzimidic acid ethyl ester (1.0 g,
1.69 mmol) was used and the procedure of Example 1(e) was followed
to afford 0.250 g of the required product. Percentage purity
(HPLC): 98.16%, (LCMS): 90.93%. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.5 (3H, m), 1.6 (2H, m), 1.75 (2H, m), 2.0 (1H, m), 2.8 (4H, m),
4.5 (1H, m), 7.1 (2H, m), 7.25 (2H, m), 7.45 (2H, d), 8.0 (3H, m),
8.1 (2H, m), 9.20 (2H, s), 9.35 (2H, s).
Example 21
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-2-naphthalenesulfonamide
a) 1,5-Bis-(4-cyano-phenoxy)-2-nitrobenzene
[0221] 4-cyanophenol 4.5 g (23.0 mmol), dissolved in 5 ml of DMF,
was added to a stirred suspension of sodium hydride 0.92 g (23.0
mmol) in 5 ml of DMF cooled to 5.degree. C. The reaction flask was
stirred for 10 min at the same temperature and this was followed by
dropwise addition (over 15 min) of 2,4-dichloronitrobenzene 2.0 g
(10.5 mmol) dissolved in 5 ml of DMF. The reaction mixture was
stirred for 6 h at 70.degree. C. The reaction mass was poured into
ice-cold water and extracted with 200 ml of ethylacetate. The
organic phase was washed with 1M Na.sub.2CO.sub.3 and saturated
brine solution. The solution was dried over sodium sulphate and
concentrated to afford an oily residue, which was purified by
column chromatography using chlorofrom-ethyl acetate (10:2) to
afford 2.5 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 6.79 (1H, d), 6.93 (1H, d), 7.06 (2H, d), 7.18 (2H, d),
7.75 (4H, d), 8.16 (1H, d).
b) 1,5-Bis-(4-cyano-phenoxy)-2-aminobenzene
[0222] Zinc dust, 0.4 g (5.3 mmol) was added portionwise to a
reaction flask containing a stirred mixture (10 min) of
1,5-bis-(4-cyano-phenoxy)-2-nitrobenzene 1.5 g (4.2 mmol) and 0.085
g (0.08 mmol) of ammonium chloride dissolved in 25 ml of methanol.
The reaction mixture was allowed to stir for 1 h at RT. Reaction
mixture was filtered through celite and the filtrate was
concentrated to afford a brown viscous residue which was
partitioned between ethyl acetate and water. The organic layer was
dried over anhydrous sodium sulfate and concentrated to afford an
oily residue, which was purified by column chromatography using
chloroform-ethyl acetate (10:1) to afford 1.3 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.10 (2H, brs), 6.85
(3H, m), 7.06 (4H, m), 7.80 (4H, m).
c) Naphthalene-2-sulfonic acid
[2,4-bis-(4-cyano-phenoxy)-phenyl]-amide
[0223] 1,5-Bis-(4-cyano-phenoxy)-2-aminobenzene 0.175 g (0.54
mmol), 2-naphthalene-sulfonyl chloride 0.148 g (0.65 mmol) and
N,N-diisopropylethylamine (DIPEA) 0.85 g (0.65 mmol) were dissolved
in 5 ml of dry toluene and refluxed for 8 h. The reaction mixture
was concentrated under reduced pressure and the residue was
partitioned between water and ethyl acetate after the pH was
adjusted to 2 with 6 N HCl. The organic phase was washed with 1M
Na.sub.2CO.sub.3 (5.times.100 ml) and saturated brine solution. The
solution was dried over sodium sulphate and concentrated to afford
an oily residue, which was purified by column chromatography using
hexane-ethyl acetate (10:2) to afford 0.190 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.45 (3H, m), 7.16
(5H, m), 7.42 (6H, m), 7.75 (2H, dd), 8.10 (2H, d), 8.35 (1H,
s).
d) Naphthalene-2-sulfonic acid
[2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]-amide
[0224] Using naphthalene-2-sulfonic acid
[2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19 g, 0.36 mmol) and
following the procedure of Example 1(d) afforded 0.13 g of the
required product. Percentage purity (LCMS): 69.6%,
(M+1)=(609.1+1).
e) Naphthalene-2-sulfonic acid
[2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0225] Using naphthalene-2-sulfonic acid
[2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]-amide (0.13 g,
0.21 mmol) and following the procedure of Example 1(e) 0.033 g of
the required product was obtained. Percentage purity (HPLC):
96.91%, (LCMS): 96.74%. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.5
(1H, s), 6.7 (3H, m), 6.95 (2H, m), 7.2 (3H, m), 7.3 (1H, s) 7.45
(1H, m), 7.55 (2H, d), 7.7 (2H, m), 7.75 (1H, m), 7.85 (2H, d),
7.95 (2H, m), 8.1 (1H, m), 8.3 (1H, s), 9.0 (3H, m), 9.15 (2H, s),
9.25 (2H.$).
Example 22
4-Fluorobenzene-sulfonic acid
[2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0226] Intermediates (a) and (b) are the same as in Example 21.
c)
N-[2,4-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulfonamide
[0227] 4-Fluorobenzene sulfonyl chloride (0.126 g, 0.65 mmol) was
added to a stirred solution of
1,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along
with other reagents as mentioned in Example 20(c) to afford 0.18 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.86
(1H, brs), 6.95 (3H, m), 7.26 (2H, d), 7.34 (1H, d), 7.54 (3H, t),
7.82 (2H, d), 7.95 (2H, d), 7.95 (2H, m).
d) 4-Fluorobenzene-sulfonic acid
[2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]-amide
[0228] Using N-[2,4-bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzene
sulfonamide (0.18 g, 0.37 mmol) and following the procedure of
Example 1(d) afforded 0.16 g of the required product. Percentage
purity (LCMS): 62.0%, (M+1)=(577.1+1).
e) 4-Fluorobenzene-sulfonic acid
[2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0229] Using 4-fluorobenzene-sulfonic acid
[2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]-amide (0.16 g,
0.27 mmol) and following the procedure of Example 1(e) 0.033 g of
the required product was obtained. Percentage purity (HPLC):
96.54%, (LCMS): 95.4%. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.5 (1H,
s), 6.75 (1H, s), 6.95 (3H, m), 7.2 (2H, d), 7.3 (2H, d) 7.4 (1H,
d), 7.75 (3H, m), 7.85 (2H, d), 8.6 (1H, s), 8.95 (3H, brs), 9.25
(3H, brs), 10.2 (1H, brs).
Example 23
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-1-naphthalenesulfonamide
[0230] Intermediates (a) and (b) are the same as in Example 21.
c) Naphthalene-1-sulfonic acid
[2,4-bis-(4-cyano-phenoxy)-phenyl]amide
[0231] 1-Naphthalene sulfonyl chloride (0.148 g, 0.65 mmol) was
added to a stirred solution of
1,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along
with other reagents as mentioned in Example 20(c) to afford 0.19 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.45
(3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 7.85 (3H,
m).
d)
2,4-Bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl-1-naphthalenesulfonamide
[0232] Using naphthalene-1-sulfonic acid
[2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19 g, 0.36 mmol) and
following the procedure of Example 1(d) afforded 0.16 g of the
required product. Percentage purity (LCMS): 55.3%,
(M+1)=(609.19+1H).
e)
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-1-naphthalenesulfonamide
[0233] Using
2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl-1-naphthalene
sulfonamide (0.16 g, 0.26 mmol) and following the procedure of
Example 1(e) 0.035 g.of the required product was obtained.
Percentage purity (HPLC): 94.73%, (LCMS): 96.0%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.55 (1H, s), 7.1 (2H, d), 7.3 (2H, m), 7.4
(2H, d), 7.75 (4H, m), 7.9 (4H, m), 8.2 (1H, d), 8.4 (1H, d), 8.5
(2H, brs), 9.1 (4H, d), 9.3 (4H, s).
Example 24
N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzamide
a) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester
[0234] Potassium carbonate 2.1 g (15.2 mmol) dissolved in DMF
solution was added to 3,5-dihydroxy-benzoic acid ethyl ester 1.5 g
(8.2 mmol) dissolved in 15 ml of DMF. This was followed by dropwise
addition of 6-chloro-nicotinonitrile 2.1 g (15.2 mmol) dissolved in
5 ml of DMF. After complete addition, the reaction mixture was
stirred at 60.degree. C. for 8-10 h. The reaction mixture was
quenched with ice cold water and extracted with ethyl acetate. The
organic layer was washed with water followed by brine, dried over
anhydrous sodium sulphate and concentrated to afford a crude solid
which was purified by column chromatography using hexane-ethyl
acetate (10:2) to afford 2.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.30 (3H, t), 4.32 (2H, q), 7.35 (2H, d),
7.52 (1H, t), 7.68 (2H, d), 8.39 (2H, d), 8.69 (2H, s).
b) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid
[0235] 2.3 g (5.9 mmol) of
3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester was
hydrolysed by using the procedure of Example 5(b) to afford 1.8
g.of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 7.34
(2H, d), 7.48 (1H, t), 7.61 (2H, d), 8.38 (2H, dd), 8.70 (2H, d),
13.5 (1H, brs).
c)
{4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbami-
c acid tert-butyl ester
[0236] Following the procedure of Example 5(c)
3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoic acid 0.35 g (0.97 mmol)
and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g,
0.97 mmol) were used to afford 0.4 g.of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.47 (9H, s), 1.72 (5H, m),
1.82 (3H, m), 3.20 (1H, m), 3.72 (1H, m), 6.74 (1H, m), 7.18 (1H,
d), 7.32 (1H, s), 7.50 (1H, brs), 7.59 (1H, s), 8.08 (1H, brs),
8.30 (2H, dd), 8.39 (1H, dd), 8.67 (2H, d).
d)
N-(4-Amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)--
benzamide
[0237] Using
{4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (0.13 g, 0.23 mmol) and following the
procedure of Example 1(d) afforded 0.12 g of the required product.
Percentage purity (LCMS): 74.6%, (M+1)=546.2.
e)
N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzam-
ide
[0238] Using
N-(4-amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)-be-
nzamide (0.12 g, 0.21 mmol) and following the procedure of Example
1(e) 0.044 g.of the required product was obtained. Percentage
purity (HPLC): 98.4%, (LCMS): 96.7%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.8-2.0 (5H, m), 3.0 (2H, m), 3.7 (3H, m), 7.32 (2H, d),
7.40 (1H, s), 7.62 (2H, d), 7.88 (3H, brs), 8.30 (2H, dd), 8.42
(1H, m), 8.62 (2H, d), 9.24 (4H, s), 9.42 (3H, s).
Example 25
4-amino-1-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-
-1-yl}-butan-1-one
[0239] Intermediates (a) and (b) are the same as in Example 24.
c)
4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-1-carboxylic
acid tert-butyl ester
[0240] Following the procedure of Example 5(c)
3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoic acid 0.6 g (1.67 mmol)
and piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 1.67
mmol) were used to afford 0.55 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.42 (9H, s), 3.45 (6H, m), 3.56 (2H,
m), 7.20 (2H, d), 7.27 (1H, t), 7.32 (2H, d), 8.37 (2H, dd), 8.70
(2H, d).
d) 4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine
[0241] Using
4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-1-carboxyli
c acid tert-butyl ester (0.5 g, 0.94 mmol) and following the
procedure of Example 9(d) afforded 0.4 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 3.20 (4H, m), 3.46 (4H, m),
5.42 (1H, brs), 7.18 (2H, d), 7.25 (1H, t), 7.31 (2H, d), 8.41 (2H,
dd), 8.75 (2H, d).
e)
4-{4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazin-1-yl}-4-oxo--
butyl)-carbamic acid tert-butyl ester
[0242] Following the procedure of Example 5(c)
4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine 0.4 g
(0.93 mmol) and 4-tert-butoxycarbonylamino-butyric acid (0.19 g,
0.93 mmol) were used to afford 0.35 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.39 (9H, s), 1.60 (2H, q),
2.32 (3H, m), 2.94 (2H, q), 3.50 (7H, m), 6.80 (1H, brs), 7.15 (1H,
d), 7.28 (1H, t), 7.32 (2H, d), 8.37 (2H, dd), 8.72 (2H, d).
f)
[4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl}-pi-
perazin-1-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester
[0243]
4-{4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazin-1-yl}-4--
oxo-butyl)-carbamic acid tert-butyl ester 0.35 g (0.57 mmol), DIPEA
0.3 g (2.28 mmol) and 0.158 g (2.28 mmol) of hydroxylamine
hydrochloride were used as described in Example 2(d) to afford 0.25
g of the required product. Percentage purity (LCMS): 86.1%,
(M+1)=677.2 (with BOC). .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40
(9H, s), 1.62 (2H, q), 2.33 (2H, m), 2.92 (3H, m), 3.18 (1H, m),
3.50 (4H, m), 3.62 (2H, m), 6.16 (3H, brs), 6.82 (2H, t), 7.08 (2H,
s), 7.18 (3H, d), 8.14 (2H, dd), 8.48 (2H, s), 9.85 (2H, brs).
g)
[4-(4-{3,5-Bis-[5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy]-be-
nzoyl}-piperazin-1-yl)-4-oxo-butyl]-carbamic acid tert-butyl
ester
[0244]
[4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl-
}-piperazin-1-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester 0.25
g (0.37 mmol) was acetylated with 0.08 g (0.8 mmol) of acetic
anhydride using the procedure of Example 2(e) to afford 0.25 g of
the required product. Percentage purity (LCMS): 86.1%, (M+1)=761.2
(with BOC). .sup.1H NMR (DMSO-d.sub.6): .delta. 1.36 (9H, s), 1.62
(2H, m), 2.14 (6H, s), 2.33 (3H, m), 2.93 (3H, m), 3.55 (6H, brs),
6.82 (1H, brs), 6.95 (4H, brs), 7.18 (5H, m), 8.18 (2H, dd), 8.50
(2H, s).
h)
(4-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-1-y-
l}-4-oxo-butyl)-carbamic acid tert-butyl ester
[0245]
[4-(4-{3,5-Bis-[5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy-
]-benzoyl}-piperazin-1-yl)-4-oxo-butyl]-carbamic acid tert-butyl
ester 0.25 g (0.32 mmol) was reduced using the procedure of Example
2(f) to afford 0.12 g of the required product. Percentage purity
(LCMS): 68.7%, (M+1)=645.3+1.
i)
4-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-1-yl-
}-4-oxo-butanylamine
[0246] Using
(4-{4-[3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-1-yl}-
-4-oxo-butyl)-carbamic acid tert-butyl ester (0.12 g, 0.18 mmol)
and following the procedure of Example 9(d) afforded 0.05 g of the
required product. Percentage purity (HPLC): 87.7%, (LCMS): 86.4%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (2H, m), 1.75 (2H, m), 2.8
(2H, m), 3.2 (8H, m), 4.2 (2H, brs), 7.22 (3H, m), 7.36 (2H, m),
7.80 (3H, brs), 8.30 (2H, m), 8.66 (2H, s), 9.22 (3H, s), 9.44 (3H,
s).
Example 26
1-[(4-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-carbamimidoyl-phenoxy-
)-benzene
a) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester
[0247] Potassium carbonate 0.611 g (4.4 mmol) was added to a
stirred solution of 3,5-dihydroxy-benzoic acid ethyl ester 0.5 g
(1.7 mmol) dissolved in 15 ml of DMF and stirred for 10 min. This
was followed by dropwise addition of 4-fluorobenzonitrile 0.82 g
(6.8 mmol), dissolved in 5 ml of DMF, and the contents of the flask
were stirred at 80.degree. C. for 4 h. The reaction mixture was
poured into ice-cold water, and extracted with ethyl acetate. The
organic phase was washed with Na.sub.2CO.sub.3 and saturated brine
solution, dried over sodium sulphate and concentrated to afford an
oily residue which was purified by column chromatography using
hexane-ethyl acetate (10:2) to afford 0.4 g of the required
product. The yield was 0.6 g. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.30 (3H, t), 4.30 (2H, q), 7.25 (2H, d), 7.32 (1H, t), 7.46 (2H,
d), 7.90 (2H, d).
b) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid
[0248] 3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester 0.6 g
(1.56 mmol) was hydrolysed by using the procedure of Example 5(b)
to afford 0.45 g of required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 7.27 (3H, d), 7.40 (2H, d), 7.92 (2H, d), 13.5 (1H,
brs).
c)
1-[(4-Boc-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-cyano-phenoxy)-
-benzene
[0249] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
(2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.287 g,
1.26 mmol) were used to afford 0.4 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.05 (2H, m), 1.30 (2H, m),
1.40 (9H, s), 1.45 (4H, m), 2.60 (1H, m), 2.94 (3H, m), 3.54 (1H,
m), 4.38 (1H, m), 6.78 (1H, t), 6.75 (2H, d), 7.04 (1H, t), 7.25
(4H, d), 7.88 (2H, d).
d)
1-[(4-Boc-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-[4-(N-hydroxy-car-
bamimidoyl)-phenoxy]-benzene
[0250] Following the procedure of Example 2(d)
1-[(4-boc-amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-cyano-phenoxy)-b-
enzene 0.4 g (0.7 mmol) and other reagents were used to afford 0.35
g of the required product. Percentage purity (LCMS): 69.2%,
(M+1)=632.2+1.
e)
1-[(4-Boc-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-[4-(N-acetyl-hydr-
oxycarbamimidoyl)-phenoxy]-benzene
[0251] Following the procedure of Example 2(e)
1-[(4-boc-amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-[4-(N-hydroxycarbam-
imidoyl)-phenoxy]-benzene 0.35 g (0.55 mmol) was used to afford 0.3
g of the required product. Percentage purity (LCMS): 51.0%,
(M+1)=716.3 (with BOC).
f)
1-[(4-Boc-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-carbamimidoyl--
phenoxy)-benzene
[0252]
1-[(4-Boc-amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-[4-(N-acetylh-
ydroxy-carbamimidoyl)-phenoxy]-benzene 0.3 g (0.41 mmol) was
reduced using the procedure of Example 2(f) to afford 0.2 g of
required product. Percentage purity (LCMS): 74.0%,
(M+1)=600.3+1.
g)
1-[(4-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-carbamimidoyl-phen-
oxy)-benzene
[0253] Using
1-[(4-boc-Amino-ethyl)-piperidine-1-carbonyl]-3,5-bis-(4-carbamimidoyl-ph-
enoxy)-benzene (0.2 g, 0.33 mmol) and following the procedure of
Example 9(d) afforded 0.06 g of the required product. Percentage
purity (HPLC): 97.85%, (LCMS): 94.26%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.05 (2H, m), 1.4-1.8 (5H, m), 2.8 (3H, m), 3.0 (1H, m),
3.4 (1H, m), 4.4 (1H, m), 6.95 (3H, brs), 7.3 (3H, d), 7.9 (6H, d),
9.1-9.6 (7H, d).
Example 27
N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide
[0254] Intermediates (a) and (b) are the same as in Example 26.
c) {4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester
[0255] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.27 g, 1.26
mmol) were used to afford 0.52 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H,
m), 3.22 (1H, m), 3.68 (1H, m), 6.78 (1H, d, J=7.8 Hz), 7.24 (2H,
d, J=9.6 Hz), 7.51 (2H, d, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.35
(1H, d, J=7.5 Hz).
d)
(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohex-
yl)-carbamic acid tert-butyl ester
[0256] Following the procedure of Example 2(d)
{4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester 0.5 g (9 mmol) and other reagents were used
to afford 0.4 g of the required product. Percentage purity (LCMS):
68.0%, (M+1)=618.2+1. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.31 (4H,
m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (1H, m), 3.68 (1H, m), 6.78
(1H, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.42 (2H, d, J=2.1 Hz),
7.75 (2H, d, J=8.7 Hz), 7.92 (4H, brs), 8.35 (1H, d, J=7.5 Hz),
11.05 (2H, brs).
e)
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cy-
clohexyl)-carbamic acid tert-butyl ester
[0257] Following the procedure as in Example 2(e)
(4-{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexy-
l)-carbamic acid tert-butyl ester 0.4 g (0.64 mmol) was used to
afford 0.45 g of the required product. Percentage purity (LCMS):
89.0%, (M+1)=702.3+1. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (4H,
m), 1.45 (9H, s), 1.75 (4H, m), 2.62 (6H, s), 3.31 (1H, m), 3.78
(1H, m), 6.81 (1H, d, J=7.8 Hz), 7.04 (2H, d, J=9.2 Hz), 7.31 (2H,
d, J=1.9 Hz), 7.58 (2H, d, J=8.6 Hz), 8.30 (5H, brs).
f)
{4-[3,5-Bis-(4-carbamimidoylphenoxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0258]
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino-
}-cyclohexyl)-carbamic acid tert-butyl ester 0.45 g (0.64 mmol) was
reduced using the procedure of Example 2(f) to afford 0.3 g of
required product. Percentage purity (LCMS): 74.0%,
(M+1)=586.2+1.
g)
N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide
[0259] Using
{4-[3,5-bis-(4-carbamimidoylphenoxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester (0.3 g, 0.51 mmol) and following the
procedure of Example 9(d) afforded 0.06 g of the required product.
Percentage purity (HPLC): 87.7%, (LCMS): 94.5%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.44 (4H, m), 1.82 (4H, m), 3.05 (2H, m),
7.15 (1H, m), 7.35 (2H, d, J=9.4 Hz), 7.50 (2H, d, J=2.0 Hz), 7.88
(2H, d, J=8.6 Hz), 8.45 (1H, m), 9.11 (4H, brs), 9.25 (4H,
brs).
Example 28
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexylam-
ine
[0260] Intermediates (a) to (d) are the same as in Example 27.
e)
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexy-
lamine
[0261] Using
(4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl-
)-carbamic acid tert-butyl ester (0.3 g, 0.48 mmol) and following
the procedure of Example 9(d) afforded 0.06 g of the required
product. Percentage purity (HPLC): 96.2%, (LCMS): 97.2%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.38 (4H, m), 1.92 (4H, m), 3.02 (2H,
m), 3.71 (2H, m), 7.04 (2H, brs), 7.23 (4H, d), 7.44 (2H, s), 7.78
(5H, d), 7.92 (3H, brs), 8.44 (2H, brs), 11.05 (2H, brs).
Example 29
3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-1-yl}-propylami-
ne
[0262] Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-1-carboxylic
acid tert-butyl ester
[0263] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 1.26 mmol)
were used to afford 0.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.40 (9H, sm), 3.35 (6H, m), 3.55 (2H, m)
7.02 (2H, d), 7.08 (1H, t), 7.26 (2H, d), 7.88 (2H, d).
d) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine
[0264] Following the procedure of Example 9(d)
4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine-1-carboxylic acid
tert-butyl ester (0.5 g, 0.95 mmol) was used to afford 0.35 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 3.15 (4H,
m), 3.45 (4H, m), 7.06 (2H, d), 7.11 (1H, t), 7.26 (4H, d), 7.90
(4H, d), 8.25 (2H, brs).
e)
(3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-propyl)-carba-
mic acid tert-butyl ester
[0265] Following the procedure of Example 11(e)
4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol)
and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.195 g, 0.82
mmol) were used to afford 0.35 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.39 (9H, s), 1.52 (2H, m), 2.35 (8H,
m), 2.95 (2H, m), 3.56 (2H, brs), 6.79 (1H, m), 6.90 (2H, d), 7.04
(1H, t), 7.25 (4H, d), 7.88 (4H, d).
f)
3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl}-piperazin-1-yl-
)-propylamine
[0266] Using
(3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-propyl)-carbami-
c acid tert-butyl ester (0.35 g, 0.60 mmol) and following the
procedure of Example 1(d) afforded 0.15 g of the required product.
Percentage purity (LCMS): 56.0%, (M+1)=573.3.
g)
3-(4-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperazin-1-yl)-prop-
ylamine
[0267] Using
3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl}-piperazin-1-yl)--
propylamine (0.15 g, 0.26 mmol) and following the procedure of
Example 1(e) afforded 0.035 g of the required product. Percentage
purity (HPLC): 90.82%, (LCMS): 91.76%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.9 (3H, m), 2.85 (3H, m), 2.8-3.2 (6H, m), 4.4 (2H, m),
7.05 (3H, brs), 7.30 (4H, d), 7.90 (6H, d), 9.1 (3H, brs), 9.30
(4H, s).
Example 30
3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-1-yl}-3-oxo-pro-
pylamine
[0268] Intermediates (a) and (b) are the same as in Example 26.
[0269] Intermediates (c) and (d) are the same as in Example 29.
e)
(3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-3-oxo-propyl)-
-carbamic acid tert-butyl ester
[0270] 3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09
mmol) and 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine (0.5 g,
1.09 mmol) and other reagents as described in Example 9(e) were
used to afford 0.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.38 (9H, s), 2.45 (2H, m), 3.14 (2H, m),
3.52 (8H, m), 6.71 (1H, brs), 7.01 (2H, s), 7.08 (1H, t), 7.28 (4H,
d), 7.89 (4H, d).
f)
3-{4-[3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-1-yl-
}-3-oxo-propylamine
[0271] Using
(3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-3-oxo-propyl)-c-
arbamic acid tert-butyl ester (0.5 g, 0.83 mmol) and following the
procedure of Example 1(d) afforded 0.25 g of the required product.
Percentage purity (LCMS): 33.3%, (M+1)=587.2+1.
g)
3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-1-yl}-3-oxo--
propylamine
[0272] Using
3-{4-[3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-1-yl}--
3-oxo-propylamine (0.25 g, 0.42 mmol) and following the procedure
of Example 1(e) afforded 0.06 g of the required product. Percentage
purity (HPLC): 98.99%, (LCMS): 91.36%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 2.1 (3H, m), 2.70 (1H, m), 3.0 (1H, m), 3.15 (3H, brs),
3.75 (3H, m), 7.0 (3H, m), 7.30 (4H, d), 7.8 (2H, m), 7.9 (4H, d),
9.1 (2H, brs), 9.30 (5H, s), 9.45 (1H, m).
Example 31
2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-1-yl}-ethylamin-
e
[0273] Intermediates (a) and (b) are the same as in Example 26.
[0274] Intermediates (c) and (d) are the same as in Example 29.
e)
(2-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-ethyl)-carbam-
ic acid tert-butyl ester
[0275] Following the procedure of Example 11(e)
4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol)
and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.183 g, 0.82
mmol) were used to afford 0.4 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.39 (9H, s), 2.28 (6H, m), 3.04 (2H,
m), 3.54 (2H, m), 6.65 (1H, brs), 6.98 (2H, d), 7.05 (1H, t), 7.25
(4H, d), 7.88 (4H, d).
f)
2-{4-[3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-1-yl-
}-ethylamine
[0276] Using
(2-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1-yl}-ethyl)-carbamic
acid tert-butyl ester (0.4 g, 0.70 mmol) and following the
procedure of Example 1(d) afforded 0.2 g of the required product.
Percentage purity (LCMS): 79.3%, (M+1)=559.2+1.
g)
2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-1-yl}-ethyla-
mine
[0277] Using
2-{4-[3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-1-yl}--
ethylamine (0.2 g, 0.35 mmol) and following the procedure of
Example 1(e) afforded 0.04 g of the required product. Percentage
purity (HPLC): 87.99%, (LCMS): 96.56%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.1 (3H, t), 3.1 (8H, m), 7.0 (3H, s), 7.30 (4H, d), 7.9
(4H, d), 8.2 (2H, brs), 9.30 (8H, s).
Example 32
N-[1-(3-Amino-propyl)-piperidin-4-yl]-3,5-bis-(4-carbamimidoyl-phenoxy)-be-
nzamide
[0278] Intermediates (a) and (b) are the same as in Example 26.
c)
4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-1-carboxylic
acid tert-butyl ester
[0279] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.252 g,
1.26 mmol) were used to afford 0.5 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (9H, s), 1.75 (2H, m),
2.82 (2H, m), 3.18 (2H, d), 3.92 (3H, m), 7.25 (5H, m), 7.54 (2H,
d), 7.88 (4H, d), 38 (1H, brs).
d) 3,5-Bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide
[0280] Using
4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-1-carboxylic
acid tert-butyl ester (0.5 g, 0.92 mmol) and following the
procedure of Example 9(d) afforded 0.35 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.60 (2H, m), 1.95 (2H, m),
3.05 (2H, m), 3.34 (2H, m), 4.08 (1H, brs), 7.24 (5H, d), 7.57 (2H,
s), 7.90 (4H, d), 8.60 (1H, brs), 8.74 (1H, brs).
e)
(3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidin-1-yl}-propyl)--
carbamic acid tert-butyl ester
[0281] Following procedure of Example 11(e)
3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.35 g (0.79
mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.188 g,
0.79 mmol) were used to afford 0.4 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.38 (9H, s), 1.52 (4H, m),
1.75 (2H, m), 1.90 (2H, m), 2.28 (2H, m), 2.82 (1H, m), 2.92 (2H,
m), 3.74 (1H, brs), 3.68 (1H, m), 6.79 (1H, brs), 7.18 (1H, t),
7.26 (4H, d), 7.52 (2H, s), 7.88 (4H, d), 8.38 (1H, d).
f)
3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino}-piperidin-
-1-yl)-propylamine
[0282] Using
(3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-piperidin-1-yl}-propyl)-ca-
rbamic acid tert-butyl ester (0.4 g, 0.67 mmol) and following the
procedure of Example 1(d) afforded 0.2 g of the required product.
Percentage purity (LCMS): 99.0% (M+1)=587.3+1.
g)
3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-piperidin-1-yl}-p-
ropylamine
[0283] Using
3-(4-{3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino}-piperidin-1-
-yl)-propylamine (0.2 g, 0.34 mmol) and following the procedure of
Example 1(e) afforded 0.04 g of the required product. Percentage
purity (HPLC): 95.27%, (LCMS): 95.15%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.80 (2H, m), 2.0 (4H, m), 2.85 (2H, m), 3.1 (4H, m), 3.5
(2H, d), 4.0 (1H, m), 7.15 (1H, s), 7.30 (4H, d), 7.5 (2H, s), 7.9
(7H, d), 8.65 (1H, d), 9.25 (8H, d), 10.1 (1H, brs).
Example 33
N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
[0284] Intermediates (a), (b) and (c) are the same as in Example
26.
d)
{4-[3,5-Bis-(4-aminomethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester
[0285] 0.05 g of Raney nickel was added to 0.3 g (0.54 mmol) of
{4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester stirred with 50 ml of 10% NH.sub.3-methanol.
The reaction mixture was stirred overnight on hydrogen gas pressure
(50 psi) at 50.degree. C. The reaction mixture was filtered through
celite and concentrated to afford 0.25 g of the required product
which was used for the next step without further purification.
Percentage purity (LCMS): 70.8%, (M+1)=560.2+1
e)
N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
[0286] Using
{4-[3,5-bis-(4-aminomethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (0.25 g, 0.44 mmol) and following the
procedure of Example 9(d) afforded 0.03 g of the required product.
Percentage purity (HPLC): 98.8%, (LCMS): 96.0%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.37 (4H, m), 1.88 (4H, m), 2.96 (1H, m),
3.70 (1H, m), 4.02 (4H, s), 6.76 (1H, s), 7.14 (4H, d), 7.25 (2H,
s), 7.51 (4H, d), 7.82 (3H, brs), 8.18 (5H, brs), 8.42 (1H,
brs).
Example 34
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazine-1-carboxylic
acid ethyl ester
[0287] Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-1-carboxylic
acid ethyl ester
[0288] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
piperazine-1-carboxylic acid tert-butyl ester (0.234 g, 1.26 mmol)
were used to afford 0.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.18 (3H, t), 3.52 (8H, m), 4.15 (2H, q),
7.00 (2H, s), 7.07 (1H, s), 7.28 (2H, d), 7.88 (2H, d).
d)
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperazine-1-c-
arboxylic acid ethyl ester
[0289] Following the procedure of Example 2(d)
4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine-1-carboxylic acid
ethyl ester 0.5 g (1.0 mmol) and other reagents were used to afford
0.4 g of the required product. Percentage purity (LCMS): 51.8%,
(M+1)=562.2+1.
e)
4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperazi-
ne-1-carboxylic acid ethyl ester
[0290] Following the procedure of Example 2(e)
4-{3,5-bis-[4-(N-hydroxy-carbarnimidoyl)-phenoxy]-benzoyl}-piperazine-1-c-
arboxylic acid ethyl ester 0.4 g (0.71 mmol) was used to afford 0.4
g of the required product. Percentage purity (LCMS): 67.6%,
(M+1)=646.2+1.
f)
4-{3,5-Bis-[4-carbamimidoyl-phenoxy]-benzoyl}-piperazine-1-carboxylic
acid ethyl ester
[0291]
4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-pipe-
razine-1-carboxylic acid ethyl ester 0.4 g (0.61 mmol) was reduced
by using the procedure of Example 2(f) to afford 0.15 g of required
product. Percentage purity (HPLC): 94.1%, (LCMS): 92.83%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t), 3.4 (8H, m), 4.05 (2H, q),
6.95 (2H, s), 7.35 (4H, d), 7.9 (4H, d), 9.06 (3H, brs), 9.3 (4H,
s).
Example 35
1-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
[0292] Intermediates (a) and (b) are the same as in Example 26.
c) 1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-quinoline
[0293] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and
decahydro-quinoline (0.175 g, 1.26 mmol) were used to afford 0.5 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40
(6H, m), 1.62 (5H, m), 1.82 (1H, m), 3.10 (1H, m), 3.20 (1H, m),
3.91 (1H, m), 4.12 (1H, m), 6.88 (1H, s), 6.95 (1H, s), 7.02 (1H,
t), 7.28 (2H, d), 7.88 (2H, d).
d)
1-[3,5-Bis-((hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-quinolin-
e
[0294] Following the procedure of Example 2(d)
1-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-quinoline 0.5 g
(1.04 mmol) and other reagents were used to afford 0.52 g of the
required product. Percentage purity (LCMS): 41.7%,
(M+1)=543.2+1.
e)
1-[3,5-Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro--
quinoline
[0295] Following the procedure of Example 2(e)
1-[3,5-bis-((N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-quinolin-
e 0.5 g (0.91 mmol) was used to afford 0.45 g of the required
product. Percentage purity (LCMS): 63.0%, (M+1)=627.2+1.
f)
1-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
[0296]
1-[3,5-Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahy-
dro-quinoline, 0.45 g (0.71 mmol) was reduced using the procedure
of Example 2(f) to afford 0.2 g of required product. Percentage
purity (HPLC): 95.37%, (LCMS): 93.43%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.7 (11H, m), 1.85 (1H, m), 3.20 (2H, m), 3.9 (1H, m), 4.05
(1H, m), 6.84 (1H, brs), 6.9 (1H, brs), 7.0 (1H, s), 7.54 (4H, d),
7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 36
3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
[0297] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide
[0298] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and
diisobutyl-amine (0.29 g, 2.24 mmol) were used to afford 0.74 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 0.72 (6H,
d), 0.88 (6H, d), 1.82 (1H, m), 2.00 (1H, m), 3.06 (2H, d), 3.24
(2H, d), 6.98 (2H, d), 7.04 (1H, t), 7.22 (4H, d), 7.89 (4H,
d).
d)
3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-N,N-diisobutyl-benzamide
[0299] Using 3,5-bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide
(0.74 g, 1.58 mmol) and following the procedure of Example 1(d)
afforded 0.8 g of the required product. Percentage purity (LCMS):
52.8%, (M+1)=559.3+1.
e) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
[0300] Using
3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-N,N-diisobutyl-benzamide
(0.8 g, 0.1.42 mmol) and following the procedure of Example 1(e)
afforded 0.36 g of the required product. Percentage purity (HPLC):
97.51%, (LCMS): 97.48%. .sup.1H NMR (DMSO-d.sub.6): .delta. 0.7
(6H, s), 0.80 (6H, s), 1.8 (1H, m), 2.0 (1H, m), 3.1 (2H, d), 3.2
(2H, d), 6.9 (2H, d), 7.0 (1H, s), 7.3 (4H, d), 7.88 (4H, d), 9.12
(4H, s), 9.28 (4H, s).
Example 37
2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
[0301] Intermediates (a) and (b) are the same as in Example 26.
c) 2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
[0302] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and
decahydro-isoquinoline (0.467 g, 3.36 mmol) were used to afford
1.25 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.30 (5H, m), 1.62 (5H, m), 1.85 (1H, m), 3.05 (1H, m), 3.18 (1H,
m), 3.51 (1H, m), 3.90 (1H, m), 4.12 (1H, m), 6.86 (1H, s), 6.95
(1H, s), 7.04 (1H, t), 7.26 (2H, d), 7.86 (2H, d).
d)
2-[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-isoq-
uinoline
[0303] Following the procedure of Example 2(d)
2-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline 1.25 g
(2.61 mmol) and other reagents were used to afford 1.3 g of the
required product. Percentage purity (LCMS): 80.0%,
(M+1)=543.2+1.
e)
1-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydr-
o-isoquinoline
[0304] Following the procedure of Example 2(e)
2-[3,5-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-isoqui-
noline 1.3 g (2.39 mmol) was acetylated to afford 1.2 g of the
required product. Percentage purity (LCMS): 70.0%,
(M+1)=627.2+1.
f)
2-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-isoquinoline
[0305]
2-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nona-
hydro-isoquinoline, 1.2 g (1.91 mmol) was reduced using the
procedure of Example 2(f) to afford 0.4 g of required product.
Percentage purity (HPLC): 95.37%, (LCMS): 93.43%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.7 (11H, m), 1.85 (1H, m), 3.20 (2H, m),
3.9 (1H, m), 4.05 (1H, m), 6.84 (1H, brs), 6.9 (1H, brs), 7.0 (1H,
s), 7.54 (4H, d), 7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 38
3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diethyl-benzamide
[0306] Intermediates (a) and (b) are same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diethyl-benzamide
[0307] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and
diethyl-amine (0.245 g, 3.36 mmol) were used to afford 1.0 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15 (6H, m),
3.22 (2H, m), 3.40 (2H, m), 6.94 (2H, d), 7.05 (1H, t), 7.25 (2H,
d), 7.88 (2H, d).
d)
N,N-Diethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzamide
[0308] Following the procedure of Example 2(d)
N,N-diethyl-3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-benzamide
1.0 g (2.43 mmol) and other reagents were used to afford 1.1 g of
the required product. Percentage purity (LCMS): 80.0%,
(M+1)=477.2+1.
e)
N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamid-
e
[0309] Following the procedure of Example 2(e)
N,N-diethyl-3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-benzamide
1.1 g (2.3 mmol) was acetylated to afford 1.0 g of the required
product. Percentage purity (LCMS): 77.0%, (M+1)=561.2+1.
f) 3,5-Bis-(4-carbonimidoyl-phenoxy)-N,N-diethyl-benzamide
[0310]
N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benz-
amide, 1.0 g (1.78 mmol) was reduced using the procedure of Example
2(f) to afford 0.35 g of required product. Percentage purity
(HPLC): 95.41%, (LCMS): 93.34%. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.02 (6H, s), 3.2 (2H, m), 3.4 (2H, m), 6.9 (2H, d), 7.0 (1H, s),
7.3 (4H, d), 7.88 (4H, d), 9.24 (3H, s), 9.30 (3H, s).
Example 39
N-(3-Amino-propyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-N-cyclopropyl-benzami-
de
[0311] Intermediates (a) and (b) are the same as in Example 26.
c)
(3-{[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-cyclopropyl-amino}-propyl)-carb-
amic acid tert-butyl ester
[0312] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and
(3-cyclopropylamino-propyl)-carbamic acid tert-butyl ester (0.72 g,
3.36 mmol) were used to afford 1.5 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.48 (1H, m), 0.65 (2H, m),
1.38 (9H, s), 1.42 (2H, m), 1.68 (2H, m), 2.95 (2H, m), 3.22 (2H,
m), 6.80 (1H, brs), 6.95 (1H, s), 7.08 (2H, m), 7.25 (4H, m), 7.88
(4H, m).
d)
[3-({3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl--
amino)-propyl]-carbamic acid tert-butyl ester
[0313] Following the procedure of Example 2(d)
(3-{[3,5-bis-(4-cyano-phenoxy)-benzoyl]-cyclopropyl-amino}-propyl)-carbam-
ic acid tert-butyl ester 1.5 g (2.71 mmol) and other reagents were
used to afford 1.3 g of the required product. Percentage purity
(LCMS): 42.8.0%, (M+1)=618.2 (with BOC).
e)
[3-({3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-cyclop-
ropyl-amino)-propyl]-carbamic acid tert-butyl ester
[0314] Following the procedure of Example 2(e)
[3-({3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-a-
mino)-propyl]-carbamic acid tert-butyl ester 1.3 g (2.1 mmol) was
acetylated to afford 1.25 g of the required product. Percentage
purity (LCMS): 83.0%, (M+1)=702.3.
f)
[3-({3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)-pr-
opyl]-carbamic acid tert-butyl ester
[0315]
[3-({3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-cy-
clopropyl-amino)-propyl]-carbamic acid tert-butyl ester, 1.25 g
(1.77 mmol) was reduced using the procedure of Example 2(f) to
afford 0.85 g of the required product. Percentage purity (LCMS):
72.0%, (M+1)=486.3+1 (de-Boc mass; -100).
g) 3,5-Bis-(4-carbamimidoyl-phenoxy)-cyclohexa-1,5-dienecarboxylic
acid (3-amino-propyl)-cyclopropyl-amide
[0316] Using
[3-({3,5-bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)-prop-
yl]-carbamic acid tert-butyl ester (0.85 g, 1.44 mmol) and
following the procedure of Example 9(d) afforded 0.2 g of the
required product. Percentage purity (HPLC): 96.18%, (LCMS): 94.22%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.50 (2H, m), 0.65 (2H, m),
1.88 (2H, m), 2.85 (3H, m), 3.49 (2H, m), 7.02 (1H, t), 7.14 (2H,
s), 7.25 (4H, d), 7.80 (2H, brs), 7.88 (4H, d), 9.22 (3H, s), 9.28
(3H, s).
Example 40
[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-dihydro-1H-quinoline
[0317] Intermediates (a) and (b) are the same as in Example 26.
c) [3,5-Bis-(4-cyano-phenoxy)-benzoyl]-3,4-dihydro-1H-quinoline
[0318] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and
1,2,3,4-tetrahydro-quinoline (0.44 g, 3.36 mmol) were used to
afford 1.3 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.92 (2H, t), 2.54 (2H, m), 3.75 (2H, t), 6.92 (2H, d),
7.08 (7H, m), 7.82 (4H, d).
d)
[3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydro-1H-q-
uinoline
[0319] Following the procedure of Example 2(d)
[3,5-bis-(4-cyano-phenoxy)-benzoyl]-3,4-dihydro-1H-quinoline 1.3 g
(2.75 mmol) and other reagents were used to afford 1.25 g of the
required product. Percentage purity (LCMS): 66.1%,
(M+1)=537.2.2+1.
e)
[3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydr-
o-1H-quinoline
[0320] Following the procedure of Example 2(e)
[3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydro-1H-qui-
noline 1.25 g (2.32 mmol) was acetylated to afford 1.2 g of the
required product. Percentage purity (LCMS): 65.5%,
(M+1)=621.2+1.
f)
[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-Dihydro-1H-quinoline
[0321]
[3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-di-
hydro-1H-quinoline, 1.2 g (1.93 mmol) was reduced using the
procedure of Example 2(f) to afford 0.75 g of required product.
Percentage purity (HPLC): 99.56%, (LCMS): 96.29%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.92 (2H, q), 2.74 (2H, t), 3.75 (2H, t),
6.85 (1H, brs), 6.90 (2H, d), 6.98 (1H, t), 7.15 (7H, m), 7.84 (4H,
d), 9.14 (4H, s), 9.26 (4H, s).
Example 41
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-carbamimidoyl-phenoxy)-
-benzene
[0322] Intermediates (a) and (b) are the same as in Example 26.
c)
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benz-
ene
[0323] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and
1,2,3,4-tetrahydro-isoquinoline (0.3 g, 2.26 mmol) were used to
afford 0.9 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 2.82 (2H, m), 3.58 (1H, m), 3.80 (1H, m), 4.08 (1H, m),
4.74 (1H, m), 7.10 (3H, m), 7.20 (4H, m), 7.28 (4H, d), 7.90 (2H,
d).
d)
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-hydroxy-carbamim-
idoyl)-phenoxy)-benzene
[0324] Following the procedure of Example 2(d)
[3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benzen-
e 0.9 g (1.9 mmol) and other reagents were used to afford 0.85 g of
the required product. Percentage purity (LCMS): 38.9%,
(M+1)=537.0+1.
e)
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-acetylhydroxy-ca-
rbamimidoyl)-phenoxy)-benzene
[0325] Following the procedure of Example 2(e)
[3,4-dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-hydroxycarbamimido-
yl)-phenoxy)-benzene 0.85 g (1.58 mmol) was acetylated to afford
0.8 g of the required product. Percentage purity (LCMS): 58.1%,
(M+1)=621.2+1.
f)
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-Bis-(4-carbamimidoyl-pheno-
xy)-benzene
[0326]
[3,4-Dihydro-1H-isoquinoline-2-carbonyl]-3,5-bis-(4-(N-acetylhydrox-
y-carbamimidoyl)-phenoxy)-benzene, 0.8 g (1.28 mmol) was reduced
using the procedure of Example 2(f) to afford 0.15 g of required
product. Percentage purity (HPLC): 93.50%, (LCMS): 94.20%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 2.80 (2H, m), 3.60 (1H, m), 3.80 (1H,
m), 4.67 (2H, m), 6.98 (2H, m), 7.05 (1H, s), 7.18 (4H, m), 7.35
(4H, d), 7.90 (4H, d), 9.10 (4H, brs), 9.28 (3H, brs).
Example 42
N-(4-Aminocyclohexyl)-3-(3-carbamimidoylbenzyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
a) 3-(4-Cyanophenoxy)-5-hydroxy benzoic acid ethyl ester
[0327] Potassium carbonate 6.7 g (48.5 mmol) followed by 4-fluoro
benzonitrile 3.3 g (27.2 mmol) in 10 ml of DMF was added to a
solution of 3,5-dihydroxy benzoic acid ethyl ester 5 g (27.4 mmol)
in 20 ml of DMF at 20.degree. C. The reaction mixture was allowed
to attain RT and was then heated to 45.degree. C. for 10 h. The
reaction mixture was quenched with ice cold water and extracted
with ethyl acetate. The organic layer was washed with water
followed by brine, dried over anhydrous sodium sulphate and
concentrated. The crude compound was purified by column
chromatography using hexane-ethyl acetate (10:2) to afford 1.15 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.3
(3H, t), 4.3 (2H, q), 6.76 (1H, s), 7.02 (1H, s), 7.36 (2H, d),
7.24 (1H, s), 7.88 (2H, d), 10.3 (1H, s).
b) 3-(3-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid ethyl
ester
[0328] Potassium carbonate K.sub.2CO.sub.3 0.44 g (3.18 mmol)
followed by 3-cyano benzylbromide 0.31 g (1.58 mmol) in 2 ml of DMF
were added to a solution of 3-(4-cyanophenoxy)-5-hydroxy benzoic
acid ethyl ester 0.45 g (1.58 mmol) in 7 ml of DMF at 20.degree. C.
The reaction mixture was allowed to attain RT and stirred
overnight. The reaction mixture was quenched with ice cold water,
extracted with ethyl acetate. The organic layer was washed with
water followed by brine, dried over anhydrous sodium sulphate and
concentrated to afford 0.51 g of a thick oily liquid. .sup.1H NMR
(CDCl.sub.3): .delta. 1.3 (3H, t), 4.3 (2H, q), 5.25 (2H, s), 6.88
(1H, s), 7.02 (2H, d), 7.34 (1H, s), 7.5 (2H, m), 7.66 (4H, m),
7.78 (1H, s).
c) 3-(3-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid
[0329] 1.6 g (4.01 mmol) of
3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 1.2 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.25 (2H,
s), 7.16 (4H, m), 7.44 (1H, s), 7.64 (1H, m), 7.9 (5H, m), 13.4
(1H, brs).
d)
{4-[3-(3-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-car-
bamic acid tert-butyl ester
[0330] Following the procedure of Example 5(c)
3-(3-cyanobenzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.46 g (1.24
mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester
(0.265 g, 1.24 mmol) were used to afford 0.52 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.40
(9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.25 (2H, s), 6.74
(1H, d), 7.02 (1H, s), 7.32 (2H, d), 7.22 (1H, s), 7.44 (1H, s),
7.64 (1H, m), 7.84 (4H, m), 7.95 (1H, s), 8.3 (1H, d).
e)
4-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phenoxy-
)benzoylamino]cyclohexylamine
[0331] Using
{4-[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carba-
mic acid tert-butyl ester (0.5 g, 0.88 mmol) and following the
procedure of Example 1(d) afforded 0.3 g of the required product.
Percentage purity (LCMS): 64.2%, (M+1)=558.2+1.
f)
N-(4-Aminocyclohexyl)-3-(3-carbamimidoylbenzyloxy)-5-(4-carbamimidoyl-p-
henoxy)benzamide
[0332] Using
4-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl
phenoxy)benzoylamino]cyclohexylamine (0.3 g, 0.53 mmol) and
following the procedure as in Example 1(e) afforded 0.16 g of the
required product. Percentage purity (HPLC): 96.67%, (LCMS): 99.51%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.9 (4H, m), 3.0
(1H, m), 3.70 (1H, m), 5.30 (2H, s), 7.0 (1H, s), 7.2 (3H, d), 7.45
(1H, s), 7.70 (1H, m), 7.8-8.0 (7H, m), 8.4 (1H, d), 9.25 (4H, d),
9.4 (4H, d).
Example 43
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbenzyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0333] Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid ethyl
ester
[0334] Using 0.66 g (2.3 mmol) of 3-(4-cyanophenoxy)-5-hydroxy
benzoic acid ethyl ester and 4-cyanobenzylbromide (0.45 g, 2.3
mmol) and following the procedure of Example 42(b) afforded 0.72 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.3
(3H, t), 4.3 (2H, q), 5.35 (2H, s), 7.16 (4H, m), 7.44 (1H, s),
7.66 (2H, s), 7.88 (4H, d).
c) 3-(4-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid
[0335] 0.72 g (1.8 mmol) of
3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 0.55 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.25 (2H,
s), 7.10 (1H, m), 7.18 (3H, m), 7.42 (1H, s), 7.66 (2H, s), 7.88
(4H, d).
d)
{4-[3-(4-Cyanobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}carb-
amic acid tert-butyl ester
[0336] Following the procedure of Example 5(c)
3-(4-cyanobenzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.55 g (1.48
mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester
(0.316 g, 1.48 mmol) were used to afford 0.75 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.40
(9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.3 (2H, s), 6.74
(1H, d), 7.02 (1H, s), 7.1 (2H, s), 7.22 (1H, s), 7.44 (1H, s),
7.66 (2H, d), 7.88 (4H, m), 8.28 (1H, d).
e)
4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phenoxy-
)-benzoylamino]cyclohexylamine
[0337] Using
{4-[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]-cyclohexyl}carba-
mic acid tert-butyl ester (0.75 g, 1.32 mmol) and following the
procedure of Example 1(d) afforded 0.35 g of the required product.
Percentage purity (LCMS): 33.7%, (M+1)=558.2+1.
f)
N-(4-Amino-cyclohexyl)-3-(4-carbarnimidoyl-benzyloxy)-5-(4-carbamimidoy-
l-phenoxy)benzamide
[0338] Using 4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy
carbonimidoyl-phenoxy)-benzoylamino]cyclohexylamine (0.35 g, 0.62
mmol) and following the procedure of Example 1(e) afforded 0.12 g
of the required product. Percentage purity (HPLC): 91.03%, (LCMS):
96.32%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.9 (4H,
m), 3.0 (1H, m), 3.70 (1H, m), 5.30 (2H, s), 7.0 (1H, s), 7.2 (3H,
d), 7.45 (1H, s), 7.70 (2H, d), 7.9 (6H, m), 8.4 (1H, m), 9.3 (7H,
t).
Example 44
N-(4-Amino-cyclohexyl)-3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-hy-
droxycarbamimidoyl)-phenoxy]-benzamide
[0339] Intermediates (a) to (d) are the same as in Example 43.
e)
(4-{3-[4-(N-Hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-hydroxy-carbamimid-
oyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl
ester
[0340] Following the procedure of Example 2(d)
{4-[3-(4-cyanobenzyloxy)-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.65
g (1.14 mmol) and other reagents were used to afford 0.52 g of the
required product. Percentage purity (LCMS): 48.2%,
(M+1)=632.3+1.
f)
N-(4-Amino-cyclohexyl)-3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-
-hydroxycarbamimidoyl)-phenoxy]-benzamide
[0341] Using
(4-{3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-hydroxy-carbamimidoy-
l)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl
ester (0.5 g, 0.8 mmol) and following the procedure of Example 9(d)
afforded 0.28 g of the required product. Percentage purity (HPLC):
96.4%, (LCMS): 96.7%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.48 (4H,
m), 1.98 (4H, m), 3.04 (1H, m), 3.76 (1H, m), 5.42 (2H, s), 7.05
(1H, s), 7.24 (3H, m), 7.48 (2H, m), 7.70 (2H, d), 7.81 (4H, d),
7.91 (3H, brs), 8.42 (1H, d), 8.72 (2H, brs), 11.04 (2H, brs).
Example 45
N-(4-Aminocyclohexyl)-3-(4-aminomethylbenzyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0342] Intermediate (a) is the same as in Example 42.
b)
3-(4-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzo-
ic acid ethyl ester
[0343] Using 0.85 g (3.0 mmol) of 3-(4-cyanophenoxy)-5-hydroxy
benzoic acid ethyl ester and (4-bromomethyl-benzyl)-carbamic acid
tert-butyl ester (0.9 g, 3.0 mmol) and following the procedure of
Example 42(b) afforded 1.32 g of the required product. .sup.1H NMR
(CDCl.sub.3): .delta. 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d), 4.3
(2H, q), 5.25 (2H, s), 7.18 (4H, m), 7.26 (2H, d), 7.4 (4H, m),
7.88 (2H, d).
c)
3-(4-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzo-
ic acid
[0344] 1.3 g (2.58 mmol) of
3-(4-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzoic
acid ethyl ester was hydrolysed using the procedure of Example 5(b)
to afford 1.1 g.of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.4 (9H, s), 4.15 (2H, d), 5.2 (2H, s),
7.08 (1H, m), 7.16 (3H, m), 7.26 (2H, d), 7.88 (2H, d), 13.2 (1H,
brs)
d) {4-[3-(4-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
[0345] Following the procedure of Example 5(c)
3-(4-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzoic
acid 1.1 g (2.31 mmol) and (4-amino-cyclohexyl)-carbamic acid
tert-butyl ester (0.494 g, 2.31 mmol) were used to afford 1.24 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H,
m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H,
d), 5.15 (2H, s), 6.74 (1H, d), 6.88 (1H, s), 7.12 (2H, d), 7.18
(1H, s), 7.26 (2H, d), 7.4 (4H, d), 7.86 (2H, d), 8.26 (1H, d).
e)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-aminomethylbenzyloxy)phenoxy]ben-
zimidic acid ethyl ester
[0346] Using
{4-[3-(4-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (1.2
g, 1.78 mmol) and following the procedure of Example 1(d) afforded
0.5 g of the required product. Percentage purity (LCMS): 52.0%,
(M+1)=516.2+1.
f)
N-(4-Aminocyclohexyl)-3-(4-aminomethylbenzyloxy)-5-(4-carbamimidoyl-phe-
noxy)benzamide
[0347] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-aminomethylbenzyloxy)phenoxy]benzi-
midic acid ethyl ester (0.5 g, 0.96 mmol) and following the
procedure of Example 1(e) afforded 0.15 g of the required product.
Percentage purity (HPLC): 96.46%, (LCMS): 98.41%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.85 (2H, m), 1.95 (2H, m),
3.0 (1H, m), 4.1 (3H, s), 5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, m),
7.5 (5H, m), 7.85 (4H, m), 8.25 (2H, brs), 8.4 (1H, d), 9.2 (4H,
s).
Example 46
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-carbami-
midoyl)-phenoxy]-benzamide
[0348] Intermediates (a) to (d) are the same as in Example 45.
e)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-c-
arbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester
[0349] Following the procedure of Example 2(d)
{4-[3-(4-(tert-butoxycarbonylamino-methyl)benzyloxy)-5-(4-cyanophenoxy)be-
nzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.6 g (0.89
mmol) and other reagents were used to afford 0.55 g of the required
product. Percentage purity (LCMS): 38.9%, (M+1)=703.3+1.
g)
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-carb-
amimidoyl)-phenoxy]-benzamide
[0350] Using
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-car-
barnimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester (0.55 g, 0.78 mmol) and following the procedure of
Example 9(d) afforded 0.15 g of the required product. Percentage
purity (HPLC): 96.9%, (LCMS): 92.4%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.40 (4H, m), 1.90 (4H, m), 3.00 (1H, m), 3.71 (1H, m),
4.15 (2H, s), 5.18 (2H, s), 6.98 (1H, s), 7.16 (3H, m), 7.40 (1H,
s), 7.50 (4H, m), 7.76 (2H, d), 7.90 (3H, brs), 8.30 (4H, brs),
8.65 (1H, brs), 11.25 (1H, brs).
Example 47
N-(4-Aminocyclohexyl)-3-(3-aminomethylbenzyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0351] Intermediate (a) is the same as in Example 42.
b)
3-(3-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzo-
ic acid ethyl ester
[0352] Using 1.4 g (4.94 mmol) of 3-(4-cyanophenoxy)-5-hydroxy
benzoic acid ethyl ester and (3-bromomethyl-benzyl)-carbamic acid
tert-butyl ester (1.48 g, 4.94 mmol) and following the procedure of
Example 42(b) afforded 1.9 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d),
4.35 (2H, q), 5.25 (2H, s), 7.18 (5H, m), 7.32 (3H, m), 7.44 (2H,
s), 7.88 (2H, d).
c)
3-(3-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzo-
ic acid
[0353] 1.9 g (3.78 mmol) of
3-(3-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzoic
acid ethyl ester was hydrolysed using the procedure of Example 5(b)
to afford 1.35 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.4 (9H, s), 4.05 (2H, s), 5.2 (2H, s), 7.1
(5H, m), 7.3 (5H, m), 7.9 (2H, m), 13.2 (1H, brs)
d)
{4-[3-(3-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)--
benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
[0354] Following the procedure of Example 5(c)
3-(3-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzoic
acid 0.65 g (1.36 mmol) and (4-amino-cyclohexyl)-carbamic acid
tert-butyl ester (0.29 g, 1.36 mmol) were used to afford 0.7 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H,
m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H,
d), 5.15 (2H, s), 6.74 (1H, d), 6.9 (1H, s), 7.10 (2H, d), 7.2 (2H,
m), 7.35 (3H, m), 7.45 (2H, m), 7.86 (2H, d), 8.26 (1H, d).
e)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(3-aminomethylbenzyloxy)phenoxy]ben-
zimidic acid ethyl ester
[0355] Using
{4-[3-(3-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (0.7
g, 1.04 mmol) and following the procedure of Example 1(d) afforded
0.3 g of the required product. Percentage purity (LCMS): 98.0%,
(M+1)=703.3+1.
f)
N-(4-Aminocyclohexyl)-3-(3-aminomethylbenzyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0356] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-aminomethylbenzyloxy)phenoxy]benzi-
midic acid ethyl ester (0.3 g, 0.58 mmol) and following the
procedure of Example 1(e) afforded 0.12 g of the required product.
Percentage purity (HPLC): 97.76%, (LCMS): 92.64%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.35 (4H, m), 1.9 (4H, m), 3.0 (2H, m), 4.1
(2H, d), 5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, m), 7.45 (3H, m), 7.55
(1H, s), 7.85 (4H, m), 8.2 (2H, brs), 8.35 (1H, d), 9.0 (2H, s),
9.25 (2H, s).
Example 48
N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-carbami-
midoyl)-phenoxy]-benzamide
[0357] Intermediates (a) to (d) are the same as in Example 47.
e)
(4-{3-[3-(tert-Butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-c-
arbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester
[0358] Following the procedure of Example 2(d)
{4-[3-(3-(tert-butoxycarbonylamino-methyl)benzyloxy)-5-(4-cyanophenoxy)be-
nzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.65 g (0.97
mmol) and other reagents were used to afford 0.6 g of the required
product. Percentage purity (LCMS): 38.9%, (M+1)=503.3+1 (de-Boc;
2.times.100).
f)
N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-carb-
amimidoyl)-phenoxy]-benzamide
[0359] Using
(4-{3-[3-(tert-butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-car-
bamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester (0.6 g, 0.85 mmol) and following the procedure of
Example 9(d) afforded 0.2 g of the required product. Percentage
purity (HPLC): 98.8%, (LCMS): 94.1%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.4 (4H, m), 1.82 (4H, m), 3.03 (1H, m), 3.65 (1H, m), 4.10
(3H, brs), 5.18 (2H, s), 6.98 (1H, s), 7.18 (3H, d), 7.4 (1H, s),
7.46 (3H, m), 7.55 (1H, s), 7.76 (2H, d), 7.88 (3H, brs), 8.25 (3H,
brs), 8.38 (1H, d), 11.10 (1H, brs).
Example 49
N-(4-Aminocyclohexyl)-3-(3-bromobenzyloxy)-5-(4-carbamimidoylphenoxy)benza-
mide
[0360] Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyanophenoxy)-5-hydroxy benzoic acid
[0361] 1.2 g (4.23 mmol) of 3-(4-cyanophenoxy)-5-hydroxy benzoic
acid ethyl ester was hydrolysed using the procedure of Example 5(b)
to afford 0.95 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.75 (1H, s), 7.0 (1H, s), 7.15 (2H, d),
7.25 (1H, s), 7.85 (2H, d), 10.2 (1H, s), 13.2 (1H, brs).
c) {4-[3-(4-Cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0362] Following the procedure of Example 5(c)
3-(4-cyanophenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 3.52
mmol) were used to afford 0.6 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m),
3.15 (1H, m), 3.7 (1H, m), 6.62 (1H, s), 6.76 (1H, d), 7.04 (1H,
s), 7.16 (3H, m), 7.86 (2H, m), 8.2 (1H, d), 10.0 (1H, s).
d)
{4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]-cyclohexyl}--
carbamic acid tert-butyl ester
[0363] Using 0.6 g (1.32 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 1-bromo-3-bromomethyl-benzene (0.33 g,
1.32 mmol) and following the procedure of Example 42(b) afforded
0.7 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),
5.2 (2H, s), 6.76 (1H, d), 7.0 (1H, s), 7.12 (2H, d), 7.2 (1H, s),
7.44 (3H, m), 7.56 (1H, d), 7.68 (1H, s), 7.84 (2H, d), 8.3 (1H,
d).
e)
4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy)phenoxy]-benzim-
idic acid ethyl ester
[0364] Using
{4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]-cyclohexyl}-ca-
rbamic acid tert-butyl ester (0.7 g, 1.12 mmol) and following the
procedure of Example 1(d) afforded 0.35 g of the required product.
Percentage purity (LCMS): 59.0%, (M+1)=503.3+1.
f)
N-(4-Aminocyclohexyl)-3-(3-bromobenzyloxy)-5-(4-carbamimidoylphenoxy)be-
nzamide
[0365] Using
4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy)phenoxy]-benzimid-
ic acid ethyl ester (0.35 g, 0.61 mmol) and following the procedure
of Example 1(e) afforded 0.15 g of the required product. Percentage
purity (HPLC): 98.8%, (LCMS): 96.6%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.40 (4H, m), 1.92 (4H, m), 3.02 (1H, m), 3.71 (1H, m),
5.20 (2H, s), 7.02 (1H, s), 7.14 (1H, s), 7.21 (2H, d), 7.42 (3H,
m), 7.58 (1H, d), 7.68 (1H, s), 7.88 (4H, d), 8.35 (1H, d), 9.12
(2H, brs), 9.26 (2H, brs).
Example 50
N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy-carbamimidoyl-
)-phenoxy]-benzamide
[0366] Intermediates (a) to (d) are the same as in Example 49.
e)
(4-{3-(3-Bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoy-
lamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0367] Following the procedure of Example 2(d)
{4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]-cyclohexyl}-ca-
rbamic acid tert-butyl ester 0.58 g (0.93 mmol) and other reagents
were used to afford 0.6 g of the required product. Percentage
purity (LCMS): 481%, (M+1)=653.2+1.
f)
N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy-carbamimid-
oyl)-phenoxy]-benzamide
[0368] Using
(4-{3-(3-bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyla-
mino}-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 0.91 mmol)
and following the procedure of Example 9(d) afforded 0.35 g of the
required product. Percentage purity (HPLC): 98.4%, (LCMS): 97.2%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (4H, m), 1.90 (4H, m),
3.00 (1H, m), 3.70 (1H, m), 5.18 (2H, s), 6.98 (1H, m), 7.11 (1H,
s), 7.18 (2H, d), 7.42 (3H, m), 7.52 (1H, d), 7.68 (1H, s), 7.78
(2H, d), 7.90 (3H, brs), 8.36 (1H, d), 8.85 (1H, brs), 11.15 (1H,
brs).
Example 51
N-(4-Aminocyclohexyl)-3-(4-bromobenzyloxy)-5-(4-carbamimidoylphenoxy)benza-
mide
[0369] Intermediates (a)-(c) are the same as in Example 49.
d)
{4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]cyclohexyl}-c-
arbamic acid tert-butyl ester
[0370] Using 1.3 g (2.88 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 1-bromo-4-bromomethyl-benzene (0.72 g,
2.88 mmol) and following the procedure of Example 42(b) afforded
1.5 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),
5.2 (2H, s), 6.78 (1H, d), 6.88 (1H, s), 7.12 (2H, d), 7.2 (1H, s),
7.4 (3H, s), 7.6 (2H, d), 7.86 (2H, d), 8.28 (1H, d).
e)
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromobenzyloxy)phenoxy]-benzimi-
dic acid ethyl ester
[0371] Using
{4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]cyclohexyl}-car-
bamic acid tert-butyl ester (0.85 g, 1.36 mmol) and following the
procedure of Example 1(d) afforded 0.7 g of the required product.
Percentage purity (LCMS): 68.08%, (M+1)=565.1+1.
f)
N-(4-Aminocyclohexyl)-3-(4-bromobenzyloxy)-5-(4-carbamimidoylphenoxy)be-
nzamide
[0372] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromobenzyloxy)phenoxy]-benzimidi-
c acid ethyl ester (0.7 g, 1.23 mmol) and following the procedure
of Example 1(e) afforded 0.32 g of the required product. Percentage
purity (HPLC): 98.39%, (LCMS): 99.72%. (DMSO-d.sub.6): .delta. 1.40
(4H, m), 1.85 (2H, m), 1.95 (2H, m), 3.0 (1H, m), 3.70 (1H, m),
5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, s), 7.45 (3H, d), 7.6 (2H, d),
7.9 (5H, m), 8.36 (1H, d), 9.26 (4H, d).
Example 52
N-(4-Amino-cyclohexyl)-3-(4-bromo-benzyloxy)-5-[4-(N-hydroxy-carbamimidoyl-
)-phenoxy]-benzamide
[0373] Intermediates (a) to (d) are the same as in Example 51.
e)
(4-{3-(4-Bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoy-
lamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0374] Following the procedure of Example 2(d)
{4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]cyclohexyl}-car-
bamic acid tert-butyl ester 0.6 g (0.96 mmol) and other reagents
were used to afford 0.45 g of the required product. Percentage
purity (LCMS): 38.9%, (M+1)=652.2+1.
f)
N-(4-Amino-cyclohexyl)-3-(4-bromo-benzyloxy)-5-[4-(N-hydroxy-carbamimid-
oyl)-phenoxy]-benzamide
[0375] Using
(4-{3-(4-bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyla-
mino}-cyclohexyl)-carbamic acid tert-butyl ester (0.45 g, 0.68
mmol) and following the procedure of Example 9(d) afforded 0.21 g
of the required product. Percentage purity (HPLC): 97.9%, (LCMS):
98.5%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (4H, m), 1.92 (4H,
m), 3.00 (1H, m), 3.70 (1H, m), 5.18 (2H, s), 6.96 (1H, m), 7.18
(3H, m), 7.42 (3H, d), 7.61 (2H, d), 7.76 (2H, d), 7.90 (3H, brs),
8.36 (1H, d), 8.85 (2H, brs), 11.14 (1H, brs).
Example 53
N-(4-Aminocyclohexyl)-3-(6-bromo
pyridine-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy)benzamide
[0376] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(6-bromopyridine-3-ylmethoxy)-5-(4-cyanophenoxy)benzoylamino]-cyc-
lohexyl}carbamic acid tert-butyl ester
[0377] Using 1.4 g (3.1 mmol) of
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester and 2-bromo-5-bromomethyl-pyridine (0.77 g,
3.1 mmol) and following the procedure of Example 42(b) afforded 1.5
g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.20
(4H, m), 1.40 (9H, s), 1.80 (4H, m), 3.2 (1H, m), 3.70 (1H, m),
5.25 (2H, s), 6.75 (1H, d), 7.0 (1H, s), 7.15 (2H, d), 7.22 (1H,
s), 7.45 (1H, s), 7.7 (1H, d), 7.85 (3H, m), 8.3 (1H, d), 8.5 (1H,
s).
e)
4-[3-(4-aminocyclohexylcarbamoyl)-5-(6-bromopyridine-3-ylmethoxy)phenox-
y]benzimidic acid ethyl ester
[0378] Using
{4-[3-(6-bromopyridine-3-ylmethoxy)-5-(4-cyanophenoxy)benzoylamino]-cyclo-
hexyl}carbamic acid tert-butyl ester (0.9 g, 1.44 mmol) and
following the procedure of Example 1(d) afforded 0.54 g of the
required product. Percentage purity (LCMS): 68.08%
(M+1)=566.1+1.
f) N-(4-Aminocyclohexyl)-3-(6-bromo
pyridine-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy)benzamide
[0379] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromobenzyloxy)phenoxy]-benzimidi-
c acid ethyl ester (0.54 g, 0.95 mmol) and following the procedure
of Example 1(e) afforded 0.14 g of the required product. Percentage
purity (HPLC): 95.76%, (LCMS): 99.15%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m), 5.2
(2H, s), 7.0 (1H, s), 7.2 (3H, m), 7.4 (1H, s), 7.7 (1H, d), 7.9
(5H, m), 8.4 (1H, d), 8.5 (1H, d), 9.2 (2H, s), 9.3 (2H, s).
Example 54
N-(4-Aminocyclohexyl)-3-(6-amino
pyridin-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy)benzamide
[0380] Intermediates (a) (c) are the same as in Example 49.
d)
{5-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-pheno-
xy)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester
[0381] Using 1.2 g (2.65 mmol) of
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester and (5-bromomethyl-pyridin-2-yl)-carbamic
acid tert-butyl ester (0.76 g, 2.65 mmol) and following the
procedure of Example 42(b) afforded 1.42 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.4 (27H, s), 1.8
(4H, m), 3.20 (1H, m), 3.75 (1H, m), 5.25 (2H, s), 6.75 (1H, d),
7.05 (1H, s), 7.15 (2H, d), 7.2 (1H, s), 7.45 (2H, m), 7.85 (2H,
d), 7.95 (1H, d), 8.25 (1H, d), 8.5 (1H, s).
e)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)-phen-
oxy]-benzimidic acid ethyl ester
[0382] Using
{5-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy-
)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (1.4
g, 2.12 mmol) and following the procedure of Example 1(d) afforded
0.64 g of the required product. Percentage purity (LCMS): 83.8%,
(M+1)=566.1+1.
f) N-(4-Aminocyclohexyl)-3-(6-amino
pyridine-3-ylmethoxy)-5-(4-carbamimidoylphenoxy)benzamide
[0383] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)-phenox-
y]-benzimidic acid ethyl ester (0.64 g, 1.27 mmol) and following
the procedure of Example 1(e) afforded 0.14 g of the required
product. Percentage purity (HPLC): 96.58%, (LCMS): 94.17%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.9 (4H, m), 3.0 (1H, m),
3.7 (1H, m), 5.05 (2H, s), 7.0 (2H, m), 7.2 (2H, d), 7.4 (1H, s),
7.86 (5H, m), 8.0 (1H, d), 8.1 (2H, s), 8.36 (1H, d), 9.08 (2H, s),
9.26 (2H, s).
Example 55
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy-methyl-
]-benzoic acid ethyl ester
[0384] Intermediates (a)-(c) are the same as in Example 49.
d)
4-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)-
-phenoxy methyl]benzoic acid ethyl ester
[0385] Using 1.2 g (2.65 mmol) of
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester and 4-bromomethyl-benzoic acid ethyl ester
(0.644 g, 2.65 mmol) and following the procedure of Example 42(b)
afforded 1.32 g of the required product. Percentage purity (LCMS):
84.4%, (M+1)=613.2+1.
e)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)pheno-
xymethyl]benzoic acid ethyl ester
[0386] Using
4-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-phenoxy)--
phenoxy methyl]benzoic acid ethyl ester (1.32 g, 2.12 mmol) and
following the procedure of Example 1(d) afforded 0.54 g of the
required product. Percentage purity (LCMS): 68.7%,
(M+1)=559.2+1.
f)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy-met-
hyl]-benzoic acid ethyl ester
[0387] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)phenoxy-
methyl]benzoic acid ethyl ester (0.54 g, 0.96 mmol) and following
the procedure of Example 1(e) afforded 0.23 g of the required
product. Percentage purity (HPLC): 97.37%, (LCMS): 97.15%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.35 (3H, t), 1.4 (4H, m), 1.95 (4H,
m), 3.0 (1H, m), 3.7 (1H, m), 4.35 (2H, q), 5.3 (2H, s) 7.0 (1H,
s), 7.2 (3H, m), 7.42 (1H, s), 7.60 (2H, d), 7.82 (4H, m), 8.0 (2H,
d), 8.38 (1H, d), 9.08 (2H, s), 9.26 (2H, s).
Example 56
4-{3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-phenethyloxyphenoxy}-benzam-
idine
[0388] Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyanophenoxy)-5-phenethyloxy benzoic acid ethyl ester
[0389] Using 1.0 g (3.53 mmol) of 3-(4-cyanophenoxy)-5-hydroxy
benzoic acid ethyl ester and (2-bromo-ethyl)-benzene (0.65 g, 3.53
mmol) and following the procedure of Example 42(b) afforded 0.95 g
of the required product. .sup.1H NMR (CDCl.sub.3): .delta. 1.35
(3H, t), 3.1 (2H, t), 4.2 (2H, t), 4.35 (2H, q), 6.78 (1H, t), 7.0
(2H, s), 7.22 (1H, m) 7.32 (5H, m), 7.42 (1H, m), 7.62 (2H, s).
c) 3-(4-Cyanophenoxy)-5-phenethyloxy benzoic acid
[0390] 0.95 g (2.45 mmol) of 3-(4-cyanophenoxy)-5-phenethyloxy
benzoic acid ethyl ester was hydrolysed using the procedure of
Example 5(b) to afford 0.6 g.of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.02 (2H, t), 4.26 (2H, t), 7.0 (1H, t),
7.18 (3H, m), 7.24 (1H, m) 7.32 (5H, m), 7.88 (2H, s), 13.4 (1H,
brs).
d)
(2-{1-[3-(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)-c-
arbamic acid tert-butyl ester
[0391] Following the procedure of Example 5(c)
3-(4-cyanophenoxy)-5-phenethyloxy benzoic acid 0.6 g (1.66 mmol)
and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.378
g, 1.66 mmol) were used to afford 0.55 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.05 (3H, m), 1.4 (9H, s), 1.55
(2H, m), 1.7 (1H, m), 2.1 (5H, s), 3.0 (5H, m), 4.2 (2H, t), 4.4
(1H, m), 6.62 (1H, s), 6.78 (2H, s), 7.14 (2H, d), 7.24 (1H, m),
7.3 (4H, d), 7.88 (2H, d).
e)
4-{3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-phenethyloxyphenoxy}-ben-
zimidic acid ethyl ester
[0392] Using
(2-{1-[3-(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)-car-
bamic acid tert-butyl ester (0.55 g, 0.96 mmol) and following the
procedure of Example 1(d) afforded 0.28 g of the required product.
Percentage purity (LCMS): 56.4%, (M+1)=515.2+1
f)
4-{3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-phenethyloxyphenoxy}-ben-
zamidine
[0393] Using
4-{3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-phenethyloxyphenoxy}-benzi-
midic acid ethyl ester (0.28 g, 0.54 mmol) and following the
procedure of Example 1(e) afforded 0.06 g of the required product.
Percentage purity (HPLC): 87.23%, (LCMS): 76.08%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.10 (3H, t), 1.50 (2H, m), 1.60 (2H, m),
1.75 (1H, m), 2.70 (1H, m), 2.85 (2H, m), 3.05 (3H, m), 3.6 (1H,
m), 4.25 (2H, t), 4.45 (1H, m), 6.6 (s), 6.8 (2H, m), 7.25 (2H, m),
7.35 (3H, s), 7.7 (2H, brs), 7.9 (2H, s), 9.05 (2H, s), 9.25 (2H,
s).
Example 57
2-{1-[3-(3-Carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl]-p-
iperidin-4-yl}-ethylamine
[0394] Intermediates (a)-(c) are the same as in Example 42.
d)
(2-{1-[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}et-
hyl)-carbamic acid tert-butyl ester
[0395] Following the procedure of Example 5(c)
3-(3-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.75 g (2.02
mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester
(0.46 g, 2.02 mmol) were used to afford 0.7 g of the required
product. Percentage purity (LCMS): 62.3%, (M+1)=480.2+1 (de-Boc
mass, -100).
e)
2-{1-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phen-
oxy)benzoyl]piperidin-4-yl}ethylamine
[0396] Using
(2-{1-[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}ethy-
l)-carbamic acid tert-butyl ester (0.7 g, 1.2 mmol) and following
the procedure of Example 1(d) afforded 0.43 g of the required
product. Percentage purity (LCMS): 49.2%, (M+1)=572.3+1.
f)
2-{1-[3-(3-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl-
]-piperidin-4-yl}ethylamine
[0397] Using 2-{1-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy
carbonimidoyl-phenoxy)benzoyl]piperidin-4-yl}ethylamine (0.43 g,
0.54 mmol) and following the procedure of Example 1(e) afforded
0.16 g of the required product. Percentage purity (HPLC): 98.59%,
(LCMS): 98.49%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10 (2H, m),
1.50 (2H, m), 4.60 (2H, m), 1.75 (1H, m), 2.80 (3H, m), 3.0 (2H,
m), 4.45 (1H, m), 5.2 (2H, s), 6.65 (1H, s), 6.9 (2H, s), 7.25 (2H,
s), 7.65 (1H, m), 7.7-7.85 (5H, m), 7.9 (3H, s), 9.1 (2H, s), 9.25
(3H, d), 9.4 (2H, s).
Example 58
2-{1-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]-pi-
peridin-4-yl}ethylamine
[0398] Intermediates (a)-(c) are the same as in Example 43.
d)
(2-{1-[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}et-
hyl)-carbamic acid tert-butyl ester
[0399] Following the procedure of Example 5(c)
3-(4-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.16
mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester
(0.49 g, 2.16 mmol) were used to afford 0.92 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10 (2H, m), 1.30
(2H, m), 1.4 (9H, s), 1.50 (2H, m), 1.75 (1H, m), 2.70 (1H, m), 2.8
(3H, m), 3.5 (1H, m), 4.4 (1H, m), 5.2 (2H, s), 6.65 (1H, s), 6.78
(1H, m), 6.88 (2H, m), 7.16 (2H, s), 7.64 (2H, d), 7.88 (4H,
m).
e)
2-{1-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phen-
oxy)benzoyl]piperidin-4-yl}ethylamine
[0400] Using
(2-{1-[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}ethy-
l)-carbamic acid tert-butyl ester (0.92 g, 1.58 mmol) and following
the procedure of Example 1(d) afforded 0.54 g of the required
product. Percentage purity (LCMS): 30.4%, (M+1)=572.3+1.
f)
2-{1-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]-
-piperidin-4-yl}ethylamine
[0401] Using 2-{1-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy
carbonimidoyl-phenoxy)benzoyl]piperidin-4-yl}ethylamine (0.54 g,
0.94 mmol) and following the procedure of Example 1(e) afforded
0.32 g of the required product. Percentage purity (HPLC): 98.97%,
(LCMS): 93.02%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10 (2H, m),
1.50 (2H, m), 1.60 (2H, m), 1.75 (1H, m), 2.85 (4H, m), 3.0 (1H,
m), 4.45 (1H, m), 5.3 (2H, s), 6.65 (1H, s), 6.9 (2H, s), 7.2 (2H,
d), 7.7 (2H, d), 7.8 (2H, brs), 7.9 (4H, t), 9.3 (6H, t).
Example 59
4-[3-(4-aminomethylbenzyloxy)-5-(4-carbamimidoylphenoxy)benzoyl]-piperazin-
e-1-carboxylic acid ethyl ester
[0402] Intermediate (a) is the same as in Example 42.
[0403] Intermediates (b) and (c) are the same as in Example 45.
d)
4-[3-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-5-(4-cyanophenoxy)-b-
enzoyl]piperazine-1-carboxylic acid ethyl ester
[0404] Following the procedure of Example 5(c)
3-(4-(tert-butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyanophenoxy)benzoic
acid 0.85 g (1.79 mmol) and piperazine-1-carboxylic acid ethyl
ester (0.283 g, 1.79 mmol) were used to afford 0.91 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.20 (3H, t),
1.40 (9H, s), 3.3 (2H, m), 3.6 (6H, m), 4.05 (2H, q), 4.15 (2H, d),
5.1 (2H, s), 6.7 (1H, s), 6.9 (2H, s), 7.18 (2H, d), 7.26 (2H, d),
7.4 (3H, d), 7.86 (2H, d), 7.86 (2H, s).
e)
4-[3-(4-aminomethylbenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]p-
iperazine-1-carboxylic acid ethyl ester
[0405] Using
4-[3-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-5-(4-cyanophenoxy)-ben-
zoyl]piperazine-1-carboxylic acid ethyl ester (0.91 g, 1.48 mmol)
and following the procedure of Example 1(d) afforded 0.34 g of the
required product. Percentage purity (LCMS): 73.3%,
(M+1)=560.2+1.
f)
4-[3-(4-Aminomethylbenzyloxy)-5-(4-carbamimidoylphenoxy)benzoyl]-pipera-
zine-1-carboxylic acid ethyl ester
[0406] Using
4-[3-(4-aminomethylbenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)-benzoyl]pi-
perazine-1-carboxylic acid ethyl ester (0.34 g, 0.6 mmol) and
following the procedure of Example 1(e) afforded 0.15 g of the
required product. Percentage purity (HPLC): 93.79%, (LCMS): 95.27%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t), 3.4 (2H, m), 3.6
(2H, m), 3.75 (6H, m), 4.1 (2H, q), 5.2 (2H, s), 6.66 (1H, s), 6.9
(2H, s), 7.22 (2H, d), 7.5 (3H, s), 7.88 (2H, d), 8.2 (2H, brs),
9.06 (2H, s), 9.25 (2H, s).
Example 60
4-[3-(4-Carbamimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl]-piper-
azine-1-carboxylic acid ethyl ester
[0407] Intermediates (a) and (b) are the same as in Example 49.
c) 4-[3-(4-Cyanophenoxy)-5-hydroxybenzoyl]piperazine-1-carboxylic
acid ethyl ester
[0408] Following the procedure of Example 5(c)
3-(4-cyanophenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and
piperazine-1-carboxylic acid ethyl ester (0.556 g, 3.52 mmol) were
used to afford 0.52 g of the required product. Percentage purity
(LCMS): 90.2%, (M+1)=395.1+1.
d)
4-[3-(4-Cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine-
-1-carboxylic acid ethyl ester
[0409] Using 0.52 g (1.31 mmol) of
4-[3-(4-cyanophenoxy)-5-hydroxybenzoyl]-piperazine-1-carboxylic
acid ethyl ester and 4-bromomethyl-benzoic acid ethyl ester (0.318
g, 1.31 mmol) and following the procedure of Example 42(b) afforded
0.61 g of the required product. Percentage purity (LCMS): 60.0%
(M+1)=557.2+1.
e)
4-[3-(4-Ethoxycarbonimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzo-
yl]piperazine-1-carboxylic acid ethyl ester
[0410] Using
4-[3-(4-cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine-1-
-carboxylic acid ethyl ester (0.6 g, 1.07 mmol) and following the
procedure of Example 1(d) afforded 0.32 g of the required product.
Percentage purity (LCMS): 42.2%, (M+1)=603.2+1.
f)
4-[3-(4-Carbamimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl]-pi-
perazine-1-carboxylic acid ethyl ester
[0411] Using
4-[3-(4-ethoxycarbonimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl-
]piperazine-1-carboxylic acid ethyl ester (0.32 g, 0.53 mmol) and
following the procedure of Example 1(e) afforded 0.15 g of the
required product. Percentage purity (HPLC): 94.77%, (LCMS): 99.8%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t), 1.35 (3H, t), 3.3
(2H, m), 3.4 (2H, m), 3.6 (4H, m), 4.1 (2H, q), 4.4 (2H, q), 5.3
(2H, s), 6.7 (1H, s), 6.9 (2H, d), 7.25 (2H, d), 7.6 (2H, d), 7.85
(2H, d), 8.0 (2H, d), 9.0 (2H, s), 9.25 (2H, s).
Example 61
4-[3-(4-Bromobenzyloxy)-5-(4-carbamimidoylphenoxy)benzoyl]piperazine-1-car-
boxylic acid ethyl ester
[0412] Intermediates (a) (c) are the same as in Example 60.
d)
4-[3-(4-Bromobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperazine-1-carboxyl-
ic acid ethyl ester
[0413] Using 0.75 g (1.89 mmol) of
4-[3-(4-cyanophenoxy)-5-hydroxybenzoyl]-piperazine-1-carboxylic
acid ethyl ester and 1-bromo-4-bromomethyl-benzene (0.472 g, 1.89
mmol) and following the procedure of Example 42(b) afforded 0.85 g
of the required product. Percentage purity (LCMS): 75.2%,
(M+1)=563.1+1.
e)
4-[3-(4-Bromobenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]-pipera-
zine-1-carboxylic acid ethyl ester
[0414] Using
4-[3-(4-bromobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperazine-1-carboxylic
acid ethyl ester (0.85 g, 1.5 mmol) and following the procedure of
Example 1(d) afforded 0.37 g of the required product. Percentage
purity (LCMS): 43.1%, (M+1)=609.1+1.
f)
4-[3-(4-Bromobenzyloxy)-5-(4-carbamimidoylphenoxy)benzoyl]piperazine-1--
carboxylic acid ethyl ester
[0415] Using
4-[3-(4-bromobenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]-piperazi-
ne-1-carboxylic acid ethyl ester (0.37 g, 0.6 mmol) and following
the procedure of Example 1(e) afforded 0.15 g of the required
product. Percentage purity (HPLC): 98.96%, (LCMS): 91.78%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t), 3.35 (6H, m), 3.6 (2H, m),
3.6 (4H, m), 4.1 (2H, q), 5.2 (2H, s), 6.68 (1H, s), 6.7 (2H, m),
7.24 (2H, d), 7.4 (2H, d), 7.6 (2H, d), 7.86 (2H, d), 8.9 (2H, s),
9.25 (2H, s).
Example 62
3-(3-Aminobenzyloxy)-N-(4-aminocyclohexyl)-5-(4-carbamimidoylphenoxy)benza-
mide
[0416] Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyanophenoxy)-5-(3-nitrobenzyloxy)benzoic acid ethyl
ester
[0417] Using 1.2 g (4.23 mmol) of 3-(4-cyanophenoxy)-5-hydroxy
benzoic acid ethyl ester and 1-bromomethyl-3-nitro-benzene (0.913
g, 4.23 mmol) and following the procedure of Example 42(b) afforded
1.43 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.3 (3H, t), 4.3 (2H, q), 5.4 (2H, s), 7.2 (4H, m), 7.45 (1H, s),
7.72 (1H, t), 7.9 (3H, m), 8.25 (1H, d), 8.35 (1H, s).
c) 3-(4-Cyanophenoxy)-5-(3-nitrobenzyloxy)benzoic acid
[0418] 1.43 g (3.41 mmol) of
3-(4-cyanophenoxy)-5-(3-nitrobenzyloxy)benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 1.1 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.4 (2H,
s), 7.16 (4H, d), 7.45 (1H, s), 7.5 (1H, t), 7.9 (3H, d), 8.22 (1H,
d), 8.34 (1H, s), 13.4 (1H, brs)
d)
{4-[3-(4-cyanophenoxy)-5-(3-nitrobenzyloxy)benzoylamino]cyclohexyl}-car-
bamic acid tert-butyl ester
[0419] Following the procedure of Example 5(c)
3-(4-cyanophenoxy)-5-(3-nitro benzyloxy)benzoic acid 1.1 g (2.81
mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.6
g, 2.81 mmol) were used to afford 1.2 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H, m), 1.4 (9H, s), 1.8
(4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.35 (2H, s), 6.78 (1H, d), 7.04
(1H, s), 7.12 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.72 (1H, t),
7.9 (3H, d), 8.2 (1H, d), 8.34 (2H, m).
e)
{4-[3-(3-aminobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}carb-
amic acid tert-butyl ester
[0420] 1.2 g (2.04 mmol) of
{4-[3-(4-cyanophenoxy)-5-(3-nitrobenzyloxy)benzoyl
amino]cyclohexyl}carbamic acid tert-butyl ester, dissolved in 10 ml
of THF, 0.455 g (8.16 mmol) of iron powder and 0.436 g (8.16 mmol)
of NH.sub.4Cl solution (5 ml water) were mixed. The resulting
reaction mixture was refluxed overnight. After completion of
reaction, the reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure. 100 ml water was
added to the concentrated mixture and the mixture was extracted
with 100 ml of ethyl acetate. The organic layer was washed with
water followed by saturated brine, dried over anhydrous sodium
sulphate and concentrated to afford crude compound which was
purified by column chromatography using hexane-ethylacetate (10:2)
to afford 0.75 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2
(1H, m), 3.7 (1H, m), 5.0 (2H, s), 5.15 (2H, s), 6.5 (2H, m), 6.62
(1H, s), 6.78 (1H, d), 6.94 (1H, s), 7.0 (1H, t), 7.12 (3H, m), 7.4
(1H, s), 7.82 (2H, d), 8.26 (1H, d).
f)
4-[3-(3-aminobenzyloxy)-5-(4-aminocyclohexylcarbamoyl)phenoxy]benzimidi-
c acid ethyl ester
[0421] Using
{4-[3-(3-aminobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}carbam-
ic acid tert-butyl ester (0.65 g, 1.16 mmol) and following the
procedure of Example 1(d) afforded 0.23 g of the required product.
Percentage purity (LCMS): 98.0%, (M+1)=502.2+1.
g)
3-(3-Aminobenzyloxy)-N-(4-aminocyclohexyl)-5-(4-carbamimidoylphenoxy)be-
nzamide
[0422] Using
4-[3-(3-aminobenzyloxy)-5-(4-aminocyclohexylcarbamoyl)phenoxy]benzimidic
acid ethyl ester (0.23 g, 0.45 mmol) and following the procedure of
Example 1(e) afforded 0.04 g of the required product. Percentage
purity (HPLC): 97.77%, (LCMS): 94.67%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.7 (1H, m), 5.10
(2H, s), 6.85 (3H, m), 6.95 (1H, s), 7.20 (4H, m), 7.40 (1H, s),
7.85 (5H, s), 8.35 (1H, d), 9.1 (2H, brs), 9.25 (2H, s).
Example 63
N-(4-Aminocyclohexyl)-3-[3-(3-aminopropionylamino)benzyloxy]-5-(4-carbamim-
idoylphenoxy)benzamide
[0423] Intermediates (a)-(e) are the same as in Example 62.
f)
{4-[3-[3-(3-tert-butoxycarbonylaminopropionylamino)benzyloxy]-5-(4-cyan-
o phenoxy)-benzoylamino]cyclohexyl}carbamic acid tert-butyl
ester
[0424] 3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09
mmol) and
{4-[3-(3-aminobenzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}carbam-
ic acid tert-butyl ester (0.6 g, 1.09 mmol) and other reagents as
described in Example 9(e) were used to afford 0.45 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m),
1.4 (18H, s), 1.8 (4H, m), 2.45 (2H, m), 3.1 (3H, m), 3.7 (2H, m),
5.15 (2H, s), 6.74 (1H, d), 6.88 (1H, m), 6.98 1H, s), 7.12 (3H,
d), 7.2 (1H, s), 7.3 (1H, t), 7.42 (1H, s), 7.54 (1H, d), 7.72 (1H,
s), 7.86 (2H, d), 8.26 (1H, d).
g)
4-{3-(4-Aminocyclohexylcarbamoyl)-5-[3-(3-aminopropionylamino)benzyloxy-
]phenoxy}benzimidic acid ethyl ester
[0425] Using
{4-[3-[3-(3-tert-butoxycarbonylaminopropionylamino)benzyloxy]-5-(4-cyano
phenoxy)-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
(0.45 g, 0.61 mmol) and following the procedure of Example 1(d)
afforded 0.15 g of the required product. Percentage purity (LCMS):
51.2%, (M+1)=573.3+1.
h)
N-(4-Aminocyclohexyl)-3-[3-(3-aminopropionylamino)benzyloxy]-5-(4-carba-
mimidoylphenoxy)benzamide
[0426] Using
4-{3-(4-aminocyclohexylcarbamoyl)-5-[3-(3-aminopropionylamino)-benzyloxy]-
phenoxy}benzimidic acid ethyl ester (0.15 g, 0.26 mmol) and
following the procedure of Example 1(e) afforded 0.03 g of the
required product. Percentage purity (HPLC): 91.6%, (LCMS): 92.3%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (4H, m), 1.92 (4H, m),
2.72 (2H, t), 3.0 (1H, m), 3.10 (2H, q), 3.72 (1H, m), 5.14 (2H,
s), 6.98 (1H, s), 7.14 (1H, s), 7.20 (2H, d), 7.35 (1H, t), 7.40
(1H, s), 7.72 (1H, s), 7.81 (3H, brs), 7.88 (61-1, d), 8.35 (1H,
d), 9.14 (2H, brs), 9.25 (2H, s), 10.24 (1H, brs).
Example 64
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylphenoxy)-5-(3-carbamimidoyl-propox-
y)benzamide
[0427] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-cyanophenoxy)-5-(3-cyanopropoxy)benzoylamino]cyclohexyl}-carba-
mic acid tert-butyl ester
[0428] Using 0.75 g (1.66 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 4-bromo-butyronitrile (0.245 g, 1.66
mmol) and following the procedure of Example 42(b) afforded 0.82 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.20
(3H, m), 1.4 (9H, s), 1.8 (4H, m), 2.05 (3H, m), 2.65 (2H, m), 3.2
(1H, m), 3.7 (1H, m), 4.1 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14
(2H, d), 7.2 (1H, s), 7.34 (1H, s), 7.86 (2H, d), 8.28 (1H, d)
e)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(3-ethoxycarbonimidoylpropoxy)pheno-
xy]benzimidic acid ethyl ester
[0429] Using
{4-[3-(4-cyanophenoxy)-5-(3-cyanopropoxy)benzoylamino]cyclohexyl}-carbami-
c acid tert-butyl ester (0.82 g, 1.58 mmol) and following the
procedure of Example 1(d) afforded 0.43 g of the required product.
Percentage purity (LCMS): 62.1%, (M+1)=510.2+1.
f)
N-(4-Aminocyclohexyl)-3-(4-carbarnimidoylphenoxy)-5-(3-carbamimidoyl
propoxy)benzamide
[0430] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-ethoxycarbonimidoylpropoxy)-phenox-
y]benzimidic acid ethyl ester (0.43 g, 0.84 mmol) and following the
procedure of Example 1(e) afforded 0.14 g of the required product.
Percentage purity (HPLC): 98.11%, (LCMS): 99.32%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.40 (4H, m), 1.9 (4H, m), 2.1 (2H, m), 2.6
(2H, m), 3.0 (2H, m), 4.1 (2H, m), 6.90 (1H, s), 7.20 (3H, m), 7.35
(1H, s), 7.85 (5H, s), 8.35 (1H, d), 8.7 (2H, brs), 8.95 (2H, s),
9.1 (2H, brs), 9.25 (2H, s).
Example 65
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbutoxy)-5-(4-carbamimidoyl-phenoxy-
)-benzamide
[0431] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-cyanobutoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbam-
ic acid tert-butyl ester
[0432] Using 0.85 g (1.88 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 5-bromo-pentanenitrile (0.304 g, 1.88
mmol) and following the procedure of Example 42(b) afforded 1.0 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25
(3H, m), 1.4 (9H, s), 1.8 (7H, m), 2.6 (3H, m), 3.2 (1H, m), 3.7
(1H, m), 4.2 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (3H, m),
7.34 (1H, s), 7.88 (2H, d), 8.28 (1H, d).
e)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)-phe-
noxy]-benzimidic acid ethyl ester
[0433] Using
{4-[3-(4-cyanobutoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbamic
acid tert-butyl ester (1.0 g, 1.87 mmol) and following the
procedure of Example 1(d) afforded 0.52 g of the required product.
Percentage purity (LCMS): 64.4%, (M+1)=524.3+1
f)
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbutoxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0434] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)-pheno-
xy]-benzimidic acid ethyl ester (0.52 g, 0.99 mmol) and following
the procedure of Example 1(e) afforded 0.23 g of the required
product. Percentage purity (HPLC): 97.4%, (LCMS): 92.3%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.41 (4H, m), 1.72 (4H, m), 1.85 (2H,
m), 1.95 (2H, m), 2.44 (2H, t), 3.00 (1H, m), 3.82 (1H, m), 4.08
(2H, m), 6.89 (1H, s), 7.12 (1H, s), 7.20 (2H, d), 7.32 (1H, s),
7.86 (4H, d), 8.34 (1H, d), 8.68 (2H, brs), 8.92 (2H, brs), 9.14
(2H, brs), 9.26 (2H, brs).
Example 66
N-(4-Aminocyclohexyl)-3-(5-carbamimidoylpentyloxy)-5-(4-carbamimidoyl-phen-
oxy)-benzamide
[0435] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(5-cyanopentyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-car-
bamic acid tert-butyl ester
[0436] Using 0.85 g (1.88 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 6-bromo-hexanenitrile (0.33 g, 1.88 mmol)
and following the procedure of Example 42(b) afforded 1.15 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (3H, m),
1.4 (9H, s), 1.6 (4H, m), 1.8 (6H, m), 3.2 (1H, m), 3.7 (1H, m),
4.05 (2H, m), 6.75 (1H, d), 6.90 (1H, s), 7.14 (3H, m), 7.34 (1H,
s), 7.88 (2H, d), 8.28 (1H, d).
e)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbonimidoyl-pentyloxy)--
phenoxy]-benzimidic acid ethyl ester
[0437] Using
{4-[3-(5-cyanopentyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carba-
mic acid tert-butyl ester (1.15 g, 2.1 mmol) and following the
procedure of Example 1(d) afforded 0.61 g of the required product.
Percentage purity (LCMS): 70.5%, (M+1)=538.3+1.
f)
N-(4-Aminocyclohexyl)-3-(5-carbamimidoylpentyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0438] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbonimidoyl-pentyloxy)-ph-
enoxy]-benzimidic acid ethyl ester (0.61 g, 1.13 mmol) and
following the procedure of Example 1(e) afforded 0.25 g of the
required product. Percentage purity (HPLC): 98.2%, (LCMS): 90.6%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.42 (4H, m), 1.72 (4H, m),
1.86 (2H, m), 1.98 (2H, m), 2.42 (2H, t), 3.00 (1H, m), 3.72 (1H,
m), 4.06 (2H, t), 6.89 (1H, s), 7.12 (1H, s), 7.20 (2H, d), 7.32
(1H, s), 7.88 (4H, d), 8.32 (1H, d), 8.68 (2H, brs), 8.90 (2H,
brs), 9.14 (2H, brs), 9.26 (2H, brs).
Example 67
5-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-penta-
noic acid ethyl ester
[0439] Intermediates (a) (c) are the same as in Example 49.
d)
5-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)-
phenoxy]pentanoic acid ethyl ester
[0440] Using 0.63 g (1.39 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 5-bromo-pentanoic acid ethyl ester (0.29
g, 1.39 mmol) and following the procedure of Example 42(b) afforded
0.71 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.2 (4H, m), 1.25 (2H, m), 1.4 (9H, s), 1.75 (9H, m), 2.35 (2H, m)
3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.75 (1H, d), 6.9 (1H, s),
7.15 (3H, d), 7.35 (1H, s), 7.85 (2H, d), 8.25 (1H, d).
e)
5-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)pheno-
xy]pentanoic acid ethyl ester
[0441] Using
5-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-phenoxy)p-
henoxy]pentanoic acid ethyl ester (0.71 g, 1.22 mmol) and following
the procedure of Example 1(d) afforded 0.36 g of the required
product. Percentage purity (LCMS): 90.9%, (M+1)=525.2+1.
f)
5-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-pe-
ntanoic acid ethyl ester
[0442] Using
5-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)phenoxy-
]pentanoic acid ethyl ester (0.36 g, 0.68 mmol) and following the
procedure of Example 1(e) afforded 0.18 g of the required product.
Percentage purity (HPLC): 96.9%, (LCMS): 95.1%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.18 (3H, t), 1.40 (4H, m), 1.72 (4H, m),
1.92 (4H, m), 2.38 (2H, t), 3.02 (1H, m), 3.72 (1H, m), 4.05 (4H,
m), 6.88 (1H, s), 7.12 (1H, s), 7.21 (2H, d), 7.30 (1H, s), 7.88
(4H, d), 8.34 (1H, d), 9.14 (2H, brs), 9.26 (2H, brs).
Example 68
6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-hexan-
oic acid ethyl ester
[0443] Intermediate (a) (c) are the same as in Example 49.
d)
6-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)-
-phenoxy]hexanoic acid ethyl ester
[0444] Using 0.84 g (1.86 mmol) of
{4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester and 6-bromo-hexaanoic acid ethyl ester (0.41
g, 1.86 mmol) and following the procedure of Example 42(b) afforded
0.95 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.15 (3H, t), 1.25 (2H, m), 1.4 (9H, s), 1.45 (3H, m), 1.6 (2H, m)
1.7 (2H, m), 1.8 (4H, m), 2.3 (2H, t), 3.2 (1H, m), 3.7 (1H, m),
4.05 (4H, m), 6.72 (1H, d), 6.88 (1H, s), 7.12 (3H, m), 7.3 (1H,
s), 7.84 (2H, d), 8.24 (1H, d).
e)
6-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)pheno-
xy]hexanoic acid ethyl ester
[0445] Using
6-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-phenoxy)--
phenoxy]hexanoic acid ethyl ester (0.95 g, 1.6 mmol) and following
the procedure of Example 1(d) afforded 0.45 g of the required
product. Percentage purity (LCMS): 90.08%, (M+1)=539.3+1.
f)
6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-he-
xanoic acid ethyl ester
[0446] Using
6-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)phenoxy-
]hexanoic acid ethyl ester (0.45 g, 0.83 mmol) and following the
procedure of Example 1(e) afforded 0.17 g of the required product.
Percentage purity (HPLC): 95.7%, (LCMS): 95.0%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.18 (3H, t), 1.42 (6H, m), 1.60 (2H, m),
1.74 (2H, m), 1.78 (2H, brs), 1.98 (2H, brs), 2.32 (2H, t), 3.02
(1H, m), 3.70 (1H, m), 4.06 (4H, m), 6.90 (1H, s), 7.12 (1H, s),
7.22 (2H, d), 7.32 (1H, s), 7.88 (4H, d), 8.35 (1H, d), 9.14 (2H,
brs), 9.28 (2H, brs).
Example 69
N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-2-chlorophenoxy)-5-(4-carbamimido-
ylphenoxy)benzamide
[0447] Intermediate (a) is the same as in Example 42.
b) 3-(2-Chloro-4-cyanophenoxy)-5-(4-cyanophenoxy)benzoic acid ethyl
ester
[0448] To 1.2 g (4.23 mmol) of
3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester, dissolved
in 10 ml of DMF, potassium carbonate 1.17 g (8.46 mmol) was added
and stirred for 30 min at RT. 1.31 g (8.46 mmol) of
3-chloro-4-fluoro-benzonitrile, dissolved in 5 ml of DMF, was added
dropwise to the reaction mixture during 15 min and final contents
were stirred at 80.degree. C. overnight. The reaction mixture was
concentrated, residue was dissolved in 200 ml of ethyl acetate and
partitioned with water. The organic layer was washed with brine
followed by of water. Organic layer was dried over anhydrous sodium
sulphate and concentrated under reduced pressure. The crude product
was subjected to column chromatography, using silica-gel and eluted
with hexane:ethyl acetate (8:2) to afford 1.4 g of pure product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.3 (3H, t), 4.3 (2H, q),
7.2-7.36 (4H, m), 7.44 (2H, dd), 7.88 (3H, m), 8.26 (1H, d).
c) 3-(2-Chloro-4-cyanophenoxy)-5-(4-cyanophenoxy)benzoic acid
[0449] 3-(2-Chloro-4-cyanophenoxy)-5-(4-cyanophenoxy)benzoic acid
ethyl ester, 1.4 g (3.34 mmol), was hydrolysed using the procedure
of Example 5(b) to afford 1.05 g of required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 7.2-7.42 (6H, m), 7.88 (3H, m) 8.26 (1H,
s), 13.8 (1H, brs).
d)
{4-[3-(2-Chloro-4-cyanophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohex-
yl}carbamic acid tert-butyl ester
[0450] Following the procedure of Example 5(c)
3-(2-chloro-4-cyanophenoxy)-5-(4-cyano phenoxy)benzoic acid 1.0 g
(2.55 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester
(0.54 g, 2.55 mmol) were used to afford 1.2 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.24 (4H, m), 1.38
(9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 6.76 (1H, d), 7.22
(4H, m), 7.5 (2H, s), 7.88 (3H, m), 8.26 (1H, d), 8.38 (1H, d).
e)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)-phen-
oxy]-3-chloro benzimidic acid ethyl ester
[0451] Using
{4-[3-(2-chloro-4-cyanophenoxy)-5-(4-cyanophenoxy)benzoylamino]-cyclohexy-
l}carbamic acid tert-butyl ester (1.2 g, 2.04 mmol) and following
the procedure of Example 1(d) afforded 0.64 g of the required
product. Percentage purity (LCMS): 44.3%, (M+1)=539.3+1.
f)
N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-2-chlorophenoxy)-5-(4-carbamim-
idoylphenoxy)benzamide
[0452] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)-phenox-
y]-3-chloro benzimidic acid ethyl ester (0.64 g, 1.1 mmol) and
following the procedure of Example 1(e) afforded 0.16 g of the
required product. Percentage purity (HPLC): 99.16%, (LCMS): 92.13%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.9 (4H, m), 3.0
(1H, s), 3.7 (1H, m) 7.16 (1H, s), 7.32 (3H, m), 7.48 (2H, s), 7.82
(1H, dd), 7.9 (4H, m), 8.14 (1H, d), 8.46 (1H, d), 9.2 (2H, s), 9.3
(2H, s), 9.38 (3H, s).
Example 70
4-[3-[4-(2-Aminoethyl)piperidine-1-carbonyl]-5-(3-aminopropoxy)phenoxy]ben-
zamidine
[0453] Intermediate (a) is the same as in Example 42.
b) 3-(3-tert-Butoxycarbonylaminopropoxy)-5-(4-cyanophenoxy)benzoic
acid ethyl ester
[0454] Following the procedure of Example 69(b)
3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester 0.9 g (3.17
mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (1.5 g,
6.34 mmol) were used to afford 0.95 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 2.05 (4H, m), 3.35 (2H, m),
3.90 (3H, s), 4.08 (2H, t), 4.72 (1H, brs), 6.78 (1H, t), 7.02 (2H,
d), 7.28 (1H, s), 7.41 (1H, s), 7.62 (2H, d), 8.05 (1H, brs).
c) 3-(3-tert-Butoxycarbonylaminopropoxy)-5-(4-cyanophenoxy)benzoic
acid
[0455]
3-(3-tert-Butoxycarbonylaminopropoxy)-5-(4-cyanophenoxy)benzoic
acid ethyl ester, 0.95 g (2.15 mmol) was hydrolysed by using the
procedure of Example 5(b) to afford 0.7 g of required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.85 (2H, t), 3.12 (2H, m),
4.02 (2H, t), 6.85 (1H, s), 6.95 (1H, s), 7.15 (3H, m), 7.32 (1H,
s), 7.85 (2H, d), 13.22 (1H, brs).
d)
{3-[3-[4-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carbonyl]-5-(4-c-
yano phenoxy)phenoxy]propyl}carbamic acid tert-butyl ester
[0456] Following the procedure of Example 5(c)
3-(3-tert-butoxycarbonylaminopropoxy)-5-(4-cyanophenoxy)benzoic
acid 0.7 g (1.69 mmol) and (4-amino-cyclohexyl)-carbamic acid
tert-butyl ester (0.38 g, 1.69 mmol) were used to afford 0.72 g of
the required product. Percentage purity (LCMS): 47.0%,
(M+1)=422.3+1 (de bisboc mass -200).
e)
4-[3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-(3-aminopropoxy)phenoxy]-
benzimidic acid ethyl ester
[0457] Using
{3-[3-[4-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carbonyl]-5-(4-cya-
nophenoxy)phenoxy]propyl}carbamic acid tert-butyl ester (0.72 g,
1.15 mmol) and following the procedure of Example 1(d) afforded
0.25 g of the required product. Percentage purity (LCMS): 63.9%,
(M+1)=468.2+1.
f)
4-[3-[4-(2-Aminoethyl)piperidine-1-carbonyl]-5-(3-aminopropoxy)phenoxy]-
benzamidine
[0458] Using
4-[3-[4-(2-aminoethyl)piperidine-1-carbonyl]-5-(3-aminopropoxy)phenoxy]be-
nzimidic acid ethyl ester (0.25 g, 0.53 mmol) and following the
procedure of Example 1(e) afforded 0.065 g of the required product.
Percentage purity (HPLC): 97.13%, (LCMS): 89.6%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.10 (2H, m), 1.50 (2H, m), 1.60-1.80 (3H,
m), 2.0 (2H, m), 2.70 (1H, m), 2.8 (2H, m), 3.0 (3H, m), 4.1 (2H,
t), 4.5 (1H, s), 6.60 (1H, s), 6.8 (2H, s), 7.20 (2H, d), 7.80 (3H,
brs), 7.9 (4H, d), 9.3 (3H, s).
Example 71
N-(4-Aminocyclohexyl)-3-(6-aminopyridine-3-yloxy)-5-(4-carbamimidoyl-pheno-
xy)-benzamide
[0459] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-Cyanophenoxy)-5-(6-nitropyridine-3-yloxy)benzoylamino]-cyclo-h-
exyl}carbamic acid tert-butyl ester
[0460] Following the procedure of Example 69(b)
{4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester 1.2 g (2.65 mmol) and
5-chloro-2-nitro-pyridine (0.84 g, 5.31 mmol) were used to afford
1.2 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.28 (3H, m), 1.4 (10H, s), 1.8 (5H, m), 3.20 (1H, m), 3.7 (1H, m),
6.75 (1H, d), 7.25 (2H, d), 7.35 (1H, d), 7.5 (2H, s), 7.8 (1H,
dd), 7.9 (2H, d), 8.35 (2H, d), 8.5 (1H, s).
e)
{4-[3-(6-Aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoylamino]-cyclohe-
xyl}carbamic acid tert-butyl ester
[0461] Following the procedure of Example 62(e)
{4-[3-(4-cyanophenoxy)-5-(6-nitro-pyridine-3-yloxy)benzoylamino]-cyclohex-
yl}carbamic acid tert-butyl ester 1.2 g (2.09 mmol) was used to
afford 0.45 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.28 (4H, m), 1.4 (10H, s), 1.8 (4H, m), 3.20 (1H, m), 3.7
(1H, m), 5.9 (2H, s), 6.5 (1H, d), 6.75 (1H, d), 6.85 (2H, s), 7.15
(3H, d), 7.3 (3H, m), 7.85 (3H, d), 8.3 (1H, m).
f) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(6-amino
pyridine-3-yloxy)phenoxy]benzimidic acid ethyl ester
[0462] Using
{4-[3-(6-aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoylamino]-cyclohexy-
l}carbamic acid tert-butyl ester (0.45 g, 0.82 mmol) and following
the procedure of Example 1(d) afforded 0.21 g of the required
product. Percentage purity (LCMS): 93.0%, (M+1)=489.2+1.
g) N-(4-Aminocyclohexyl)-3-(6-amino
pyridine-3-yloxy)-5-(4-carbamimidoyl phenoxy)benzamide
[0463] Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(6-amino
pyridine-3-yloxy)-phenoxy]benzimidic acid ethyl ester (0.21 g, 0.42
mmol) and following the procedure of Example 1(e) afforded 0.065 g
of the required product. Percentage purity (HPLC): 95.3%, (LCMS):
90.3%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.39 (4H, m), 1.9 (4H,
m), 3.0 (1H, m), 3.70 (1H, m), 6.88 (1H, d), 7.02 (1H, s), 7.24
(2H, d), 7.36 (2H, d), 7.72 (1H, d), 7.86 (5H, d), 7.96 (1H, s),
8.42 (1H, d), 9.23 (4H, d).
Example 72
N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-carbamimidoylphenoxy)-benzam-
ide
[0464] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-Cyanophenoxy)-5-(4-nitrophenoxy)benzoylamino]cyclohexyl}-carba-
mic acid tert-butyl ester
[0465] Following the procedure of Example 69(b)
{4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester 1.1 g (2.43 mmol) and
1-chloro-4-nitro-benzene (0.765 g, 4.86 mmol) were used to afford
0.94 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),
6.7 (1H, d), 7.25 (5H, m), 7.55 (2H, m), 7.8 (2H, d), 8.3 (2H, d),
8.4 (1H, d).
e)
{4-[3-(4-Aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carba-
mic acid tert-butyl ester
[0466] Following the procedure of Example 62(e)
{4-[3-(4-cyanophenoxy)-5-(4-nitro
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.94
g (1.64 mmol) was used to afford 0.39 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H, m), 1.40 (9H, s), 1.8
(4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.1 (2H, s), 6.6 (2H, d), 6.76
(2H, m), 6.82 (2H, d), 7.14 (2H, d), 7.26 (2H, s), 7.86 (2H, d),
8.28 (1H, d).
f)
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-aminophenoxy)phenoxy]-benzimidic
acid ethyl ester
[0467] Using
{4-[3-(4-aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbami-
c acid tert-butyl ester (0.39 g, 0.71 mmol) and following the
procedure of Example 1(d) afforded 0.16 g of the required product.
Percentage purity (LCMS): 80.0%, (M+1)=488.2+1
g)
N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-carbamimidoylphenoxy)-ben-
zamide
[0468] Using
4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-aminophenoxy)phenoxy]-benzimidic
acid ethyl ester (0.16 g, 0.32 mmol) and following the procedure of
Example 1(e) afforded 0.05 g of the required product. Percentage
purity (HPLC): 97.05%, (LCMS): 96.25%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m), 6.85
(1H, s), 7.0 (4H, s), 7.3 (4H, d), 7.85 (5H, d), 8.4 (1H, d), 9.2
(2H, s), 9.3 (2H, d).
Example 73
N-(4-Aminocyclohexyl)-3-[4-(3-aminopropionylamino)phenoxy]-5-(4-carbamimid-
oylphenoxy)benzamide
[0469] Intermediates (a)-(e) are the same as in Example 72.
f)
{4-[3-[4-(3-tert-Butoxycarbonylaminopropionylamino)phenoxy]-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
[0470] 3-tert-Butoxycarbonylamino-propionic acid (0.31 g, 1.63
mmol) and
{4-[3-(4-aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbami-
c acid tert-butyl ester (0.884 g, 1.63 mmol) and other reagents as
described in Example 9(e) were used to afford 0.75 g.of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m),
1.4 (18H, s), 1.8 (4H, m), 2.4 (2H, m), 3.2 (3H, m), 3.7 (1H, m),
6.72 (1H, d), 6.88 (2H, m), 7.06 (2H, d), 7.16 (2H, d), 7.32 (2H,
s), 7.64 (2H, d), 7.86 (2H, d), 8.3 (1H, d).
g)
4-{3-(4-Aminocyclohexylcarbamoyl)-5-[4-(3-aminopropionylamino)phenoxy]p-
henoxy}benzimidic acid ethyl ester
[0471] Using
{4-[3-[4-(3-tert-butoxycarbonylaminopropionylamino)phenoxy]-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
(0.75 g, 1.05 mmol) and following the procedure of Example 1(d)
afforded 0.34 g of the required product. Percentage purity (LCMS):
85.9%, (M+1)=559.2+1.
h)
N-(4-Aminocyclohexyl)-3-[4-(3-aminopropionylamino)phenoxy]-5-(4-carbami-
midoylphenoxy)benzamide
[0472] Using
4-{3-(4-aminocyclohexylcarbamoyl)-5-[4-(3-aminopropionylamino)phenoxy]phe-
noxy}benzimidic acid ethyl ester (0.34 g, 0.60 mmol) and following
the procedure of Example 1(e) afforded 0.14 g of the required
product. Percentage purity (HPLC): 96.79%, (LCMS): 92.82%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.35 (4H, m), 1.9 (4H, m), 2.7 (2H, t),
2.95 (2H, m), 3.1 (2H, m), 6.9 (1H, s), 7.1 (2H, d), 7.3 (4H, d),
7.65 (2H, d), 7.85 (8H, m), 8.4 (1H, d), 9.1 (2H, s), 9.25 (2H, s),
10.35 (1H, s).
Example 74
N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-carbamimido-
ylphenoxy)benzamide
[0473] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-Cyano-3-methylphenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohex-
yl}carbamic acid tert-butylester
[0474] Following the procedure of Example 69(b)
{4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester 0.85 g (1.88 mmol) and
4-fluoro-2-methyl-benzonitrile (0.508 g, 3.76 mmol) were used to
afford 0.76 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 2.45 (3H, s), 3.15
(1H, m), 3.7 (1H, m), 6.72 (1H, d), 7.02 (1H, d), 7.2 (4H, m), 7.5
(2H, s), 7.8 (1H, d), 7.88 (2H, d), 8.34 (1H, d).
e)
(4-{3-[4-(N-Hydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy-carb-
amimidoyl)phenoxy]benzoylamino}cyclohexyl)carbamic acid
tert-butylester
[0475] Following the procedure of Example 2(d)
{4-[3-(4-cyano-3-methylphenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl-
}carbamic acid tert-butylester 0.76 g (1.34 mmol) and other
appropriate reagents were used to afford 0.64 g of the required
product. Percentage purity (LCMS): 44.5%, (M+1)=632.3+1.
f)
(4-{3-[4-(N-Acetylhydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydrox-
y-carbamimidoyl)phenoxy]benzoylamino}cyclohexyl)carbamic acid
tert-butylester
[0476] Following the procedure of Example 2(e)
(4-{3-[4-(N-hydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy-carbam-
imidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid
tert-butylester 0.64 g (1.01 mmol) was used to afford 0.52 g of the
required product. Percentage purity (LCMS): 49.7%, (M+1)=716.3.
g)
{4-[3-(4-Carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)-benz-
oylamino]cyclohexyl}carbamic acid tert-butylester
[0477]
(4-{3-[4-(N-Acetylhydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-ac-
etyl-hydroxy-carbamimidoyl)phenoxy]benzoylamino}cyclohexyl)carbamic
acid tert-butylester 0.52 g (0.72 mmol) was reduced using the
procedure of Example 2(f) to afford 0.25 g of required product.
Percentage purity (LCMS): 44.5%, (M+1)=600.3+1.
h)
N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-carbamim-
idoylphenoxy)benzamide
[0478] Using
{4-[3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)-benzoy-
lamino]cyclohexyl}carbamic acid tert-butylester (0.25 g, 0.41 mmol)
and following the procedure of Example 9(d) afforded 0.05 g of the
required product. Percentage purity (HPLC): 97.87%, (LCMS): 97.27%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (4H, m), 1.85 (2H, m), 1.95
(2H, m), 2.4 (3H, s), 3.0 (1H, s), 3.7 (1H, m) 7.0 (1H, s), 7.1
(1H, d), 7.18 (1H, s), 7.28 (2H, d), 7.46 (2H, s), 7.54 (1H, s),
7.88 (5H, m), 8.44 (1H, d), 9.14 (2H, s), 9.28 (6H, s).
Example 75
N-(4-Aminocyclohexyl)-3,5-bis-(4-carbamimidoylbenzyloxy)benzamide
a) 3,5-Bis(4-cyanophenoxy)benzoic acid ethyl ester
[0479] To a solution of 3,5-dihydroxy benzoic acid ethyl ester 1.2
g (6.58 mmol), dissolved in 10 ml DMF, was added K.sub.2CO.sub.3
3.63 g (26.32 mmol) followed by 4-bromomethyl-benzonitrile 5.16 g
(26.32 mmol) in 5 ml of DMF at 20.degree. C. The reaction mixture
was allowed to attain RT and then heated to 35.degree. C. for 8 h.
The solvent was removed under reduced pressure and the residue was
dissolved in 200 ml of ethyl acetate. The organic layer was washed
with brine and water. Organic phase was dried over anhydrous sodium
sulphate and solvent was removed under reduced pressure. The crude
product was subjected to column chromatography and eluted using
hexane:ethyl acetate (8:2) to afford 2.1 g of purified product.
.sup.1H NMR (DMSO-d.sub.6): 1.3 (3H, t), 4.3 (2H, q), 5.3 (4H, s),
7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
b) 3,5-Bis(4-cyanophenoxy)benzoic acid
[0480] 2.1 g (5.46 mmol) of 3,5-bis(4-cyanophenoxy)benzoic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to
afford 1.65 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
5.2 (4H, s), 6.8 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H,
d).
c) {4-[3,5-Bis(4-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0481] 3,5-Bis(4-cyanophenoxy)benzoic acid (0.75 g, 2.1 mmol) and
(4-amino-cyclo-hexyl)-carbamic acid tert-butyl ester (0.45 g, 2.1
mmol) and other reagents as described in Example 9(e) were used to
afford 0.82 g.of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.70 (2H, m), 5.25
(4H, s), 6.72 (1H, m), 6.84 (1H, s), 7.12 (2H, s), 7.64 (4H, d),
7.86 (4H, d), 8.18 (1H, m).
d)
N-(4-Aminocyclohexyl)-3,5-bis-(4-ethoxycarbonimidoylbenzyloxy)benzamide
[0482] Using
{4-[3,5-Bis(4-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic acid
tert-butyl ester (0.82 g, 1.41 mmol) and following the procedure of
Example 1(d) afforded 0.32 g of the required product. Percentage
purity (LCMS): 49.4%, (M+1)=572.3+1.
e)
N-(4-Aminocyclohexyl)-3,5-bis-(4-carbamimidoylbenzyloxy)benzamide
[0483] Using
N-(4-aminocyclohexyl)-3,5-bis-(4-ethoxycarbonimidoylbenzyloxy)-benzamide
(0.32 g, 0.55 mmol) and following the procedure of Example 1(e)
afforded 0.07 g of the required product. Percentage purity (HPLC):
98.01%, (LCMS): 99.73%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.4
(4H, m), 1.8 (2H, m), 2.0 (2H, m), 3.0 (1H, m), 3.70 (1H, m), 5.3
(4H, s), 6.9 (1H, s), 7.15 (2H, d), 7.7 (4H, d), 7.85 (4H, s), 7.9
(3H, m), 8.3 (1H, m), 9.3 (8H, s).
Example 76
2-{1-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethylam-
ine
[0484] Intermediates (a) and (b) are the same as in Example 75.
c)
(2-{1-[3,5-Bis-(4-cyanobenzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester
[0485] 3,5-Bis(4-cyanophenoxy)benzoic acid (0.64 g, 1.79 mmol) and
(2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.408 g,
1.79 mmol) and other reagents as described in Example 9(e) were
used to afford 0.72 g of the required product. Percentage purity
(LCMS): 88.39,%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.3 (2H, m),
1.35 (9H, m), 1.5 (3H, m), 1.7 (1H, m), 2.98 (2H, m), 3.45 (2H, m),
5.25 (4H, s), 6.58 (2H, s), 6.76 (2H, m), 7.65 (4H, d), 7.88 (4H,
d).
d)
2-{1-[3,5-Bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl]piperidine-4-yl}--
ethylamine
[0486] Using
(2-{1-[3,5-bis-(4-cyanobenzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester (0.72 g, 1.21 mmol) and following the
procedure of Example 1(d) afforded 0.34 g of the required product.
Percentage purity (LCMS): 49.9%, (M+1)=586.3+1.
e)
2-{1-[3,5-Bis-(4-ethoxycarbamimidoylbenzyloxy)benzoyl]piperidine-4-yl}--
ethylamine
[0487] Using
2-{1-[3,5-bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl]piperidine-4-yl}-et-
hylamine (0.34 g, 0.58 mmol) and following the procedure of Example
1(e) afforded 0.17 g of the required product. Percentage purity
(HPLC): 96.25%, (LCMS): 97.96%. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.05 (2H, m), 1.50-1.8 (5H, m), 2.8 (4H, m), 3.5 (1H, m), 4.4 (1H,
m), 5.25 (4H, s), 6.60 (2H, s), 6.8 (1H, brs), 7.65 (4H, d), 7.85
(6H, d), 9.4 (7H, s).
Example 77
N-(4-Aminocyclohexyl)-3,5-bis-(3-carbamimidoylbenzyloxy)benzamide
a) 3,5-Bis(3-cyanophenoxy)benzoic acid ethyl ester
[0488] 3,5-Dihydroxy benzoic acid ethyl ester (1.45 g, 7.95 mmol)
and 3-bromomethyl-benzonitrile (6.23 g, 31.8 mmol) and other
reagents as described in Example 75(a) were used to afford 2.3 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): 1.15 (3H, t),
4.15 (2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d),
7.86 (4H, d).
b) 3,5-Bis(3-cyanophenoxy)benzoic acid
[0489] 2.3 g (5.98 mmol) of 3,5-bis(3-cyanophenoxy)benzoic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to
afford 1.85 g.of the required product. .sup.1H NMR (DMSO-d.sub.6):
6.86 (1H, s), 7.2 (2H, d), 7.62 (2H, s), 7.82 (4H, m), 7.94 (2H,
s).
c) {4-[3,5-Bis(3-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0490] 3,5-Bis(3-cyanophenoxy)benzoic acid (1.2 g, 3.36 mmol) and
(4-amino-cyclo-hexyl)-carbamic acid tert-butyl ester (0.72 g, 3.36
mmol) and other reagents as described in Example 9(e) were used to
afford 1.33 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.20 (1H, m), 3.70
(1H, m), 5.25 (4H, s), 6.74 (1H, m), 6.86 (1H, s), 7.16 (2H, s),
7.64 (2H, t), 7.82 (4H, t), 7.94 (2H, s), 8.22 (1H, d)
d)
4-[3,5-Bis(3-ethoxycarbonimidoylbenzyloxy)benzoylamino]cyclohexylamine
[0491] Using
{4-[3,5-bis(3-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic acid
tert-butyl ester (1.33 g, 2.3 mmol) and following the procedure of
Example 1(d) afforded 0.91 g of the required product. Percentage
purity (LCMS): 14.8%, (M+1)=572.3+1.
e)
N-(4-Aminocyclohexyl)-3,5-bis-(3-carbamimidoylbenzyloxy)benzamide
[0492] Using
4-[3,5-Bis(3-ethoxycarbonimidoylbenzyloxy)benzoylamino]cyclohexyl-amine
(0.91 g, 1.58 mmol) and following the procedure of Example 1(e)
afforded 0.16 g of the required product. Percentage purity (HPLC):
98.81%, (LCMS) 97.40%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (4H,
m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m), 5.25 (4H, s), 6.9 (1H,
s), 7.15 (2H, d), 7.7 (2H, t), 7.80 (4H, t), 7.9 (5H, s), 8.3 (1H,
m), 9.4 (8H, s).
Example 78
2-{1-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethyl-a-
mine
[0493] Intermediates (a) and (b) are the same as in Example 77.
c)
(2-{1-[3,5-Bis-(3-cyanobenzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester
[0494] 3,5-Bis(3-cyanophenoxy)benzoic acid (0.6 g, 1.68 mmol) and
(2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.383 g,
1.68 mmol) and other reagents as described in Example 9(e) were
used to afford 0.65 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.25 (2H, m), 1.4 (9H, s), 1.5 (3H, m), 1.7
(2H, m), 2.7 (2H, m), 2.9 (3H, m), 4.4 (1H, m), 5.25 (4H, s), 6.6
(2H, s), 6.80 (2H, brs), 7.62 (2H, t), 7.82 (4H, m), 7.94 (2H,
s).
d)
2-{1-[3,5-Bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl-
}-ethylamine
[0495] Using
(2-{1-[3,5-bis-(3-cyanobenzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester (0.65 g, 1.09 mmol) and following the
procedure of Example 1(d) afforded 0.43 g of the required product.
Percentage purity (LCMS): 36.1%, (M+1)=-586.3+1.
e)
2-{1-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethy-
lamine
[0496] Using
2-{1-[3,5-bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}--
ethylamine (0.43 g, 0.73 mmol) and following the procedure of
Example 1(e) afforded 0.081 g of the required product. Percentage
purity (HPLC): 97.84%, (LCMS): 98.96%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.0 (2H, m), 1.50-1.6 (4H, m), 1.75 (1H, m), 2.7 (1H, m),
2.8-3.0 (4H, m), 4.45 (1H, m), 5.4 (4H, s), 6.6 (2H, s), 6.8 (1H,
brs), 7.65 (2H, m), 7.75 (6H, brs), 7.9 (2H, s), 9.45 (8H, s).
Example 79
N-(4-Aminocyclohexyl)-2,4-bis-(4-carbamimidoylbenzyloxy)benzamide
a) [4-(2,4-Dihydroxybenzoylamino)cyclohexyl]carbamic acid
tert-butyl ester
[0497] 2,4-Dihydroxy benzoic acid (1.6 g, 10.38 mmol) and
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (2.22 g, 10.38
mmol) and other reagents as described in Example 9(e) were used to
afford 0.95 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.20 (4H, m), 1.4 (9H, m), 2.1 (4H, m), 3.2 (1H, m), 3.7
(1H, m), 6.2 (2H, d), 6.74 (1H, s), 7.7 (1H, s), 8.26 (1H, s), 10.0
(1H, brs), 13.0 (1H, brs).
b) {4-[2,4-Bis-(4-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0498] [4-(2,4-Dihydroxybenzoylamino)cyclohexyl]carbamic acid
tert-butyl ester (0.95 g, 2.71 mmol) and 4-bromomethyl-benzonitrile
(2.12 g, 10.84 mmol) and other reagents as described in Example
75(a) were used to afford 1.2 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.20 (5H, m), 1.4 (9H, m), 1.75 (4H,
m), 3.6 (1H, m), 5.3 (4H, s), 6.7 (1H, s), 6.85 (1H, s), 7.35 (2H,
d), 7.5 (1H, s), 7.75 (4H, d), 7.9 (4H, s).
c)
4-[2,4-Bis-(4-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-am-
ine
[0499] Using
{4-[2,4-bis-(4-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic acid
tert-butyl ester (1.2 g, 2.06 mmol) and following the procedure of
Example 1(d) afforded 0.61 g of the required product. Percentage
purity (LCMS): 56.9%, (M+1)=572.3+1.
d)
4-[2,4-Bis-(4-carbamimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
[0500] Using
4-[2,4-bis-(4-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amin-
e (0.61 g, 1.06 mmol) and following the procedure of Example 1(e)
afforded 0.24 g of the required product. Percentage purity (HPLC):
97.52%, (LCMS): 96.14%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10
(2H, m), 1.35 (2H, m), 2.85 (4H, m), 2.9 (1H, m), 3.6 (1H, m), 5.3
(4H, d), 6.75 (1H, d), 6.9 (1H, s), 7.7 (3H, m), 7.75-8.0 (8H, m),
8.35 (1H, d), 8.7 (2H, brs), 8.95 (2H, s), 9.1 (2H, brs), 9.2-9.5
(7H, s).
Example 80
2-{1-[2,4-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethyl-a-
mine
a) {2-[1-(2,4-Dihydroxybenzoyl)piperidin-4-yl]ethyl}carbamic acid
tert-butyl ester
[0501] 2,4-Dihydroxy benzoic acid (1.25 g, 8.11 mmol) and
(2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.85 g,
8.11 mmol) and other reagents as described in Example 9(e) were
used to afford 1.13 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.05 (2H, m), 1.25 (2H, m), 1.4 (9H, s),
1.65 (2H, m), 2.75 (2H, m), 2.95 (2H, m), 3.15 (1H, m), 4.0 (2H,
m), 6.24 (2H, m), 6.78 (1H, m), 6.9 (1H, d), 9.6 (2H, brs).
b)
(2-{1-[2,4-Bis-(4-cyano-benzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic
acid tert-butyl ester
[0502] {2-[1-(2,4-Dihydroxybenzoyl)piperidin-4-yl]ethyl}carbamic
acid tert-butyl ester (1.13 g, 3.1 mmol) and
4-bromomethyl-benzonitrile (2.43 g, 12.4 mmol) and other reagents
as described in Example 75(a) were used to afford 1.3 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35 (8H, s),
2.1 (4H, s), 2.9 (3H, m), 4.55 (4H, d), 5.25 (3H, s), 5.5 (2H, t),
6.8 (1H, m), 7.3 (1H, d), 7.4 (1H, d), 7.5 (4H, d), 7.66 (1H, d),
7.8 (3H, m), 7.86 (2H, m).
c)
2-{1-[2,4-Bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl-
}-ethylamine
[0503] Using
(2-{1-[2,4-bis-(4-cyano-benzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic
acid tert-butyl ester (1.3 g, 2.18 mmol) and following the
procedure of Example 1(d) afforded 0.52 g of the required product.
Percentage purity (LCMS): 71.2%, (M+1)=586.3+1.
d)
2-{1-[2,4-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethy-
l-amine
[0504] Using
2-{1-[2,4-bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}--
ethylamine (0.52 g, 0.88 mmol) and following the procedure of
Example 1(e) afforded 0.19 g of the required product. Percentage
purity (HPLC): 90.96%, (LCMS): 98.53%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.0 (1H, m), 1.30 (1H, m), 1.5 (3H, m), 1.7 (1H, m), 2.7
(4H, m), 2.9 (1H, m), 3.4 (1H, m), 4.5 (1H, m), 5.30 (4H, d), 6.65
(1H, d), 6.8 (1H, s), 7.15 (1H, m), 7.7 (7H, m), 7.85 (4H, d) 9.2
(4H, s), 9.35 (4H, s).
Example 81
N-(4-Aminocyclohexyl)-2,4-bis(3-carbamimidoylbenzyloxy)benzamide
[0505] Intermediate (a) is the same as in Example 79(a).
b) {4-[2,4-Bis-(3-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0506] [4-(2,4-Dihydroxybenzoylamino)cyclohexyl]carbamic acid
tert-butyl ester (0.85 g, 2.42 mmol) and 3-bromomethyl-benzonitrile
(1.89 g, 9.68 mmol) and other reagents as described in Example
75(a) were used to afford 0.75 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.4 (9H, s), 1.75 (4H, m), 3.15 (1H,
m), 3.65 (2H, m), 4.55 (1H, m), 5.25 (4H, s), 6.72 (2H, m), 6.9
(1H, s), 7.7 (6H, m), 7.85 (4H, m), 7.94 (1H, s), 8.04 (1H, s).
c)
4-[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-am-
ine
[0507] Using
{4-[2,4-bis-(3-cyanobenzyloxy)benzoylamino]cyclohexyl}carbamic acid
tert-butyl ester (0.75 g, 1.29 mmol) and following the procedure of
Example 1(d) afforded 0.32 g of the required product. Percentage
purity (LCMS): 90.7%, (M+1)=572.3+1.
d)
4-[2,4-Bis-(3-carbamimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
[0508] Using
4-[2,4-bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amin-
e (0.32 g, 0.55 mmol) and following the procedure of Example 1(e)
afforded 0.08 g of the required product. Percentage purity (HPLC):
95.22%, (LCMS): 93.7%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (2H,
m), 1.40 (2H, m), 1.9 (4H, m), 2.95 (1H, m), 3.7 (1H, m), 5.35 (4H,
d), 6.75 (1H, d), 6.9 (1H, s), 7.7 (5H, m), 7.85 (7H, m), 9.1-9.4
(8H, s).
Example 82
2-{1-[2,4-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethylam-
ine
[0509] Intermediate (a) is the same as in Example 80(a).
b)
(2-{1-[2,4-Bis(3-cyanobenzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic
acid tert-butyl ester
[0510] {2-[1-(2,4-Dihydroxybenzoyl)piperidin-4-yl]ethyl}carbamic
acid tert-butyl ester (1.05 g, 2.88 mmol) and
3-bromomethyl-benzonitrile (2.25 g, 11.5 mmol) and other reagents
as described in Example 75(a) were used to afford 1.15 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (9H, s),
2.1 (2H, d), 2.6 (1H, m), 2.95 (4H, m), 3.45 (1H, m), 4.5 (2H, m),
5.2 (4H, s), 6.7 (2H, d), 6.84 (1H, d), 7.14 (1H, dd), 7.52 (1H,
m), 7.62 (3H, d), 7.7 (2H, d), 7.8 (5H, m), 7.95 (1H, s).
c)
2-{1-[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl-
}-ethylamine
[0511] Using
(2-{1-[2,4-Bis(3-cyanobenzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic
acid tert-butyl ester (1.15 g, 1.93 mmol) and following the
procedure of Example 1(d) afforded 0.41 g of the required product.
Percentage purity (LCMS): 62.5%, (M+1)=586.3+1.
d)
2-{1-[2,4-Bis-(3-carbarnimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-eth-
yl-amine
[0512] Using
2-{1-[2,4-bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}--
ethylamine (0.41 g, 0.69 mmol) and following the procedure of
Example 1(e) afforded 0.16 g of the required product. Percentage
purity (HPLC): 91.53%, (LCMS) 95.59%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.9 (2H, m), 1.25 (2H, m), 1.5 (3H, m), 1.75 (1H, m), 2.8
(3H, m), 2.9 (1H, m), 3.4 (2H, m), 4.5 (1H, m), 5.25 (3H, d), 6.55
(1H, s), 6.7 (1H, d), 6.9 (1H, d), 7.3 (1H, m), 7.8 (8H, m) 7.9
(1H, s), 9.25 (3H, d), 9.4 (3H, s).
Example 83
4-[3-(4-Aminomethylphenoxy)-5-(4-carbamimidoylphenoxy)benzoyl]-1-carboxyli-
c acid ethyl ester
[0513] Intermediates (a)-(c) are the same as in Example 62.
d)
4-[3-(4-Aminomethylphenoxy)-5-hydroxybenzoyl]piperazine-1-carboxylic
acid ethyl ester
[0514] Raney nickel (0.1 g, 1.7 mmols) was added to a stirred
solution of 4-[3-(4-cyano
phenoxy)-5-hydroxybenzoyl]piperazine-1-carboxylic acid ethyl ester
(0.5 g, 1.26 mmols) dissolved in methanolic ammonia (50 ml) and the
reaction mixture was heated to 50.degree. C. in Paar apparatus
under 50 Psi hydrogen gas pressure for 3 h. The reaction mixture
was cooled and filtered through celite pad. The filtrate was
concentrated to afford 0.4 g of the required product which was used
for the next step without further purification. Percentage purity
(LCMS): 74.3%, (M+1)=399.1+1.
e)
4-[3-(4-(tert-Butoxycarbonylaminomethyl)-phenoxy)-5-hydroxybenzoyl]-pip-
erazine-1-carboxylic acid ethyl ester
[0515] (Boc).sub.2O (0.24 g, 1.1 mmols) was added slowly with
stirring to 4-[3-(4-aminomethyl
phenoxy)-5-hydroxybenzoyl]piperazine-1-carboxylic acid ethyl ester
(0.4 g, 1.0 mmols) in 1,4-dioxane and water (1:1) and stirring was
continued for 3 h at RT. The reaction mixture was quenched with ice
cold water and extracted with ethyl acetate. The organic layer was
washed with water followed by brine and dried over anhydrous sodium
sulphate and concentrated to afford 0.3 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.20 (3H, t), 1.4 (9H, s), 3.5
(8H, ms), 4.2 (4H, m), 6.38 (2H, d), 6.48 (1H, s), 7.02 (2H, d),
7.28 (2H, d), 7.4 (1H, m), 9.8 (1H, s).
f)
4-[3-[4-(tert-Butoxycarbonylaminomethyl)-phenoxy]-5-(4-cyano-phenoxy)-b-
enzoyl]piperazine-1-carboxylic acid ethyl ester
[0516] Using 0.3 g (0.6 mmol) of
4-[3-(4-cyanophenoxy)-5-hydroxybenzoyl]piperazine-1-carboxylic acid
ethyl ester and 4-fluorobenzonitrile (0.19 g, 1.5 mmol) and
following the procedure of Example 42(b) afforded 0.38 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t),
1.4 (9H, s), 3.3 (2H, m), 3.4 (4H, m), 3.55 (2H, m), 4.05 (2H, q),
4.15 (2H, m), 6.84 (3H, m), 7.1 (2H, d), 7.26 (4H, d), 7.4 (1H, m),
7.88 (2H, s).
g)
4-[3-(4-Aminomethylphenoxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]pip-
erazine-1-carboxylic acid ethyl ester
[0517] Using
4-[3-[4-(tert-butoxycarbonylaminomethyl)-phenoxy]-5-(4-cyano-phenoxy)-ben-
zoyl]piperazine-1-carboxylic acid ethyl ester (0.38 g, 0.63 mmol)
and following the procedure of Example 1(d) afforded 0.17 g of the
required product. Percentage purity (LCMS): 81.7%,
(M+1)=546.2+1.
h)
4-[3-(4-Aminomethylphenoxy)-5-(4-carbamimidoylphenoxy)benzoyl]-piperazi-
ne-1-carboxylic acid ethyl ester
[0518] Using
4-[3-(4-aminomethylphenoxy)-5-(4-ethoxycarbonimidoylphenoxy)-benzoyl]pipe-
razine-1-carboxylic acid ethyl ester (0.17 g, 0.31 mmol) and
following the procedure of Example 1(e) afforded 0.07 g of the
required product. Percentage purity (HPLC): 97.62%, (LCMS): 94.31%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (3H, t), 3.35 (2H, m), 3.55
(2H, m), 3.9 (6H, m), 4.1 (2H, q), 6.8 (1H, s), 6.85 (2H, m), 7.20
(2H, d), 7.3 (2H, d), 7.5 (2H, d), 7.9 (2H, d), 8.2 (3H, brs), 9.1
(2H, s), 9.3 (2H, s).
Example 84
N-(4-Aminocyclohexyl)-3-(4-aminomethylphenoxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0519] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-[4-Aminomethylphenoxy]-5-hydroxybenzoylamino]cyclohexyl}carbamic
acid tert-butyl ester
[0520] Using
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (2.0 g, 4.43 mmol) and following the
procedure of Example 83(d) afforded 1.5 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H, m), 1.4 (9H, s), 1.8
(4H, m), 3.2 (1H, m), 3.7 (3H, m), 6.48 (1H, s), 6.78 (1H, d), 6.9
(1H, s), 7.0 (2H, m), 7.38 (1H, m), 8.18 (1H, d).
e)
{4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]--
cyclohexyl}carbamic acid tert-butyl ester
[0521] Using 1.5 g (3.29 mmol) of
{4-[3-[4-aminomethylphenoxy]-5-hydroxybenzoyl-amino]cyclohexyl}carbamic
acid tert-butyl ester and boc-anhydride (0.787 g, 3.61 mmol) and
following the procedure of Example 83(e) afforded 1.4 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (3H, m),
1.4 (18H, s), 1.8 (4H, m), 3.2 (2H, m), 3.7 (1H, m), 4.15 (2H, d),
6.45 (1H, s), 6.7 (1H, d), 6.9 (1H, s), 7.0 (3H, d), 7.25 (2H, d),
7.4 (1H, brs), 8.15 (1H, d), 9.8 (1H, s).
f)
{4-[3-[4-(tert-Butoxycarbonylaminomethyl)phenoxy]-5-(4-cyanophenoxy)ben-
zoylamino]cyclohexyl}carbamic acid tert-butyl ester
[0522] Using 1.4 g (2.51 mmol) of
{4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cy-
clohexyl}carbamic acid tert-butyl ester and 4-fluoro-benzonitrile
(0.76 g, 6.27 mmol) and following the procedure of Example 42(b)
afforded 1.53 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.3 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2
(1H, m), 3.7 (1H, m), 4.15 (2H, d), 6.72 (1H, d), 7.20 (1H, s),
7.06 (2H, d), 7.18 (2H, d), 7.28 (2H, d), 7.38 (3H, d), 7.86 (2H,
s), 8.3 (1H, d).
g)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy]-b-
enzimidic acid ethyl ester
[0523] Using
{4-[3-[4-(tert-butoxycarbonylaminomethyl)phenoxy]-5-(4-cyanophenoxy)benzo-
ylamino]cyclohexyl}carbamic acid tert-butyl ester (1.53 g, 2.32
mmol) and following the procedure of Example 1(d) afforded 1.15 g
of the required product. Percentage purity (LCMS): 33.53%,
(M+1)=502.2+1.
h)
N-(4-Aminocyclohexyl)-3-(4-aminomethylphenoxy)-5-(4-carbamimidoyl
phenoxy)benzamide
[0524] Using
4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy]-ben-
zimidic acid ethyl ester (1.15 g, 2.28 mmol) and following the
procedure of Example 1(e) afforded 0.75 g of the required product.
Percentage purity (HPLC): 96.64%, (LCMS): 96.88%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.45 (4H, t), 1.90 (4H, m), 3.0 (1H, m),
3.7 (1H, m), 4.05 (2H, d), 6.9 (1H, s), 7.18 (2H, d), 7.26 (2H, d),
7.38 (2H, s), 7.52 (2H, d), 7.88 (4H, d), 8.22 (2H, brs), 8.42 (1H,
d), 9.2 (2H, brs), 9.3 (2H, s).
Example 85
(4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-
-phenoxy}-benzyl)-carbamic acid ethyl ester
[0525] Intermediates (a) to (d) are the same as in Example 84.
e)
(4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}--
cyclohexyl)-carbamic acid tert-butyl ester
[0526] To 1.0 g (2.19 mmol) of
{4-[3-(4-aminomethyl-phenoxy)-5-hydroxy-benzoyl-amino]-cyclohexyl}-carbam-
ic acid tert-butyl ester, dissolved in 5 ml of THF, 0.13 g (5.47
mmol) of sodium hydride was added at 0.degree. C. and the mixture
was stirred for 15 min at same temperature. 0.26 g (2.40 mmol) of
ethylchloroformate, dissolved in 2 ml of THF, was added dropwise to
the stirred solution during 10 min and then the reaction mixture
was stirred at RT for 6 h. After reaction completion, solvent was
removed under reduced pressure and the obtained residue was
dissolved in 200 ml of ethyl acetate. Organic layer was washed with
(3.times.100 ml) of brine followed by water (2.times.100 ml).
Organic phase was dried over anhydrous sodium sulphate and
concentrated under reduced pressure to afford 0.56 g of required
product which was used for the next step without further
purification. Percentage purity (LCMS): 59.7%, (M+1)=527.2+1.
f)
(4-{3-(4-Cyano-phenoxy)-5-[4-(ethoxycarbonylamino-methyl)-phenoxy]-benz-
oylamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0527] Using 0.56 g (1.06 mmol) of
(4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-cy-
clohexyl)-carbamic acid tert-butyl ester and 4-fluoro-benzonitrile
(0.32 g, 2.65 mmol) and following the procedure of Example 42(b)
afforded 0.61 g of the required product. Percentage purity (LCMS):
45.2%, (M+1)=628.3+1.
g) (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester
[0528] Following the procedure of Example 2(d)
(4-{3-(4-cyano-phenoxy)-5-[4-(ethoxy-carbonylamino-methyl)-phenoxy]-benzo-
ylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.61 g (0.97
mmol) and other reagents were used to afford 0.68 g of the required
product. Percentage purity (LCMS): 38.9%, (M+1)=661.3+1.
h)
(4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)-pheno-
xy]-phenoxy}-benzyl)-carbamic acid ethyl ester
[0529] Using
(4-{3-[4-(ethoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy
carbamimidoyl)-phenoxy}-benzoylamino]-cyclohexyl)-carbamic acid
tert-butyl ester (0.68 g, 1.02 mmol) and following the procedure of
Example 9(d) afforded 0.28 g of the required product. Percentage
purity (HPLC): 97.5%, (LCMS): 96.6%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.24 (3H, t), 1.38 (4H, m), 1.92 (4H, m), 3.0 (1H, m), 3.8
(1H, m), 4.00 (2H, q), 4.20 (2H, d), 6.88 (1H, s), 7.06 (2H, d),
7.22 (2H, d), 7.32 (4H, m), 7.65 (2H, m), 7.78 (5H, m), 8.18 (1H,
d), 11.0 (1H, brs).
Example 86
4-[3-(4-Aminomethylphenoxy)-5-(octahydroquinoline-1-carbonyl)-phenoxy]-ben-
zmidine
[0530] Intermediates (a) and (b) are the same as in Example 49.
c)
4-[3-Hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzonitrile
[0531] 3-(4-Cyano-phenoxy)-5-hydroxy-benzoic acid (1.5 g, 5.87
mmol) and decahydro-quinoline (0.89 g, 6.45 mmol) and other
reagents as described in Example 9(e) were used to afford 1.6 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35 (6H,
m), 1.80 (7H, m), 3.0 (1H, m), 3.6 (1H, m), 4.5 (1H, m), 6.44 (1H,
s), 6.54 (2H, m), 7.16 (2H, d), 7.88 (2H, d), 10.1 (1H, brs).
d)
[3-(4-aminomethylphenoxy)-5-hydroxyphenyl]-(octahydroquinolin-1-yl)meth-
anone
[0532] Using
4-[3-hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzonitrile
(1.6 g, 4.27 mmol) and following the procedure of Example 83(d)
afforded 1.2 g of the required product. Percentage purity (LCMS):
94.5%, (M+1)=661.3+1.
e)
{4-[3-hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzyl}carbamic
acid tert-butyl ester
[0533] Using 1.2 g (3.17 mmol) of
[3-(4-aminomethylphenoxy)-5-hydroxyphenyl]-(octahydroquinolin-1-yl)methan-
one and boc-anhydride (0.76 g, 3.48 mmol) and following the
procedure of Example 83(e) afforded 1.34 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (8H, m), 1.40 (9H, s),
1.55 (2H, m), 1.75 (4H, m), 3.0 (1H, m), 3.55 (1H, m), 4.1 (2H, d),
6.24 (1H, s), 6.42 (2H, s), 7.0 (2H, d), 7.26 (2H, d), 7.4 (1H, t),
9.8 (1H, s).
f)
{4-[3-(4-Cyanophenoxy)-5-(octahydroquinoline-1-carbonyl)phenoxy]benzyl}-
-carbamic acid tert-butyl ester
[0534] Using 1.34 g (2.79 mmol) of
{4-[3-hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzyl}carbamic
acid tert-butyl ester and 4-fluorobenzonitrile (0.84 g, 6.97 mmol)
and following the procedure of Example 42(b) afforded 1.6 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (8H, m),
1.40 (9H, s), 1.8 (8H, m), 4.1 (2H, d), 6.68 (1H, s), 6.82 (2H, s),
7.08 (2H, d), 7.22 (2H, d), 7.28 (2H, d), 7.4 (1H, t), 7.88 (2H,
d).
g)
{4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-carbo-
nyl)-phenoxyl]-benzyl}carbamic acid tert-butyl ester
[0535] Following the procedure of Example 2(d)
{4-[3-(4-cyanophenoxy)-5-(octahydro-quinoline-1-carbonyl)phenoxy]benzyl}--
carbamic acid tert-butyl ester 1.6 g (2.76 mmol) and other reagents
were used to afford 1.43 g of the required product. Percentage
purity (LCMS): 54.6%, (M+1)=612.3+1.
h)
{4-[3-[4-(N-acetylhydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-
-carbonyl)phenoxy]benzyl}carbamic acid tert-butyl ester
[0536]
{4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-c-
arbonyl)-phenoxyl]benzyl}carbamic acid tert-butyl ester, 1.4 g
(2.28 mmol) was acetylated with 0.26 g (2.5 mmol) of acetic
anhydride using the procedure of Example 2(e) to afford 1.04 g of
the required product. Percentage purity (LCMS): 36.1%,
(M+1)=654.3+1.
i)
4-[3-(4-Aminomethylphenoxy)-5-(octahydroquinoline-1-carbonyl)phenoxy]be-
nzmidine
[0537] 1.0 g (1.52 mmol) of
{4-[3-[4-(N-acetylhydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-c-
arbonyl)phenoxyl]benzyl}carbamic acid tert-butyl ester was reduced
using the procedure of Example 2(f) to afford 0.43 g of the
required product. Percentage purity (HPLC): 83.4%, (LCMS): 96.26%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.3 (5H, m), 1.55 (2H, m), 1.75
(5H, m), 2.7 (1H, m), 3.05 (1H, m), 4.0 (2H, d), 4.25 (1H, m), 4.45
(1H, m), 6.75 (4H, m), 7.2 (2H, d), 7.3 (2H, d), 7.55 (2H, d), 7.9
(2H, d), 8.4 (3H, brs), 9.1 (2H, s), 9.4 (2H, s)
Example 87
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6-di-
fluoro-phenoxy)-benzamide
[0538] Intermediates (a) and (e) are the same as in Example 84.
f)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2,6-difl-
uoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl
ester
[0539] Using 0.5 g (0.89 mmol) of
{4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cy-
clohexyl}carbamic acid tert-butyl ester and
3,4,5-trifluoro-benzonitrile (0.34 g, 2.22 mmol) and following the
procedure of Example 42(b) afforded 0.4 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.38 (18H, d),
1.78 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.74 (1H,
d), 6.90 (1H, s), 7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40
(1H, m), 8.08 (2H, d), 8.32 (1H, d).
g)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(-
N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester
[0540] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2,6-difluo-
ro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl
ester (0.4 g, 0.57 mmol) and following the procedure of Example
2(d) afforded 0.45 g of the required product. Percentage purity
(LCMS): 83.53%, (M+1)=525.2+1 (de-bis BOC product mass).
h)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(-
N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester
[0541] Using
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N--
hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester (0.45 g, 0.62 mmol) and following the
procedure of Example 2(e) afforded 0.5 g of the required product.
Percentage purity (LCMS): 81.00%, (M+1)=667.2+1 (de-BOC product
mass).
i)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl--
2,6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester
[0542]
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-
-4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carba-
mic acid tert-butyl ester 0.5 g (0.65 mmol) was reduced using the
procedure of Example 2(f) to afford 0.3 g of the required product.
Percentage purity (LCMS): 85.0%, (M+1)=709.3+1.
j)
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6-
-difluoro-phenoxy)-benzamide
[0543] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2,-
6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester (0.3 g, 0.42 mmol) and following the procedure of
Example 9(d) afforded 0.15 g of the required product. Percentage
purity (HPLC): 97.83%, (LCMS): 92.22%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.44 (4H, m), 1.88 (4H, m), 3.02 (1H, m), 3.48 (1H, m),
4.05 (2H, d), 6.92 (1H, s), 7.14 (2H, d), 7.25 (2H, d), 7.50 (2H,
d), 7.90 (5H, m), 8.25 (3H, brs), 8.44 (1H, d), 9.52 (4H, d).
Example 88
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2-trif-
luoromethyl-phenoxy)-benzamide
[0544] Intermediates (a) and (e) are the same as in Example 84.
g)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2-triflu-
oromethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester
[0545] Using 0.46 g (0.82 mmol) of
{4-[3-[4-tert-butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cy-
clohexyl}carbamic acid tert-butyl ester and
4-fluoro-3-tri-fluoromethylbenzonitrile (0.313 g, 1.65 mmol) and
following the procedure of Example 42(b) afforded 0.3 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m),
1.38 (18H, d), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H,
d), 6.75 (1H, d), 7.02 (1H, s), 7.08 (2H, d), 7.20 (1H, d), 7.28
(2H, d), 7.41 (3H, m), 8.1 (1H, m), 8.38 (2H, m).
h)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethy-
l-4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester
[0546] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2-tri-fluo-
romethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester (0.3 g, 0.41 mmol) and following the procedure of
Example 2(d) afforded 0.3 g of the required product. Percentage
purity (LCMS): 75.8%, (M+1)=557.2+1 (de-bis BOC product mass).
i)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethy-
l-4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carb-
amic acid tert-butyl ester
[0547] Using
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl--
4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester (0.3 g, 0.39 mmol) and following the
procedure of Example 2(e) afforded 0.35 g of the required product.
Percentage purity (LCMS): 59.00%, (M+1)=699.2+1 (de-BOC product
mass).
j)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl--
2-trifluoromethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester
[0548]
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluorom-
ethyl-4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)--
carbamic acid tert-butyl ester 0.35 g (0.47 mmol) was reduced using
the procedure of Example 2(f) to afford 0.2 g of the required
product. Percentage purity (LCMS): 70.0%, (M+1)=741.3+1.
k)
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2-t-
rifluoromethyl-phenoxy)-benzamide
[0549] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2,-
6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester (0.3 g, 0.42 mmol) and following the procedure of
Example 9(d) afforded 0.15 g of the required product. Percentage
purity (HPLC): 99.55%, (LCMS): 96.52%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.44 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 3.0 (1H, m), 3.6
(1H, m), 4.05 (2H, d), 7.08 (1H, s), 7.22 (2H, d), 7.30 (1H, d),
7.42 (2H, d), 7.52 (2H, d), 7.88 (3H, brs), 8.08 (1H, d), 8.22 (2H,
brs), 8.28 (1H, s), 8.48 (1H, d), 9.45 (4H, d).
Example 89
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-2,6-difluoro-phenoxy)-5-(4-carbami-
midoyl-phenoxy)-benzamide
a) 3-(4-Cyano-2,6-difluoro-phenoxy)-5-hydroxy-benzoic acid ethyl
ester
[0550] Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and
3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and
following the procedure of Example 42(a) afforded 1.2 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (3H, t),
4.27 (2H, q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H,
d), 10.20 (1H, brs).
b)
3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy--
benzoic acid ethyl ester
[0551] 0.9 g (2.82 mmol) of
3-(4-cyano-2,6-difluoro-phenoxy)-5-hydroxy-benzoic acid ethyl ester
was dissolved in 50 ml of methanol and 1.23 g (5.64 mmol) of
di-tert-butyl dicarbonate was slowly added at 0.degree. C. Nickel
chloride (60.0 mg, 0.28 mmol) and sodium borohydride (0.75 g, 19.74
mmol) were added at 0.degree. C. at 10 min interval each. After
complete addition the reaction mixture was stirred at RT for 30
min. Then 0.3 g (3.22 mmol) of diethylenetriamine was added during
15 min and finally reaction mixture was stirred for 2 h at RT.
Reaction progress was monitored by TLC. The reaction mixture was
concentrated under reduced pressure and partitioned between water
(100 ml) and ethyl acetate (100 ml). The organic phase was washed
with 2.times.100 ml solution of saturated sodium bicarbonate
solution and then with 2.times.100 ml of saturated brine solution,
dried over sodium sulphate and concentrated. The crude residue was
purified by column chromatography using hexane-ethyl acetate (10:2)
to afford 0.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.25 (3H, t), 1.40 (9H, s), 4.18 (2H, d),
4.28 (2H, q) 6.60 (1H, s), 6.84 (1H, s), 7.10 (1H, s), 7.18 (2H,
d), 7.54 (1H, t), 10.2 (1H, brs).
c)
3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
-phenoxy)-benzoic acid ethyl ester
[0552] Using 0.5 g (1.18 mmol) of
3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy-be-
nzoic acid ethyl ester and 4-fluorobenzonitrile (0.21 g, 1.77 mmol)
and following the procedure of Example 42(b) afforded 0.3 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (3H, t),
1.42 (9H, s), 4.2 (2H, d), 4.28 (2H, q), 7.22 (6H, m), 7.32 (1H,
s), 7.54 (1H, t), 7.90 (2H, d).
d)
3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
-phenoxy)-benzoic acid
[0553] 1.1 g (2.09 mmol) of
3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-p-
henoxy)-benzoic acid ethyl ester was hydrolysed using the procedure
of Example 5(b) to afford 0.8 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.42 (9H, s), 4.22 (2H, d), 7.25 (7H,
m), 7.52 (1H, m), 7.90 (2H, s), 12.4 (1H, brs).
e)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-c-
yano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl
ester
[0554]
3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-c-
yano-phenoxy)-benzoic acid (0.6 g, 1.2 mmol) and
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.28 g, 1.3
mmol) and other reagents as described in Example 9(e) were used to
afford 0.4 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.24 (4H, m), 1.42 (18H, s), 1.8 (4H, m), 3.18 (1H, m),
3.64 (1H, m), 4.20 (2H, d), 6.74 (1H, d), 7.0 (1H, s), 7.16 (4H,
m), 7.24 (1H, s), 7.38 (1H, s), 7.54 (1H, t), 7.88 (2H, d), 36 (1H,
d).
f)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(-
N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester
[0555] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cya-
no-phenoxy)-benzoylamino]-cyclohexyl}-carbamie acid tert-butyl
ester (0.53 g, 0.76 mmol) and following the procedure of Example
2(d) afforded 0.6 g of the required product. Percentage purity
(LCMS): 74.23%, (M+1)=725.3+1.
g)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(-
N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester
[0556] Using
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N--
hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic
acid tert-butyl ester (0.6 g, 0.82 mmol) and following the
procedure of Example 2(e) afforded 0.6 g of the required product.
Percentage purity (LCMS): 21.0%, (M+1)=667.2+1 (de-BOC product
mass).
h)
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-c-
arbamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester
[0557]
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5--
[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carba-
mic acid tert-butyl ester 0.6 g (0.78 mmol) was reduced using the
procedure of Example 2(f) to afford 0.35 g of the required product.
Percentage purity (LCMS): 75.0%, (M+1)=709.3+1.
i)
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-2,6-difluoro-phenoxy)-5-(4-carb-
amimidoyl-phenoxy)-benzamide
[0558] Using
{4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-car-
bamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid
tert-butyl ester (0.35 g, 0.49 mmol) and following the procedure of
Example 9(d) afforded 0.15 g of the required product. Percentage
purity (HPLC): 98.72%, (LCMS): 96.32%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.38 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 2.98 (1H, m),
3.65 (1H, m), 4.14 (2H, d), 6.98 (1H, t), 7.22 (3H, m), 7.38 (1H,
s), 7.50 (2H, d), 7.90 (5H, m), 8.45 (3H, m), 9.30 (4H, d).
Example 90
1-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperidine-4-carboxylic
acid
[0559] Intermediates (a) and (b) are the same as in Example 26.
c) 1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic
acid ethyl ester
[0560] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.6 g (1.68 mmol) and
piperidine-4-carboxylic acid ethyl ester (0.31 g, 2.02 mmol) were
used to afford 0.54 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.18 (3H, t), 1.5 (2H, m), 1.82 (2H, m),
2.6 (1H, m), 2.90 (1H, m), 3.12 (1H, m), 3.52 (1H, m), 4.08 (21-1,
q), 4.25 (1H, m), 6.96 (2H, d), 7.06 (1H, t), 7.26 (4H, d), 7.88
(4H, d).
d) 1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic
acid
[0561] 0.48 g (0.96 mmol) of
1-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to
afford 0.4 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.28 (2H, m), 1.5 (2H, m), 1.82 (2H, m), 3.10 (1H, m), 3.58
(1H, m), 4.24 (1H, m), 6.98 (1H, d), 7.16 (2H, m), 7.25 (4H, m),
7.88 (4H, m), 12.5 (1H, brs).
e)
1-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidine-4-c-
arboxylic acid
[0562] Using
1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
(0.4 g, 0.85 mmol) and following the procedure of Example 2(d)
afforded 0.4 g of the required product. Percentage purity (LCMS):
95.0%, (M+1)=531.0+1.
f)
1-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperidine-4-carboxylic
acid
[0563]
1-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidine-
-4-carboxylic acid 0.4 g (0.74 mmol) was reduced using the
procedure of Example 2(f) to afford 0.1 g of the required product.
Percentage purity (HPLC): 95.33%, (LCMS): 98.43%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.48 (2H, m), 1.85 (2H, m), 2.92 (1H, m),
3.10 (1H, m), 3.58 (1H, m), 4.25 (2H, m), 6.92 (2H, d), 7M (1H, t),
7.32 (4H, d), 7.88 (4H, d), 9.12 (4H, brs), 9.28 (4H, brs).
Example 91
4-{1-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperidin-4-yl}-butyric
acid
[0564] Intermediates (a) and (b) are the same as in Example 26.
c) 4-{1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidin-4-yl}-butyric
acid ethyl ester
[0565] Following the procedure of Example 5(c)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.37 mmol) and
4-piperidin-4-yl-butyric acid ethyl ester (0.68 g, 3.7 mmol) were
used to afford 0.9 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.20 (4H, m), 1.52 (5H, m), 1.70 (1H, m),
2.3 (2H, t), 2.68 (1H, m), 3.6 (3H, s), 4.4 (2H, q), 4.25 (1H, m),
6.95 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
d)
4-(1-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-
-yl)-butyric acid ethyl ester
[0566] Using
4-{1-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidin-4-yl}-butyric
acid ethyl ester (1.0 g, 1.91 mmol) and following the procedure of
Example 2(d) afforded 1.1 g of the required product. Percentage
purity (LCMS): 28.2%, (M+1)=589.2+1.
e)
4-(1-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-piper-
idin-4-yl)-butyric acid ethyl ester
[0567] Using
4-(1-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-y-
l)-butyric acid ethyl ester (1.0 g, 1.65 mmol) and following the
procedure of Example 2(e) afforded 0.6 g of the required product.
Percentage purity (LCMS): 38.0%, (M+1)=673.2+1.
f)
4-(1-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-buty-
ric acid ethyl ester
[0568]
4-(1-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-p-
iperidin-4-yl)-butyric acid ethyl ester 0.6 g (0.87 mmol) was
reduced using the procedure of Example 2(f) to afford 0.14 g of the
required product. Percentage purity (HPLC): 90.04%, (LCMS): 81.94%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.20 (2H, m), 1.52 (4H, m),
1.70 (1H, m), 2.30 (2H, t), 2.7 (2H, m), 3.0 (1H, m), 3.6 (3H, s),
4.4 (2H, m), 6.9 (2H, s), 7.0 (1H, s), 7.32 (4H, d), 7.88 (4H, d),
9.25 (8H, brs).
Example 92
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-be-
nzoic acid
[0569] Intermediates (a) (c) are the same as in Example 49.
d)
{4-[3-(4-Cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoylamino]-cyclohexyl}--
carbamic acid tert-butyl ester
[0570] Using 3.0 g (6.6 mmol) of
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester and 4-fluorobenzaldehyde (1.66 g, 13.3 mmol)
and following the procedure of Example 42(b) afforded 2.2 g of the
required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m),
1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.68 (1H, m), 6.75 (1H, d),
7.25 (4H, m), 7.50 (2H, s), 7.82 (2H, d), 7.95 (2H, d), 8.38 (1H,
d), 9.94 (1H, s).
e)
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenox-
y)-phenoxy]-benzoic acid
[0571] 0.5 g (0.9 mmol) of
{4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-amino]-cyclohexyl}-c-
arbamic acid tert-butyl ester was dissolved in 15 ml of THF and
0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of
water, was added to THF solution at 10.degree. C. during 10 min.
The reaction mixture stirred over night at RT. Reaction progress
was monitored by TLC. Reaction mixture was filtered through celite
and washed with THF and thus obtained mother liquor was
concentrated under vacuo. Product was crystallized with ethyl
acetate to afford 0.25 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m),
3.18 (1H, m), 3.66 (1H, m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H,
d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
f)
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenox-
y)-phenoxy]-benzoic acid benzyl ester
[0572] 0.6 g (1.05 mmol) of
4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid was dissolved in 5 ml of DMF. At 0.degree.
C. 50 mg (0.35 mmol) of potassium carbonate followed by 45 mg (0.26
mmol) benzylbromide were added and the reaction mixture was stirred
for 4 h at RT. Reaction progress was monitored by TLC. Upon
completion of the reaction the contents were diluted with 50 ml of
ice-water and extracted with 3.times.50 ml of ethyl acetate, dried
over anhydrous sodium sulphate and concentrated under vacuo. Thus
obtained crude residue was purified by column chromatography using
60-120 mesh silica-gel and eluted with ethylacetate:hexane (1:9) to
give 0.38 mg of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.66
(1H, m), 5.36 (2H, s), 6.76 (1H, d), 7.22 (5H, m), 7.46 (7H, m),
7.88 (2H, d), 8.05 (2H, d), 8.36 (1H, d).
g)
4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-hydroxyca-
rbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester
[0573] Using
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid benzyl ester (0.4 g, 0.61 mmol) and
following the procedure of Example 2(d) afforded 0.39 g of the
required product. Percentage purity (LCMS): 52.0%,
(M+1)=694.3+1.
h)
4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-acetyl-hy-
droxycarbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester
[0574] Using
4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarb-
amimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester (0.39 g,
0.56 mmol) and following the procedure of Example 2(e) afforded
0.41 g of the required product. Percentage purity (LCMS): 53.0%,
(M+1)=680.5+1 (Boc-acidmass).
i)
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-carbamimidoy-
l-phenoxy)-phenoxy]-benzoic acid
[0575]
4-{3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-acety-
lhydroxy-carbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester
0.41 g (0.56 mmol) was reduced using the procedure of Example 2(f)
to afford 0.13 g of the required product. Percentage purity (LCMS):
74.1%, (M+1)=587.1+1.
j)
N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide
[0576] Using
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-carbam-imidoyl-
-phenoxy)-phenoxy]-benzoic acid (0.13 g, 0.22 mmol) and following
the procedure of Example 9(d) afforded 35 mg of the required
product. Percentage purity (HPLC): 97.00%, (LCMS): 93.86%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.40 (4H, m), 1.92 (4H, m), 3.02 (1H,
m), 3.70 (1H, m), 7.02 (1H, s), 7.15 (2H, d), 7.35 (2H, d), 7.45
(2H, d), 7.76 (1H, brs), 7.88 (4H, dd), 8.40 (1H, d), 8.88 (2H,
brs), 9.25 (2H, brs).
Example 93
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-be-
nzoic acid ethyl ester
[0577] Intermediates (a) (c) are the same as in Example 49.
d)
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenox-
y)-phenoxy]-benzoic acid ethyl ester
[0578] Using 2.0 g (4.4 mmol) of
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester and 4-fluoro-benzoic acid ethyl ester (1.2 g,
6.6 mmol) and following the procedure of Example 42(b) afforded 1.8
g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35
(4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 4.30
(2H, q), 6.75 (1H, d), 7.20 (5H, m), 7.48 (2H, d), 7.88 (2H, d),
8.00 (2H, d), 8.36 (1H, d).
e)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)-ph-
enoxy]-benzoic acid ethyl ester
[0579] Using
4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid ethyl ester (0.6 g, 1.0 mmol) and following
the procedure of Example 1(d) afforded 0.55 g of the required
product. Percentage purity (LCMS): 96.0%, (M+1)=545.4+1.
f)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-
-benzoic acid
[0580] Using
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)-phen-
oxy]-benzoic acid (0.45 g, 0.82 mmol) and following the procedure
of Example 1(e) afforded 0.25 g of the required product. Percentage
purity (HPLC): 97.88%, (LCMS): 95.45%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.45 (4H, m), 1.95 (4H, m), 3.0 (2H, m), 3.4 (1H, m), 4.34
(2H, m), 7.1 (1H, s), 7.18 (2H, d), 7.3 (2H, d), 7.5 (2H, d) 7.9
(4H, m), 8.0 (2H, d), 8.4 (1H, m), 9.00 (2H, brs), 9.26 (2H,
brs).
Example 94
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-phenoxy)-
-benzamide
[0581] Intermediates (a)-(e) are the same as in Example 92.
f)
{4-[3-(4-Carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclo-hex-
yl}-carbamic acid tert-butyl ester
[0582] 0.6 g (1.05 mmol) of
4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid was dissolved in 15 ml of THF. At
-10.degree. C. 0.18 ml (1.57 mmol) of N-methylmorpholine was added.
The reaction mixture was stirred for 15 min at 0.degree. C. 0.14 ml
(1.36 mmol) of tert-butylchloroformate was added and the reaction
mixture was stirred for 1 h at RT. Further 6.0 ml of 30% of ammonia
solution was added during 10 min at 0.degree. C. and reaction
progress was monitored by TLC. Upon completion of the reaction the
contents were diluted with 50 ml ethyl acetate. Organic layer was
separated and washed with 3.times.50 ml saturated sodium
bicarbonate solution, dried over anhydrous sodium sulphate and
concentrated under reduced pressure to afford 0.4 g of the required
product. Percentage purity (LCMS): 60.0%, (M+1)=570.2.
g)
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamoyl-phenoxy)-phenoxy]-ben-
zimidic acid ethyl ester
[0583] Using
{4-[3-(4-carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-
-carbamic acid tert-butyl ester (0.45 g, 0.79 mmol) and following
the procedure of Example 1(d) afforded 0.48 g of the required
product. Percentage purity (LCMS): 77.0%, (M+1)=516.1+1.
h)
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-pheno-
xy)-benzamide
[0584] Using
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamoyl-phenoxy)-phenoxy]-benzi-
midic acid ethyl ester (0.48 g, 0.93 mmol) and following the
procedure of Example 1(e) afforded 0.055 g of the required product.
Percentage purity (HPLC): 97.22%, (LCMS): 93.33%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.45 (4H, m), 1.90 (4H, m), 3.0 (1H, m),
3.7 (1H, m), 7.0 (1H, s), 7.15 (2H, d) 7.32 (3H, d), 7.45 (2H, d),
7.88 (6H, m), 8.40 (1H, d), 8.88 (2H, brs), 9.25 (2H, brs).
Example 95
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclohexanecarboxylic
acid ethyl ester
[0585] Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexanecarboxylic
acid ethyl ester
[0586] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.6 mmol) and
4-amino-cyclohexanecarboxylic acid ethyl ester (0.48 g, 2.6 mmol)
were used to afford 0.5 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.34 (5H, m), 1.41 (5H, m), 1.92 (4H, m),
2.1 (1H, t), 3.81 (1H, m), 4.12 (2H, q), 7.04 (4H, dd), 7.51 (2H,
s), 7.89 (3H, d), 8.41 (1H, d). Percentage purity (HPLC):
89.3%.
d)
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclo-hex-
anecarboxylic acid ethyl ester
[0587] 0.6 g (1.17 mmol) of
4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexane-carboxylic
acid ethyl ester was dissolved in 30 ml of ethanol and 0.2 ml (9.4
mmol) of 50% aqueous solution of hydroxylamine was added at RT
during 5 min. The reaction mixture stirred for 6 h at 80.degree. C.
Reaction progress was monitored by TLC. Reaction mixture was cooled
to RT and solvent was removed under reduced pressure and thus
obtained crude product, yield 0.6 g, was subjected to the next step
without further purification. Percentage purity (HPLC): 80%,
(LCMS): 83.3%, (M+1)=575.23+1.
e)
4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyc-
lohexanecarboxylic acid ethyl ester
[0588] Using
4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexane-
carboxylic acid ethyl ester (0.6 g, 1.14 mmol) and following the
procedure of Example 2(e) afforded 0.5 g of the required product.
Percentage purity (LCMS): 55.3%, (M+1)=659.3+1.
f)
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclohexanecarboxyli-
c acid ethyl ester
[0589] Using
4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclo-
hexanecarboxylic acid ethyl ester (0.45 g, 0.68 mmol) and following
the procedure of Example 2(f) afforded 0.25 g of the required
product. Percentage purity (HPLC): 92.31%, (LCMS): 91.81%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.1 (3H, t), 1.31 (4H, m), 1.90 (4H,
m), 2.21 (1H, m), 3.0 (1H, m), 4.12 (2H, q), 7.21 (7H, dd), 7.90
(4H, d), 8.52 (1H, d), 9.21 (8H, d).
Example 96
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
[0590] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
[0591] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.1 g (0.28 mmol) and
4-amino-cyclohexanol (0.046 g, 0.42 mmol) were used to afford 0.05
g of the required product. Percentage purity (LCMS): 92.3%,
(M+1)=453.1+1.
d)
3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohexyl)-b-
enzamide
[0592] Using
3,5-bis-(4-cyano-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide (0.5
g, 1.10 mmol) and following the procedure of Example 95(d) afforded
0.45 g of the required product. Percentage purity (LCMS): 81.1%,
(M+1)=519.3+1.
e)
3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohe-
xyl)-benzamide
[0593] Using
3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohexyl)-ben-
zamide (0.5 g, 0.96 mmol) and following the procedure of Example
2(e) afforded 0.40 g of the required product. Percentage purity
(LCMS): 49.2%, (M+1)=603.3+1.
f)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
[0594] Using
3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohexy-
l)-benzamide (0.4 g, 0.66 mmol) and following the procedure of
Example 2(f) afforded 0.2 g of the required product. Percentage
purity (HPLC): 97.19%, (LCMS): 93.81%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.21 (4H, m), 1.89 (4H, m), 3.11 (1H, m), 3.7 (1H, m), 7.11
(1H, t), 7.45 (4H, d), 7.51 (2H, d), 7.88 (4H, d), 8.40 (1H, d),
9.4 (8H, d).
Example 97
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(6-amino-pyridin-3-ylox-
y)-benzamide
[0595] Intermediates (a) and (e) are the same as in Example 84.
f)
(4-{3-(6-Nitro-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino-methyl)--
phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl
ester
[0596] Following the procedure of Example 69(b)
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamin-
o}-cyclohexyl)-carbamic acid tert-butyl ester 0.4 g (0.72 mmol) and
5-bromo-2-nitro-pyridine (0.17 g, 0.86 mmol) were used to afford
0.3 g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.31 (18H, d), 1.8 (4H, d), 3.20 (2H, m), 3.8 (2H, m), 4.1 (2H, d),
7.35 (3H, d), 7.4 (3H, m), 7.9 (1H, d), 8.35 (2H, d), 8.5 (1H,
s).
g)
(4-{3-(6-Amino-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino-methyl)--
phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl
ester
[0597] Following the procedure of Example 62(e)
(4-{3-(6-Nitro-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino-methyl)-ph-
enoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.3
g (0.44 mmol) was used to afford 0.2 g of the required product.
Percentage purity (LCMS): 68.4%, (M+1)=647.3+1.
h)
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(6-amino-pyridin-3-y-
loxy)-benzamide
[0598] Using
(4-{3-(6-Amino-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino-methyl)-ph-
enoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.2 g, 0.30 mmol) and following the procedure of Example 9(d)
afforded 0.15 g of the required product. Percentage purity (HPLC):
95.31%, (LCMS): 97.4%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28
(4H, m), 1.91 (4H, dd), 2.91 (1H, m), 3.8 (1H, m), 4.1 (2H, d),
6.91 (2H, m), 7.21 (4H, m), 7.51 (2H, d), 7.91 (5H, m), 8.3 (3H,
brs) 8.45 (1H, d).
Example 98
4-[3-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-5-(4-aminomethyl-phenoxy)-p-
henoxy]-benzamidine
[0599] Intermediates (a) and (b) are the same as in Example 49.
c)
(2-{1-[3-(4-Cyano-phenoxy)-5-hydroxy-benzoyl]-piperidin-4-yl}-ethyl)-ca-
rbamic acid tert-butyl ester
[0600] Following the procedure of Example 9(e)
3-(4-cyanophenoxy)-5-hydroxy benzoic acid 1.6 g (6.3 mmol) and
(2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.43 g,
6.27 mmol) were used to afford 2.0 g of the required product.
Percentage purity (LCMS): 79.6%, (M+1)=465.2+1.
d)
[2-(1-{3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoy-
l}-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester
[0601] Nickelchloride (0.1 g, 0.4 mmols) and Boc-anhydride (1.9 g,
0.8 mmol) were added to a stirred solution of
(2-{1-[3-(4-cyano-phenoxy)-5-hydroxy-benzoyl]-piperidin-4-yl}-ethyl)-carb-
amic acid tert-butyl ester (2.0 g, 4.3 mmol) dissolved in methanol
(50 ml) at 0.degree. C. Sodiumborohydride (1.1 g, 30.1 mmol) was
added in portions over 30 min at 0.degree. C. The obtained reaction
mixture was stirred at RT for 2 h. After reaction completion
solvent was evaporated under vacuo. Thus obtained residue was
partitioned between ethylacetate (150 ml) and saturated solution of
sodiumbicarbonate (75 ml) and stirred to get a clear layer. Organic
layer was separated and further washed with saturated aqueous
solution of sodiumbicarbonate and dried over anhydrous sodium
sulphate. Thus obtained crude product was subjected to column
chromatography using silica gel as an absorbent and eluted using
ethylacetate:hexane (20:80) mixture to afford 1.2 g of the required
product. Percentage purity (LCMS): 68.2%, (M+1)=569.1+1.
e)
(2-{1-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-pheno-
xy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl
ester
[0602] Using 1.2 g (2.1 mmol) of
[2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoyl}-
-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester and
4-fluorobenzonitrile (0.5 g, 4.2 mmol) and following the procedure
of Example 42(b) afforded 0.610 g of the required product.
Percentage purity (LCMS): 89.1%, (M+1)=670.3+1.
f)
[2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy--
carbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-ethyl]-carbamic
acid tert-butyl ester
[0603] Using
(2-{1-[3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy-
)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester
(0.8 g, 1.19 mmol) and following the procedure of Example 95(d)
afforded 0.76 g of the required product. Percentage purity (LCMS):
69.14%, (M+1)=703.2+1.
g)
[2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetyl-h-
ydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-ethyl]-carbamic
acid tert-butyl ester
[0604] Using
[2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-ca-
rbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-ethyl]-carbamic acid
tert-butyl ester (0.75 g, 1.07 mmol) and following the procedure of
Example 2(e) afforded 0.80 g of the required product. Percentage
purity (LCMS): 73.97%, (M+1)=745.2+1.
h)
(2-{1-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimido-
yl-phenoxy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid
tert-butyl ester
[0605]
[2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acet-
yl
hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-ethyl]-carbamic
acid tert-butyl ester 0.8 g (1.07 mmol) was reduced using the
procedure of Example 2(f) to afford 0.70 g of the required product.
Percentage purity (LCMS): 92.8%, (M+1)=687.1+1.
i)
4-[3-[4-(2-Amino-ethyl)-piperidine-1-carbonyl]-5-(4-aminomethyl-phenoxy-
)-phenoxy]-benzamidine
[0606] Using
(2-{1-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-
-phenoxy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl
ester (0.70 g, 1.02 mmol) and following the procedure of Example
9(d) afforded 0.20 g of the required product. Percentage purity
(HPLC): 98.22%, (LCMS): 95.01%. .sup.1H NMR (DMSO-d.sub.6): .delta.
1.21 (6H, m), 2.82 (4H, s), 3.02 (2H, m), 3.5 (2H, m), 4.52 (1H,
m), 6.81 (3H, d), 7.21 (4H, dd), 7.51 (2H, d), 7.88 (2H, d).
Example 99
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-ph-
enoxy)-benzamide
[0607] Intermediates (a) (e) are the same as in Example 92.
f)
{4-[3-(4-Cyano-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylamino]-cyc-
lohexyl}-carbamic acid tert-butyl ester
[0608] 0.7 g (1.22 mmol) of
4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid was dissolved in 10 ml of DMF. At 0.degree.
C. 0.125 mg (1.83 mmol) of N-methylaminehydrochloride, 0.37 mg
(1.96 mmol) of EDC, 0.2 mg (1.47 mmol) of HOBt and 0.49 ml (2.69
mmol) of DIPEA were added and the resulting reaction mixture was
stirred overnight at RT. Reaction progress was monitored by TLC.
After reaction completion, mixture was diluted with ice-water and
thus obtained white solid was filtered off and washed with water
and then with hexane. Thus obtained crude product was subjected to
column chromatography using silica-gel as an adsorbent and the
product was eluted with 50-70% of ethylacetate:hexane mixture to
afford 0.45 g of the required product. Percentage purity (LCMS):
91.9%, (M+1)=484.1+1. .sup.1H NMR (DMSO-d6): .delta. 1.21 (4H, d),
1.31 (9H, s), 1.92 (4H, s), 2.81 (3H, d), 3.11 (1H, s), 3.71 (1H,
s), 6.81 (1H, s), 7.35 (6H, d), 7.91 (4H, s), 8.32 (2H, d)
g)
{4-[3-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl-phenoxy-
)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
[0609] Using
{4-[3-(4-Cyano-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylamino]-cyclo-
hexyl}-carbamic acid tert-butyl ester (0.61 g, 1.04 mmol) and
following the procedure of Example 95(d) afforded 0.56 g of the
required product. Percentage purity (LCMS): 89.6%,
(M+1)=617.1+1.
h)
{4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylam-
ino]-cyclohexyl}-carbamic acid tert-butyl ester
[0610] Using
4{4-[3-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl-phenoxy)-
-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.56 g,
0.90 mmol) and following the procedure of Example 2(e) afforded
0.53 g of the required product. (LCMS): 91.7%, (M+1)=659.1+1.
i)
{4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoyl-a-
mino]-cyclohexyl}-carbamic acid tert-butyl ester
[0611] Using
{4-[3-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl-phe-
noxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(0.53 g, 0.80 mmol) and following the procedure of Example 2(f)
afforded 0.25 g of the required product. (LCMS): 94.5%.
(M+1)=601.1+1.
j)
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-
-phenoxy)-benzamide
[0612] Using
{4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylamin-
o]-cyclohexyl}-carbamic acid tert-butyl ester (0.50 g, 0.83 mmol)
and following the procedure of Example 9(d) afforded 0.40 g of the
required product. Percentage purity (HPLC): 98.72%, (LCMS): 97.22%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.31 (4H, m), 1.92 (4H, d),
2.81 (3H, d), 3.02 (1H, brs), 3.62 (1H, brs), 7.22 (7H, m), 7.91
(7H, m) 8.40 (2H, d), 9.12 (4H, d).
Example 100
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-dimethyl-carbamoyl-
-phenoxy)-benzamide
[0613] Intermediates (a) (e) are the same as in Example 92.
f)
{4-[3-(4-Cyano-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)-benzoylamino]-c-
yclohexyl}-carbamic acid tert-butyl ester
[0614] Using
4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid (0.7 g, 1.225 mmol) and following the
procedure of Example 99(f) afforded 0.51 g of the required product.
Percentage purity (LCMS): 93.7%, (M+1)=598.1+1.
g)
(4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-pheno-
xy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0615] Using
{4-[3-(4-cyano-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)-benzoylamino]-cyc-
lohexyl}-carbamic acid tert-butyl ester (0.6 g, 1.01 mmol) and
following the procedure of Example 95(d) afforded 0.57 g of the
required product. Percentage purity (LCMS): 93.2%,
(M+1)=631.1+1.
h)
(4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)-
-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl
ester
[0616] Using
(4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy-
]-benzoylamino}-cyclohexyl)-carbamie acid tert-butyl ester (0.57 g,
0.91 mmol) and following the procedure of Example 2(e) afforded
0.61 g of the required product. .sup.1H NMR (DMSO-d6): .delta. 1.31
(9H, s), 1.35 (3H, s), 1.95 (4H, s), 2.91 (1H, s) 3.02 (3H, s),
3.11 (1H, s), 3.2 (3H, s), 3.8 (1H, s), 6.81 (1H, s), 7.22 (3H, d),
7.55 (4H, s), 7.92 (2H, s), 8.20 (1H, s).
i)
{4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)-benzoyl-
amino]-cyclohexyl}-carbamic acid tert-butyl ester
[0617] Using
(4-{3-(4-dimethylcarbamoyl-phenoxy)-5-[4-(N-acetylhydroxy-carbamimidoyl)--
phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.61 g, 0.91 mmol) and following the procedure of Example 2(f)
afforded 0.55 g of the required product. Percentage purity (LCMS):
82.1%, (M+1)=615.1+1.
j)
N-(4-amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-dimethylcarbamo-
yl-phenoxy)-benzamide
[0618] Using
{4-[3-(4-carbamimidoyl-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)-benzoylam-
ino]-cyclohexyl}-carbamic acid tert-butyl ester (0.55 g, 0.89 mmol)
and following the procedure of Example 9(d) afforded 200 mg of the
required product. Percentage purity (HPLC): 95.01%, (LCMS): 95.82%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.21 (4H, m), 1.92 (4H, d),
2.91 (7H, s), 3.51 (1H, m), 7.21 (7H, d), 7.32 (2H, d), 7.56 (4H,
d), 7.88 (5H, m), 8.45 (1H, m), 9.25 (2H, s), 9.31 (2H, s).
Example 101
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methoxy-carbamoyl--
phenoxy)-benzamide
[0619] Intermediates (a) (e) are the same as in Example 92.
f)
{4-[3-(4-Cyano-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoylamino]-cy-
clohexyl}-carbamic acid tert-butyl ester
[0620] Using
4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
-phenoxy]-benzoic acid (0.9 g, 1.6 mmol) and following the
procedure of Example 99(f) afforded 0.73 g of the required product.
.sup.1H NMR (DMSO-d6): .delta. 1.25 (15H, d), 1.92 (4H, d), 3.78
(4H, s), 6.81 (1H, d), 7.21 (5H, m), 7.51 (2H, d), 7.91 (4H, dd),
8.30 (1H, d).
g)
{4-[3-[4-(N-hydroxycarbamimidoyl)-phenoxy]-5-(4-methoxycarbamoyl-phenox-
y)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
[0621] Using
{4-[3-(4-cyano-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoylamino]-cycl-
ohexyl}-carbamic acid tert-butyl ester (0.85 g, 0.14 mmol) and
following the procedure of Example 95(d) afforded 0.87 g of the
required product. Percentage purity (LCMS): 94.4%,
(M+1)=633.2+1.
h)
({4-[3-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-5-(4-methoxycarbamoyl-
-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl
ester
[0622] Using
{4-[3-[4-(N-hydroxycarbamimidoyl)-phenoxy]-5-(4-methoxycarbamoyl-phenoxy)-
-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.87 g,
1.4 mmol) and following the procedure of Example 2(e) afforded 0.89
g of the required product. Percentage purity (LCMS): 64.5%,
(M+1)=675.1+1.
i)
{4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoyla-
mino]-cyclohexyl}-carbamic acid tert-butyl ester
[0623] Using
({4-[3-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-5-(4-methoxy-carbamoyl--
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(0.89 g, 1.3 mmol) and following the procedure of Example 2(f)
afforded 0.81 g of the required product. Percentage purity (LCMS):
92.5%, (M+1)=617.1+1.
j)
N-(4-amino-cyclohexyl)-3-(4-carbarnimidoyl-phenoxy)-5-(4-methoxycarbamo-
yl-phenoxy)-benzamide
[0624] Using
{4-[3-(4-carbamimidoyl-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoylami-
no]-cyclohexyl}-carbamic acid tert-butyl ester (0.8 g, 1.3 mmol)
and following the procedure of Example 9(d) afforded 0.09 mg of the
required product. Percentage purity (HPLC): 95.11%, (LCMS): 96.41%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.24 (4H, m), 1.92 (4H, m),
3.11 (2H, brs), 3.92 (3H, s), 7.22 (5H, m), 7.51 (2H, d), 7.91 (7H,
m), 8.22 (1H, d), 9.25 (2H, s), 9.31 (2H, s), 11.91 (1H, brs).
Example 102
N-(4-amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-[4-(N-hydroxy-carbamimi-
doyl)-phenoxy]-benzamide
[0625] Intermediates (a) (f) are the same as in Example 84.
g)
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-car-
bamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester
[0626] Using
{4-[3-[4-(tert-butoxycarbonylaminomethyl)phenoxy]-5-(4-cyanophenoxy)benzo-
ylamino]cyclohexyl}carbamic acid tert-butyl ester (0.3 g, 0.45
mmol) and following the procedure of Example 95(d) afforded 0.35 g
of the required product. Percentage purity (LCMS): 64.5%,
(M+1)=689.3+1.
h)
N-(4-amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-[4-(N-hydroxy-carbam-
imidoyl)-phenoxy]-benzamide
[0627] Using 0.3 g (0.43 mmol) of
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxycarbam-
imidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid
tert-butyl ester and following the procedure of Example 9(d)
afforded 0.15 g of the required product. Percentage purity (HPLC):
98.81%, (LCMS): 95.62%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2
(4H, m), 1.8 (4H, m), 2.9 (1H, m), 3.8 (1H, m), 4.15 (2H, d), 6.7
(1H, t), 7.3 (6H, m), 7.5 (2H, d), 7.7 (2H, d), 7.9 (3H, d), 8.2
(3H, brs), 8.4 (1H, d), 10.9 (1H, brs).
Example 103
3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoic acid 4-amino-cyclohexyl
ester
[0628] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester
[0629] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.8 mmol) and
(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.69 g, 2.8
mmol) were used to afford 0.8 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.21 (4H, m), 1.32 (4H, m), 3.12 (1H,
m), 3.32 (1H, m), 4.51 (2H, s), 5.21 (2H, s), 7.3 (10H, m), 7.89
(2H, d).
d) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoic acid
4-benzyloxy-carbonylamino-cyclohexyl ester
[0630] Following the procedure of Example 2(d)
3,5-bis-(4-cyano-phenoxy)-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester 0.8 g (1.36 mmol) and
other reagents were used to afford 0.7 g of the required product.
Percentage purity (LCMS): 73.2%, (M+1) 653.2+1.
e) 3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester
[0631] Following the procedure as in Example 2(e)
3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester 0.7 g (1.22 mmol) was
used to afford 0.7 g of the required product. Percentage purity
(LCMS): 63.8%, (M+1) 737.2+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoic acid
4-amino-cyclohexyl ester
[0632] 3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoic
acid 4-benzyloxycarbonylamino-cyclohexyl ester 0.7 g (0.9 mmol) was
reduced using the procedure of Example 2(f) to afford 0.45 g of the
required product. Percentage purity (HPLC): 99.21%, (LCMS): 97.9%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.21 (4H, m), 1.9 (4H, m), 3.1
(1H, m), 3.2 (1H, m), 4.91 (1H, brs), 7.35 (6H, m), 8.01 (7H, m),
9.2 (8H, d).
Example 104
3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoic acid
4-amino-cyclohexyl ester
[0633] Intermediate (a) is the same as in Example 42.
b)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoic
acid ethyl ester
[0634] Using 1.3 g (4.5 mmol) of
3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester and
following the procedure of Example 95(d) afforded 1.1 g of the
required product. Percentage purity (LCMS): 48.4%, (M+1)
387.1+1.
c)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-ben-
zoic acid ethyl ester
[0635] Using
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoic
acid ethyl ester (1.1 g, 2.48 mmol) and following the procedure of
Example 42(b) afforded 0.95 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.21 (2H, m), 1.32 (9H, s), 3.81 (1H, s),
4.21 (2H, d), 4.35 (2H, m), 7.32 (9H, m), 7.91 (2H, d).
d)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-ben-
zoic acid
[0636] 0.95 g (2.06 mmol) of
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid ethyl ester was hydrolysed using the procedure of Example
5(b) to afford 0.85 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.2 (9H, s), 4.1 (3H, s), 7.21 (9H, m) 7.9
(2H, d), 13.4 (1H, brs).
e)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-ben-
zoic acid 4-benzyloxycarbonylamino-cyclohexyl ester
[0637] Following the procedure of Example 9(e)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid (0.85 g, 1.85 mmol) and (4-hydroxy-cyclohexyl)-carbamic
acid benzyl ester (0.50 g, 2.03 mmol) were used to afford 0.5 g of
the required product. Percentage purity (LCMS): 67.0%, (M+1)
691.2+1.
f)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-carbami-
midoyl)-phenoxy]-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl
ester
[0638] Using
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid 4-benzyloxycarbonylamino-cyclohexyl ester (0.6 g, 0.87
mmol) and following the procedure of Example 95(d) afforded 0.6 g
of the required product. Percentage purity (LCMS): 69.3%,
(M+1)=724+1.
g)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetylhydroxy-c-
arbamimidoyl)-phenoxy]-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester
[0639] Using
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-carbamimi-
doyl)-phenoxy]-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl
ester (0.6 g, 0.82 mmol) and following the procedure as in Example
2(e) afforded 0.55 g of the required product. Percentage purity
(LCMS): 69.1. %, (M+1)=766.2+1.
h)
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-phen-
oxy)-benzoic acid 4-amino-cyclohexyl ester
[0640]
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetylhydro-
xy-carbamimidoyl)-phenoxy]-benzoic acid
4-benzyloxycarbonylamino-cyclohexyl ester 0.55 g (0.71 mmol) was
reduced using the procedure of Example 2(f) to afford 0.5 g of the
required product. Percentage purity (LCMS): 54.6%,
(M+1)=574.2+1.
i) 3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoic
acid 4-amino-cyclohexyl ester
[0641]
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl--
phenoxy)-benzoic acid 4-amino-cyclohexyl ester 0.5 g (0.87 mmol)
was treated using procedure of Example 9(d) to afford 0.2 g of the
required product. Percentage purity (HPLC): 94.21%, (LCMS): 96.9%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.91 (4H, m), 3.1
(1H, m), 4.11 (2H, brs), 4.8 (1H, m), 7.21 (7H, m), 7.9 (4H, m),
8.2 (3H, m), 9.11 (4H, d).
Example 105
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-2-naphthylsulphonamide
[0642] Intermediates (a) and (b) are the same as in Example 26.
c) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-carbamic acid tert-butyl
ester
[0643] A mixture of 3,5-bis-(4-cyano-phenoxy)-benzoic acid (2.0 g,
5.6 mmol), diphenylphosphorylazide (1.2 ml, 5.6 mmol) and DIPEA (1
ml, 5.6 mmol) were dissolved in 20 ml of tert-butanol and stirred
overnight at 80.degree. C. Reaction mixture was cooled and diluted
with 50 ml saturated solution of sodiumhydrogencarbonate and
extracted with ethylacetate (3.times.50 ml). Combined organic layer
was washed with 2.times.50 ml saturated solution of brine and dried
over anhydrous sodium sulphate. Solvent was evaporated under vacuo
and thus obtained crude product was subjected to column
chromatography using silica gel as an absorbent and eluted with
10-20% mixture of ethylacetate and hexane to afford 1.0 g of the
required product. Percentage purity (LCMS): 89.6%,
(M+1)=427.1+1.
d) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine
[0644] Following the procedure of Example 9(d)
[3,5-bis-(4-cyano-phenoxy)-phenyl]-carbamic acid tert-butyl ester
1.0 g (2.34 mmol) and other reagents were used to afford 0.7 g of
the required product. Percentage purity (LCMS): 95.0%,
(M+1)=327.1+1.
e) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-2-naphthylsulphonamide
[0645] [3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine (0.35 g, 1.07 mmol)
and 2-naphthyl-sulphonyl chloride (0.29 g, 1.28 mmol) were
dissolved in 10 ml of dichloromethane and cooled to 0.degree. C.
Further 0.18 ml (2.14 mmol) of pyridine and 15 mg (0.107 mmol) of
DMAP was added to the reaction mixture and allowed to stirred
overnight at RT. After completion, reaction mixture was diluted
with 50 ml of dichloromethane and washed with 50 ml 1N HCl solution
and then with brine. Organic layer was dried over anhydrous sodium
sulphate and concentrated under vacuo. Thus obtained crude product
was subjected to column chromatography and eluted with ethylacetate
and hexane mixture to afford 0.4 g of the required product.
Percentage purity (LCMS): 90.4% M+1=517.1+1.
f)
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthyl-sulpho-
namide
[0646] Following the procedure of Example 95(d)
[3,5-bis-(4-cyano-phenoxy)-phenyl]-2-naphthylsulphonamide 0.45 g
(0.83 mmol) was afforded 0.41 g of the required product. Percentage
purity (LCMS): 94.3%, (M-1)=583.2-1.
g)
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthyl--
sulphonamide
[0647]
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthylsul-
phonamide 0.41 g (0.71 mmol) was acetylated using the procedure of
Example 2(e) to afford 0.43 g of the required product. Percentage
purity (LCMS): 88.3%, (M+1)=667.2+1.
h)
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-2-naphthylsulphonamide
[0648]
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-2-napht-
hyl-sulphonamide 0.43 g (0.644 mmol) was reduced using the
procedure of Example 2(f) to afford 0.23 g of the required product.
Percentage purity (HPLC): 96.1%, (LCMS): 97.01%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.7 (1H, s), 6.8 (2H, s), 7.15 (4H, d), 8.1
(3H, t), 8.45 (1H, s), 9.2 (6H, brs), 10.8 (1H, brs).
Example 106
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide
[0649] Intermediates (a) to (d) are the same as in Example 105.
e)
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide
[0650] Following the procedure of Example 105(e)
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (0.08 g, 0.24 mmols) and
4-fluoro-benzenesulfonyl chloride (0.05 g, 0.27 mmol) were used to
afford 0.05 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 6.56 (3H, d), 7.22 (4H, d), 7.51 (2H, d), 7.95 (6H, d).
f)
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-benzene--
sulphonamide
[0651]
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide 0.4
g (0.82 mmol) was subjected to form N-hydroxycarbamimidoyl using
the procedure of Example 95(d) to afford 0.4 g of the required
product. .sup.1H NMR (DMSO-d.sub.6): .delta. 6.56 (3H, d), 7.22
(4H, d), 7.51 (2H, d), 7.95 (6H, d), 9.12 (1H, brs).
g)
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-be-
nzenesulphonamide
[0652]
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-benz-
ene-sulphonamide 0.4 g (0.72 mmol) was acetylated using the
procedure of Example 2(e) to afford 0.42 g of the required product.
Percentage purity (LCMS): 57.3%, (M+1)=635.2+1.
h)
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-4-Fluoro-benzenesulphonamide
[0653]
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluor-
o-benzene-sulphonamide 0.42 g (0.66 mmol) was reduced using the
procedure of Example 2(f) to afford 0.15 g of the required product.
Percentage purity (HPLC): 95.71%, (LCMS): 94.7%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.71 (3H, d), 7.15 (4H, d), 7.51 (2H, t),
7.91 (6H, d), 9.2 (8H, d), 10.9 (1H, s).
Example 107
4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0654] Intermediates (a) to (d) are the same as in Example 105.
e)
{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester
[0655] N-methylmorpholine (0.75 ml, 6.57 mmol) and
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate methanaminium (2.35 g, 6.16 mmol) were added to
the stirred solution of racemic mixture of
4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.67 g, 2.05
mmol), dissolved in 5.0 ml of DMF. Further 0.50 g (2.05 mmol) of
{4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester, dissolved in 5 ml of DMF, was added to the
reaction mixture at RT and resulting mixture was allowed to stirred
overnight at RT. After reaction completion, mixture was poured into
ice-water to afford white solid compound which was filtered off and
dissolved in ethylacetate and organic layer was washed with
2.times.50 ml of saturated sodiumhydrogencarbonate and then with
water. Organic layer was dried over anhydrous sodium sulphate and
concentrated under vacuo to afford the crude product which was
subjected to column chromatography using silica gel as an absorbent
and eluted with 40-60% ethylacetate:hexane mixture to afford 0.65 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25
(9H, s), 1.32 (4H, m), 2.31 (4H, m), 3.21 (1H, m), 3.52 (1H, m),
6.12 (1H, s), 7.21 (6H, d), 7.91 (4H, d), 10.01 (1H, s).
f)
(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclo-
hexyl)-carbamic acid tert-butyl ester
[0656]
{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester 0.8 g (1.44 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.86 g of the required product. Percentage purity (LCMS):
93.4%, (M+1)=618.2+1.
g)
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-
-cyclohexyl)-carbamic acid tert-butyl ester
[0657]
(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-c-
yclohexyl)-carbamic acid tert-butyl ester 0.86 g (1.39 mmol) was
acetylated using the procedure of Example 2(e) to afford 0.89 g of
the required product. Percentage purity (LCMS): 88.8%,
(M+1)=702.2+1.
h)
{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carb-
amic acid tert-butyl ester
[0658]
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcarbam-
oyl}-cyclohexyl)-carbamic acid tert-butyl ester 0.89 g (1.26 mmol)
was reduced using the procedure of Example 2(f) to afford 0.7 g of
the required product. (LCMS): 93.3%, (M+1)=586.2+1.
i) 4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0659]
{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}--
carbamic acid tert-butyl ester 0.7 g (1.19 mmol) was reduced using
the procedure of Example 9(d) to afford 0.4 g of the required
product. Percentage purity (HPLC): 97.81%, (LCMS): 100%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.31 (4H, m), 1.9 (4H, m), 2.2 (1H, m),
3.2 (1H, m), 6.7 (1H, s), 7.21 (6H, dd), 7.91 (7H, d), 9.31 (8H,
s), 10.1 (1H, s).
Example 108
Trans-4-amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0660] Intermediates (a) to (d) are the same as in Example 105.
e)
{Trans-4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbam-
ic acid tert-butyl ester
[0661] Following the procedure of Example 107(e)
trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 10.4 g
(42.79 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (14.0 g,
42.79 mmol) were used to afford 12 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (4H, m), 1.31 (9H, s), 1.8
(4H, d), 2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2
(6H, m) 7.91 (4H, dd), 10.0 (1H, s).
f)
(Trans-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-
-cyclohexyl)-carbamic acid tert-butyl ester
[0662]
{Trans-4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-ca-
rbamic acid tert-butyl ester 5.0 g (9.05 mmol) was subjected to
form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 5.2 g of the required product. Percentage purity (LCMS):
88.9%, (M+1)=618.2+1.
g)
(Trans-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl-car-
bamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
[0663]
(Trans-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbam-
oyl}-cyclohexyl)-carbamic acid tert-butyl ester 5.2 g (8.40 mmol)
was acetylated using the procedure of Example 2(e) to afford 5.50 g
of the required product. Percentage purity (LCMS): 91.6%,
(M+1)=702.1+1.
h)
{Trans-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl-
}-carbamic acid tert-butyl ester
[0664]
(Trans-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl-
-carbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 5.5 g (7.831
mmol) was reduced using the procedure of Example 2(f) to afford 4.2
g of the required product. Percentage purity (LCMS): 98.3%,
(M+1)=586.1+1.
i) Trans-4-amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0665]
{Trans-4-[3,5-bis-(4-carbarnimidoyl-phenoxy)-phenylcarbamoyl]-cyclo-
hexyl}-carbamic acid tert-butyl ester 3.8 g (6.47 mmol) was reduced
using the procedure of Example 9(d) to afford 2.5 g of the required
product. Percentage purity (HPLC): 99.1%, (LCMS): 99.9%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.22 (4H, m), 1.9 (4H, m), 2.1 (1H, d),
3.1 (1H, m), 6.7 (1H, s), 7.35 (5H, m), 7.91 (7H, d), 9.25 (8H, d),
10.3 (1H, brs).
Example 109
1-(2-Amino-ethyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0666] Intermediates (a) to (d) are the same as in Example 105.
e)
4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic
acid tert-butyl ester
[0667] Following the procedure of Example 9(e)
piperidine-1,4-dicarboxylic acid mono-tert-butyl ester 0.7 g (3.05
mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.0 g, 3.05
mmol) were used to afford 0.85 g of the required product. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d),
2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2 (6H, m),
7.91 (4H, dd), 10.0 (1H, brs).
f) 4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidine
[0668] Following the procedure of Example 9(d)
4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine-1-carboxylic
acid tert-butyl ester (0.85 g, 1.579 mmol) was used to afford 0.54
g of the required product. Percentage purity (LCMS): 90.6%,
(M+1)=438.1+1.
g)
(2-{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidin-1-yl}-ethyl-
)-carbamic acid tert-butyl ester
[0669] Following the procedure of Example 11(e)
4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine (0.8 g,
1.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.49
g, 2.19 mmol) were used to afford 0.4 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (9H, s), 1.42 (4H, m), 2.31
(3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76
(1H, s), 7.26 (6H, m,), 7.86 (4H, d).
h)
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-pi-
peridin-1-yl)-ethyl]-carbamic acid tert-butyl ester
[0670]
(2-{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidin-1-yl}-e-
thyl)-carbamic acid tert-butyl ester 0.4 g (0.687 mmol) was
subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 0.4 g of the required product. Percentage
purity (LCMS): 91.1%, (M+1)=647.2+1.
i)
[2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl-carbam-
oyl}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester
[0671]
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl-
}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester 0.4 g
(0.618 mmol) was acetylated using the procedure of Example 2(e) to
afford 0.45 g of the required product. Percentage purity (LCMS):
61.9%, (M+1)=731.2+1.
j)
(2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin-1-y-
l}-ethyl)-carbamic acid tert-butyl ester
[0672]
[2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcar-
bamoyl}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester 0.5 g
(0.68 mmol) was reduced using the procedure of Example 2(f) to
afford 0.4 g of the required product. Percentage purity (LCMS):
100%, (M+1)=615.2+1.
k) 1-(2-Amino-ethyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0673]
(2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin-
-1-yl}-ethyl)-carbamic acid tert-butyl ester 0.4 g (0.65 mmol) was
reduced using the procedure of Example 9(d) to afford 0.25 g of the
required product. Percentage purity (HPLC): 98.91%, (LCMS): 99.6%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.22 (4H, m), 2.1 (4H, m), 2.8
(2H, t), 3.2 (2H, m), 3.5 (1H, m), 6.1 (1H, s), 7.2 (5H, d), 7.9
(4H, d), 8.22 (2H, brs), 9.2 (8H, d), 9.6 (1H, brs), 10.5 (1H,
s).
Example 110
1-(3-Amino-propionyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0674] Intermediates (a) to (f) are the same as in Example 109.
g)
(3-{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidin-1-yl}-3-oxo-
-propyl)-carbamic acid tert-butyl ester
[0675] Following the procedure of Example 9(e)
4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.0 g
(2.28 mmol) and 3-tert-butoxycarbonylamino-propionic acid (0.431 g,
2.28 mmol) were used to afford 0.95 g of the required product.
.sup.1H NMR (DMSO-d6): .delta. 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H,
m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76 (1H,
s), 7.26 (6H, m), 7.86 (4H, d), 10.01 (1H, s).
h)
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-pi-
peridin-1-yl)-ethyl]-carbamic acid tert-butyl ester
[0676]
(3-{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidin-1-yl}-3-
-oxo-propyl)-carbamic acid tert-butyl ester 1.0 g (1.64 mmol) was
subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 1.0 g of the required product. Percentage
purity (LCMS): 98.5%, (M+1)=675.2+1.
i)
[2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl-carbam-
oyl}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester
[0677]
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl-
}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester 1.0 g (1.48
mmol) was acetylated using the procedure of Example 2(e) to afford
0.1 g of the required product. Percentage purity (LCMS): 99.9%,
(M+1)=759.2+1.
j)
(3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin-1-y-
l}-3-oxo-propyl)-carbamic acid tert-butyl ester
[0678]
[2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcar-
bamoyl}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester 1.1 g
(1.45 mmol) was reduced using the procedure of Example 2(f) to
afford 0.93 g of the required product. Percentage purity (LCMS):
99.9%, (M+1)=643.2+2.
k) 1-(3-Amino-propionyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0679]
(3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin-
-1-yl}-3-oxo-propyl)-carbamic acid tert-butyl ester 0.93 g (1.44
mmol) was reduced using the procedure of Example 9(d) to afford 0.3
g of the required product. Percentage purity (HPLC): 97.9%, (LCMS):
94.9%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (4H, m), 1.92 (4H,
m), 2.5 (2H, m), 3.05 (3H, m), 4.1 (1H, d), 6.7 (1H, s), 7.35 (6H,
m), 7.6 (2H, brs), 7.9 (4H, d), 9.2 (7H, d), 10.4 (1H, s).
Example 111
1-(2-Hydroxy-ethyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0680] Intermediates (a) to (f) are the same as in Example 109.
g) 1-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide
[0681] Following the procedure of Example 11(e)
4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.5 g
(3.42 mmol) and 2-bromoethanol (0.647 g, 4.79 mmol) were used to
afford 1.1 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 2.11 (4H, m), 2.52 (2H, m), 3.15 (4H, m), 3.21 (1H, m),
3.31 (1H, m), 4.21 (1H, t), 6.76 (1H, s), 7.31 (6H, d), 7.92 (4H,
d).
h) 1-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-hydroxy carbamimidoyl)-phenoxy]-phenyl}-amide
[0682] 1-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide 1.1 g (2.28 mmol) was
subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 1.3 g of the required product. Percentage
purity (LCMS): 96.7%, (M+1)=548.2+1.
i) 1-(2-Hydroxy-ethyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0683] 1-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide 1.3 g
(2.37 mmol) was reduced using the procedure of Example 2(f) to
afford 0.55 g of the required product. Percentage purity (HPLC):
97.18%, (LCMS): 98.8%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.91
(4H, m), 3.2 (6H, m), 3.5 (5H, m), 6.7 (1H, s), 7.35 (6H, d), 7.91
(4H, d), 9.25 (8H, d), 10.5 (1H, s).
Example 112
Cis-4-amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0684] Intermediates (a) to (d) are the same as in Example 106.
e)
{Cis-4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester
[0685] Following the procedure of Example 9(e)
cis-4-tert-butoxycarbonylamino-cyclo-hexanecarboxylic acid 1.0 g
(4.15 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.34 g,
4.15 mmol) were used to afford 1.5 g of the required product.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.4 (9H, s), 2.3 (4H, m), 2.81
(1H, m), 3.15 (4H, m), 3.5 (1H, m), 6.71 (1H, s), 6.81 (1H, brs),
7.21 (6H, m), 7.92 (4H, d), 10.0 (1H, brs).
f)
(cis-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}-c-
yclohexyl)-carbamic acid tert-butyl ester
[0686]
{Cis-4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carb-
amic acid tert-butyl ester 1.56 g (2.82 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 1.5 g of the required product. Percentage purity (LCMS):
99.9%, (M+1)=618.2+1.
g)
(Cis-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl-carba-
moyl}-cyclohexyl)-carbamic acid tert-butyl ester
[0687]
(Cis-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoy-
l}-cyclohexyl)-carbamic acid tert-butyl ester 1.5 g (0.82 mmol) was
acetylated using the procedure of Example 2(e) to afford 1.4 g of
the required product. Percentage purity (LCMS): 68.0%,
(M+1)=702.2+1.
h)
{Cis-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}--
carbamic acid tert-butyl ester
[0688]
(Cis-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylca-
rbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 1.4 g (2.1
mmol) was reduced using the procedure of Example 2(f) to afford 1.2
g of the required product. Percentage purity (LCMS): 100%,
(M+1)=586.2+1.
i) Cis-4-amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0689]
{Cis-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohex-
yl}-carbamic acid tert-butyl ester 1.2 g (2.1 mmol) was reduced
using the procedure of Example 9(d) to afford 1.0 g of the required
product. Percentage purity (HPLC): 98.7%, (LCMS): 100%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.82 (4H, m), 1.9 (4H, m), 3.11 (1H, m),
3.8 (1H, m), 6.7 (1H, s), 7.21 (6H, d), 7.91 (7H, d), 9.21 (8H, d),
10.1 (1H, s).
Example 113
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-amine
[0690] Intermediates (a) to (d) are the same as in Example 105.
e) {3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenyl}-amine
[0691] [3,5-Bis-(4-cyano-phenoxy)-phenyl]amine 0.3 g (0.917 mmol)
was subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 0.34 g of the required product. Percentage
purity (LCMS): 100.0%, (M+1)=393.1+1.
f) [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-amine
[0692] {3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenyl}-amine
0.34 g (0.864 mmol) was reduced using the procedure of Example 2(f)
to afford 0.15 g of the required product. Percentage purity (HPLC):
96.6%, (LCMS): 99.5%. .sup.1H NMR (DMSO-d.sub.6): .delta. 5.9 (1H,
t), 6.2 (2H, d), 7.35 (4H, d), 7.9 (4H, d), 9.11 (4H, brs), 9.25
(4H, brs).
Example 114
1-(2-Amino-ethyl)-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0693] Intermediates (a) to (1) are the same as in Example 109.
g) 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide
[0694] Following the procedure of Example 11(e)
4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.5 g
(3.42 mmol) and bromomethylcyclopropane (0.647 g, 4.79 mmol) were
used to afford 1.0 g of the required product. Percentage purity
(LCMS): 73.1%, (M+1)=492.1+1.
h) 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
[0695] 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide 1.0 g (2.03 mmol) was
subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 1.1 g of the required product. Percentage
purity (LCMS): 100.0%, (M+1)=558.2+1.
i) 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-acetylhydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
[0696] 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide 1.1 g
(1.97 mmol) was acetylated using the procedure of Example 2(e) to
afford 1.6 g of the required product. Percentage purity (LCMS):
57.70%, (M+1)=642.2+1.
j) 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0697] 1-Cyclopropylmethyl-piperidine-4-carboxylic acid
{3,5-bis-[4-(N-acetylhydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
1.6 g (2.49 mmol) was reduced using the procedure of Example 2(f)
to afford 0.8 g of the required product. Percentage purity (HPLC):
99.01%, (LCMS): 98.9%. .sup.1H NMR (DMSO-d.sub.6): .delta. 0.3 (2H,
d), 0.6 (2H, d), 1.1 (1H, m), 1.82 (4H, m), 3.05 (4H, m), 3.1 (2H,
d), 6.7 (1H, s), 7.2 (5H, d), 7.98 (4H, d), 9.11 (8H, brs), 9.55
(1H, brs), 10.5 (1H, s).
Example 115
N-(4-Amino-cyclohexyl)-3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-benza-
mide
[0698] Intermediates (a) to (c) are the same as in Example 27.
d)
(4-{3,5-Bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-benzoylamino}-cyclohe-
xyl)-carbamic acid tert-butyl ester
[0699] Triethylamine (2.5 ml, 1.81 mmol) was added to the
suspension of
{4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (1.0 g, 1.81 mmol) in 15 ml of ethanol at
55.degree. C. O-methyl-hydroxylamine hydrochloride solution (0.91 g
in 3 ml of water (30% w/w)) and mercaptoacetic acid (0.51 ml, 7.24
mmol) were added to the reaction mixture at 55.degree. C. under
inert nitrogen atmosphere. Reaction mixture was stirred under
nitrogen atmosphere at 90.degree. C. for 40 h. After reaction
completion, solvent was removed under vacuo and the residue was
poured into ice-water to obtain white solid product which was
filtered off and washed with water and hexane to afford 0.7 g of
the required product. Percentage purity (LCMS): 69.3%,
(M+1)=646+1.
e)
N-(4-Amino-cyclohexyl)-3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-be-
nzamide
[0700] Using
(4-{3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexy-
l)-carbamic acid tert-butyl ester (0.8 g, 1.23 mmol) and following
the procedure of Example 9(d) afforded 0.51 g of the required
product. Percentage purity (HPLC): 98.3%, (LCMS) 98.9%. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.24 (4H, m), 1.82 (4H, m), 3.05 (1H, m),
3.51 (1H, m), 3.9 (6H, s), 6.9 (1H, t), 7.25 (4H, d), 7.45 (2H, d),
7.88 (4H, d), 7.9 (3H, brs), 8.45 (1H, d).
Example 116
4-Amino-cyclohexanecarboxylic acid
[3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0701] Intermediate (a) to (c) are same as in Example 104.
d) 3-(4-Aminomethyl-phenoxy)-5-(4-cyano-phenoxy)-benzoic acid ethyl
ester
[0702] Using 10.0 g (20.48 mmol) of
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid ethyl ester and following the procedure of Example 9(d)
afforded 7.4 g of the required product. Percentage purity (LCMS):
82.0%, (M+1)=388.4+1.
e)
3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid ethyl ester
[0703] Mixture of 7.4 g (15.1 mmol) of
3-(4-aminomethyl-phenoxy)-5-(4-cyano-phenoxy)-benzoic acid ethyl
ester, benzyl chloro formate (3.8 g, 22.6 mmol) and triethylamine
(4.6 g, 45.4 mmol) were stirred overnight at RT. After reaction
completion solvent was removed under reduced pressure and thus
obtained residue was dissolved in ice-water and extracted with 500
ml.times.2 of ethylacetate. Organic layer was dried over anhydrous
sodium sulphate, solvent was removed and thus obtained crude
product was purified by column chromatography using silica-gel as
an adsorbent and eluted with ethylacetate:hexane (10:90) to afford
8.0 g of the required product. Percentage purity (LCMS): 87.2%,
(M+1)=522.5+1.
f)
3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzo-
ic acid
[0704] 8.0 g (15.32 mmol) of
3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic
acid ethyl ester was hydrolysed using the procedure of Example 5(b)
to afford 7.0 g of the required product. Percentage purity (LCMS):
91.6%, (M+1)=494.5+1.
g)
[3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-phen-
yl]-carbamic acid tert-butyl ester
[0705] Using 7.0 g (14.1 mmol) of
3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic
acid and following the procedure of Example 105(c) afforded 3.5 g
of the required product. Percentage purity (LCMS): 65.0%,
(M+1)=565.6+1.
h) {4-[3-Amino-5-(4-cyano-phenoxy)-phenoxy]-benzyl}-carbamic acid
benzyl ester
[0706] Using 1.0 g (1.76 mmol) of
[3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-phenyl-
]-carbamic acid tert-butyl ester and following the procedure of
Example 9(d) afforded 0.90 g of the required product. Percentage
purity (LCMS): 89.2%, (M+1)=465.5+1.
i)
{4-[3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-p-
henylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0707] Using 0.9 g (1.93 mmol) of
{4-[3-amino-5-(4-cyano-phenoxy)-phenoxy]-benzyl}-carbamic acid
benzyl ester and 0.47 g (1.93 mmol) of
(4-amino-cyclohexyl)-carbamic acid tert-butyl ester, and following
the procedure of Example 9(e) afforded 1.0 g of the required
product. Percentage purity (LCMS): 91.0%, (M+1)=690.7+1.
j)
(4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-carba-
mimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid
tert-butyl ester
[0708]
{4-[3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenox-
y)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.9
g (1.30 mmol) was subjected to form N-hydroxycarbamimidoyl using
the procedure of Example 95(d) to afford 1.0 g of the required
product. Percentage purity (LCMS): 74.4%, (M+1)=723.8+1.
k)
(4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetylhydroxy-
-30 carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic
acid tert-butyl ester
[0709]
(4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy-c-
arbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid
tert-butyl ester 1.0 g (1.38 mmol) was acetylated using the
procedure of Example 2(e) to afford 1.10 g of the required product.
Percentage purity (LCMS): 78.2%, (M+1)=765.8+1.
l)
{4-[3-(4-Aminomethyl-phenoxy)-5-(4-carbarnimidoyl-phenoxy)-phenylcarbam-
oyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0710]
(4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetylhyd-
roxy-carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic
acid tert-butyl ester 1.1 g (1.43 mmol) was reduced using the
procedure of Example 2(f) to afford 0.8 g of the required product.
Percentage purity (LCMS): 54.2%, (M+1)=573.2+1.
l) 4-Amino-cyclohexanecarboxylic acid
[3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0711]
{4-[3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-phenylcar-
bamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.80 g (1.39
mmol) was treated using the procedure of Example 9(d) to afford
0.50 g of the required product. Percentage purity (HPLC): 98.3%,
(LCMS): 100.0%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.44 (4H, m),
1.82 (4H, m), 3.05 (2H, m), 6.51 (1H, s), 7.15 (6H, m), 7.50 (2H,
d), 8.02 (5H, d), 8.45 (2H, m), 9.11 (4H, brs), 10.11 (1H,
brs).
Example 117
4-Amino-cyclohexanecarboxylic acid
[3-(2-amino-1H-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl-phenoxy)-phenyl]-
-amide
[0712] Intermediates (a) and (b) are the same as in Example 49.
c) [3-(4-Cyano-phenoxy)-5-hydroxy-phenyl]-carbamic acid tert-butyl
ester
[0713] Using 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid (1.4 g, 5.4
mmol) and following the procedure of Example 105(c) afforded 1.0 g
of the required product. Percentage purity (LCMS): 86.7%,
(M+1)=326.3+1.
d) [3-(4-Cyano-phenoxy)-5-hydroxy-phenyl]-amine
[0714] Using [3-(4-cyano-phenoxy)-5-hydroxy-phenyl]-carbamic acid
tert-butyl ester (1.0 g, 3.06 mmol) and following the procedure of
Example 9(d) afforded 0.67 g of the required product. Percentage
purity (LCMS): 92.5%, (M+1)=226.2+1.
e)
{Trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-ca-
rbamic acid tert-butyl ester
[0715] Following the procedure of Example 9(e)
Trans-4-tert-butoxycarbonylamino-15 cyclohexanecarboxylic acid 0.72
g (2.96 mmol) and [3-(4-cyano-phenoxy)-5-hydroxy-phenyl]-amine
(0.67 g, 2.96 mmol) were used to afford 1.0 g of the required
product. Percentage purity (LCMS): 73.5%, (M+1)=451.5+1.
f)
{Trans-4-[3-(3-amino-4-nitro-phenoxy)-5-(4-cyano-phenoxy)-phenyl-carbam-
oyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0716] Using
{trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-carb-
amic acid tert-butyl ester (1.5 g, 5.29 mmol) and
5-fluoro-2-nitro-phenylamine (0.91 g, 5.82 mmol) following the
procedure of Example 42(b) afforded 1.6 g of the required product
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.45 (9H, s), 1.8 (4H, m), 2.5
(4H, m), 3.2 (1H, m), 6.48 (2H, m), 6.75 (1H, d), 7.24 (2H, m),
7.51 (4H, m), 7.78 (2H, d), 8.05 (1H, d), 8.38 (1H, d).
g)
{Trans-4-[3-(4-cyano-phenoxy)-5-(3,4-diamino-phenoxy)-phenylcarbamoyl]--
cyclohexyl}-carbamic acid tert-butyl ester
[0717]
{Trans-4-[3-(3-amino-4-nitro-phenoxy)-5-(4-cyano-phenoxy)-phenyl-ca-
rbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 1.7
mmol), zinc (1.11 g, 17.02 mmol) and ammoniumchloride (0.91 g,
17.02 mmol) were dissolved in 20 ml of methanol and stirred for 2 h
at 60.degree. C. After reaction completion contents were filtered
through celite and filetrate was concentrated to afford 0.8 g of
the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.45 (9H,
s), 1.78 (4H, m), 2.45 (4H, m), 3.2 (1H, m), 4.42 (2H, s), 6.45
(2H, m), 6.5 (1H, d), 6.71 (2H, m), 7.15 (2H, d), 7.3 (2H, s), 7.8
(2H, d), 8.28 (1H, d).
h)
{Trans-4-[3-(2-amino-1H-benzoimidazol-5-yloxy)-5-(4-cyano-phenoxy)-phen-
ylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0718]
{Trans-4-[3-(4-cyano-phenoxy)-5-(3,4-diamino-phenoxy)-phenylcarbamo-
yl]-cyclohexyl}-carbamic acid tert-butyl ester (0.9 g, 1.61 mmol)
and canogenbromide (0.25 g, 2.42 mmol) were dissolved in 10 ml of
ethanol and stirred at 80.degree. C. for 4 h. After reaction
completion mixture was cooled to RT and concentrated under vacuo to
afford 0.9 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.4 (9H, s), 1.8 (4H, m), 2.5 (4H, m), 3.1 (1H, m), 3.8
(1H, m), 6.46 (1H, brs), 6.7 (1H, d), 6.95 (3H, m), 7.17 (5H, m),
7.4 (4H, m), 7.78 (2H, d), 8.4 (1H, d), 8.51 (2H, s), 12.4 (2H,
brs).
i)
(Trans-4-{3-(2-amino-1H-benzoimidazol-5-yloxy)-5-[4-(N-hydroxy-carbamim-
idoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid
tert-butyl ester
[0719]
{Trans-4-[3-(2-amino-1H-benzoimidazol-5-yloxy)-5-(4-cyano-phenoxy)--
phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.9 g
(1.54 mmol) was subjected to form N-hydroxycarbamimidoyl using the
procedure of Example 95(d) to afford 0.85 g of the required
product. Percentage purity (LCMS): 100.0%, (M+1)=615.3+1.
j)
{Trans-4-[3-(2-Amino-1H-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl-pheno-
xy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0720]
(Trans-4-{3-(2-amino-1H-benzoimidazol-5-yloxy)-5-[4-(N-hydroxy-carb-
amimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid
tert-butyl ester 0.85 g (1.38 mmol) was reduced using the procedure
of Example 2(f) to afford 0.7 g of the required product. Percentage
purity (LCMS): 99.8%, (M+1)=599.2+1.
k) 4-Amino-cyclohexanecarboxylic acid
[3-(2-amino-1H-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl-phenoxy)-phenyl]-
-amide
[0721]
{4-[3-(2-Amino-1H-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl-phenoxy-
)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.7 g
(0.45 mmol) was treated using the procedure of Example 9(d) to
afford 0.23 g of the required product. Percentage purity (HPLC):
96.9%, (LCMS): 100%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40 (4H,
m), 1.82 (4H, m), 3.0 (1H, m), 3.67 (1H, m), 6.92 (2H, m), 7.12
(1H, s), 7.22 (2H, d), 7.38 (3H, m), 7.78 (5H, m), 8.40 (1H, d),
8.62 (2H, s), 9.25 (4H, brs).
Example 118
4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-benzyloxy)-phenyl]-amide
[0722] Intermediates (a) and (b) are the same as in Example 75.
c) [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl
ester
[0723] Using 3,5-bis-(4-cyano-benzyloxy)-benzoic acid (1.6 g, 4.2
mmol) and following the procedure of Example 105(c) afforded 0.65 g
of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.3
(9H, s), 5.2 (4H, s), 6.48 (1H, s), 6.9 (2H, d), 7.72 (2H, m), 7.81
(2H, d), 7.91 (4H, m) 9.52 (1H, s).
d) [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-amine
[0724] Using [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-carbamic acid
tert-butyl ester (0.6 g, 1.32 mmol) and following the procedure of
Example 9(d) afforded 0.37 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 5.2 (4H, s), 6.48 (1H, s), 6.9 (2H, d),
7.72 (2H, m), 7.81 (2H, d), 7.91 (4H, m).
e)
{4-[3,5-Bis-(4-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester
[0725] Following the procedure of Example 107(e)
trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.255 g
(1.04 mmol) and [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-amine (0.37 g,
1.04 mmol) were used to afford 0.39 g of the required product.
Percentage purity (LCMS): 94.8%, (M-1)=580.0-1.
f)
(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyc-
lohexyl)-carbamic acid tert-butyl ester
[0726]
{4-[3,5-Bis-(4-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbam-
ic acid tert-butyl ester 0.39 g (0.672 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.4 g of the required product. Percentage purity (LCMS):
100.0%, (M+1)=646.2+1.
g)
{4-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-ca-
rbamic acid tert-butyl ester
[0727] Acetic anhydride (0.36 ml, 3.72 mmol) was added to the
solution of
(4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyclo-
hexyl)-carbamic acid tert-butyl ester (0.40 g, 0.62 mmol) in 10 ml
of acetic acid and reaction mixture was stirred for 3 h. After
completion of reaction, at RT zinc dust (0.4 g, 6.2 mmol) was added
and resulting mixture was stirred over night. Recation mixture was
filtered through celite and filterate was concentrated to dryness.
Product was washed with cold diethyl ether and dried to afford 0.52
g of the required product. Percentage purity (LCMS): 100.0%,
(M-1)=615.2-1.
h) 4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-benzyloxy)-phenyl]-amide
[0728]
{4-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl-
}-carbamic acid tert-butyl ester 0.52 g (0.846 mmol) was treated
using the procedure of Example 9(d) to afford 0.3 g of the required
product. Percentage purity (HPLC): 94.49%, (LCMS): 99.4%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.24 (4H, m), 1.41 (4H, m), 2.1 (1H,
m), 2.31 (1H, m), 5.2 (4H, s), 6.71 (1H, s), 7.01 (3H, s), 7.90
(8H, dd), 9.11 (1H, s), 9.25 (8H, brs).
Example 119
4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(3-carbamimidoyl-benzyloxy)-phenyl]-amide
[0729] Intermediates (a) and (b) are the same as in Example 77.
c) [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl
ester
[0730] Using 3,5-bis-(3-cyano-benzyloxy)-benzoic acid (2.2 g, 5.7
mmol) and following the procedure of Example 105(c) afforded 0.85 g
of the required product.
d) [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-amine
[0731] Using [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-carbamic acid
tert-butyl ester (0.8 g, 1.76 mmol) and following the procedure of
Example 9(d) afforded 0.6 g of the required product. Percentage
purity (LCMS): 100.0%, (M+1)=355.0+1.
e)
{4-[3,5-Bis-(3-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbamic
acid tert-butyl ester
[0732] Following the procedure of Example 107(e)
trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.41 g
(1.68 mmol) and [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-amine (0.6 g,
1.68 mmol) were used to afford 0.61 g of the required product.
Percentage purity (LCMS): 79.8%, (M-1)=580.0-1.
f)
(4-{3,5-Bis-[3-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyc-
lohexyl)-carbamic acid tert-butyl ester
[0733]
{4-[3,5-Bis-(3-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbam-
ic acid tert-butyl ester 0.6 g (1.03 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.615 g of the required product. Percentage purity (LCMS):
100%, (M+1)=646.2+1.
g)
{4-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-ca-
rbamic acid tert-butyl ester
[0734] Using
(4-{3,5-bis-[3-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyclo-
hexyl)-carbamic acid tert-butyl ester 0.61 g (0.94 mmol) and
following the procedure of Example 118(g) afforded 0.6 g of the
required product. Percentage purity (LCMS): 100%, (M-1)=614.-1.
h) 4-Amino-cyclohexanecarboxylic acid
[3,5-bis-(3-carbamimidoyl-benzyloxy)-phenyl]-amide
[0735]
{4-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl-
}-carbamic acid tert-butyl ester 0.6 g (0.97 mmol) was treated
using the procedure of Example 9(d) to afford 0.3 g of the required
product. Percentage purity (HPLC): 85.98%, (LCMS): 98.14%. .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.44 (4H, m), 1.82 (4H, m), 3.05 (1H,
m), 3.31 (1H, m), 5.2 (4H, s), 6.71 (1H, s), 7.15 (2H, s), 7.88
(2H, m), 7.9 (8H, m), 9.11 (4H, brs), 9.25 (6H, brs), 10.01 (1H,
s).
Example 120
Trans-4-methyl-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
##STR00020##
[0737] Intermediates (a) to (d) are the same as in Example 105.
e) Trans-4-methyl-cyclohexanecarboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide
[0738] Following the procedure of Example 107(e)
trans-4-methyl-cyclohexanecarboxylic acid 0.21 g-(1.52 mmol) and
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (0.50 g, 1.52 mmol) were
used to afford 0.65 g of the required product. Percentage purity
(LCMS): 85.4%, (M+1)=451.1+1.
f) Trans-4-methyl-cyclohexanecarboxylic acid
{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
[0739] Trans-4-methyl-cyclohexanecarboxylic acid
[3,5-bis-(4-cyano-phenoxy)-phenyl]-amide 0.65 g (1.44 mmol) was
subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 0.80 g of the required product. Percentage
purity (LCMS): 82.7%, (M+1)=517.2+1.
g) Trans-4-methyl-cyclohexanecarboxylic acid
{3,5-bis-[4-(N-acetylhydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
[0740] Trans-4-methyl-cyclohexanecarboxylic acid
{3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide 0.80 g
(1.54 mmol) was acetylated using the procedure of Example 2(e) to
afford 1.00 g of the required product. Percentage purity (LCMS):
82.7%, (M+1)=601.2+1.
h) Trans-4-methyl-cyclohexanecarboxylic acid
[3,5-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
[0741] Trans-4-methyl-cyclohexanecarboxylic acid
{3,5-bis-[4-(N-acetylhydroxy-carbamimidoyl)-phenoxy]-phenyl}-amide
1.00 g (1.66 mmol) was reduced using the procedure of Example 2(f)
to afford 0.40 g of the required product. Percentage purity (HPLC):
98.4%, (LCMS): 98.2%. .sup.1H NMR (DMSO-d.sub.6): .delta. 0.9 (5H,
m), 1.32 (3H, m), 1.7 (4H, m), 2.2 (1H, m), 3.05 (2H, m), 7.31 (6H,
m), 7.92 (4H, d), 9.1 (4H, brs), 9.3 (4H, brs), 10.1 (1H, s).
Example 121
4-[3-[(4-Amino-cyclohexanecarbonyl)-amino]-5-(4-carbamimidoyl-phenoxy)-phe-
noxy]-benzamide
[0742] Intermediates (a) (e) are the same as in Example 117.
f)
{Trans-4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-phenylcarbamoyl]-cyc-
lohexyl}-carbamic acid tert-butyl ester
[0743] Following the procedure of Example 42(b)
{trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbarnoyl]-cyclohexyl}-car-
bamic acid tert-butyl ester (1.0 g, 2.21 mmol) and
4-fluorobenzaldehyde (0.475 ml, 4.43 mmol) were used to afford 0.4
g of the required product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.11
(4H, m), 1.29 (9H, s), 1.8 (4H, m), 2.11 (1H, m), 3.15 (1H, m),
6.82 (1H, d), 7.34 (6H, m), 7.86 (2H, d), 7.92 (2H, d), 10.11 (1H,
s).
g)
4-[3-[(Trans-4-tert-butoxycarbonylamino-cyclohexanecarbonyl)-amino]-5-(-
4-cyano-phenoxy)-phenoxy]-benzoic acid
[0744] Following the procedure of Example 92(e)
{trans-4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-phenylcarbamoyl]-cyclo-
hexyl}-carbamic acid tert-butyl ester (0.4 g, 0.72 mmol) was used
to afford 0.15 g of the required product. .sup.1H NMR
(DMSO-d.sub.6): .delta. 1.21 (9H, s), 1.32 (4H, m), 1.8 (4H, m),
2.11 (1H, m), 2.62 (1H, m), 6.62 (1H, s), 6.81 (1H, m), 7.26 (5H,
m), 7.92 (3H, dd), 10.1 (1H, s).
h)
{Trans-4-[3-(4-carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-phenylcarbamoyl]--
cyclohexyl}-carbamic acid tert-butyl ester
[0745] Following the procedure of Example 94(f)
4-[3-[(trans-4-tert-butoxycarbonyl-amino-cyclohexanecarbonyl)-amino]-5-(4-
-cyano-phenoxy)-phenoxy]-benzoic acid (0.15 g, 0.26 mmol) was used
to afford 0.12 g of the required product. Percentage purity (LCMS):
86.7%, (M+1)=570.2+1.
i)
(Trans-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy-
]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
[0746]
{Trans-4-[3-(4-carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-phenylcarbamo-
yl]-cyclohexyl}-carbamic acid tert-butyl ester 0.12 g (0.21 mmol)
was subjected to form N-hydroxycarbamimidoyl using the procedure of
Example 95(d) to afford 0.12 g of the required product. Percentage
purity (LCMS): 55.5%, (M+1)=603.2+1.
j)
(Trans-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)-p-
henoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl
ester
[0747]
(Trans-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phe-
noxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
0.12 g (0.198 mmol) was acetylated using the procedure of Example
2(e) to afford 0.13 g of the required product. Percentage purity
(LCMS): 50.0%, (M+1)=645+1.
k)
{Trans-4-[3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-phenoxy)-phenyl-ca-
rbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
[0748]
(Trans-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoy-
l)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl
ester 0.13 g (0.2 mmol) was reduced using the procedure of Example
2(f) to afford 0.1 g of the required product. Percentage purity
(LCMS): 73.6%, (M+1)=587+1.
l)
4-[3-[(Trans-4-amino-cyclohexanecarbonyl)-amino]-5-(4-carbamimidoyl-phe-
noxy)-phenoxy]-benzamide
[0749]
{Trans-4-[3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-phenoxy)-pheny-
l-carbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.1 g (0.17
mmol) was treated using the procedure of Example 9(d) to afford
0.03 g of the required product. Percentage purity (HPLC): 97.1%,
(LCMS): 100.0% (M+1). .sup.1H NMR (DMSO-d.sub.6): .delta. 1.44 (4H,
m), 1.82 (4H, m), 2.2 (1H, t), 3.05 (1H, m), 6.71 (1H, s), 7.11
(2H, s), 7.30 (3H, m), 7.88 (7H, m), 9.1 (2H, brs), 9.25 (2H, brs),
10.1 (1H, s).
Example 122
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(1-cyclopropylmethyl-piperidin-4-yl)-b-
enzamide
[0750] Intermediates (a) (d) are the same as in Example 32.
e)
3,5-Bis-(4-cyano-phenoxy)-N-(1-cyclopropylmethyl-piperidin-4-yl)-benzam-
ide
[0751] Following procedure of Example 11(e)
3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14
mmol) and bromomethyl-cyclopropane (0.231 g, 1.71 mmol) were used
to afford 0.4 g of the required product. Percentage purity (LCMS):
45.0%, (M+1)=492.2+1
f)
N-(1-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-hydroxycarbamimido-
yl)-phenoxy]-benzamide
[0752]
3,5-Bis-(4-cyano-phenoxy)-N-(1-cyclopropylmethyl-piperidin-4-yl)-be-
nzamide 0.4 g (0.812 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.4 g of the required product. Percentage purity (LCMS):
100%, (M+1)=558+1.
g)
N-(1-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-acetylhydroxy-carb-
amimidoyl)-phenoxy]-benzamide
[0753]
N-(1-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-hydroxycarbami-
midoyl)-phenoxy]-benzamide 0.4 g (0.716 mmol) was acetylated using
the procedure of Example 2(e) to afford 0.45 g of the required
product. Percentage purity (LCMS): 29.1%, (M+1)=642.2+1.
h)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(1-cyclopropylmethyl-piperidin-4-yl-
)-benzamide
[0754]
N-(1-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-acetylhydroxy--
carbamimidoyl)-phenoxy]-benzamide 0.45 g (0.7 mmol) was reduced
using the procedure of Example 2(f) to afford 0.25 g of the
required product. Percentage purity (HPLC): 97.24%, (LCMS): 100%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.3 (2H, m), 0.6 (2H, d), 1.1
(1H, m), 1.82 (2H, m), 2.13 (3H, m), 3.05 (4H, m), 3.6 (2H, d),
7.15 (1H, m), 7.22 (2H, m), 7.40 (4H, d), 7.5 (2H, d), 7.9 (4H, d),
8.6 (1H, d), 9.21 (8H, brs), 9.6 (1H, brs).
Example 123
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-b-
enzamide
[0755] Intermediates (a) (d) are the same as in Example 32.
e)
3,5-Bis-(4-cyano-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-benzam-
ide
[0756] Following procedure of Example 11(e)
3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14
mmol) and 2-bromoethanol (0.214 g, 1.71 mmol) were used to afford
0.4 g of the required product. Percentage purity (LCMS): 76.2%,
(M+1)=482+1.
f)
3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-[1-(2-hydroxy-ethyl)-pip-
eridin-4-yl]-benzamide
[0757]
3,5-Bis-(4-cyano-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-be-
nzamide 0.4 g (0.829 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.4 g of the required product. Percentage purity (LCMS):
100%, (M+1)=548.2+1.
g)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl-
]-benzamide
[0758] To a stirred solution of
3,5-bis-(4-carbamimidoyl-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]--
benzamide 0.35 g (0.638 mmol) in 15 ml of methanol, ammonium
formate (201 mg, 3.192 mmol) followed by acetic acid (0.36 ml) were
added. After 10 min stirring, under inert atmosphere of nitrogen
Pd/C (102 mg, 0.957 mmol) was added and resulting mixture was
further stirred for 5 h at 60.degree. C. Reaction progress was
monitored by TLC. Reaction mixture was cooled to RT and filtered
through celite and washed with methanol (20 ml). Thus obtained
filterate was concentrated under vacuo to afford 0.15 g of the
required product. Percentage purity (HPLC): 95.4%, (LCMS): 100%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.82 (2H, m), 2.01 (2H, m), 3.2
(4H, m), 3.61 (4H, m), 4.01 (1H, m), 7.21 (1H, s), 7.35 (4H, d),
7.50 (2H, d), 7.91 (4H, d), 8.6 (1H, d), 9.2 (8H, brs), 9.4 (1H,
brs).
Example 124
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-piperidine-1-carboxylic
acid ethyl ester
[0759] Intermediates (a) (d) are the same as in Example 32.
e)
4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-1-carboxylic
acid ethyl ester
[0760] Following procedure of Example 11(e)
3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14
mmol) and ethyl choroformate (0.186 g, 1.71 mmol) were used to
afford 0.4 g of the required product. .sup.1H NMR (DMSO-d.sub.6):
.delta. 21 (3H, t), 1.42 (4H, m), 1.81 (3H, d), 2.92 (2H, m), 4.12
(2H, m), 7.26 (5H, d), 7.52 (2H, d), 7.92 (4H, d), 8.41 (1H,
d).
f)
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-piperidin-
e-1-carboxylic acid ethyl ester
[0761]
4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-1-carboxylic
acid ethyl ester 0.4 g (0.784 mmol) was subjected to form
N-hydroxycarbamimidoyl using the procedure of Example 95(d) to
afford 0.40 g of the required product. Percentage purity (LCMS):
87.6%, (M+1)=576.2+1.
g)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl-
]-benzamide
[0762]
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-piper-
idine-1-carboxylic acid ethyl ester 0.4 g (0.52 mmol) was subjected
to reduction using the procedure of Example 123(g) to afford 0.2 g
of the required product. Percentage purity (HPLC): 97.4%, (LCMS):
100%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.22 (3H, m), 1.41 (2H,
m), 1.7 (2H, d), 2.81 (2H, brs), 4.1 (5H, q), 7.21 (1H, t), 7.35
(4H, d), 7.50 (2H, d), 7.9 (4H, d), 8.45 (1H, d), 9.2 (8H,
brs).
Example 125
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexyl-benzamide
[0763] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-cyclohexyl-benzamide
[0764] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.4 mmol) and
cyclohexylamine (0.14 g, 1.4 mmol) were used to afford 0.61 g of
the required product. Percentage purity (LCMS): 78.1%,
(M+1)=437.0+1.
d)
N-Cyclohexyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzamide
[0765] Following the procedure of Example 95(d)
3,5-bis-(4-cyano-phenoxy)-N-cyclo-hexyl-benzamide 0.61 g (1.4 mmol)
and other reagents were used to afford 0.65 g of the required
product. Percentage purity (LCMS): 85.1.0%, (M+1)=503.1+1.
e)
N-Cyclohexyl-3,5-bis-[4-(N-acetylhydroxycarbarnimidoyl)-phenoxy]-benzam-
ide
[0766] Following the procedure of Example 2(e)
N-cyclohexyl-3,5-bis-[4-(N-hydroxy-carbamimidoyl)-phenoxy]-benzamide
0.65 g (1.29 mmol) was used to afford 0.76 g of the required
product. Percentage purity (LCMS): 39.0%, (M+1)=587.2+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexyl-benzamide
[0767]
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino-
}-cyclo-hexyl)-carbamic acid tert-butyl ester 0.76 g (1.29 mmol)
was reduced using the procedure of Example 2(f) to afford 0.25 g of
the required product. Percentage purity (HPLC): 95.01%, (LCMS):
100%. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.22 (4H, m), 1.91 (6H,
m), 3.11 (1H, t), 7.15 (1H, s), 7.2 (4H, d), 7.50 (2H, d), 7.78
(4H, d), 8.45 (1H, d), 9.21 (8H, brs).
Example 126
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexylmethyl-benzamide
[0768] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-cyclohexylmethyl-benzamide
[0769] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and
cyclohexylmethylamine (0.143 g, 1.26 mmol) were used to afford 0.60
g of the required product. Percentage purity (LCMS): 97.6%,
(M+1)=451.1+1.
d)
N-Cyclohexylmethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzami-
de
[0770] Following the procedure of Example 95(d)
3,5-bis-(4-cyano-phenoxy)-N-cyclo-hexylmethyl-benzamide 0.60 g
(1.22 mmol) and other reagents were used to afford 0.65 g of the
required product. Percentage purity (LCMS): 89.0%,
(M+1)=517.2+1.
e)
N-Cyclohexylmethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-b-
enzamide
[0771] Following the procedure of Example 2(e)
N-cyclohexylmethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzamide
0.65 g (1.16 mmol) was used to afford 0.5 g of the required
product. Percentage purity (LCMS): 72.0%, (M+1)=601.2+1.
f)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexylmethyl-benzamide
[0772]
N-Cyclohexylmethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenox-
y]-benzamide 0.5 g (0.78 mmol) was reduced using the procedure of
Example 2(f) to afford 0.25 g of the required product. Percentage
purity (HPLC) 98.9%, (LCMS): 100%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.8 (2H, t), 1.2 (3H, m), 1.62 (6H, d), 3.1 (2H, t), 7.15
(1H, s), 7.25 (4H, d), 7.50 (2H, d), 7.91 (4H, d), 8.61 (1H, t),
9.25 (4H, brs).
Example 127
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide
[0773] Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide
[0774] Following the procedure of Example 9(e)
3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and
4-methylcyclohexylamine (0.143 g, 1.26 mmol) were used to afford
0.6 g of the required product. Percentage purity (LCMS): 84.6%,
(M+1)=451.1+1.
d)
3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohexyl)-be-
nzamide
[0775] Following the procedure of Example 95(d)
3,5-bis-(4-cyano-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide 0.6 g
(1.22 mmol) and other reagents were used to afford 0.65 g of the
required product. Percentage purity (LCMS): 43.8%,
(M+1)=517.2+1.
e)
3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohex-
yl)-benzamide
[0776] Following the procedure as in Example 2(e)
3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohexyl)-benz-
amide 0.65 g (1.16 mmol) was used to afford 0.7 g of the required
product. Percentage purity (LCMS): 75.2%, (M+1)=601.2+1.
f)
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide
[0777]
3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cycl-
ohexyl)-benzamide 0.7 g (1.16 mmol) was reduced using the procedure
of Example 2(f) to afford 0.25 g of required product. Percentage
purity (HPLC): 97.7%, (LCMS): 97.1%. .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.9 (3H, d), 1.3 (4H, m), 1.52 (4H, m), 3.05 (1H, m), 3.61
(1H, m), 7.15 (1H, m), 7.42 (4H, d), 7.50 (2H, t), 7.91 (4H, d),
9.11 (4H, brs), 9.25 (4H, brs).
Example 128
N-(4-Amino-cyclohexyl)-3-(3-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-ben-
zamide
[0778] Intermediates (a) and (c) are the same as in Example 49.
d)
{4-[3-(3-Bromo-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino}-cyclohexyl]-c-
arbamic acid tert-butyl ester
[0779]
{4-[3-(4-Cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbami-
c acid isopropyl ester (1.0 g, 2.2 mmol) and copper acetate (0.4 g,
2.2 mmol), dissolved in 30 ml of dichloromethane, were charged in a
100 ml capacity seal-tube. 3-bromophenyl boronic acid (0.667 g,
3.32 mmol), 4 .ANG. molecular sieves (3.0 g) and 0.438 g (5.53
mmol) of pyridine, in 20 ml of dichloromethane, was added to the
reaction mixture in a sealed-tube and reaction mixture was stirred
at RT for 20 h. After reaction completion 2.0 g of silica-gel was
added and the mixture was filtered. Thus obtained filterate was
concentrated under reduced pressure and subjected to column
chromatography to afford 0.3 g of the required product. Percentage
purity (LCMS): 86.0%, (M+1)=605.1+1.
e)
(4-{3-(3-Bromo-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl--
amino}-cyclohexyl)-carbamic acid tert-butyl ester
[0780] Following the procedure of Example 95(d)
{4-[3-(3-bromo-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-car-
bamic acid tert-butyl ester 0.3 g (0.49 mmol) and other reagents
were used to afford 0.30 g of the required product. Percentage
purity (LCMS): 72.0%, (M+1)=581.8+1 (Boc acid).
f)
(4-{3-(3-Bromo-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-be-
nzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0781] Following the procedure of Example 2(e)
(4-{3-(3-bromo-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylami-
no}-cyclohexyl)-carbamic acid tert-butyl ester 0.30 g (4.69 mmol)
was used to afford 0.31 g of the required product. Percentage
purity (LCMS): 71.0%, (M+1)=580.1+1 (de-Boc).
g)
{4-[3-(3-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclo-
hexyl}-carbamic acid tert-butyl ester
[0782]
{4-[3-{4-[(acetyl-hydroxy-amino)-imino-methyl]-phenoxy}-5-(3-bromo--
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
0.31 g (4.55 mmol) was reduced using the procedure of Example 2(f)
to afford 0.25 g of the required product. Percentage purity (LCMS):
60.0%, (M+1)=623.9+1
h)
{4-[3-(3-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclo-
hexyl}-carbamic acid tert-butyl ester
[0783]
{4-[3-(3-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]-c-
yclo-hexyl}-carbamic acid tert-butyl ester 0.25 g (4.01 mmol) was
treated using the procedure of Example 9(d) to afford 0.1 g of the
required product. Percentage purity (HPLC): 96.2%, (LCMS): 97.8%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.41 (4H, d), 1.9 (4H, m), 3.05
(1H, m), 7.15 (1H, m), 7.21 (1H, m), 7.42 (4H, d), 7.91 (5H, d),
8.5 (1H, d), 9.11 (2H, brs), 9.25 (2H, brs).
Example 129
N-(4-amino-cyclohexyl)-3-(4-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-ben-
zamide
[0784] Intermediates (a) and (c) are the same as in Example 49.
d)
{4-[3-(4-Bromo-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-c-
arbamic acid tert-butyl ester
[0785] Following the procedure of Example 128(c)
{4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (1.0 g, 2.21 mmol) and 4-bromo phenyl boronic
acid (0.67 g, 3.32 mmol) were used to afford 0.32 g of the required
product. Percentage purity (LCMS): 55.7%, (M+1)=605.1+1 (de-Boc;
-100).
e)
(4-{3-(4-Bromo-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyla-
mino}-cyclohexyl)-carbamic acid tert-butyl ester
[0786] Following the procedure of Example 95(d)
3{4-[3-(4-Bromo-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-ca-
rbamic acid tert-butyl ester 0.32 g (0.52 mmol) and other reagents
were used to afford 0.30 g of the required product. Percentage
purity (LCMS): 37.5%, (M+1)=640.1+1.
f)
(4-{3-(4-Bromo-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-be-
nzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
[0787] Following the procedure as in Example 2(e)
(4-{3-(4-bromo-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylami-
no}-cyclohexyl)-carbamic acid tert-butyl ester 0.30 g (4.69 mmol)
was used to afford 0.31 g of the required product. Percentage
purity (LCMS): 38.6%, (M+1)=584+1 (de-Boc; -100).
g)
{4-[3-(4-Bromo-phenoxy)-5-(4-carbarnimidoyl-phenoxy)-benzoylamino]-cycl-
ohexyl}-carbamic acid tert-butyl ester
[0788]
{4-[3-{4-[(Acetyl-hydroxy-amino)-imino-methyl]-phenoxy}-5-(4-bromo--
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
0.31 g (4.55 mmol) was reduced using the procedure of Example 2(f)
to afford 0.25 g of the required product. Percentage purity (LCMS):
22.8%, (M+1)=522.1+1 (de-Boc; -100).
h)
N-(4-amino-cyclohexyl)-3-(4-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)--
benzamide
[0789]
{4-[3-(4-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]-c-
yclo-hexyl}-carbamic acid tert-butyl ester 0.1 g (4.01 mmol) was
treated using the procedure of Example 9(d) to afford 0.1 g of the
required product. Percentage purity (HPLC): 93.6%, (LCMS): 100%.
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.41 (4H, d), 1.9 (4H, m), 3.05
(1H, m), 3.61 (1H, m), 7.15 (1H, m), 7.21 (1H, m), 7.42 (1H, d),
7.6 (1H, d), 7.91 (4H, d), 8.5 (1H, d), 9.11 (2H, brs), 9.25 (2H,
brs).
ABBREVIATIONS
[0790] DMF--N,N-dimethylformamide [0791] THF--Tetrahydrofuran
[0792] TEA--Triethyl Amine [0793]
EDC--1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
[0794] HOBT--hydroxybenzotriazole [0795]
DIPEA--N,N-diisopropylethylamine [0796]
PyBop--Benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate [0797] Na.sub.2CO.sub.3--Sodium carbonate
[0798] RT--Room temperature
* * * * *