CA2700051A1 - Small molecule bradykinin b1 receptor antagonists - Google Patents
Small molecule bradykinin b1 receptor antagonists Download PDFInfo
- Publication number
- CA2700051A1 CA2700051A1 CA2700051A CA2700051A CA2700051A1 CA 2700051 A1 CA2700051 A1 CA 2700051A1 CA 2700051 A CA2700051 A CA 2700051A CA 2700051 A CA2700051 A CA 2700051A CA 2700051 A1 CA2700051 A1 CA 2700051A1
- Authority
- CA
- Canada
- Prior art keywords
- optionally substituted
- hydrogen atom
- mmol
- compound
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- 239000003144 bradykinin B1 receptor antagonist Substances 0.000 title description 2
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- -1 or wherein W is N Chemical group 0.000 claims description 110
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 98
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 52
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- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000005843 halogen group Chemical group 0.000 claims description 37
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Abstract
Disclosed are compounds of formula (I) which are bradykinin B1 receptor (B1R) antagonists. These compounds are useful to treat diseases or relieve adverse symptoms associated with inflammation and pain. The inven-tion encompasses novel compounds and acceptable derivatives thereof, phar-maceutical compositions and methods for prophylaxis and treatment of diseases involving inflammation and pain.
Description
Small molecule bradykinin B 1 receptor antagonists This invention relates to the field of biologically active pharmaceutical compounds and specifically to selective antagonists to the bradykinin B 1 receptor (B 1 R) and their uses for treating conditions and diseases responsive to bradykinin B 1 receptor such as inflammatory and pain-associated disorders.
The biological actions of kinins are mediated by two major G-protein coupled receptors B1R and= B2R. The B2R is constitutively expressed under physiological conditions in a variety of cells while the B1R is induced under pathophysiological conditions such as tissue damage or inflammation in several cell types including endothelial, smooth muscle cells, blood cells and neurons (Regoli and Barabe, Pharmacol. Rev. 1980, 32, 1-46;
Marceau et al., Pharmacol. Rev. 1998, 50, 357-386): This makes the B1R a particularly attractive drug target. Activation of the B1R produces a range of pro-inflammatory effects including edema, pain and promotion of blood-borne leukocyte trafficking (Calixto et al., Br.
J. Pharmacol.
2004,143,.803-818).
Bradykinin (BK) and Kallidin (KD) are peptidic kinins which act on the B2R and mediate acute physiological actions of kinins on the cardiovascular, renal, nervous and immune system. BK and kallidin are metabolized by carboxypeptidase N and M, which remove the carboxy-terminal arginine residue to generate des-Arg-9-BK (DABK) or des-Arg-10-kallidin (DAKD). DAKD is the only known natural ligand for the human B1R
whereas des-Arg-9-BK activates the B 1 R in rodents. DAKD acting specifically on the human B 1 R
appears to be an important mediator of inflammation and pain in man (Leeb-Lundberg et al., Pharmacol. Rev. 2005, 57, 27-77).
Numerous peptide and non-peptide antagonists of B 1 R have been described in the prior art as novel therapeutics for the treatment of pain and inflammation (Chen et al., Expert Opin.
Ther. Targets 2007, 11, 21-35). For instance, W003066577, W003065789, W005016886, W004019868, US20060122236 disclose biphenyl compounds and W09725315 discloses sulphonamide compounds that are B1R antagonists.
The biological actions of kinins are mediated by two major G-protein coupled receptors B1R and= B2R. The B2R is constitutively expressed under physiological conditions in a variety of cells while the B1R is induced under pathophysiological conditions such as tissue damage or inflammation in several cell types including endothelial, smooth muscle cells, blood cells and neurons (Regoli and Barabe, Pharmacol. Rev. 1980, 32, 1-46;
Marceau et al., Pharmacol. Rev. 1998, 50, 357-386): This makes the B1R a particularly attractive drug target. Activation of the B1R produces a range of pro-inflammatory effects including edema, pain and promotion of blood-borne leukocyte trafficking (Calixto et al., Br.
J. Pharmacol.
2004,143,.803-818).
Bradykinin (BK) and Kallidin (KD) are peptidic kinins which act on the B2R and mediate acute physiological actions of kinins on the cardiovascular, renal, nervous and immune system. BK and kallidin are metabolized by carboxypeptidase N and M, which remove the carboxy-terminal arginine residue to generate des-Arg-9-BK (DABK) or des-Arg-10-kallidin (DAKD). DAKD is the only known natural ligand for the human B1R
whereas des-Arg-9-BK activates the B 1 R in rodents. DAKD acting specifically on the human B 1 R
appears to be an important mediator of inflammation and pain in man (Leeb-Lundberg et al., Pharmacol. Rev. 2005, 57, 27-77).
Numerous peptide and non-peptide antagonists of B 1 R have been described in the prior art as novel therapeutics for the treatment of pain and inflammation (Chen et al., Expert Opin.
Ther. Targets 2007, 11, 21-35). For instance, W003066577, W003065789, W005016886, W004019868, US20060122236 disclose biphenyl compounds and W09725315 discloses sulphonamide compounds that are B1R antagonists.
In view of the severe conditions associated with overshooting and thus pathological inflammation and pain, both acute and chronic, there is a need for novel compounds that are effective in selectively blocking activation of B 1 receptors.
Therefore, the problem underlying the present invention is to provide highly selective B 1 R antagonists, preferably having improved'properties over the B 1 R
antagonists of the prior art.
In a first embodiment of the first aspect the problem underlying the instant application is solved by a compound of the formula (I):
T
I
a N
R B-E-G
A
0 K l~
or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein A is: i) an optionally substituted 5- or 6-membered cycloalkyl;
ii) an optionally substituted 5- or 6-membered heterocycloalkyl;
iii) an optionally substituted 6-membered aryl; or iv) an optionally substituted 5- or 6-membered heteroaryl;
T is a hydrogen atom, or joined to B to form i) an optionally substituted heterocycloalkyl; or ii) an optionally substituted heteroaryl;
B is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optional ly substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or R4 \ / R5 ~ W~ =
wherein W is N, alkyl, heteroalkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R4, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R5 to form, together with W, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl;
R5, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with W, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl;
Therefore, the problem underlying the present invention is to provide highly selective B 1 R antagonists, preferably having improved'properties over the B 1 R
antagonists of the prior art.
In a first embodiment of the first aspect the problem underlying the instant application is solved by a compound of the formula (I):
T
I
a N
R B-E-G
A
0 K l~
or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein A is: i) an optionally substituted 5- or 6-membered cycloalkyl;
ii) an optionally substituted 5- or 6-membered heterocycloalkyl;
iii) an optionally substituted 6-membered aryl; or iv) an optionally substituted 5- or 6-membered heteroaryl;
T is a hydrogen atom, or joined to B to form i) an optionally substituted heterocycloalkyl; or ii) an optionally substituted heteroaryl;
B is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optional ly substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or R4 \ / R5 ~ W~ =
wherein W is N, alkyl, heteroalkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R4, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R5 to form, together with W, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl;
R5, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with W, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl;
E, if present, is a heteroalkyl or a heteroaralkyl;
G, if present, is an alkyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, a alkylcycloalkyl, a heterocycloalkylalkyl, a heteroaryl, or a heteroaralkyl K is Ri - N
\ R 2 wherein R' and RZ are each independently selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6heteroalkyl, or form, together with N, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
and R3 is a hydrogen atom, C1- or C2alkyl, cyano, or a halogen atom.
In a second embodiment of the first aspect which is also an embodiment of the first embodiment of the first aspect A is I I
XX3 or XI X3 \Z_~ \z ~= ~=
wherein X1, X2, and X3 are each independently selected from N, 0, S, NR", CR", or CR"R"', wherein R' and R"' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heterbalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a third embodiment of the first aspect which is also an embodiment of the first or the 5 second embodiment of the first aspect A is selected from Rx Rx N X"'~N X N/ X
X / N~~.f~
\ Rx \ Rx ~.. srinn 1).1 .nrinr Rx Rx R"
N O NRx N NRx \
\ \ N-J~ ~'~ R)e ~ \.
.niinr Rx1 Rx3 Rx~ R~ Rxt' Rx3' O Rx, or NRx R'Q R'Q 112, s \ ' `
wherein Ri1', Ri2', and R"3' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and XisNH,0,orS.
G, if present, is an alkyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, a alkylcycloalkyl, a heterocycloalkylalkyl, a heteroaryl, or a heteroaralkyl K is Ri - N
\ R 2 wherein R' and RZ are each independently selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6heteroalkyl, or form, together with N, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
and R3 is a hydrogen atom, C1- or C2alkyl, cyano, or a halogen atom.
In a second embodiment of the first aspect which is also an embodiment of the first embodiment of the first aspect A is I I
XX3 or XI X3 \Z_~ \z ~= ~=
wherein X1, X2, and X3 are each independently selected from N, 0, S, NR", CR", or CR"R"', wherein R' and R"' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heterbalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a third embodiment of the first aspect which is also an embodiment of the first or the 5 second embodiment of the first aspect A is selected from Rx Rx N X"'~N X N/ X
X / N~~.f~
\ Rx \ Rx ~.. srinn 1).1 .nrinr Rx Rx R"
N O NRx N NRx \
\ \ N-J~ ~'~ R)e ~ \.
.niinr Rx1 Rx3 Rx~ R~ Rxt' Rx3' O Rx, or NRx R'Q R'Q 112, s \ ' `
wherein Ri1', Ri2', and R"3' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and XisNH,0,orS.
In a fou.rth embodiment of the first aspect which is also an embodiment of the first embodiment of the first aspect A is I I
VWL ~N~
12 13 or I'Z 13 Y Y
wherein Yl, Yz, Y3 and Y4 are each independently selected from N, 0, S, NRy, CRY, or CRyRy', wherein Rj' and Ry' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a fifth embodiment of the first aspect which is also an embodiment of the first embodiment or the fourth embodiment of the first aspect A is selected from Rv7 Rva Rva N N ~N
I / N A--/
Ry2 Ry2 R~ Rn RY3 I s j`~` ~`n'vI
Rya Ryl RY4 RyYi RYa \ N
N N I N I
R
y Ry2 / n / Ry3 ~u' ,rv Inr Ryl Ry1 Ry' Rya Ry" O Ryl NRY Rv1' Rya Rn NRy Rn Ry3 NRY RY3 Ry~' Ry2 VX^^P RY3 vn- Rya n1v~n Ryl .ivlnr Rya Ryl .nli/vRya Ryl Ry1, Ryl" Rya or Ry" Rya Ry2 RY3 0 RY3 Rn Ry3 Rn R~ R~ Ryz Rv3 ~ I I
wherein RY, Ryl, R'Z, Ry3, Ry4, RY', Ryl', Ry2', Ry3', and Ry4' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
VWL ~N~
12 13 or I'Z 13 Y Y
wherein Yl, Yz, Y3 and Y4 are each independently selected from N, 0, S, NRy, CRY, or CRyRy', wherein Rj' and Ry' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a fifth embodiment of the first aspect which is also an embodiment of the first embodiment or the fourth embodiment of the first aspect A is selected from Rv7 Rva Rva N N ~N
I / N A--/
Ry2 Ry2 R~ Rn RY3 I s j`~` ~`n'vI
Rya Ryl RY4 RyYi RYa \ N
N N I N I
R
y Ry2 / n / Ry3 ~u' ,rv Inr Ryl Ry1 Ry' Rya Ry" O Ryl NRY Rv1' Rya Rn NRy Rn Ry3 NRY RY3 Ry~' Ry2 VX^^P RY3 vn- Rya n1v~n Ryl .ivlnr Rya Ryl .nli/vRya Ryl Ry1, Ryl" Rya or Ry" Rya Ry2 RY3 0 RY3 Rn Ry3 Rn R~ R~ Ryz Rv3 ~ I I
wherein RY, Ryl, R'Z, Ry3, Ry4, RY', Ryl', Ry2', Ry3', and Ry4' are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a sixth embodiment of the first aspect which is also an embodiment of the first, fourth or fifth embodiment of the first aspect A is Ry4 Ry' Ry4 N ~ ~
I or I
Rn ~ Ry,~ Ry2 /
wherein Ryl, R'2, Ry3 and Ry4 are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a seventh embodiment of the first aspect which is also an embodiment of the sixth embodiment of the first aspect RYl is a hydrogen atom.
In a eigth embodiment of the first aspect which is also an embodiment of the sixth or seventh embodiment of the first aspect Ryz is a hydrogen atom, halogen atom, or CI-C6alkyl; and RY4 is a hydrogen atom or halogen atom.
In a ninth embodiment of the first aspect which is also an embodiment of the sixth to eigth embodiment of the first aspect Ry2 is a hydrogen atom.
I or I
Rn ~ Ry,~ Ry2 /
wherein Ryl, R'2, Ry3 and Ry4 are each independently selected from hydrogen atom, halogen atom, =0, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
In a seventh embodiment of the first aspect which is also an embodiment of the sixth embodiment of the first aspect RYl is a hydrogen atom.
In a eigth embodiment of the first aspect which is also an embodiment of the sixth or seventh embodiment of the first aspect Ryz is a hydrogen atom, halogen atom, or CI-C6alkyl; and RY4 is a hydrogen atom or halogen atom.
In a ninth embodiment of the first aspect which is also an embodiment of the sixth to eigth embodiment of the first aspect Ry2 is a hydrogen atom.
In a tenth embodiment of the first aspect which is also an embodiment of the sixth to ninth embodiment of the first aspect RY3 is a hydrogen atom or halogen atom.
In a eleventh embodiment of the first aspect which is also an embodiment of the sixth to tenth embodiment of the first aspect RY4 is a hydrogen atom or halogen atom.
In a twelfth embodiment of the first aspect which is also an embodiment of the first to eleventh embodiment of the first aspect T is a hydrogen atom.
In a 13th embodiment of the first aspect which is also an embodiment of the first to twelfth embodiment of the first aspect K is selected from s- ~N s \N
S \N N
or In a 14th embodiment of the first aspect which is also an embodiment of the first to 13th embodiment of the first aspect K is selected from J .~
XN or >SN-j In a 15th embodiment of the first aspect which is also an embodiment of the first to 14'' embodiment of the first aspect K is XN
In a 16'` embodiment of the first aspect which is also an embodiment of the first to 14th embodiment of the first aspect K is XNJ
In a 17th embodiment of the first aspect which is also an embodiment of the first to 16th embodiment of the first aspect B is heteroalkyl, heteroaryl, or R 4 \ R5 ~r\
wherein W is N, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl;
R4, if present, is a hydrogen atom, alkyl, heteroalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, aralkyl, heteroaralkyl or joined to R5 to form, together with N, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl; and R5, if present, is a hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with N, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl.
In an 18th embodiment of the first aspect which is also an embodiment of the first to 17th embodiment of the first aspect B is -YaB-CO-LB- or -YaB-CO-R $-, wherein YaB is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
LB is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and R B is an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
In a 19th embodiment of the first aspect which is also an embodiment of the first to 18th embodiment of the first aspect B is In a 20'h embodiment of the first aspect which is also an embodiment of the first to 18'b embodiment of the first aspect B is rS
O
wherem R4 is methyl, ethyl or isopropyl.
In a 2l St embodiment of the first aspect which is also an embodiment of the first to 17th embodiment of the first aspect B is In a 22"d embodiment of the first aspect which is also an embodiment of the first to 21s' embodiment of the first aspect E is -YaE-CO-LE-, -YaE-CO-WE-, -YaE-NR E-CO-RdE-, -YaE-NR E-CO-LE- -YaE-WE-CO-NRdE-LE-, or -YaE-NWE-CS-NRdE-LE-, wherein YaE is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R E is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-Cgalkenyl or an optionally substituted C2-CBalkynyl, provided that R~E is not a hydrogen atom in -YaE-CO-R E-;
RdE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-Cgalkynyl; and LE is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.
In a 23`d embodiment of the first aspect which is also an embodiment of the first to 22 d embodiment of the first aspect G is alkyl, cycloalkyl, -YaG-O-RcG, -YaG-CO-NRaGRbG, -YaG_S-R G, -YaG-SO-RcG, -YaG-SO2-RcG, heteroaryl, alkylcycloalkyl, or heterocycloalkyl, wherein YaG is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
RaG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to RbG
to form a 4- to 10-membered cycloalkyl or heterocycloalkyl;
RbG is a hydrogen atom, a C1-C6a1ky1, a C2-C6alkenyl or a C2-C6alkynyl, or is joined to RaG to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; and R G is an optionally substituted C1-CBalkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
In a 24th embodiment of the first aspect which is also an embodiment of the first, fourth to six, twelfth, 17t' or 22 d embodiment of the first aspect the compound is represented by formula (II):
H
B-E
Rya Y, Ry3 Rn o K (II) wherein Y' is N, CH or CF;
K is selected from XN or xN-J
~
R3 is a hydrogen atom or methyl;
RY2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
Ry3 is a hydrogeri atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
RY4 is a hydrogen atom or halogen atom;
B is -YaB-CO-LB-, -YaB-CO-RB-, or R \ R5 ~
O
5 wherein Y'*'B is a bond;
R $ is an optionally substituted C1-Cgalkyl or an optionally substituted C2-C8alkenyl;
LB is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally . substituted heteroaryl, or heteroaralkyl;
W is alkyl or N;
R4, if present, is a hydrogen atom, alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
R5, if present, is a hydrogen atom or alkyl;
E is -YbE-NRdE-CO-LE-, wherein ybE is a bond, a C1-C6alkylene, or a C2-C6alkenylene;
RdE is a hydrogen atom, a Cl-C6alkyl, or C2-C6alkenyl; and LE is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl.
In a 25th embodiment of the first aspect which is also an embodiment of the first, fourth to sixth, twelfth, 13th, 17th to 20th, 22nd or 23`d embodiment of the first aspect the compound is represented by formulas (III) or (IV):
H H YN
Rya 0 Ry4 0 Y~ Yi I ~ I
Ry3 Rn RY3 Ry2 K (III) ic (IV) wherein Yl is N, CH or CF;
K is selected from XN or XN-j R3 is a hydrogen atom or methyl;
R'2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
Ry3 is a hydrogen atom, halogen atom, C1-C6allcyl, or C1-C6heteroalkyl;
Ry4 is a hydrogen atom or halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -YaF-NR E-CO-RdE-, -YaF--NR E-CO-LE-, -YaE-NR E-CO-NRaE-LE-, or -Y,,E-NRcE-CS-NRdE-LE-, wherein YaE is a bond or C1-C6alkylene;
R~E is a hydrogen atom, C1-C6alkyl, or C2-C6alkenyl;
RdE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl group;
LE is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl;
G, if present, is cycloalkyl, -YaG-CO-NRacRbG, -YaG_C_ReG, -YaG_S_ReG' _YaG_SO-R`G, or -YaG-SO2-ReG, wherein YaG is a bond or C1-C6alkylene;
RaG is a hydrogen atom or C1-C6alkyl;
RbG is a hydrogen atom or C1-C6alkyl; and ReG 1S C1-C6alkyl.
In a 26th embodiment of the first aspect which is also an embodiment of the -25L~
embodiment of the first aspect the compound is represented by formula (V):
H
Rs N N/ LE
H
Ry4 Y, Rvs RYl K (=) wherein Y', K, R3, RYZ, RY3, Ry4, and LE are as defined in 25h embodiment of the first aspect.
In a 27h embodiment of the first aspect which is also an embodiment of the 25th embodiment of the first aspect the compound is represented by formula (VI):
H
N
R J" LE
H
. . y Ry4 1 Y, Ry3 Ry2 -c (VI) wherein Y', K, R3, RY2, Ry3, RY4, and LE are as defined in claim 25.
In a 28th embodiment of the first= aspect which is also an embodiment of the 2411` to 271' embodiment of the first aspect Ry3 is a hydrogen atom.
In a 29th embodiment of the first aspect which is also an embodiment of the 2411 to 28I' embodiment of the first aspect wherein R2 is a hydrogen atom.
In a 3& embodiment of the first aspect which is also an embodiment of the first, fourth to sixth, ninth, tenth, twelfth, 13th, 17th, 215t, 22 nd or 23a embodiment of the first aspect the compound is represented by formula (VII):
H
N N
Ry4 I
y, E-G
K (VII) wherein Yl is N, CH or CF;
K is selected from ?'N ~\N
XN or XN-j _j RY4 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -YaE-CO-LE-, wherein YaE is a bond or C1-C6alkylene;
LE is heterocycloalkyl; and 10 G is alkylcycloalkyl, heterocycloalkylalkyl, aryl or heteroaryl.
In a 31st embodiment of the first aspect which is also an embodiment of the 30I' embodiment of the first aspect 15 R'4 is a hydrogen atom or halogen atom.
In a 32nd embodiment of the first aspect which is also an embodiment of the first to 31St embodiment of the first aspect wherein 20 the stereogenic center to which R3 is attached to is in the (R) configuration; and R3 is methyl.
In a 33`d embodiment of the first aspect. which is also an embodiment of the first to 32nd embodiment of the first aspect the compound exhibits an IC50 of 500 nM or less in a standard in vitro BK B 1 receptor-mediated assay.
In a first embodiment of the second aspect the problem underlying the instant application is solved by a compound, which is preferably a compound according to any one of the first to 33rd embodiment of the first aspect, which compound is selected from compounds 1 to 282 of Table 1.
In a first embodiment of the third aspect the problem underlying the instant application is solved by a pharmaceutical composition comprising one or more compounds according to any embodiment of the first and second aspect, optionally, at least one carrier substance, excipient and/or adjuvant.
In a second embodiment of the third aspect which is also an embodiment of the first embodiment of the third aspect,the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal therapeutic system, a suppository, or a pharmaceutical device.
In a first embodiment of the fourth aspect the problem underlying the instant application is solved by the use of a compound or of a pharmaceutical composition according to any embodiment of the first to third aspect for the manufacture of a medicament for the treatment and/or prevention of a disease or a condition.
In a second embodiment of the fourth aspect which is also an embodiment of the first embodiment of the fourth aspect the condition or disease is responsive to BK
BIR
modulation.
In a third embodiment of the fourth aspect which is also an embodiment of the first or second embodiment of the fourth aspect the condition or disease is selected from the group comprising inflammatory diseases, immunology disorders and pain.
In a fourth embodiment of the fourth aspect which'is also an embodiment of the third embodiment of the fourth aspect the inflammatory disease or immunology disorder is selected from the group comprising inflammatory bowel disease, rheumatoid arthritis, gouty arthritis, atherosclerosis and associated fibrotic conditions In a fifth embodiment of the fourth aspect which is also an embodiment of the third embodiment of the fourth aspect the pain is selected form the group comprising visceral pain, neuropathic pain, complex regional pain syndrome CRPS and inflammatory pain.
In a first embodiment of the fifth aspect the problem underlying the instant application is solved by a method for inhibiting binding of DAKD, KD and DABK to a BK B 1 receptor in vitro, the method comprising contacting the BK B 1 receptor with at least one compound or a pharmacologically acceptable salt, solvate, or hydrate thereof according to any embodiment of the first to third aspect under conditions and in an amount sufficient to detectably inhibit binding of DAKD, KD and DABK to the BK B 1 receptor.
In a first embodiment of the sixth aspect the problem underlying the instant application is solved by a method for localizing or detecting a BK B1 receptor in a tissue, preferably a tissue section, in vitro, comprising:
(a) contacting a sample of said tissue presumably containing the BK B 1 receptor with a detectably labeled compound according to any embodiment of the first to third aspect under conditions that permit binding of the compound to the BK B 1 receptor; and (b) detecting the compound bound to the BK B I receptor or detecting the binding of the compound to the BK B 1 receptor.
In a second embodiment of the sixth aspect which is also an embodiment of the first embodiment of the sixth aspect the compound is radiolabeled, fluorescence-labeled or luminescence labeled, or labeled with an antibody.
In a first embodiment of the seventh aspect the problem underlying the instant application is solved by a method for the treatment of a subject which is in need of such treatment, comprising the administration of a compound or of a pharmaceutical composition according to any embodiment of the first to third aspect.
It will be acknowledged by the person skilled in the art that any compound which is generated by any combination of the individual generic groups of formula (I) as disclosed herein shall be encompassed by the instant invention.
The compounds shown in the following Table 1 are embodiments of formula (I) according to the present invention.
Table 1:
Comp Comp Structure M+H+ Structure M+H+
ound ound N O N 1~O
~H \H OH
e V NN
NJ 436.1 7. ~ 414.1 O
H ~ O N~~-CF3 2. N 503.1 8. 456.1 O N O N
N~ 0 N N O
\ O H ~/ \=N H N
3. 460.2 9. N 436.1 O N O N
N O N O
O H ~\ CF3 O H /NN
4. - 502.1 10. NJ 438.1 O N O N~
H
N O N~ O Yl~ O H O H
5. N- 449.1 11. 462.1 O N O )6 N`j~~ O N~ O
~CF3 p H~Cf3 O H
6. OH 470.1 12. N N 506.1 Comp Comp Structure M+H+ Structure M+H;
ound ound H_~~ N 0 y\ N O
O H O H /\ CF3 13. N 439.0 20. N- 503.2 O N O N
N~ O N
N
O H CF3 O H ~\ Br 14. 570.1 21. 513.1 O N O N
N H O N~H~ F
~ O h-CF I s 15. F
~ 520.1 22. 426.2 O N O N
N O N O
N Y~A
O H~ O H
QcF3 16. ~N ~ 455.1 23. 508.2 O N O N
N N N
~ O H ~\ CF3 ~ O H H
17. - 520.1 24. F3C 517.1 F
O N O N
Cs HN ~
CF3 H \
N O H lc~7 N O O
18, 520.0 25. I~ cF, 585.1 F
O N O N
N~ O F N H S
~ ~
H QN' ~F O H -'( N_ 19. 434.1 26, 466.0 Comp + Comp +
Structure M+H Structure M+H
ound ound N~ O N~ O
O H ~\ F 0 H CI
27. ~ 470.1 34. 502.0 F ci O N O N
N O N O
N F
O H ~\ CF3 O H ~\ F
28. 520.1 35. 486.1 CI
O N O N
N O
O H o H/\
29. F 476.1 36 N H CHFZ 542.1 0 ~
N O N O
N
H
30. 477.1 H A 37. N CF3 560.1 ~
N O
O N
N`~ 0 H
n H`N N
YK-31. ~1-CI 469.1 38. ~ 506.1 O N
TT N
O N
N` ~ 0 H
H`N N 0 O oH ~
32. ~ r- _~ 435.1 N
39. N H CF3 574.2 O N
O N
N O
N
xo H ~ \ F
33. 452.1 Comp Structure M+H+ Comp Structure M+H+
ound ound N~O N0 1~ N
O
N~\ 485.2 40. - 580.1 47. O
Br O N O N
N O N O
~H 10~ \H -N
O CN O
41. - 477.1 48. 465.1 F
O N O N
N~ 0 N p 0 O H Y NN OY\H
42. NJ 434.0 49. N 460.2 N
O N O N
/
H
O
O H \ CF3 O H _ F
43. N- 505.1 50. ~ F 484.1 O N't' O N
N\ ~ O N` ~ 0 ~O( H \ CF3 ~O( H / CF3 44. - 522.1 51. 1 \ 436.1 ~ F CI
N` ` ~ 0 N 0 ~ N
O H /\ O H CF3 45. NJ 436.1 52 - 518.1 HO
O N O )3 HYV N 0 H~ O
N N
H O H ~\ CF3 46. 434.1 53 532.1 O\
Comp + Comp +
Structure M+H Structure M+H
ound ound N O N O
O H CF3 O H O\ M+
54. 501.3 61. +N-/ 479.2 /
N N
O H CF3 0 H Q_SCF, 55. 518.2 62. 534.2 F
O N O N
/
N~ O N~ 0 O H OH N O H /NN
56. 451.2 63. N 437.1 O N O N
N 0 NYK 0 yvt 'O H \ O N 0 H CF3 57. 1 ~ \ 494.1 64. 521.1 _O F
N O N O
O H N N i O H CF3 58. NJ 436.1 65. 504.1 O N O N
N N
O H 1\N F 0 H 1\N
59. NJ 450.2 66. NJ 454.2 rsl O N O N
N O N O
N yl~t 60. NJ 454.1 67. - 538.2 !s) F
O N O N
0s) Comp Structure M+H+ Comp Structure M+H+
ound ound Hy~ N O N~ O
F O H CF3 O H OCF, 68. ~/ - 538.2 75. ~/ - 552.1 F CI
O N O N
H N N~ O
rw 69. o H 410.1 76. o H N=/ 436.1 (s~
O N O N~
H O
\ O H. i NN H
424.1 0 N
70. N 77. N 422.1 O N~
O N
H
N
0 H N p O
~
~\N
71. NJ 410.1 F 0 H CF3 78. 507.1 O N
O N
H O
N
O H ~ N Hy~ O
72. ~J 466.3 F o H/\ cF, 79. 524.1 O N" v F
O N
H O
N
O N \ S H
O
/ .
73 _ CF3 550.1 F o H CF580. 521.1 O N
O N
H O
N
0 H ~\ SO CF3 N N
74. 566.1 0 H CF, 81. 491.1 O N
N'J"
Comp Structure M+H+ Comp Structure M+H`
ound ound H O N O
N (w HN
82. 503.2 89. oF' 538.2 F
O N (s) O N
(R) N O N O
fR) N
H ~ F 0 H CF3 83. N'o 467.1 90. 'Irl 538.3 (s) F
O N O N
(w H O N O
N (R) HN
O H ~\ OH F O
84. ~~. - 506.0 91. - cF' 526.2 O NI~ O N
H
O O
N~ (sN HN
O H 9,_OH F , O
85. 516.0 92. cF~ 538.1 O )611 O N
~
N ~) N
F 0 H ~\ CF3 F ~ 0 H CF3 86.. - 512.1 93. 521.1 N F N (s) O " O
(R) N O NH O
N N~
~ \
87. H CF3 F - 524.3 O
94. 372.1 F
N
N N
88. F 507.3 95. i - 538.0 fs) F
O N O N
.~ js) Comp Comp Structure M+H` Structure M+H' ound ound H O N O
N
(R) N
96. 538.0 102. - 520.2 F
~ (S) F
p N~ O N
N O N~ O
N (R) N
97. N 537.2 103. ~ ~ - 520.3 F
(s) ' fR) O N O N
(R) (R) H N
N O (R) N YH O H / CF, cl / o cF, 104. N 503.2 98. F 554.2 o N(s) (S) , O N `, (S) (R1 H
N O
(R N
Hy~ N 0 O H CF3 cl o H 105. 503.2 ~. / \ CF3 ~ ' (R) 99. F 554.0 o N
(s) (R1 O N ~
I ~N
(S~ N N
~N
~ NJ
F / O
N 106. 0 517.3 CI H O N
F 554.0 100.
t-~(R
) H
N
N O N\
(R) N 107. 0 500.2 101. 520.2 o N
(s/ F
O N
tR) Comp Comp Structure M+H; Structure M+H+
ound ound N H O
H N ^N HN
f O
N~ N 114. N 438.2 108. ~ 0 498.2 N-O N
O )1 H
HN
N N\ O
N I/ N 115. N N 426.1 109. ~ 0 475.3 o N'~
O N
O
N ) ~, CF3 fw N
H N\ p H ~ ~
N 116. 534.1 110. p 492.2 0 N
N fs O
CF
(R) r a H N O 'H ~ ~
rN 117. ~ 534.1 F F
111. ~/ 0 515.2 o N
O N
/ N H VF F
fRlv (~~
N N\
H F N 118. o 550.3 112. 516.2 O
p N~ N
H
H N O
N N\ N N OHN
F 119. CF3 548.3 113. p 537.3 0 N~ N F
Comp Structure M+H+ Comp Structure M+H+
ound ound O H
N
N \ CF3 r~1 OH
\ N I/ F O
120. F 534.0 126. 349.1 (s) O N
O N
(R) H
H N
N HN OH
rw O F 0 0 127. 377.1 121. 562.1 F O N
O N
N~ N \ F
5JN)LgCF3 F /
128. 488.1 122. F 508.1 F
/ NI N~ OH
N \ F 0 H
F \ O \
123. 452.2 129. cF' 536.0 O N
N N
F F
O N F ~H
124. 406.0 130. 484.0 N N
O O
H
N
OH N N \ CF3 \ O F O H I/
125. 1331.1 131. 520.0 Comp Comp +
Structure M+H+ Structure M+H
ound ound 132. 503.1 138. 405.1 ~ 1 6 NIN S~
N ~ H
F O ~ // N
F 0 H cF, 139. 459.1 133. 444.1 0 N
O N
H
N O 0 F NH CF3 140. F H -S.N.N
474.0 134. ct 554.0 0 N
. H O
N lf-K-F O H Vo N~ o` 141. Br 521.9 N
O H I~ O N
135. 425.2 O
O N N
N
0 142. 473.0 JR~ H 0 N
136. F 550.1 H O
N
O
N H
F
O ~
0 143. 0'N 456.9 H
N
137. 510.0 Comp Comp Structure M+H+ Structure M+H`
ound ound HO
N~ N
N.N CF3 F O H ~ H I/
144. 'N~o 471.0 150. F 495.1 O N N
O
H O
N
N H NN ~ CF3 F O H ~ H I/
145. 0/ N 443.0 151. F 509.1 OH
N O
H O O
F O HN
146. A",-ND)o 457.0 (RNH O F F
o N 152. I~ t 534.2 F
F
N N1/` O~
N II H
147. F3C O H O 588.2 0 N
153. 533.2 O N ~ J~/
/H_ O
H O N~N F
N N F O H
F o H
N 154. 521.2 148. ,r ci 537.1 O N
N O N
N F O H N
F 0 H 155. 442.1 149. 517.2 O N
Comp Structure . M+H + Comp Structure M+H+
oand ound NH
N H CF
F 0 ~ ~O N~
456.2 HN
156.
F ~
162. 510.2 O N
O~
H n O N
N
II N
157. 469.2 NH -N CF3 O N
HN
F F
163. 527.2 N Y~4 F \ O H ~\ F O N
158. 495.2 NC
O N N O
N~
F O H
N 164. SYN 474.2 ~H NH2 N O N
159. 467.2 O N NH4\ CF3 ~Q ~ +r F N 0 H F 165. F \.., 537.2 160. cI 504.2 o N
-O
' + N
N~Ni~ ^ /CI ~
F O H (171 NJ NH 1~ CF3 161. 487.2 o 0 HN
0 N 166. F " 537.2 oN
Comp + Comp +
Structure M+H Structure M+H
ound ound CI H
O ~ N~N" `N
~ ~ F 0 H , J
NH N
173. /
440.2 167. 486.2 0 N
o \I
N~ O F F
F \ O H F
~
0 174. / N- 545.2 N~ F
F 0 H I y O N
168. / F
506.2 O N N O F F
O F O H I/
H F
N
YVN F 175. I/ Br H 598.1 F \ O F ~ /
169. F 524.2 o N
O N
P
H O N O
F \ O ~O
170. 499.3 HN
176. F == 443.2 O N
O
N I \ \ - ~/
NY"
F 0 H N,N ~
S N
171. 504.2 HN-~~
>==O
HN
177. F 448.2 H O
N
F O H ~ N O
\ N N- ( 172. 454.2 Comp + Comp +
Structure M+H Structure M+H
ound ound H O F F
NY7N)\
N CI O H F
6 183. 537.2 O NH
O N
178. HN 474.2 F
~
M N F
N 184. 495.2 O N~~
O
N
N N
O NH F 0 H N~ oj~~, 185. 530.3 179. HN 462.2 ~/ ~
H_ O N
F
(i H I \ H
186. F 527.2 H O F F
O
N~H \ F ~
180. 511.2 0 0 O ~j_ O H
F
187. F 541.3 H O F F
N O N
N
181. 537.2 H o 0 NY `N NI~
0 N~ F 0 H H
188. F 541.3 .,, F
CI H N 0 182. 511.2 N
O N \ N
189. 510.2 Comp ~ Comp ,.
Structure M+H Structure M+H
ound ound H-jr7 O 0 O
N N N F
F O H ~ NH H F
190. N 510.2 F - F
195. F 556.2 F
O N
O~~
1~-(~ /-NH
N~H N H
N N~
O F O HN
F I \ N~
191. 501.2 196. 510.3 F
O N
O N
O
H N g N I\ F
F O / O H N
197. 473.2 192. 494.3 O N
H O
N
N
H I
F 0 ~ OH
NH H F F 198. 501.2 F
193. F N 539.2 o N
F
O N N ~
N N
F \ O H S`N
H
199. 460.2 N HI ~
N
F I O NO O N
194. 484.2 O N H O F
N F
~H
200. OH 504.2 Comp + Comp Structure M+H Structure M+H+
ound ound N H O F F
N ~N Nu N, N
F O H~ i II H F
N N F 0 ~
N
H
201. 483.2 207. 538.2 O N N
O
F NY7H ~~ H^ H O F F 0 N NYN'N/~\
202. 524.3 F o H ~~ F
N
o N 208. 0 528.2 N` ii /
F \ i0( H I /
203. 523.3 F
NN, H I\ F
O N y F O
N
I
0 209. o" 514.2 N y NN~N N
i J
F O H
NNH
204. 460.2 O N H O F
\
NyNk NI F
F 0 H +' 0 210. ~ o_ 540.2 H
N~N, N N
N NH
205. 486.3 O F F
O N H N,~
F O H IN F
211. 524.2 H O F F
N N. 0 N
F
206. 512.2 O N
"
J
Comp Structure M+H+ Comp Structure M+H+
ound ound O N~ O
N~N O N
H ~ ~N F \ O H N
212. F o /P 476.2 217. N (N 523.3 O N
O N
H O
N
I
NH H
F
N\ N 218. O H 511.3 H
213. F 0 o 501.2 N H
O
H~ O
N
~
N 0 H I N" 'N^
219. H 497.3 F F
N
F
N
H
F
N~ H VF
F
N N N,N 214. F O H o 539.2 O H F 220. F 541.2 N
N
F
F F VFF
H N~N.
N
)rN
N 215. F O H O 556.2 F O H F 221. i F 515.2 O N O N~
N O F F F N_ F \ O H ~~N F O
F N
216. N={ N-~ 511.3 HN~
H 222. F HN O 586.2 I \ .
N
O
Comp + Comp +
Structure M+H Structure M+H
ound ound H
N~NN F N~N F
V
H F O H
223. F 541.2 228. F 506.2 O N O N
HN-N
O ~ ~N
r% \ N 0 HN--i H~O ~-~ O
F F F HN 229. F NH -' 501.2 224. F 539.2 F
F
N
N O
O
O N
N
O
H
-~
HN HN
225. F F F F 539.2 NH
~ I_F 230. 491.2 F
N
O N
O
F
O
N !
F F NH NH H
F
226. F - 556.2 F o H o~
\~
0 231. 499.3 N
N
O
F F
F
N' O
N F
O _ F F
227. F NH 555.2 232. F N 525.2 F
O N
N
Comp + Comp Structure M+H Structure M+H+
ound ound N F F
N F F
CI O H J\ N
233. I r N~ F 538.2 0 O N ~-N
239. HN 484.2 F n O O
234. L N ~~ HN 0 N " 428.2 N
N ~
o-N~ O N, H~ \ I
F O O
235. S1'N 493.1 CI NH
CI ~
O N 240. F HN 503.2 =,õ
H O F F
N N, O N ~ H ~ , F N
236. F 523.2 H O
O N N N
F H~ , ~
241. N 489.2 N F
O N
F
237. cl 522.2 O F
N, F
O N N
F O H F
N- 242. F 555.2 / CI
\ N
O
HN
~O
HN
238. F 276.2 H O F F
N
~ \ N ~ F
p 243. F 528.2 N 0 N~\
Comp + Comp +
Structure M+H Structure M+H
ound ound N N, &C, N , CF, F O H/F F \ N o H I~
N 250. I N 497.9 244. 554.2 /
J
H O
H 0 NYN,N CF3 NY"N ~ F F 0 H N
F 0 H 251. 511.9 F F
245. ci 540.2 O N
O N J
H O
N N, N CF3 H O F F (R) Y H ~
/
N F F ~ 0 CI O H 252. F 500.9 246. F 554.2 O N
O N-~ J
N ~ F F H ~ 0 N ~ F N N2N CF3 CI 0 H ~ N F ~) O H I/
247. 512.2 253. F 514.9 0 J~\ O N'~
H O F F
N N.N
Y H F NiN ` O
F 537.2 ,N~
248. 0 NH
a0:
N o 254. NH 503.0 H 0 F F F /\ F
N
H O
249. 1 F 520.0 --1 O N (s) rw Comp + Comp +
Structure M+H Structure M+H
ound ound ('' o N~~/ ~ F F
NH 0 ~N`N \
F
O NH H /
(RJ
255. NH 500.0 260. F \ F 554.9 F ~ F
O~ I /
(S) ~ O N
N
(R) H F
N N. O F F
(w Y H V F O N.N
256. cl o 530.9 ~ H I N F
261. F 537.9 F too') o ~ )V OY N. N F NH H
F F
(RJ F~-F F 568.9 0 y NF
V 257.
N
NH H O N(S) 262. F F 595.0 (R) I
O F F (5f N
/
O yHN \ I F (RJ
NH ~ F H O
258. ci (R) 556.9 "y N,N ~ CF3 CI "'N O H
263. F 557.9 O O N
6(R) ) H O O N
N NY0 N' ~CF3 \N CI H ~ r 259. 496.1 264. :" " 540.9 Comp + ComP +
Structure M+H Structure M+H
ound ound H O H p N N, \ CF3 N N, '"
~ Y H
H
265. pl N p F 531.8 271. CI I~ p N I"i 504.0 0 N-\ O N--'-O F
NuN,N CF3 H~ V
F
CI IOI H N N N, 266. " 514.9 (w Y " H 272. F o 577.0 O N'\ F
~ (s) O N
H O
rw N \ F
Y N \
F O H r H 0 F. 267. CF3 565.8 tom CI H N F
~ CF 273.
539.9 ) O FF O\/N, N VF 'N( H H H O
(R) N N, 268. N F 541.9 CI \) o I i I"~
274. " f"+~ 530.0 (S) (5) O )v,) 0 N
(F) F O N,N CF3 O N,N ~p`
N
NH H ~/ NH H
(R) (R) 269. F( N F 515.8 275. ol I\ 491.9 r N O N rs) J (w O N-~
O N, ~ H 276. F CI N F 567.8 rw N \ /
270. F N 498.8 CF' ~
O N
J
Comp +
Structure M+H
ound O F F
OYN.N
F
NH H
277. N F 498.0 O NI~~
ON, Y , F
NH H \ I
278. I~ N F 524.0 i (s) O N
(R) O,N
~N /
F
NH H \
(R) 512.0 279. N F
O N--l H ~ F F
N N, (R) O H \ I F
280. ~ F 538.0 (s) nv H VF
NuN.
N I' H CI 0 281. F 517.0 o N~\
H ~ F F
N N.N \
CI O H I/ F
282. F 543.0 B 1 R antagonists provided herein exhibit high activity on human B 1 R, i. e., an inhibition constant (IC50) for competition with binding of labelled DAKD to human B1R of less than 5 micromolar or very high activity on human 131R, i.e., an IC50 for competition with the binding of labelled DA.KD to human B 1 R of preferably less than 50 nanomolar. In certain embodiments, such antagonists exhibit a high activity on B I R of species other than human, i.e., an IC50 for competition with binding of labelled DAKD to rabbit B 1 R
and cynomolgus monkey of less than 5 micromolar.
The activity and more specifically pharmacological activity of the B1R
antagonists according to the present invention can be assessed using appropriate in vitro assays. For instance, the IC50 values of the antagonists according to the present invention for B I R may be determined via a radioligand binding assay, such as the assay provided in Example 24, which is thus an embodiment of a standard in vitro BK B1R-mediated assay. Inhibitory effects of the B 1 R antagonists provided herein for B 1 R may be determined, for example, via calcium mobilization assay, such as the assay provided in Exarnple 25.
Preferred compounds of the invention have an IC50 (half-maximal inhibitory concentration) of about 5 micromolar or less, still more preferably an IC50 of about 500 nM or less, or even 50 nM or less, even more preferably an IC50 of about 10 nM or less, or even 1 nanomolar or less in the assays mentioned above.
The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one B 1 R modulator as described herein, in combination with a physiologically acceptable carrier or excipient. Processes for preparing such pharmaceutical compositions are also provided. Such compositions are particularly useful in the treatment of B 1 R-mediated diseases as described below.
These and other aspects of the present invention will become apparent upon reference to the following detailed description.
Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified.
Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include i1C,13C, and 14C.
Compounds according to the formulas provided herein, which have one or more stereogenic centers, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%; 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
Certain compounds are described herein using a general formula that includes variables such as, e.g., A, Rl, Ra, W, Y, Z. Unless otherwise specified, each variable within such a formula is defmed independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, the group may be unsubstituted or substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i. e., compounds that can be isolated, characterized and tested for biological activity.
A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include 5 mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, 10 formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CHz)n-COOH where n is any integer from 0 to 4, i.e., 0, 1, 2, 3, or 4, and the like. Similarly, pharmaceutically acceptable 15 cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting 20 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
25 It will be apparent that each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.
30 A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, i.e., =0, then 2 hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C(=0)- and a loss of aromaticity. For example a pyridyl group substituted by oxo is a pyridone.
The expression alkyl preferably refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms, for example an ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two, more preferably one, double bond(s) and alkynyl groups have one or two, more preferably one, triple bond(s).
Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced each independently of the others by a halogen atom, preferably F or Cl, such as, for example, a 2,2,2-trichloroethyl or a trifluoromethyl group.
The expression heteroalkyl preferably refers to an alkyl, alkenyl or alkynyl group, for example heteroalkenyl, heteroalkynyl, in which one or more, preferably 1, 2 or 3 carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom, preferably oxygen, sulphur or nitrogen.
The expression heteroalkyl furthermore preferably refers to a carboxylic acid or to a group derived from a carboxylic acid such as, for example; acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, alkylcarbamoylalkyl, alkylcarbamoyloxyalkyl, alkylureidoalkyl, or alkoxycarbonyloxy.
Examples of heteroalkyl groups are groups of formulas -S-Ya-L, -S-Ya-CO-NRaRb, -Ya-NR -CO-NRaRb, -Ya-NW-CO-O-Rd, -Ya-NRc-CO-Rd, -Ya-NR -CO-NRd-L, -Ya-NR -CS-NRd-L, -Ya-O-CO-NRaRb, -Ya-CO-NRaRb, -O-Ya-CO-NRaRb, -Ya-Ne-CO-L2 -Ya-O-CO-O-R , -Ya-O-CO-Rc, -Ya-O-Rc, -Ya-CO-L, -Ya-NRaRb, Rc-S-Ya-, Ra-N(Rb)-Ya-, Rc-CO-Ya-, R -O-CO-Ya-, Rc-CO-O-Ya-, Rc-CO-N(Rb)-Ya-, Ra-N(R)-CO-Ya-, Rc-SO-Ya-, W-SO2-Ya-, -Ya-NR -SOZ-NRaRb, -Ya-SO2-NRaRb, -Ya-NR -SOZ-Rd, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-C(=NRa)-N(R )-Ya-, R -S-CO-Ya-, R -CO-S-Ya-, R -S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, R -S-CO-O-Ya-, R -O-CO-S-Ya-, R -S-CO-S-Ya-; wherein Ra being a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to Rb to form a 4-to 10-membered cycloalkyl or heterocycloalkyl; Rb being a hydrogen atom, a C1-C6alky1, a C2-C6alkenyl or a C2-C6alkynyl , or taken together with Ra to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; Rc being a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl; Rd being a hydrogen atom, optionally substituted C1-Cgalkyl, optionally substituted C2-C8alkenyl or optionally substituted C2-C8alkynyl; L being a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and Ya being a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene group; each heteroalkyl group containing at least one carbon atom and it being possible for one or more hydrogen atoms to have been replaced by fluorine or chlorine atoms. Certain compounds are described herein using formulas that include the variables captioned above which variables carry a superscripted B, E or G as an extension, for example, LB, YaE, or R G. Unless otherwise specified, the definition of these variables corresponds to the above definition of the respective variable, i.e. LB and LE are defined as L; YaB, YaE, and YaG are defined as ya; RcB, R E, and RcG are defined as Rc; etc. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethyl-amino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diiso-propylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, isobutyrylamino-methyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups. An example of a heteroalkylene group is a group of formulas -CH2CH(OH)- or -CONH-.
The expression cycloalkyl preferably refers to a saturated or partially unsaturated cyclic group that contains one or more rings, preferably 1 or 2, containing from 3 to 14 ring carbon atoms, preferably froin 3 to 10, more preferably 3, 4, 5, 6 or 7, ring carbon atoms. In an embodiment a partially unsaturated cyclic group has one, two or more double bonds, such as a cycloalkenyl group. The expression cycloalkyl preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NHZ, =NH, CN, CF3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of a cycloalkyl group is a cyclo-propyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbomyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclo-hexyl or cyclohex-2-enyl group.
The expression heterocycloalkyl preferably refers to a cycloalkyl group as defined above in which one or more, preferably 1, 2 or 3, ring carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom, preferably oxygen, sulphur or nitrogen. A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from.3 to 10, more preferably 3, 4, 5, 6 or 7, ring atoms.
The expression heterocycloalkyl preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or NO2 groups. Examples are a piperidyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also a lactam, a lactone, a cyclic imide and a cyclic anhydride.
The expression alkylcycloalkyl preferably refers to a group containing both cycloalkyl and also an alkyl, alkenyl or alkynyl group in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynyl-cycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two ring systems having from 3 to 10, preferably 3, 4, 5, 6 or 7, carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms, the cyclic groups being optionally substituted.
The expression heteroalkylcycloalkyl preferably refers to alkylcycloalkyl groups as defmed above in which one or more, preferably 1, 2 or 3, carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom, preferably oxygen, sulphur or nitrogen. A heteroalkylcycloalkyl group preferably contains 1 or 2 ring systems having from 3 to 10, preferably 3, 4, 5, 6 or 7, ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are allcylheterocycloalkyl, heterocycloalkylalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, hetero-alkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being optionally substituted and saturated or mono-, di- or tri-u.nsaturated.
The expression aryl or Ar preferably refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10, more preferably 6, ring carbon atoms. The expression aryl (or Ar) preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, CN, CF3 or NO2 groups.
Examples are a phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
The expression heteroaryl preferably refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10, more preferably 5 or 6, ring atoms, and contains one or more, preferably 1, 2, 3 or 4, oxygen, nitrogen, phosphorus or sulphur ring atoms, preferably 0, S or N. The expression heteroaryl preferably refers 10 furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, NH2, =NH, CN, CF3 or NO2 groups. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, 3-pyrazolyl and 15 isoquinolinyl.
The expression aralkyl preferably refers to a group containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-20 cycloalkyl and alkylarylcycloalkenyl groups. Specific -examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 H-indene, tetralin, dihydro-naphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indan.
An aralkyl group preferably contains one or two aromatic ring systems, 1 or 2 rings, containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups 25 containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or .6 ring carbon atoms.
The expression heteroaralkyl preferably refers to an aralkyl group as defined above in which one or more, preferably 1, 2, 3 or 4, carbon atoms have been replaced each 30 independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulphur atom, preferably oxygen, sulphur or nitrogen, that is to say to groups containing both aryl or heteroaryl and also. alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A
heteroaralkyl group preferably contains one or two aromatic ring systems, 1 or 2 rings, containing from 5 or 6 to ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of 5 those carbon atoms having been replaced each independently of the others by oxygen, sulphur or nitrogen atoms.
Examples of heteroaralkyl groups are arylheteroalkyl, arylheterocycloalkyl, arylhetero-cycloalkenyl, arylalkylheterocycloalkyl, atylalkenylheterocycloalkyl, arylalkynylhetero-10 cycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylhetero-cycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkyl-heterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl, heteroalkylheteroarylalkyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroiso-quinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.
The expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl refer to groups in which one or more hydrogen atoms of such groups have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or groups.
The expression "optionally substituted" as used in conncetion with any group refers to a group in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or NO2 groups. This expression refers furthermore to a group in which one or more hydrogen atoms have been replaced each independently of the others by an unsubstituted C1-C6alkyl, unsubstituted C2-C6alkenyl, unsubstituted C2-C6alkynyl, unsubstituted C1-C6hetero-alkyl, unsubstituted C3-Clocycloalkyl, unsubstituted C2-C9heterocycloalkyl, unsubstituted C6-Cloaryl, unsubstituted C1-C9heteroaryl, unsubstituted C7-ClZaralkyl or unsubstituted C2-Cllheteroaralkyl group.
The expression "halogen" as preferably used herein means fluorine, chlorine, bromine, iodine.
As used herein a wording defming the limits of a range of length such as, e.
g., "from 1 to 5" means any integer from I to 5, i. e. 1, 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned. is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
The therapeutic use of compounds of formula (I), their pharmacologically acceptable salts, solvates and hydrates and also formulations and pharmaceutical compositions containing the same are within the scope of the present invention. The present invention also relates to the use of those compounds of formula (I) as active ingredients in the preparation or manufacture of a medicament:
The pharmaceutical compositions according to the present invention comprise at least one compound of formula (I) and, optionally, one or more carrier substances, excipients and/or adjuvants. Pharmaceutical compositions may additionally comprise, for example, one or more of water, buffers such as, e.g., neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates such as e.g., glucose, mannose, sucrose or dextrans, mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
Furthermore, one or more other active ingredients may, but need not, be included in the pharmaceutical compositions provided herein. For instance, the compounds of the invention may advantageously be employed in combination with an antibiotic, anti-fungal, or anti-viral agent, an-anti histamine, a non-steroidal anti-inflammatory drug, a disease modifying anti-rheumatic drug, a cytostatic drug, a drug with smooth muscle activity modulatory activity or mixtures of the aforementioned.
Pharmaceutical compositions may be formulated for any appropriate route of administration, including, for example, topical such as, e.g., transdermal or ocular, oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular such as, e.g., intravenous, intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilizate. Formulation for topical administration may be preferred for certain conditions such as, e.g., in the treatment of skin conditions such as bums or itch.
Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and . palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as, e.g., corn starch or alginic acid, binding agents such as, e.g., starch, gelatin or acacia, and lubricating agents such as, e.g., magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as, e.g., calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as, e.g., peanut oil, liquid paraffm or olive oil.
Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as, e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as, e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as, e.g., arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions may also be in the form of oil-in-water emulsions.
The oily phase may be a vegetable oil such as, e.g., olive oil or arachis oil, a mineral oil such as, e.g., liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums such as, e.g., gum acacia or gum tragacanth, naturally-occurring phosphatides such as, e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as, e.g., sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as, e.g., polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and/or flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene 5 glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
Compounds may be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye. Formulations for topical 10 administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols such as, e.g., ethanol or isopropyl alcohol or glycerin; glycols such 15 as, e.g., butylene, isoprene or propylene glycol; aliphatic alcohols such as, e.g., lanolin;
mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols including oils, such as, e.g., mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials, both 20 non-volatile and volatile; and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
25 Examples of such components are described in Martindale The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
A topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches. The physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the fmal product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the fmal product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffm, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents such as, e.g., witch hazel, alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
An example of a suitable topical vehicle for formulation of a gel is:
hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%);
propylene glycol (5.1%); and Polysorbate 80 (1.9%). An example of a suitable topical vehicle for formulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%); Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
Typical modes of delivery for topical compositions include application using the fmgers;
application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying including mist, aerosol or foam spraying; dropper application; sprinkling;
soaking; and rinsing. Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration as a transdermal patch.
A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. Such formulations are particularly useful for the treatment of asthma or other respiratory.conditions. For inhalation formulations, the compounds provided herein may be delivered via any inhalation methods known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered via an. aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
Pharmaceutical compositions may also be prepared in the form of suppositories such as e.g., for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Pharmaceutical compositions may be formulated as sustained release formulations such as, i.e., a formulation such as a capsule that creates a slow release of modulator following administration. Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively. constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
For the prevention and/or treatment of diseases mediated by BK or analogues thereof, the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements. Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day, about 0.5 mg to about 7 g per patient per day. The daily dose may be administered as a single dose or in a plurality of doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, i.e. other drugs being used to treat the patient, and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
B 1 R antagonists of formula (I) according to the present invention may be used preferably 5 as antagonists of B 1 R in a variety of applications, both in vitro and in vivo. B 1 R antagonists according to the present invention may be used to inhibit the binding of BK B
1 R ligands such as, e.g., DAKD, to B1R in vitro or in vivo. BK B1R antagonist(s) provided herein are preferably administered to a patient such as, e.g., a human, orally or topically, and are present within at least one body fluid or tissue of the patient while modulating BK B
1 R activity.
10 Accordingly, the present invention further provides methods for treating patients suffering from conditions responsive to B 1 R modulation as mentioned above. As used herein, the term "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms, or therapeutic, i.e., after the onset of symptoms, in order to 15 reduce the severity and/or duration of symptoms. A condition is "responsive to B 1 R
modulation" if modulation of B 1 R activity results in alleviation or curing of the condition or a symptom thereof. Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, with dosages as described herein.
Due to the involvement of the bradykinin B 1 receptor in various diseases, the antagonists according to the present invention are effective in the treatment and/or prevention of a condition or a disease responsive to BK B 1 R modulation as is apparent from the prior art and in particular from references recited herein. Animal models of these diseases are generally well known in the art and may be used to evaluating compounds of the present invention for their potential utilities. Apart from that, the compounds according to thepresent invention are also useful in diagnosis of such diseases and other applications including, but not limited to, their use as research tools in vivo and in vitro.
Compounds of this invention are antagonists of the BK B1R and as such are useful in the treatment and prevention of diseases and conditions mediated through the BK
receptor pathway such as inflammation, immunology disorders and pain. The compounds are preferably effective in the treatment or prevention of inflammation such as, but not limited to, persistent or chronic inflammatory diseases, immunology disorders, autoimmune diseases, neurogenic inflammation, inflammation associated edema and fibrosis. This includes but is not limited to gastrointestinal inflammation, septic shock, diseases of the skin, diseases of the respiratory pathway and vasculopathies. The compounds are preferably also effective in the 'treatment or prevention of pain such as chronic pain, inflammatory pain, visceral pain and neuropathic pain. This includes but is not limited to complex regional pain syndrome (CRPS).
It is within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
In the following the various diseases and conditions that are responsive to B
modulation and the use of the compounds according to the present invention in specific methodology and diagnostics are further specified.
Inflammatory Diseases and Immunology Disorders Within the present application the term "inflammatory diseases" preferably encompasses, but is not limited to, disorders such as acute-phase reaction, local and systemic inflammation and inflammation caused by other diseases whatever type, etiology or pathogenesis and caused by those inflammatory diseases specified within this application.
Within the present application the term "immunology disorders" preferably encompasses, but is not limited to, disorders such as hyperesthesia, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodelling, myasthenia gravis, immunosuppression, immune-complex diseases, over- and underproduction of antibodies and vasculitis.
Due to the involvement of the bradykinin B1 receptor in various diseases, the BI
antagonists according to the present invention are preferably effective in the treatmentlprevention of a condition or a disease responsive to BK B1R
modulation as is i.a.
apparent from the references cited herein. Accordingly, the compounds according to the invention are effective in the treatment/prevention of inflammatory diseases such as but not limited to inflammatory bowel disease including Crohn's disease and ulcerative colitis (Stadnicki et al., Am. J. Physiol. Gastrointest Liver Physiol. 2005, 289(2), G361-6; Devani et al., Am. J. Gastroenerol 2002, 97(8), 2026-32; Devani et al., Dig. Liv.
Disease 2005, 37(9), 665-73), irritable bowel syndrome, enterocolitis, liver diseases, pancreatitis, gall bladder diseases, smooth muscle relaxants for the treatment of spasms of the gastrointestinal tract or uterus. They may also be used in kidney disease like nephritis, bladder disease like cystitis, interstitial cystitis, eye diseases like uveitis, retinitis, glaucoma, and ear diseases such as otitis media. They may also be used in inflammatory skin diseases such as psoriasis, eczema, atopic diseases, dermatitis and itching. The compounds are effective in joint and bone diseases such as juvenile or adult onset rheumatoid arthritis and gouty arthritis (Cassim et al., Pharmacol.
Ther. 2002, 94, 1-34; Sha.rma et al., Exp. Toxic Pathol. 1994, 46, 421-433;
Brechter et al., Arthr. Rheum. 2007, 56(3), 910-923), ankylosing spondylitis, adult onset or pediatric onset like systemic onset juvenile idiopathic arthritis, Still's disease, psoriatic arthritis and osteoarthritis. The compounds are also effective in edema associated with bums, sprains or fracture, cerebral edema, closed head injury and angioedema. They may be used to treat immunology disorders like diabetic vasculopathy, type I diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic vasculopathy, post capillary resistance or diabetic syndromes associated with insulits such as, e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion. Additionally they may be used in CNS
disorders like multiple sclerosis, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, Parkinson's disease. They may also be used in cardiovascular disease such as congestive heart failure, myocardial infarct, systemic inflammatory response syndrome (SIRS), ischemia-reperfusion injury and atherosclerosis (Raidoo et al., Immunopharmacol 1997, 36(2-3), 153-60; McLean et al., Cardiovasc. Res. 2000, 48, 194-210).
They may also be used in vascular disorders like vasculitis, septic shock, antihypovolemic and/or anti-hypotensive agents, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder. Furthermore the compounds may be used to treat fibrotic diseases such as but not limited to pulmonary fibrosis, renal fibrosis, liver fibrosis, progressive sclerosis and recurrent stricture formation in Crohn's disease (Goldstein et al., J Biol. Chem. 1984, 259(14), 9263-8; Ricupero et al., J. Biol. Chem.
2000, 275(17), 12475-80; Romero et al., J Biol. Chem. 2005, 15, 14378-14384).
They are also effective in disorders of the respiratory pathways in asthma, atopic or non-atopic asthma, occupational asthma, exercise-induced bronchoconstriction, bronchitis, pneumoconiosis including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabaccosis and byssinosis, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, pneumonia, allergic rhinitis, vasomotor rhinitis and pleurisy.
These compounds according to the present invention may also be used to treat auto-inflammatory diseases such as familial Mediterranean fever (FMF), tumor-necrosis factor receptor associated periodic syndrome (TRAPS), neonatal onset multisystem inflammatory disease (NOMID), familial cold autoinflammatory syndrome (FCAS) including familial cold urticaria (FCU), pyogenic arthritis pyoderma gangrenosum acne (PAPA) syndrome and Muckle-Wells disease.
Pain Within the present application the term "pain" preferably encompasses, but is not limited to, centrally and peripherally mediated pain, vascular pain, visceral pain, inflammatory mediated pain, neuralgic pain, referred pain, nociceptive pain, reflectory pain, psychosomatic pain, acute pain such as caused by acute injury, trauma or surgery of bones, muscle, tissue, soft tissue, orRans, pain after insectbites, post-stroke pain syndrome, post-surgery pain, progressive disease related pain and chronic pain (Calixto et al., Br. J.
Pharmacol. 2004, 143, 803-818; Chen et al., Expert Opin. Ther. Targets 2007, 11(1), 21-35; Porreca et.al., J.
Pharmacol. Exp. Ther. 2006, 318(1), 195-205; Ferreira et al., J. Neurosc.
2005, 25(9), 2405-12; Conley et al., Eur. J. Pharm. 2005, 527(1-3), 44-51; Levy and Zochodne, Pain 2000, 86(3), 265-71; Yamaguchi-Sase et al., *Inflamm. Res. 2003, 52(4), 164-9).
The compounds according to the present invention are preferably also effective in the treatment and/or prevention of pain including but not limited to inflammatory pain of various origins such as rheumatoid arthritis or gout, visceral pain as pancreatitis, interstitial cystitis, renal or gall bladder colic, neuropathic pain as postherpetic neuralgia, complex regional pain syndrome, phantom limb pain, root avulsions, trigeminal neuralgia, painful traumatic mononeuropathy, painful polyneuropathy, vulvodynia, central pain syndromes potentially caused by any lesion at any level of the peripheral and/or central nervous system, postsurgical pain syndromes as postmastectomy syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain as muscular injury and fibromyalgia, perioperative pain as from general surgery, chronic pain, dysmennorhea as well as pain associated with angina. Additionally these compounds are preferably effective against back pain, headache, cluster headache, migraine including prophylactic and acute use, hyperalgesia, and fever.
Furthermore, compounds of the invention are useful as analgesic agent for use during general and monitored anesthesia.
Diagnostic and further applications The present invention also provides methods for localizing or detecting a B 1 R in a tissue, preferably a tissue section, which methods involve contacting the tissue sample presumably containing B1R with a detectably labelled compound according to the present invention under conditions that perrnit binding of the compound to the B1R and detecting the bound compound. Such methods and their respective conditions are known to those skilled in the art and include, for example, the radioligand binding assay disclosed in Example 24.
The present invention also provides methods of inhibiting the binding of DAKD
or any other B1R ligand to a B1R which methods involve contacting a solution containing a B1R
antagonist compound disclosed herein with cells expressing B1R under conditions and in an amount sufficient to detectably inhibit binding of DAKD or any other substance to B 1 R. Such methods and their respective conditions are known to those skilled in the art and include, for example, the calcium mobilization assay disclosed in Example 25.
It is also within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
For various applications, the compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity 5 label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates. These labelled compounds of this invention are useful for mapping the location of BK
receptors in vivo, ex vivo, in vitro and in situ such as, e.g. in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like to characterize those receptors in living subjects or other 10 materials. The labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.
The compounds of formula (I) according to the present invention have improved 15 properties when compared to B 1 R antagonists known in the state of the art, especially, improved selectivity, low toxicity, low drug drug interaction, improved bioavailability especially with regard to oral administration, improved metabolic stability, improved stability in microsomal degradation assay, and improved solubility.
20 The present invention is now further illustrated by the following examples from which further features, embodiments and advantages of the present invention may be taken.
EXAMPLES
25 Abbreviations used in the following examples are as follows:
amu is atomic mass unit ACN is acetonitrile AgNO3 is silver nitrate B 1 R is B 1 receptor 30 BK is bradykinin BSA is bovine serum albumin conc. is concentrated DAKD is des-Arg-lO-kallidin DCM is dichloromethane DIPEA is diisopropyethylamine DMAP is 4-N,N-dimethylaminopyridine DMEM is Dulbecco's modified Eagle's medium DMF is N,N-dimethylformamide DMSO is dimethylsulfoxide EA is ethyl acetate FBS is fetal bovine serum FCS is fetal calf serum hishour HATU is 2-(1H-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate HCI is hydrochloric acid HEK is human embryonic kidney HEPES is 4-2-hydroxyethyl-l-piperazineethanesulfonic acid HOBt is N-hydroxybenzotriazole HPLC is high performance liquid chromatography K2C03 is potassium carbonate IL is interleukine LiOH is lithium hydroxide NaCI is sodium chloride Na2CO3 is sodium carbonate Na2SZO3 is sodium thiosulfate NaOH is sodium hydroxide NaHCO3 is sodium hydrogencarbonate NH4CI is ammonium chloride NH4OH is ammonia Pd(OAc)Z is palladium (II) acetate PBS is phosphate-buffered saline PIPES is piperazine-N,N'-bis(2-ethanesulfonic acid) RP is reverse phase RT is room temperature sat. is saturated tBu is tert. butyl TFA is trifluoroacetate or trifluoroacetic acid THF is tetrahydrofuran TPP is Techno Plastic Products AG
WSC is (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride Materials and methods The materials and methods as well as general methods are further illustrated by the following examples:
Solvents:
15. Solvents were used in the specified quality without further purification.
Acetonitrile (Gradient grade, J.T. Baker); dichloromethane (for synthesis, Merck Eurolab);
diethylether (for synthesis, Merck Eurolab); N,N-dimethylformamide (LAB, Merck Eurolab);
dioxane (for synthesis, Aldrich); methanol (for synthesis, Merck Eurolab).
Water:
Milli-Q Plus, Millipore, demineralized.
Chemicals:
Chemicals were synthesized according to or in analogy to literature procedures or purchased from Advanced ChemTech (Bamberg, Deutschland), Sigma-Aldrich-Fluka (Deisenhofen, Germany), Bachem (Heidelberg, Germany), J.T. Baker (Phillipsburg, USA), Lancaster (Muhlheim/Main, Germany), Merck Eurolab (Darmstadt, Germany), Neosystem (Strasbourg, France), Novabiochem (Bad Soden, Germany, from 2003 Merck Biosciences, Darmstadt, Germany) Acros (Geel, Belgium, distribution company Fisher Scientific GmbH, Schwerte, Germany), Peptech (Cambridge, MA, USA), Synthetech (Albany, OR, USA), Pharmacore (High Point, NC, USA) and Anaspec (San Jose, CA, USA) or other companies and used in the assigned quality without further purification.
If not stated differently, concentrations are given as percent by volume.
RP-HPLC-MS analyses:
For analytic chromatography a Hewlett Packard 1100-system (degasser G1322A, quaternary pump G1311A, automatic sample changer G1313A, column heater G
1316A, variable UV detector G1314A) together with an ESI-MS (Finnigan LCQ ion trap mass spectrometer) was used. The system was controlled by "navigator version 1.1 sp1" software (Finnigan). As impact gas in the ion trap helium was used. For chromatographic separation a RP-18-column (Vydac 218 TP5215, 2.1 x 150 mm, 5 m, C18, 300 A with a pre column (Merck) was used at 30 C and a flow of 0.3 mUmin using a linear gradient for all chromatograms (5-95% B for 25 min, linear, A: 0.05% TFA in water and B: 0.05%
TFA in CH3CN). LJV detection wa s done at X = 220 nm. The retention times (Rt) are indicated in the decimal system (e.g. 1.9 min = 1 min 54 s) and are referring to detection in the mass spectrometer. The dead time between injection and UV detection (HPLC) was 1.65 min, and between UV detection and mass detection 0.21 min. The accuracy of the mass spectrometer was approx. 0.5 amu.
HPLC/MS analyses were performed by injection of 5 l, using a linear gradient from 95:5 to 5:95 in 9.5 min (A: 0.05% TFA in water and B: 0.05% TFA in ACN). RP columns were from Phenomenex (Type Luna C-18, 3 m, .50 x 2.00 mm, flow 0.3 ml, HPLC at room temperature); Mass spectrometer: ThermoFinniga n Advantage and/or LCQ Classic (both ion trap), ESI ionization, helium served as impact gas in the ion trap. Excalibur version 1.3 and/or. 1.2 was used as software. Retention times (Rt) are indicated in the decimal system (e.g. 1.9 min = 1 min 54 s).
Preparative HPLC:
Preparative HPLC separations were done using Vydac R18-RP columns with the following gradient solvents: 0.05% TFA in H20 and B: 0.05% TFA in CH3CN
Compounds were named using AutoNom version 2.2 (Beilstein Informationssysteme Copyright 1988-1998, Beilstein Institut fiir Literatur der Organischen Chemie licensed to Beilstein Chemiedaten and Software GmbH) Preparation of compounds:
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.
Specific examples for the preparation of compounds of formula (I) are provided in the following examples. Unless otherwise, specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by the present invention.
Example 1 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{l-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-anzide (Compound 1) ~ N/ ~(' j O HN H ~N
O
Method 1:
A. (R)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (R)-1-(4-Bromo-phenyl)-ethylamine hydrochloride (2.50 g, 10.57 mmol) was added portionwise to a stirred solution of di-tert-butyl dicarbonate (2.77 g, 12.68 mmol) and triethylamine (3.24 mL, 23.25 mmol) in ACN (40 mL). After stirring for 18 h at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound. MS (m/z): 230.0 [M+H+-OtBu]
B. (R)-4-(1-tert-Butoxycarbonylamino-ethyl)-benzoic acid methyl ester To a stirred suspension of (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (3.18 g, 10.58 mmol), 1,4-bis-(diphenylphosphino)butane (0.32 g, 0.74 mmol) and Pd(OAc)2 (0.16 g, 0.74 mmol) in anhydrous DMSO (25 mL) under an atmosphere of nitrogen were added triethylamine (8.85 mL, 63.46 mmol) and anhydrous methanol (10 mL).
After stirring 5 at 70 C under an atmosphere of carbon monoxide for 48 h the mixture was concentrated in vacuo and the residue was partitioned between EA (200 mL) and sat. NaHCO3 solution (200 mL). After extraction of the aqueous layer with EA (2 x 200 mL) the combined organic layers were dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS
10 (m/z): 208.2 [M+H+-OtBu]
C. (R)-4-(1-tert-Butoxycarbonylamino-ethyl)-benzoic acid A mixture of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid methyl ester (1.16 g, 4.16 mmol) and LiOH (1 M solution in H20, 25 mL) in dioxane (25 mL) was stirred at RT for 15 3 h. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCI solution and the aqueous layer was extracted with EA (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 209.9 [M+H+-tBu]
D. (R)-{ 1-[4-(2,5-cis/trans-Dimethyl-pynrolidine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester 2,5-cis/trans-Dimethyl-pyrrolidine (0.76 mL, 6.27 mmol) was added to a stirred solution of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (0.83 g, 3.14 mmol), WSC (0.72 g, 3.76 mmol), HOBt (0.51 g, 3.76 mmol) 'and triethylamine (2.19 mL, 15.68 mmol) in DCM/DMF 9:1 (10 mL). After stirring overnight at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound. MS (m/z): 347.0 [M+H+]
E. (R)-[4-(1-Amino-ethyl)-phenyl]-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone A solution of (R)-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.56 g, 1.62 mmol) and TFA (5 mL) in DCM (45 mL) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and 1 N NaOH solution (50 mL). After extraction of the aqueous layer with DCM (2 x 50 mL) the combined organic layers were dried over NaZSO4, filtered and concentrated in vacuo to give the title compound. MS (m/z): 247.2 [M+H+]
F. (R)-(1-{1-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (R)-[4-(1-Amino-ethyl)-phenyl]-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone (10.0 mg, 0.041 mmol) was added to a stirred solution of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (9.8 mg, 0.049 mmol), WSC (9.3 mg, 0.049 mmol), HOBt (6.6 mg, 0.049 mmol) and N-methylmorpholine (22.3 L, 0.203 mmol) in DMF (1 mL).
After stirring overnight at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS (m/z): 429.9 [M+H+]
G. (R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-1-carbonyl)-phenyl]-ethyl} -amide A solution of (R)-(1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (8.0 mg, 0.019 mmol) and TFA
(100 L) in DCM (900 L) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo to give the title compound as the TFA salt. MS (m/z): 330.0 [M+H+]
H. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl] -ethylcarbamoyl } -cyclopropyl)-amide (R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide (10.0 mg, 0.030 mmol) was reacted with pyrimidine-5-carboxylic acid (4.5 mg, 0.036 mmol) according to the synthesis of (1-{l-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 436.1 [1VI+H+]
Method 2:
Reactions A-D were performed based upon literature (Dickins et al., Chem. Eur.
J. 1999, 5, 1095-1105) A. (R)-N- [ 1-(4-Bromo-phenyl)-ethyl] -acetamide Acetyl chloride (2.13 mL, 30.0 mmol) was added dropwise at -15 C to a stirring solution of (R)-1-(4-bromo-phenyl)-ethylamine (5.00 g, 25.0 mmol) and triethylamine (4.53 mL, 32.5 mmol) in diethylether (750 mL). The reaction mixture was allowed to warm to RT
over 2 h and then poured into 500 mL of water. The organic layer was washed with 0.1 N
HCl solution (1 x 500 mL) and with water (1 x 500 mL), dried over K2C03, filtered and concentrated in vacuo to give the title compound. MS (m/z): 243.8 [M+H']
B. (R)-N-[ 1-(4-Cyano-phenyl)-ethyl]-acetamide To a stirred solution of (R)-N-[1-(4-bromo-phenyl)-ethyl]-acetamide (3.47 g, 14.3 mmol) in anhydrous DMF (30 mL) under an atmosphere of nitrogen was added copper(I)cyanide (2.70 g, 30.1 mmol). After stirring at 180 C overnight the reaction mixture was concentrated in vacuo and the residue carefully poured into 6 N HCI solution (60 mL). The aqueous layer was extracted with DCM (3 x 100 mL). The organic layer was washed with water (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS
(m/z): 188.9 [M+H+]
C. (R)-4-(1-Amino-ethyl)-benzoic acid A solution of (R)-N-[1-(4-cyano-phenyl)-ethyl]-acetamide (1.67 g, 8.87 mmol) in 6 N
HCl solution (27 mL) was stirred at 120 C overnight. The solvent was removed in vacuo and the solid was washed with diethylether, filtered and dried to give the title compound as the HCl salt. MS (m/z): 165.9 [M+H+]
D. (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester 3 Drops of HCl conc. were added to a stirred solution of (R)-4-(1-amino-ethyl)-benzoic acid (1.79 g, 8.87 mmol) in methanol (25 mL). After stirring the mixture at 85 C for 3 h the solvent was removed in vacuo to give the title compound as the HCI salt. MS
(m/z): 179.8 [M+H+]
E. (R)-4-{1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester (420 mg, 2.34 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (560 mg, 2.81 mmol) according to the synthesis of (R)-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester to give (R)-4-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. The tert-butyl ester (103 mg, 0.284 mmol) was treated with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide to give the title compound as the TFA salt. MS (m/z): 262.9 [M+H+]
F. (R)-4-[1-({1-[(Pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (R)-4-{1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester (74.5 mg, 0.284 mmol) was added- to a stirred solution of pyrimidine-5-carboxylic acid (42.3 mg, 0.341 mmol), HATU (129.6 mg, 0.341 mmol) and DIPEA (247.3 L, 1.420 mmol) in DMF (2 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL).
After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound which was used for the next reaction without further purification. MS (m/z): 368.9 [M+H{]
G. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl} -cyclopropyl)-amide (R)-4-[ 1-( { 1-[(Pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (192 mg, 0.521 mmol) was reacted with LiOH according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid to give (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl } -amino)-ethyl]-benzoic acid.
Subsequent reaction with 2,5-cis/trans-dimethyl-pyrrolidine according to the synthesis of (R)-(1- { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester yielded the title compound as the TFA salt. MS
(m/z): 436.1 [M+H-`]
Example 2 Synthesis of (R)-1V- { 1-[ 1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide (Compound 43) nw-- -11 H NFi~~
O ~
O
A. (R)-4- { 1- [(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-amino] -ethyl } -benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester (1.03 g, 4.77 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (0.80 g, 3.97 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. The crude compound was purified by flash chromatography on silica gel (elution with n-hexane/EA 3:7) to give the title compound. MS
(m/z): 362.7 [M+H+]
B. (R)-4-{ 1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-N,N-diisopropyl-benzamide (R)-4-{ 1-[(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid inethyl ester (423 mg, 1.17 mmol) was reacted with LiOH according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid to give (R)-4-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid. The benzoic acid (59.6 mg, 0.171 mmol) was reacted with diisopropyl-amine (71.9 L, 0.513 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound- by reversed phase HPLC using.a gradient of ACN in water with 0.1%
TFA and subsequent reaction with TFA according to the synthesis of (R)-1-amino- .
cyclopropanecarboxylic acid { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide yielded the title compound as the TFA salt. MS (m/z): 332.0 [M+H+]
C. (R)-N-{ 1-[1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide 3-Bromo-5-trifluoromethyl-pyridine (1.00 g, 4.42 mmol) was reacted with carbon monoxide according to the synthesis of (R)-4-(l-tert-butoxycarbonylamino-ethyl)-benzoic acid methyl ester to give 5-trifluoromethyl-nicotinic acid methyl ester.
Hydrolysis of the methyl ester according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid and subsequent reaction of the benzoic acid (4.80 mg, 0.025 mmol) with (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-N,N-diisopropyl-benzamide (4.20 mg, 0.013 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound as 5 the TFA salt (purification of the crude compound by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA). MS (m/z): 505.1 [M+l-1"]
Example 3 Synthesis of (R)-N-{ 1-[1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-10 cyclopropyl}-3-fluoro-5-trifluoromethyl-benzamide (Compund 44) P-1 -f\ /
N--( NHR~
H
O `
`
F O
(R)-4- { 1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl } -N,N-diisopropyl-benzamide (4.2 mg, 0.013 mmol) was reacted with 3-fluoro-5-trifluoromethyl-benzoic acid (5.3 mg, 0.025 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-15 cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA yielded the title copound as the TFA salt. MS (m/z): 522.1 [M+IV]
Example 4 20 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-((2R,5S')-2,5-dimethyl-pyrrolidine-l-carbonyl]-phenyl)-ethylcarbamoyl}-cyclopropyl)-amide (Compound 45) N ~
rN
w O H~J
I \ N
(s) O N
(R) Reactions A-C were performed based upon literature (Katritzky et al., J. Org.
Chem.
1999, 64, 1979-1985) 25 A. (3S,5R,7aR)-5-(Benzotriazol-l-yl)-3-phenyl[2,1-b]oxazolopyrrolidine A mixture of 2,5-dimethoxytetrahydrofuran (2.94 mL, 22.7 mmol) and 0.1 N HCl (90 mL) was refluxed for 1 h and then cooled to RT. A solution of benzotriazole (2.70 g, 22.7 mmol) and (S)-(+)-2-amino-2-phenyl-ethanol (3.11 g, 22.7 mmol) in DCM (220 mL) was added to the cooled mixture, which was then stirred overnight. The reaction mixture was washed with 2 N NaOH (3 x 70 mL) and water (2 x 70 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue was recrystallized from EA to give the title compound. 'H NMR 6 2.20-2.26 (m, 1H), 2.55-2.57 (m, 3H), 3.61-3.68 (m, 1H), 4.44-4.45 (m, 2H), 5.16-5.17 (m, 1H), 5.90-5.94 (m, 1H), 7.03-7.08 (m, 5H), 7.21-7.26 (m, 2H), 7.44-7.46 (d, J= 7Hz, 1 H), 7.90-7.93 (d, J= 7Hz, 1 H) B. (2S)-(2-(2R,5S)-2,5-Dimethyltetrahydro-lH-l-pyrrolyl-2-phenylethan-l-o1 A solution of methylmagnesiumbromide (3M in diethylether, 2.20 mL, 6.53 mmol) was added dropwise at 0 C to a stirred solution of (3S,5R,7aR)-5-(benzotriazol-l-yl)-3-phenyl[2,1-b]oxazolopyrrolidine (500 mg, 1.63 mmol) in dry THF (33 mL) under nitrogen.
After stirring at RT overnight the reaction mixture was washed with 2 N NaOH (3 x 40 mL) and water (2 x 40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS (m/z): 220.0 [M+H+]
C. (2R,5S)-2,5-Dimethyltetrahydro-lH-1-pyrrolidinium chloride (2S)-(2-(2R,5S')-2,5-Dimethyltetrahydro-lH-l-pyrrolyl-2-phenylethan-l-o1(100 mg, 0.46 mmol) was dissolved in methanol (9 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator (Thales Nanotechnology, H-1031 Budapest, Zahony utca 7(Graphisoft Park), Hungary. Website: http://
www.thalesnano.com), which contained a cartridge of 10% palladium on carbon as catalyst.
The hydrogenation was done at RT under a pressure of 10 bar. The solution of the product was treated with 20 drops of HCI conc. while stirring at RT for 30 minutes.
The solvent was evaporated in vacuo and the resulting product was washed with diethylether to give the title compound as the HCI salt. MS (m/z): 100.00 [M+H+]
D. (R)-pyrimidine-5-carboxylic acid (1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl]-phenyl)-ethylcarbamoyl}-cyclopropyl)-amide (R)-4- { 1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl } -benzoic acid (30 mg, 0.086 mmol) was reacted with (2R,5S)-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (23 mg, 0.172 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester to give (R)-(1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester. Subsequent reaction with TFA
according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide yielded (R)-1-amino-cyclopropanecarboxylic acid {1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide. Subsequent reaction with pyrimidine-5-carboxylic acid according to the synthesis of (R)-4-[1-( { 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude product by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA yielded the title compound as the TFA salt. MS (m/z): 436.1 [M+H+]
Example 5 Synthesis of (R)-N-(1-{1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 55) O H
F
O N
(R)-4- { 1-[(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-arnino]-ethyl}-benzoic acid (60 mg, 0.17 mmol) was reacted with 2,5-cis/trans-dimethyl-2,5-dihydro-IH-pyrrole (33 mg, 0.34 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester to give (R)-(1-{1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethylcarbamoyl} -cyclopropyl)-carbamic acid tert-butyl ester. Subsequent reaction with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid { 1 -[4-(2,5-cis/trans-dimethyl-pyrrolidine- 1 -carbonyl)-phenyl]-ethyl}-amide yielded (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethyl} -amide.
Subsequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({ 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbenyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude product. by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA yielded the title compound as the TFA salt. MS
(m/z): 518.2 [M+H+]
Example 6 Synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide (Compound 60) H J0~ ^
N N" ~ `N
F O H I N) O N
A. 3-Fluoro-4-methyl-benzoic acid methyl ester Chloro-trimethyl-silane (3.64 mL, 28.8 mmol) was added to a stirring solution of 3-fluoro-4-methyl-benzoic acid (1.11 g, 7.20 mmol) in methanol (24 mL). After stirring at RT
overnight the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane) to give. the title compound. GC/MS
(m/z): 168.0 Reaction B was performed based upon literature (Gauuan et al., Bioorg. Med.
Chem.
2002, 10, 3013-3021) B. 3-Fluoro-4-formyl-benzoic acid methyl ester After stirring a suspension of 3-fluoro-4-methyl-benzoic acid methyl ester (500 mg, 2.97 mmol), 1-bromo-pyrrolidine-2,5-dione (1.73 g, 8.33 mmol) and benzoyl peroxide (53.1 mg, 0.47 mmol) in tetrachloromethane (36 mL) at 80 C overnight the mixture was concentrated in vacuo and the residue was partitioned between EA (150 mL) and water (100 mL).
The organic layer was washed with sat. NaHCO3 solution (1 x 100 mL), water (1 x 100 mL) and sat. NaC1 solution (1 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue, a mixture of 4-bromomethyl-3-fluoro-benzoic acid methyl ester and 4-dibromomethyl-3-fluoro-benzoic acid methyl ester, was used in the following step without further purification. The residue (50 mg, 0.30 mmol) was dissolved in acetone (2 mL) and water (0.4 mL) and AgNO3 (171 mg, 0.87 mmol) were added.
The flask was covered with aluminum foil to avoid decomposition of the AgNO3. The mixture was stirred at RT overnight. After filtration of the mixture and evaporation of the solvent, the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (15 mL).
The organic layer was washed with water (1 x 15 mL) and sat. NaC1 solution (1 x 15 mL), dried over NaZSO4, filtered and concentrated in vacuo to give the title compound. GC/MS
(m/z): 182.2 C. (R,S)-3-Fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester Methylmagnesiumbromide (3M solution in diethylether, 0.99 mL, 2.96 mmol) was added dropwise at -80 C to a stirring solution of 3-fluoro-4-formyl-benzoic acid methyl ester (450 mg, 2.47 mmol) in dry THF (10 mL) under nitrogen. After stirring for 80 minutes 5 mL 2 M
HCI solution were added and the mixture was allowed to warm to RT. Sat. NaCl solution was added (100 mL) and the mixture was extracted with EA (4 x 100 mL). The organic layer was dried over NazSOa, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 6:1) to give the title compound.
GC/MS (m/z): 198.2 D. (R,S)-4-(1-Azido-ethyl)-3-fluoro-benzoic acid methyl ester Methanesulfonyl chloride (120 L, 1.55 mmol) was dissolved in 500 L DCM and then added dropwise at 0 C to a stirred solution of (R,S)-3-fluoro-4-(l-hydroxy-ethyl)-benzoic acid methyl ester (154 mg, 0.78 mmol), DMAP (4.7 mg, 0.04 mmol) and triethylamine (1.08 mL, 7.77 mmol) in DCM (4 mL). After stirring at 0 C for 30 minutes, 10 mL water were added and the mixture was extracted with DCM (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give cis/trans-3-fluoro-4-(1-methanesulfonyloxy-ethyl)-benzoic acid methyl ester, which was used in the following step without further purification. The residue was stirred with sodium azide (204 mg, 4.66 mmol) in ACN (4 nzL) at 60 C overnight. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. GC/MS (m/z): 223.0 E. (R,S)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (R,S)-4-(1-Azido-ethyl)-3-fluoro-benzoic acid methyl ester (158 mg, 0.71 mmol) was dissolved in methanol (14 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator, which contained a cartridge of 10% palladium on carbon as catalyst. The hydrogenation was done at RT under a pressure of 1 bar. The solvent was evaporated to give the title compound. MS (m/z): 197.8 [M+I-i+]
F. (R,S)-3-Fluoro-4-[1-({ 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (R,S)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (27.4 mg, 0.14 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with 10 TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with pyrimidine-5-carboxylic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title coumpound. MS (m/z):
386.9 [M+H+]
G. (R,S)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl} -cyclopropyl)-amide (R, S)-3-Fluoro-4-[1-( { 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl} -amino)-ethyl]-benzoic acid methyl ester (73.0 mg, 0.19 mmol) was reacted with LiOH
according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid.
Subsequent reaction of the benzoic acid (13.0 mg, 0.04 mmol) with 2,5-cis/trans-dimethyl-pyrrolidine (4.30 L, 0.04 mmol) according to the synthesis of (R)-4-[l-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA yielded the title copound as the TFA salt. MS (m/z): 454.1 [M+H+]
Example 7 Synthesis of (R,S)-N-(1-{ 1=[5-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide (Compound 65) N ~ CF3 ~ ~
N ~ O H
N
O N
Reaction A was performed based on literarture (Chong et al., J. Med. Chem.
2004, 47, 5230-5234) A. 6-Hydroxymethyl-nicotinic acid methyl ester Sodiumborhydride (0.51 g, 13.5 mmol) was added portionwise at 0 C to a stirring suspension of pyridine-2,5-dicarboxylic acid dimethyl ester (1.05 g, 5.38 mmol) and calcium choride (2.39 g, 21.5 mmol) in THF/methanol 1:2 (33 mL). After stirring overnight at 0 C 20 mL water were added and the solvent was removed in vacuo. The aqueous residue was extraxted with DCM (3 x 30 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1) to give the title compound. MS (m/z): 167.9 [M+H+]
B. 6-Formyl-nicotinic acid methyl ester Dess-Martin reagent (207 mg, 0.49 mmol) was added to a stirring solution of 6-hydroxymethyl-nicotinic acid methyl ester (55 mg, 0.33 mmol) in DCM (17 mL).
After stirring for 3 h the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound.
GCMS (m/z): 165.2 C. (R,S)-6-(1-Hydroxy-ethyl)-nicotinic acid methyl ester 6-Formyl-nicotinic acid methyl ester (47 mg, 0.28 mmol) was reacted with methylmagnesium bromide according to the synthesis of (R,S)-3-fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester to give the title compound which was used in the following reation without further purification. MS (m/z): 182.0 [M+H+]
D. (R, S)-6-(1-Am.ino-ethyl)-nicotinic acid methyl ester The reaction of (R,S)-6-(l-hydroxy-ethyl)-nicotinic acid methyl ester (150 mg, 0.83 mmol) with methanesulfonyl chloride and subsequent reaction with sodium azide according to the synthesis of (R,S)-4-(l-azido-ethyl)-3-fluoro-benzoic acid methyl ester yielded (R,S)-6-(1-azido-ethyl)-nicotinic acid methyl ester. Hydrogenation of the methyl ester according to the synthesis of (R,S)-4-(1-amino-ethyl)-3-fluoro-benzoic acid methyl ester yielded the title compound. MS (m/z): 181.0 [M+H+]
E. (R,S)-(1-{ 1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (R,S)-6-(1-Amino-ethyl)-nicotinic acid methyl ester (116 mg, 0.64 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid according to the synthesis of (R)-4-[ l -({ 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl} -amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA yielded (R,S)-6-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-nicotinic acid methyl ester as the TFA
salt. Reaction of the methyl ester with LiOH and subsequent reaction with 2,5-cis/trans-dimethyl-pyrrolidine according to the synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide yielded the title compound as the TFA salt. MS (rn/z): 431.0 [M+H+]
. F. (R,S)-N-(1-{1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl} -cyclopropyl)-5-trifluoromethyl-nicotinamide (R,S)-(1-{ 1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (33.6 mg, 0.08 mmol) was treated with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide.
Subsequent reaction with 5-trifluoromethyl-nicotinic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA yielded the title compound as the TFA salt. MS (m/z):
504.1 [M+H+]
Example 8 Synthesis of N-(1-(4-(2,5-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-1-(1-hydroxy cyclopropanecarboxamido)cyclopropanecarboxamide (Compound 7) gN ~ O O OH
\ ~ HN
O ~NH
(R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide (10.0 mg, 0.03 mmol) was reacted with 1-hydroxy-cyclopropanecarboxylic acid (2.8 mg, 0.03 mmol) according to the synthesis of (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester to give the title copound as the TFA salt. MS (m/z):
414.1 [M+H+]
Example 9 Synthesis of N-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide (Compound 78) N~ CF3 F O H I
N
O )3 A. 3-Fluoro-4-formyl-benzoic acid A solution of 3-fluoro-4-formyl-benzoic acid methyl ester (200 mg, 1.10 mmol) and LiOH (1.5 mL) in ACN (1.5 mL) was stirred at RT for 1 h and then 1 h at 40 C.
The solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt.
GC/MS (m/z):
168.0 B. 4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde 2,5-cis/trans-Dimethyl-pyrrolidine (264 mg, 2.67 mmol) was added to a stirring solution of 3-fluoro-4-formyl-benzoic acid (150 mg, 0.89 mmol), WSC (256 mg, 1.34 mmol) and HOBt (180 mg, 1.34 mmol) in DMF (3 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS
(m/z): 250.2 [M+H+]
C. (4-Aminomethyl-3-fluoro-phenyl)-(2,5-cis/trans-dimethyl-pyrrolidin-l-yl)-methanone A mixture of 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde (50.0 mg, 0.20 mmol), titanium-tetra-isopropylate (570 mg, 2.00 mmol) and ammonia (7N
solution in ethanol, 1 mL) was stirred at RT overnight. Sodiumborhydride (23.0 mg, 0.60 mmol) was added. After stirring for 2 h the solvent was removed in vacuo and the residue was partitioned between EA (20 mL) and sat. NaHCO3 solution (20 mL). The aqueous layer was extracted with EA (3 x 20 mL), the organic layer was 'dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS (m/z): 251.1 [M+H+]
D. { 1-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (4-Aminomethyl-3-fluoro-phenyl)-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone (50.1 mg, 0.20 mmol) was added to a stirring solution of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (80.5 mg, 0.40 mmol), WSC (77.0 mg, 0.40 mmol), HOBt (54.0 mg, 0.40 mmol) and diisopropylamine (100 L, 0.60 mmol) in DMF (1 mL). After stirring for 3 h at RT the sqlvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 433.9 [M+H+]
E. 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-carbonyl)-2-fluoro-benzylamide A solution of {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (33 mg, 0.08 mmol) and TFA
(300 L) in DCM (2700 L) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS (m/z): 334.1 [M+H+]
F. 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamide 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamide (13 mg, 0.04 mmol) was reacted with 5-trifluoromethyl-nicotinic acid (33 mg, 0.08 mmol) according to the synthesis of {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-1-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 507.1 [M+H+]
Example 10 Synthesis of (R)-N-(1-{ 1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-5 phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 90) ~CF3 N
tNN ~ 0 F H ~/
F
J
A. 3-Fluoro-4-[(2-methyl-propane-2-sulfnylimino)-methyl]-benzoic acid methyl ester A mixture of 3-fluoro-4-formyl-benzoic acid methyl ester (529 mg, 2.91 mmol), (S)-(-)2-methyl-propane-2-sulfinic acid amide (352 mg, 2.91 mmol), pyridinium p-toluenesulfonate 10 (36 mg, 0.15 mmol) and magnesium sulfate (5.20 g, 43.7 mmol) in DCM (8 mL) was stirred at RT for 2 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. MS
(m/z): 285.8 [M+H+]
15 B. (R)-3-Fluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-benzoic acid methyl ester Methyl magnesium chloride (22% in THF, 520 L, 1.49 mmol) was added dropwise at -60 C to a stirred solution of 3-fluoro-4-[(2-methyl-propane-2-sulfinylimino)-methyl]-benzoic acid methyl ester (386 mg, 1.35 mmol) in DCM (7 mL). After stirring for 4 h at -60 C sat.
20 ammonium chloride solution (25 mL) was added. The aqueous layer was extracted with DCM
(4 x 25 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1) to give the title compound. MS (m/z): 301.8 [M+H+]
25 C. (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester A solution of (R)-3-fluoro-4-[1-(2-methyl-propane-2-sulfmylamino)-ethyl]-benzoic acid methyl ester (61 mg, 0.21 mmol) and HCl (4N solution in dioxan, 320 L, 1.28 mmol) was stirred at RT for 30 minutes. The solvent was removed in vacuo and the residue was recristallized from diethylether to give the title compound as the HCl salt.
MS (m/z): 197.8 [NI+H+]
D. (R)-3-Fluoro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (35 mg, 0.15 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound.
MS (m/z): 470.8 [M+H+]
E. (R)-N-(1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl } -cyclopropyl)-3 -fluoro-5-trifluoromethyl-benzamide (R)-3-Fluoro-4-(1- { [ 1-(3 -fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]
-amino}-ethyl)-benzoic acid methyl ester (98 mg, 0.21 mmol) was reacted with LiOH
according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid.
Subsequent reaction of the benzoic acid (8.4 mg, 0.02 mrnol) with (2R,5S)-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (3.2 mg, 0.024 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA yielded the title compound as the TFA salt. MS (m/z): 538.3 [M+H+]
Example 11 Synthesis of { 6-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino] -pyridin-3 -yl } -(4-pyridin-4-yl-piperazin-1-yl)-methanone (Compound 106) N N~ N
F
O N
A. 6-tert-Butoxycarbonylamino-nicotinic acid methyl ester 6-Amino-nicotinic acid methyl ester (1.00 g, 6.57 mmol) was added portionwise to a stirring solution of di-tert-butyl dicarbonate (1.72 g, 7.89 mmol) in tert-butanol (20 mL).
After stirring for 4 days at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. MS (m/z): 252.8 [M+H+]
B. 6-tert-Butoxycarbonylamino-nicotinic acid A mixture of 6-tert-butoxycarbonylamino-nicotinic acid methyl ester (1.62 g, 6.40 mmol) and LiOH (1M solution in H20, 40 mL) in dioxane (40 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCI solution and the aqueous layer was extracted with EA (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (mlz): 238.8 [M+H+]
C. [5-(4-Pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester 1-Pyridin-4-yl-piperazine (123 mg, 0.75 mmol) was added to a stirring solution of 6-tert-butoxycarbonylamino-nicotinic acid (90 mg, 0.38 mmol), WSC (86 mg, 0.45 mmol) and HOBt (61 mg, 0.45 mmol) in DMF (3 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS
(m/z): 384.0 [M+W]
D. (6-Amino-pyridin-3 -yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone A solution of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (24 mg, 0.06 mmol) and TFA (5 mL) in DCM (5 mL) was stirred at RT
for 4 h.
The reaction mixture was concentrated in vacuo to give the title compound as the TFA salt.
MS (m/z): 284.2 [M+H+]
E. 4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde 3-Fluoro-4-formyl-benzoic acid (46 mg, 0.28 mmol) was reacted with 2,5-cis/trans-dimethyl-pyrrolidine (34 L, 0.28 mmol) according to the synthesis of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 250.1 [M+H+]
F. {6-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone A mixture of (6-amino-pyridin-3-yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone (17.5 mg, 0.062 mmol), 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde (11.0 mg, 0.044 mmol) and titanium-tetra-isopropylate (62.5 mg, 0.220 mmol) in dichloroethane (2 mL) was stirred at RT overnight. Sodiumtriacetoxyborhydride (18.6 mg, 0.088 mmol) was added and the mixture was stirred at RT for additional 3 h. The solvent was removed in vacuo and the residue was partitioned between EA (20 mL) and sat. NaHCO3 solution (20 mL). The aqueous layer was extracted with EA (2 x 20 mL), the organic layer was dried over NaZSOa, filtered and concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA
salt. MS
(m/z): 517.3 [M+H+]
Example 12 Synthesis of {6-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-2-fluoro-benzylainino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone (Compound 111).
=N
N N ^\ N I /
F Nf ,,) O
)~/
A. 3-Fluoro-4- { [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl} -benzoic acid methyl ester (6-Amino-pyridin-3-yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone (92 mg, 0.32 mmol) was reacted with 3-fluoro-4-formyl-benzoic acid methyl ester (65 mg, 0.35 mmol) according to the synthesis of {6-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone to give the title compound, which was used in the following step without further purification.
MS (m/z):450.3 [M+H+]
B. {6-[4-(2,5-cis/trans-Dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-2-fluoro-benzylamino] -pyridin-3 -yl } -(4-pyridin-4-yl-piperazin-1-yl)-methanone 3-Fluoro-4- { [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl} -benzoic acid methyl ester (110 mg, 0.23 mmol) was reacted with LiOH according to the synthesis of 3-fluoro-4-formyl-benzoic acid to give 3-fluoro-4-{[5-(4-pyridin-4-yl-piperazine-1-carbonyl)-pyridin-2-ylamino]-methyl}-benzoic acid. The benzoic acid (18 mg, 0.04 mmol) was reacted with 2,5-cis/trans-dimethyl-2,5-dihydro-lH-pyrrolidin (25 L, 0.20 mmol) according to the synthesis of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS
(m/z): 515.2 [M+Hj Example 13 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl}-1-methyl-ethyl)-amide (Compound 115) N
fRJ O
H / ~ N
YV
N~
O N'l A. (R)-4- [ 1-(9H-Fluoren-9-ylmethoxycarbonylamino)-ethyl] -benzoic acid Trimethylsilyl chloride (3.14 mL, 24.8 mmol) was added to a solution of (R)-4-(1-amino-ethyl)-benzoic acid (2.00 g, 9.92 mmol) in DCM (50 mL). The mixture was heated to reflux for 2 h then cooled to RT and triethylamine (5.53 mL, 39.7 mmol) was added dropwise followed by 9-fluorenylmethyl chloroformate (2.82 g, 10.9 mmol). The reaction mixture was stirred at RT overnight and then concentrated in vacuo. The residue was stirred in sat. sodium carbonate solution and acidified with 2 N hydrochloric acid. The resulting aqueous solution was extracted with diethylether (2 x 150 mL) and the organic layer was dried over Na2SOa, filtered and concentrated in vacuo to give the title compound. MS (m/z): 387.7 [M+W]
B. Resin-bound (R)-4-(1-amino-ethyl)-benzoic acid 4-[1-(9H-Fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid (296 mg, 0.8 mmol) and DIPEA (332 L, 1.9 mmol) were dissolved in DCM (8 mL). The solution was added to 2-chlorotrityl chloride resin (loading: 1.4 mmol/g, 1.09 g, 1.5 mmol) swollen in DCM (8 mL) and the mixture was shaken at RT for 30 minutes. The mixture was quenched with methanol (800 L). The resin was filtered and washed with DCM/methanol/DIPEA (16:3:3, 1 x 10 mL) and DMF (3 x 10 mL). Piperidin (25% solution in DMF, 10 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF (6 x 10 mL) and dried 5 in vacuo to give the title compound with an expected loading of 45% (0.65 mmol/g).
C. Resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionic acid (63 mg, 0.19 mmol), HATU (74 mg, 0.19 mmol) and DIPEA (68 L, 0.39 mmol) in DMF (1 mL) 10 was stirred at RT for 5 minutes and then added to resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (100 mg, 0.07 mmol) swollen in DCM (1 mL). The mixture was shaken at RT
for 1.5 h and then quenched with methanol. The resin was filtered and washed with DMF (4 x 2 mL) to give resin-bound 4- { 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product.
15 MS (m/z): 472.9 [M+H+]. Piperidin (25% solution in DMF, 4 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF (6 x 10 mL) and dried in vacuo to give the title compound.
D. Resin-bound (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionyl 20 amino } -ethyl)-benzoic acid Resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid (100 mg, 0.065 mmol) was reacted with 5-pyrimidinecarboxylic acid according to the synthesis of resin-bound 4-{ 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product. MS
(m/z): 356.9 25 [M+H+]
E. (R)-4-(1-{2-Methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid A suspension of resin-bound (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-30 propionylamino}-ethyl)-benzoic acid (100 mg, 0.065 mmol) in 1,1,1,3,3,3,-hexafluoro-2-propanol/DCM (4:1, 2.5 mL) was shaken at RT for 3 h. The resin was filtered and washed with DCM (2 x 3 mL). The filtrate was concentrated in vacuo to give the title compound. MS
(m/z): 356.9 [M+H+]
F. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl }-1-methyl-ethyl)-amide N-Ethylisopropylamine (41 L, 0.337 mmol) was added to a stirred solution of (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid (12.0 mg, 0.034 mmol) and HATU (12.8 mg, 0.034 mmol) in DMF (0.4 mL). Affter stirring overnight the reaction mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 426.1 [M+M
Example 14 Synthesis of (R)-N-(cyclopropyl-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl} -methyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 116) ~R~~ \ F
(R) O H
~
~
O N
A. Resin-bound (R)=4-[1-(2-amino-2-cyclopropyl-acetylamino)-ethyl]-benzoic acid Resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (58.7 mg, 0.038 mmol) was reacted with (R)-cyclopropyl-[(9H-fluoren-9-ylmethoxycarbonylamino)]-acetic acid (38.6 mg, 0.114 mmol) according to the synthesis of 4-{ 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product 4-{ 1-[2-cyclopropyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-ethyl}-benzoic acid. MS (m/z): 485.0 [M+H+]. Deprotection with piperidin according to the synthesis of resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid yielded the title compound.
B. (R)-N-(Cyclopropyl-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl } -methyl)-3 -fluoro-5 -trifluoromethyl-benzamide Resin-bound (R)-4-[1-(2-amino-2-cyclopropyl-acetylamino)-ethyl]-benzoic acid (58.7 mg, 0.038 mmol) was reacted with 3-fluoro-5-trifluoromethylbenzoic acid (15.8 mg, 0.076 mmol) according to the synthesis of 4-{1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. Cleavage with 1,1,1,3,3,3,-hexafluoro-2-propanol/DCM according to the synthesis of (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid (12 mg, 0.034 mmol) yielded 4-{1-[2-cyclopropyl-2-(3-fluoro-5-trifluoromethyl-benzoylamino)-acetylamino]-ethyl}-benzoic acid.
Reaction of the acid (12.5 mg, 0.028 mmol) with 2,5-cis/trans-dimethylpyrrolidin (6.8 L, 0.055 mmol) according to the synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4=(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl}-1-methyl-ethyl)-amide yielded the title compound as the TFA salt. MS (m/z): 534.1 [M+W]
Example 15 Synthesis of (R,S)-N-(1-{ 1-[2-chloro-4-((2R,5R)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 100) H O
N
CI O H ~ \ F
~ / - F3C
'(R) O
(R1 A. 3-Chloro-4-methyl-benzoic acid methyl ester Chloro-trimethyl-silane (6.0 mL, 46.9 mmol) was added to a stirring solution of 3-chloro-4-methyl-benzoic acid (2.0 g, 11.7 mmol) in methanol (40 mL). After stirring at RT ovemight the solvent was removed in vacuo to give the title compound, which was used in.the, following step without further purification. GC/MS (m/z): 184 B. 3-Chloro-4-formyl-benzoic acid methyl ester After stirring a suspension of 3-chloro-4-methyl-benzoic acid methyl ester (1.04 g, 5.61 mmol), 1-bromo-pyrrolidine-2,5-dione (3.26 g, 15.7 mmol) and benzoyl peroxide (100.2 mg, 0.88 mmol) in tetrachloromethane (68 mL) at 80 C overnight the mixture was concentrated in vacuo and the residue was partitioned between EA (300 mL) and water (200 mL).
The organic layer was washed with sat. NaHCO3 solution, (1 x 200 mL), water (1 x 200 mL) and sat. NaCI solution (1 x 200 mL). The organic layer was dried over NaZSO4, filtered and concentrated in vacuo. The residue, a mixture of 4-bromomethyl-3-chloro-benzoic acid methyl ester and 4-dibromomethyl-3-chloro-benzoic acid methyl ester, was used in the following step without further purification. The residue (1.48 g, 5.61 mmol) was dissolved in acetone (45 mL) and water (9 mL) and AgNO3 (3.22 g, 16.3 mmol) were added. The flask was covered with aluminum foil to avoid decomposition of the AgNO3. The mixture was stirred at RT overnight. After filtration of the mixture and evaporation of the solvent, the residue was partitioned between EA (700 mL) and sat. NaHCO3 solution (350 mL).
The organic layer was washed with water (1 x 350 mL) and sat. NaCI solution (1 x 350 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound.
GC/MS (m/z): 198 C. (R,S)-4-(1-Azido-ethyl)-3-chloro-benzoic acid methyl ester 3-Chloro-4-formyl-benzoic acid methyl ester (398 mg, 2.01 mmol) was reacted with methylmagnesiumbromide according to the synthesis of (R,S)-3-fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester. Reaction of the ester with methanesulfonyl chloride and subsequent reaction with sodium azide according to the synthesis of (R,S)-4-(1-azido-ethyl)-3-fluoro-benzoic acid methyl ester yielded the title compound. GC/MS (m/z):
D. (R, S)-4-( l-Amino-ethyl)-3-chloro-benzoic acid methyl ester (R,S)-4-(1-Azido-ethyl)-3-chloro-benzoic acid methyl ester (181 mg, 0.76 mmol) was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator according to the synthesis of (R,S)-4-(1-amino-ethyl)-3-fluoro-benzoic acid methyl ester to give the title compound. MS (m/z): 213.8 [M+H+]
E. (R,S)-3-Chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid methyl ester (R,S)-4-(1-Amino-ethyl)-3-chloro-benzoic acid methyl ester (17.7 mg, 0.083 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound.
MS (m/z): 472.9 [M+H+]
F. (R,S)-N-(1-{ 1-[2-Chloro-4-((2R,5R)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (R, S)-3-Chloro-4-(1- { [ l -(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropane carbonyl]-amino}-ethyl)-benzoic acid methyl ester (40.3 mg, 0.083 mmol) was treated with LiOH (1.4 ml) to give (R,S)-3-chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid. Subsequent reaction of the benzoic acid with (2R,5R)-2,5-dimethyl-pyrrolidine according to the synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide yielded the title compound as the TFA salt.
MS (m/z):
554.0 [M+H+]
Example 16 Synthesis of (R,S)-N-(1-{ 1-[2-Chloro-4-((2S,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 99) H .O
N
CI O H F
F3C!
N(s ) .~ (sl Reactions A-D were performed based on literarture (Schlessinger et al., Tetrahedron Lett.
1987, 28, 2083-2086) A. (2-Hydroxy-1(S)-methyl-ethyl)-carbamic acid benzyl ester Lithium aluminium hydride (10.2 g, 0.27 mol) was suspended in anhydrous THF
(450 mL). To this mixture L-Alanine (12.0 g, 0.13 mol) was added portionwise at 0 C. The mixture was refluxed overnight and then cooled to 0 C. 2 N NaOH solution (70 mL) was added. After stirring at RT for 3 h, the mixture was filtered and the solids were washed with THF. The solids were suspended in THF (250 mL) and the mixture was refluxed for 1 h.
The solution was filtered and the solids were washed with THF. This procedure was repeated twice. To the combined THF solutions was added 2 N NaOH solution (170 mL) and benzyl chloroformate (25.3 g, 0.15 mol). After stirring 1 h, the biphasic system was separated and the aqueous layer was extracted with EA (1 x 50 mL). The organic layer was dried over Na2SO4i filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/cyclohexane yielded the title compound.
B. (S)-Toluene-4-sulfonic acid 2-benzyloxycarbonylamino-propyl ester To a solution of (2-hydroxy-1(S)-methyl-ethyl)-carbamic acid benzyl ester (12.0 g, 0.06 mol) in pyridine (190 mL) was added p-toluenesulfonyl chloride (4.40 g, 0.11 mol) at 0 C.
After stirring at RT overnight, diethyl ether (50 mL) was added. The mixture was filtered and the solids were washed with diethyl ether. The organic extract was washed with 0.5N H2SO4 solution (3 x 20 mL), 5% NaHCO3 solution (1 x 20 mL) and sat. NaCI solution (1 x 20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/n-hexane yielded the title compound.
C. (S)-Toluene-(2-iodo-l-methyl-ethyl)-carbamic acid benzyl ester To a solution of (S)-toluene-4-sulfonic acid 2-benzyloxycarbonylamino-propyl ester (12.3 g, 0.03 mol) in acetone (113 mL) was added solid sodium iodide (50.7 g, 0.34 mol) at 0 C.
After stirring at 0 C for 30 minutes, the reaction mixture was- stirred at RT
for 48 h. The solvent was removed in vacuo at RT. The residue was suspended in EA. The mixture was filtered and the solids were washed with EA. The organic extract was washed with H20 (2 x 20 mL), 5% Na2SZO3 solution (1 x 20 mL) and sat. NaCI solution (1 x 20 mL), dried over NaZSO4, filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/n-hexane yielded the title compound.
D. (S')- (1-Methyl-pent-4-enyl)-carbamic acid benzyl ester Allyl magnesium chloride (19.0 mL, 0.038 mol, 2 M solution in THF) was added dropwise to a stirring suspension of copper iodide (3.60 g, 0.019 mol) in anhydrous THF (64 mL) at -78 C. Upon completion of the addition, the mixture was warmed to -36 C
for 5 minutes, then cooled to -78 C, and (S)-toluene-(2-iodo-l-methyl-ethyl)-carbamic acid benzyl ester (4.00 g, 0.013 mol) in THF (19 mL) was added dropwise. After stirring at -36 C for 6 h, sat. NH4C1 solution (10 mL) was added and the mixture was allowed to warm to RT. The solvent was removed in vacuo. The residue was suspended in diethyl ether. The mixture was filtered and the solids were washed with diethyl ether. The organic extract was washed with sat. NaCI solution (1 x 20 mL), NH4OH solution (3 x 20 mL) and sat. NaCI
solution (1 x 20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/diethyl ether 1:1) to give the title compound. MS (m/z): 233.8 [M+H+]
Reaction E was performed based on literature (Harding et al., J. Org. Chem.
1981, 46, 3920-3922) E. (2S,5S)-2,5-Dimethyl-pyrrolidine-l-carboxylic acid benzyl ester.
Mercuric acetate (2.05 g, 6.43 mmol) was added to a stirring solution of (S)-(1-methyI-pent-4-enyl)-carbamic acid benzyl ester (1.00 g, 4.29 mmol) in THF (43 mL).
The mixture was purged with nitrogen, covered with aluminum foil and stirred at RT
overnight. A solution of sodium borhydride (160 mg, 4.24 nvnol) in 2 N NaOH (0.32 mL) was added dropwise and the mixture was stirred at RT overnight. Sat. Na2CO3 solution (3 mL) was added. After stirring at RT for 4 h, the solvent was removed in vacuo. The residue was diluted with diethyl ether and extracted with sat. Na2CO3 solution (3 x 15 mL). The aqueous layer was extracted with diethyl ether (3 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/ methanol 30:1) to give the title compound. MS (m/z): 233.8 [M+H+]
F. (2S,5S)-2,5-Dimethyl-pyrrolidine (2S,5S)-2,5-Dimethyl-pyrrolidine-l-carboxylic acid benzyl ester (100 mg, 0.43 mmol) was dissolved in methanol (9 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator, which contained a cartridge of 10% palladium on carbon as catalyst. The hydrogenation was done at RT under a pressure of 10 bar. 20 drops of concentrated HCI were added. The solvent was evaporated to give the title compound as the HCl salt. MS (m/z): 100.0 [M+H*]
G. (R,S)-N-(1-{1-[2-Chloro-4-((2S,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl } -cyclopropyl)-3 -fluoro- 5 -trifluoromethyl-benzamide (R,S)-3-Chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropane carbonyl]-amino}-ethyl)-benzoic acid was reacted with (2S,5S)-2,5-dimethyl-pyrrolidine according to the synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl } -cyclopropyl)-amide to give the title compound as the TFA salt. MS (m/z): 554.0 [M+H+]
Example 17 Synthesis of N-((1R)-1-(4-(2,5-cis/trans-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 150) H H O
N N,N ~ F
rw o H ~ , CF, O N
First step of reaction A was performed based on literarture (Gibson et al., J.
Org. Chem.
1999, 64, 7388-7394) A. Resin-bound (R)-4-(1-(hydrazinecarboxamido)ethyl) benzoic acid Hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (150 mg, 0.59 mmol) was suspended in DCM (5 mL) and sat. NaHCO3 solution (5 mL). The biphasic mixture was stirred at 0 C for 5 minutes. The two layers were allowed to separate and phosgene (20%
solution in toluene, 1.3 mL, 2.95 mmol) was added via syringe to the organic phase. The mixture was stirred at 0 C for 10 minutes, the layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one. The crude product (350 mg, 0.483. mmol) was dissolved in DCM (2 mL) and added to a suspension of resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA showed the right product (R)-4-(1-(2=(((9H-fluoren-9-yl)methoxy)carbonyl)hydrazinecarboxamido)ethyl) benzoic acid. MS
(m/z): 445.8 [M+H+]. Piperidin (20% solution in DMF, 4 mL) was added and the mixture was shaken for 15 minutes. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and dried in vacuo. A test cleavage with TFA showed the right product. MS
(m/z): 223.8 [M+H+]
B. (R)-4-(1-(2-(3-Fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl) benzoic acid A solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083mo1) HATU
(31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM (1 znL) was added to resin-bound (R)-4-(1-(hydrazinecarboxamido)ethyl)benzoic. acid (106 mg, 0.069 mmol).
The mixture was shaken 2 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL).
The suspension was shaken at RT for 30 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase 1-iPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound. MS (m/z): 413.8 [M+H+]
C. N-((1 R)-1-(4-(2, 5 -cis/trans-Dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide 2,5-cis/trans-Dimethyl-pyrrolidine (4.7 mg, 0.047 mmol) was added to a solution of (R)-4-(1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl)benzoic acid (16.2 mg, 0.039 mmol), WSC (9.0 mg, 0.047 mmol) and collidine (25.8 L, 0.196 mmol) in DCM/DMF 9:1 (1 mL). After stirring overnight at RT, the mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN
in water with 0.1 % TFA to give the title compound. MS (m/z): 495.1 [M+H+]
Example 18 Synthesis of N-((1R)-1-(4-(2,5-cis/trans-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamide (Compound 151) N N, F
~ H
~
O N
Reaction A and the first step of reaction B were performed based-on literarture (Gibson et al., J. Org.Chem. 1999, 64, 7388-7394) A. N-Methyl-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester Methylhydrazine (173 l, 3.26 mmol) was added at -78 C to a stirring solution of di-tert-butyl dicarbonate (924 mg, 4.23 mmol) in DCM (5 mL). The solution was allowed to warm to RT and stirred at RT for 30 minutes. 9H-Fluorenylmethyl chloroformate (842 mg, 3.26 mmol) and ethyl-diisopropyl-amine (664 l, 3.91 mmol) were added dropwise and the mixture was stirred at RT for 8 h. TFA (5 ml) was added and the mixture stirred for additional 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 7:3) to give the title compound MS (m/z):
268.8 [M+H+]
B. (R)-4-(1-(2-(3-Fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamido) ethyl) benzoic acid Phosgene (20% solution in toluene, 3.43 ml, 6.51 mmol) was added dropwise at 10 C to a stirred solution of N-methyl-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (1.81 g, 3.26 mmol) in dioxane (15 ml). The mixture was stirred at 10 C for 5 minutes and then stirred at RT for 1.5 h. The mixture was concentrated in vacuo to give (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)-2-methylhydrazinecarboxylate. The crude product (68.5 mg, 0.207 mmol) was dissolved in DCM (1 mL) and added to a suspension of resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA
showed the right product (R)-4-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-methylhydrazinecarboxamido)ethyl)benzoic acid. MS (m/z): 459.8 [M+H+].
Piperidin (20%
solution in DMF, 4 mL) was added and the mixture was shaken for 30 minutes to give resin-bound (R)-4-(1-(1-methylhydrazinecarboxamido)ethyl)benzoic acid. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and a solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083 mmol), HATU (31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM/DMF 2:1 (1.5 ml) was added. The mixture was shaken 4 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL). The suspension was shaken at RT for 20 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound. MS (m/z):
427.7 [M+H+]
C. N-((1R)-1-(4-(2,5-cis/trans-Dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamide 2,5-cis/trans-Dimethyl-pyrrolidine (2.8 mg, 0.028 mmol) was added to a solution of (R)-4-(1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamido)ethyl)benzoic acid (10 mg, 0.023 mmol), WSC (5.4 mg, 0.028 mmol) and collidine (15.4 L, 0.117 mmol) in DCM/DMF 9:1 (1 mL). After stirring overnight at RT, the mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN
in water with 0.1% TFA to give the title compound. MS (m/z):-509.0 [M+H+]
Example 19 Synthesis of N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 268) F
VF
OyN,N NH H (f+) F F
N
(S, O N
(RI
A. 5 -Bromo-3 -fluoro-pyridine-2-carbonitrile H2SO4 (1 ml, 5 mol) was added to a TBAF solution in THF (657 ml, 0.66 mol, 1 M).
DMF (200 mL) were added at -40 C until the suspension became a clear solution.
5-bromo-3-nitropyridin-2-carbonitrile (50.0 g, 0.22 mol) in DMF (800 mL) were added slowly. The solution was stirred at -40 C for 30 min, till starting material could not be detected by TLC
(n-hex/EA 5:1). The reaction was quenched with 2 M HCI (500 ml) at -40 C to afford pH 3.
'The mixture was extracted twice with EA. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purifieded by chromatography on silica gel.
B. 5-Bromo-3 -fluoro-pyridine-2-carboxylic acid Conc. HCl (300 mL) were added to 5-Bromo=3-fluoro-pyridine-2-carbonitrile (21.0 g, 0.11 mol) and stirred over night at 60 C. After evaporation ether was added and the suspension was stirred for additional time. The solid was collected and dried.
The crude product was used without any further purification. MS (m/z): 219.8 [M+H+]
C. 5-Bromo-3 -fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide TEA (17.4 ml, 0.13 mol), EDCI (83.2 g, 0.43 mol), HOBt (2.90 g, 0.02 mol) and N,O-Dimethylhydroxylamine x HCI (25.0 g, 0.26 mol) were added to a solution of 5-Bromo-3-fluoro-pyridine-2-carboxylic acid (55.5 g, 0.22 mol) in DMF (1000 mL). After stirring overnight the solvent was reduced in vacuo. EA and brine were added and the aq. layer was extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel. MS (m/z): 262.8 [M+H']
D. 5 -Bromo-3 -fluoro-pyridine-2-carbaldehyde 1M LiA1H4 in THF (50 ml, 0.05 mol) was added slowly at -78 C to a solution of bromo-3-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (29.0 g, 0.11 mol) in THF
(350 mL) After 20 min stirring at -78 C the mixture was quenched with water and brine and allowed to come to room temperature. EA was added and the suspension was filtered over celite. The aq. layer was extracted with EA and the combined organic layers were washed with brine and dried over sodium sulfate. After evaporation the crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 203.9 [M+H{]
E. 2-Methyl-propane-2-sulfinic acid 5-bromo-3-fluoro-pyridin-2-ylmethyleneamide (R)-(+)-2-Methyl-2-propansulfinamide (11.6 g, 0.10 mol), magnesium sulfate (115 g, 0.10 mol), PPTS (2.40 g, 0.01 mol) and cesium carbonate (33.7 g, 0.10 mol) were added to a solution of 5-bromo-3-fluoro-pyridine-2-carbaldehyd (19.5 g, 0.10 mol) in DCM
(600 ml).
After stirring over night the reaction was filtered over celite and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA).
MS (m/z): 306.6 [M+H+]
F. 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-amide Methylmagnesium chloride solution (29.9 ml, 0.09 mol, 22% in THF) was added slowly to a solution of 2-methyl-propane-2-sulfinic acid 5-bromo-3-fluoro-pyridin-2-ylmethyleneamide (17.5 g, 0.06 mol) in DCM (570 mL) at -55 C. The reaction mixture was quenched with brine after stirring for 20 minutes at -55 C. Celite was added and the suspension was filtered. The layers were separated and the aq. layer was extracted with DCM.
The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA).
MS (m/z): 322.6 [M+H+]
G. 5-Fluoro-6-[1-(2-methyl-propane-2-sulfmylamino)-ethyl]-nicotinic acid methyl ester To a stirred suspension of 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-amide (1.40 g, 4.33 mmol), 1,4-bis-(diphenylphosphino)ferrocene (0.53 g, 0.96 mmol) and Pd(OAc)2 (0.21 g, 0.91 mmol) in anhydrous DMSO (10 mL) under an atmosphere of nitrogen were added triethylamine (3.6 mL, 26.0 mmol) and anhydrous methanol (4 mL). After stirring at 70 C under an atmosphere of carbon monoxide for 14 h the mixture was concentrated in vacuo and the residue was partitioned between EA
(200 mL) and sat. NaHCO3 solution (200 mL). After extraction of the aqueous layer with EA
(2 x 200 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS (m/z): 302.7 [M+M
H. 6-((1R)-1-(1,1-Dimethylethylsulfinamido)ethyl)-5-fluoronicotinic acid To a solution of 5 -fluoro-6- [1-(2-methyl-propane-2-sulfmylamino)-ethyl] -nicotinic acid methyl ester (910 mg, 3.01 mmol) in MeOH (1.5 mL) and H20 (0.5 mL) was added LiOH
(215 mg, 9.03 mmol). The solution was stirred overnight then concentrated. The residue was dissolved in 15% MeOH/CH2C12 and filtered through a short silica column to remove inorganic salts. Crude 6-((1R)-1-(1,1-dimethylethylsulfmamido)ethyl)-5-fluoronicotinic acid was determined to be of sufficient purity for the next reactions. MS (m/z):
288.7 [M+H+]
1. N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide 6-((1R)-1-(1,1-Dimethylethylsulfinamido)ethyl)-5-fluoronicotinic acid (50.0 mg, 0.17 mmol) was added to a stirred solution of (2R,5S')-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (Example 4C) (35.3 mg, 0.26 mmol), HATU (65.9 mg, 0.17 mmol) and DIPEA (151 L, 0.87 mmol) in DMF (1.7 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with n-hexane/EA 5:1). MS (m/z): 369.8 [M+H+]
J. (6-((R)-1-Aminoethyl)-5-fluoropyridin-3-yl)((2R,5S)-2,5-dimethylpyrrolidin-l-yl)methanone hydrochloride To N-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (50 mg, 0.14 mmol) is added a solution of HCl in MeOH (3 N, 1 mL). The reaction mixture is stirred at RT for 2 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction.
MS (m/z): 265.9 [M+H+]
K. tert-Butyl 2-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
tert-Butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (46 mg, 0.21 mmol) was dissolved in THF (2 mL) treated with DIPEA (361 L, 2.07 mmol) and cooled to 0 C before a solution of (6-((R)-1-aminoethyl)-5-fluoropyridin-3-yl)((2R,5S)-2,5-dimethylpyrrolidin-l-yl)methanone hydrochloride (25 mg, 0.08 mmol) with DIPEA (32 L, 0.18 mmol) in THF(2 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT
for 14 h. The mixture was poured into EA and washed sequentially with HCl (1 N), sat.
NaHCO3, and brine before being dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography on silica gel (elution with n-hexane/EA 3:1).
MS (m/z):
451.9 [M+H+]
L. N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3 -fluoropyridin-2-yl)ethyl)-1-ethyl-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide To tert-butyl2-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (25 mg, 0.06 mmol) is added a solution of HCl in MeOH (3N, 1 mL). The reaction mixture is stirred at RT for 2 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
The hydrochloride (20 mg, 0.05 mmol) is dissolved in DMF (0.5 mL), treated with DIPEA (90 L, 0.52 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (10 mg, 0.08 mmol) and stirred 2 h at RT. Then the mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA to give the title compound. MS (m/z): 541.8 [M+H+]
Example 20 Synthesis of (R)-N-(1-(2-chloro-4-(diethylcarbamoyl)phenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 256) . I F F
Oy N.N ~
F
NH H /
CI F
O N
A. Methyl4-((tert-butylsulfinylimino)methyl)-3-chlorobenzoate The synthesis of 3-chloro-4-formyl-benzoic acid methyl ester is described in Example 15B.
(S)-(-)-2-Methyl-2-propansulfinamide (1.26 g, 10.4 mol), magnesium sulfate (12.5 g, 104 mmol), PPTS (0.52 g, 2.08 mol) were added to a solution of 3-chloro-4-formyl-benzoic acid methyl ester (2.07 g, 10.4 mmol) in DCM (52 ml). After stirring over night the reaction was filtered over celite and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 301.7 [M+H+]
B. Methyl3-chloro-4-((1R)-1-(1,1-dimethylethylsulfinamido)ethyl)benzoate Methylmagnesium chloride solution (3.4 ml, 9.75 mmol, 22% in. THF) was added slowly to a solution of methyl 4-((tert-butylsulfmylimino)methyl)-3-chlorobenzoate (1.73 g, 5.73 mmol) in DCM (30 mL) at -55 C. The reaction mixture was quenched with brine after stirring for 1 h at -55 C. Celite was added and the suspension was filtered. The layers were separated and the aq. layer was extracted with DCM. The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 317.8 [M+H+]
C. (R)-Methyl4-(1-aminoethyl)-3 -chlorobenzoate hydrochloride To methyl 3-chloro-4-((1R)-1-(1,1-dimethylethylsulfmamido)ethyl)benzoate (199 mg, 0.63 mmol) is added a solution of HCl in MeOH (3N, 10 mL). - The reaction mixture is stirred at RT for 1 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction. MS (m/z): 213.8 [M+I+]
D. (R)-tert-Butyl 2-(1-(2-chloro-4-(methoxycarbonyl)phenyl)ethylcarbamoyl)-2-ethyl hydrazinecarboxylate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (417 mg, 1.87 mmol) was dissolved in THF (2 mL) treated with DIPEA (718 L, 4.11 mmol) and cooled to 0 C before a solution of (R)-methyl 4-(1-aminoethyl)-3-chlorobenzoate hydrochloride (79 mg, 0.32 mmol) with DIPEA (121 L, 0.69 mmol) in THF (2 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT for 14 h. The mixture was poured into EA
and washed sequentially with HCl (1 N), sat. NaHCO3, and brine before being dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography on 'silica gel (elution with n-hexane/EA). MS (m/z): 399.7 [M+H+]
E. (R)-Methyl 3-chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl) hydrazinecarboxamido)ethyl)benzoate To (R)-tert-butyl 2-(1-(2-chloro-4-(methoxycarbonyl)phenyl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (75 mg, 0.19 mmol) is added a solution of HCI in MeOH (3 N, 2 mL). The reaction mixture is stirred at RT for 14 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction.
The hydrochloride (63 mg, 0.19 mmol) is dissolved in DMF (1.0 mL), treated with DIPEA (163 L, 0.94 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (47 mg, 0.21 mmol) and stirred 2 h at RT. Then the mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 489.6 [M+H+]
F. (R)-N-(1-(2-Chloro-4-(diethylcarbamoyl)phenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To a solution of (R)-methyl 3-chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl)benzoate (92 mg, 0.19 mmol) in Dioxan (2 mL) was added a 2 N solution of LiOH in water (1 mL) and the reaction was stirred for 3 h. Then the organic solvent is removed in vacuo, the water layer was extracted twice with EA and the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was used in the next step without further purification.
(R)-3-Chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazine carboxamido)ethyl)benzoic acid (27.0 mg, 0.06 mmol) was added to a stirred solution of diethylamine (44.0 mg, 0.60 mmol) and HATU (22.9 mg, 0.06 mmol) in DMF (1.5 mL).
After stirring for 2 h the reaction mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA
to give the title compound. MS (m/z): 530.9 [M+H+]
Example 21 Synthesis of N-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl) ethyl)-1-ethyl-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 263) ! V F
OyN. 1 NH
H ci F
N
(s) O N
(W
A. Dimethyl 3-chloropyridine-2,5-dicarboxylate Dimethyl 3-chloropyridine-2,5-dicarboxylate was synthesized according to literature (Hendrickson et al. Org. Lett. 2004, 3-5).
Pyridine-2,5-dicarboxylic acid (10.0 g, 60.0 mmol) was suspended in 300 mL
0.2% (w/w) aq. Na2WO4 (0.6 g). To this solution was added H202 in water (30% w/w, 34 mL, 315 mmol).
The resulting mixture was stirred and heated at 80-85 C for 10 hours. The resulting solid was collected by filtration and washed with cold water. Drying the material under high vacuum overnight yielded pyridine-2,5-dicarboxylic acid N-oxide, which was used in the next step without further purification.
To a solution of thionyl chloride (17.4 mL, 240 mmol) in DCM (500 mL) was added DMF (5 mL) at 0 C. Pyridine-2,5-dicarboxylic acid N-oxide from the first step was added into this mixture portionwise. The resulting mixture was heated at 65 C for 2 hours. The reaction was cooled to RT then placed in an ice-bath. The reaction was quenched with methanol (100 mL) slowly at 0 C. The solvent was removed in vacuo and the crude product was partitioned between DCM (200 mL) and aq. NaHCO3 (sat. 100 mL). The organic layer was separated and the aqueous layer was extracted with additional DCM (2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo.
Purification of the crude oil through a short plug of silica gel using hexane/ethyl acetate (4:1) afforded dimethyl3-chloropyridine-2,5-dicarboxylate. GC/MS (m/z): 229.0 B. Methyl 5-chloro-6-(hydroxymethyl)nicotinate To a solution of dimethyl 3-chloropyridine-2,5-dicarboxylate (1.0 g, 4.4 mmol) in THF
(10 mL) and MeOH (20 mL) was added powdered calcium chloride (3.9 g, 35 mmol).
The suspension was cooled to 0 C and sodium borohydride (416 mg, 11.0 mmol) was added portionwise. The resulting mixture was stirred for 3 h at 0 C and poured into ice-water (200 mL), and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was removed in vacuo to yield methyl 5-chloro-6-(hydroxymethyl)nicotinate which was used in the next step without further purification.
GC/MS (m/z): 201.0 C. Methyl 5-chloro-6-formylnicotinate To a solution of methyl 5-chloro-6-(hydroxymethyl)nicotinate (3.2 g, 15.8 mmol) in DCM (20 mL) was added Dess-Martin periodinane (10.1 g, 23.7 mmol). The solution was stirred for 1 h, diluted with DCM and filtered over a pad of Celite. After evaporation of the solvent in vacuo the crude material was purified by flash chromatography (hexane/ethyl acetate 3:1) to give the title compound. GC/MS (m/z): 201.0 D. (R)-Methyl 6-((tert-butylsulfinylimino)methyl)-5-chloronicotinate To a solution of (R)-(-)-2-methyl-2-propanesulfinamide (0.73 g, 6.0 mmol) in DCM (25 mL) was added methyl 5-chloro-6-formylnicotinate (1.2 g, 6.0 mmol), pyridinium p-toluenesulfonate (0.15 mg, 0.6 mmol), magnesium sulphate (7.2 g, 60 mmol) and freshly powdered caesium carbonate (1.9 g, 6.0 mmol). The reaction was stirred at RT
for 6 h. The mixture was filtered through celite, washed with DCM, and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography (0-10% ethyl acetate in hexanes) to provide the title compound. MS (m/z): 302.6 [M+H+]
E. Methyl 5-chloro-6-((R)-1-((R)-1,1-dimethylethylsulfmamido)ethyl)nicotinate Methyl magnesium chloride (22% in THF, 2.1 mL, 6.0 mmol) was added dropwise at -60 C to a stirred solution of (R)-methyl 6-((tert-butylsulfinylimino)methyl)-5-chloronicotinate (1.2 g, 4.0 mmol) in DCM (30 mL). After stirring for 30 min at -60 C, sat.
ammonium chloride solution (40 mL) was added. The aqueous layer was extracted with DCM
(4 x 25 ml), the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA 1:1) to give the tiltle compound. MS (m/z): 318.8 [M+H+]
F. (R)-Methyl 6-(1-aminoethyl)-5-chloronicotinate hydrochloride A. solution of methyl 5-chloro-6-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl) nicotinate (230 mg, 0.72 mmol) and HCl (3N solution in MeOH, 2 mL) was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue was recristallized from diethylether to give the title compound as the HCl salt. MS (m/z): 214.8 [M+H+]
G. (R)-Methyl 6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-chloronicotinate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (443 mg, 1.99 mmol) was dissolved in THF (2.5 mL) treated with DIPEA (705 L, 3.98 mmol) and cooled to before a solution of (R)-methyl 6-(1-aminoethyl)-5-chloronicotinate hydrochloride (100 mg, 0.40 mmol) with DIPEA (155 L, 0.88 mmol) in THF (2.5 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT for 14 h. The mixture was poured into EA and washed sequentially with HCl (1 N), sat. NaHCO3, and brine before being dried (MgSO4), filtered, and, concentrated. The product was purified by flash chromatography on silica gel (elution with hexane/EA). MS (m/z): 400.8 [M+H+]
H. (R)-6-(1-(2-(tert-Butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (R)-Methyl 6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinate (220 mg, 0.55 mmol) was dissolved in ACN (5.mL), treated with LiOH (1M
solution in water, 3.5 mL) and stirred 13 h at RT. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCl solution and the aqueous layer was extracted with EA (3 x) and DCM/iPrOH
(4:1, 3 x).. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.
The resulting title compound was used for the next reaction without purification. MS (m/z):
386.8 [M+H+]
I. tert-Butyl 2-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (2R,5S)-2,5-Dimethylpyrrolidine hydrochloride (105 mg, 0.78 mmol) was added to a stirred solution of (R)-6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (150 mg, 0.39 mmol), WSC (149 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol) and DIPEA (330 L, 1.94 mmol) in DCM (2.5 mL). After stirring overnight at RT the solvent was removed in vacuo and the crude product was partitioned between EE
and aq.
NaZCO3. The organic layer was separated and the aqueous layer was extracted with additional EA (2 x). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 467.9 [M+H+]
J. N-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To tert-Butyl 2-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (180 mg, 0.39 mmol) is added a solution of HC1 in MeOH (3N, 20 mL). The reaction mixture is stirred at RT for 13 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
N-((R)-1-(3 -Chloro-5 -((2R, 5S)-2, 5 -dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethylhydrazinecarboxamide hydrochloride (8.0 mg, 0.02 mmol) was added to a stirred solution of 3-fluoro-5-(trifluoromethyl)benzoic acid (9.1 mg, 0.04 mmol), WSC
(8.3 mg, 0.04 mmol), HOBt (5.9 mg, 0.04 mmol) and DIPEA (19 L, 0.11 mmol) in DMF (0.2 mL).
After stirring overnight at RT the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound. MS (m/z): 557.9 [M+IT"]
Example 22 Synthesis of (R)-5-chloro-N,N-diethyl-6-(1-(1-ethyl-2-(3-fluoro-5-(trifluoiomethyl) benzoyl)hydrazinecarboxamido)ethyl)nicotinamide (Compound 265) F
OvN. VF N 1 NH H !RI
CI N F
O N
J
A. (R)-tert-Butyl 2-(1-(3-chloro-5-(diethylcarbamoyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate Diethylamine (31 mg, 0.42 mmol) was added to a solution of (R)-6-,(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (82 mg, 0.21 mmol), WSC (82 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and DIPEA (180 L, 1.06.
mmol) in DCM (1.5 mL). After stirring overnight at RT the solvent was removed in vacuo and the crude product was partitioned between EE and aq. Na2CO3. The organic layer was separated and the aqueous layer was extracted with additional EA (2 x). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification.
MS (m/z): 441.9 [M+H+]
B. N-((R)-1-(3-Chloro-5-((2R,5S')-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To (R)-tert-butyl 2-(1-(3-chloro-5-(diethylcarbamoyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (93 mg, 0.21 mmol) is added a solution of HC1 in MeOH (3N, 15 mL). The reaction mixture is stirred at RT for 13 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
(R)-5-Chloro-N,N-diethyl-6-(1-(1-ethylhydrazinecarboxamido)ethyl)nicotinamide hydrochloride (8.3 mg, 0.02 mmol) was added to a stirred solution of 3-fluoro-(trifluoromethyl)benzoic acid (10 mg, 0.05 mmol), WSC (9.3 mg, 0.05 mmol), HOBt (6.6 mg, 0.05 mmol) and DIPEA (22 L, 0.12 mmol) in DMF (0.2 mL). After stirring overnight at RT
the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA to give the title compound. MS (m/z): 531.8 [M+H+]
Example 23 Synthesis of (R)-N-(1-(4-(diethylcarbamoyl)-2-fluorophenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 221) F
VF
OYN, NH H (R) F ~ F
O N'\
A. (R)-4-(1-(((9H-Fluoren-9-yl)methoxy)carbonylamino)ethyl)-3 -fluorobenzoic acid (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (Example lOC) (100 mg, 0.43 mmol) was stirred in 6 N HCl solution (10 mL) at reflux overnight. Solvent was reduced in vacuo to give (R)-4-(1-aminoethyl)-3-fluorobenzoic acid hydrochloride. To the crude product (94 mg, 0.43 mmol) dissolved in DCM (2 mL), chlorotrimethylsilane (135 L, 1.07 mmol) was added. After stirring at reflux for few minutes, (9H-fluoren-9-yl)methyl carbonochloridate and triethylamine (230 mL, 1.7 mmol) were added at RT and the solution was stirred overnight. The residue was concentrated in vacuo and sat. Na2CO3 solution (50 mL) was added. After acidification of the aqueous solution with 2 N HCL
(pH=3), the aqueous layer was extracted with EA (2 x 30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with DCM/methano12:1).
MS (m/.z):
405.8 [M+H+]
B. Resin-bound (R)-4-(1-aminoethyl)-3-fluorobenzoic acid (R)-4-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-3-fluorobenzoic acid (324 mg, 0.8 mmol) and DIPEA (332 jiL, 1.9 mmol) were dissolved in DCM (8 mL). The solution was added to 2-chlorotrityl chloride resin (loading: 1.4 mmol/g, 1.09 g, 1.5 mmol) swollen in DCM (8 mL) and the mixture was shaken at RT for 30 minutes. The mixture was quenched with methanol (800 L). The resin was filtered and washed with DCM/methanol/DIPEA
(16:3:3, 1 x 10 mL) and DMF (3 x 10 mL). Piperidin (25% solution in DMF, 10 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF
(6 x 10 mL) and dried in vacuo to give the title compound with an expected loading of 45%
(0.65 mmol/g).
C. (91Y-Fluoren-9-yl)methyl2-ethylhydrazinecarboxylate To a solution of (9H-fluoren-9-yl)methyl hydrazinecarboxylate (500 mg, 1.97 mmol) in ethanol (9.8 mL), acetaldehyde (86.7 mg, 1.97 mmol) was added and the mixture was refluxed overnight. To this solution acetic acid (124 L, 2.16 mmol) and sodium cyanotrihydroborate (136 mg, 2.16 mmol) were added. After stirring at RT
overnight the solvent was reduced in vacuo and'the residue was partitioned between EA (30 mL) and sat.
NaCI solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1). MS (m/z): 282.7 [M+H+]
D. (R)-4-(1-(1-Ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido) ethyl)-3-fluorobenzoic acid Phosgene (20% solution in toluene, 0.463 ml, 0.88 mmol) was added dropwise at 0 C to a stirred solution of (9H-fluoren-9-yl)methyl2-ethylhydrazinecarboxylate (125 mg, 0.44 mmol) in DCM (4.4 ml). The mixture was stirred at 0 C for 30 minutes and then concentrated in vacuo to give (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate. The crude product (68.5 mg, 0.207 mmol) was dissolved in DCM (1 mL) and added to a suspension of resin-bound (R)-4-(1-aminoethyl)-3-fluorobenzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA showed the right product (R)-4-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-ethylhydrazinecarboxamido)ethyl)-3 -fluorobenzoic acid.
MS (m/z): 491.7 [M+H+]. Piperidin (20% solution in DMF, 4 mL) was added and the mixture was shaken for 30 min to give resin-bound (R)-4-(1-(1-ethylhydrazinecarboxamido)ethyl)-3-fluorobenzoic acid. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and a solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083mo1), HATU (31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM/DMF 2:1 (1.5 ml) was added. The mixture was shaken 4 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL). The suspension was shaken at RT for 20 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound. MS (m/z): 459.6 [M+H+]
E. (R)-N-(1-(4-(Diethylcarbamoyl)-2-fluorophenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxarnide (R)-4-(1-( I -Ethyl-2-(3 -fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido) ethyl)-3-fluorobenzoic acid (12 mg, 0.028 rnmol) was added to a stirred solution of diethylamine (5.7 L, 0.055 mmol), HATU (10.6 mg, 0.028 mmol) and DIPEA (23.4 L, 0.14 mmol) in DMF (1.5 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA
to give the title compound. MS (m/z): 514.8 [M+H}]
Biological evaluation:
Example 24 Radioligand binding assay Assessing the affinity of selected compounds to bind to the BK B 1 receptor of different species.
Radioligand binding assays were performed using HEK923 cells that can be induced by tetracycline to express the human, rabbit, mouse, dog, pig or rat B 1 receptor.
The genes for the BK B1R of human, rat, mouse,. rabbit, dog, and pig were generated synthetically (GENEART, Regensburg) using a gene design and a codon usage optimized for stable expression in human cells. All receptor genes were stably and isogenically expressed by insertion into an identical position in the genome by using the Flp-In system from Invitrogen with the host cell line Flp-In T-REx HEK293 (human embryonic kidney) together with either the pcDNA5/FRT/TO-vector (for stable but tetracyclin-inducible expression). The latter was used in particular for all B 1 R subtypes, to avoid problems with a potential constitutive activity of these receptors that may prohibit the growth and selection of stably expressing clones.
For all receptor types the respective HEK293 cells bearing the respective transgene were cultured in DMEM high glucose medium supplemented with 10% FCS. At 80%
confluence cells were harvested from culture flasks by trypsinization and resuspended in DMEM 10%
FCS containing 5 g/ mL tetracycline. Cells were seeded in poly-lysine coated flat bottom 96 well plates (TPP) at appr. 80.000 cells/well and used in the binding assay after an overnight incubation at 37 C.
The cell plates were washed 2x with icecold PBS and kept on ice during the whole assay.
Test compounds were assayed at 10 different concentrations diluted in half-log steps in duplicate wells. Compounds were diluted in assay binding buffer (40mM PIPES, 109 mM
NaCI, 5mM KCI, 0.1% Glucose, 0.05% BSA, 2mM CaC12, 1 mM MgC12, 60 mM NaOH; pH
7.4) containing the protease inhibitors Captopril (100 M), 1,10-Phenanthroline (20 M) and Bacitracin (500 M). 1nM 3H-DAKD (Perkin Elmer) and the antagonist compound dilutions were prepared in a dilution plate which also included controls to assess total binding (1 nM
3H-DAKD) and non-specific binding (1 nM 3H DAKD + 10 mM DAKD). 100 L from the dilution plate was added to the cell plate and incubated for 90 minutes on ice. After that supernatants were aspirated and the plates were washed 4x with icecold PBS
followed by the addition of 200 gL dissociation buffer (0.5 M NaCI, 0.2 M acetic acid) for 10 minutes on ice.
Supematants were transferred into 6 mL scintillation vials (Sarstedt) containing 2 mL of scintillation solution (Ultima Gold, Perkin-Elmer), mixed well and subsequently measured in a Packard Topcount Scintillation counter. Specific binding to B1R was defined as the difference between total binding and non-specific binding wells. Total specific binding was set to 100% binding and 0% inhibition. Specific counts in the presence of compounds were plotted against compound concentration (log M). ICSo values were calculated by fitting a 4-parameter logistic function to the concentration-response data using non-linear regression (Xlfit, IDBS ID Business Solutions Ltd.). The compounds of this invention have affinity for the B1R in the above assay as demonstrated by results of less than 5 M.
Example 25 Functional assay for BK BI antagonists The potency and efficacy of the compounds in this invention to antagonize the was determined in a cell-based fluorescent calcium-mobilization assay. The assay measures the ability of test compounds to inhibit BK B 1R agonist-induced increase of intracellular free Calcium in different cell lines. Endogenous B1R expression was induced by IL-lbeta pretreatment of human embryonal lung fibroblasts IMR-90. B1R of several non-human species (rat, mouse, rabbit, dog and pig) were expressed recombinantly after Tetracyclirie induction in HEK 293 cells bearing the respective transgene.
Calcium-indicator-loaded cells were preincubated in the absence or presence of different concentrations of test compounds followed by stimulation of with selective B1R
agonist peptide. B1R agonist-induced calcium mobilization was monitored using the FlexStation fluorescence imaging plate reader platform.
IMR-90 human embryonal lung fibroblast cells (ATCC# CCL 186) were cultured in DMEM high (4.5g/1) glucose supplemented with 15% FCS and 4mM Glutamine.
Confluent cells were harvested by trypsinization after 5d of culture and seeded into black wall/clear bottom 96-well plates (Costar# 3603) at 40.000 cells/well. After an overnight incubation (appr. 12-16h) cells were treated with 1.36 ng/ mL human recombinant IL-10 in DMEM
15%FBS for 4h at 37 C to induce B1R upregulation. Thereafter cells were washed 2x with prewarmed Hank's balanced salt solution/20 mM HEPES buffer and subsequently loaded with fluorescent calcium indicator dye no-wash Calcium 3 assay kit (Molecular Devices) at 37 C for lh in the presence of anion transport inhibitor probenecid at 2.5 mM.
Test compounds were assayed at 7 concentrations in duplicate wells. Compound addition plates contain 5x fmal concentrations of test compounds or controls in 5% DMSO. The test compounds were added in 5 L followed by a 10 minute equilibration phase at 37 C in an incubator. Plates were then placed in the FlexStation II unit (Molecular Devices) which was set to 37 C. The addition of 50 L of the B1R agonist desArgKallidin (DAKD, Bachem) was carried out in the FlexStation II while continuously monitoring Ca-dependent fluorescence increase. Fluorescence peak heights were calculated by subtracting mean of baseline from maximum peak height. Peak heights were plotted as a function of test compound concentration while peak height without antagonist addition was defined as 100% response and 0% inhibition. Relative fluorescence peak heights were used to calculate the degree of of inhibition of the B1R agonist response by test compound. IC50 values were calculated by fitting a 4-parameter logistic function to the concentration-response data using non-linear regression (Xlfit, IDBS ID Business Solutions Ltd.). The compounds of this invention have affinity for the B1R in the above assay as demonstrated by results of less than 5 M.
Most preferred compounds of formula (I) exhibited IC50 values of less than 50 nanomolar in this assay.
The features of the present invention disclosed in the specification, the claims and/or the drawings may both separately and in any combination thereof be material for realizing the invention in various forms thereof.
In a eleventh embodiment of the first aspect which is also an embodiment of the sixth to tenth embodiment of the first aspect RY4 is a hydrogen atom or halogen atom.
In a twelfth embodiment of the first aspect which is also an embodiment of the first to eleventh embodiment of the first aspect T is a hydrogen atom.
In a 13th embodiment of the first aspect which is also an embodiment of the first to twelfth embodiment of the first aspect K is selected from s- ~N s \N
S \N N
or In a 14th embodiment of the first aspect which is also an embodiment of the first to 13th embodiment of the first aspect K is selected from J .~
XN or >SN-j In a 15th embodiment of the first aspect which is also an embodiment of the first to 14'' embodiment of the first aspect K is XN
In a 16'` embodiment of the first aspect which is also an embodiment of the first to 14th embodiment of the first aspect K is XNJ
In a 17th embodiment of the first aspect which is also an embodiment of the first to 16th embodiment of the first aspect B is heteroalkyl, heteroaryl, or R 4 \ R5 ~r\
wherein W is N, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl;
R4, if present, is a hydrogen atom, alkyl, heteroalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, aralkyl, heteroaralkyl or joined to R5 to form, together with N, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl; and R5, if present, is a hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with N, i) an optionally substituted cycloalkyl;
ii) an optionally substituted heterocycloalkyl;
iii) an optionally substituted aryl; or iv) an optionally substituted heteroaryl.
In an 18th embodiment of the first aspect which is also an embodiment of the first to 17th embodiment of the first aspect B is -YaB-CO-LB- or -YaB-CO-R $-, wherein YaB is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
LB is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and R B is an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
In a 19th embodiment of the first aspect which is also an embodiment of the first to 18th embodiment of the first aspect B is In a 20'h embodiment of the first aspect which is also an embodiment of the first to 18'b embodiment of the first aspect B is rS
O
wherem R4 is methyl, ethyl or isopropyl.
In a 2l St embodiment of the first aspect which is also an embodiment of the first to 17th embodiment of the first aspect B is In a 22"d embodiment of the first aspect which is also an embodiment of the first to 21s' embodiment of the first aspect E is -YaE-CO-LE-, -YaE-CO-WE-, -YaE-NR E-CO-RdE-, -YaE-NR E-CO-LE- -YaE-WE-CO-NRdE-LE-, or -YaE-NWE-CS-NRdE-LE-, wherein YaE is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R E is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-Cgalkenyl or an optionally substituted C2-CBalkynyl, provided that R~E is not a hydrogen atom in -YaE-CO-R E-;
RdE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-Cgalkynyl; and LE is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.
In a 23`d embodiment of the first aspect which is also an embodiment of the first to 22 d embodiment of the first aspect G is alkyl, cycloalkyl, -YaG-O-RcG, -YaG-CO-NRaGRbG, -YaG_S-R G, -YaG-SO-RcG, -YaG-SO2-RcG, heteroaryl, alkylcycloalkyl, or heterocycloalkyl, wherein YaG is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
RaG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to RbG
to form a 4- to 10-membered cycloalkyl or heterocycloalkyl;
RbG is a hydrogen atom, a C1-C6a1ky1, a C2-C6alkenyl or a C2-C6alkynyl, or is joined to RaG to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; and R G is an optionally substituted C1-CBalkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
In a 24th embodiment of the first aspect which is also an embodiment of the first, fourth to six, twelfth, 17t' or 22 d embodiment of the first aspect the compound is represented by formula (II):
H
B-E
Rya Y, Ry3 Rn o K (II) wherein Y' is N, CH or CF;
K is selected from XN or xN-J
~
R3 is a hydrogen atom or methyl;
RY2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
Ry3 is a hydrogeri atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
RY4 is a hydrogen atom or halogen atom;
B is -YaB-CO-LB-, -YaB-CO-RB-, or R \ R5 ~
O
5 wherein Y'*'B is a bond;
R $ is an optionally substituted C1-Cgalkyl or an optionally substituted C2-C8alkenyl;
LB is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally . substituted heteroaryl, or heteroaralkyl;
W is alkyl or N;
R4, if present, is a hydrogen atom, alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
R5, if present, is a hydrogen atom or alkyl;
E is -YbE-NRdE-CO-LE-, wherein ybE is a bond, a C1-C6alkylene, or a C2-C6alkenylene;
RdE is a hydrogen atom, a Cl-C6alkyl, or C2-C6alkenyl; and LE is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl.
In a 25th embodiment of the first aspect which is also an embodiment of the first, fourth to sixth, twelfth, 13th, 17th to 20th, 22nd or 23`d embodiment of the first aspect the compound is represented by formulas (III) or (IV):
H H YN
Rya 0 Ry4 0 Y~ Yi I ~ I
Ry3 Rn RY3 Ry2 K (III) ic (IV) wherein Yl is N, CH or CF;
K is selected from XN or XN-j R3 is a hydrogen atom or methyl;
R'2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
Ry3 is a hydrogen atom, halogen atom, C1-C6allcyl, or C1-C6heteroalkyl;
Ry4 is a hydrogen atom or halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -YaF-NR E-CO-RdE-, -YaF--NR E-CO-LE-, -YaE-NR E-CO-NRaE-LE-, or -Y,,E-NRcE-CS-NRdE-LE-, wherein YaE is a bond or C1-C6alkylene;
R~E is a hydrogen atom, C1-C6alkyl, or C2-C6alkenyl;
RdE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl group;
LE is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl;
G, if present, is cycloalkyl, -YaG-CO-NRacRbG, -YaG_C_ReG, -YaG_S_ReG' _YaG_SO-R`G, or -YaG-SO2-ReG, wherein YaG is a bond or C1-C6alkylene;
RaG is a hydrogen atom or C1-C6alkyl;
RbG is a hydrogen atom or C1-C6alkyl; and ReG 1S C1-C6alkyl.
In a 26th embodiment of the first aspect which is also an embodiment of the -25L~
embodiment of the first aspect the compound is represented by formula (V):
H
Rs N N/ LE
H
Ry4 Y, Rvs RYl K (=) wherein Y', K, R3, RYZ, RY3, Ry4, and LE are as defined in 25h embodiment of the first aspect.
In a 27h embodiment of the first aspect which is also an embodiment of the 25th embodiment of the first aspect the compound is represented by formula (VI):
H
N
R J" LE
H
. . y Ry4 1 Y, Ry3 Ry2 -c (VI) wherein Y', K, R3, RY2, Ry3, RY4, and LE are as defined in claim 25.
In a 28th embodiment of the first= aspect which is also an embodiment of the 2411` to 271' embodiment of the first aspect Ry3 is a hydrogen atom.
In a 29th embodiment of the first aspect which is also an embodiment of the 2411 to 28I' embodiment of the first aspect wherein R2 is a hydrogen atom.
In a 3& embodiment of the first aspect which is also an embodiment of the first, fourth to sixth, ninth, tenth, twelfth, 13th, 17th, 215t, 22 nd or 23a embodiment of the first aspect the compound is represented by formula (VII):
H
N N
Ry4 I
y, E-G
K (VII) wherein Yl is N, CH or CF;
K is selected from ?'N ~\N
XN or XN-j _j RY4 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -YaE-CO-LE-, wherein YaE is a bond or C1-C6alkylene;
LE is heterocycloalkyl; and 10 G is alkylcycloalkyl, heterocycloalkylalkyl, aryl or heteroaryl.
In a 31st embodiment of the first aspect which is also an embodiment of the 30I' embodiment of the first aspect 15 R'4 is a hydrogen atom or halogen atom.
In a 32nd embodiment of the first aspect which is also an embodiment of the first to 31St embodiment of the first aspect wherein 20 the stereogenic center to which R3 is attached to is in the (R) configuration; and R3 is methyl.
In a 33`d embodiment of the first aspect. which is also an embodiment of the first to 32nd embodiment of the first aspect the compound exhibits an IC50 of 500 nM or less in a standard in vitro BK B 1 receptor-mediated assay.
In a first embodiment of the second aspect the problem underlying the instant application is solved by a compound, which is preferably a compound according to any one of the first to 33rd embodiment of the first aspect, which compound is selected from compounds 1 to 282 of Table 1.
In a first embodiment of the third aspect the problem underlying the instant application is solved by a pharmaceutical composition comprising one or more compounds according to any embodiment of the first and second aspect, optionally, at least one carrier substance, excipient and/or adjuvant.
In a second embodiment of the third aspect which is also an embodiment of the first embodiment of the third aspect,the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal therapeutic system, a suppository, or a pharmaceutical device.
In a first embodiment of the fourth aspect the problem underlying the instant application is solved by the use of a compound or of a pharmaceutical composition according to any embodiment of the first to third aspect for the manufacture of a medicament for the treatment and/or prevention of a disease or a condition.
In a second embodiment of the fourth aspect which is also an embodiment of the first embodiment of the fourth aspect the condition or disease is responsive to BK
BIR
modulation.
In a third embodiment of the fourth aspect which is also an embodiment of the first or second embodiment of the fourth aspect the condition or disease is selected from the group comprising inflammatory diseases, immunology disorders and pain.
In a fourth embodiment of the fourth aspect which'is also an embodiment of the third embodiment of the fourth aspect the inflammatory disease or immunology disorder is selected from the group comprising inflammatory bowel disease, rheumatoid arthritis, gouty arthritis, atherosclerosis and associated fibrotic conditions In a fifth embodiment of the fourth aspect which is also an embodiment of the third embodiment of the fourth aspect the pain is selected form the group comprising visceral pain, neuropathic pain, complex regional pain syndrome CRPS and inflammatory pain.
In a first embodiment of the fifth aspect the problem underlying the instant application is solved by a method for inhibiting binding of DAKD, KD and DABK to a BK B 1 receptor in vitro, the method comprising contacting the BK B 1 receptor with at least one compound or a pharmacologically acceptable salt, solvate, or hydrate thereof according to any embodiment of the first to third aspect under conditions and in an amount sufficient to detectably inhibit binding of DAKD, KD and DABK to the BK B 1 receptor.
In a first embodiment of the sixth aspect the problem underlying the instant application is solved by a method for localizing or detecting a BK B1 receptor in a tissue, preferably a tissue section, in vitro, comprising:
(a) contacting a sample of said tissue presumably containing the BK B 1 receptor with a detectably labeled compound according to any embodiment of the first to third aspect under conditions that permit binding of the compound to the BK B 1 receptor; and (b) detecting the compound bound to the BK B I receptor or detecting the binding of the compound to the BK B 1 receptor.
In a second embodiment of the sixth aspect which is also an embodiment of the first embodiment of the sixth aspect the compound is radiolabeled, fluorescence-labeled or luminescence labeled, or labeled with an antibody.
In a first embodiment of the seventh aspect the problem underlying the instant application is solved by a method for the treatment of a subject which is in need of such treatment, comprising the administration of a compound or of a pharmaceutical composition according to any embodiment of the first to third aspect.
It will be acknowledged by the person skilled in the art that any compound which is generated by any combination of the individual generic groups of formula (I) as disclosed herein shall be encompassed by the instant invention.
The compounds shown in the following Table 1 are embodiments of formula (I) according to the present invention.
Table 1:
Comp Comp Structure M+H+ Structure M+H+
ound ound N O N 1~O
~H \H OH
e V NN
NJ 436.1 7. ~ 414.1 O
H ~ O N~~-CF3 2. N 503.1 8. 456.1 O N O N
N~ 0 N N O
\ O H ~/ \=N H N
3. 460.2 9. N 436.1 O N O N
N O N O
O H ~\ CF3 O H /NN
4. - 502.1 10. NJ 438.1 O N O N~
H
N O N~ O Yl~ O H O H
5. N- 449.1 11. 462.1 O N O )6 N`j~~ O N~ O
~CF3 p H~Cf3 O H
6. OH 470.1 12. N N 506.1 Comp Comp Structure M+H+ Structure M+H;
ound ound H_~~ N 0 y\ N O
O H O H /\ CF3 13. N 439.0 20. N- 503.2 O N O N
N~ O N
N
O H CF3 O H ~\ Br 14. 570.1 21. 513.1 O N O N
N H O N~H~ F
~ O h-CF I s 15. F
~ 520.1 22. 426.2 O N O N
N O N O
N Y~A
O H~ O H
QcF3 16. ~N ~ 455.1 23. 508.2 O N O N
N N N
~ O H ~\ CF3 ~ O H H
17. - 520.1 24. F3C 517.1 F
O N O N
Cs HN ~
CF3 H \
N O H lc~7 N O O
18, 520.0 25. I~ cF, 585.1 F
O N O N
N~ O F N H S
~ ~
H QN' ~F O H -'( N_ 19. 434.1 26, 466.0 Comp + Comp +
Structure M+H Structure M+H
ound ound N~ O N~ O
O H ~\ F 0 H CI
27. ~ 470.1 34. 502.0 F ci O N O N
N O N O
N F
O H ~\ CF3 O H ~\ F
28. 520.1 35. 486.1 CI
O N O N
N O
O H o H/\
29. F 476.1 36 N H CHFZ 542.1 0 ~
N O N O
N
H
30. 477.1 H A 37. N CF3 560.1 ~
N O
O N
N`~ 0 H
n H`N N
YK-31. ~1-CI 469.1 38. ~ 506.1 O N
TT N
O N
N` ~ 0 H
H`N N 0 O oH ~
32. ~ r- _~ 435.1 N
39. N H CF3 574.2 O N
O N
N O
N
xo H ~ \ F
33. 452.1 Comp Structure M+H+ Comp Structure M+H+
ound ound N~O N0 1~ N
O
N~\ 485.2 40. - 580.1 47. O
Br O N O N
N O N O
~H 10~ \H -N
O CN O
41. - 477.1 48. 465.1 F
O N O N
N~ 0 N p 0 O H Y NN OY\H
42. NJ 434.0 49. N 460.2 N
O N O N
/
H
O
O H \ CF3 O H _ F
43. N- 505.1 50. ~ F 484.1 O N't' O N
N\ ~ O N` ~ 0 ~O( H \ CF3 ~O( H / CF3 44. - 522.1 51. 1 \ 436.1 ~ F CI
N` ` ~ 0 N 0 ~ N
O H /\ O H CF3 45. NJ 436.1 52 - 518.1 HO
O N O )3 HYV N 0 H~ O
N N
H O H ~\ CF3 46. 434.1 53 532.1 O\
Comp + Comp +
Structure M+H Structure M+H
ound ound N O N O
O H CF3 O H O\ M+
54. 501.3 61. +N-/ 479.2 /
N N
O H CF3 0 H Q_SCF, 55. 518.2 62. 534.2 F
O N O N
/
N~ O N~ 0 O H OH N O H /NN
56. 451.2 63. N 437.1 O N O N
N 0 NYK 0 yvt 'O H \ O N 0 H CF3 57. 1 ~ \ 494.1 64. 521.1 _O F
N O N O
O H N N i O H CF3 58. NJ 436.1 65. 504.1 O N O N
N N
O H 1\N F 0 H 1\N
59. NJ 450.2 66. NJ 454.2 rsl O N O N
N O N O
N yl~t 60. NJ 454.1 67. - 538.2 !s) F
O N O N
0s) Comp Structure M+H+ Comp Structure M+H+
ound ound Hy~ N O N~ O
F O H CF3 O H OCF, 68. ~/ - 538.2 75. ~/ - 552.1 F CI
O N O N
H N N~ O
rw 69. o H 410.1 76. o H N=/ 436.1 (s~
O N O N~
H O
\ O H. i NN H
424.1 0 N
70. N 77. N 422.1 O N~
O N
H
N
0 H N p O
~
~\N
71. NJ 410.1 F 0 H CF3 78. 507.1 O N
O N
H O
N
O H ~ N Hy~ O
72. ~J 466.3 F o H/\ cF, 79. 524.1 O N" v F
O N
H O
N
O N \ S H
O
/ .
73 _ CF3 550.1 F o H CF580. 521.1 O N
O N
H O
N
0 H ~\ SO CF3 N N
74. 566.1 0 H CF, 81. 491.1 O N
N'J"
Comp Structure M+H+ Comp Structure M+H`
ound ound H O N O
N (w HN
82. 503.2 89. oF' 538.2 F
O N (s) O N
(R) N O N O
fR) N
H ~ F 0 H CF3 83. N'o 467.1 90. 'Irl 538.3 (s) F
O N O N
(w H O N O
N (R) HN
O H ~\ OH F O
84. ~~. - 506.0 91. - cF' 526.2 O NI~ O N
H
O O
N~ (sN HN
O H 9,_OH F , O
85. 516.0 92. cF~ 538.1 O )611 O N
~
N ~) N
F 0 H ~\ CF3 F ~ 0 H CF3 86.. - 512.1 93. 521.1 N F N (s) O " O
(R) N O NH O
N N~
~ \
87. H CF3 F - 524.3 O
94. 372.1 F
N
N N
88. F 507.3 95. i - 538.0 fs) F
O N O N
.~ js) Comp Comp Structure M+H` Structure M+H' ound ound H O N O
N
(R) N
96. 538.0 102. - 520.2 F
~ (S) F
p N~ O N
N O N~ O
N (R) N
97. N 537.2 103. ~ ~ - 520.3 F
(s) ' fR) O N O N
(R) (R) H N
N O (R) N YH O H / CF, cl / o cF, 104. N 503.2 98. F 554.2 o N(s) (S) , O N `, (S) (R1 H
N O
(R N
Hy~ N 0 O H CF3 cl o H 105. 503.2 ~. / \ CF3 ~ ' (R) 99. F 554.0 o N
(s) (R1 O N ~
I ~N
(S~ N N
~N
~ NJ
F / O
N 106. 0 517.3 CI H O N
F 554.0 100.
t-~(R
) H
N
N O N\
(R) N 107. 0 500.2 101. 520.2 o N
(s/ F
O N
tR) Comp Comp Structure M+H; Structure M+H+
ound ound N H O
H N ^N HN
f O
N~ N 114. N 438.2 108. ~ 0 498.2 N-O N
O )1 H
HN
N N\ O
N I/ N 115. N N 426.1 109. ~ 0 475.3 o N'~
O N
O
N ) ~, CF3 fw N
H N\ p H ~ ~
N 116. 534.1 110. p 492.2 0 N
N fs O
CF
(R) r a H N O 'H ~ ~
rN 117. ~ 534.1 F F
111. ~/ 0 515.2 o N
O N
/ N H VF F
fRlv (~~
N N\
H F N 118. o 550.3 112. 516.2 O
p N~ N
H
H N O
N N\ N N OHN
F 119. CF3 548.3 113. p 537.3 0 N~ N F
Comp Structure M+H+ Comp Structure M+H+
ound ound O H
N
N \ CF3 r~1 OH
\ N I/ F O
120. F 534.0 126. 349.1 (s) O N
O N
(R) H
H N
N HN OH
rw O F 0 0 127. 377.1 121. 562.1 F O N
O N
N~ N \ F
5JN)LgCF3 F /
128. 488.1 122. F 508.1 F
/ NI N~ OH
N \ F 0 H
F \ O \
123. 452.2 129. cF' 536.0 O N
N N
F F
O N F ~H
124. 406.0 130. 484.0 N N
O O
H
N
OH N N \ CF3 \ O F O H I/
125. 1331.1 131. 520.0 Comp Comp +
Structure M+H+ Structure M+H
ound ound 132. 503.1 138. 405.1 ~ 1 6 NIN S~
N ~ H
F O ~ // N
F 0 H cF, 139. 459.1 133. 444.1 0 N
O N
H
N O 0 F NH CF3 140. F H -S.N.N
474.0 134. ct 554.0 0 N
. H O
N lf-K-F O H Vo N~ o` 141. Br 521.9 N
O H I~ O N
135. 425.2 O
O N N
N
0 142. 473.0 JR~ H 0 N
136. F 550.1 H O
N
O
N H
F
O ~
0 143. 0'N 456.9 H
N
137. 510.0 Comp Comp Structure M+H+ Structure M+H`
ound ound HO
N~ N
N.N CF3 F O H ~ H I/
144. 'N~o 471.0 150. F 495.1 O N N
O
H O
N
N H NN ~ CF3 F O H ~ H I/
145. 0/ N 443.0 151. F 509.1 OH
N O
H O O
F O HN
146. A",-ND)o 457.0 (RNH O F F
o N 152. I~ t 534.2 F
F
N N1/` O~
N II H
147. F3C O H O 588.2 0 N
153. 533.2 O N ~ J~/
/H_ O
H O N~N F
N N F O H
F o H
N 154. 521.2 148. ,r ci 537.1 O N
N O N
N F O H N
F 0 H 155. 442.1 149. 517.2 O N
Comp Structure . M+H + Comp Structure M+H+
oand ound NH
N H CF
F 0 ~ ~O N~
456.2 HN
156.
F ~
162. 510.2 O N
O~
H n O N
N
II N
157. 469.2 NH -N CF3 O N
HN
F F
163. 527.2 N Y~4 F \ O H ~\ F O N
158. 495.2 NC
O N N O
N~
F O H
N 164. SYN 474.2 ~H NH2 N O N
159. 467.2 O N NH4\ CF3 ~Q ~ +r F N 0 H F 165. F \.., 537.2 160. cI 504.2 o N
-O
' + N
N~Ni~ ^ /CI ~
F O H (171 NJ NH 1~ CF3 161. 487.2 o 0 HN
0 N 166. F " 537.2 oN
Comp + Comp +
Structure M+H Structure M+H
ound ound CI H
O ~ N~N" `N
~ ~ F 0 H , J
NH N
173. /
440.2 167. 486.2 0 N
o \I
N~ O F F
F \ O H F
~
0 174. / N- 545.2 N~ F
F 0 H I y O N
168. / F
506.2 O N N O F F
O F O H I/
H F
N
YVN F 175. I/ Br H 598.1 F \ O F ~ /
169. F 524.2 o N
O N
P
H O N O
F \ O ~O
170. 499.3 HN
176. F == 443.2 O N
O
N I \ \ - ~/
NY"
F 0 H N,N ~
S N
171. 504.2 HN-~~
>==O
HN
177. F 448.2 H O
N
F O H ~ N O
\ N N- ( 172. 454.2 Comp + Comp +
Structure M+H Structure M+H
ound ound H O F F
NY7N)\
N CI O H F
6 183. 537.2 O NH
O N
178. HN 474.2 F
~
M N F
N 184. 495.2 O N~~
O
N
N N
O NH F 0 H N~ oj~~, 185. 530.3 179. HN 462.2 ~/ ~
H_ O N
F
(i H I \ H
186. F 527.2 H O F F
O
N~H \ F ~
180. 511.2 0 0 O ~j_ O H
F
187. F 541.3 H O F F
N O N
N
181. 537.2 H o 0 NY `N NI~
0 N~ F 0 H H
188. F 541.3 .,, F
CI H N 0 182. 511.2 N
O N \ N
189. 510.2 Comp ~ Comp ,.
Structure M+H Structure M+H
ound ound H-jr7 O 0 O
N N N F
F O H ~ NH H F
190. N 510.2 F - F
195. F 556.2 F
O N
O~~
1~-(~ /-NH
N~H N H
N N~
O F O HN
F I \ N~
191. 501.2 196. 510.3 F
O N
O N
O
H N g N I\ F
F O / O H N
197. 473.2 192. 494.3 O N
H O
N
N
H I
F 0 ~ OH
NH H F F 198. 501.2 F
193. F N 539.2 o N
F
O N N ~
N N
F \ O H S`N
H
199. 460.2 N HI ~
N
F I O NO O N
194. 484.2 O N H O F
N F
~H
200. OH 504.2 Comp + Comp Structure M+H Structure M+H+
ound ound N H O F F
N ~N Nu N, N
F O H~ i II H F
N N F 0 ~
N
H
201. 483.2 207. 538.2 O N N
O
F NY7H ~~ H^ H O F F 0 N NYN'N/~\
202. 524.3 F o H ~~ F
N
o N 208. 0 528.2 N` ii /
F \ i0( H I /
203. 523.3 F
NN, H I\ F
O N y F O
N
I
0 209. o" 514.2 N y NN~N N
i J
F O H
NNH
204. 460.2 O N H O F
\
NyNk NI F
F 0 H +' 0 210. ~ o_ 540.2 H
N~N, N N
N NH
205. 486.3 O F F
O N H N,~
F O H IN F
211. 524.2 H O F F
N N. 0 N
F
206. 512.2 O N
"
J
Comp Structure M+H+ Comp Structure M+H+
ound ound O N~ O
N~N O N
H ~ ~N F \ O H N
212. F o /P 476.2 217. N (N 523.3 O N
O N
H O
N
I
NH H
F
N\ N 218. O H 511.3 H
213. F 0 o 501.2 N H
O
H~ O
N
~
N 0 H I N" 'N^
219. H 497.3 F F
N
F
N
H
F
N~ H VF
F
N N N,N 214. F O H o 539.2 O H F 220. F 541.2 N
N
F
F F VFF
H N~N.
N
)rN
N 215. F O H O 556.2 F O H F 221. i F 515.2 O N O N~
N O F F F N_ F \ O H ~~N F O
F N
216. N={ N-~ 511.3 HN~
H 222. F HN O 586.2 I \ .
N
O
Comp + Comp +
Structure M+H Structure M+H
ound ound H
N~NN F N~N F
V
H F O H
223. F 541.2 228. F 506.2 O N O N
HN-N
O ~ ~N
r% \ N 0 HN--i H~O ~-~ O
F F F HN 229. F NH -' 501.2 224. F 539.2 F
F
N
N O
O
O N
N
O
H
-~
HN HN
225. F F F F 539.2 NH
~ I_F 230. 491.2 F
N
O N
O
F
O
N !
F F NH NH H
F
226. F - 556.2 F o H o~
\~
0 231. 499.3 N
N
O
F F
F
N' O
N F
O _ F F
227. F NH 555.2 232. F N 525.2 F
O N
N
Comp + Comp Structure M+H Structure M+H+
ound ound N F F
N F F
CI O H J\ N
233. I r N~ F 538.2 0 O N ~-N
239. HN 484.2 F n O O
234. L N ~~ HN 0 N " 428.2 N
N ~
o-N~ O N, H~ \ I
F O O
235. S1'N 493.1 CI NH
CI ~
O N 240. F HN 503.2 =,õ
H O F F
N N, O N ~ H ~ , F N
236. F 523.2 H O
O N N N
F H~ , ~
241. N 489.2 N F
O N
F
237. cl 522.2 O F
N, F
O N N
F O H F
N- 242. F 555.2 / CI
\ N
O
HN
~O
HN
238. F 276.2 H O F F
N
~ \ N ~ F
p 243. F 528.2 N 0 N~\
Comp + Comp +
Structure M+H Structure M+H
ound ound N N, &C, N , CF, F O H/F F \ N o H I~
N 250. I N 497.9 244. 554.2 /
J
H O
H 0 NYN,N CF3 NY"N ~ F F 0 H N
F 0 H 251. 511.9 F F
245. ci 540.2 O N
O N J
H O
N N, N CF3 H O F F (R) Y H ~
/
N F F ~ 0 CI O H 252. F 500.9 246. F 554.2 O N
O N-~ J
N ~ F F H ~ 0 N ~ F N N2N CF3 CI 0 H ~ N F ~) O H I/
247. 512.2 253. F 514.9 0 J~\ O N'~
H O F F
N N.N
Y H F NiN ` O
F 537.2 ,N~
248. 0 NH
a0:
N o 254. NH 503.0 H 0 F F F /\ F
N
H O
249. 1 F 520.0 --1 O N (s) rw Comp + Comp +
Structure M+H Structure M+H
ound ound ('' o N~~/ ~ F F
NH 0 ~N`N \
F
O NH H /
(RJ
255. NH 500.0 260. F \ F 554.9 F ~ F
O~ I /
(S) ~ O N
N
(R) H F
N N. O F F
(w Y H V F O N.N
256. cl o 530.9 ~ H I N F
261. F 537.9 F too') o ~ )V OY N. N F NH H
F F
(RJ F~-F F 568.9 0 y NF
V 257.
N
NH H O N(S) 262. F F 595.0 (R) I
O F F (5f N
/
O yHN \ I F (RJ
NH ~ F H O
258. ci (R) 556.9 "y N,N ~ CF3 CI "'N O H
263. F 557.9 O O N
6(R) ) H O O N
N NY0 N' ~CF3 \N CI H ~ r 259. 496.1 264. :" " 540.9 Comp + ComP +
Structure M+H Structure M+H
ound ound H O H p N N, \ CF3 N N, '"
~ Y H
H
265. pl N p F 531.8 271. CI I~ p N I"i 504.0 0 N-\ O N--'-O F
NuN,N CF3 H~ V
F
CI IOI H N N N, 266. " 514.9 (w Y " H 272. F o 577.0 O N'\ F
~ (s) O N
H O
rw N \ F
Y N \
F O H r H 0 F. 267. CF3 565.8 tom CI H N F
~ CF 273.
539.9 ) O FF O\/N, N VF 'N( H H H O
(R) N N, 268. N F 541.9 CI \) o I i I"~
274. " f"+~ 530.0 (S) (5) O )v,) 0 N
(F) F O N,N CF3 O N,N ~p`
N
NH H ~/ NH H
(R) (R) 269. F( N F 515.8 275. ol I\ 491.9 r N O N rs) J (w O N-~
O N, ~ H 276. F CI N F 567.8 rw N \ /
270. F N 498.8 CF' ~
O N
J
Comp +
Structure M+H
ound O F F
OYN.N
F
NH H
277. N F 498.0 O NI~~
ON, Y , F
NH H \ I
278. I~ N F 524.0 i (s) O N
(R) O,N
~N /
F
NH H \
(R) 512.0 279. N F
O N--l H ~ F F
N N, (R) O H \ I F
280. ~ F 538.0 (s) nv H VF
NuN.
N I' H CI 0 281. F 517.0 o N~\
H ~ F F
N N.N \
CI O H I/ F
282. F 543.0 B 1 R antagonists provided herein exhibit high activity on human B 1 R, i. e., an inhibition constant (IC50) for competition with binding of labelled DAKD to human B1R of less than 5 micromolar or very high activity on human 131R, i.e., an IC50 for competition with the binding of labelled DA.KD to human B 1 R of preferably less than 50 nanomolar. In certain embodiments, such antagonists exhibit a high activity on B I R of species other than human, i.e., an IC50 for competition with binding of labelled DAKD to rabbit B 1 R
and cynomolgus monkey of less than 5 micromolar.
The activity and more specifically pharmacological activity of the B1R
antagonists according to the present invention can be assessed using appropriate in vitro assays. For instance, the IC50 values of the antagonists according to the present invention for B I R may be determined via a radioligand binding assay, such as the assay provided in Example 24, which is thus an embodiment of a standard in vitro BK B1R-mediated assay. Inhibitory effects of the B 1 R antagonists provided herein for B 1 R may be determined, for example, via calcium mobilization assay, such as the assay provided in Exarnple 25.
Preferred compounds of the invention have an IC50 (half-maximal inhibitory concentration) of about 5 micromolar or less, still more preferably an IC50 of about 500 nM or less, or even 50 nM or less, even more preferably an IC50 of about 10 nM or less, or even 1 nanomolar or less in the assays mentioned above.
The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one B 1 R modulator as described herein, in combination with a physiologically acceptable carrier or excipient. Processes for preparing such pharmaceutical compositions are also provided. Such compositions are particularly useful in the treatment of B 1 R-mediated diseases as described below.
These and other aspects of the present invention will become apparent upon reference to the following detailed description.
Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified.
Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include i1C,13C, and 14C.
Compounds according to the formulas provided herein, which have one or more stereogenic centers, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%; 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
Certain compounds are described herein using a general formula that includes variables such as, e.g., A, Rl, Ra, W, Y, Z. Unless otherwise specified, each variable within such a formula is defmed independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, the group may be unsubstituted or substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i. e., compounds that can be isolated, characterized and tested for biological activity.
A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include 5 mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, 10 formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CHz)n-COOH where n is any integer from 0 to 4, i.e., 0, 1, 2, 3, or 4, and the like. Similarly, pharmaceutically acceptable 15 cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting 20 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
25 It will be apparent that each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.
30 A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, i.e., =0, then 2 hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C(=0)- and a loss of aromaticity. For example a pyridyl group substituted by oxo is a pyridone.
The expression alkyl preferably refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms, for example an ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two, more preferably one, double bond(s) and alkynyl groups have one or two, more preferably one, triple bond(s).
Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced each independently of the others by a halogen atom, preferably F or Cl, such as, for example, a 2,2,2-trichloroethyl or a trifluoromethyl group.
The expression heteroalkyl preferably refers to an alkyl, alkenyl or alkynyl group, for example heteroalkenyl, heteroalkynyl, in which one or more, preferably 1, 2 or 3 carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom, preferably oxygen, sulphur or nitrogen.
The expression heteroalkyl furthermore preferably refers to a carboxylic acid or to a group derived from a carboxylic acid such as, for example; acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, alkylcarbamoylalkyl, alkylcarbamoyloxyalkyl, alkylureidoalkyl, or alkoxycarbonyloxy.
Examples of heteroalkyl groups are groups of formulas -S-Ya-L, -S-Ya-CO-NRaRb, -Ya-NR -CO-NRaRb, -Ya-NW-CO-O-Rd, -Ya-NRc-CO-Rd, -Ya-NR -CO-NRd-L, -Ya-NR -CS-NRd-L, -Ya-O-CO-NRaRb, -Ya-CO-NRaRb, -O-Ya-CO-NRaRb, -Ya-Ne-CO-L2 -Ya-O-CO-O-R , -Ya-O-CO-Rc, -Ya-O-Rc, -Ya-CO-L, -Ya-NRaRb, Rc-S-Ya-, Ra-N(Rb)-Ya-, Rc-CO-Ya-, R -O-CO-Ya-, Rc-CO-O-Ya-, Rc-CO-N(Rb)-Ya-, Ra-N(R)-CO-Ya-, Rc-SO-Ya-, W-SO2-Ya-, -Ya-NR -SOZ-NRaRb, -Ya-SO2-NRaRb, -Ya-NR -SOZ-Rd, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-C(=NRa)-N(R )-Ya-, R -S-CO-Ya-, R -CO-S-Ya-, R -S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, R -S-CO-O-Ya-, R -O-CO-S-Ya-, R -S-CO-S-Ya-; wherein Ra being a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to Rb to form a 4-to 10-membered cycloalkyl or heterocycloalkyl; Rb being a hydrogen atom, a C1-C6alky1, a C2-C6alkenyl or a C2-C6alkynyl , or taken together with Ra to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; Rc being a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl; Rd being a hydrogen atom, optionally substituted C1-Cgalkyl, optionally substituted C2-C8alkenyl or optionally substituted C2-C8alkynyl; L being a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and Ya being a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene group; each heteroalkyl group containing at least one carbon atom and it being possible for one or more hydrogen atoms to have been replaced by fluorine or chlorine atoms. Certain compounds are described herein using formulas that include the variables captioned above which variables carry a superscripted B, E or G as an extension, for example, LB, YaE, or R G. Unless otherwise specified, the definition of these variables corresponds to the above definition of the respective variable, i.e. LB and LE are defined as L; YaB, YaE, and YaG are defined as ya; RcB, R E, and RcG are defined as Rc; etc. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethyl-amino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diiso-propylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, isobutyrylamino-methyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups. An example of a heteroalkylene group is a group of formulas -CH2CH(OH)- or -CONH-.
The expression cycloalkyl preferably refers to a saturated or partially unsaturated cyclic group that contains one or more rings, preferably 1 or 2, containing from 3 to 14 ring carbon atoms, preferably froin 3 to 10, more preferably 3, 4, 5, 6 or 7, ring carbon atoms. In an embodiment a partially unsaturated cyclic group has one, two or more double bonds, such as a cycloalkenyl group. The expression cycloalkyl preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NHZ, =NH, CN, CF3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of a cycloalkyl group is a cyclo-propyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbomyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclo-hexyl or cyclohex-2-enyl group.
The expression heterocycloalkyl preferably refers to a cycloalkyl group as defined above in which one or more, preferably 1, 2 or 3, ring carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom, preferably oxygen, sulphur or nitrogen. A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from.3 to 10, more preferably 3, 4, 5, 6 or 7, ring atoms.
The expression heterocycloalkyl preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or NO2 groups. Examples are a piperidyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also a lactam, a lactone, a cyclic imide and a cyclic anhydride.
The expression alkylcycloalkyl preferably refers to a group containing both cycloalkyl and also an alkyl, alkenyl or alkynyl group in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynyl-cycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two ring systems having from 3 to 10, preferably 3, 4, 5, 6 or 7, carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms, the cyclic groups being optionally substituted.
The expression heteroalkylcycloalkyl preferably refers to alkylcycloalkyl groups as defmed above in which one or more, preferably 1, 2 or 3, carbon atoms have been replaced each independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom, preferably oxygen, sulphur or nitrogen. A heteroalkylcycloalkyl group preferably contains 1 or 2 ring systems having from 3 to 10, preferably 3, 4, 5, 6 or 7, ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are allcylheterocycloalkyl, heterocycloalkylalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, hetero-alkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being optionally substituted and saturated or mono-, di- or tri-u.nsaturated.
The expression aryl or Ar preferably refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10, more preferably 6, ring carbon atoms. The expression aryl (or Ar) preferably refers furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, CN, CF3 or NO2 groups.
Examples are a phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
The expression heteroaryl preferably refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10, more preferably 5 or 6, ring atoms, and contains one or more, preferably 1, 2, 3 or 4, oxygen, nitrogen, phosphorus or sulphur ring atoms, preferably 0, S or N. The expression heteroaryl preferably refers 10 furthermore to groups in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, NH2, =NH, CN, CF3 or NO2 groups. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, 3-pyrazolyl and 15 isoquinolinyl.
The expression aralkyl preferably refers to a group containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-20 cycloalkyl and alkylarylcycloalkenyl groups. Specific -examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 H-indene, tetralin, dihydro-naphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indan.
An aralkyl group preferably contains one or two aromatic ring systems, 1 or 2 rings, containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups 25 containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or .6 ring carbon atoms.
The expression heteroaralkyl preferably refers to an aralkyl group as defined above in which one or more, preferably 1, 2, 3 or 4, carbon atoms have been replaced each 30 independently of the others by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulphur atom, preferably oxygen, sulphur or nitrogen, that is to say to groups containing both aryl or heteroaryl and also. alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A
heteroaralkyl group preferably contains one or two aromatic ring systems, 1 or 2 rings, containing from 5 or 6 to ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of 5 those carbon atoms having been replaced each independently of the others by oxygen, sulphur or nitrogen atoms.
Examples of heteroaralkyl groups are arylheteroalkyl, arylheterocycloalkyl, arylhetero-cycloalkenyl, arylalkylheterocycloalkyl, atylalkenylheterocycloalkyl, arylalkynylhetero-10 cycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylhetero-cycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkyl-heterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl, heteroalkylheteroarylalkyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroiso-quinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.
The expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl refer to groups in which one or more hydrogen atoms of such groups have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or groups.
The expression "optionally substituted" as used in conncetion with any group refers to a group in which one or more hydrogen atoms have been replaced each independently of the others by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, CN, CF3 or NO2 groups. This expression refers furthermore to a group in which one or more hydrogen atoms have been replaced each independently of the others by an unsubstituted C1-C6alkyl, unsubstituted C2-C6alkenyl, unsubstituted C2-C6alkynyl, unsubstituted C1-C6hetero-alkyl, unsubstituted C3-Clocycloalkyl, unsubstituted C2-C9heterocycloalkyl, unsubstituted C6-Cloaryl, unsubstituted C1-C9heteroaryl, unsubstituted C7-ClZaralkyl or unsubstituted C2-Cllheteroaralkyl group.
The expression "halogen" as preferably used herein means fluorine, chlorine, bromine, iodine.
As used herein a wording defming the limits of a range of length such as, e.
g., "from 1 to 5" means any integer from I to 5, i. e. 1, 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned. is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
The therapeutic use of compounds of formula (I), their pharmacologically acceptable salts, solvates and hydrates and also formulations and pharmaceutical compositions containing the same are within the scope of the present invention. The present invention also relates to the use of those compounds of formula (I) as active ingredients in the preparation or manufacture of a medicament:
The pharmaceutical compositions according to the present invention comprise at least one compound of formula (I) and, optionally, one or more carrier substances, excipients and/or adjuvants. Pharmaceutical compositions may additionally comprise, for example, one or more of water, buffers such as, e.g., neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates such as e.g., glucose, mannose, sucrose or dextrans, mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
Furthermore, one or more other active ingredients may, but need not, be included in the pharmaceutical compositions provided herein. For instance, the compounds of the invention may advantageously be employed in combination with an antibiotic, anti-fungal, or anti-viral agent, an-anti histamine, a non-steroidal anti-inflammatory drug, a disease modifying anti-rheumatic drug, a cytostatic drug, a drug with smooth muscle activity modulatory activity or mixtures of the aforementioned.
Pharmaceutical compositions may be formulated for any appropriate route of administration, including, for example, topical such as, e.g., transdermal or ocular, oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular such as, e.g., intravenous, intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilizate. Formulation for topical administration may be preferred for certain conditions such as, e.g., in the treatment of skin conditions such as bums or itch.
Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and . palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as, e.g., corn starch or alginic acid, binding agents such as, e.g., starch, gelatin or acacia, and lubricating agents such as, e.g., magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as, e.g., calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as, e.g., peanut oil, liquid paraffm or olive oil.
Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as, e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as, e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as, e.g., arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions may also be in the form of oil-in-water emulsions.
The oily phase may be a vegetable oil such as, e.g., olive oil or arachis oil, a mineral oil such as, e.g., liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums such as, e.g., gum acacia or gum tragacanth, naturally-occurring phosphatides such as, e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as, e.g., sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as, e.g., polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and/or flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene 5 glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
Compounds may be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye. Formulations for topical 10 administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols such as, e.g., ethanol or isopropyl alcohol or glycerin; glycols such 15 as, e.g., butylene, isoprene or propylene glycol; aliphatic alcohols such as, e.g., lanolin;
mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols including oils, such as, e.g., mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials, both 20 non-volatile and volatile; and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
25 Examples of such components are described in Martindale The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
A topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches. The physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the fmal product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the fmal product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffm, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents such as, e.g., witch hazel, alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
An example of a suitable topical vehicle for formulation of a gel is:
hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%);
propylene glycol (5.1%); and Polysorbate 80 (1.9%). An example of a suitable topical vehicle for formulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%); Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
Typical modes of delivery for topical compositions include application using the fmgers;
application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying including mist, aerosol or foam spraying; dropper application; sprinkling;
soaking; and rinsing. Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration as a transdermal patch.
A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. Such formulations are particularly useful for the treatment of asthma or other respiratory.conditions. For inhalation formulations, the compounds provided herein may be delivered via any inhalation methods known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered via an. aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
Pharmaceutical compositions may also be prepared in the form of suppositories such as e.g., for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Pharmaceutical compositions may be formulated as sustained release formulations such as, i.e., a formulation such as a capsule that creates a slow release of modulator following administration. Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively. constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
For the prevention and/or treatment of diseases mediated by BK or analogues thereof, the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements. Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day, about 0.5 mg to about 7 g per patient per day. The daily dose may be administered as a single dose or in a plurality of doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, i.e. other drugs being used to treat the patient, and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
B 1 R antagonists of formula (I) according to the present invention may be used preferably 5 as antagonists of B 1 R in a variety of applications, both in vitro and in vivo. B 1 R antagonists according to the present invention may be used to inhibit the binding of BK B
1 R ligands such as, e.g., DAKD, to B1R in vitro or in vivo. BK B1R antagonist(s) provided herein are preferably administered to a patient such as, e.g., a human, orally or topically, and are present within at least one body fluid or tissue of the patient while modulating BK B
1 R activity.
10 Accordingly, the present invention further provides methods for treating patients suffering from conditions responsive to B 1 R modulation as mentioned above. As used herein, the term "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms, or therapeutic, i.e., after the onset of symptoms, in order to 15 reduce the severity and/or duration of symptoms. A condition is "responsive to B 1 R
modulation" if modulation of B 1 R activity results in alleviation or curing of the condition or a symptom thereof. Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, with dosages as described herein.
Due to the involvement of the bradykinin B 1 receptor in various diseases, the antagonists according to the present invention are effective in the treatment and/or prevention of a condition or a disease responsive to BK B 1 R modulation as is apparent from the prior art and in particular from references recited herein. Animal models of these diseases are generally well known in the art and may be used to evaluating compounds of the present invention for their potential utilities. Apart from that, the compounds according to thepresent invention are also useful in diagnosis of such diseases and other applications including, but not limited to, their use as research tools in vivo and in vitro.
Compounds of this invention are antagonists of the BK B1R and as such are useful in the treatment and prevention of diseases and conditions mediated through the BK
receptor pathway such as inflammation, immunology disorders and pain. The compounds are preferably effective in the treatment or prevention of inflammation such as, but not limited to, persistent or chronic inflammatory diseases, immunology disorders, autoimmune diseases, neurogenic inflammation, inflammation associated edema and fibrosis. This includes but is not limited to gastrointestinal inflammation, septic shock, diseases of the skin, diseases of the respiratory pathway and vasculopathies. The compounds are preferably also effective in the 'treatment or prevention of pain such as chronic pain, inflammatory pain, visceral pain and neuropathic pain. This includes but is not limited to complex regional pain syndrome (CRPS).
It is within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
In the following the various diseases and conditions that are responsive to B
modulation and the use of the compounds according to the present invention in specific methodology and diagnostics are further specified.
Inflammatory Diseases and Immunology Disorders Within the present application the term "inflammatory diseases" preferably encompasses, but is not limited to, disorders such as acute-phase reaction, local and systemic inflammation and inflammation caused by other diseases whatever type, etiology or pathogenesis and caused by those inflammatory diseases specified within this application.
Within the present application the term "immunology disorders" preferably encompasses, but is not limited to, disorders such as hyperesthesia, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodelling, myasthenia gravis, immunosuppression, immune-complex diseases, over- and underproduction of antibodies and vasculitis.
Due to the involvement of the bradykinin B1 receptor in various diseases, the BI
antagonists according to the present invention are preferably effective in the treatmentlprevention of a condition or a disease responsive to BK B1R
modulation as is i.a.
apparent from the references cited herein. Accordingly, the compounds according to the invention are effective in the treatment/prevention of inflammatory diseases such as but not limited to inflammatory bowel disease including Crohn's disease and ulcerative colitis (Stadnicki et al., Am. J. Physiol. Gastrointest Liver Physiol. 2005, 289(2), G361-6; Devani et al., Am. J. Gastroenerol 2002, 97(8), 2026-32; Devani et al., Dig. Liv.
Disease 2005, 37(9), 665-73), irritable bowel syndrome, enterocolitis, liver diseases, pancreatitis, gall bladder diseases, smooth muscle relaxants for the treatment of spasms of the gastrointestinal tract or uterus. They may also be used in kidney disease like nephritis, bladder disease like cystitis, interstitial cystitis, eye diseases like uveitis, retinitis, glaucoma, and ear diseases such as otitis media. They may also be used in inflammatory skin diseases such as psoriasis, eczema, atopic diseases, dermatitis and itching. The compounds are effective in joint and bone diseases such as juvenile or adult onset rheumatoid arthritis and gouty arthritis (Cassim et al., Pharmacol.
Ther. 2002, 94, 1-34; Sha.rma et al., Exp. Toxic Pathol. 1994, 46, 421-433;
Brechter et al., Arthr. Rheum. 2007, 56(3), 910-923), ankylosing spondylitis, adult onset or pediatric onset like systemic onset juvenile idiopathic arthritis, Still's disease, psoriatic arthritis and osteoarthritis. The compounds are also effective in edema associated with bums, sprains or fracture, cerebral edema, closed head injury and angioedema. They may be used to treat immunology disorders like diabetic vasculopathy, type I diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic vasculopathy, post capillary resistance or diabetic syndromes associated with insulits such as, e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion. Additionally they may be used in CNS
disorders like multiple sclerosis, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, Parkinson's disease. They may also be used in cardiovascular disease such as congestive heart failure, myocardial infarct, systemic inflammatory response syndrome (SIRS), ischemia-reperfusion injury and atherosclerosis (Raidoo et al., Immunopharmacol 1997, 36(2-3), 153-60; McLean et al., Cardiovasc. Res. 2000, 48, 194-210).
They may also be used in vascular disorders like vasculitis, septic shock, antihypovolemic and/or anti-hypotensive agents, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder. Furthermore the compounds may be used to treat fibrotic diseases such as but not limited to pulmonary fibrosis, renal fibrosis, liver fibrosis, progressive sclerosis and recurrent stricture formation in Crohn's disease (Goldstein et al., J Biol. Chem. 1984, 259(14), 9263-8; Ricupero et al., J. Biol. Chem.
2000, 275(17), 12475-80; Romero et al., J Biol. Chem. 2005, 15, 14378-14384).
They are also effective in disorders of the respiratory pathways in asthma, atopic or non-atopic asthma, occupational asthma, exercise-induced bronchoconstriction, bronchitis, pneumoconiosis including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabaccosis and byssinosis, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, pneumonia, allergic rhinitis, vasomotor rhinitis and pleurisy.
These compounds according to the present invention may also be used to treat auto-inflammatory diseases such as familial Mediterranean fever (FMF), tumor-necrosis factor receptor associated periodic syndrome (TRAPS), neonatal onset multisystem inflammatory disease (NOMID), familial cold autoinflammatory syndrome (FCAS) including familial cold urticaria (FCU), pyogenic arthritis pyoderma gangrenosum acne (PAPA) syndrome and Muckle-Wells disease.
Pain Within the present application the term "pain" preferably encompasses, but is not limited to, centrally and peripherally mediated pain, vascular pain, visceral pain, inflammatory mediated pain, neuralgic pain, referred pain, nociceptive pain, reflectory pain, psychosomatic pain, acute pain such as caused by acute injury, trauma or surgery of bones, muscle, tissue, soft tissue, orRans, pain after insectbites, post-stroke pain syndrome, post-surgery pain, progressive disease related pain and chronic pain (Calixto et al., Br. J.
Pharmacol. 2004, 143, 803-818; Chen et al., Expert Opin. Ther. Targets 2007, 11(1), 21-35; Porreca et.al., J.
Pharmacol. Exp. Ther. 2006, 318(1), 195-205; Ferreira et al., J. Neurosc.
2005, 25(9), 2405-12; Conley et al., Eur. J. Pharm. 2005, 527(1-3), 44-51; Levy and Zochodne, Pain 2000, 86(3), 265-71; Yamaguchi-Sase et al., *Inflamm. Res. 2003, 52(4), 164-9).
The compounds according to the present invention are preferably also effective in the treatment and/or prevention of pain including but not limited to inflammatory pain of various origins such as rheumatoid arthritis or gout, visceral pain as pancreatitis, interstitial cystitis, renal or gall bladder colic, neuropathic pain as postherpetic neuralgia, complex regional pain syndrome, phantom limb pain, root avulsions, trigeminal neuralgia, painful traumatic mononeuropathy, painful polyneuropathy, vulvodynia, central pain syndromes potentially caused by any lesion at any level of the peripheral and/or central nervous system, postsurgical pain syndromes as postmastectomy syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain as muscular injury and fibromyalgia, perioperative pain as from general surgery, chronic pain, dysmennorhea as well as pain associated with angina. Additionally these compounds are preferably effective against back pain, headache, cluster headache, migraine including prophylactic and acute use, hyperalgesia, and fever.
Furthermore, compounds of the invention are useful as analgesic agent for use during general and monitored anesthesia.
Diagnostic and further applications The present invention also provides methods for localizing or detecting a B 1 R in a tissue, preferably a tissue section, which methods involve contacting the tissue sample presumably containing B1R with a detectably labelled compound according to the present invention under conditions that perrnit binding of the compound to the B1R and detecting the bound compound. Such methods and their respective conditions are known to those skilled in the art and include, for example, the radioligand binding assay disclosed in Example 24.
The present invention also provides methods of inhibiting the binding of DAKD
or any other B1R ligand to a B1R which methods involve contacting a solution containing a B1R
antagonist compound disclosed herein with cells expressing B1R under conditions and in an amount sufficient to detectably inhibit binding of DAKD or any other substance to B 1 R. Such methods and their respective conditions are known to those skilled in the art and include, for example, the calcium mobilization assay disclosed in Example 25.
It is also within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
For various applications, the compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity 5 label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates. These labelled compounds of this invention are useful for mapping the location of BK
receptors in vivo, ex vivo, in vitro and in situ such as, e.g. in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like to characterize those receptors in living subjects or other 10 materials. The labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.
The compounds of formula (I) according to the present invention have improved 15 properties when compared to B 1 R antagonists known in the state of the art, especially, improved selectivity, low toxicity, low drug drug interaction, improved bioavailability especially with regard to oral administration, improved metabolic stability, improved stability in microsomal degradation assay, and improved solubility.
20 The present invention is now further illustrated by the following examples from which further features, embodiments and advantages of the present invention may be taken.
EXAMPLES
25 Abbreviations used in the following examples are as follows:
amu is atomic mass unit ACN is acetonitrile AgNO3 is silver nitrate B 1 R is B 1 receptor 30 BK is bradykinin BSA is bovine serum albumin conc. is concentrated DAKD is des-Arg-lO-kallidin DCM is dichloromethane DIPEA is diisopropyethylamine DMAP is 4-N,N-dimethylaminopyridine DMEM is Dulbecco's modified Eagle's medium DMF is N,N-dimethylformamide DMSO is dimethylsulfoxide EA is ethyl acetate FBS is fetal bovine serum FCS is fetal calf serum hishour HATU is 2-(1H-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate HCI is hydrochloric acid HEK is human embryonic kidney HEPES is 4-2-hydroxyethyl-l-piperazineethanesulfonic acid HOBt is N-hydroxybenzotriazole HPLC is high performance liquid chromatography K2C03 is potassium carbonate IL is interleukine LiOH is lithium hydroxide NaCI is sodium chloride Na2CO3 is sodium carbonate Na2SZO3 is sodium thiosulfate NaOH is sodium hydroxide NaHCO3 is sodium hydrogencarbonate NH4CI is ammonium chloride NH4OH is ammonia Pd(OAc)Z is palladium (II) acetate PBS is phosphate-buffered saline PIPES is piperazine-N,N'-bis(2-ethanesulfonic acid) RP is reverse phase RT is room temperature sat. is saturated tBu is tert. butyl TFA is trifluoroacetate or trifluoroacetic acid THF is tetrahydrofuran TPP is Techno Plastic Products AG
WSC is (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride Materials and methods The materials and methods as well as general methods are further illustrated by the following examples:
Solvents:
15. Solvents were used in the specified quality without further purification.
Acetonitrile (Gradient grade, J.T. Baker); dichloromethane (for synthesis, Merck Eurolab);
diethylether (for synthesis, Merck Eurolab); N,N-dimethylformamide (LAB, Merck Eurolab);
dioxane (for synthesis, Aldrich); methanol (for synthesis, Merck Eurolab).
Water:
Milli-Q Plus, Millipore, demineralized.
Chemicals:
Chemicals were synthesized according to or in analogy to literature procedures or purchased from Advanced ChemTech (Bamberg, Deutschland), Sigma-Aldrich-Fluka (Deisenhofen, Germany), Bachem (Heidelberg, Germany), J.T. Baker (Phillipsburg, USA), Lancaster (Muhlheim/Main, Germany), Merck Eurolab (Darmstadt, Germany), Neosystem (Strasbourg, France), Novabiochem (Bad Soden, Germany, from 2003 Merck Biosciences, Darmstadt, Germany) Acros (Geel, Belgium, distribution company Fisher Scientific GmbH, Schwerte, Germany), Peptech (Cambridge, MA, USA), Synthetech (Albany, OR, USA), Pharmacore (High Point, NC, USA) and Anaspec (San Jose, CA, USA) or other companies and used in the assigned quality without further purification.
If not stated differently, concentrations are given as percent by volume.
RP-HPLC-MS analyses:
For analytic chromatography a Hewlett Packard 1100-system (degasser G1322A, quaternary pump G1311A, automatic sample changer G1313A, column heater G
1316A, variable UV detector G1314A) together with an ESI-MS (Finnigan LCQ ion trap mass spectrometer) was used. The system was controlled by "navigator version 1.1 sp1" software (Finnigan). As impact gas in the ion trap helium was used. For chromatographic separation a RP-18-column (Vydac 218 TP5215, 2.1 x 150 mm, 5 m, C18, 300 A with a pre column (Merck) was used at 30 C and a flow of 0.3 mUmin using a linear gradient for all chromatograms (5-95% B for 25 min, linear, A: 0.05% TFA in water and B: 0.05%
TFA in CH3CN). LJV detection wa s done at X = 220 nm. The retention times (Rt) are indicated in the decimal system (e.g. 1.9 min = 1 min 54 s) and are referring to detection in the mass spectrometer. The dead time between injection and UV detection (HPLC) was 1.65 min, and between UV detection and mass detection 0.21 min. The accuracy of the mass spectrometer was approx. 0.5 amu.
HPLC/MS analyses were performed by injection of 5 l, using a linear gradient from 95:5 to 5:95 in 9.5 min (A: 0.05% TFA in water and B: 0.05% TFA in ACN). RP columns were from Phenomenex (Type Luna C-18, 3 m, .50 x 2.00 mm, flow 0.3 ml, HPLC at room temperature); Mass spectrometer: ThermoFinniga n Advantage and/or LCQ Classic (both ion trap), ESI ionization, helium served as impact gas in the ion trap. Excalibur version 1.3 and/or. 1.2 was used as software. Retention times (Rt) are indicated in the decimal system (e.g. 1.9 min = 1 min 54 s).
Preparative HPLC:
Preparative HPLC separations were done using Vydac R18-RP columns with the following gradient solvents: 0.05% TFA in H20 and B: 0.05% TFA in CH3CN
Compounds were named using AutoNom version 2.2 (Beilstein Informationssysteme Copyright 1988-1998, Beilstein Institut fiir Literatur der Organischen Chemie licensed to Beilstein Chemiedaten and Software GmbH) Preparation of compounds:
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.
Specific examples for the preparation of compounds of formula (I) are provided in the following examples. Unless otherwise, specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by the present invention.
Example 1 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{l-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-anzide (Compound 1) ~ N/ ~(' j O HN H ~N
O
Method 1:
A. (R)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (R)-1-(4-Bromo-phenyl)-ethylamine hydrochloride (2.50 g, 10.57 mmol) was added portionwise to a stirred solution of di-tert-butyl dicarbonate (2.77 g, 12.68 mmol) and triethylamine (3.24 mL, 23.25 mmol) in ACN (40 mL). After stirring for 18 h at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound. MS (m/z): 230.0 [M+H+-OtBu]
B. (R)-4-(1-tert-Butoxycarbonylamino-ethyl)-benzoic acid methyl ester To a stirred suspension of (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (3.18 g, 10.58 mmol), 1,4-bis-(diphenylphosphino)butane (0.32 g, 0.74 mmol) and Pd(OAc)2 (0.16 g, 0.74 mmol) in anhydrous DMSO (25 mL) under an atmosphere of nitrogen were added triethylamine (8.85 mL, 63.46 mmol) and anhydrous methanol (10 mL).
After stirring 5 at 70 C under an atmosphere of carbon monoxide for 48 h the mixture was concentrated in vacuo and the residue was partitioned between EA (200 mL) and sat. NaHCO3 solution (200 mL). After extraction of the aqueous layer with EA (2 x 200 mL) the combined organic layers were dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS
10 (m/z): 208.2 [M+H+-OtBu]
C. (R)-4-(1-tert-Butoxycarbonylamino-ethyl)-benzoic acid A mixture of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid methyl ester (1.16 g, 4.16 mmol) and LiOH (1 M solution in H20, 25 mL) in dioxane (25 mL) was stirred at RT for 15 3 h. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCI solution and the aqueous layer was extracted with EA (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 209.9 [M+H+-tBu]
D. (R)-{ 1-[4-(2,5-cis/trans-Dimethyl-pynrolidine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester 2,5-cis/trans-Dimethyl-pyrrolidine (0.76 mL, 6.27 mmol) was added to a stirred solution of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (0.83 g, 3.14 mmol), WSC (0.72 g, 3.76 mmol), HOBt (0.51 g, 3.76 mmol) 'and triethylamine (2.19 mL, 15.68 mmol) in DCM/DMF 9:1 (10 mL). After stirring overnight at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound. MS (m/z): 347.0 [M+H+]
E. (R)-[4-(1-Amino-ethyl)-phenyl]-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone A solution of (R)-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.56 g, 1.62 mmol) and TFA (5 mL) in DCM (45 mL) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and 1 N NaOH solution (50 mL). After extraction of the aqueous layer with DCM (2 x 50 mL) the combined organic layers were dried over NaZSO4, filtered and concentrated in vacuo to give the title compound. MS (m/z): 247.2 [M+H+]
F. (R)-(1-{1-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (R)-[4-(1-Amino-ethyl)-phenyl]-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone (10.0 mg, 0.041 mmol) was added to a stirred solution of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (9.8 mg, 0.049 mmol), WSC (9.3 mg, 0.049 mmol), HOBt (6.6 mg, 0.049 mmol) and N-methylmorpholine (22.3 L, 0.203 mmol) in DMF (1 mL).
After stirring overnight at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS (m/z): 429.9 [M+H+]
G. (R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-1-carbonyl)-phenyl]-ethyl} -amide A solution of (R)-(1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (8.0 mg, 0.019 mmol) and TFA
(100 L) in DCM (900 L) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo to give the title compound as the TFA salt. MS (m/z): 330.0 [M+H+]
H. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl] -ethylcarbamoyl } -cyclopropyl)-amide (R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide (10.0 mg, 0.030 mmol) was reacted with pyrimidine-5-carboxylic acid (4.5 mg, 0.036 mmol) according to the synthesis of (1-{l-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 436.1 [1VI+H+]
Method 2:
Reactions A-D were performed based upon literature (Dickins et al., Chem. Eur.
J. 1999, 5, 1095-1105) A. (R)-N- [ 1-(4-Bromo-phenyl)-ethyl] -acetamide Acetyl chloride (2.13 mL, 30.0 mmol) was added dropwise at -15 C to a stirring solution of (R)-1-(4-bromo-phenyl)-ethylamine (5.00 g, 25.0 mmol) and triethylamine (4.53 mL, 32.5 mmol) in diethylether (750 mL). The reaction mixture was allowed to warm to RT
over 2 h and then poured into 500 mL of water. The organic layer was washed with 0.1 N
HCl solution (1 x 500 mL) and with water (1 x 500 mL), dried over K2C03, filtered and concentrated in vacuo to give the title compound. MS (m/z): 243.8 [M+H']
B. (R)-N-[ 1-(4-Cyano-phenyl)-ethyl]-acetamide To a stirred solution of (R)-N-[1-(4-bromo-phenyl)-ethyl]-acetamide (3.47 g, 14.3 mmol) in anhydrous DMF (30 mL) under an atmosphere of nitrogen was added copper(I)cyanide (2.70 g, 30.1 mmol). After stirring at 180 C overnight the reaction mixture was concentrated in vacuo and the residue carefully poured into 6 N HCI solution (60 mL). The aqueous layer was extracted with DCM (3 x 100 mL). The organic layer was washed with water (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS
(m/z): 188.9 [M+H+]
C. (R)-4-(1-Amino-ethyl)-benzoic acid A solution of (R)-N-[1-(4-cyano-phenyl)-ethyl]-acetamide (1.67 g, 8.87 mmol) in 6 N
HCl solution (27 mL) was stirred at 120 C overnight. The solvent was removed in vacuo and the solid was washed with diethylether, filtered and dried to give the title compound as the HCl salt. MS (m/z): 165.9 [M+H+]
D. (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester 3 Drops of HCl conc. were added to a stirred solution of (R)-4-(1-amino-ethyl)-benzoic acid (1.79 g, 8.87 mmol) in methanol (25 mL). After stirring the mixture at 85 C for 3 h the solvent was removed in vacuo to give the title compound as the HCI salt. MS
(m/z): 179.8 [M+H+]
E. (R)-4-{1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester (420 mg, 2.34 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (560 mg, 2.81 mmol) according to the synthesis of (R)-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester to give (R)-4-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. The tert-butyl ester (103 mg, 0.284 mmol) was treated with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide to give the title compound as the TFA salt. MS (m/z): 262.9 [M+H+]
F. (R)-4-[1-({1-[(Pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (R)-4-{1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester (74.5 mg, 0.284 mmol) was added- to a stirred solution of pyrimidine-5-carboxylic acid (42.3 mg, 0.341 mmol), HATU (129.6 mg, 0.341 mmol) and DIPEA (247.3 L, 1.420 mmol) in DMF (2 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL).
After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound which was used for the next reaction without further purification. MS (m/z): 368.9 [M+H{]
G. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl} -cyclopropyl)-amide (R)-4-[ 1-( { 1-[(Pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (192 mg, 0.521 mmol) was reacted with LiOH according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid to give (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl } -amino)-ethyl]-benzoic acid.
Subsequent reaction with 2,5-cis/trans-dimethyl-pyrrolidine according to the synthesis of (R)-(1- { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester yielded the title compound as the TFA salt. MS
(m/z): 436.1 [M+H-`]
Example 2 Synthesis of (R)-1V- { 1-[ 1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide (Compound 43) nw-- -11 H NFi~~
O ~
O
A. (R)-4- { 1- [(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-amino] -ethyl } -benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-benzoic acid methyl ester (1.03 g, 4.77 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (0.80 g, 3.97 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. The crude compound was purified by flash chromatography on silica gel (elution with n-hexane/EA 3:7) to give the title compound. MS
(m/z): 362.7 [M+H+]
B. (R)-4-{ 1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl}-N,N-diisopropyl-benzamide (R)-4-{ 1-[(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid inethyl ester (423 mg, 1.17 mmol) was reacted with LiOH according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid to give (R)-4-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid. The benzoic acid (59.6 mg, 0.171 mmol) was reacted with diisopropyl-amine (71.9 L, 0.513 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound- by reversed phase HPLC using.a gradient of ACN in water with 0.1%
TFA and subsequent reaction with TFA according to the synthesis of (R)-1-amino- .
cyclopropanecarboxylic acid { 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide yielded the title compound as the TFA salt. MS (m/z): 332.0 [M+H+]
C. (R)-N-{ 1-[1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide 3-Bromo-5-trifluoromethyl-pyridine (1.00 g, 4.42 mmol) was reacted with carbon monoxide according to the synthesis of (R)-4-(l-tert-butoxycarbonylamino-ethyl)-benzoic acid methyl ester to give 5-trifluoromethyl-nicotinic acid methyl ester.
Hydrolysis of the methyl ester according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid and subsequent reaction of the benzoic acid (4.80 mg, 0.025 mmol) with (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-N,N-diisopropyl-benzamide (4.20 mg, 0.013 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound as 5 the TFA salt (purification of the crude compound by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA). MS (m/z): 505.1 [M+l-1"]
Example 3 Synthesis of (R)-N-{ 1-[1-(4-diisopropylcarbamoyl-phenyl)-ethylcarbamoyl]-10 cyclopropyl}-3-fluoro-5-trifluoromethyl-benzamide (Compund 44) P-1 -f\ /
N--( NHR~
H
O `
`
F O
(R)-4- { 1-[(1-Amino-cyclopropanecarbonyl)-amino]-ethyl } -N,N-diisopropyl-benzamide (4.2 mg, 0.013 mmol) was reacted with 3-fluoro-5-trifluoromethyl-benzoic acid (5.3 mg, 0.025 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-15 cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA yielded the title copound as the TFA salt. MS (m/z): 522.1 [M+IV]
Example 4 20 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-((2R,5S')-2,5-dimethyl-pyrrolidine-l-carbonyl]-phenyl)-ethylcarbamoyl}-cyclopropyl)-amide (Compound 45) N ~
rN
w O H~J
I \ N
(s) O N
(R) Reactions A-C were performed based upon literature (Katritzky et al., J. Org.
Chem.
1999, 64, 1979-1985) 25 A. (3S,5R,7aR)-5-(Benzotriazol-l-yl)-3-phenyl[2,1-b]oxazolopyrrolidine A mixture of 2,5-dimethoxytetrahydrofuran (2.94 mL, 22.7 mmol) and 0.1 N HCl (90 mL) was refluxed for 1 h and then cooled to RT. A solution of benzotriazole (2.70 g, 22.7 mmol) and (S)-(+)-2-amino-2-phenyl-ethanol (3.11 g, 22.7 mmol) in DCM (220 mL) was added to the cooled mixture, which was then stirred overnight. The reaction mixture was washed with 2 N NaOH (3 x 70 mL) and water (2 x 70 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue was recrystallized from EA to give the title compound. 'H NMR 6 2.20-2.26 (m, 1H), 2.55-2.57 (m, 3H), 3.61-3.68 (m, 1H), 4.44-4.45 (m, 2H), 5.16-5.17 (m, 1H), 5.90-5.94 (m, 1H), 7.03-7.08 (m, 5H), 7.21-7.26 (m, 2H), 7.44-7.46 (d, J= 7Hz, 1 H), 7.90-7.93 (d, J= 7Hz, 1 H) B. (2S)-(2-(2R,5S)-2,5-Dimethyltetrahydro-lH-l-pyrrolyl-2-phenylethan-l-o1 A solution of methylmagnesiumbromide (3M in diethylether, 2.20 mL, 6.53 mmol) was added dropwise at 0 C to a stirred solution of (3S,5R,7aR)-5-(benzotriazol-l-yl)-3-phenyl[2,1-b]oxazolopyrrolidine (500 mg, 1.63 mmol) in dry THF (33 mL) under nitrogen.
After stirring at RT overnight the reaction mixture was washed with 2 N NaOH (3 x 40 mL) and water (2 x 40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS (m/z): 220.0 [M+H+]
C. (2R,5S)-2,5-Dimethyltetrahydro-lH-1-pyrrolidinium chloride (2S)-(2-(2R,5S')-2,5-Dimethyltetrahydro-lH-l-pyrrolyl-2-phenylethan-l-o1(100 mg, 0.46 mmol) was dissolved in methanol (9 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator (Thales Nanotechnology, H-1031 Budapest, Zahony utca 7(Graphisoft Park), Hungary. Website: http://
www.thalesnano.com), which contained a cartridge of 10% palladium on carbon as catalyst.
The hydrogenation was done at RT under a pressure of 10 bar. The solution of the product was treated with 20 drops of HCI conc. while stirring at RT for 30 minutes.
The solvent was evaporated in vacuo and the resulting product was washed with diethylether to give the title compound as the HCI salt. MS (m/z): 100.00 [M+H+]
D. (R)-pyrimidine-5-carboxylic acid (1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl]-phenyl)-ethylcarbamoyl}-cyclopropyl)-amide (R)-4- { 1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl } -benzoic acid (30 mg, 0.086 mmol) was reacted with (2R,5S)-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (23 mg, 0.172 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester to give (R)-(1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester. Subsequent reaction with TFA
according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide yielded (R)-1-amino-cyclopropanecarboxylic acid {1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide. Subsequent reaction with pyrimidine-5-carboxylic acid according to the synthesis of (R)-4-[1-( { 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude product by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA yielded the title compound as the TFA salt. MS (m/z): 436.1 [M+H+]
Example 5 Synthesis of (R)-N-(1-{1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 55) O H
F
O N
(R)-4- { 1-[(1-tert-Butoxycarbonylamino-cyclopropanecarbonyl)-arnino]-ethyl}-benzoic acid (60 mg, 0.17 mmol) was reacted with 2,5-cis/trans-dimethyl-2,5-dihydro-IH-pyrrole (33 mg, 0.34 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester to give (R)-(1-{1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethylcarbamoyl} -cyclopropyl)-carbamic acid tert-butyl ester. Subsequent reaction with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid { 1 -[4-(2,5-cis/trans-dimethyl-pyrrolidine- 1 -carbonyl)-phenyl]-ethyl}-amide yielded (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-phenyl]-ethyl} -amide.
Subsequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({ 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbenyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude product. by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA yielded the title compound as the TFA salt. MS
(m/z): 518.2 [M+H+]
Example 6 Synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide (Compound 60) H J0~ ^
N N" ~ `N
F O H I N) O N
A. 3-Fluoro-4-methyl-benzoic acid methyl ester Chloro-trimethyl-silane (3.64 mL, 28.8 mmol) was added to a stirring solution of 3-fluoro-4-methyl-benzoic acid (1.11 g, 7.20 mmol) in methanol (24 mL). After stirring at RT
overnight the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane) to give. the title compound. GC/MS
(m/z): 168.0 Reaction B was performed based upon literature (Gauuan et al., Bioorg. Med.
Chem.
2002, 10, 3013-3021) B. 3-Fluoro-4-formyl-benzoic acid methyl ester After stirring a suspension of 3-fluoro-4-methyl-benzoic acid methyl ester (500 mg, 2.97 mmol), 1-bromo-pyrrolidine-2,5-dione (1.73 g, 8.33 mmol) and benzoyl peroxide (53.1 mg, 0.47 mmol) in tetrachloromethane (36 mL) at 80 C overnight the mixture was concentrated in vacuo and the residue was partitioned between EA (150 mL) and water (100 mL).
The organic layer was washed with sat. NaHCO3 solution (1 x 100 mL), water (1 x 100 mL) and sat. NaC1 solution (1 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue, a mixture of 4-bromomethyl-3-fluoro-benzoic acid methyl ester and 4-dibromomethyl-3-fluoro-benzoic acid methyl ester, was used in the following step without further purification. The residue (50 mg, 0.30 mmol) was dissolved in acetone (2 mL) and water (0.4 mL) and AgNO3 (171 mg, 0.87 mmol) were added.
The flask was covered with aluminum foil to avoid decomposition of the AgNO3. The mixture was stirred at RT overnight. After filtration of the mixture and evaporation of the solvent, the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (15 mL).
The organic layer was washed with water (1 x 15 mL) and sat. NaC1 solution (1 x 15 mL), dried over NaZSO4, filtered and concentrated in vacuo to give the title compound. GC/MS
(m/z): 182.2 C. (R,S)-3-Fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester Methylmagnesiumbromide (3M solution in diethylether, 0.99 mL, 2.96 mmol) was added dropwise at -80 C to a stirring solution of 3-fluoro-4-formyl-benzoic acid methyl ester (450 mg, 2.47 mmol) in dry THF (10 mL) under nitrogen. After stirring for 80 minutes 5 mL 2 M
HCI solution were added and the mixture was allowed to warm to RT. Sat. NaCl solution was added (100 mL) and the mixture was extracted with EA (4 x 100 mL). The organic layer was dried over NazSOa, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 6:1) to give the title compound.
GC/MS (m/z): 198.2 D. (R,S)-4-(1-Azido-ethyl)-3-fluoro-benzoic acid methyl ester Methanesulfonyl chloride (120 L, 1.55 mmol) was dissolved in 500 L DCM and then added dropwise at 0 C to a stirred solution of (R,S)-3-fluoro-4-(l-hydroxy-ethyl)-benzoic acid methyl ester (154 mg, 0.78 mmol), DMAP (4.7 mg, 0.04 mmol) and triethylamine (1.08 mL, 7.77 mmol) in DCM (4 mL). After stirring at 0 C for 30 minutes, 10 mL water were added and the mixture was extracted with DCM (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give cis/trans-3-fluoro-4-(1-methanesulfonyloxy-ethyl)-benzoic acid methyl ester, which was used in the following step without further purification. The residue was stirred with sodium azide (204 mg, 4.66 mmol) in ACN (4 nzL) at 60 C overnight. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. GC/MS (m/z): 223.0 E. (R,S)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (R,S)-4-(1-Azido-ethyl)-3-fluoro-benzoic acid methyl ester (158 mg, 0.71 mmol) was dissolved in methanol (14 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator, which contained a cartridge of 10% palladium on carbon as catalyst. The hydrogenation was done at RT under a pressure of 1 bar. The solvent was evaporated to give the title compound. MS (m/z): 197.8 [M+I-i+]
F. (R,S)-3-Fluoro-4-[1-({ 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester (R,S)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (27.4 mg, 0.14 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with 10 TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with pyrimidine-5-carboxylic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title coumpound. MS (m/z):
386.9 [M+H+]
G. (R,S)-Pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl} -cyclopropyl)-amide (R, S)-3-Fluoro-4-[1-( { 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl} -amino)-ethyl]-benzoic acid methyl ester (73.0 mg, 0.19 mmol) was reacted with LiOH
according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid.
Subsequent reaction of the benzoic acid (13.0 mg, 0.04 mmol) with 2,5-cis/trans-dimethyl-pyrrolidine (4.30 L, 0.04 mmol) according to the synthesis of (R)-4-[l-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA yielded the title copound as the TFA salt. MS (m/z): 454.1 [M+H+]
Example 7 Synthesis of (R,S)-N-(1-{ 1=[5-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide (Compound 65) N ~ CF3 ~ ~
N ~ O H
N
O N
Reaction A was performed based on literarture (Chong et al., J. Med. Chem.
2004, 47, 5230-5234) A. 6-Hydroxymethyl-nicotinic acid methyl ester Sodiumborhydride (0.51 g, 13.5 mmol) was added portionwise at 0 C to a stirring suspension of pyridine-2,5-dicarboxylic acid dimethyl ester (1.05 g, 5.38 mmol) and calcium choride (2.39 g, 21.5 mmol) in THF/methanol 1:2 (33 mL). After stirring overnight at 0 C 20 mL water were added and the solvent was removed in vacuo. The aqueous residue was extraxted with DCM (3 x 30 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1) to give the title compound. MS (m/z): 167.9 [M+H+]
B. 6-Formyl-nicotinic acid methyl ester Dess-Martin reagent (207 mg, 0.49 mmol) was added to a stirring solution of 6-hydroxymethyl-nicotinic acid methyl ester (55 mg, 0.33 mmol) in DCM (17 mL).
After stirring for 3 h the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound.
GCMS (m/z): 165.2 C. (R,S)-6-(1-Hydroxy-ethyl)-nicotinic acid methyl ester 6-Formyl-nicotinic acid methyl ester (47 mg, 0.28 mmol) was reacted with methylmagnesium bromide according to the synthesis of (R,S)-3-fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester to give the title compound which was used in the following reation without further purification. MS (m/z): 182.0 [M+H+]
D. (R, S)-6-(1-Am.ino-ethyl)-nicotinic acid methyl ester The reaction of (R,S)-6-(l-hydroxy-ethyl)-nicotinic acid methyl ester (150 mg, 0.83 mmol) with methanesulfonyl chloride and subsequent reaction with sodium azide according to the synthesis of (R,S)-4-(l-azido-ethyl)-3-fluoro-benzoic acid methyl ester yielded (R,S)-6-(1-azido-ethyl)-nicotinic acid methyl ester. Hydrogenation of the methyl ester according to the synthesis of (R,S)-4-(1-amino-ethyl)-3-fluoro-benzoic acid methyl ester yielded the title compound. MS (m/z): 181.0 [M+H+]
E. (R,S)-(1-{ 1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (R,S)-6-(1-Amino-ethyl)-nicotinic acid methyl ester (116 mg, 0.64 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid according to the synthesis of (R)-4-[ l -({ 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl} -amino)-ethyl]-benzoic acid methyl ester. Purification of the crude compound by reversed phase HPLC
using a gradient of ACN in water with 0.1% TFA yielded (R,S)-6-{1-[(1-tert-butoxycarbonylamino-cyclopropanecarbonyl)-amino]-ethyl}-nicotinic acid methyl ester as the TFA
salt. Reaction of the methyl ester with LiOH and subsequent reaction with 2,5-cis/trans-dimethyl-pyrrolidine according to the synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide yielded the title compound as the TFA salt. MS (rn/z): 431.0 [M+H+]
. F. (R,S)-N-(1-{1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl} -cyclopropyl)-5-trifluoromethyl-nicotinamide (R,S)-(1-{ 1-[5-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (33.6 mg, 0.08 mmol) was treated with TFA according to the synthesis of (R)-1-amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide.
Subsequent reaction with 5-trifluoromethyl-nicotinic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA yielded the title compound as the TFA salt. MS (m/z):
504.1 [M+H+]
Example 8 Synthesis of N-(1-(4-(2,5-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-1-(1-hydroxy cyclopropanecarboxamido)cyclopropanecarboxamide (Compound 7) gN ~ O O OH
\ ~ HN
O ~NH
(R)-1-Amino-cyclopropanecarboxylic acid {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethyl}-amide (10.0 mg, 0.03 mmol) was reacted with 1-hydroxy-cyclopropanecarboxylic acid (2.8 mg, 0.03 mmol) according to the synthesis of (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester to give the title copound as the TFA salt. MS (m/z):
414.1 [M+H+]
Example 9 Synthesis of N-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-5-trifluoromethyl-nicotinamide (Compound 78) N~ CF3 F O H I
N
O )3 A. 3-Fluoro-4-formyl-benzoic acid A solution of 3-fluoro-4-formyl-benzoic acid methyl ester (200 mg, 1.10 mmol) and LiOH (1.5 mL) in ACN (1.5 mL) was stirred at RT for 1 h and then 1 h at 40 C.
The solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt.
GC/MS (m/z):
168.0 B. 4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde 2,5-cis/trans-Dimethyl-pyrrolidine (264 mg, 2.67 mmol) was added to a stirring solution of 3-fluoro-4-formyl-benzoic acid (150 mg, 0.89 mmol), WSC (256 mg, 1.34 mmol) and HOBt (180 mg, 1.34 mmol) in DMF (3 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS
(m/z): 250.2 [M+H+]
C. (4-Aminomethyl-3-fluoro-phenyl)-(2,5-cis/trans-dimethyl-pyrrolidin-l-yl)-methanone A mixture of 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde (50.0 mg, 0.20 mmol), titanium-tetra-isopropylate (570 mg, 2.00 mmol) and ammonia (7N
solution in ethanol, 1 mL) was stirred at RT overnight. Sodiumborhydride (23.0 mg, 0.60 mmol) was added. After stirring for 2 h the solvent was removed in vacuo and the residue was partitioned between EA (20 mL) and sat. NaHCO3 solution (20 mL). The aqueous layer was extracted with EA (3 x 20 mL), the organic layer was 'dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS (m/z): 251.1 [M+H+]
D. { 1-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (4-Aminomethyl-3-fluoro-phenyl)-(2,5-cis/trans-dimethyl-pyrrolidin-1-yl)-methanone (50.1 mg, 0.20 mmol) was added to a stirring solution of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (80.5 mg, 0.40 mmol), WSC (77.0 mg, 0.40 mmol), HOBt (54.0 mg, 0.40 mmol) and diisopropylamine (100 L, 0.60 mmol) in DMF (1 mL). After stirring for 3 h at RT the sqlvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 433.9 [M+H+]
E. 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-carbonyl)-2-fluoro-benzylamide A solution of {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (33 mg, 0.08 mmol) and TFA
(300 L) in DCM (2700 L) was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS (m/z): 334.1 [M+H+]
F. 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamide 1-Amino-cyclopropanecarboxylic acid 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamide (13 mg, 0.04 mmol) was reacted with 5-trifluoromethyl-nicotinic acid (33 mg, 0.08 mmol) according to the synthesis of {1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-1-carbonyl)-2-fluoro-benzylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 507.1 [M+H+]
Example 10 Synthesis of (R)-N-(1-{ 1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-5 phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 90) ~CF3 N
tNN ~ 0 F H ~/
F
J
A. 3-Fluoro-4-[(2-methyl-propane-2-sulfnylimino)-methyl]-benzoic acid methyl ester A mixture of 3-fluoro-4-formyl-benzoic acid methyl ester (529 mg, 2.91 mmol), (S)-(-)2-methyl-propane-2-sulfinic acid amide (352 mg, 2.91 mmol), pyridinium p-toluenesulfonate 10 (36 mg, 0.15 mmol) and magnesium sulfate (5.20 g, 43.7 mmol) in DCM (8 mL) was stirred at RT for 2 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. MS
(m/z): 285.8 [M+H+]
15 B. (R)-3-Fluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-benzoic acid methyl ester Methyl magnesium chloride (22% in THF, 520 L, 1.49 mmol) was added dropwise at -60 C to a stirred solution of 3-fluoro-4-[(2-methyl-propane-2-sulfinylimino)-methyl]-benzoic acid methyl ester (386 mg, 1.35 mmol) in DCM (7 mL). After stirring for 4 h at -60 C sat.
20 ammonium chloride solution (25 mL) was added. The aqueous layer was extracted with DCM
(4 x 25 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1) to give the title compound. MS (m/z): 301.8 [M+H+]
25 C. (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester A solution of (R)-3-fluoro-4-[1-(2-methyl-propane-2-sulfmylamino)-ethyl]-benzoic acid methyl ester (61 mg, 0.21 mmol) and HCl (4N solution in dioxan, 320 L, 1.28 mmol) was stirred at RT for 30 minutes. The solvent was removed in vacuo and the residue was recristallized from diethylether to give the title compound as the HCl salt.
MS (m/z): 197.8 [NI+H+]
D. (R)-3-Fluoro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid methyl ester (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (35 mg, 0.15 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound.
MS (m/z): 470.8 [M+H+]
E. (R)-N-(1-{1-[4-((2R,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl } -cyclopropyl)-3 -fluoro-5-trifluoromethyl-benzamide (R)-3-Fluoro-4-(1- { [ 1-(3 -fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]
-amino}-ethyl)-benzoic acid methyl ester (98 mg, 0.21 mmol) was reacted with LiOH
according to the synthesis of (R)-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid.
Subsequent reaction of the benzoic acid (8.4 mg, 0.02 mrnol) with (2R,5S)-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (3.2 mg, 0.024 mmol) according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester and purification of the crude compound by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA yielded the title compound as the TFA salt. MS (m/z): 538.3 [M+H+]
Example 11 Synthesis of { 6-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino] -pyridin-3 -yl } -(4-pyridin-4-yl-piperazin-1-yl)-methanone (Compound 106) N N~ N
F
O N
A. 6-tert-Butoxycarbonylamino-nicotinic acid methyl ester 6-Amino-nicotinic acid methyl ester (1.00 g, 6.57 mmol) was added portionwise to a stirring solution of di-tert-butyl dicarbonate (1.72 g, 7.89 mmol) in tert-butanol (20 mL).
After stirring for 4 days at RT the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound. MS (m/z): 252.8 [M+H+]
B. 6-tert-Butoxycarbonylamino-nicotinic acid A mixture of 6-tert-butoxycarbonylamino-nicotinic acid methyl ester (1.62 g, 6.40 mmol) and LiOH (1M solution in H20, 40 mL) in dioxane (40 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCI solution and the aqueous layer was extracted with EA (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (mlz): 238.8 [M+H+]
C. [5-(4-Pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester 1-Pyridin-4-yl-piperazine (123 mg, 0.75 mmol) was added to a stirring solution of 6-tert-butoxycarbonylamino-nicotinic acid (90 mg, 0.38 mmol), WSC (86 mg, 0.45 mmol) and HOBt (61 mg, 0.45 mmol) in DMF (3 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound as the TFA salt. MS
(m/z): 384.0 [M+W]
D. (6-Amino-pyridin-3 -yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone A solution of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (24 mg, 0.06 mmol) and TFA (5 mL) in DCM (5 mL) was stirred at RT
for 4 h.
The reaction mixture was concentrated in vacuo to give the title compound as the TFA salt.
MS (m/z): 284.2 [M+H+]
E. 4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde 3-Fluoro-4-formyl-benzoic acid (46 mg, 0.28 mmol) was reacted with 2,5-cis/trans-dimethyl-pyrrolidine (34 L, 0.28 mmol) according to the synthesis of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS (m/z): 250.1 [M+H+]
F. {6-[4-(2,5-cis/trans-Dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone A mixture of (6-amino-pyridin-3-yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone (17.5 mg, 0.062 mmol), 4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzaldehyde (11.0 mg, 0.044 mmol) and titanium-tetra-isopropylate (62.5 mg, 0.220 mmol) in dichloroethane (2 mL) was stirred at RT overnight. Sodiumtriacetoxyborhydride (18.6 mg, 0.088 mmol) was added and the mixture was stirred at RT for additional 3 h. The solvent was removed in vacuo and the residue was partitioned between EA (20 mL) and sat. NaHCO3 solution (20 mL). The aqueous layer was extracted with EA (2 x 20 mL), the organic layer was dried over NaZSOa, filtered and concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA
salt. MS
(m/z): 517.3 [M+H+]
Example 12 Synthesis of {6-[4-(2,5-cis/trans-dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-2-fluoro-benzylainino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone (Compound 111).
=N
N N ^\ N I /
F Nf ,,) O
)~/
A. 3-Fluoro-4- { [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl} -benzoic acid methyl ester (6-Amino-pyridin-3-yl)-(4-pyridin-4-yl-piperazin-1-yl)-methanone (92 mg, 0.32 mmol) was reacted with 3-fluoro-4-formyl-benzoic acid methyl ester (65 mg, 0.35 mmol) according to the synthesis of {6-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-benzylamino]-pyridin-3-yl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone to give the title compound, which was used in the following step without further purification.
MS (m/z):450.3 [M+H+]
B. {6-[4-(2,5-cis/trans-Dimethyl-2,5-dihydro-pyrrole-l-carbonyl)-2-fluoro-benzylamino] -pyridin-3 -yl } -(4-pyridin-4-yl-piperazin-1-yl)-methanone 3-Fluoro-4- { [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl} -benzoic acid methyl ester (110 mg, 0.23 mmol) was reacted with LiOH according to the synthesis of 3-fluoro-4-formyl-benzoic acid to give 3-fluoro-4-{[5-(4-pyridin-4-yl-piperazine-1-carbonyl)-pyridin-2-ylamino]-methyl}-benzoic acid. The benzoic acid (18 mg, 0.04 mmol) was reacted with 2,5-cis/trans-dimethyl-2,5-dihydro-lH-pyrrolidin (25 L, 0.20 mmol) according to the synthesis of [5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester to give the title compound as the TFA salt. MS
(m/z): 515.2 [M+Hj Example 13 Synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4-(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl}-1-methyl-ethyl)-amide (Compound 115) N
fRJ O
H / ~ N
YV
N~
O N'l A. (R)-4- [ 1-(9H-Fluoren-9-ylmethoxycarbonylamino)-ethyl] -benzoic acid Trimethylsilyl chloride (3.14 mL, 24.8 mmol) was added to a solution of (R)-4-(1-amino-ethyl)-benzoic acid (2.00 g, 9.92 mmol) in DCM (50 mL). The mixture was heated to reflux for 2 h then cooled to RT and triethylamine (5.53 mL, 39.7 mmol) was added dropwise followed by 9-fluorenylmethyl chloroformate (2.82 g, 10.9 mmol). The reaction mixture was stirred at RT overnight and then concentrated in vacuo. The residue was stirred in sat. sodium carbonate solution and acidified with 2 N hydrochloric acid. The resulting aqueous solution was extracted with diethylether (2 x 150 mL) and the organic layer was dried over Na2SOa, filtered and concentrated in vacuo to give the title compound. MS (m/z): 387.7 [M+W]
B. Resin-bound (R)-4-(1-amino-ethyl)-benzoic acid 4-[1-(9H-Fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid (296 mg, 0.8 mmol) and DIPEA (332 L, 1.9 mmol) were dissolved in DCM (8 mL). The solution was added to 2-chlorotrityl chloride resin (loading: 1.4 mmol/g, 1.09 g, 1.5 mmol) swollen in DCM (8 mL) and the mixture was shaken at RT for 30 minutes. The mixture was quenched with methanol (800 L). The resin was filtered and washed with DCM/methanol/DIPEA (16:3:3, 1 x 10 mL) and DMF (3 x 10 mL). Piperidin (25% solution in DMF, 10 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF (6 x 10 mL) and dried 5 in vacuo to give the title compound with an expected loading of 45% (0.65 mmol/g).
C. Resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionic acid (63 mg, 0.19 mmol), HATU (74 mg, 0.19 mmol) and DIPEA (68 L, 0.39 mmol) in DMF (1 mL) 10 was stirred at RT for 5 minutes and then added to resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (100 mg, 0.07 mmol) swollen in DCM (1 mL). The mixture was shaken at RT
for 1.5 h and then quenched with methanol. The resin was filtered and washed with DMF (4 x 2 mL) to give resin-bound 4- { 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product.
15 MS (m/z): 472.9 [M+H+]. Piperidin (25% solution in DMF, 4 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF (6 x 10 mL) and dried in vacuo to give the title compound.
D. Resin-bound (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionyl 20 amino } -ethyl)-benzoic acid Resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid (100 mg, 0.065 mmol) was reacted with 5-pyrimidinecarboxylic acid according to the synthesis of resin-bound 4-{ 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product. MS
(m/z): 356.9 25 [M+H+]
E. (R)-4-(1-{2-Methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid A suspension of resin-bound (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-30 propionylamino}-ethyl)-benzoic acid (100 mg, 0.065 mmol) in 1,1,1,3,3,3,-hexafluoro-2-propanol/DCM (4:1, 2.5 mL) was shaken at RT for 3 h. The resin was filtered and washed with DCM (2 x 3 mL). The filtrate was concentrated in vacuo to give the title compound. MS
(m/z): 356.9 [M+H+]
F. (R)-Pyrimidine-5-carboxylic acid (1-{1-[4-(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl }-1-methyl-ethyl)-amide N-Ethylisopropylamine (41 L, 0.337 mmol) was added to a stirred solution of (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid (12.0 mg, 0.034 mmol) and HATU (12.8 mg, 0.034 mmol) in DMF (0.4 mL). Affter stirring overnight the reaction mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 426.1 [M+M
Example 14 Synthesis of (R)-N-(cyclopropyl-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl} -methyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 116) ~R~~ \ F
(R) O H
~
~
O N
A. Resin-bound (R)=4-[1-(2-amino-2-cyclopropyl-acetylamino)-ethyl]-benzoic acid Resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (58.7 mg, 0.038 mmol) was reacted with (R)-cyclopropyl-[(9H-fluoren-9-ylmethoxycarbonylamino)]-acetic acid (38.6 mg, 0.114 mmol) according to the synthesis of 4-{ 1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. A test cleavage with TFA showed the right product 4-{ 1-[2-cyclopropyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-ethyl}-benzoic acid. MS (m/z): 485.0 [M+H+]. Deprotection with piperidin according to the synthesis of resin-bound (R)-4-[1-(2-amino-2-methyl-propionylamino)-ethyl]-benzoic acid yielded the title compound.
B. (R)-N-(Cyclopropyl-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl } -methyl)-3 -fluoro-5 -trifluoromethyl-benzamide Resin-bound (R)-4-[1-(2-amino-2-cyclopropyl-acetylamino)-ethyl]-benzoic acid (58.7 mg, 0.038 mmol) was reacted with 3-fluoro-5-trifluoromethylbenzoic acid (15.8 mg, 0.076 mmol) according to the synthesis of 4-{1-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-ethyl}-benzoic acid. Cleavage with 1,1,1,3,3,3,-hexafluoro-2-propanol/DCM according to the synthesis of (R)-4-(1-{2-methyl-2-[(pyrimidine-5-carbonyl)-amino]-propionylamino}-ethyl)-benzoic acid (12 mg, 0.034 mmol) yielded 4-{1-[2-cyclopropyl-2-(3-fluoro-5-trifluoromethyl-benzoylamino)-acetylamino]-ethyl}-benzoic acid.
Reaction of the acid (12.5 mg, 0.028 mmol) with 2,5-cis/trans-dimethylpyrrolidin (6.8 L, 0.055 mmol) according to the synthesis of (R)-pyrimidine-5-carboxylic acid (1-{1-[4=(ethyl-isopropyl-carbamoyl)-phenyl]-ethylcarbamoyl}-1-methyl-ethyl)-amide yielded the title compound as the TFA salt. MS (m/z): 534.1 [M+W]
Example 15 Synthesis of (R,S)-N-(1-{ 1-[2-chloro-4-((2R,5R)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 100) H O
N
CI O H ~ \ F
~ / - F3C
'(R) O
(R1 A. 3-Chloro-4-methyl-benzoic acid methyl ester Chloro-trimethyl-silane (6.0 mL, 46.9 mmol) was added to a stirring solution of 3-chloro-4-methyl-benzoic acid (2.0 g, 11.7 mmol) in methanol (40 mL). After stirring at RT ovemight the solvent was removed in vacuo to give the title compound, which was used in.the, following step without further purification. GC/MS (m/z): 184 B. 3-Chloro-4-formyl-benzoic acid methyl ester After stirring a suspension of 3-chloro-4-methyl-benzoic acid methyl ester (1.04 g, 5.61 mmol), 1-bromo-pyrrolidine-2,5-dione (3.26 g, 15.7 mmol) and benzoyl peroxide (100.2 mg, 0.88 mmol) in tetrachloromethane (68 mL) at 80 C overnight the mixture was concentrated in vacuo and the residue was partitioned between EA (300 mL) and water (200 mL).
The organic layer was washed with sat. NaHCO3 solution, (1 x 200 mL), water (1 x 200 mL) and sat. NaCI solution (1 x 200 mL). The organic layer was dried over NaZSO4, filtered and concentrated in vacuo. The residue, a mixture of 4-bromomethyl-3-chloro-benzoic acid methyl ester and 4-dibromomethyl-3-chloro-benzoic acid methyl ester, was used in the following step without further purification. The residue (1.48 g, 5.61 mmol) was dissolved in acetone (45 mL) and water (9 mL) and AgNO3 (3.22 g, 16.3 mmol) were added. The flask was covered with aluminum foil to avoid decomposition of the AgNO3. The mixture was stirred at RT overnight. After filtration of the mixture and evaporation of the solvent, the residue was partitioned between EA (700 mL) and sat. NaHCO3 solution (350 mL).
The organic layer was washed with water (1 x 350 mL) and sat. NaCI solution (1 x 350 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 9:1) to give the title compound.
GC/MS (m/z): 198 C. (R,S)-4-(1-Azido-ethyl)-3-chloro-benzoic acid methyl ester 3-Chloro-4-formyl-benzoic acid methyl ester (398 mg, 2.01 mmol) was reacted with methylmagnesiumbromide according to the synthesis of (R,S)-3-fluoro-4-(1-hydroxy-ethyl)-benzoic acid methyl ester. Reaction of the ester with methanesulfonyl chloride and subsequent reaction with sodium azide according to the synthesis of (R,S)-4-(1-azido-ethyl)-3-fluoro-benzoic acid methyl ester yielded the title compound. GC/MS (m/z):
D. (R, S)-4-( l-Amino-ethyl)-3-chloro-benzoic acid methyl ester (R,S)-4-(1-Azido-ethyl)-3-chloro-benzoic acid methyl ester (181 mg, 0.76 mmol) was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator according to the synthesis of (R,S)-4-(1-amino-ethyl)-3-fluoro-benzoic acid methyl ester to give the title compound. MS (m/z): 213.8 [M+H+]
E. (R,S)-3-Chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid methyl ester (R,S)-4-(1-Amino-ethyl)-3-chloro-benzoic acid methyl ester (17.7 mg, 0.083 mmol) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and then treated with TFA according to the synthesis of (R)-4-{1-[(1-amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester. Susequent reaction with 3-fluoro-5-trifluoromethyl-benzoic acid according to the synthesis of (R)-4-[1-({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-ethyl]-benzoic acid methyl ester yielded the title compound.
MS (m/z): 472.9 [M+H+]
F. (R,S)-N-(1-{ 1-[2-Chloro-4-((2R,5R)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (R, S)-3-Chloro-4-(1- { [ l -(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropane carbonyl]-amino}-ethyl)-benzoic acid methyl ester (40.3 mg, 0.083 mmol) was treated with LiOH (1.4 ml) to give (R,S)-3-chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropanecarbonyl]-amino}-ethyl)-benzoic acid. Subsequent reaction of the benzoic acid with (2R,5R)-2,5-dimethyl-pyrrolidine according to the synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{ 1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl}-cyclopropyl)-amide yielded the title compound as the TFA salt.
MS (m/z):
554.0 [M+H+]
Example 16 Synthesis of (R,S)-N-(1-{ 1-[2-Chloro-4-((2S,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl}-cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide (Compound 99) H .O
N
CI O H F
F3C!
N(s ) .~ (sl Reactions A-D were performed based on literarture (Schlessinger et al., Tetrahedron Lett.
1987, 28, 2083-2086) A. (2-Hydroxy-1(S)-methyl-ethyl)-carbamic acid benzyl ester Lithium aluminium hydride (10.2 g, 0.27 mol) was suspended in anhydrous THF
(450 mL). To this mixture L-Alanine (12.0 g, 0.13 mol) was added portionwise at 0 C. The mixture was refluxed overnight and then cooled to 0 C. 2 N NaOH solution (70 mL) was added. After stirring at RT for 3 h, the mixture was filtered and the solids were washed with THF. The solids were suspended in THF (250 mL) and the mixture was refluxed for 1 h.
The solution was filtered and the solids were washed with THF. This procedure was repeated twice. To the combined THF solutions was added 2 N NaOH solution (170 mL) and benzyl chloroformate (25.3 g, 0.15 mol). After stirring 1 h, the biphasic system was separated and the aqueous layer was extracted with EA (1 x 50 mL). The organic layer was dried over Na2SO4i filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/cyclohexane yielded the title compound.
B. (S)-Toluene-4-sulfonic acid 2-benzyloxycarbonylamino-propyl ester To a solution of (2-hydroxy-1(S)-methyl-ethyl)-carbamic acid benzyl ester (12.0 g, 0.06 mol) in pyridine (190 mL) was added p-toluenesulfonyl chloride (4.40 g, 0.11 mol) at 0 C.
After stirring at RT overnight, diethyl ether (50 mL) was added. The mixture was filtered and the solids were washed with diethyl ether. The organic extract was washed with 0.5N H2SO4 solution (3 x 20 mL), 5% NaHCO3 solution (1 x 20 mL) and sat. NaCI solution (1 x 20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/n-hexane yielded the title compound.
C. (S)-Toluene-(2-iodo-l-methyl-ethyl)-carbamic acid benzyl ester To a solution of (S)-toluene-4-sulfonic acid 2-benzyloxycarbonylamino-propyl ester (12.3 g, 0.03 mol) in acetone (113 mL) was added solid sodium iodide (50.7 g, 0.34 mol) at 0 C.
After stirring at 0 C for 30 minutes, the reaction mixture was- stirred at RT
for 48 h. The solvent was removed in vacuo at RT. The residue was suspended in EA. The mixture was filtered and the solids were washed with EA. The organic extract was washed with H20 (2 x 20 mL), 5% Na2SZO3 solution (1 x 20 mL) and sat. NaCI solution (1 x 20 mL), dried over NaZSO4, filtered and concentrated in vacuo. Crystallisation of the crude compound from THF/n-hexane yielded the title compound.
D. (S')- (1-Methyl-pent-4-enyl)-carbamic acid benzyl ester Allyl magnesium chloride (19.0 mL, 0.038 mol, 2 M solution in THF) was added dropwise to a stirring suspension of copper iodide (3.60 g, 0.019 mol) in anhydrous THF (64 mL) at -78 C. Upon completion of the addition, the mixture was warmed to -36 C
for 5 minutes, then cooled to -78 C, and (S)-toluene-(2-iodo-l-methyl-ethyl)-carbamic acid benzyl ester (4.00 g, 0.013 mol) in THF (19 mL) was added dropwise. After stirring at -36 C for 6 h, sat. NH4C1 solution (10 mL) was added and the mixture was allowed to warm to RT. The solvent was removed in vacuo. The residue was suspended in diethyl ether. The mixture was filtered and the solids were washed with diethyl ether. The organic extract was washed with sat. NaCI solution (1 x 20 mL), NH4OH solution (3 x 20 mL) and sat. NaCI
solution (1 x 20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/diethyl ether 1:1) to give the title compound. MS (m/z): 233.8 [M+H+]
Reaction E was performed based on literature (Harding et al., J. Org. Chem.
1981, 46, 3920-3922) E. (2S,5S)-2,5-Dimethyl-pyrrolidine-l-carboxylic acid benzyl ester.
Mercuric acetate (2.05 g, 6.43 mmol) was added to a stirring solution of (S)-(1-methyI-pent-4-enyl)-carbamic acid benzyl ester (1.00 g, 4.29 mmol) in THF (43 mL).
The mixture was purged with nitrogen, covered with aluminum foil and stirred at RT
overnight. A solution of sodium borhydride (160 mg, 4.24 nvnol) in 2 N NaOH (0.32 mL) was added dropwise and the mixture was stirred at RT overnight. Sat. Na2CO3 solution (3 mL) was added. After stirring at RT for 4 h, the solvent was removed in vacuo. The residue was diluted with diethyl ether and extracted with sat. Na2CO3 solution (3 x 15 mL). The aqueous layer was extracted with diethyl ether (3 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/ methanol 30:1) to give the title compound. MS (m/z): 233.8 [M+H+]
F. (2S,5S)-2,5-Dimethyl-pyrrolidine (2S,5S)-2,5-Dimethyl-pyrrolidine-l-carboxylic acid benzyl ester (100 mg, 0.43 mmol) was dissolved in methanol (9 mL). The solution was subjected to continuous flow hydrogenation utilizing a Thales H-Cube flow hydrogenator, which contained a cartridge of 10% palladium on carbon as catalyst. The hydrogenation was done at RT under a pressure of 10 bar. 20 drops of concentrated HCI were added. The solvent was evaporated to give the title compound as the HCl salt. MS (m/z): 100.0 [M+H*]
G. (R,S)-N-(1-{1-[2-Chloro-4-((2S,5S)-2,5-dimethyl-pyrrolidine-l-carbonyl)-phenyl]-ethylcarbamoyl } -cyclopropyl)-3 -fluoro- 5 -trifluoromethyl-benzamide (R,S)-3-Chloro-4-(1-{[1-(3-fluoro-5-trifluoromethyl-benzoylamino)-cyclopropane carbonyl]-amino}-ethyl)-benzoic acid was reacted with (2S,5S)-2,5-dimethyl-pyrrolidine according to the synthesis of (R,S)-pyrimidine-5-carboxylic acid (1-{1-[4-(2,5-cis/trans-dimethyl-pyrrolidine-l-carbonyl)-2-fluoro-phenyl]-ethylcarbamoyl } -cyclopropyl)-amide to give the title compound as the TFA salt. MS (m/z): 554.0 [M+H+]
Example 17 Synthesis of N-((1R)-1-(4-(2,5-cis/trans-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 150) H H O
N N,N ~ F
rw o H ~ , CF, O N
First step of reaction A was performed based on literarture (Gibson et al., J.
Org. Chem.
1999, 64, 7388-7394) A. Resin-bound (R)-4-(1-(hydrazinecarboxamido)ethyl) benzoic acid Hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (150 mg, 0.59 mmol) was suspended in DCM (5 mL) and sat. NaHCO3 solution (5 mL). The biphasic mixture was stirred at 0 C for 5 minutes. The two layers were allowed to separate and phosgene (20%
solution in toluene, 1.3 mL, 2.95 mmol) was added via syringe to the organic phase. The mixture was stirred at 0 C for 10 minutes, the layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one. The crude product (350 mg, 0.483. mmol) was dissolved in DCM (2 mL) and added to a suspension of resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA showed the right product (R)-4-(1-(2=(((9H-fluoren-9-yl)methoxy)carbonyl)hydrazinecarboxamido)ethyl) benzoic acid. MS
(m/z): 445.8 [M+H+]. Piperidin (20% solution in DMF, 4 mL) was added and the mixture was shaken for 15 minutes. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and dried in vacuo. A test cleavage with TFA showed the right product. MS
(m/z): 223.8 [M+H+]
B. (R)-4-(1-(2-(3-Fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl) benzoic acid A solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083mo1) HATU
(31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM (1 znL) was added to resin-bound (R)-4-(1-(hydrazinecarboxamido)ethyl)benzoic. acid (106 mg, 0.069 mmol).
The mixture was shaken 2 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL).
The suspension was shaken at RT for 30 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase 1-iPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound. MS (m/z): 413.8 [M+H+]
C. N-((1 R)-1-(4-(2, 5 -cis/trans-Dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide 2,5-cis/trans-Dimethyl-pyrrolidine (4.7 mg, 0.047 mmol) was added to a solution of (R)-4-(1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl)benzoic acid (16.2 mg, 0.039 mmol), WSC (9.0 mg, 0.047 mmol) and collidine (25.8 L, 0.196 mmol) in DCM/DMF 9:1 (1 mL). After stirring overnight at RT, the mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN
in water with 0.1 % TFA to give the title compound. MS (m/z): 495.1 [M+H+]
Example 18 Synthesis of N-((1R)-1-(4-(2,5-cis/trans-dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamide (Compound 151) N N, F
~ H
~
O N
Reaction A and the first step of reaction B were performed based-on literarture (Gibson et al., J. Org.Chem. 1999, 64, 7388-7394) A. N-Methyl-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester Methylhydrazine (173 l, 3.26 mmol) was added at -78 C to a stirring solution of di-tert-butyl dicarbonate (924 mg, 4.23 mmol) in DCM (5 mL). The solution was allowed to warm to RT and stirred at RT for 30 minutes. 9H-Fluorenylmethyl chloroformate (842 mg, 3.26 mmol) and ethyl-diisopropyl-amine (664 l, 3.91 mmol) were added dropwise and the mixture was stirred at RT for 8 h. TFA (5 ml) was added and the mixture stirred for additional 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 7:3) to give the title compound MS (m/z):
268.8 [M+H+]
B. (R)-4-(1-(2-(3-Fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamido) ethyl) benzoic acid Phosgene (20% solution in toluene, 3.43 ml, 6.51 mmol) was added dropwise at 10 C to a stirred solution of N-methyl-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (1.81 g, 3.26 mmol) in dioxane (15 ml). The mixture was stirred at 10 C for 5 minutes and then stirred at RT for 1.5 h. The mixture was concentrated in vacuo to give (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)-2-methylhydrazinecarboxylate. The crude product (68.5 mg, 0.207 mmol) was dissolved in DCM (1 mL) and added to a suspension of resin-bound (R)-4-(1-amino-ethyl)-benzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA
showed the right product (R)-4-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-methylhydrazinecarboxamido)ethyl)benzoic acid. MS (m/z): 459.8 [M+H+].
Piperidin (20%
solution in DMF, 4 mL) was added and the mixture was shaken for 30 minutes to give resin-bound (R)-4-(1-(1-methylhydrazinecarboxamido)ethyl)benzoic acid. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and a solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083 mmol), HATU (31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM/DMF 2:1 (1.5 ml) was added. The mixture was shaken 4 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL). The suspension was shaken at RT for 20 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound. MS (m/z):
427.7 [M+H+]
C. N-((1R)-1-(4-(2,5-cis/trans-Dimethylpyrrolidine-l-carbonyl)phenyl)ethyl)-2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamide 2,5-cis/trans-Dimethyl-pyrrolidine (2.8 mg, 0.028 mmol) was added to a solution of (R)-4-(1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)-1-methylhydrazinecarboxamido)ethyl)benzoic acid (10 mg, 0.023 mmol), WSC (5.4 mg, 0.028 mmol) and collidine (15.4 L, 0.117 mmol) in DCM/DMF 9:1 (1 mL). After stirring overnight at RT, the mixture was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN
in water with 0.1% TFA to give the title compound. MS (m/z):-509.0 [M+H+]
Example 19 Synthesis of N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 268) F
VF
OyN,N NH H (f+) F F
N
(S, O N
(RI
A. 5 -Bromo-3 -fluoro-pyridine-2-carbonitrile H2SO4 (1 ml, 5 mol) was added to a TBAF solution in THF (657 ml, 0.66 mol, 1 M).
DMF (200 mL) were added at -40 C until the suspension became a clear solution.
5-bromo-3-nitropyridin-2-carbonitrile (50.0 g, 0.22 mol) in DMF (800 mL) were added slowly. The solution was stirred at -40 C for 30 min, till starting material could not be detected by TLC
(n-hex/EA 5:1). The reaction was quenched with 2 M HCI (500 ml) at -40 C to afford pH 3.
'The mixture was extracted twice with EA. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purifieded by chromatography on silica gel.
B. 5-Bromo-3 -fluoro-pyridine-2-carboxylic acid Conc. HCl (300 mL) were added to 5-Bromo=3-fluoro-pyridine-2-carbonitrile (21.0 g, 0.11 mol) and stirred over night at 60 C. After evaporation ether was added and the suspension was stirred for additional time. The solid was collected and dried.
The crude product was used without any further purification. MS (m/z): 219.8 [M+H+]
C. 5-Bromo-3 -fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide TEA (17.4 ml, 0.13 mol), EDCI (83.2 g, 0.43 mol), HOBt (2.90 g, 0.02 mol) and N,O-Dimethylhydroxylamine x HCI (25.0 g, 0.26 mol) were added to a solution of 5-Bromo-3-fluoro-pyridine-2-carboxylic acid (55.5 g, 0.22 mol) in DMF (1000 mL). After stirring overnight the solvent was reduced in vacuo. EA and brine were added and the aq. layer was extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel. MS (m/z): 262.8 [M+H']
D. 5 -Bromo-3 -fluoro-pyridine-2-carbaldehyde 1M LiA1H4 in THF (50 ml, 0.05 mol) was added slowly at -78 C to a solution of bromo-3-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (29.0 g, 0.11 mol) in THF
(350 mL) After 20 min stirring at -78 C the mixture was quenched with water and brine and allowed to come to room temperature. EA was added and the suspension was filtered over celite. The aq. layer was extracted with EA and the combined organic layers were washed with brine and dried over sodium sulfate. After evaporation the crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 203.9 [M+H{]
E. 2-Methyl-propane-2-sulfinic acid 5-bromo-3-fluoro-pyridin-2-ylmethyleneamide (R)-(+)-2-Methyl-2-propansulfinamide (11.6 g, 0.10 mol), magnesium sulfate (115 g, 0.10 mol), PPTS (2.40 g, 0.01 mol) and cesium carbonate (33.7 g, 0.10 mol) were added to a solution of 5-bromo-3-fluoro-pyridine-2-carbaldehyd (19.5 g, 0.10 mol) in DCM
(600 ml).
After stirring over night the reaction was filtered over celite and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA).
MS (m/z): 306.6 [M+H+]
F. 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-amide Methylmagnesium chloride solution (29.9 ml, 0.09 mol, 22% in THF) was added slowly to a solution of 2-methyl-propane-2-sulfinic acid 5-bromo-3-fluoro-pyridin-2-ylmethyleneamide (17.5 g, 0.06 mol) in DCM (570 mL) at -55 C. The reaction mixture was quenched with brine after stirring for 20 minutes at -55 C. Celite was added and the suspension was filtered. The layers were separated and the aq. layer was extracted with DCM.
The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA).
MS (m/z): 322.6 [M+H+]
G. 5-Fluoro-6-[1-(2-methyl-propane-2-sulfmylamino)-ethyl]-nicotinic acid methyl ester To a stirred suspension of 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-amide (1.40 g, 4.33 mmol), 1,4-bis-(diphenylphosphino)ferrocene (0.53 g, 0.96 mmol) and Pd(OAc)2 (0.21 g, 0.91 mmol) in anhydrous DMSO (10 mL) under an atmosphere of nitrogen were added triethylamine (3.6 mL, 26.0 mmol) and anhydrous methanol (4 mL). After stirring at 70 C under an atmosphere of carbon monoxide for 14 h the mixture was concentrated in vacuo and the residue was partitioned between EA
(200 mL) and sat. NaHCO3 solution (200 mL). After extraction of the aqueous layer with EA
(2 x 200 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 19:1) to give the title compound. MS (m/z): 302.7 [M+M
H. 6-((1R)-1-(1,1-Dimethylethylsulfinamido)ethyl)-5-fluoronicotinic acid To a solution of 5 -fluoro-6- [1-(2-methyl-propane-2-sulfmylamino)-ethyl] -nicotinic acid methyl ester (910 mg, 3.01 mmol) in MeOH (1.5 mL) and H20 (0.5 mL) was added LiOH
(215 mg, 9.03 mmol). The solution was stirred overnight then concentrated. The residue was dissolved in 15% MeOH/CH2C12 and filtered through a short silica column to remove inorganic salts. Crude 6-((1R)-1-(1,1-dimethylethylsulfmamido)ethyl)-5-fluoronicotinic acid was determined to be of sufficient purity for the next reactions. MS (m/z):
288.7 [M+H+]
1. N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide 6-((1R)-1-(1,1-Dimethylethylsulfinamido)ethyl)-5-fluoronicotinic acid (50.0 mg, 0.17 mmol) was added to a stirred solution of (2R,5S')-2,5-dimethyltetrahydro-lH-1-pyrrolidinium chloride (Example 4C) (35.3 mg, 0.26 mmol), HATU (65.9 mg, 0.17 mmol) and DIPEA (151 L, 0.87 mmol) in DMF (1.7 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with n-hexane/EA 5:1). MS (m/z): 369.8 [M+H+]
J. (6-((R)-1-Aminoethyl)-5-fluoropyridin-3-yl)((2R,5S)-2,5-dimethylpyrrolidin-l-yl)methanone hydrochloride To N-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (50 mg, 0.14 mmol) is added a solution of HCl in MeOH (3 N, 1 mL). The reaction mixture is stirred at RT for 2 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction.
MS (m/z): 265.9 [M+H+]
K. tert-Butyl 2-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
tert-Butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (46 mg, 0.21 mmol) was dissolved in THF (2 mL) treated with DIPEA (361 L, 2.07 mmol) and cooled to 0 C before a solution of (6-((R)-1-aminoethyl)-5-fluoropyridin-3-yl)((2R,5S)-2,5-dimethylpyrrolidin-l-yl)methanone hydrochloride (25 mg, 0.08 mmol) with DIPEA (32 L, 0.18 mmol) in THF(2 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT
for 14 h. The mixture was poured into EA and washed sequentially with HCl (1 N), sat.
NaHCO3, and brine before being dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography on silica gel (elution with n-hexane/EA 3:1).
MS (m/z):
451.9 [M+H+]
L. N-((R)-1-(5-((2R,5S)-2,5-Dimethylpyrrolidine-l-carbonyl)-3 -fluoropyridin-2-yl)ethyl)-1-ethyl-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide To tert-butyl2-((R)-1-(5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)-3-fluoropyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (25 mg, 0.06 mmol) is added a solution of HCl in MeOH (3N, 1 mL). The reaction mixture is stirred at RT for 2 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
The hydrochloride (20 mg, 0.05 mmol) is dissolved in DMF (0.5 mL), treated with DIPEA (90 L, 0.52 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (10 mg, 0.08 mmol) and stirred 2 h at RT. Then the mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA to give the title compound. MS (m/z): 541.8 [M+H+]
Example 20 Synthesis of (R)-N-(1-(2-chloro-4-(diethylcarbamoyl)phenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 256) . I F F
Oy N.N ~
F
NH H /
CI F
O N
A. Methyl4-((tert-butylsulfinylimino)methyl)-3-chlorobenzoate The synthesis of 3-chloro-4-formyl-benzoic acid methyl ester is described in Example 15B.
(S)-(-)-2-Methyl-2-propansulfinamide (1.26 g, 10.4 mol), magnesium sulfate (12.5 g, 104 mmol), PPTS (0.52 g, 2.08 mol) were added to a solution of 3-chloro-4-formyl-benzoic acid methyl ester (2.07 g, 10.4 mmol) in DCM (52 ml). After stirring over night the reaction was filtered over celite and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 301.7 [M+H+]
B. Methyl3-chloro-4-((1R)-1-(1,1-dimethylethylsulfinamido)ethyl)benzoate Methylmagnesium chloride solution (3.4 ml, 9.75 mmol, 22% in. THF) was added slowly to a solution of methyl 4-((tert-butylsulfmylimino)methyl)-3-chlorobenzoate (1.73 g, 5.73 mmol) in DCM (30 mL) at -55 C. The reaction mixture was quenched with brine after stirring for 1 h at -55 C. Celite was added and the suspension was filtered. The layers were separated and the aq. layer was extracted with DCM. The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 317.8 [M+H+]
C. (R)-Methyl4-(1-aminoethyl)-3 -chlorobenzoate hydrochloride To methyl 3-chloro-4-((1R)-1-(1,1-dimethylethylsulfmamido)ethyl)benzoate (199 mg, 0.63 mmol) is added a solution of HCl in MeOH (3N, 10 mL). - The reaction mixture is stirred at RT for 1 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction. MS (m/z): 213.8 [M+I+]
D. (R)-tert-Butyl 2-(1-(2-chloro-4-(methoxycarbonyl)phenyl)ethylcarbamoyl)-2-ethyl hydrazinecarboxylate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (417 mg, 1.87 mmol) was dissolved in THF (2 mL) treated with DIPEA (718 L, 4.11 mmol) and cooled to 0 C before a solution of (R)-methyl 4-(1-aminoethyl)-3-chlorobenzoate hydrochloride (79 mg, 0.32 mmol) with DIPEA (121 L, 0.69 mmol) in THF (2 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT for 14 h. The mixture was poured into EA
and washed sequentially with HCl (1 N), sat. NaHCO3, and brine before being dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography on 'silica gel (elution with n-hexane/EA). MS (m/z): 399.7 [M+H+]
E. (R)-Methyl 3-chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl) hydrazinecarboxamido)ethyl)benzoate To (R)-tert-butyl 2-(1-(2-chloro-4-(methoxycarbonyl)phenyl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (75 mg, 0.19 mmol) is added a solution of HCI in MeOH (3 N, 2 mL). The reaction mixture is stirred at RT for 14 h and then concentrated to dryness. No purification step is required, and the isolated title compound is utilized in the next reaction.
The hydrochloride (63 mg, 0.19 mmol) is dissolved in DMF (1.0 mL), treated with DIPEA (163 L, 0.94 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (47 mg, 0.21 mmol) and stirred 2 h at RT. Then the mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (n-hexan/EA). MS (m/z): 489.6 [M+H+]
F. (R)-N-(1-(2-Chloro-4-(diethylcarbamoyl)phenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To a solution of (R)-methyl 3-chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido)ethyl)benzoate (92 mg, 0.19 mmol) in Dioxan (2 mL) was added a 2 N solution of LiOH in water (1 mL) and the reaction was stirred for 3 h. Then the organic solvent is removed in vacuo, the water layer was extracted twice with EA and the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was used in the next step without further purification.
(R)-3-Chloro-4-(1-(1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazine carboxamido)ethyl)benzoic acid (27.0 mg, 0.06 mmol) was added to a stirred solution of diethylamine (44.0 mg, 0.60 mmol) and HATU (22.9 mg, 0.06 mmol) in DMF (1.5 mL).
After stirring for 2 h the reaction mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA
to give the title compound. MS (m/z): 530.9 [M+H+]
Example 21 Synthesis of N-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl) ethyl)-1-ethyl-2-(3 -fluoro-5 -(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 263) ! V F
OyN. 1 NH
H ci F
N
(s) O N
(W
A. Dimethyl 3-chloropyridine-2,5-dicarboxylate Dimethyl 3-chloropyridine-2,5-dicarboxylate was synthesized according to literature (Hendrickson et al. Org. Lett. 2004, 3-5).
Pyridine-2,5-dicarboxylic acid (10.0 g, 60.0 mmol) was suspended in 300 mL
0.2% (w/w) aq. Na2WO4 (0.6 g). To this solution was added H202 in water (30% w/w, 34 mL, 315 mmol).
The resulting mixture was stirred and heated at 80-85 C for 10 hours. The resulting solid was collected by filtration and washed with cold water. Drying the material under high vacuum overnight yielded pyridine-2,5-dicarboxylic acid N-oxide, which was used in the next step without further purification.
To a solution of thionyl chloride (17.4 mL, 240 mmol) in DCM (500 mL) was added DMF (5 mL) at 0 C. Pyridine-2,5-dicarboxylic acid N-oxide from the first step was added into this mixture portionwise. The resulting mixture was heated at 65 C for 2 hours. The reaction was cooled to RT then placed in an ice-bath. The reaction was quenched with methanol (100 mL) slowly at 0 C. The solvent was removed in vacuo and the crude product was partitioned between DCM (200 mL) and aq. NaHCO3 (sat. 100 mL). The organic layer was separated and the aqueous layer was extracted with additional DCM (2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo.
Purification of the crude oil through a short plug of silica gel using hexane/ethyl acetate (4:1) afforded dimethyl3-chloropyridine-2,5-dicarboxylate. GC/MS (m/z): 229.0 B. Methyl 5-chloro-6-(hydroxymethyl)nicotinate To a solution of dimethyl 3-chloropyridine-2,5-dicarboxylate (1.0 g, 4.4 mmol) in THF
(10 mL) and MeOH (20 mL) was added powdered calcium chloride (3.9 g, 35 mmol).
The suspension was cooled to 0 C and sodium borohydride (416 mg, 11.0 mmol) was added portionwise. The resulting mixture was stirred for 3 h at 0 C and poured into ice-water (200 mL), and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was removed in vacuo to yield methyl 5-chloro-6-(hydroxymethyl)nicotinate which was used in the next step without further purification.
GC/MS (m/z): 201.0 C. Methyl 5-chloro-6-formylnicotinate To a solution of methyl 5-chloro-6-(hydroxymethyl)nicotinate (3.2 g, 15.8 mmol) in DCM (20 mL) was added Dess-Martin periodinane (10.1 g, 23.7 mmol). The solution was stirred for 1 h, diluted with DCM and filtered over a pad of Celite. After evaporation of the solvent in vacuo the crude material was purified by flash chromatography (hexane/ethyl acetate 3:1) to give the title compound. GC/MS (m/z): 201.0 D. (R)-Methyl 6-((tert-butylsulfinylimino)methyl)-5-chloronicotinate To a solution of (R)-(-)-2-methyl-2-propanesulfinamide (0.73 g, 6.0 mmol) in DCM (25 mL) was added methyl 5-chloro-6-formylnicotinate (1.2 g, 6.0 mmol), pyridinium p-toluenesulfonate (0.15 mg, 0.6 mmol), magnesium sulphate (7.2 g, 60 mmol) and freshly powdered caesium carbonate (1.9 g, 6.0 mmol). The reaction was stirred at RT
for 6 h. The mixture was filtered through celite, washed with DCM, and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography (0-10% ethyl acetate in hexanes) to provide the title compound. MS (m/z): 302.6 [M+H+]
E. Methyl 5-chloro-6-((R)-1-((R)-1,1-dimethylethylsulfmamido)ethyl)nicotinate Methyl magnesium chloride (22% in THF, 2.1 mL, 6.0 mmol) was added dropwise at -60 C to a stirred solution of (R)-methyl 6-((tert-butylsulfinylimino)methyl)-5-chloronicotinate (1.2 g, 4.0 mmol) in DCM (30 mL). After stirring for 30 min at -60 C, sat.
ammonium chloride solution (40 mL) was added. The aqueous layer was extracted with DCM
(4 x 25 ml), the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA 1:1) to give the tiltle compound. MS (m/z): 318.8 [M+H+]
F. (R)-Methyl 6-(1-aminoethyl)-5-chloronicotinate hydrochloride A. solution of methyl 5-chloro-6-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl) nicotinate (230 mg, 0.72 mmol) and HCl (3N solution in MeOH, 2 mL) was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue was recristallized from diethylether to give the title compound as the HCl salt. MS (m/z): 214.8 [M+H+]
G. (R)-Methyl 6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-chloronicotinate Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate were synthesised according to literature (Bailey et al. J. Med. Chem. 2004, 47, 3788-3799).
Tert-butyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate (443 mg, 1.99 mmol) was dissolved in THF (2.5 mL) treated with DIPEA (705 L, 3.98 mmol) and cooled to before a solution of (R)-methyl 6-(1-aminoethyl)-5-chloronicotinate hydrochloride (100 mg, 0.40 mmol) with DIPEA (155 L, 0.88 mmol) in THF (2.5 mL) was added all at once. The reaction was maintained at 0 C (1 h) and then stirred at RT for 14 h. The mixture was poured into EA and washed sequentially with HCl (1 N), sat. NaHCO3, and brine before being dried (MgSO4), filtered, and, concentrated. The product was purified by flash chromatography on silica gel (elution with hexane/EA). MS (m/z): 400.8 [M+H+]
H. (R)-6-(1-(2-(tert-Butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (R)-Methyl 6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinate (220 mg, 0.55 mmol) was dissolved in ACN (5.mL), treated with LiOH (1M
solution in water, 3.5 mL) and stirred 13 h at RT. The mixture was concentrated in vacuo and EA (150 mL) was added. The pH of the aqueous layer was adjusted to 4 by the addition of 1 N HCl solution and the aqueous layer was extracted with EA (3 x) and DCM/iPrOH
(4:1, 3 x).. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.
The resulting title compound was used for the next reaction without purification. MS (m/z):
386.8 [M+H+]
I. tert-Butyl 2-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (2R,5S)-2,5-Dimethylpyrrolidine hydrochloride (105 mg, 0.78 mmol) was added to a stirred solution of (R)-6-(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (150 mg, 0.39 mmol), WSC (149 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol) and DIPEA (330 L, 1.94 mmol) in DCM (2.5 mL). After stirring overnight at RT the solvent was removed in vacuo and the crude product was partitioned between EE
and aq.
NaZCO3. The organic layer was separated and the aqueous layer was extracted with additional EA (2 x). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 467.9 [M+H+]
J. N-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To tert-Butyl 2-((R)-1-(3-chloro-5-((2R,5S)-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (180 mg, 0.39 mmol) is added a solution of HC1 in MeOH (3N, 20 mL). The reaction mixture is stirred at RT for 13 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
N-((R)-1-(3 -Chloro-5 -((2R, 5S)-2, 5 -dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethylhydrazinecarboxamide hydrochloride (8.0 mg, 0.02 mmol) was added to a stirred solution of 3-fluoro-5-(trifluoromethyl)benzoic acid (9.1 mg, 0.04 mmol), WSC
(8.3 mg, 0.04 mmol), HOBt (5.9 mg, 0.04 mmol) and DIPEA (19 L, 0.11 mmol) in DMF (0.2 mL).
After stirring overnight at RT the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 % TFA to give the title compound. MS (m/z): 557.9 [M+IT"]
Example 22 Synthesis of (R)-5-chloro-N,N-diethyl-6-(1-(1-ethyl-2-(3-fluoro-5-(trifluoiomethyl) benzoyl)hydrazinecarboxamido)ethyl)nicotinamide (Compound 265) F
OvN. VF N 1 NH H !RI
CI N F
O N
J
A. (R)-tert-Butyl 2-(1-(3-chloro-5-(diethylcarbamoyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate Diethylamine (31 mg, 0.42 mmol) was added to a solution of (R)-6-,(1-(2-(tert-butoxycarbonyl)-1-ethylhydrazinecarboxamido)ethyl)-5-chloronicotinic acid (82 mg, 0.21 mmol), WSC (82 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and DIPEA (180 L, 1.06.
mmol) in DCM (1.5 mL). After stirring overnight at RT the solvent was removed in vacuo and the crude product was partitioned between EE and aq. Na2CO3. The organic layer was separated and the aqueous layer was extracted with additional EA (2 x). The combined organic layer was dried (Na2SO4), filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification.
MS (m/z): 441.9 [M+H+]
B. N-((R)-1-(3-Chloro-5-((2R,5S')-2,5-dimethylpyrrolidine-l-carbonyl)pyridin-2-yl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide To (R)-tert-butyl 2-(1-(3-chloro-5-(diethylcarbamoyl)pyridin-2-yl)ethylcarbamoyl)-2-ethylhydrazinecarboxylate (93 mg, 0.21 mmol) is added a solution of HC1 in MeOH (3N, 15 mL). The reaction mixture is stirred at RT for 13 h and then concentrated to dryness. No purification step is required, and the isolated hydrochloride is utilized in the next reaction.
(R)-5-Chloro-N,N-diethyl-6-(1-(1-ethylhydrazinecarboxamido)ethyl)nicotinamide hydrochloride (8.3 mg, 0.02 mmol) was added to a stirred solution of 3-fluoro-(trifluoromethyl)benzoic acid (10 mg, 0.05 mmol), WSC (9.3 mg, 0.05 mmol), HOBt (6.6 mg, 0.05 mmol) and DIPEA (22 L, 0.12 mmol) in DMF (0.2 mL). After stirring overnight at RT
the residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1 %
TFA to give the title compound. MS (m/z): 531.8 [M+H+]
Example 23 Synthesis of (R)-N-(1-(4-(diethylcarbamoyl)-2-fluorophenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamide (Compound 221) F
VF
OYN, NH H (R) F ~ F
O N'\
A. (R)-4-(1-(((9H-Fluoren-9-yl)methoxy)carbonylamino)ethyl)-3 -fluorobenzoic acid (R)-4-(1-Amino-ethyl)-3-fluoro-benzoic acid methyl ester (Example lOC) (100 mg, 0.43 mmol) was stirred in 6 N HCl solution (10 mL) at reflux overnight. Solvent was reduced in vacuo to give (R)-4-(1-aminoethyl)-3-fluorobenzoic acid hydrochloride. To the crude product (94 mg, 0.43 mmol) dissolved in DCM (2 mL), chlorotrimethylsilane (135 L, 1.07 mmol) was added. After stirring at reflux for few minutes, (9H-fluoren-9-yl)methyl carbonochloridate and triethylamine (230 mL, 1.7 mmol) were added at RT and the solution was stirred overnight. The residue was concentrated in vacuo and sat. Na2CO3 solution (50 mL) was added. After acidification of the aqueous solution with 2 N HCL
(pH=3), the aqueous layer was extracted with EA (2 x 30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with DCM/methano12:1).
MS (m/.z):
405.8 [M+H+]
B. Resin-bound (R)-4-(1-aminoethyl)-3-fluorobenzoic acid (R)-4-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-3-fluorobenzoic acid (324 mg, 0.8 mmol) and DIPEA (332 jiL, 1.9 mmol) were dissolved in DCM (8 mL). The solution was added to 2-chlorotrityl chloride resin (loading: 1.4 mmol/g, 1.09 g, 1.5 mmol) swollen in DCM (8 mL) and the mixture was shaken at RT for 30 minutes. The mixture was quenched with methanol (800 L). The resin was filtered and washed with DCM/methanol/DIPEA
(16:3:3, 1 x 10 mL) and DMF (3 x 10 mL). Piperidin (25% solution in DMF, 10 mL) was added and the mixture was shaken for 20 minutes. The resin was filtered, washed with DMF
(6 x 10 mL) and dried in vacuo to give the title compound with an expected loading of 45%
(0.65 mmol/g).
C. (91Y-Fluoren-9-yl)methyl2-ethylhydrazinecarboxylate To a solution of (9H-fluoren-9-yl)methyl hydrazinecarboxylate (500 mg, 1.97 mmol) in ethanol (9.8 mL), acetaldehyde (86.7 mg, 1.97 mmol) was added and the mixture was refluxed overnight. To this solution acetic acid (124 L, 2.16 mmol) and sodium cyanotrihydroborate (136 mg, 2.16 mmol) were added. After stirring at RT
overnight the solvent was reduced in vacuo and'the residue was partitioned between EA (30 mL) and sat.
NaCI solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by flash chromatography on silica gel (elution with n-hexane/EA 1:1). MS (m/z): 282.7 [M+H+]
D. (R)-4-(1-(1-Ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido) ethyl)-3-fluorobenzoic acid Phosgene (20% solution in toluene, 0.463 ml, 0.88 mmol) was added dropwise at 0 C to a stirred solution of (9H-fluoren-9-yl)methyl2-ethylhydrazinecarboxylate (125 mg, 0.44 mmol) in DCM (4.4 ml). The mixture was stirred at 0 C for 30 minutes and then concentrated in vacuo to give (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)-2-ethylhydrazinecarboxylate. The crude product (68.5 mg, 0.207 mmol) was dissolved in DCM (1 mL) and added to a suspension of resin-bound (R)-4-(1-aminoethyl)-3-fluorobenzoic acid (106 mg, 0.069 mmol), swollen in DCM (5 mL) and collidine (136 L, 1.035 mmol). The mixture was shaken 90 minutes at RT. The resin was filtered and washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL). A test cleavage with TFA showed the right product (R)-4-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-ethylhydrazinecarboxamido)ethyl)-3 -fluorobenzoic acid.
MS (m/z): 491.7 [M+H+]. Piperidin (20% solution in DMF, 4 mL) was added and the mixture was shaken for 30 min to give resin-bound (R)-4-(1-(1-ethylhydrazinecarboxamido)ethyl)-3-fluorobenzoic acid. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and a solution of 3-fluoro-5-trifluoromethyl-benzoic acid (17.2 mg, 0.083mo1), HATU (31.5 mg, 0.083 mmol) and collidine (45.4 L, 0.345 mmol) in DCM/DMF 2:1 (1.5 ml) was added. The mixture was shaken 4 h at RT. The resin was filtered, washed with DMF (4 x 2 mL), methanol (4 x 2 mL) and DCM (4 x 2 mL) and suspended in DCM (1 mL) and TFA (1 mL). The suspension was shaken at RT for 20 minutes. The resin was filtered and washed with DCM (2 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA to give the title compound. MS (m/z): 459.6 [M+H+]
E. (R)-N-(1-(4-(Diethylcarbamoyl)-2-fluorophenyl)ethyl)-1-ethyl-2-(3-fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxarnide (R)-4-(1-( I -Ethyl-2-(3 -fluoro-5-(trifluoromethyl)benzoyl)hydrazinecarboxamido) ethyl)-3-fluorobenzoic acid (12 mg, 0.028 rnmol) was added to a stirred solution of diethylamine (5.7 L, 0.055 mmol), HATU (10.6 mg, 0.028 mmol) and DIPEA (23.4 L, 0.14 mmol) in DMF (1.5 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound which was purified by reversed phase HPLC using a gradient of ACN in water with 0.1% TFA
to give the title compound. MS (m/z): 514.8 [M+H}]
Biological evaluation:
Example 24 Radioligand binding assay Assessing the affinity of selected compounds to bind to the BK B 1 receptor of different species.
Radioligand binding assays were performed using HEK923 cells that can be induced by tetracycline to express the human, rabbit, mouse, dog, pig or rat B 1 receptor.
The genes for the BK B1R of human, rat, mouse,. rabbit, dog, and pig were generated synthetically (GENEART, Regensburg) using a gene design and a codon usage optimized for stable expression in human cells. All receptor genes were stably and isogenically expressed by insertion into an identical position in the genome by using the Flp-In system from Invitrogen with the host cell line Flp-In T-REx HEK293 (human embryonic kidney) together with either the pcDNA5/FRT/TO-vector (for stable but tetracyclin-inducible expression). The latter was used in particular for all B 1 R subtypes, to avoid problems with a potential constitutive activity of these receptors that may prohibit the growth and selection of stably expressing clones.
For all receptor types the respective HEK293 cells bearing the respective transgene were cultured in DMEM high glucose medium supplemented with 10% FCS. At 80%
confluence cells were harvested from culture flasks by trypsinization and resuspended in DMEM 10%
FCS containing 5 g/ mL tetracycline. Cells were seeded in poly-lysine coated flat bottom 96 well plates (TPP) at appr. 80.000 cells/well and used in the binding assay after an overnight incubation at 37 C.
The cell plates were washed 2x with icecold PBS and kept on ice during the whole assay.
Test compounds were assayed at 10 different concentrations diluted in half-log steps in duplicate wells. Compounds were diluted in assay binding buffer (40mM PIPES, 109 mM
NaCI, 5mM KCI, 0.1% Glucose, 0.05% BSA, 2mM CaC12, 1 mM MgC12, 60 mM NaOH; pH
7.4) containing the protease inhibitors Captopril (100 M), 1,10-Phenanthroline (20 M) and Bacitracin (500 M). 1nM 3H-DAKD (Perkin Elmer) and the antagonist compound dilutions were prepared in a dilution plate which also included controls to assess total binding (1 nM
3H-DAKD) and non-specific binding (1 nM 3H DAKD + 10 mM DAKD). 100 L from the dilution plate was added to the cell plate and incubated for 90 minutes on ice. After that supernatants were aspirated and the plates were washed 4x with icecold PBS
followed by the addition of 200 gL dissociation buffer (0.5 M NaCI, 0.2 M acetic acid) for 10 minutes on ice.
Supematants were transferred into 6 mL scintillation vials (Sarstedt) containing 2 mL of scintillation solution (Ultima Gold, Perkin-Elmer), mixed well and subsequently measured in a Packard Topcount Scintillation counter. Specific binding to B1R was defined as the difference between total binding and non-specific binding wells. Total specific binding was set to 100% binding and 0% inhibition. Specific counts in the presence of compounds were plotted against compound concentration (log M). ICSo values were calculated by fitting a 4-parameter logistic function to the concentration-response data using non-linear regression (Xlfit, IDBS ID Business Solutions Ltd.). The compounds of this invention have affinity for the B1R in the above assay as demonstrated by results of less than 5 M.
Example 25 Functional assay for BK BI antagonists The potency and efficacy of the compounds in this invention to antagonize the was determined in a cell-based fluorescent calcium-mobilization assay. The assay measures the ability of test compounds to inhibit BK B 1R agonist-induced increase of intracellular free Calcium in different cell lines. Endogenous B1R expression was induced by IL-lbeta pretreatment of human embryonal lung fibroblasts IMR-90. B1R of several non-human species (rat, mouse, rabbit, dog and pig) were expressed recombinantly after Tetracyclirie induction in HEK 293 cells bearing the respective transgene.
Calcium-indicator-loaded cells were preincubated in the absence or presence of different concentrations of test compounds followed by stimulation of with selective B1R
agonist peptide. B1R agonist-induced calcium mobilization was monitored using the FlexStation fluorescence imaging plate reader platform.
IMR-90 human embryonal lung fibroblast cells (ATCC# CCL 186) were cultured in DMEM high (4.5g/1) glucose supplemented with 15% FCS and 4mM Glutamine.
Confluent cells were harvested by trypsinization after 5d of culture and seeded into black wall/clear bottom 96-well plates (Costar# 3603) at 40.000 cells/well. After an overnight incubation (appr. 12-16h) cells were treated with 1.36 ng/ mL human recombinant IL-10 in DMEM
15%FBS for 4h at 37 C to induce B1R upregulation. Thereafter cells were washed 2x with prewarmed Hank's balanced salt solution/20 mM HEPES buffer and subsequently loaded with fluorescent calcium indicator dye no-wash Calcium 3 assay kit (Molecular Devices) at 37 C for lh in the presence of anion transport inhibitor probenecid at 2.5 mM.
Test compounds were assayed at 7 concentrations in duplicate wells. Compound addition plates contain 5x fmal concentrations of test compounds or controls in 5% DMSO. The test compounds were added in 5 L followed by a 10 minute equilibration phase at 37 C in an incubator. Plates were then placed in the FlexStation II unit (Molecular Devices) which was set to 37 C. The addition of 50 L of the B1R agonist desArgKallidin (DAKD, Bachem) was carried out in the FlexStation II while continuously monitoring Ca-dependent fluorescence increase. Fluorescence peak heights were calculated by subtracting mean of baseline from maximum peak height. Peak heights were plotted as a function of test compound concentration while peak height without antagonist addition was defined as 100% response and 0% inhibition. Relative fluorescence peak heights were used to calculate the degree of of inhibition of the B1R agonist response by test compound. IC50 values were calculated by fitting a 4-parameter logistic function to the concentration-response data using non-linear regression (Xlfit, IDBS ID Business Solutions Ltd.). The compounds of this invention have affinity for the B1R in the above assay as demonstrated by results of less than 5 M.
Most preferred compounds of formula (I) exhibited IC50 values of less than 50 nanomolar in this assay.
The features of the present invention disclosed in the specification, the claims and/or the drawings may both separately and in any combination thereof be material for realizing the invention in various forms thereof.
Claims (45)
1. A compound of the formula (I):
or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein A is: i) an optionally substituted 5- or 6-membered cycloalkyl;
ii) an optionally substituted 5- or 6-membered heterocycloalkyl;
iii) an optionally substituted 6-membered aryl; or iv) an optionally substituted 5- or 6-membered heteroaryl;
T is a hydrogen atom, or joined to B to form i) an optionally substituted heterocycloalkyl; or ii) an optionally substituted heteroaryl;
B is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or wherein W is N, alkyl, heteroalkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R4, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R5 to form, together with W, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl;
R5, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with W, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl;
E, if present, is a heteroalkyl or a heteroaralkyl;
G, if present, is an alkyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, a alkylcycloalkyl, a heterocycloalkylalkyl, a heteroaryl, or a heteroaralkyl K is wherein R1 and R2 are each independently selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6heteroalkyl, or form, together with N, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
and R3 is a hydrogen atom, C1- or C2alkyl, cyano, or a halogen atom.
or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein A is: i) an optionally substituted 5- or 6-membered cycloalkyl;
ii) an optionally substituted 5- or 6-membered heterocycloalkyl;
iii) an optionally substituted 6-membered aryl; or iv) an optionally substituted 5- or 6-membered heteroaryl;
T is a hydrogen atom, or joined to B to form i) an optionally substituted heterocycloalkyl; or ii) an optionally substituted heteroaryl;
B is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or wherein W is N, alkyl, heteroalkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R4, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkylcycloalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R5 to form, together with W, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl;
R5, if present, is hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with W, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl;
E, if present, is a heteroalkyl or a heteroaralkyl;
G, if present, is an alkyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, a alkylcycloalkyl, a heterocycloalkylalkyl, a heteroaryl, or a heteroaralkyl K is wherein R1 and R2 are each independently selected from C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6heteroalkyl, or form, together with N, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
and R3 is a hydrogen atom, C1- or C2alkyl, cyano, or a halogen atom.
2. The compound according to claim 1, wherein A is wherein X1, X2, and X3 are each independently selected from N, O, S, NR x, CR
x, or CR x R x', wherein R x and R x' are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
x, or CR x R x', wherein R x and R x' are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
3. The compound according to claim 1 or claim 2, wherein A is selected from wherein R x, R x1, R12, R x3, R x', R x1', R x2', and R x' are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and X is NH, O, or S.
4. The compound according to claim 1, wherein A is wherein Y1, Y2, Y3 and Y4 are each independently selected from N, O, S, NR y, CR y, or CR y R y', wherein R y and R y' are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
5. The compound according to claim 1 or claim 4, wherein A is selected from wherein R y, R y1, R y2, R y3, R y4, R y', R y1', R y2', R y3', and R y4' are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
6. The compound according to any one of claims 1, 4 or 5, wherein A is wherein R y1, R y2, R y3 and R y4 are each independently selected from hydrogen atom, halogen atom, =O, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
7. The compound according to claim 6, wherein R y1 is a hydrogen atom.
8. The compound according to claim 6 or claim 7, wherein R y2 is a hydrogen atom, halogen atom, or C1-C6alkyl; and R y4 is a hydrogen atom or halogen atom.
9. The compound according to any one of claims 6 to 8, wherein R y2 is a hydrogen atom.
10. The compound according to any one of claims 6 to 9, wherein R y3 is a hydrogen atom or halogen atom.
11. The compound according to any one of claims 6 to 10, wherein R y4 is a hydrogen atom or halogen atom.
12. The compound according to any one of claims 1 to 11, wherein T is a hydrogen atom.
13. The compound according to any one of claims 1 to 12, wherein K is selected from
14. The compound according to any one of claims 1 to 13, wherein K is selected from
15. The compound according to any one of claims 1 to 14, wherein K is
16. The compound according to any one of claims 1 to 14, wherein K is
17. The compound according to any one of claims 1 to 16, wherein B is heteroalkyl, heteroaryl, or wherein W is N, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl;
R4, if present, is a hydrogen atom, alkyl, heteroalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, aralkyl, heteroaralkyl or joined to R5 to form, together with N, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl; and R5, if present, is a hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with N, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl.
R4, if present, is a hydrogen atom, alkyl, heteroalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, aralkyl, heteroaralkyl or joined to R5 to form, together with N, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl; and R5, if present, is a hydrogen atom, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkylcycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl or joined to R4 to form, together with N, v) an optionally substituted cycloalkyl;
vi) an optionally substituted heterocycloalkyl;
vii) an optionally substituted aryl; or viii) an optionally substituted heteroaryl.
18. The compound according to any one of claims 1 to 17, wherein B is -Y aB-CO-L B- or -Y aB-CO-R cB-, wherein Y aB is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
L B is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and R cB is an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
L B is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl; and R cB is an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
19. The compound according to any one of claims 1 to 18, wherein B is
20. The compound according to any one of claims 1 to 18, wherein B is wherein R4 is methyl, ethyl or isopropyl.
21. The compound according to any one of claims 1 to 17, wherein B is
22. The compound according to any one of claims 1 to 21, wherein E is -Y aE-CO-L E--Y aE-CO-R cE-, -Y aE-NR cE-CO-R dE-, -Y aE-NR cE-CO-L E-, -Y aE-NR cE-CO-NR
dE-L E-, or -Y aE-NR cE-CS-NR dE-L E-, wherein Y aE is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R cE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl, provided that R cE is not a hydrogen atom in -Y aE-CO-R cE-;
R dE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl; and L E is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.
dE-L E-, or -Y aE-NR cE-CS-NR dE-L E-, wherein Y aE is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R cE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl, provided that R cE is not a hydrogen atom in -Y aE-CO-R cE-;
R dE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl; and L E is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl.
23. The compound according to any one of claims 1 to 22, wherein G is alkyl, cycloalkyl, -Y aG-O-R cG, -Y aG-CO-NR aG R bG, -Y aG-S-R cG, -Y aG-SO-R cG, -Y aG-SO2-R
cG, heteroaryl, alkylcycloalkyl, or heterocycloalkyl, wherein Y aG is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R aG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to R bG
to form a 4- to 10-membered cycloalkyl or heterocycloalkyl;
R bG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl or a C2-C6alkynyl, or is joined to R aG to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; and R cG is an optionally substituted Cl-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
cG, heteroaryl, alkylcycloalkyl, or heterocycloalkyl, wherein Y aG is a bond, a C1-C6alkylene, a C2-C6alkenylene or a C2-C6alkynylene;
R aG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C2-C6alkynyl, or is joined to R bG
to form a 4- to 10-membered cycloalkyl or heterocycloalkyl;
R bG is a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl or a C2-C6alkynyl, or is joined to R aG to form a 4- to 10-membered cycloalkyl or heterocycloalkyl; and R cG is an optionally substituted Cl-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl.
24. The compound according to any one of claims 1, 4 to 6, 12, 17, or 22, wherein the compound is represented by formula (II):
wherein Y1 is N, CH or CF;
K is selected from R3 is a hydrogen atom or methyl;
R y2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
R y3 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
R y4 is a hydrogen atom or halogen atom;
B is -Y aB-CO-L B-, -Y aB-CO-R cB-, or wherein Y aB is a bond;
R cB is an optionally substituted C1-C8alkyl or an optionally substituted C2-C8alkenyl;
L B is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl;
W is alkyl or N;
R4, if present, is a hydrogen atom, alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
R5, if present, is a hydrogen atom or alkyl;
E is -Y bE-NR dE-CO-L E-, wherein Y bE is a bond, a C1-C6alkylene, or a C2-C6alkenylene;
R dE is a hydrogen atom, a C1-C6alkyl, or C2-C6alkenyl; and L E is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl.
wherein Y1 is N, CH or CF;
K is selected from R3 is a hydrogen atom or methyl;
R y2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
R y3 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
R y4 is a hydrogen atom or halogen atom;
B is -Y aB-CO-L B-, -Y aB-CO-R cB-, or wherein Y aB is a bond;
R cB is an optionally substituted C1-C8alkyl or an optionally substituted C2-C8alkenyl;
L B is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl;
W is alkyl or N;
R4, if present, is a hydrogen atom, alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
R5, if present, is a hydrogen atom or alkyl;
E is -Y bE-NR dE-CO-L E-, wherein Y bE is a bond, a C1-C6alkylene, or a C2-C6alkenylene;
R dE is a hydrogen atom, a C1-C6alkyl, or C2-C6alkenyl; and L E is a cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or heteroaralkyl.
25. The compound according to any one of claims 1, 4 to 6, 12, 13, 17 to 20, 22 or 23, wherein the compound is represented by formulas (III) or (IV):
wherein Y1 is N, CH or CF;
K is selected from R3 is a hydrogen atom or methyl;
R y2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
R y3 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
R y4 is a hydrogen atom or halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -Y aE-NR cE-CO-R dE-, -Y aE-NR cE-CO-L E-, -Y aE-NR cE-CO-NR dE -L E-, or -Y aE-NR cE-CS-NR dE-L E-, wherein Y aE is a bond or C1-C6alkylene;
R cE is a hydrogen atom, C1-C6alkyl, or C2-C6alkenyl;
R dE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl group;
L E is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl;
G, if present, is cycloalkyl, -Y aG-CO-NR aG R bG,-Y aG-O-R eG,-Y aG-S-R eG,-Y
aG-SO-R eG, or -Y aG-SO2-R eG, wherein Y aG is a bond or C1-C6alkylene;
R aG is a hydrogen atom or C1-C6alkyl;
R bG is a hydrogen atom or C1-C6alkyl; and R eG is C1-C6alkyl.
wherein Y1 is N, CH or CF;
K is selected from R3 is a hydrogen atom or methyl;
R y2 is a hydrogen atom, halogen atom, or C1-C6alkyl;
R y3 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
R y4 is a hydrogen atom or halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -Y aE-NR cE-CO-R dE-, -Y aE-NR cE-CO-L E-, -Y aE-NR cE-CO-NR dE -L E-, or -Y aE-NR cE-CS-NR dE-L E-, wherein Y aE is a bond or C1-C6alkylene;
R cE is a hydrogen atom, C1-C6alkyl, or C2-C6alkenyl;
R dE is a hydrogen atom, an optionally substituted C1-C8alkyl, an optionally substituted C2-C8alkenyl or an optionally substituted C2-C8alkynyl group;
L E is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or heteroaralkyl;
G, if present, is cycloalkyl, -Y aG-CO-NR aG R bG,-Y aG-O-R eG,-Y aG-S-R eG,-Y
aG-SO-R eG, or -Y aG-SO2-R eG, wherein Y aG is a bond or C1-C6alkylene;
R aG is a hydrogen atom or C1-C6alkyl;
R bG is a hydrogen atom or C1-C6alkyl; and R eG is C1-C6alkyl.
26. The compound according to claim 25, wherein the compound is represented by formula (V):
wherein Y1, K, R3, R y2, R y3, R y4, and L E are as defined in claim 25.
wherein Y1, K, R3, R y2, R y3, R y4, and L E are as defined in claim 25.
27. The compound according to claim 25, wherein the compound is represented by formula (VI):
wherein Y1, K, R3, R y2, R y3, R y4, and L E are as defined in claim 25.
wherein Y1, K, R3, R y2, R y3, R y4, and L E are as defined in claim 25.
28. The compound according to any one of claims 24 to 27, wherein R3 is a hydrogen atom.
29. The compound according to any one of claims 24 to 28, wherein R y2 is a hydrogen atom.
30. The compound according to any one of claims 1, 4 to 6, 9, 10, 12, 13, 17, 21, 22, or 23, wherein the compound is represented by formula (VII):
wherein Y1 is N, CH or CF;
K is selected from R y4 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -Y aE-CO-L E-, wherein Y aE is a bond or C1-C6alkylene;
L E is heterocycloalkyl; and G is alkylcycloalkyl, heterocycloalkylalkyl, aryl or heteroaryl.
wherein Y1 is N, CH or CF;
K is selected from R y4 is a hydrogen atom, halogen atom, C1-C6alkyl, or C1-C6heteroalkyl;
E is -Y aE-CO-L E-, wherein Y aE is a bond or C1-C6alkylene;
L E is heterocycloalkyl; and G is alkylcycloalkyl, heterocycloalkylalkyl, aryl or heteroaryl.
31. The compound according to claim 30, wherein R y4 is a hydrogen atom or halogen atom.
32. The compound according to any one of claims 1 to 31, wherein the stereogenic center to which R3 is attached to is in the (R) configuration;
and R3 is methyl.
and R3 is methyl.
33. The compound, salt, solvate or hydrate thereof, according to any one of claims 1 to 32, wherein the compound exhibits an IC50 of 500 nM or less in a standard in vitro BK B1 receptor-mediated assay.
34. A compound, preferably a compound according to any one of claims 1 to 33, which compound is selected from compounds 1 to 282 of Table 1.
35. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 34 and, optionally, at least one carrier substance, excipient and/or adjuvant.
36. The pharmaceutical composition according to claim 35, wherein the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal therapeutic system, a suppository, or a pharmaceutical device.
37. Use of a compound or of a pharmaceutical composition according to any one of claims 1 to 36 for the manufacture of a medicament for the treatment and/or prevention of a disease or a condition.
38. The use according to claim 37, wherein the condition or disease is responsive to BK
B1R modulation.
B1R modulation.
39. The use according to claim 37 or claim 38, wherein the condition or disease is selected from the group comprising inflammatory diseases, immunology disorders and pain.
40. The use according to claim 39, wherein the inflammatory disease or immunology disorder is selected from the group comprising inflammatory bowel disease, rheumatoid arthritis, gouty arthritis, atherosclerosis and associated fibrotic conditions
41. The use according to claim 39, wherein the pain is selected form the group comprising visceral pain, neuropathic pain, complex regional pain syndrome CRPS and inflammatory pain.
42. A method for inhibiting binding of DAKD, KD and DABK to a BK B1 receptor in vitro, the method comprising contacting the BK B1 receptor with at least one compound or a pharmacologically acceptable salt, solvate, or hydrate thereof according to any one of claims 1 to 36 under conditions and in an amount sufficient to detectably inhibit binding of DAKD, KD and DABK to the BK B1 receptor.
43. A method for localizing or detecting a BK B1 receptor in a tissue, preferably a tissue section, in vitro, comprising:
(a) contacting a sample of said tissue presumably containing the BK B1 receptor with a detectably labeled compound according to any one of claims 1 to 36o under conditions that permit binding of the compound to the BK B1 receptor; and (b) detecting the compound bound to the BK B1 receptor or detecting the binding of the compound to the BK B1 receptor.
(a) contacting a sample of said tissue presumably containing the BK B1 receptor with a detectably labeled compound according to any one of claims 1 to 36o under conditions that permit binding of the compound to the BK B1 receptor; and (b) detecting the compound bound to the BK B1 receptor or detecting the binding of the compound to the BK B1 receptor.
44. The method according to claim 43, wherein the compound is radiolabeled, fluorescence-labeled or luminescence labeled, or labeled with an antibody.
45. A method for the treatment of a subject which is in need of such treatment, comprising the administration of a compound or of a pharmaceutical composition according to any one of claims 1 to 36.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP07018396 | 2007-09-19 | ||
EP07018396.7 | 2007-09-19 | ||
PCT/EP2008/007919 WO2009036996A2 (en) | 2007-09-19 | 2008-09-19 | Small molecule bradykinin b1 receptor antagonists |
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CA2700051A1 true CA2700051A1 (en) | 2009-03-26 |
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CA2700051A Abandoned CA2700051A1 (en) | 2007-09-19 | 2008-09-19 | Small molecule bradykinin b1 receptor antagonists |
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EP (1) | EP2195288A2 (en) |
JP (1) | JP2010539204A (en) |
AR (1) | AR068509A1 (en) |
AU (1) | AU2008300822A1 (en) |
CA (1) | CA2700051A1 (en) |
TW (1) | TW200930710A (en) |
WO (1) | WO2009036996A2 (en) |
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CA2722704A1 (en) * | 2008-04-28 | 2009-11-05 | Zalicus Pharmaceuticals Ltd. | Cyclylamine derivatives as calcium channel blockers |
EP2344176A1 (en) * | 2008-09-18 | 2011-07-20 | Jerini AG | Use of bradykinin b1 receptor antagonists in intestinal fibrosis treatment |
SG185524A1 (en) | 2010-05-12 | 2012-12-28 | Vertex Pharma | Compounds useful as inhibitors of atr kinase |
MX2012015023A (en) * | 2010-06-30 | 2013-04-03 | Fujifilm Corp | Novel nicotinamide derivatives or salts thereof. |
US8937073B2 (en) | 2010-08-20 | 2015-01-20 | Boehringer Ingelheim International Gmbh | Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists |
HUP1000598A2 (en) | 2010-11-05 | 2012-09-28 | Richter Gedeon Nyrt | Indole derivatives |
RU2576623C2 (en) | 2011-12-28 | 2016-03-10 | Фуджифилм Корпорэйшн | Novel nicotinamide derivative or its salt |
BR102014028162A2 (en) * | 2013-11-12 | 2015-09-08 | Dow Agrosciences Llc | process for fluorination of compounds |
US20210317092A1 (en) | 2016-12-23 | 2021-10-14 | Bayer Pharma Aktiengesellschaft | Tetrazole containing compounds |
JOP20190156B1 (en) | 2016-12-23 | 2023-09-17 | Bayer Pharma AG | Carboxylic acid aromatic amides as antagonists of bradykinin b1 receptor |
WO2020113094A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
AR118982A1 (en) * | 2019-05-23 | 2021-11-17 | Pharvaris Gmbh | CYCLIC BRADYKININ RECEPTOR ANTAGONISTS |
TW202229258A (en) * | 2020-09-29 | 2022-08-01 | 日商日本歐愛特農業科技股份有限公司 | Novel piperazine compound or the salt thereof |
WO2024059495A1 (en) * | 2022-09-12 | 2024-03-21 | The Regents Of The University Of California | Methods of preparing ergoline analogs |
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CH441366A (en) * | 1961-06-09 | 1967-08-15 | Hoffmann La Roche | Process for the preparation of substituted hydrazine compounds |
EP0186817B1 (en) * | 1984-12-10 | 1989-08-02 | Nissan Chemical Industries Ltd. | 3(2h)pyridazinone, process for its preparation and anti-allergic agent containing it |
JPS6425763A (en) * | 1987-04-24 | 1989-01-27 | Mitsubishi Chem Ind | Pyrazoles and insecticide and acaricide containing said pyrazoles as active ingredient |
US5216165A (en) * | 1990-10-03 | 1993-06-01 | American Home Products Corporation | N-substituted aminoquinolines as analgesic agents |
NZ240863A (en) * | 1991-09-11 | 1995-04-27 | Mcneilab Inc | Substituted 4-aryl piperidine and 4-aryl piperazine derivatives, preparation and pharmaceutical compositions thereof |
FR2790472B1 (en) * | 1999-03-04 | 2001-04-06 | Synthelabo | DERIVATIVES OF CYCLOBUTENE-3, 4-DIONE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
FR2792635B1 (en) * | 1999-04-20 | 2001-06-01 | Synthelabo | CYCLOBUTENE-3,4-DIONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
AU2001271022B2 (en) * | 2000-07-05 | 2006-08-17 | Astellas Pharma Inc. | Propane-1,3-dione derivatives |
GB0115515D0 (en) * | 2001-06-25 | 2001-08-15 | Ferring Bv | Oxytocin agonisys |
SE0104326D0 (en) * | 2001-12-19 | 2001-12-19 | Astrazeneca Ab | Therapeutic heterocycles |
WO2003055866A1 (en) * | 2001-12-21 | 2003-07-10 | Bayer Pharmaceuticals Corporation | Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents |
CN100558718C (en) * | 2002-10-23 | 2009-11-11 | 詹森药业有限公司 | Piperazinyl and diazacyclo heptyl benzene methane amide and thiobenzamide |
BR0315055A (en) * | 2002-11-02 | 2005-08-16 | Aventis Pharma Gmbh | Pyrimidin-4,6-dicarboxylic acid diacids for selective collagenase inhibition |
WO2005014576A1 (en) * | 2003-08-12 | 2005-02-17 | Takeda Pharmaceutical Company Limited | Isoquinolinone derivative, process for producing the same and use thereof |
WO2005035534A1 (en) * | 2003-10-08 | 2005-04-21 | Ono Pharmaceutical Co., Ltd. | Heterocyclic bicyclo ring and heterocyclic tricyclo ring compounds and drugs comprising the same |
US20050261327A1 (en) * | 2004-05-20 | 2005-11-24 | Bock Mark G | 2-(Bicyclo)alkylamino-derivatives as mediatores of chronic pain and inflammation |
AU2006250354A1 (en) * | 2005-05-23 | 2006-11-30 | Japan Tobacco Inc. | Pyrazole compound and therapeutic agent for diabetes comprising the same |
JP2007191461A (en) * | 2005-05-23 | 2007-08-02 | Japan Tobacco Inc | Pyrazole compound and antidiabetic containing the same |
EP1981855A2 (en) * | 2005-12-30 | 2008-10-22 | Alantos Pharmaceuticals Holding, Inc. | Substituted bis-amide metalloprotease inhibitors |
WO2007129195A2 (en) * | 2006-05-04 | 2007-11-15 | Pfizer Products Inc. | 4-pyrimidine-5-amino-pyrazole compounds |
EP2143714B1 (en) * | 2007-04-04 | 2013-06-05 | Kowa Company, Ltd. | Tetrahydroisoquinoline compound |
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2008
- 2008-09-15 AR ARP080104000A patent/AR068509A1/en not_active Application Discontinuation
- 2008-09-19 CA CA2700051A patent/CA2700051A1/en not_active Abandoned
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- 2008-09-19 AU AU2008300822A patent/AU2008300822A1/en not_active Abandoned
- 2008-09-19 TW TW097136164A patent/TW200930710A/en unknown
- 2008-09-19 EP EP08802425A patent/EP2195288A2/en not_active Withdrawn
- 2008-09-19 JP JP2010525265A patent/JP2010539204A/en active Pending
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TW200930710A (en) | 2009-07-16 |
JP2010539204A (en) | 2010-12-16 |
EP2195288A2 (en) | 2010-06-16 |
AR068509A1 (en) | 2009-11-18 |
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WO2009036996A2 (en) | 2009-03-26 |
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