U.S. patent application number 15/933790 was filed with the patent office on 2018-07-26 for new bicyclic compounds as atx inhibitors.
This patent application is currently assigned to Hoffmann-La Roche Inc.. The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Patrick Di Giorgio, Jerome Hert, Daniel Hunziker, Patrizio Mattei, Markus Rudolph, Petra Schmitz.
Application Number | 20180208602 15/933790 |
Document ID | / |
Family ID | 54199041 |
Filed Date | 2018-07-26 |
United States Patent
Application |
20180208602 |
Kind Code |
A1 |
Di Giorgio; Patrick ; et
al. |
July 26, 2018 |
NEW BICYCLIC COMPOUNDS AS ATX INHIBITORS
Abstract
The invention provides novel compounds having the general
formula (I) ##STR00001## wherein R.sup.1, R.sup.2, R.sup.9, Y, W,
m, n, p and q are as defined herein, compositions including the
compounds and methods of using the compounds.
Inventors: |
Di Giorgio; Patrick; (Basel,
CH) ; Hert; Jerome; (Basel, CH) ; Hunziker;
Daniel; (Basel, CH) ; Mattei; Patrizio;
(Basel, CH) ; Rudolph; Markus; (Basel, CH)
; Schmitz; Petra; (Basel, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Little Falls |
NJ |
US |
|
|
Assignee: |
Hoffmann-La Roche Inc.
Little Falls
NJ
|
Family ID: |
54199041 |
Appl. No.: |
15/933790 |
Filed: |
March 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP2016/072243 |
Sep 20, 2016 |
|
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15933790 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
C07D 487/04 20130101; C07D 519/00 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 519/00 20060101 C07D519/00; A61P 27/02 20060101
A61P027/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 2015 |
EP |
15186645.6 |
Claims
1. Compounds of formula (I) ##STR00038## wherein R.sup.1 is
substituted phenyl, substituted phenyl-C.sub.1-6-alkyl, substituted
phenoxy-C.sub.1-6-alkyl, substituted phenyl-C.sub.2-6-alkenyl,
substituted phenyl-C.sub.2-6-alkynyl, substituted pyridinyl,
substituted pyridinyl-C.sub.1-6-alkyl, substituted
pyridinyl-C.sub.2-6-alkenyl, substituted
pyridinyl-C.sub.2-6-alkynyl, substituted thiophenyl, substituted
thiophenyl-C.sub.1-6-alkyl, substituted
thiophenyl-C.sub.2-6-alkenyl or substituted
thiophenyl-C.sub.2-6-alkynyl, wherein substituted phenyl,
substituted phenyl-C.sub.1-6-alkyl, substituted
phenoxy-C.sub.1-6-alkyl, substituted phenyl-C.sub.2-6-alkenyl,
substituted phenyl-C.sub.2-6-alkynyl, substituted pyridinyl,
substituted pyridinyl-C.sub.1-6-alkyl, substituted
pyridinyl-C.sub.2-6-alkenyl, substituted
pyridinyl-C.sub.2-6-alkynyl, substituted thiophenyl, substituted
thiophenyl-C.sub.1-6-alkyl, substituted
thiophenyl-C.sub.2-6-alkenyl and substituted
thiophenyl-C.sub.2-6-alkynyl are substituted by R.sup.3, R.sup.4
and R.sup.5; Y is --OC(O)-- or --C(O)--; W is --C(O)--,
--S(O).sub.2-- or --CR.sup.6R.sup.7-; R.sup.2 is selected from the
ring systems B, F, L, M, O, Z, AF, AG, AH, AJ, AN, AO, AP, AQ, AR,
AS, AT, AU and AV; ##STR00039## ##STR00040## R.sup.3 is halogen,
hydroxy, cyano, C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl,
halo-C.sub.1-6-alkoxy, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy, C.sub.3-8-cycloalkoxy,
C.sub.3-8-cycloalkoxy-C.sub.1-6-alkyl, C.sub.1-6-alkylamino,
C.sub.1-6-alkylcarbonylamino, C.sub.3-8-cycloalkylcarbonylamino,
C.sub.1-6-alkyltetrazolyl,
C.sub.1-6-alkyltetrazolyl-C.sub.1-6-alkyl or
heterocycloalkyl-C.sub.1-6-alkoxy; R.sup.4 and R.sup.5 are
independently selected from H, halogen, hydroxy, cyano,
C.sub.1-6-alkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl,
halo-C.sub.1-6-alkoxy, hydroxy-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8cycloalkyl-C.sub.1-6-alkoxy, C.sub.3-8-cycloalkoxy,
C.sub.3-8-cycloalkoxy-C.sub.1-6-alkyl,
C.sub.1-6-alkylcarbonylamino, C.sub.3-8-cycloalkylcarbonylamino,
C.sub.1-6-alkyltetrazolyl,
C.sub.1-6-alkyltetrazolyl-C.sub.1-6-alkyl or
heterocycloalkyl-C.sub.1-6-alkoxyl; R.sup.6 is H or
C.sub.1-6-alkyl; R.sup.7 is H, C.sub.1-6-alkyl, halogen,
halo-C.sub.1-6-alkyl or C.sub.1-6-alkoxy; R.sup.9 is halogen,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy; m, n, p and q are
independently selected from 1 or 2; r is 1, 2 or 3; or
pharmaceutically acceptable salts.
2. A compound according to claim 1, wherein R.sup.1 is substituted
phenyl-C.sub.1-6-alkyl or substituted pyridinyl, wherein
substituted phenyl-C.sub.1-6-alkyl and substituted
pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3, R.sup.4 and
R.sup.5; Y is a --OC(O)-- or --C(O)--; W is --C(O)--; R.sup.2 is
selected from the ring systems O, AJ, AN and AO; R.sup.3 is
halo-C.sub.1-6-alkoxy or tetrahydropyranyl-C.sub.1-6-alkoxy;
R.sup.4 is H or C.sub.3-8-cycloalkyl; R.sup.5 is H; R.sup.6 is
C.sub.1-6-alkyl; R.sup.9 is halogen, C.sub.1-6-alkyl or
C.sub.1-6-alkoxy; m, n, p and q are 1; or pharmaceutically
acceptable salts.
3. A compound according to claim 1 or 2, wherein R.sup.1 is
substituted phenyl-C.sub.1-6-alkyl or substituted pyridinyl,
wherein substituted phenyl-C.sub.1-6-alkyl and substituted
pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3, R.sup.4 and
R.sup.5.
4. A compound according to any one of claims 1 to 4, wherein Y is
--C(O)--.
5. A compound according to any one of claims 1 to 2, wherein
R.sup.2 is selected from the ring systems O, AJ, AN and AO.
6. A compound according to any one of claims 1 to 6, wherein
R.sup.2 is selected from the ring systems AJ and AO.
7. A compound according to any one of claims 1 to 7, wherein
R.sup.3 is halo-C.sub.1-6-alkoxy or
tetrahydropyranyl-C.sub.1-6-alkoxy.
8. A compound according to any one of claims 1 to 9, wherein
R.sup.4 is H or C.sub.3-8-cycloalkyl.
9. A compound according to any one of claims 1 to 11, wherein
R.sup.5 is H.
10. A compound according to any one of claims 1 to 12, wherein
R.sup.6 is C.sub.1-6-alkyl.
11. A compound according to any one of claims 1 to 13, wherein
R.sup.7 is H.
12. A compound according to any one of claims 1 to 13, wherein
R.sup.9 is C.sub.1-6-alkoxy.
13. A compound according to any one of claims 1 to 15, wherein m,
n, p and q are 1.
14. A compound according to any one of claims 1 to 17, wherein
R.sup.1 is substituted phenyl-C.sub.1-6-alkyl or substituted
pyridinyl, wherein substituted phenyl-C.sub.1-6-alkyl and
substituted pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3,
R.sup.4 and R.sup.5; Y is --C(O)--; W is --C(O)--; R.sup.2 is
selected from the ring systems AJ and AO; R.sup.3 is
halo-C.sub.1-6-alkoxy or tetrahydropyranyl-C.sub.1-6-alkoxy;
R.sup.4 is H or C.sub.3..sub.8-cycloalkyl; R.sup.5 is H; R.sup.6 is
is C.sub.1-6-alkyl; R.sup.7 is H; R.sup.9 is C.sub.1-6-alkoxy; m,
n, p and q are 1 or pharmaceutically acceptable salts.
15. A compound according to any one of claims 1 to 20, selected
from
trans-5-(1H-benzotriazole-5-carbonyl)-3a-fluoro-hexahydro-pyrrolo[3,4-c]p-
yrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]-
pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1-
H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-metho-
xy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriazol-5-yl-
)methanone;
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]p-
yrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-5-[3a-methoxy-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-3,4,6,6a--
tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-3-methyl-1H-benzimidazol-2-
-one;
trans-5-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3-
a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carbonyl]-3-methy-
l-1H-benzimidazol-2-one; trans-[3a-m
ethoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a--
tetrahydro-1H-pyrrolo[3,4-c]pyrrol
-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
trans-1-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbon-
yl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluorometho-
xy)phenyl]propan-1-one;
trans-1-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbon-
yl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(tri-
fluoromethoxy)phenyl]propan-1-one;
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
trans-[3a-methoxy-5-(1,4,
6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H--
pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl-
]methanone;
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
(+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-
-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(-)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
(-)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-
-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid4-trifluoromethoxy-benzyl ester; and
pharmaceutically acceptable salts thereof.
16. A compound according to any one of claims 1 to 21, selected
from
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1-
H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-metho-
xy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriazol-5-yl-
)methanone;
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; and
pharmaceutically acceptable salts thereof.
17. A process to prepare a compound according to any one of claims
1 to 22 comprising the reaction of a compound of formula (II) in
the presence of a compound of formula (III), wherein R.sup.1,
R.sup.2, R.sup.9, m, n, p and q are as defined in any one of claims
1 to 22 and W is --C(O)--. ##STR00041##
18. A compound according to any one of claims 1 to 22 for use as
therapeutically active substance.
19. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 22 and a therapeutically inert carrier.
20. The use of a compound according to any one of claims 1 to 22
for the treatment or prophylaxis of ocular conditions.
21. A compound according to any one of claims 1 to 22 for the
treatment or prophylaxis of ocular conditions.
22. The use of a compound according to any one of claims 1 to 22
for the preparation of a medicament for the treatment or
prophylaxis of ocular conditions.
23. A method for the treatment or prophylaxis ocular conditions,
which method comprises administering an effective amount of a
compound according to any one of claims 1 to 22.
24. A compound according to any one of claims 1 to 22, when
manufactured according to a process of claim 26.
25. The invention as hereinbefore described.
Description
[0001] The present invention relates to organic compounds useful
for therapy or prophylaxis in a mammal, and in particular to
autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic
acid (LPA) production and thus modulators of LPA levels and
associated signaling, for the treatment or prophylaxis of renal
conditions, liver conditions, inflammatory conditions, conditions
of the nervous system, conditions of the respiratory system,
vascular and cardiovascular conditions, fibrotic diseases, cancer,
ocular conditions, metabolic conditions, cholestatic and other
forms of chronic pruritus and acute and chronic organ transplant
rejection.
[0002] The present invention provides novel compounds of formula
(I)
##STR00002##
wherein [0003] R.sup.1 is substituted phenyl, substituted
phenyl-C.sub.1-6-alkyl, substituted phenoxy-C.sub.1-6-alkyl,
substituted phenyl-C.sub.2-6-alkenyl, substituted
phenyl-C.sub.2-6-alkynyl, substituted pyridinyl, substituted
pyridinyl-C.sub.1-6-alkyl, substituted pyridinyl-C.sub.2-6-alkenyl,
substituted pyridinyl-C.sub.2-6-alkynyl, substituted thiophenyl,
substituted thiophenyl-C.sub.1-6-alkyl, substituted
thiophenyl-C.sub.2-6-alkenyl or substituted
thiophenyl-C.sub.2-6-alkynyl, wherein substituted phenyl,
substituted phenyl-C.sub.1-6-alkyl, substituted
phenoxy-C.sub.1-6-alkyl, substituted phenyl-C.sub.2-6-alkenyl,
substituted phenyl-C.sub.2-6-alkynyl, substituted pyridinyl,
substituted pyridinyl-C.sub.1-6-alkyl, substituted
pyridinyl-C.sub.2-6-alkenyl, substituted
pyridinyl-C.sub.2-6-alkynyl, substituted thiophenyl, substituted
thiophenyl-C.sub.1-6-alkyl, substituted
thiophenyl-C.sub.2-6-alkenyl and substituted
thiophenyl-C.sub.2-6-alkynyl are substituted by R.sup.3, R.sup.4
and R.sup.5; [0004] Y is --OC(O)-- or --C(O)--; [0005] W is
--C(O)--, --S(O).sub.2-- or --CR.sup.6R.sup.7--; [0006] R.sup.2 is
selected from the ring systems B, F, L, M, O, Z, AF, AG, AH, AJ,
AN, AO, AP, AQ, AR, AS, AT, AU and AV;
##STR00003## ##STR00004##
[0007] R.sup.3 is halogen, hydroxy, cyano, C.sub.1-6-alkoxy,
C.sub.1-6-alkoxy-C.sub.1-6-alkyl, halo-C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy, C.sub.3-8-cycloalkoxy,
C.sub.3-8-cycloalkoxy-C.sub.1-6-alkyl, C.sub.1-6-alkylamino,
C.sub.1-6-alkylcarbonylamino, C.sub.3-8-cycloalkylcarbonylamino,
C.sub.1-6-alkyltetrazolyl,
C.sub.1-6-alkyltetrazolyl-C.sub.1-6-alkyl or
heterocycloalkyl-C.sub.1-6-alkoxy; [0008] R.sup.4 and R.sup.5 are
independently selected from H, halogen, hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkoxy-C.sub.1-6-alkyl, halo-C.sub.1-6-alkoxy,
hydroxy-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy, C.sub.3-8-cycloalkoxy,
C.sub.3-8-cycloalkoxy-C.sub.1-6-alkyl,
C.sub.1-6-alkylcarbonylamino, C.sub.3-8-cycloalkylcarbonylamino,
C.sub.1-6-alkyltetrazolyl,
C.sub.1-6-alkyltetrazolyl-C.sub.1-6-alkyl or
heterocycloalkyl-C.sub.1-6-alkoxy; [0009] R.sup.6 is H or
C.sub.1-6-alkyl; [0010] R.sup.7 is H, C.sub.1-6-alkyl, halogen,
halo-C.sub.1-6-alkyl or C.sub.1-6-alkoxy; [0011] R.sup.9 is
halogen, C.sub.1-6-alkyl or C.sub.1-6-alkoxy; [0012] m, n, p and q
are independently selected from 1 or 2; [0013] r is 1, 2 or 3;
[0014] or pharmaceutically acceptable salts.
[0015] Autotaxin (ATX) is a secreted enzyme also called
ectonucleotide pyrophosphatase/phosphodiesterase 2 or
lysophospholipase D that is important for converting
lysophosphatidyl choline (LPC) to the bioactive signaling molecule
lysophosphatidic acid (LPA). It has been shown that plasma LPA
levels are well correlated with ATX activity and hence ATX is
believed to be an important source of extracellular LPA. Early
experiments with a prototype ATX inhibitor have shown that such a
compound is able to inhibit the LPA synthesizing activity in mouse
plasma. Work conducted in the 1970s and early 1980s has
demonstrated that LPA can elicit a wide range of cellular
responses; including smooth muscle cell contraction, platelet
activation, cell proliferation, chemotaxis and others. LPA mediates
its effects via signaling to several G protein coupled receptors
(GPCRs); the first members were originally denoted Edg (endothelial
cell differentiation gene) receptors or ventricular zone
gene-1(vzg-1) but are now called LPA receptors. The prototypic
group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7.
Recently, three additional LPA receptors LPA4/p2y9/GPR23,
LPA5/GPR92 and LPA6/p2Y5 have been described that are more closely
related to nucleotide-selective purinergic receptors than to the
prototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved
in a large range of physiological and pathophysiological functions,
including, for example, nervous system function, vascular
development, cardiovascular physiology, reproduction, immune system
function, chronic inflammation, tumor metastasis and progression,
organ fibrosis as well as obesity and/or other metabolic diseases
such as diabetes mellitus. Therefore, increased activity of ATX
and/or increased levels of LPA, altered LPA receptor expression and
altered responses to LPA may contribute to the initiation,
progression and/or outcome of a number of different
pathophysiological conditions related to the ATX/LPA axis.
[0016] In accordance with the invention, the compounds of formula
(I) or their pharmaceutically acceptable salts and esters can be
used for the treatment or prophylaxis of diseases, disorders or
conditions that are associated with the activity of autotaxin
and/or the biological activity of lysophosphatidic acid (LPA).
[0017] The compounds of formula (I) or their pharmaceutically
acceptable salts and esters herein inhibit autotaxin activity and
therefore inhibit LPA production and modulate LPA levels and
associated signaling. Autotaxin inhibitors described herein are
useful as agents for the treatment or prevention of diseases or
conditions in which ATX activity and/or LPA signaling participates,
is involved in the etiology or pathology of the disease, or is
otherwise associated with at least one symptom of the disease. The
ATX-LPA axis has been implicated for example in angiogenesis,
chronic inflammation, autoimmune diseases, fibrotic diseases,
cancer and tumor metastasis and progression, ocular conditions,
metabolic conditions such as obesity and/or diabetes mellitus,
conditions such as cholestatic or other forms of chronic pruritus
as well as acute and chronic organ transplant rejection.
[0018] Objects of the present invention are the compounds of
formula (I) and their aforementioned salts and esters and their use
as therapeutically active substances, a process for the manufacture
of the said compounds, intermediates, pharmaceutical compositions,
medicaments containing the said compounds, their pharmaceutically
acceptable salts or esters, the use of the said compounds, salts or
esters for the treatment or prophylaxis of disorders or conditions
that are associated with the activity of ATX and/or the biological
activity of lysophosphatidic acid (LPA), particularly in the
treatment or prophylaxis of renal conditions, liver conditions,
inflammatory conditions, conditions of the nervous system,
conditions of the respiratory system, vascular and cardiovascular
conditions, fibrotic diseases, cancer, ocular conditions, metabolic
conditions, cholestatic and other forms of chronic pruritus and
acute and-chronic organ transplant rejection, and the use of the
said compounds, salts or esters for the production of medicaments
for the treatment or prophylaxis of renal conditions, liver
conditions, inflammatory conditions, conditions of the nervous
system, conditions of the respiratory system, vascular and
cardiovascular conditions, fibrotic diseases, cancer, ocular
conditions, metabolic conditions, cholestatic and other forms of
chronic pruritus and acute and chronic organ transplant rejection.
More particulary, the compounds of formula (I) and their
aforementioned salts and esters and their use as therapeutically
active substances, a process for the manufacture of the said
compounds, intermediates, pharmaceutical compositions, medicaments
containing the said compounds, their pharmaceutically acceptable
salts or esters, the use of the said compounds, salts or esters for
the treatment or prophylaxis of ocular conditions, furthermore
particularly glaucoma.
[0019] The term "C.sub.1-6-alkoxy" denotes a group of the formula
--O--R', wherein R' is an C.sub.1-6-alkyl group. Examples of
C.sub.1-6-alkoxy group include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular example
is methoxy.
[0020] The term "C.sub.2-6-alkenyl" denotes a monovalent linear or
branched hydrocarbon group of 2 to 6 carbon atoms with at least one
double bond. Particular example is ethylenyl.
[0021] The term "C.sub.1-6-alkoxy-C.sub.1-6-alkyl" denotes a
C.sub.1-6-alkyl group wherein at least one of the hydrogen atoms of
the C.sub.1-6-alkyl group is replaced by a C.sub.1-6-alkoxy group.
Particular examples are methoxymethyl, methoxyethyl, ethoxymethyl,
ethoxyethyl, iso-propoxymethyl and iso-propoxyethyl.
[0022] The term "C.sub.1-6-alkyl" denotes a monovalent linear or
branched saturated hydrocarbon group of 1 to 6 carbon atoms.
Examples of C.sub.1-6-alkyl include methyl, ethyl, propyl,
isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl.
Particular alkyl groups include methyl, ethyl, isopropyl, n-butyl
and sec-butyl.
[0023] The term "C.sub.1-6-alkylamino" a group of the formula
--NH--R', wherein R' is an C.sub.1-6-alkyl group. Particular
C.sub.1-6-alkylamino is a group of the formula --NH--R', wherein R'
is ter-butyl.
[0024] The term "C.sub.1-6-alkylcarbonylamino" denotes a group of
the formula --NH--C(O)--R', wherein R' is an C.sub.1-6-alkyl group.
Particular C.sub.1-6-alkylcarbonylamino is a group of the formula
--NH--C(O)--R', wherein R' is ter-butyl.
[0025] The term "C.sub.1-6-alkyltetrazolyl" denotes tetrazolyl
group substituted with one C.sub.1-6-alkyl group. Particular
C.sub.1-6-alkyltetrazolyl is methyltetrazolyl.
[0026] The term "C.sub.1-6-alkyltetrazolyl-C.sub.1-6-alkyl" denotes
C.sub.1-6-alkyl group wherein one of the hydrogen atoms of the
C.sub.1-6-alkyl group is replaced by a C.sub.1-6-alkyltetrazolyl
group. Particular example is methyltetrazolylmethyl.
[0027] The term "C.sub.2-6-alkynyl" denotes a monovalent linear or
branched hydrocarbon group of 2 to 6 carbon atoms with at least one
triple bond.
[0028] The term "amino" denotes the --NH.sub.2 group.
[0029] The term "aminosulfonyl" denotes --S(O).sub.2--NH.sub.2
group.
[0030] The term "cyano" denotes a --C.ident.N group.
[0031] The term "C.sub.3-8-cycloalkoxy" denotes a group of the
formula --O--R', wherein R' is a C.sub.3-8-cycloalkyl.
[0032] The term "C.sub.3-8-cycloalkoxy-C.sub.1-6-alkyl" denotes a
C.sub.1-6-alkyl group wherein at least one of the hydrogen atoms of
the alkyl group is replaced by a C.sub.3-8-cycloalkoxy group.
[0033] The term "C.sub.3-8-cycloalkyl" denotes a monovalent
saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 ring
carbon atoms. Bicyclic means a ring system consisting of two
saturated carbocycles having two carbon atoms in common. Examples
for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl,
cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic
C.sub.3-8-cycloalkyl are bicyclo[2.2.1]heptanyl or
bicyclo[2.2.2]octanyl. Particular C.sub.3-8-cycloalkyl group is
cyclopropyl.
[0034] The term "C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy" denotes a
C.sub.1-6-alkoxy group wherein at least one of the hydrogen atoms
of the alkyl group is replaced by a C.sub.3-8-cycloalkyl group.
[0035] The term "C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl" denotes a
C.sub.1-6-alkyl group wherein at least one of the hydrogen atoms of
the alkyl group is replaced by a C.sub.3-8-cycloalkyl group.
[0036] The term "C.sub.3-8-cycloalkylcarbonylamino" denotes a group
of the formula --NH--C(O)--R', wherein R' is a C.sub.3-8-cycloalkyl
group.
[0037] The term "halo-C.sub.1-6-alkoxy" denotes a C.sub.1-6-alkoxy
group wherein at least one of the hydrogen atoms of the alkoxy
group has been replaced by the same or different halogen atoms.
Particular examples are trifluoromethoxy.
[0038] The term "halogen" and "halo" are used interchangeably
herein and denote fluoro, chloro, bromo or iodo. Particular
halogens are chloro and fluoro.
[0039] The term "halo-C.sub.1-6-alkyl" denotes a C.sub.1-6-alkyl
group wherein at least one of the hydrogen atoms of the
C.sub.1-6-alkyl group has been replaced by the same or different
halogen atoms. Particular examples are trifluoromethyl.
[0040] The term "heterocycloalkyl" denotes a monovalent saturated
or partly unsaturated mono-or bicyclic ring system of 4 to 9 ring
atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O
and S, the remaining ring atoms being carbon. Bicyclic means
consisting of two cycles having two ring atoms in common, i.e. the
bridge separating the two rings is either a single bond or a chain
of one or two ring atoms. Examples for monocyclic saturated
heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl,
tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl,
1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl,
homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated
heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl,
8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl,
3-oxa-9-aza-bicyclo[3.3.1]nonyl, or
3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated
heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,
tetrahydro-pyridinyl, or dihydropyranyl. Particular example of
heterocycloalkyl group is tetrahydropyranyl.
[0041] The term "heterocycloalkyl-C.sub.1-6-alkoxy" denotes a
C.sub.1-6-alkoxy group wherein at least one of the hydrogen atoms
of the alkyl group is replaced by a heterocycloalkyl group.
Particular example of heterocycloalkyl-C.sub.1-6-alkoxy is
tetrahydropyranyl-C.sub.1-6-alkoxy, more particularly
tetrahydropyranylmethoxy.
[0042] The term "hydroxy" denotes a --OH group.
[0043] The term "hydroxy-C.sub.1-6-alkyl" denotes a C.sub.1-6-alkyl
group wherein one of the hydrogen atoms of the alkyl group is
replaced by a hydroxy group. Particular examples are hydroxymethyl
and hydroxyethyl.
[0044] The term "phenoxy" denotes a group of the formula --O--R',
wherein R' is a phenyl group.
[0045] The term "phenoxy-C.sub.1-6-alkyl" denotes a C.sub.1-6-alkyl
group wherein one of the hydrogen atoms of the alkyl group is
replaced by a phenoxy group.
[0046] The term "phenyl-C.sub.2-6-alkenyl" denotes a
C.sub.2-6-alkenyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a phenyl group. Particular example of
phenyl-C.sub.2-6-alkenyl is phenylethenyl.
[0047] The term "phenyl-C.sub.1-6-alkyl" denotes a C.sub.1-6-alkyl
group wherein one of the hydrogen atoms of the alkyl group is
replaced by a phenyl group. Particular examples of
phenyl-C.sub.1-6-alkyl are phenylmethyl and phenylethyl.
[0048] The term "phenyl-C.sub.2-6-alkynyl" denotes a
C.sub.2-6-alkynyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a phenyl group.
[0049] The term "pyridinyl-C.sub.2-6-alkenyl" denotes a
C.sub.2-6-alkenyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a pyridinyl group.
[0050] The term "pyridinyl-C.sub.1-6-alkyl" denotes a
C.sub.1-6-alkyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a pyridinyl group. Particular example of
pyridinyl-C.sub.1-6-alkyl is pyridinylmethyl, more particularly
2-pyridinylmethyl.
[0051] The term "pyridinyl-C.sub.2-6-alkynyl" denotes a
C.sub.2-6-alkynyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a pyridinyl group.
[0052] The term "thiophenyl-C.sub.2-6-alkenyl" denotes a
C.sub.2-6-alkenyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a thiophenyl group.
[0053] The term "thiophenyl-C.sub.1-6-alkyl" denotes a
C.sub.1-6-alkyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a thiophenyl group.
[0054] The term "thiophenyl-C.sub.2-6-alkynyl" denotes a
C.sub.2-6-alkynyl group wherein one of the hydrogen atoms of the
alkyl group is replaced by a thiophenyl group.
[0055] The term "pharmaceutically acceptable salts" refers to those
salts which retain the biological effectiveness and properties of
the free bases or free acids, which are not biologically or
otherwise undesirable. The salts are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid and the like, in particular hydrochloric
acid, and organic acids such as acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic
acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,
N-acetylcystein and the like. In addition, these salts may be
prepared by addition of an inorganic base or an organic base to the
free acid. Salts derived from an inorganic base include, but are
not limited to, the sodium, potassium, lithium, ammonium, calcium,
magnesium salts and the like. Salts derived from organic bases
include, but are not limited to salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins,
such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, ethanolamine, lysine, arginine,
N-ethylpiperidine, piperidine, polyimine resins and the like.
Particular pharmaceutically acceptable salts of compounds of
formula (I) are the hydrochloride salts, methanesulfonic acid salts
and citric acid salts.
[0056] "Pharmaceutically acceptable esters" means that compounds of
general formula (I) may be derivatised at functional groups to
provide derivatives which are capable of conversion back to the
parent compounds in vivo. Examples of such compounds include
physiologically acceptable and metabolically labile ester
derivatives, such as methoxymethyl esters, methylthiomethyl esters
and pivaloyloxymethyl esters. Additionally, any physiologically
acceptable equivalents of the compounds of general formula (I),
similar to the metabolically labile esters, which are capable of
producing the parent compounds of general formula (I) in vivo, are
within the scope of this invention.
[0057] The term "protecting group" (PG) denotes a group which
selectively blocks a reactive site in a multifunctional compound
such that a chemical reaction can be carried out selectively at
another unprotected reactive site in the meaning conventionally
associated with it in synthetic chemistry. Protecting groups can be
removed at the appropriate point. Exemplary protecting groups are
amino-protecting groups, carboxy-protecting groups or
hydroxy-protecting groups. Particular protecting groups are the
tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),
fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further
particular protecting groups are the tert-butoxycarbonyl (Boc) and
the fluorenylmethoxycarbonyl (Fmoc) groups. More particular
protecting group is the tert-butoxycarbonyl (Boc) group.
[0058] The abbreviation uM means microMolar and is equivalent to
the symbol .mu.M.
[0059] The abbreviation uL means microliter and is equivalent to
the symbol .mu.L.
[0060] The abbreviation ug means microgram and is equivalent to the
symbol .mu.g.
[0061] The compounds of formula (I) can contain several asymmetric
centers and can be present in the form of optically pure
enantiomers, mixtures of enantiomers such as, for example,
racemates, optically pure diastereoisomers, mixtures of
diastereoisomers, diastereoisomeric racemates or mixtures of
diastereoisomeric racemates.
[0062] According to the Cahn-Ingold-Prelog Convention the
asymmetric carbon atom can be of the "R" or "S" configuration.
[0063] Also an embodiment of the present invention are compounds
according to formula (I) as described herein and pharmaceutically
acceptable salts or esters thereof, in particular compounds
according to formula (I) as described herein and pharmaceutically
acceptable salts thereof, more particularly compounds according to
formula (I) as described herein.
[0064] A particular embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
[0065] R.sup.1 is substituted phenyl-C.sub.1-6-alkyl or substituted
pyridinyl, wherein substituted phenyl-C.sub.1-6-alkyl and
substituted pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3,
R.sup.4 and R.sup.5; [0066] Y is a --OC(O)-- or --C(O)--; [0067] W
is --C(O)--; [0068] R.sup.2 is selected from the ring systems O,
AJ, AN and AO; [0069] R.sup.3 is halo-C.sub.1-6-alkoxy or
tetrahydropyranyl-C.sub.1-6-alkoxy; [0070] R.sup.4 is H or
C.sub.3-8-cycloalkyl; [0071] R.sup.5 is H; [0072] R.sup.6 is
C.sub.1-6-alkyl; [0073] R.sup.9 is halogen, C.sub.1-6-alkyl or
C.sub.1-6-alkoxy; [0074] m, n, p and q are 1; [0075] or
pharmaceutically acceptable salts.
[0076] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.1 is substituted phenyl-C.sub.1-6-alkyl or substituted
pyridinyl, wherein substituted phenyl-C.sub.1-6-alkyl and
substituted pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3,
R.sup.4 and R.sup.5.
[0077] A particular embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein Y
is --C(O)--.
[0078] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.2 is selected from the ring systems O, AJ, AN and AO.
[0079] A particular embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.2 is selected from the ring systems AJ and AO.
[0080] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.3 is halo-C.sub.1-6-alkoxy or
tetrahydropyranyl-C.sub.1-6-alkoxy.
[0081] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.4 is H or C.sub.3-8-cycloalkyl.
[0082] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.5 is H.
[0083] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.6 is C.sub.1-6-alkyl.
[0084] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.7 is H.
[0085] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
R.sup.9 is C.sub.1-6-alkoxy.
[0086] Another embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein m,
n, p and q are 1.
[0087] A particular embodiment of the present invention provides
compounds according to formula (I) as described herein, wherein
[0088] R.sup.1 is substituted phenyl-C.sub.1-6-alkyl or substituted
pyridinyl, wherein substituted phenyl-C.sub.1-6-alkyl and
substituted pyridinyl-C.sub.1-6-alkyl are substituted by R.sup.3,
R.sup.4 and R.sup.5; [0089] Y is --C(O)--; [0090] W is --C(O)--;
[0091] R.sup.2 is selected from the ring systems AJ and AO; [0092]
R.sup.3 is halo-C.sub.1-6-alkoxy or
tetrahydropyranyl-C.sub.1-6-alkoxy; [0093] R.sup.4 is H or
C.sub.3-8-cycloalkyl; [0094] R.sup.5 is H; [0095] R.sup.6 is is
C.sub.1-6-alkyl; [0096] R.sup.7 is H; [0097] R.sup.9 is
C.sub.1-6-alkoxy; [0098] m, n, p and q are 1 [0099] or
pharmaceutically acceptable salts. [0100] Particular examples of
compounds of formula (I) as described herein are selected from
[0101]
trans-5-(1H-benzotriazole-5-carbonyl)-3a-fluoro-hexahydro-pyrrolo[3,4-c]p-
yrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; [0102]
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]-
pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; [0103]
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1-
H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
[0104]
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3-
a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriaz-
ol-5-yl)methanone; [0105]
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]p-
yrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; [0106]
trans-5-[3a-methoxy-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-3,4,6,6a--
tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-3-methyl-1H-benzimidazol-2-
-one; [0107]
trans-5-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-met-
hoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carbonyl]-3-methyl-1H--
benzimidazol-2-one; [0108]
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl-
)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]
pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
[0109]
trans-1-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-
-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluo-
romethoxy)phenyl]propan-1-one; [0110]
trans-1-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbon-
yl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(tri-
fluoromethoxy)phenyl]propan-1-one; [0111]
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; [0112]
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl-
)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-e]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-
-4-ylmethoxy)pyridin-4-yl]methanone; [0113]
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; [0114]
(+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-
-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
[0115]
(-)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
[0116]
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; [0117]
(-)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-
-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
[0118]
(+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
[0119] and pharmaceutically acceptable salts thereof.
[0120] Further particular examples of compounds of formula (I) as
described herein are selected from [0121]
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1-
H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
[0122]
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3-
a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriaz-
ol-5-yl)methanone; [0123]
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl-
)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopro-
pyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; [0124] and
pharmaceutically acceptable salts thereof.
[0125] Processes for the manufacture of compounds of formula (I) as
described herein are an object of the invention.
[0126] The preparation of compounds of formula (I) of the present
invention may be carried out in sequential or convergent synthetic
routes. Syntheses of the invention are shown in the following
general schemes. The skills required for carrying out the reactions
and purifications of the resulting products are known to those
persons skilled in the art. In case a mixture of enantiomers or
diastereoisomers is produced during a reaction, these enantiomers
or diastereoisomers can be separated by methods described herein or
known to the man skilled in the art such as e.g. (chiral)
chromatography or crystallization. The substituents and indices
used in the following description of the processes have the
significance given herein.
[0127] Compounds of general formula (I) can be synthesised from
amine precursor 1 and appropriate reagents, using methods well
known in the art.
[0128] The preparation of compounds of formula (I) of the present
invention may be carried out in sequential or convergent synthetic
routes. Syntheses of the invention are shown in the following
general schemes. The skills required for carrying out the reactions
and purifications of the resulting products are known to those
persons skilled in the art. In case a mixture of enantiomers or
diastereoisomers is produced during a reaction, these enantiomers
or diastereoisomers can be separated by methods described herein or
known to the man skilled in the art such as e.g. (chiral)
chromatography or crystallization. The substituents and indices
used in the following description of the processes have the
significance given herein.
[0129] The present invention provides novel compounds of formula
(I)
##STR00005##
[0130] Compounds of general formula (I) can be synthesised from
amine precursor 1 and appropriate reagents, using methods well
known in the art.
##STR00006##
[0131] For instance, amine 1 is reacted with a suitable carboxylic
acid of formula R.sup.1--COOH (2) leading to a compound of formula
(I), wherein Y is --C(O)--. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethyl amino)pyridine.
[0132] Amine 1 can also be reacted with suitable acylating reagents
such as acyl chlorides of formula R.sup.1--COCl (3) to lead to
compounds of formula (I), wherein Y is --C(O)--. The reaction is
performed in a solvent such as dichloromethane, tetrahydrofuran, or
N,N-dimethylformamide, in the presence of a base such as
triethylamine or 4-methylmorpholine, at temperatures between
0.degree. C. and 80.degree. C.
[0133] Alternatively, amine 1 is reacted with a suitable
chloroformate ester of formula R.sup.1--OC(O)C--Cl (4), or with an
imidazole-1-carboxylate ester of formula (3), leading to a compound
of formula (I) wherein Y is --OC(O)--.
##STR00007##
[0134] The reaction is performed in a suitable solvent such as
dichloromethane, tetrahydrofuran, N,N-dimethylformamide,
acetonitrile, acetone, water, or mixtures thereof, in the presence
of a base, e.g., triethylamine, diisopropylethylamine, pyridine,
potassium hydrogencarbonate, potassium carbonate, at temperatures
between 0.degree. C. and the boiling point of the solvent or
solvent mixture.
[0135] Chloroformate esters 4 are commercially available or can be
synthesised from the corresponding alcohol of formula R.sup.1--OH,
by reaction with phosgene or a phosgene equivalent (e.g.,
diphosgene, triphosgene), as described in the literature.
[0136] Imidazole-1-carboxylate esters 5 are synthesised from the
corresponding alcohols of formula R.sup.1--OH, by reaction with
1,1'-carbonyldiimidazole. The reaction is performed at room
temperature, in a solvent such as dichloromethane, tetrahydrofuran
or acetonitrile. The imidazole-1-carboxylate esters 5 are typically
not isolated but directly reacted with amines 1 as described
above.
[0137] Alcohols of formula R.sup.1--OH are commercially available
or can be produced by methods described herein or known in the
art.
[0138] Carboxylic acids (2) and acyl halides (3) are commercially
available or can be prepared as described herein or in the
literature.
[0139] Amines of general formula 1 are synthesised from suitably
protected precursors 6.
##STR00008##
[0140] Suitable protective groups (PG) are tert-butoxycarbonyl or
benzyloxycarbonyl. The deprotection of intermediates 6 can be
performed using methods and reagents known in the art.
[0141] For instance, in the case where PG is benzyloxycarbonyl, the
deprotection may be performed by hydrogenation at pressures between
1 bar and 100 bar, in the presence of a suitable catalyst such as
palladium on activated charcoal, at temperatures between 20.degree.
C. and 150.degree. C. in solvents such as methanol or ethanol.
[0142] Alternatively, in the case where PG is tert-butoxycarbonyl,
the deprotection may be performed in the presence of a suitable
acid, e.g., hydrochloric acid or trifluoroacetic acid, in a solvent
such as water, 2-propanol, dichloromethane, or 1,4-dioxane at
temperatures between 0.degree. C. and 30.degree. C.
[0143] Intermediates 6, wherein A is N are represented by general
structure 6A.
##STR00009##
[0144] PG is a suitable protective group, e.g., tert-butoxycarbonyl
or benzyloxycarbonyl.
[0145] Intermediates 6A can be produced from amine precursors of
general formula 7 by reaction with appropriate reagents, using
methods known in the art.
##STR00010##
[0146] For instance, 7 is reacted with alkylating agents of general
formula X--CR.sup.6R.sup.7--R.sup.2 (8) where X is a leaving group
such as Cl, Br, I, or OSO.sub.2CH.sub.3, leading to 6A, wherein W
is --CR.sup.6R.sup.7--. This reaction is performed in a solvent
such as tetrahydrofuran or N,N-dimethylformamide, in the presence
of a base, e.g. triethylamine or potassium carbonate, at
temperatures between 0.degree. C. and 100.degree. C.
[0147] Alternatively, for compounds of formula 6A, wherein W is
--CR.sup.6R.sup.7--, R.sup.6 is hydrogen, alkyl or cycloalkyl, and
R.sup.7 is H, amine 7 is reacted with aldehydes or ketones of
general formula R.sup.6--C(O)R.sup.2 (9) in a reductive amination
reaction, leading to 6A. This reaction is performed in the presence
of a suitable reducing agent, e.g., sodium borohydride or sodium
triacetoxyboro-hydride, in a solvent such as methanol, acetic acid,
tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at
temperatures between 0.degree. C. and 50.degree. C.
[0148] Alternatively, amine 7 is reacted with a suitable carboxylic
acid of formula R.sup.2--COOH (10), leading to compounds of formula
6A, wherein W is --C(O)--. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethyl amino)pyridine.
[0149] Alternatively, amine 7 is reacted with a suitable sulfonyl
chloride of formula R.sup.2-SO.sub.2Cl(11), leading to compounds of
formula 6A, wherein W is --S(O.sub.2). The reaction is performed in
a suitable solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethyl-formamide, acetonitrile, acetone, water, or mixtures
thereof, in the presence of a base, e.g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate,
potassium carbonate, at temperatures between 0.degree. C. and the
boiling point of the solvent or solvent mixture.
[0150] Alternatively, amine 7 is reacted with a suitable
N-(chlorocarbonyl)amine of formula R.sup.2--N(R.sup.10)--C(O)Cl
(12) leading to compounds of formula 6A, wherein W is
--C(O)--NR.sup.10--, or with an isocyanate of formula R.sup.2--NCO
(13), leading to compounds of formula 6A, wherein W is
--C(O)--NR.sup.10 and R.sup.10 is H.
[0151] Alternatively, amine 7 is reacted with phosgene or phosgene
equivalent (diphosgene, triphosgene) in the presence of a base
(e.g., pyridine, triethylamine) in a solvent such as
dichloromethane or tetrahydrofuran, to provide the corresponding
N-(chlorocarbonyl)amine of formula 14, which is then reacted with
amine of formula HN(R.sup.10)R.sup.2 (15), in the presence of a
base such as triethylamine or diisopropylethylamine, in a solvent
such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide,
leading to compounds of formula 6A, wherein W is
--C(O)--NR.sup.10--.
##STR00011##
[0152] Alternatively, amine 7 is reacted with phosgene or a
phosgene equivalent (diphosgene, triphosgene) in the presence of a
base (e.g., pyridine, triethylamine), in a solvent such as
dichloromethane or tetrahydrofuran, to the corresponding
N-(chlorocarbonyl)amine of formula 14, which is then reacted with
amines of formula H--O or H-AO, in the presence of a base such as
triethylamine or diisopropylethylamine, in a solvent such as
dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, leading
to compounds of formula 6A, wherein W is --C(O)-- and R.sup.2 is O
or AO.
[0153] Alternatively, amine 7 is reacted with a suitable
chloroformate of formula R.sup.2--O--C(O)--Cl (16) or with an
imidazole-1-carboxylate ester (17), leading to compounds of formula
6A, wherein W is --C(O)--O--. The reaction is performed in a
suitable solvent, e.g., acetonitrile or N,N-dimethylformamide,
optionally in the presence of a base, e.g., diisopropylethylamine
or triethylamine, at temperatures between 0.degree. C. and
100.degree. C.
##STR00012##
[0154] Chloroformates 16 are commercially available or can be
prepared from the corresponding alcohols of formula R.sup.2--OH, by
reaction with phosgene or a phosgene equivalent (e.g., diphosgene,
triphosgene) as described herein or in the literature.
[0155] Imidazole-1-carboxylate esters 17 can be prepared from the
corresponding alcohols of formula R.sup.2--OH, by reaction with
1,1'-carbonyldiimidazole as described herein or in the
literature.
[0156] N-(Chlorocarbonyl)amines 12 are synthesised from the
corresponding amines 15 by reaction with phosgene or a phosgene
equivalent (diphosgene, triphosgene, 1,1'-carbonyldiimidazole) as
described in the literature.
[0157] Isocyanates 13 are commercially available or can be prepared
from the corresponding amines of formula R.sup.2--NH.sub.2, by
reaction with phosgene or a phosgene equivalent (e.g., diphosgene,
triphosgene, 1,1'-carbonyldiimidazole) as described in the
literature.
[0158] Amines 7, alkylating agents 8, aldehydes/ketones 9,
carboxylic acids 10, sulfonyl chlorides 11, and amines 15 are
commercially available or can be synthesised as described herein or
in the literature.
[0159] Carbamates 6 wherein A is CH, and W is --C(O)--N(R.sup.10),
are represented by general formula 6B, wherein R.sup.14 is N(
R.sup.10) R.sup.2. Carbamates 6 wherein A is CH, W is --C(O)-- and
R.sup.2 is O or AO are also represented by general formula 6B,
wherein R.sup.14 is O or AO.
##STR00013##
[0160] Amide 6B is produced from carboxylic acid 18 by coupling
reaction with an amine of formula HN(R.sup.10)R.sup.2 (15), H--O or
H-AO.
##STR00014##
[0161] The reaction is performed in the presence of a coupling
agent such as 1,1'-carbonyldiimidazole, N,N'
-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethylamino)pyridine.
[0162] Carboxylic acids 18 are commercially available or can be
produced as described in the literature.
[0163] Compounds of formula (I), wherein A is N can be produced
from amine precursors of general formula 19 by reaction with
appropriate reagents, using methods known in the art.
##STR00015##
[0164] For instance, an amine of formula 19 is reacted with
alkylating agents of general formula X--CR.sup.6R.sup.7--R.sup.2
(8) where X is a leaving group such as Cl, Br, I, or
OSO.sub.2CH.sub.3, leading to compounds of formula (I), wherein A
is N and W is --CR.sup.6R.sup.7--. This reaction is performed in a
solvent such as tetrahydrofuran or N,N-dimethylformamide, in the
presence of a base, e.g., triethylamine or potassium carbonate, at
temperatures between 0.degree. C. and 100.degree. C.
[0165] Alternatively, an amine of formula 19 is reacted with
aldehydes or ketones of general formula R.sup.6--C(O)--R.sup.2 (9)
in a reductive amination reaction, leading to compounds of formula
(I) wherein A is N, W is --CR.sup.6R.sup.7--, R.sup.6 is hydrogen,
alkyl or cycloalkyl, and R.sup.7 is H. This reaction is performed
in the presence of a suitable reducing agent, e.g. sodium
borohydride or sodium triacetoxyborohydride, in a solvent such as
methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or
mixtures thereof, at temperatures between 0.degree. C. and
50.degree. C.
[0166] Alternatively, amine 19 is reacted with a suitable
carboxylic acid of formula R.sup.2--COOH (10), leading to compounds
of formula (I) wherein A is N and W is --C(O)--. The reaction is
performed in the presence of a coupling agent such as
1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethylamino)pyridine.
[0167] Alternatively, amine 19 is reacted with a suitable sulfonyl
chloride of formula R.sup.2--SO.sub.2Cl (11), leading to (I)
wherein A is N and W is --S(O.sub.2). The reaction is performed in
a suitable solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures
thereof, in the presence of a base, e.g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate,
potassium carbonate, at temperatures between 0.degree. C. and the
boiling point of the solvent or solvent mixture.
[0168] Alternatively, amine 19 is reacted with a suitable
N-(chlorocarbonyl)amine of formula R.sup.2--N(R.sup.10)--C(O)--Cl
(12) leading to compounds of formula (I), wherein W is
--C(O)--NR.sup.10--, or with an isocyanate of formula R.sup.2--NCO
(13), leading to compounds of formula (I), wherein W is
--C(O)--NR.sup.10 and R.sup.10 is H. The reaction is performed in a
suitable solvent, e.g., acetonitrile or N,N-dimethylformamide,
optionally in the presence of a base, e.g., diisopropylethylamine
or triethylamine, at temperatures between 0.degree. C. and
100.degree. C.
[0169] Alternatively, amine 19 is reacted with a suitable
chloroformate of formula R.sup.2--O--C(O)--Cl (16) or with an
imidazole-l-carboxylate ester (17), leading to compounds of formula
(I), wherein W is --C(O)--O--. The reaction is performed in a
suitable solvent, e.g., acetonitrile or N,N-dimethylformamide,
optionally in the presence of a base, e.g., diisopropylethylamine
or triethylamine, at temperatures between 0.degree. C. and
100.degree. C.
[0170] Alternatively, amine 19 is reacted with phosgene or phosgene
equivalent (diphosgene, triphosgene) in the presence of a base
(e.g., pyridine, triethylamine) in a solvent such as
dichloromethane or tetrahydrofuran, to provide the corresponding
N-(chlorocarbonyl)amine of formula 20, which is then reacted with
amine of formula HN(R.sup.10)R.sup.2 (15), in the presence of a
base such as triethylamine or diisopropylethylamine, in a solvent
such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide,
leading to compounds of formula (I), wherein W is
--C(O)--NR.sup.10--.
##STR00016##
[0171] Alternatively, amine 19 is reacted with phosgene or a
phosgene equivalent (diphosgene, triphosgene) in the presence of a
base (e.g., pyridine, triethylamine), in a solvent such as
dichloromethane or tetrahydrofuran, to the corresponding
N-(chlorocarbonyl)amine of formula 20, which is then reacted with
amines of formula H--O or H-AO, in the presence of a base such as
triethylamine or diisopropylethylamine, in a solvent such as
dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, leading
to compounds of formula (I), wherein W is --C(O)-- and R.sup.2 is O
or AO.
[0172] Amines 19 can be synthesised from their tert-butyl carbamate
derivatives of formula 21 by carbamate deprotection. The
deprotection may be performed in the presence of a suitable acid,
e.g., hydrochloric acid or trifluoroacetic acid, in a solvent such
as water, 2-propanol, dichloromethane, or 1,4-dioxane, at
temperatures between 0.degree. C. and 30.degree. C.
##STR00017##
[0173] tert-Butyl carbamates 21 can be synthesised from amine
precursors of formula 22 and appropriate reagents, using methods
well known in the art.
##STR00018##
[0174] For instance, amine 22 is reacted with a suitable carboxylic
acid of formula R.sup.1--COOH (2) leading to compounds of formula
21, wherein Y is --C(O)--. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethyl amino)pyridine.
[0175] Amine 22 can also be reacted with suitable acylating
reagents, such as acyl chlorides of formula R.sup.1--COCl (3) to
provide compounds of formula 21, wherein Y is --C(O)--. The
reaction is performed in a solvent such as dichloromethane,
tetrahydrofuran, or N,N-dimethylformamide, in the presence of a
base such as triethylamine or 4-methylmorpholine, at temperatures
between 0.degree. C. and 80.degree. C.
[0176] Alternatively, amine 22 is reacted with a suitable
chloroformate ester of formula R.sup.1--O--C(O)--Cl (4), or with an
imidazole-l-carboxylate ester of formula 5, leading to a compound
of formula 21, wherein Y is --OC(O)--. The reaction is performed in
a suitable solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures
thereof, in the presence of a base, e.g., triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate,
potassium carbonate, at temperatures between 0.degree. C. and the
boiling point of the solvent or solvent mixture.
[0177] Alternatively, amine 22 can be reacted with a phosgene or a
phosgene equivalent (e.g., triphosgene) to the corresponding
N-chlorocarbonylamine 22A, in the presence of a base (e.g.,
pyridine) in a suitable solvent, e.g., dichloromethane, at
temperatures between -78.degree. C. and +20.degree. C.
N-Chlorocarbonylamine 22A is then reacted with alcohol of formula
R.sup.1--OH, leading to a compound of formula 21, wherein Y is
--OC(O)--. This reaction is performed in a suitable solvent (e.g.,
acetonitrile of dichloromethane) in the presence of a suitable base
(e.g., sodium hydride, pyridine or polystyrene-bound
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine), at temperatures between 20.degree. C. and the boiling point
of the solvent.
##STR00019##
[0178] Amines of formula 22 are commercially available or can be
produced as described herein or in the literature.
[0179] Amines of formula 22 are commercially available or can be
produced as described herein or in the literature.
[0180] Compounds of formula (I), wherein A is CH and W is
--C(O)--NR.sup.10--can be produced from carboxylic acid precursors
of general formula 23 by reaction with appropriate amine reagents
of general formula HN(R.sup.10)R.sup.2 (15). Likewise, compounds of
formula (I), wherein A is CH, W is C(O), and R.sup.2 is O or AO,
can be produced from carboxylic acid precursors of general formula
19 by reaction with appropriate amine reagents of general formula
H--O or H-AO, using methods known in the art.
##STR00020##
[0181] For instance, this reaction is performed in the presence of
a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethylamino)pyridine.
[0182] Compounds of formula (I), wherein A is CH and W is
--C(O)--O-- can be produced from carboxylic acid precursors of
general formula 23 by reaction with appropriate alcohols of general
formula R.sup.2--OH, using methods known in the art.
[0183] For instance, this reaction is performed in the presence of
a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between --40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethylamino)pyridine.
[0184] Alternatively, the reaction is performed in two steps
wherein carboxylic acid 19 is first converted to acid chloride 24,
using methods and reagents known in the art, e.g., thionyl chloride
or oxalyl chloride. Acid chloride 24 is then reacted with alcohol
R.sup.2--OH in a suitable solvent, e.g., dichloromethane or
acetonitrile, optionally in the presence of a catalyst, e.g.,
pyridine or 4-(dimethylamino)pyridine, at temperatures between
-40.degree. C. and +100.degree. C.
##STR00021##
[0185] Carboxylic acids 23 can be produced from the corresponding
ester precursors 25, wherein R.sup.a is lower alkyl, e.g. methyl or
ethyl, using methods and reagents known in the art. For instance,
the reaction is performed in the presence of a base, e.g.,
potassium hydroxide, sodium hydroxide, or lithium hydroxide, in
solvents such as water, methanol, ethanol, tetrahydrofuran, or
mixtures thereof, at temperatures between 20.degree. C. and
100.degree. C.
##STR00022##
[0186] Compounds of formula 25 can be synthesised from amine
precursors of formula 26 and appropriate reagents, using methods
well known in the art.
##STR00023##
[0187] For instance, amine 21 is reacted with a suitable carboxylic
acid of formula R.sup.1--COOH (2) leading to compounds of formula
25, wherein Y is --C(O)--. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between ''40.degree. C. and
80.degree. C. in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethyl amino)pyridine.
[0188] Amine 25 can also be reacted with suitable acylating
reagents, such as acyl chlorides of formula R.sup.1--COCl (3) to
lead to compounds of formula 26, wherein Y is --C(O)--. The
reaction is performed in a solvent such as dichloromethane,
tetrahydrofuran, or N,N-dimethylformamide, in the presence of a
base such as triethylamine or 4-methylmorpholine, at temperatures
between 0.degree. C. and 80.degree. C.
[0189] Alternatively, amine 26 is reacted with a suitable
chloroformate ester of formula R.sup.1--O--C(O)--Cl (4), or with an
imidazole-1-carboxylate ester of formula 5, leading to a compound
of formula 25, wherein Y is --OC(O)--. The reaction is performed in
a suitable solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures
thereof, in the presence of a base, e.g., triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate,
potassium carbonate, at temperatures between 0.degree. C. and the
boiling point of the solvent or solvent mixture.
[0190] Alternatively, amine 26 can be reacted with a phosgene or a
phosgene equivalent (e.g., triphosgene) to the corresponding
N-chlorocarbonylamine 26A, in the presence of a base (e.g.,
pyridine) in a suitable solvent, e.g., dichloromethane, at
temperatures between -78.degree. C. and +20.degree. C.
N-Chlorocarbonylamine 26A is then reacted with alcohol of formula
R.sup.1--OH, leading to a compound of formula 25, wherein Y is
--OC(O)--. This reaction is performed in a suitable solvent (e.g.,
acetonitrile of dichloromethane) in the presence of a suitable base
(e.g., sodium hydride, pyridine or polystyrene-bound
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine), at temperatures between 20.degree. C. and the boiling point
of the solvent.
##STR00024##
[0191] Amines of general formula 26 are synthesised from suitably
protected precursors 27.
##STR00025##
[0192] Suitable protective groups (PG) are tert-butoxycarbonyl or
benzyloxycarbonyl. The deprotection of intermediates 27 can be
performed using methods and reagents known in the art.
[0193] For instance, in the case where PG is benzyloxycarbonyl, the
deprotection may be performed by hydrogenation at pressures between
1 bar and 100 bar, in the presence of a suitable catalyst such as
palladium on activated charcoal, at temperatures between 20.degree.
C. and 150.degree. C., in solvents such as methanol or ethanol.
[0194] Alternatively, in the case where PG is tert-butoxycarbonyl,
the deprotection may be performed in the presence of a suitable
acid, e.g, hydrochloric acid or trifluoroacetic acid, in a solvent
such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at
temperatures between 0.degree. C. and 30.degree. C.
[0195] Esters 27, wherein R.sup.a is methyl or ethyl, are produced
from carboxylic acids 18, using methods and reagents known in the
art. For instance, 18 alkylated with methyl iodide or ethyl
bromide, in the presence of a base, e.g., potassium carbonate, in a
solvent such as N,N-dimethylformamide, at -20.degree. C. and
+30.degree. C., leading to the methyl or ethyl ester 27,
respectively.
[0196] Also an embodiment of the present invention is a process to
prepare a compound of formula (I) as defined above comprising the
reaction of a compound of formula (II) in the presence of a
compound of formula (III);
##STR00026##
[0197] wherein R.sup.1, R.sup.2, R.sup.9, m, n, p and q are as
defined above and W is --C(O)--.
[0198] In particular, in the presence of a coupling agent such as
1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate , particularly
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate, in an aprotic solvent such as
dichloromethane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone and mixtures thereof, particularly
N,N-dimethylformamide, in the presence or absence of a base such as
triethylamine, diisopropylethylamine, 4-methylmorpholine and/or
4-(dimethylamino)pyridine, particularly in the presence of
4-methylmorpholine and at a temperature comprised between
-78.degree. C. and reflux, particularly between -10.degree. C. and
room temperature.
[0199] Also an object of the present invention is a compound
according to formula (I) as described herein for use as a
therapeutically active substance.
[0200] Likewise an object of the present invention is a
pharmaceutical composition comprising a compound according to
formula (I) as described herein and a therapeutically inert
carrier.
[0201] A particular embodiment of the present invention is a
compound according to formula (I) as described herein for the
treatment or prophylaxis of ocular conditions, particularly
glaucoma.
[0202] The present invention also relates to the use of a compound
according to formula (I) as described herein for the preparation of
a medicament for the treatment or prophylaxis of ocular conditions,
particularly glaucoma.
[0203] Also an object of the invention is a method for the
treatment or prophylaxis of ocular conditions, particularly
glaucoma, which method comprises administering an effective amount
of a compound according to formula (I) as described herein.
[0204] Renal conditions include, but are not limited to, acute
kidney injury and chronic renal disease with and without
proteinuria including end-stage renal disease (ESRD). In more
detail, this includes decreased creatinine clearance and decreased
glomerular filtration rate, micro-albuminuria, albuminuria and
proteinuria, glomerulosclerosis with expansion of reticulated
mesangial matrix with or without significant hypercellularity
(particularly diabetic nephropathy and amyloidosis), focal
thrombosis of glomerular capillaries (particularly thrombotic
microangiopathies), global fibrinoid necrosis, ischemic lesions,
malignant nephrosclerosis (such as ischemic retraction, reduced
renal blood flow and renal arteriopathy), swelling and
proliferation of intracapillary (endothelial and mesangial) and/or
extracapillary cells (crescents) like in glomerular nephritis
entities, focal segmental glomerular sclerosis, IgA nephropathy,
vasculitides/systemic diseases as well as acute and chronic kidney
transplant rejection.
[0205] Liver conditions include, but are not limited to, liver
cirrhosis, hepatic congestion, cholestatic liver disease including
pruritus, nonalcoholic steatohepatitis and acute and chronic liver
transplant rejection.
[0206] Inflammatory conditions include, but are not limited to,
arthritis, osteoarthritis, multiple sclerosis, systemic lupus
erythematodes, inflammatory bowel disease, abnormal evacuation
disorder and the like as well as inflammatory airways diseases such
as idiopathic pulmonary fibrosis (IPF), chronic obstructive
pulmonary disease (COPD) or chronic asthma bronchiale.
[0207] Further conditions of the respiratory system include, but
are not limited to, other diffuse parenchymal lung diseases of
different etiologies including iatrogenic drug-induced fibrosis,
occupational and/or environmental induced fibrosis, systemic
diseases and vasculitides, granulomatous diseases (sarcoidosis,
hypersensitivity pneumonia), collagen vascular disease, alveolar
proteinosis, Langerhans cell granulomatosis,
lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak
Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage
disorders, familial interstitial lung disease), radiation induced
fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute
respiratory distress syndrome (ARDS).
[0208] Conditions of the nervous system include, but are not
limited to, neuropathic pain, schizophrenia, neuro-inflammation
(e.g. astrogliosis), peripheral and/or autonomic (diabetic)
neuropathies and the like.
[0209] Vascular conditions include, but are not limited to,
atherosclerosis, thrombotic vascular disease as well as thrombotic
microangiopathies, proliferative arteriopathy (such as swollen
myointimal cells surrounded by mucinous extracellular matrix and
nodular thickening), atherosclerosis, decreased vascular compliance
(such as stiffness, reduced ventricular compliance and reduced
vascular compliance), endothelial dysfunction and the like.
[0210] Cardiovascular conditions include, but are not limited to,
acute coronary syndrome, coronary heart disease, myocardial
infarction, arterial and pulmonary hypertension, cardiac arrhythmia
such as atrial fibrillation, stroke and other vascular damage.
[0211] Fibrotic diseases include, but are not limited to myocardial
and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary
fibrosis, skin fibrosis, scleroderma and encapsulating
peritonitis.
[0212] Cancer and cancer metastasis include, but are not limited
to, breast cancer, ovarian cancer, lung cancer, prostate cancer,
mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers
and progression and metastatic aggressiveness thereof.
[0213] Ocular conditions include, but are not limited to,
proliferative and non-proliferative (diabetic) retinopathy, dry and
wet age-related macular degeneration (AMD), macular edema, central
arterial/venous occlusion, traumatic injury, glaucoma and the like.
Particularly, the ocular condition is glaucoma.
[0214] Metabolic conditions include, but are not limited to,
obesity and diabetes.
[0215] Also an embodiment of the present invention are compounds of
formula (I) as described herein, when manufactured according to any
one of the described processes.
Assay Procedures
[0216] Production of Human Full Length ATX, with and without His
Tag
[0217] Autotaxin (ATX-ENPP2) cloning: cDNA was prepared from
commercial human hematopoietic cells total RNA and used as template
in overlapping PCR to generate a full length human ENPP2 ORF with
or without a 3'-6.times.His tag. These full length inserts were
cloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA
sequences of several single clones were verified. The DNA from a
correct full length clone was used to transfect Hek293 cells for
verification of protein expression. The sequence of the encoded
ENPP2 conforms to Swissprot entry Q13822, with or without the
additional C-terminal 6.times.His tag.
ATX Fermentation: Recombinant protein was produced by large-scale
transient transfection in 20 L controlled stirred tank bioreactors
(Sartorius). During cell growth and transfection, temperature,
stirrer speed, pH and dissolved oxygen concentration were
maintained at 37.degree. C., 120 rpm, 7.1 and 30% DO, respectively.
FreeStyle 293-F cells (Invitrogen) were cultivated in suspension in
FreeStyle 293 medium (Invitrogen) and transfected at ca.
1-1.5.times.10E6 cells/mL with above plasmid DNAs using X-tremeGENE
Ro-1539 (commercial product, Roche Diagnostics) as complexing
agent. Cells were fed a concentrated nutrient solution (J Immunol
Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium
butyrate (2 mM) at 72 h post-transfection and harvested at 96 h
post-transfection. Expression was analyzed by Western Blot,
enzymatic assay and/or analytical IMAC chromatography. After
cooling the cell suspension to 4.degree. C. in a flow-through heat
exchanger, cell separation and sterile filtration of supernatant
was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and
Sartopore 2 XLG (Sartorius) filter units. The supernatant was
stored at 4.degree. C. prior to purification.
[0218] ATX Purification: 20 liter of culture supernatant were
conditioned for ultrafiltration by adding Brij 35 to a final
concentration of 0.02% and by adjusting the pH to 7.0 using 1 M
HCl. Then the supernatant was first microfiltred through a 0.2 m
Ultran-Pilot Open Channel PES filter (Whatman) and afterwards
concentrated to 1 liter through an Ultran-Pilot Screen Channel PES
filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography,
NiSO.sub.4 was added to a final concentration of 1 mM. The cleared
supernatant was then applied to a HisTrap column (GE Healthcare)
previously equilibrated in 50 mM Na.sub.2HPO.sub.4 pH 7.0, 0.5 M
NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN.sub.3. The column was
washed stepwise with the same buffer containing 20 mM , 40 mM and
50 mM imidazole, respectively. The protein was subsequently eluted
using a linear gradient to 0.5 M imidazole in 15 column volumes.
ATX containing fractions were pooled and concentrated using an
Amicon cell equipped with a 30 kDa PES filter membrane. The protein
was further purified by size exclusion chromatography on Superdex
S-200 prep grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH
8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN.sub.3. Final
yield of protein after purification was 5-10 mg ATX per liter of
culture supernatant. The protein was stored at -80.degree. C.
Human ATX Enzyme Inhibition Assay
[0219] ATX inhibition was measured by a fluorescence quenching
assay using a specifically labeled substrate analogue (MR121
substrate). To obtain this MR121 substrate, BOC and TBS protected
6-amino-hexanoic acid
(R)-3-({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionyal-
mino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propyl ester
(Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled with
MR121 fluorophore (CAS 185308-24-1,
1-(3-carboxypropyl)-11-ethyl-1,2,3,4,
8,9,10,11-octahydro-dipyrido[3,2-b:2',3'-i]phenoxazin-13-ium) on
the free amine of the ethanolamine side and then, after
deprotection, subsequently with tryptophan on the side of the
aminohexanoic acid. Assay working solutions were made as follows:
[0220] Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM K Cl, 1 mM
CaCl.sub.2, 1 mM MgCl.sub.2, 0.01% Triton-X-100, pH 8.0; [0221] ATX
solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM
bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02%
NaN.sub.3), diluted to 1.4-2.5.times. final concentration in assay
buffer; [0222] MR121 substrate solution: MR121 substrate stock
solution (800 .mu.M MR121 substrate in DMSO), diluted to
2-5.times.final concentration in assay buffer. [0223] Test
compounds (10 mM stock in DMSO, 8 .mu.L) were obtained in 384 well
sample plates (Corning Costar #3655) and diluted with 8 .mu.L DMSO.
Row-wise serial dilutions were made by transferring 8 .mu.L cpd
solution to the next row up to row O. The compound and control
solutions were mixed five times and 2 .mu.L were transferred to 384
well assay plates (Corning Costar # 3702). Then, 15 .mu.L of 41.7
nM ATX solution was added (30 nM final concentration), mixed five
times and then incubated for 15 minutes at 30.degree. C. 10 .mu.L
of MR121 substrate solution was added (1 .mu.M final
concentration), mixed 30 times and then incubated for 15 minutes at
30 .degree. C. [0224] Fluorescence was then measured every 2
minutes for 1 hour (Perkin Elmer plate: vision multimode reader);
light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630/690 nm)
and IC.sub.50 values were calculated from these readouts.
TABLE-US-00001 [0224] Example ATX IC50 (.mu.M) 1.00 0.005 1.01
0.012 1.02 0.01 1.03 0.013 1.04 0.013 1.05 0.018 1.06 0.002 2.00
0.012 2.01 0.03 2.02 0.12 2.03 0.018 3.00 0.006 3.01 0.02 3.02
0.012 3.03 0.019 4.00 0.01 4.01 0.008 4.02 0.006 4.03 0.007
[0225] Compounds of formula (I) and their pharmaceutically
acceptable salts or esters thereof as described herein have
IC.sub.50 values between 0.00001 .mu.M and 1000 .mu.M particular
compounds have IC.sub.50 values between 0.0005 .mu.M and 500 .mu.M
further particular compounds have IC.sub.50 values between 0.0005
.mu.M and 50 .mu.M more particular compounds have IC.sub.50 values
between 0.0005 .mu.M and 5 .mu.M. These results have been obtained
by using the enzymatic assay described above.
[0226] The compounds of formula (I) and their pharmaceutically
acceptable salts can be used as medicaments (e.g. in the form of
pharmaceutical preparations). The pharmaceutical preparations can
be administered internally, such as orally (e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatin capsules,
solutions, emulsions or suspensions), nasally (e.g. in the form of
nasal sprays), rectally (e.g. in the form of suppositories) or
topical ocularly (e.g. in the form of solutions, ointments, gels or
water soluble polymeric inserts). However, the administration can
also be effected parenterally, such as intramuscularly,
intravenously, or intraocularly (e.g. in the form of sterile
injection solutions).
[0227] The compounds of formula (I) and their pharmaceutically
acceptable salts can be processed with pharmaceutically inert,
inorganic or organic adjuvants for the production of tablets,
coated tablets, dragees, hard gelatin capsules, injection solutions
or topical formulations Lactose, corn starch or derivatives
thereof, talc, stearic acid or its salts etc. can be used, for
example, as such adjuvants for tablets, dragees and hard gelatin
capsules.
[0228] Suitable adjuvants for soft gelatin capsules, are, for
example, vegetable oils, waxes, fats, semi-solid substances and
liquid polyols, etc.
[0229] Suitable adjuvants for the production of solutions and
syrups are, for example, water, polyols, saccharose, invert sugar,
glucose, etc.
[0230] Suitable adjuvants for injection solutions are, for example,
water, alcohols, polyols, glycerol, vegetable oils, etc.
[0231] Suitable adjuvants for suppositories are, for example,
natural or hardened oils, waxes, fats, semi-solid or liquid
polyols, etc.
[0232] Suitable adjuvants for topical ocular formulations are, for
example, cyclodextrins, mannitol or many other carriers and
excipients known in the art.
[0233] Moreover, the pharmaceutical preparations can contain
preservatives, solubilizers, viscosity-increasing substances,
stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
flavorants, salts for varying the osmotic pressure, buffers,
masking agents or antioxidants. They can also contain still other
therapeutically valuable substances.
[0234] The dosage can vary in wide limits and will, of course, be
fitted to the individual requirements in each particular case. In
general, in the case of oral administration a daily dosage of about
0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg
per kg body weight (e.g. about 300 mg per person), divided into
preferably 1-3 individual doses, which can consist, for example, of
the same amounts, should it be appropriate. In the case of topical
administration, the formulation can contain 0.001% to 15% by weight
of medicament and the required dose, which can be between 0.1 and
25 mg in can be administered either by single dose per day or per
week, or by multiple doses (2 to 4) per day, or by multiple doses
per week It will, however, be clear that the upper or lower limit
given herein can be exceeded when this is shown to be
indicated.
[0235] The invention is illustrated hereinafter by Examples, which
have no limiting character.
[0236] In case the preparative examples are obtained as a mixture
of enantiomers, the pure enantiomers can be obtained by methods
described herein or by methods known to those skilled in the art,
such as e.g. chiral chromatography or crystallization.
EXAMPLES
[0237] All examples and intermediates were prepared under nitrogen
atmosphere if not specified otherwise.
[0238] Abbreviations: aq..dbd.aqueous; CAS--RN.dbd.Chemical
Abstracts Service Registry Number; HPLC.dbd.high performance liquid
chromatography; MS.dbd.mass spectrum; PS--BEMP
.dbd.polystyrene-bound
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine; sat. .dbd.saturated
Example 1
[0239]
trans-5-(1H-Benzotriazole-5-carbonyl)-3a-fluoro-hexahydro-pyrrolo[3-
,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester
##STR00027##
[0240] To a suspension of
trans-3a-fluoro-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 4.01;
139 mg, 361 .mu.mol), 4-methylmorpholine (183 mg, 1.81 mmol) and
1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CAS--RN 23814-12-2;
58.9 mg, 361 .mu.mol) in N,N-dimethylformamide (3 mL) was added
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate (137 mg, 361 .mu.mol) at room temperature,
then after 16 h the reaction mixture was partitioned between sat.
aq. sodium hydrogen carbonate solution and ethyl acetate/2
methyltetrahydrofuran 4:1. The organic layers was washed with sat.
aq. ammonium chloride solution and brine, dried over magnesium
sulfate, filtered and evaporated. Chromatography (silica gel;
gradient dichloromethane to dichloromethane/methanol/25% aq.
ammonia solution 90:10:0.25) afforded the title compound (158 mg
89%). Light yellow foam, MS: 494.2 (M+H).sup.+.
[0241] The following examples were produced in analogy to example
1, replacing
trans-3a-fluoro-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
4-trifluoromethoxy-benzyl ester hydrochloride by the appropriate
amine and 1H-benzo[d][1,2,3]triazole-5-carboxylic acid by the
appropriate carboxylic acid.
TABLE-US-00002 Ex. Systematic name Amine/Carboxylic acid MS, m/e
1.01
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3-
,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy-benzyl ester
##STR00028## trans-3a-fluoro-hexahydro-
pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl
ester hydrochloride (intermediate 4.01)/
1H-benzo[d][1,2,3]triazole-5- carboxylic acid (CAS-RN 23814-12- 2)
506.2 (M + H).sup.+ 1.02
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahy-
dro-1H-
pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]-propan-1-
-one ##STR00029## trans-1-(3a- methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)-3-(4- (trifluoromethoxy)phenyl)propan-1- one
dihydrochloride (intermediate 6.01)/1H-benzo[d][1,2,3]triazole-5-
carboxylic acid (CAS-RN 23814-12- 2) 502.3 (M - H).sup.- 1.03
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-
methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-
benzotriazol-5-yl)methanone ##STR00030##
trans-(2-cyclopropyl-6-((tetrahydro-
2H-pyran-4-yl)methoxy)pyridin-4- yl)3a-methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)methanone dihydrochloride (intermediate 6)/
1H-benzo[d][1,2,3]triazole-5- carboxylic acid (CAS-RN 23814-12- 2)
547.3 (M + H).sup.+ 1.04
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,-
4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy-benzyl ester
##STR00031## trans-3a-methyl-hexahydro-
pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl
ester hydrochloride (intermediate 4)/1H-
benzo[d][1,2,3]triazole-5-carboxylic acid (CAS-RN 23814-12-2) 490.2
(M + H).sup.+ 1.05
trans-5-[3a-methoxy-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-3,4,-
6,6a-tetrahydro-
1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-3-methyl-1H-benzimidazol-2-one
##STR00032## trans-1-(3a- methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)-3-(4- (trifluoromethoxy)phenyl)propan-1- one
dihydrochloride (intermediate 6.01)/3-methyl-2-oxo-2,3-dihydro-
1H-benzo[d]imidazole-5-carboxylic acid (CAS-RN 863564-77-6) 533.2
(M + H).sup.+ 1.06
trans-5-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-
3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carbonyl]-
3-methyl-1H-benzimidazol-2-one ##STR00033##
trans-(2-cyclopropyl-6-((tetrahydro-
2H-pyran-4-yl)methoxy)pyridin-4- yl)3a-methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)methanone dihydrochloride (intermediate 6)/3-
methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carboxylic acid
(CAS-RN 863564-77-6) 576.3 (M + H).sup.+
Example 2
[0242]
trans-[3a-Methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-ca-
rbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-
-(oxan-4-ylmethoxy)pyridin-4-yl]methanone
##STR00034##
[0243] Step 1:
trans-2-[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methox-
y-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl
chloride
[0244] To a solution of
(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)(trans-3-
a-methoxyhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
dihydrochloride (intermediate 6; 288 mg, 577 .mu.mol) and
N,N-diisopropylethylamine (186 mg, 1.44 mmol) in dichloromethane
(10 mL) was added a solution of triphosgene (85.6 mg, 288 .mu.mol)
in dichloromethane (10 mL) at 0.degree. C. After 11/2 h the ice
bath was removed, then after another 21/2 h the reaction mixture
was partitioned between 1 M aq. hydrochloric acid solution and
dichloromethane. The organic layer was dried over magnesium
sulfate, filtered and evaporated to afford the title compound (230
mg, 86%), which was used directly in the next step. White
solid.
Step 2:
trans-[3a-Methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5--
carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-
-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone
[0245] To a clear colorless solution of
trans-2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methox-
y-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl chloride
(140 mg, 302 .mu.mol) in dichloromethane (10 mL) was added solution
of N,N-diisopropylethylamine (117 mg, 905 .mu.mol) and
4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (CAS--RN
706757-05-3; 37.5 mg, 302 .mu.mol) in N,N-dimethylformamide (10 mL)
at room temperature, then after 15 h the reaction mixture was
partitioned between water and dichlormethane. The organic layer was
washed with brine, dried over magnesium sulfate, filtered and
evaporated. Chromatography (silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25)
afforded the title compound (85 mg, 51%). White solid. MS: 550.3
(MH).sup.-.
[0246] The following examples were produced in analogy to example
2, replacing
(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-y-
l)(trans-3a-methoxyhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
dihydrochloride by the appropriate amine 1 and
4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine by the
appropriate amine 2
TABLE-US-00003 Ex. Systematic name Amine 1 / Amine 2 MS, m/e 2.01
##STR00035## trans-1-(3a- methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)-3-(4- (trifluoromethoxy)phenyl)propan-1- one
dihydrochloride (intermediate 6.01) / 4,5,6,7-tetrahydro-1H-
[1,2,3]triazolo[4,5-c]pyridine (CAS RN 706757-05-3) 507.3 (M -
H).sup.- 2.02 ##STR00036## trans-1-(3a-
methoxyhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-3-(4-
(trifluoromethoxy)phenyl)propan-1- one dihydrochloride
(intermediate 6.01) / 4,5,6,7-tetrahydro-
isoxazolo[5,4-c]pyridin-3(2H)-one (CAS-RN 64603-91-4) 525.2 (M +
H).sup.+ 2.03 ##STR00037## trans-(2-cyclopropyl-6-((tetrahydro-
2H-pyran-4-yl)methoxy)pyridin-4- yl)3a-methoxyhexahydropyrrolo[3,4-
c]pyrrol-2(1H)-yl)methanone dihydrochloride (intermediate 6) /
4,5,6,7-tetrahydro-isoxazolo[5,4- c]pyridin-3(2H)-one (CAS-RN
64603-91-4) 566.3 (M - H).sup.-
Examples 3 and 4
[0247]
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-ca-
rbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-
-(oxan-4-ylmethoxy)pyridin-4-yl]methanone, enantiomer 1 and
enantiomer 2
[0248] Racemic
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl-
)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-
-4-ylmethoxy)pyridin-4-yl]methanone (example 2; 85 mg, 154 .mu.mol)
was separated by preparative HPLC using Chiralpak AD as the
stationary phase and heptane/ethanol/ammonium acetate 60:40:0.004
as the eluent. This produced the faster eluting enantiomer 1
(example 3; 22 mg, 26%; light yellow foam, MS: 552.4 (M+H).sup.+)
and the slower eluting enantiomer 2 (example 4; 16 mg, 19%; white
foam, MS: 552.4 (M+H).sup.+).
[0249] The following examples were produced in analogy to examples
3 and 4 by chiral HPLC separation of their racemates, using
stationary phase and eluent as indicated below.
TABLE-US-00004 Optical Stationary phase; Ex. Starting material
(racemic) rotation sign eluent MS, m/e 3.01
trans-[5-(3-hydroxy-5,7-dihydro- n. a. (faster Chiralpak AD; 568.3
4H-[1,2]oxazolo[5,4-c]pyridine-6- eluting heptane/ethanol/ (M +
H).sup.+ carbonyl)-3a-methoxy-3,4,6,6a- enantiomer) ammonium
acetate 4.01 tetrahydro-1H-pyrrolo[3,4- n. a. (slower 60:40:0.004
568.3 c]pyrrol-2-yl]-[2-cyclopropyl-6- eluting (M + H).sup.+
(oxan-4-ylmethoxy)pyridin-4- enantiomer) yl]methanone (example
2.03) 3.02 trans-5-(1H-benzotriazole-5- (+) Chiralpak AD; 490.3
carbonyl)-3a-methyl-hexahydro- heptane/ethanol/ (M + H).sup.+ 4.02
pyrrolo[3,4-c]pyrrole-2-carboxylic (-) ammonium acetate 490.2 acid
4-trifluoromethoxy-benzyl 60:40:0.004 (M + H).sup.+ ester (example
1.04) 3.03 trans-5-(1H-benzotriazole-5- (-) Chiralpak AD; 506.2
carbonyl)-3a-methoxy-hexahydro- heptane/ethanol/ (M + H).sup.+ 4.03
pyrrolo[3,4-c]pyrrole-2-carboxylic (+) ammonium acetate 506.2 acid
4-trifluoromethoxy-benzyl 60:40:0.004 (M + H).sup.+ ester (example
1.01)
Intermediates
Intermediate 1
[0250] trans-tert-Butyl
3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Step 1:
trans-Dimethyl 1-benzyl-3-methylpyrrolidine-3,4-dicarboxylate
[0251] A solution of
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (CAS-RN
93102-05-7; 1.74 g, 17.0 mmol) in dichloromethane (5 mL) was added
to an ice-cooled mixture of dimethyl 2-methylfumarate (CAS-RN
617-53-8; 1.00 g, 6.32 mmol) and trifluoroacetic acid (79.3 mg, 696
.mu.mol) in dichloromethane (10 mL) at 0-5.degree. C. The resulting
yellow solution was allowed to reach room temperature over 20 h,
then partitioned between sat. aq. hydrogencarbonate solution and
dichloromethane. The organic layer was washed with brine, dried
over magnesium sulfate, filtered and evaporated. Chromatography
(silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25)
afforded the title compound (1.61 g, 87%). Light yellow oil, MS:
292.2 (M+H).sup.+.
Step 2: trans-1-tert-Butyl 3,4-dimethyl
3-methylpyrrolidine-1,3,4-tricarboxylate
[0252] A solution of trans-dimethyl
1-benzyl-3-methylpyrrolidine-3,4-dicarboxylate (1.56 g, 5.35 mmol)
and di-tert-butyl dicarbonate (1.29 g, 5.89 mmol) in methanol (20
mL) was stirred at room temperature under a hydrogen atmosphere (1
bar) in the presence of palladium (10% on activated charcoal, 165
mg, 1.55 mmol). After 3 h insoluble material was removed by
filtration through diatomaceous earth and the filtrate was
concentrated. Chromatography (silica gel; gradient heptane to ethyl
acetate/heptane 1:1) afforded the title compound (1.47 g, 91%).
Colourless oil, MS: 202.1 (M+H-Me.sub.3COCO).sup.+.
Step 3: trans-tert-Butyl
3,4-bis(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate
[0253] A solution of trans-1-tert-butyl 3,4-dimethyl
3-methylpyrrolidine-1,3,4-tricarboxylate (1.47 g, 4.87 mmol) in
tetrahydrofuran (12 mL) was cooled to 0.degree. C. and treated with
lithium borohydride solution (2 M in tetrahydrofuran, 5.47 mL, 10.9
mmol), then after 30 min the ice bath was removed and the reaction
mixture was stirred at room temperature. After 18 h excess reagent
was destroyed by slow addition of 1 M aq. hydrochloric acid
solution at 0.degree. C. to pH 1. The resulting clear solution was
extracted with dichloromethane, the organic layer was washed with
water and brine, dried over magnesium sulfate, filtered and
evaporated. Chromatography (silica gel, heptane-ethyl acetate
gradient) afforded the title compound (1.05 g, 88%). Colourless
viscous oil, MS: 190.1 (M+H-isobutene).sup.+.
Step 4: trans-tert-Butyl
3-methyl-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate
[0254] Methanesulfonyl chloride (1.41 g, 12.4 mmol) was added
dropwise at 0.degree. C. to a clear colourless solution of
trans-tert-butyl
3,4-bis(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (1.01 g,
4.12 mmol) and N,N-diisopropylethylamine (3.19 g, 24.7 mmol) in
dichloromethane (10 mL) was cooled to 0 .degree. C. After 30 min
the reaction mixture was partitioned between sat. aq. ammonium
chloride solution and dichloromethane. The organic layer was washed
with sat. aq. sodium hydrogencarbonate-solution and brine, dried
over magnesium sulfate, filtered and evaporated. Chromatography
(silica gel, heptane-ethyl acetate gradient) afforded the title
compound (1.53 g, 92%). Yellow viscous oil, MS: 346.1
(M+H-isobutene).sup.+.
Step 5: trans-tert-Butyl
5-benzyl-3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
[0255] To a solution of trans-tert-butyl
3-methyl-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate
(1.52 g, 3.79 mmol) in toluene (20 mL) were added triethylamine
(1.15 g, 11.4 mmol) and benzylamine (811 mg, 7.57 mmol). The
reaction mixture was heated at reflux, then after 20 h another
portion of triethylamine (1.15 g, 11.4 mmol) and benzylamine (811
mg, 7.57 mmol) was added, then after another 20 h at reflux the
reaction mixture was washed with 1 M aq. sodium hydroxide solution
and brine, dried over magnesium sulfate, filtered and evaporated.
Chromatography (silica gel, heptane-ethyl acetate gradient)
afforded the title compound (875 mg, 73%). Light yellow solid, MS:
317.2 (M+H).sup.+.
Step 6: trans-tert-Butyl
3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
[0256] A solution of (3aR,6aR)-tert-butyl
5-benzyl-3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(870 mg, 2.75 mmol) in methanol (10 mL) was stirred at room
temperature under a hydrogen atmosphere (1 bar) in the presence of
palladium (10% on activated charcoal, 146 mg, 1.37 mmol), then
after 5 h insoluble material was removed by filtration through
diatomaceous earth. The filtrate was evaporated to afford the title
compound (640 mg, 93%) containing ca. 10% of methanol. Colourless
viscous oil, MS: 227.2 (M+H).sup.+.
Intermediate 2
[0257] trans-tert-butyl
3a-fluorohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
[0258] The title compound was produced in analogy to intermediate
1, replacing dimethyl 2-methylfumarate by diethyl 2-fluorofumarate
(CAS--RN 4495-77-6). Colourless viscous oil, MS: 231.2
(M+H).sup.+.
Intermediate 3
[0259] trans-tert-Butyl
3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
[0260] The title compound was produced in analogy to intermediate
1, replacing dimethyl 2-methylfumarate by dimethyl
2-methoxyfumarate (CAS--RN 2215-05-6). Colourless viscous oil, MS:
243.2 (M+H).sup.+.
Intermediate 4
[0261] trans-3a-Methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic
acid 4-trifluoromethoxy-benzyl ester hydrochloride Step 1:
trans-2-tert-Butyl 5-(4-(trifluoromethoxy)benzyl)
3a-methyltetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
[0262] To a solution of (4-(trifluoromethoxy)phenyl)methanol (474
mg, 2.47 mmol) in acetonitrile (20 mL) was added
1,1'-carbonyldiimidazole (413 mg, 2.47 mmol) and the reaction
mixture was heated to 50.degree. C., then after 3 h triethylamine
(1.25 g, 12.3 mmol) and trans-tert-butyl
3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(intermediate 1; 621 mg, 2.47 mmol) were added and the reaction
mixture was heated at reflux. After 15 h the reaction mixture was
partitioned between ethyl acetate sat. aq. sodium hydrogen
carbonate solution. The organic layer was washed with aq. sat.
ammonium chloride solution and brine, dried over magnesium sulfate,
filtered and evaporated. Chromatography (silica gel; gradient
dichloromethane to dichloromethane/methanol/25% aq. ammonia
solution 95:5:0.25) afforded the title compound (821 mg, 75%).
Light yellow oil, MS: 389.2 (M+H-isobutene).sup.-.
Step 2:
trans-3a-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
4-trifluoromethoxy-benzyl ester hydrochloride
[0263] A solution of trans-2-tert-butyl
5-(4-(trifluoromethoxy)benzyl)
3a-methyltetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
(812 mg, 1.83 mmol) and hydrochloric acid solution (5-6 M in
2-propanol, 10.2 mL, 51.2 mmol) in 2-propanol (5 mL) was stirred
for 15 h at room temperature, then concentrated to dryness. The
residue was triturated in tert-butyl methyl ether and the
precipitate collected by filtration to produce the title compound
(662 mg, 95%). White solid, MS: 345.1 (M+H).sup.+.
Intermediate 4.01
[0264] trans-3a-Fluoro-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic
acid 4-trifluoromethoxy-benzyl ester
[0265] The title compound was produced in analogy to intermediate
4, replacing trans-tert-butyl
3a-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by
trans-tert-butyl
3a-fluorohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(intermediate 2). White solid, MS: 349.1 (M+H).sup.+.
Intermediate 5
[0266]
trans-3a-Methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
3-(2,2-dimethyl-propionylamino)-5-trifluoromethyl-pyridin-2-ylmethyl
ester dihydrochloride Step 1: trans-tert-Butyl
5-(chlorocarbonyl)-3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxy-
late
[0267] To a solution of trans-tert-butyl
3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(intermediate 3; 440 mg, 1.82 mmol) and pyridine (646 mg, 8.17
mmol) in dichloromethane (5 mL) was added dropwise a solution of
triphosgene (242 mg, 817 .mu.mol) in dichloromethane (4 mL) at
0.degree. C. After 30 min the ice bath was removed, then after 4 h
the reaction mixture was partitioned between dichloromethane and 1
M aq. hydrochloric acid solution. The organic layer was washed with
water and brine, dried over magnesium sulfate, filtered, and
evaporated to afford the title compound (372 mg, 67%) as a light
yellow foam.
Step 2: trans-2-tert-Butyl
5-((3-pivalamido-5-(trifluoromethyl)pyridin-2-yl)methyl)
3a-methoxytetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
[0268] To a solution of trans-tert-butyl
5-(chlorocarbonyl)-3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxy-
late (370 mg, 1.21 mmol) in acetonitrile (25 mL) was added
N-(2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide
(intermediate 8; 335 mg, 1.21 mmol) and PS--BEMP (CAS--RN
1446424-86-7; 1.5 g, 1.21 mmol). The orange suspension was heated
at reflux for 21 h, then insoluble material was removed by
filtration. To the filtrate was added PS-Trisamine (CAS--RN
1226492-10-9; 315 mg, 1.21 mmol) and the reaction mixture was
stirred at room temperature for 18 h, then insoluble material was
removed by filtration and the filtrate was evaporated.
Chromatography (silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia 95:5:0.25) produced the
title compound (333 mg, 50%). White foam, MS: 545.3
(M+H).sup.-.
Step 3:
trans-3a-Methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
3-(2,2-dimethyl-propionylamino)-5-trifluoromethyl-pyridin-2-ylmethyl
ester dihydrochloride
[0269] A solution of trans-2-tert-butyl
5-((3-pivalamido-5-(trifluoromethyl)pyridin-2-yl)methyl)
3a-methoxytetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
(325 mg, 597 .mu.mol) and hydrochloric acid solution (5-6 M in
2-propanol, 3.34 mL, 16.7 mmol) in 2-propanol (2 mL) was stirred at
room temperature for 18 h, then the reaction mixture was
concentrated to dryness. The residue was triturated in tert-butyl
methyl ether and the precipitate collected by filtration to afford
the title copound (291 mg, 94%). White solid, MS: 445.2
(M+H).sup.+.
Intermediate 6
[0270]
trans-(2-Cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-
-yl)3a-methoxyhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
dihydrochloride Step 1: trans-tert-Butyl
5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-3a-m-
ethoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
[0271] To a solution of trans-tert-butyl
3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (500 mg,
2.06 mmol) in N,N-dimethylformamide (40 mL) were added
2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinic
acid (intermediate 7; 572 mg, 2.06 mmol) and 4-methylmorpholine
(1.04 g, 10.3 mmol). The solution was cooled to 0.degree. C., then
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate (824 mg, 2.17 mmol) was added. The ice bath
was removed, then after 96 h the reaction mixture was partitioned
between sodium hydrogencarbonate solution and ethyl
acetate/2-methyltetrahydrofuran 4:1. The organic layer was washed
with sat. aq. ammonium chloride solution and brine, dried over
magnesium sulfate, filtered, and evaporated. Chromatography (silica
gel; gradient dichloromethane to dichloromethane/methanol/25% aq.
ammonia solution 90:10:0.25 afforded the title compound (977 mg;
94%). Yellow viscous oil, MS: 502.3 (M+H).sup.+.
Step 2:
trans-(2-Cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-
-4-yl)3a-methoxyhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
dihydrochloride
[0272] A solution of trans-tert-butyl
5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-3a-m-
ethoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (977 mg,
1.95 mmol) and hydrochloric acid solution (5-6 M in 2-propanol,
8.57 mL, 42.8 mmol). in 2-propanol (8 mL) was stirred at room
temperature for 16 h, then the reaction mixture was concentrated to
dryness. The residue was triturated in tert-butyl methyl ether and
the precipitate collected by filtration to afford the title
compound (858 mg, 88%). White solid, MS: 402.3 (M+H).sup.+.
Intermediate 6.01
[0273]
trans-1-(3a-methoxyhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(4-(tr-
ifluoromethoxy)phenyl)propan-1-one dihydrochloride
[0274] The title compound was produced in analogy to example 6,
replacing
2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinic
acid by 3-(4-(trifluoromethoxy)phenyl)propanoic acid. Brown viscous
oil, MS: 359.2 (M+H).sup.+.
Intermediate 7
[0275]
2-Cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinic
acid Step 1: Methyl
6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate
[0276] A suspension of
6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (CAS--RN
150190-28-6; 400 mg, 2.23 mmol) in methanol (4 mL) and sulfuric
acid (12 .mu.L) was added was heated at 70.degree. C. for 48 h,
then concentrated in vacuo. The residue was suspended in
dichloromethane (10 mL), then insoluble material was removed by
filtration and the filtrate evaporated to produce the title
compound (427 mg, 99%). Light brown semisolid, MS: 194.1
(M+H).sup.+.
Step 2: Methyl
2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate
[0277] To a stirring suspension of methyl
6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (212 mg, 1.1
mmol) in acetonitrile (5 mL) were added potassium carbonate (455
mg, 3.29 mmol) and 4-(iodomethyl)tetrahydro-2H-pyran (CAS--RN
101691-94-5; 744 mg, 3.29 mmol). The reaction mixture was heated at
80.degree. C. for 16 h and then evaporated in vacuo. The residue
was purified by chromatography (silica gel; heptane-ethyl acetate
gradient) to produce the title compound (188 mg, 59%). Colourless
oil, MS: 292.2 (M+H).sup.+.
Step 3:
2-Cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinic
acid
[0278] To a solution of methyl
2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinate
(184 mg, 632 .mu.mol) in tetrahydrofuran (2 mL) and water (2 mL)
was added lithium hydroxide monohydrate (53.0 mg, 1.26 mmol) and
the resulting mixture stirred at room temperature for 16 h. The
mixture was partially evaporated in order to remove the
tetrahydrofuran. The aqueous phase was partitioned between 1 M aq.
hydrochloric acid solution and ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate, filtered and
evaporated to give the title compound (218 mg, quant.). Colourless
oil, MS: 276.1 (M-H).sup.-.
Intermediate 8
N-(2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide
[0279] Step 1: Methyl
3-pivalamido-5-(trifluoromethyl)picolinate
[0280] To a brown solution of methyl
3-amino-5-(trifluoromethyl)picolinate (CAS--RN 866775-17-9; 2.00 g,
8.63 mmol) in pyridine (25 mL) was added pivaloyl chloride (2.08 g,
17.3 mmol) at 0.degree. C. After 20 min the ice-bath was removed,
then after 5 h the reaction mixture was partitioned between 1 M aq.
hydrochloric acid solution and ethyl acetate. The organic layer was
washed with water and brine, dried over magnesium sulfate, filtered
and evaporated. Chromatography (silica gel; heptante-ethyl acetate
gradient) afforded the title compound (2.46 g, 92%). Light yellow
solid, MS: 305.1 (M+H).sup.+.
Step 2:
N-(2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide
[0281] To a clear light yellow solution of methyl
3-pivalamido-5-(trifluoromethyl)picolinate (2.45 g, 8.05 mmol) in
tetrahydrofuran (60 mL) was added a solution of calcium chloride
(1.79 g, 16.1 mmol) in ethanol (60 mL), then sodium borohydride
(914 mg, 24.2 mmol) was added in three portions over a period of 30
min. The white suspension was stirred for 90 min at room
temperature, then partitioned between water and sat. aq. ammonium
chloride solution. The organic layer was washed with brine, dried
over magnesium sulfate, filtered, and evaporated. Chromatography
(silica gel; heptane-ethyl acetate gradient) afforded the title
compound (1.97 g; 89%). Light yellow viscous oil, MS: 277.1
(M+H).sup.-.
Intermediate 9
[0282]
3-Fluoro-4-(trans-3a-fluorooctahydropyrrolo[3,4-c]pyrrole-2-carbony-
l)benzenesulfonamide hydrochloride Step 1: trans-tert-butyl
3a-fluoro-5-(2-fluoro-4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2-
(1H)-carboxylate
[0283] The title compound was produced in analogy to intermediate
6, step 1, replacing trans-tert-butyl
3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by
trans-tert-butyl
3a-fluorohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and
2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxyl)methoxy)isonicotinic
acid by 2-fluoro-4-sulfamoylbenzoic acid (CAS--RN 714968-42-0).
Light yellow foam, MS: 432.2 (M+H).sup.-.
Step 2:
3-Fluoro-4-(trans-3a-fluorooctahydropyrrolo[3,4-c]pyrrole-2-carbo-
nyl)benzenesulfonamide hydrochloride
[0284] The title compound was produced in analogy to intermediate
6, step 2 from trans-tert-butyl
3a-fluoro-5-(2-fluoro-4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2-
(1H)-carboxylate. White solid, MS: 332.0 (M+H).sup.+.
Example A
[0285] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of tablets of the
following composition:
[0286] Per Tablet
TABLE-US-00005 Active ingredient 200 mg Microcrystalline cellulose
155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20
mg 425 mg
Example B
[0287] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of capsules of the
following composition:
[0288] Per Capsule
TABLE-US-00006 Active ingredient 100.0 mg Corn starch 20.0 mg
Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg
* * * * *