U.S. patent application number 15/603280 was filed with the patent office on 2017-09-07 for substituted oxazole- and thiazole-based carboxamide and urea derivatives as vanilloid receptor ligands ii.
The applicant listed for this patent is MEDIFRON DBT INC.. Invention is credited to Gregor BAHRENBERG, Thomas CHRISTOPH, Nils DAMANN, Robert FRANK-FOLTYN, Sven FRORMANN, Christopher HABERMANN, Jeewoo LEE, Bernhard LESCH, Derek SAUNDERS, Klaus SCHIENE, Hannelore STOCKHAUSEN.
Application Number | 20170253586 15/603280 |
Document ID | / |
Family ID | 51986972 |
Filed Date | 2017-09-07 |
United States Patent
Application |
20170253586 |
Kind Code |
A1 |
FRANK-FOLTYN; Robert ; et
al. |
September 7, 2017 |
Substituted Oxazole- and Thiazole-Based Carboxamide and Urea
Derivatives as Vanilloid Receptor Ligands II
Abstract
The invention relates to oxazole and thiazole-based carboxamide
and urea derivatives as vanilloid receptor ligands, to
pharmaceutical compositions containing these compounds and also to
these compounds for use in the treatment and/or prophylaxis of pain
and further diseases and/or disorders.
Inventors: |
FRANK-FOLTYN; Robert;
(Beiseforth, DE) ; HABERMANN; Christopher;
(Aachen, DE) ; BAHRENBERG; Gregor;
(Monschau-Konzen, DE) ; LESCH; Bernhard; (Aachen,
DE) ; DAMANN; Nils; (Hurth, DE) ; SCHIENE;
Klaus; (Juchen, DE) ; STOCKHAUSEN; Hannelore;
(Hurtgenwald, DE) ; CHRISTOPH; Thomas; (Aachen,
DE) ; FRORMANN; Sven; (Aachen, DE) ; SAUNDERS;
Derek; (Aachen, DE) ; LEE; Jeewoo; (Seoul,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEDIFRON DBT INC. |
Seoul |
|
KR |
|
|
Family ID: |
51986972 |
Appl. No.: |
15/603280 |
Filed: |
May 23, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP2015/002362 |
Nov 24, 2015 |
|
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15603280 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 413/12 20130101; C07D 263/32 20130101; A61P 25/00 20180101;
A61P 43/00 20180101; C07D 413/14 20130101; C07D 277/28 20130101;
A61P 25/04 20180101; C07D 263/30 20130101; C07D 417/14 20130101;
A61P 19/02 20180101; A61P 29/00 20180101; A61P 29/02 20180101 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 413/14 20060101 C07D413/14; C07D 413/12 20060101
C07D413/12; C07D 417/12 20060101 C07D417/12; C07D 277/28 20060101
C07D277/28; C07D 263/32 20060101 C07D263/32 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 2014 |
EP |
14003949.6 |
Claims
1. A substituted compound of general formula (I), ##STR00020##
wherein X represents O or S; Y represents O, S or N--CN; Z
represents N(R.sup.3b) or C(R.sup.4aR.sup.4b); R.sup.1 represents
aryl or heteroaryl, wherein said aryl or heteroaryl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from the group consisting of H, F, Cl,
Br, CN, OH, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy;
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; C.sub.1-4-alkylS(.dbd.O),
hydroxy-C.sub.1-4-alkylS(.dbd.O), halo-C.sub.1-4-alkylS(.dbd.O),
cyano-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkylS(.dbd.O).sub.2,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2,
halo-C.sub.1-4-alkylS(.dbd.O).sub.2,
cyano-C.sub.1-4-alkylS(.dbd.O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O).sub.2, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocyclo-alkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N, R.sup.2
represents C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl or
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl; R.sup.3a and R.sup.3b each
independently represent H, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl or C.sub.1-4-alkoxy-C.sub.1-4-alkyl; R.sup.4a
and R.sup.4b each independently represent H, F, Cl, CN,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl or C.sub.1-4-alkoxy-C.sub.1-4-alkyl; or
R.sup.4a and R.sup.4b together with the carbon atom connecting them
form a C.sub.3-6-cycloalkyl or a C.sub.3-7-heterocycloalkyl; and Ar
represents aryl or heteroaryl, wherein said aryl or heteroaryl may
be condensed with an aromatic or aliphatic ring to form a bicycle,
and wherein said aryl or heteroaryl and said condensed aromatic or
aliphatic ring each independently may be unsubstituted or mono- or
independently polysubstituted by one or more substituents, selected
from the group consisting of F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
hydroxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.1-4-alkylS(.dbd.O),
hydroxy-C.sub.1-4-alkylS(.dbd.O), halo-C.sub.1-4-alkylS(.dbd.O),
cyano-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkylS(.dbd.O).sub.2,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2,
halo-C.sub.1-4-alkylS(.dbd.O).sub.2,
cyano-C.sub.1-4-alkylS(.dbd.O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O).sub.2,
C.sub.1-4-alkylS(.dbd.O)C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(.dbd.O)C.sub.1-4-alkyl,
C.sub.1-4-alkylS(.dbd.O).sub.2C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2C.sub.1-4-alkyl, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocycloalkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cyclo-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)-(hydroxy-C.sub.1-4-alkyl)N,
(H).sub.2NC.sub.1-4-alkyl,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)-(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-hetero-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl-
), H.sub.2NC(.dbd.O), (C.sub.1-4-alkyl)(H)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(halo-C.sub.1-4-alkyl)(H)N--C(.dbd.O),
(cyano-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)--NC(.dbd.O),
(C.sub.3-6-cycloalkyl)(H)NC(.dbd.O),
(C.sub.3-7-heterocyclo-alkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-6-cyclo-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(.dbd.O),
H.sub.2NS(.dbd.O).sub.2, (C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(halo-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(cyano-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(C.sub.3-6-cycloalkyl)(H)N S(.dbd.O).sub.2,
(C.sub.3-7-heterocycloalkyl)(H)NS(.dbd.O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-7-heterocyclo-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
H.sub.2NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)S(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)S(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, (C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-hetero-cycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; aryl,
heteroaryl, (aryl)C.sub.1-4-alkyl or (heteroaryl)C.sub.1-4-alkyl,
wherein said aryl or heteroaryl may be unsubstituted or mono- or
independently polysubstituted by one or more substituents, selected
from the group consisting of H, F, Cl, Br, CN, OH, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
optionally in the form of a single stereoisomer or a mixture of
stereoisomers, in the form of the free compound and/or a
physiologically acceptable salt or a solvate thereof.
2. The substituted compound according to claim 1, wherein Y
represents O.
3. The substituted compound according to claim 1, wherein R.sup.3a
represents H.
4. The substituted compound according to claim 1, wherein Z
represents N(R.sup.3b), wherein R.sup.3b represents H; or Z
represents C(R.sup.4aR.sup.4b), wherein R.sup.4a represents
CH.sub.3 and R.sup.4b represents H or wherein R.sup.4a and R.sup.4b
each represent H.
5. The substituted compound according to claim 1, wherein R.sup.2
represents CH.sub.3, CFH.sub.2, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3.
6. The substituted compound according to claim 1, wherein R.sup.1
represents ##STR00021## wherein n is 0, 1, 2 or 3; R.sup.5
represents F, Cl, Br, CN, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy and
each R.sup.6 independently is selected from the group consisting of
F, Cl, Br, CN, OH, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy, C.sub.1-4-alkylS(.dbd.O),
hydroxy-C.sub.1-4-alkylS(.dbd.O), C.sub.1-4-alkylS(.dbd.O).sub.2,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
H.sub.2NC(.dbd.O), (C.sub.1-4-alkyl)(H)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl).sub.2NC(.dbd.O), H.sub.2NS(.dbd.O).sub.2
(C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
C.sub.3-6-cycloalkyl, (C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-heterocycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; aryl,
heteroaryl, (aryl)C.sub.1-4-alkyl or (heteroaryl)C.sub.1-4-alkyl,
wherein said aryl or heteroaryl may be unsubstituted or mono- or
independently polysubstituted by one or more substituents, selected
from the group consisting of H, F, Cl, Br, CN, OH, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy.
7. The substituted compound according to claim 1, wherein the
compound of general formula (I) has general formula (Ia)
##STR00022## wherein X represents O or S; Z represents N(R.sup.3b)
or C(R.sup.4aR.sup.4b); n is 0, 1 or 2; R.sup.2 represents
CH.sub.3, CFH.sub.2, CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3, R.sup.3b independently
represent H, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl or
C.sub.1-4-alkoxy-C.sub.1-4-alkyl; R.sup.4a and R.sup.4b each
independently represent H, F, Cl or C.sub.1-4-alkyl; R.sup.5
represents F, Cl, Br, CN, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy and
each R.sup.6 independently is selected from the group consisting of
F, Cl, Br, CN, OH, C.sub.1-4-alkyl, CF.sub.3,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
C.sub.1-4-alkylS(.dbd.O), C.sub.1-4-alkylS(.dbd.O).sub.2, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (C.sub.1-4-alkyl).sub.2N, H.sub.2NC(.dbd.O),
(C.sub.1-4-alkyl)(H)NC(.dbd.O) and
(C.sub.1-4-alkyl).sub.2NC(.dbd.O); and Ar represents aryl or
heteroaryl, wherein said aryl or heteroaryl may be condensed with
an aromatic or aliphatic ring to form a bicycle, and wherein said
aryl or heteroaryl and said condensed aromatic or aliphatic ring
each independently may be unsubstituted or mono- or independently
polysubstituted by one or more substituents, selected from the
group consisting of F, Cl, Br, CN, OH, .dbd.O, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
hydroxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.1-4-alkylS(.dbd.O),
hydroxy-C.sub.1-4-alkylS(.dbd.O), halo-C.sub.1-4-alkylS(.dbd.O),
cyano-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O),
C.sub.1-4-alkylS(.dbd.O).sub.2,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2,
halo-C.sub.1-4-alkylS(.dbd.O).sub.2,
cyano-C.sub.1-4-alkylS(.dbd.O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(.dbd.O).sub.2,
C.sub.1-4-alkylS(.dbd.O)C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(.dbd.O)C.sub.1-4-alkyl,
C.sub.1-4-alkylS(.dbd.O).sub.2C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(.dbd.O).sub.2C.sub.1-4-alkyl, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocycloalkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N,
(H).sub.2NC.sub.1-4-alkyl,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl)-
, H.sub.2NC(.dbd.O), (C.sub.1-4-alkyl)(H)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(halo-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(cyano-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(C.sub.3-6-cycloalkyl)-(H)NC(.dbd.O),
(C.sub.3-7-heterocycloalkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N--C(.dbd.O),
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-7-heterocyclo-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(.dbd.O),
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(.dbd.O),
H.sub.2NS(.dbd.O).sub.2, (C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(halo-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(cyano-C.sub.1-4-alkyl)(H)N--S(.dbd.O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2,
(C.sub.3-6-cycloalkyl)(H)NS(.dbd.O).sub.2,
(C.sub.3-7-heterocycloalkyl)(H)NS(.dbd.O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-7-heterocyclo-alkyl)(C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2,
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NS(.dbd.O).sub.2,
H.sub.2NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)(H)N--S(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)(H)NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl).sub.2NS(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)S(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)S(.dbd.O).sub.2N(H)C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, (C.sub.3-6-cyclo-alkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-heterocycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; aryl,
heteroaryl, (aryl)C.sub.1-4-alkyl or (heteroaryl)C.sub.1-4-alkyl,
wherein said aryl or heteroaryl may be unsubstituted or mono- or
independently polysubstituted by one or more substituents, selected
from the group consisting of H, F, Cl, Br, CN, OH, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
optionally in the form of a single stereoisomer or a mixture of
stereoisomers, in the form of the free compound and/or a
physiologically acceptable salt or a solvate thereof.
8. The substituted compound according to claim 7, wherein n is
0.
9. The substituted compound according to claim 1, wherein R.sup.5
is F, Cl, CN, CH.sub.3, CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3,
OCH.sub.3, OCF.sub.3, OCHF.sub.2 or CH.sub.2OCH.sub.3.
10. The substituted compound according to claim 1, wherein Ar is
selected from phenyl or pyridinyl, wherein said phenyl or pyridinyl
may be condensed with an aromatic or aliphatic ring to form a
bicycle, and wherein said phenyl or pyridinyl and said condensed
aromatic or aliphatic ring each independently may be unsubstituted
or mono- or independently polysubstituted by one or more
substituents, selected from the group consisting of F, Cl, Br, CN,
OH, .dbd.O, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy, H.sub.2N, (C.sub.1-4-alkyl)(H)N,
(hydroxy-C.sub.1-4-alkyl)(H)N, H.sub.2NC(.dbd.O),
(C.sub.1-4-alkyl)(H)NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(.dbd.O),
(C.sub.1-4-alkyl).sub.2NC(.dbd.O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(.dbd.O) and
C.sub.3-6-cycloalkyl.
11. The substituted compound according to claim 1, wherein Ar is
selected from ##STR00023## ##STR00024## each unsubstituted or mono-
or independently polysubstituted by one or more substituents,
wherein said substituent(s) are selected from the group consisting
of F, Cl, Br, CN, .dbd.O, OH, CH.sub.3, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, CH(CH.sub.3).sub.2,
(CH.sub.2).sub.3CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, OCH.sub.3,
OCF.sub.3, OCHF.sub.2, CH.sub.2OCH.sub.3, CH.sub.2OCF.sub.3,
CH.sub.2OH, CH.sub.2CH.sub.2OH, OCH.sub.2CH.sub.2OH,
N(H)CH.sub.2CH.sub.2OH, N(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2OCH.sub.2CH.sub.2OH, CH.sub.2N(H)CH.sub.2CH.sub.2OH,
CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(.dbd.O).sub.2N(H)CH.sub.3,
CH.sub.2N(H)S(.dbd.O).sub.2NH.sub.2,
CH.sub.2N(H)S(.dbd.O).sub.2CH.sub.3, ##STR00025##
12. The substituted compound according to claim 1, wherein Ar is
selected from ##STR00026## ##STR00027## wherein G is CH or CF.
13. A pharmaceutical composition comprising at least one
substituted compound according to claim 1.
14. A substituted compound according to claim 1 for use in the
treatment and/or prophylaxis of one or more diseases and/or
disorders selected from the group consisting of pain.
15. A method of treatment and/or prophylaxis of disorders and/or
diseases selected from the group consisting of pain in a mammal
comprising administering an effective amount of at least one
compound according to claim 1 to the mammal.
16. The substituted compound according to claim 4, wherein Z
represents N(R.sup.3b), wherein R.sup.3b represents H.
17. The substituted compound according to claim 5, wherein R.sup.2
represents CF.sub.3 or C(CH.sub.3).sub.3.
18. The substituted compound according to claim 14, wherein the
pain is selected from the group consisting of acute pain, chronic
pain, neuropathic pain, visceral pain and joint pain.
19. The method according to claim 15, wherein the pain is selected
from the group consisting of acute pain, chronic pain, neuropathic
pain, visceral pain and joint pain.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of PCT/EP2015/002362,
filed Nov. 24, 2015, which claims the benefit of EP Application No.
14003949.6, filed Nov. 24, 2014. Both of these applications are
hereby incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The invention relates to substituted oxazole and
thiazole-based carboxamide and urea derivatives as vanilloid
receptor ligands, to pharmaceutical compositions containing these
compounds and also to these compounds for use in the treatment
and/or prophylaxis of pain and further diseases and/or
disorders.
BACKGROUND OF THE INVENTION
[0003] The treatment of pain, in particular of neuropathic pain, is
very important in medicine. There is a worldwide demand for
effective pain therapies. The urgent need for action for a
patient-focused and target-oriented treatment of chronic and
non-chronic states of pain, this being understood to mean the
successful and satisfactory treatment of pain for the patient, is
also documented in the large number of scientific studies which
have recently appeared in the field of applied analgesics or basic
research on nociception.
[0004] The subtype 1 vanilloid receptor (VR1/TRPV1), which is often
also referred to as the capsaicin receptor, is a suitable starting
point for the treatment of pain, in particular of pain selected
from the group consisting of acute pain, chronic pain, neuropathic
pain and visceral pain. This receptor is stimulated inter alia by
vanilloids such as capsaicin, heat and protons and plays a central
role in the formation of pain. In addition, it is important for a
large number of further physiological and patho-physiological
processes and is a suitable target for the therapy of a large
number of further disorders such as, for example, migraine,
depression, neurodegenerative diseases, cognitive disorders, states
of anxiety, epilepsy, coughs, diarrhoea, pruritus, inflammations,
disorders of the cardiovascular system, eating disorders,
medication dependency, misuse of medication and urinary
incontinence.
[0005] There is a demand for further compounds having comparable or
better properties, not only with regard to affinity to vanilloid
receptors 1 (VR1/TRPV1 receptors) per se (potency, efficacy).
[0006] Thus, it may be advantageous to improve the metabolic
stability, the solubility in aqueous media or the permeability of
the compounds. These factors can have a beneficial effect on oral
bioavailability or can alter the PK/PD
(pharmacokinetic/pharmacodynamic) profile; this can lead to a more
beneficial period of effectiveness, for example. A weak or
non-existent interaction with transporter molecules, which are
involved in the ingestion and the excretion of pharmaceutical
compositions, is also to be regarded as an indication of improved
bioavailability and at most low interactions of pharmaceutical
compositions. Furthermore, the interactions with the enzymes
involved in the decomposition and the excretion of pharmaceutical
compositions should also be as low as possible, as such test
results also suggest that at most low interactions or no
interactions at all, of pharmaceutical compositions are to be
expected.
[0007] It was therefore an object of the invention to provide novel
compounds, preferably having advantages over the prior-art
compounds. The compounds should be suitable in particular as
pharmacological active ingredients in pharmaceutical compositions,
preferably in pharmaceutical compositions for the treatment and/or
prophylaxis of disorders or diseases which are at least partially
mediated by vanilloid receptors 1 (VR1/TRPV1 receptors).
[0008] This object is achieved by the subject matter described
herein.
[0009] It has surprisingly been found that the substituted
compounds of general formula (I), as given below, display
outstanding affinity to the subtype 1 vanilloid receptor (VR1/TRPV1
receptor) and are therefore particularly suitable for the
prophylaxis and/or treatment of disorders or diseases which are at
least partially mediated by vanilloid receptors 1 (VR1/TRPV1).
[0010] Particularly suitable are substituted compounds of general
formula (I), as given below, that in addition to their activity
with regard to the VR1-receptor show one or more additional
advantageous properties, for example, suitable potency, suitable
efficacy, no increase in body temperature and/or heat pain
threshold; appropriate solubility in biologically relevant media
such as aqueous media, in particular in aqueous media at a
physiologically acceptable pH value, such as in buffer systems, for
instance in phosphate buffer systems; suitable metabolic stability
and diversity (e.g. sufficient stability towards the oxidative
capabilities of hepatic enzymes such as cytochrome P450 (CYP)
enzymes and sufficient diversity with regard to the metabolic
elimination via these enzymes); and the like.
[0011] In a first aspect of the present invention, the present
invention relates to a substituted compound of general formula
(I),
##STR00001##
wherein [0012] X represents O or S; [0013] Y represents O, S or
N--CN; [0014] Z represents N(R.sup.3b) or C(R.sup.4aR.sup.4b);
[0015] R.sup.1 represents aryl or heteroaryl, [0016] wherein said
aryl or heteroaryl may be unsubstituted or mono- or independently
polysubstituted by one or more substituents, selected from the
group consisting of H, F, Cl, Br, CN, OH, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
C.sub.1-4-alkylS(O), hydroxy-C.sub.1-4-alkylS(O),
halo-C.sub.1-4-alkylS(O), cyano-C.sub.1-4-alkylS(O),
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O), C.sub.1-4-alkylS(O).sub.2,
hydroxy-C.sub.1-4-alkylS(O).sub.2, halo-C.sub.1-4-alkylS(O).sub.2,
cyano-C.sub.1-4-alkylS(O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O).sub.2, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocycloalkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N and
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N, [0017]
R.sup.2 represents C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl or
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl; [0018] R.sup.3a and
R.sup.3b each independently represent H, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl or C.sub.1-4-alkoxy-C.sub.1-4-alkyl; [0019]
R.sup.4a and R.sup.4b each independently represent H, F, Cl, CN,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl or C.sub.1-4-alkoxy-C.sub.1-4-alkyl; [0020]
or [0021] R.sup.4a and R.sup.4b together with the carbon atom
connecting them form a C.sub.3-6-cycloalkyl or a
C.sub.3-7-heterocycloalkyl; [0022] Ar represents aryl or
heteroaryl, [0023] wherein said aryl or heteroaryl may be condensed
with an aromatic or aliphatic ring to form a bicycle, [0024] and
wherein said aryl or heteroaryl and said condensed aromatic or
aliphatic ring each independently may be unsubstituted or mono- or
independently polysubstituted by one or more substituents, selected
from the group consisting of F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
hydroxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.1-4-alkylS(O),
hydroxy-C.sub.1-4-alkylS(O), halo-C.sub.1-4-alkylS(O),
cyano-C.sub.1-4-alkylS(O), C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O),
C.sub.1-4-alkylS(O).sub.2, hydroxy-C.sub.1-4-alkylS(O).sub.2,
halo-C.sub.1-4-alkylS(O).sub.2, cyano-C.sub.1-4-alkylS(O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O).sub.2,
C.sub.1-4-alkylS(O)C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(O)C.sub.1-4-alkyl,
C.sub.1-4-alkylS(O).sub.2C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(O).sub.2C.sub.1-4-alkyl, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocycloalkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N,
(H).sub.2NC.sub.1-4-alkyl,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl)-
, H.sub.2NC(O), (C.sub.1-4-alkyl)(H)NC(O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(O), (halo-C.sub.1-4-alkyl)(H)NC(O),
(cyano-C.sub.1-4-alkyl)(H)NC(O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)NC(O),
(C.sub.3-6-cyclo-alkyl)(H)NC(O),
(C.sub.3-7-heterocycloalkyl)(H)NC(O), (C.sub.1-4-alkyl).sub.2NC(O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)NC(O),
(hydroxy-C.sub.1-4-alkyl).sub.2NC(O),
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(O),
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(O),
H.sub.2NS(O).sub.2, (C.sub.1-4-alkyl)(H)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(halo-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(cyano-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)--NS(O).sub.2,
(C.sub.3-6-cycloalkyl)(H)NS(O).sub.2,
(C.sub.3-7-heterocycloalkyl)(H)NS(O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-7-hetero-cycloalkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(O).sub.2,
(C.sub.3-6-cycloalkyl)-(hydroxy-C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)-NS(O).sub.2,
H.sub.2NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)(H)NS(O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)(H)NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl).sub.2NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)S(O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)S(O).sub.2N(H)C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, (C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-heterocycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, [0025] wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
[0026] aryl, heteroaryl, (aryl)C.sub.1-4-alkyl or
(heteroaryl)C.sub.1-4-alkyl, [0027] wherein said aryl or heteroaryl
may be unsubstituted or mono- or independently polysubstituted by
one or more substituents, selected from the group consisting of H,
F, Cl, Br, CN, OH, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy and
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; optionally in the form of a
single stereoisomer or a mixture of stereoisomers, in the form of
the free compound and/or a physiologically acceptable salt or a
solvate thereof.
DETAILED DESCRIPTION
[0028] The term "single stereoisomer" preferably means in the sense
of the present invention an individual enantiomer or diastereomer.
The term "mixture of stereoisomers" means in the sense of this
invention the racemate and mixtures of enantiomers and/or
diastereomers in any mixing ratio.
[0029] The term "physiologically acceptable salt" preferably
comprises in the sense of this invention a salt of at least one
compound according to the present invention and at least one
physiologically acceptable acid or base. A physiologically
acceptable salt of at least one compound according to the present
invention and at least one physiologically acceptable acid
preferably refers in the sense of this invention to a salt of at
least one compound according to the present invention with at least
one inorganic or organic acid which is physiologically
acceptable--in particular when used in human beings and/or other
mammals. A physiologically acceptable salt of at least one compound
according to the present invention and at least one physiologically
acceptable base preferably refers in the sense of this invention to
a salt of at least one compound according to the present invention
as an anion with at least one preferably inorganic cation, which is
physiologically acceptable--in particular when used in human beings
and/or other mammals.
[0030] The term "physiologically acceptable solvate" preferably
comprises in the sense of this invention an adduct of one compound
according to the present invention and/or a physiologically
acceptable salt of at least one compound according to the present
invention with distinct molecular equivalents of one solvent or
more solvents.
[0031] Unless otherwise specified, the term "C.sub.1-C.sub.4-alkyl"
("(C.sub.1-C.sub.4)-alkyl") is understood to mean branched and
unbranched alkyl groups consisting of 1 to 4 carbon atoms which is
optionally mono- or polysubstituted. Examples of
C.sub.1-C.sub.4-alkyl are methyl, ethyl, n-propyl, 1-methylethyl
(2-propyl; isopropyl), n-butyl, 1-methylpropyl (2-butyl),
2-methylpropyl, 1,1-dimethylethyl (2-(2-methyl)propyl; tert-butyl).
C.sub.1-C.sub.3-alkyl are particularly preferred, in particular
methyl, ethyl n-propyl or iso-propyl. Unless otherwise stated, the
definitions of propyl and butyl encompass all possible isomeric
forms of the individual radicals.
[0032] Unless otherwise specified, the term
"C.sub.1-C.sub.4-alkoxy" is understood to mean branched and
unbranched alkyl groups consisting of 1 to 4 carbon atoms which are
linked to the subordinate structure residue via an oxygene atom and
which is optionally mono- or polysubstituted. Examples of
C.sub.1-C.sub.4-alkoxy are OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, O(CH.sub.2).sub.3CH.sub.3,
OCH(CH.sub.3).sub.2, OCH.sub.2CH(CH.sub.3).sub.2,
OCH(CH.sub.3)(CH.sub.2CH.sub.3), OC(CH.sub.3).sub.3.
C.sub.1-C.sub.3-alkoxy are particularly preferred, in particular
OCH.sub.3, OCH.sub.2CH.sub.3 or OCH(CH.sub.3).sub.2.
[0033] Unless otherwise specified, a "halo-C.sub.1-4-alkyl" is
understood to be a C.sub.1-4-alkyl in which at least one hydrogen
is exchanged for a halogen atom, preferably F, Cl or Br,
particularly preferably F. The halo-C.sub.1-4-alkyl can be branched
or unbranched and optionally mono- or polysubstituted. Preferred
halo-C.sub.1-4-alkyl are CHF.sub.2, CH.sub.2F, CF.sub.3,
CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3.
Halo-C.sub.1-C.sub.3-alkyl are more preferred, in particular
CHF.sub.2, CH.sub.2F, CF.sub.3, CH.sub.2CH.sub.2F,
CH.sub.2CHF.sub.2 and CH.sub.2CF.sub.3. Unless otherwise specified,
a "halo-C.sub.1-4-alkoxy" is understood to be a C.sub.1-4-alkoxy in
which at least one hydrogen is exchanged for a halogen atom,
preferably F, Cl or Br, particularly preferably F. The
halo-C.sub.1-4-alkoxy can be branched or unbranched and optionally
mono- or polysubstituted. Preferred halo-C.sub.1-4-alkoxy are
OCHF.sub.2, OCH.sub.2F, OCF.sub.3, OCH.sub.2CFH.sub.2,
OCH.sub.2CF.sub.2H, OCH.sub.2CF.sub.3. Halo-C.sub.1-3-alkoxy are
preferred, in particular OCHF.sub.2, OCH.sub.2F, OCF.sub.3,
OCH.sub.2CFH.sub.2, OCH.sub.2CF.sub.2H, OCH.sub.2CF.sub.3.
[0034] Unless otherwise specified, a "hydroxy-C.sub.1-4-alkyl"
radical is to be a C.sub.1-4-alkyl in which at least one hydrogen
is exchanged for a hydroxyl group. The hydroxy-C.sub.1-4-alkyl can
be branched or unbranched and optionally mono- or polysubstituted.
hydroxy-C.sub.1-3-alkyl are preferred, in particular CH.sub.2OH,
CH.sub.2CH.sub.2OH and CH.sub.2CH.sub.2CH.sub.2OH. Unless otherwise
specified, a "cyano-C.sub.1-4-alkyl" is understood to be a
C.sub.1-4-alkyl in which at least one hydrogen is exchanged for a
cyano group. The cyano-C.sub.1-4-alkyl can be branched or
unbranched and optionally mono- or polysubstituted.
Cyano-C.sub.1-3-alkyl are preferred, in particular CH.sub.2CN,
CH.sub.2CH.sub.2CN and CH.sub.2CH.sub.2CH.sub.2CN. Unless otherwise
specified, a "C.sub.1-4-alkoxy-C.sub.1-4-alkyl" is understood to be
a C.sub.1-4-alkyl in which at least one hydrogen is exchanged for
C.sub.1-4-alkoxy. The C.sub.1-4-alkoxy-C.sub.1-4-alkyl can be
branched or unbranched and optionally mono- or polysubstituted.
C.sub.1-4-alkoxy-C.sub.1-3-alkyl are preferred, in particular
CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3 and
CH.sub.2OCH(CH.sub.3).sub.2.
[0035] Unless otherwise specified, a "hydroxy-C.sub.1-4-alkoxy", a
"cyano-C.sub.1-4-alkoxy" and a "C.sub.1-4-alkoxy-C.sub.1-4-alkoxy"
each is understood to be a C.sub.1-4-alkoxy in which at least one
hydrogen is exchanged for a hydroxyl, a cyano or a
C.sub.1-4-alkoxy. The hydroxy-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy can be
branched or unbranched and optionally mono- or polysubstituted.
Preferred hydroxy-C.sub.1-4-alkoxy are OCH.sub.2CH.sub.2OH and
OCH.sub.2CH.sub.2CH.sub.2OH. Preferred cyano-C.sub.1-4-alkoxy are
OCH.sub.2CN, OCH.sub.2CH.sub.2CN and OCH.sub.2CH.sub.2CH.sub.2CN.
Preferred C.sub.1-4-alkoxy-C.sub.1-4-alkoxy are
OCH.sub.2CH.sub.2OCH.sub.3, OCH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
OCH(CH.sub.3)OCH.sub.3, OCH.sub.2CH.sub.2OCH.sub.2CH.sub.3 and
OCH.sub.2CH.sub.2OCH(CH.sub.3).sub.2.
[0036] The term "C.sub.3-6-cycloalkyl" means for the purposes of
this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or
6 carbon atoms, wherein the hydrocarbons in each case can be
unsubstituted or mono- or polysubstituted. The C.sub.3-6-cycloalkyl
can be bound to the respective superordinate general structure via
any desired and possible ring member of the C.sub.3-6-cycloalkyl.
The C.sub.3-6-cycloalkyl can also be condensed with further
saturated, (partially) unsaturated, (hetero)cyclic, aromatic or
heteroaromatic ring systems, i.e. with cycloalkyl,
heterocycloalkyl, aryl or heteroaryl residues. Preferred
C.sub.3-6-cycloalkyls are selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, in particular
cyclopropyl.
[0037] The terms "C.sub.3-7-heterocycloalkyl" mean for the purposes
of this invention heterocycloaliphatic saturated or unsaturated
(but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7
ring members, in which in each case at least one, if appropriate
also two, three or four carbon atoms are replaced by a heteroatom
or a heteroatom group each selected independently of one another
from the group consisting of O, S, S(.dbd.O), S(.dbd.O).sub.2, N,
NH and N(C.sub.1-6-alkyl) such as N(CH.sub.3), wherein the ring
members can be unsubstituted or mono- or polysubstituted. The
C.sub.3-7-heterocycloalkyl can also be condensed with further
saturated, (partially) unsaturated, (hetero)cyclic, aromatic or
heteroaromatic ring systems, i.e. with cycloalkyl,
heterocycloalkyl, aryl or heteroaryl residues. The
C.sub.3-7-heterocycloalkyl may be bound to the superordinate
general structure via any possible ring member of the
heterocycloalkyl if not indicated otherwise.
[0038] The term "aryl" for the purpose of this invention represents
phenyl, 1-naphthyl or 2-naphthyl, wherein the aryl can be
unsubstituted or mono- or polysubstituted.
[0039] The term "heteroaryl" for the purpose of this invention
represents a cyclic aromatic residue containing at least 1, if
appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms
are each selected independently of one another from the group S, N
and O and the heteroaryl residue can be unsubstituted or mono- or
polysubstituted; in the case of substitution on the heteroaryl, the
substituents can be the same or different and be in any desired and
possible position of the heteroaryl. The binding to the
superordinate general structure can be carried out via any desired
and possible ring member of the heteroaryl residue if not indicated
otherwise. It is preferable for the heteroaryl residue to be
selected from the group consisting of benzofuranyl,
benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,
benzotriazolyl, benzo-oxazolyl, benzooxadiazolyl, quinazolinyl,
quinoxalinyl, carbazolyl, quinolinyl, dibenzo-furanyl,
dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl,
indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl,
isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxa-diazolyl,
phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl
(2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl,
pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl),
triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.
[0040] For the purpose of this invention, the term "said aryl or
heteroaryl may be condensed with an aromatic or aliphatic ring to
form a bicycle" is understood as meaning a bicyclic ring system
wherein at least one ring is aromatic and wherein the link to the
superordinate general structure is via an atom of aryl or
heteroaryl. The bicyclic ring system may be fully aromatic
(condensation of aryl or heteroaryl with an aromatic ring, so an
aryl or heteroaryl moiety) or partially aromatic (condensation of
aryl or heteroaryl with a non-aromatic ring, so a cycloalkyl or
heterocycloalkyl moiety).
[0041] In connection with non-aromatic moieties such as "alkyl",
"alkoxy", "cycloalkyl" and "heterocycloalkyl", in the context of
this invention the term "substituted" is understood as meaning
replacement of a hydrogen radical by a substituent selected from
the group consisting of .dbd.O, OH, CN, F, Cl, Br, I, SH,
(C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.2-C.sub.4)-alkinyl, (C.sub.1-C.sub.4)-hydroxyalkyl,
(C.sub.1-C.sub.4)-cyanoalkyl, (C.sub.1-C.sub.4)-alkoxy,
(C.sub.1-C.sub.4)-thioalkyl, (C.sub.1-C.sub.4)-haloalkyl,
(C.sub.1-C.sub.4)-thiohaloalkyl, (C.sub.1-C.sub.4)-haloalkoxy,
(C.sub.1-C.sub.4)-alkyl-S--(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.3)-alkyl,
(C.sub.3-C.sub.7)-heterocycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl, N((C.sub.1-C.sub.4)-alkyl).sub.2,
NHCO(C.sub.1-C.sub.4)-alkyl, NHCOO(C.sub.1-C.sub.4)-alkyl,
NH--C(O)NH.sub.2, NHCONH(C.sub.1-C.sub.4)-alkyl,
NHCON((C.sub.1-C.sub.4)-alkyl).sub.2,
NH((C.sub.1-C.sub.4)-alkyl)COO(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)-CONH.sub.2,
NH((C.sub.1-C.sub.4)-alkyl)CONH(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)CON((C.sub.1-C.sub.4)-alkyl).sub.2,
NHS(O).sub.2OH, NHS(O).sub.2(C.sub.1-C.sub.4)-alkyl,
NHS(O).sub.2O(C.sub.1-C.sub.4)-alkyl, NHS(O).sub.2NH.sub.2,
NHS(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
NHS(O).sub.2N((C.sub.1-C.sub.4)-alkyl).sub.2,
NH((C.sub.1-C.sub.4)-alkyl)-S(O).sub.2OH,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2O(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2NH.sub.2,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
CO.sub.2H, CO(C.sub.1-C.sub.4)-alkyl, COO(C.sub.1-C.sub.4)-alkyl,
OCO(C.sub.1-C.sub.4)-alkyl, OCOO(C.sub.1-C.sub.4)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl,
CON((C.sub.1-C.sub.4)-alkyl).sub.2, OCONH(C.sub.1-C.sub.4)-alkyl,
OCON((C.sub.1-C.sub.4)-alkyl).sub.2,
OS(O).sub.2(C.sub.1-C.sub.4)-alkyl, OS(O).sub.2OH,
OS(O).sub.2(C.sub.1-C.sub.4)-alkyl, OS(O).sub.2NH.sub.2,
OS(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
OS(O).sub.2N((C.sub.1-C.sub.4)-alkyl).sub.2,
S(O)(C.sub.1-C.sub.4)-alkyl, S(O).sub.2(C.sub.1-C.sub.4)-alkyl,
S(O).sub.2OH, S(O).sub.2O(C.sub.1-C.sub.4)-alkyl,
S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-C.sub.4)-alkyl, and
S(O).sub.2N((C.sub.1-C.sub.4)-alkyl).sub.2. If a moiety is
substituted with more than 1 substituent, e.g. by 2, 3, 4, or 5
substituents, these substituents may be present either on different
or on the same atoms, e.g. as in the case of CF.sub.3 or
CH.sub.2CF.sub.3, or at different places, as in the case of
CH(Cl)CHCl.sub.2. Substitution with more than 1 substituent may
include identical or different substituents, such as, for example,
in the case of CH(OH)CHCl.sub.2. Preferably, the substituents may
be selected from the group consisting of F, Cl, Br, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OH, CN, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-alkoxy,
(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2, NH(C.sub.1-C.sub.4)-alkyl,
N((C.sub.1-C.sub.4)-alkyl).sub.2, NHCO(C.sub.1-C.sub.4)-alkyl,
NHCONH(C.sub.1-C.sub.4)-alkyl,
NHCON((C.sub.1-C.sub.4)-alkyl).sub.2,
NHS(O).sub.2(C.sub.1-C.sub.4)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.4)-alkyl, CON((C.sub.1-C.sub.4)-alkyl).sub.2,
S(O)(C.sub.1-C.sub.4)-alkyl and
S(O).sub.2(C.sub.1-C.sub.4)-alkyl.
[0042] In connection with aromatic moieties such as "aryl" and
"heteroaryl", in the context of this invention the term
"substituted" is understood as meaning replacement of a hydrogen
radical by a substituent selected from the group consisting of OH,
halogen, CN, SH, nitro, (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.4)-alkenyl, (C.sub.2-C.sub.4)-alkinyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-cyanoalkyl,
(C.sub.1-C.sub.4)-alkoxy, (C.sub.1-C.sub.4)-thioalkyl,
(C.sub.1-C.sub.4)-haloalkyl, (C.sub.1-C.sub.4)-thiohaloalkyl,
(C.sub.1-C.sub.4)-haloalkoxy,
(C.sub.1-C.sub.4)-alkyl-S--(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-Cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.3)-alkyl,
(C.sub.3-C.sub.7)-heterocycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl, N((C.sub.1-C.sub.4)-alkyl).sub.2,
NHCO(C.sub.1-C.sub.4)-alkyl, NHCOO(C.sub.1-C.sub.4)-alkyl,
NHC(O)NH.sub.2, NHCONH(C.sub.1-C.sub.4)-alkyl,
NHCON((C.sub.1-C.sub.4)-alkyl).sub.2,
NH((C.sub.1-C.sub.4)-alkyl)COO(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)CONH.sub.2,
NH((C.sub.1-C.sub.4)-alkyl)CONH(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)CON((C.sub.1-C.sub.4)-alkyl).sub.2,
NHS(O).sub.2OH, NHS(O).sub.2(C.sub.1-C.sub.4)-alkyl,
NHS(O).sub.2O(C.sub.1-C.sub.4)-alkyl, NH--S(O).sub.2NH.sub.2,
NHS(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
NH--S(O).sub.2N((C.sub.1-C.sub.4)-alkyl).sub.2,
NH((C.sub.1-C.sub.4)-alkyl)-S(O).sub.2OH,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)-S(O).sub.2O(C.sub.1-C.sub.4)-alkyl,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2NH.sub.2,
NH((C.sub.1-C.sub.4)-alkyl)S(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
CO.sub.2H, CO(C.sub.1-C.sub.4)-alkyl, COO(C.sub.1-C.sub.4)-alkyl,
OCO(C.sub.1-C.sub.4)-alkyl, OCOO(C.sub.1-C.sub.4)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl,
CON((C.sub.1-C.sub.4)-alkyl).sub.2, OCONH(C.sub.1-C.sub.4)-alkyl,
OCON((C.sub.1-C.sub.4)-alkyl).sub.2,
OS(O).sub.2(C.sub.1-C.sub.4)-alkyl, OS(O).sub.2OH,
OS(O).sub.2(C.sub.1-C.sub.4)-alkoxy, OS(O).sub.2NH.sub.2,
OS(O).sub.2NH(C.sub.1-C.sub.4)-alkyl,
OS(O).sub.2--N((C.sub.1-C.sub.4)-alkyl).sub.2,
S(O)(C.sub.1-C.sub.4)-alkyl, S(O).sub.2(C.sub.1-C.sub.4)-alkyl,
S(O).sub.2OH, S(O).sub.2O(C.sub.1-C.sub.4)-alkyl,
S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-C.sub.4)-alkyl, and
S(O).sub.2N((C.sub.1-C.sub.4)-alkyl).sub.2. If a moiety is
substituted with more than 1 substituent, e.g. by 2, 3, 4, or 5
substituents, these substituents may be identical or different.
Preferably, the substituents may be selected from the group
consisting of F, Cl, Br, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OH, CN, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-hydroxyalkyl,
(C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl, N((C.sub.1-C.sub.4)-alkyl).sub.2,
NHCO(C.sub.1-C.sub.4)-alkyl, NHCONH(C.sub.1-C.sub.4)-alkyl,
NHCON((C.sub.1-C.sub.4)-alkyl).sub.2,
NHS(O).sub.2(C.sub.1-C.sub.4)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.4)-alkyl, CON((C.sub.1-C.sub.4)-alkyl).sub.2,
S(O)(C.sub.1-C.sub.4)-alkyl and
S(O).sub.2(C.sub.1-C.sub.4)-alkyl.
[0043] Within the scope of the present invention, the symbol
##STR00002##
used in the formulae denotes a link of a corresponding residue to
the respective superordinate general structure.
[0044] In one embodiment of the first aspect of the invention, the
compound according to general formula (I) is characterized in that
Y represents O.
[0045] In another embodiment of the first aspect of the invention,
the compound according to general formula (I) is characterized in
that R.sup.3a represents H.
[0046] In another embodiment of the first aspect of the invention,
the compound according to general formula (I) is characterized in
that [0047] Z represents N(R.sup.3b), wherein R.sup.3b represents
H; or [0048] Z represents C(R.sup.4aR.sup.4b), wherein R.sup.4a
represents CH.sub.3 and R.sup.4b represents H or wherein R.sup.4a
and R.sup.4b each represent H.
[0049] In a preferred embodiment of the invention, Z represents
C(R.sup.4aR.sup.4b), wherein R.sup.4a represents CH.sub.3 and
R.sup.4b represents H, therefore being in one enantiomeric
form.
[0050] Preferably, Z represents C(R.sup.4aR.sup.4b), wherein
R.sup.4a represents CH.sub.3 and R.sup.4b represents H, and the
carbon atom bearing the residues R.sup.4a and R.sup.4b has the
(R)-configuration or has the (S)-configuration:
##STR00003##
[0051] More preferably, the compound according to general formula
(I) is characterized in that [0052] Z represents N(R.sup.3b),
wherein R.sup.3b represents H.
[0053] In yet another embodiment of the first aspect of the
invention, the compound according to general formula (I) is
characterized in that R.sup.2 represents CH.sub.3, CFH.sub.2,
CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2 or
C(CH.sub.3).sub.3.
[0054] In a preferred embodiment of the invention, the compound
according to general formula (I) is characterized in that R.sup.2
represents CF.sub.3 or C(CH.sub.3).sub.3.
[0055] In another preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) is
characterized in that [0056] R.sup.1 represents
##STR00004##
[0056] wherein [0057] n is 0, 1, 2 or 3; [0058] R.sup.5 represents
F, Cl, Br, CN, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy and
[0059] each R.sup.6 independently is selected from the group
consisting of F, Cl, Br, CN, OH, C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
C.sub.1-4-alkylS(O), hydroxy-C.sub.1-4-alkylS(O),
C.sub.1-4-alkylS(O).sub.2, hydroxy-C.sub.1-4-alkylS(O).sub.2,
H.sub.2N, (C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
H.sub.2NC(O), (C.sub.1-4-alkyl)(H)NC(O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(O), (C.sub.1-4-alkyl).sub.2NC(O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(hydroxy-C.sub.1-4-alkyl).sub.2N--C(O), H.sub.2NS(O).sub.2
(C.sub.1-4-alkyl)(H)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)N--S(O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(O).sub.2, C.sub.3-6-cycloalkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-heterocycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, [0060] wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
[0061] aryl, heteroaryl, (aryl)C.sub.1-4-alkyl or
(heteroaryl)C.sub.1-4-alkyl, [0062] wherein said aryl or heteroaryl
may be unsubstituted or mono- or independently polysubstituted by
one or more substituents, selected from the group consisting of H,
F, Cl, Br, CN, OH, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy and
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy.
[0063] Preferably, [0064] R.sup.1 is selected from the group
consisting of
##STR00005## ##STR00006##
[0065] Particularly preferably, R.sup.1 represents
##STR00007##
[0066] Even more preferably, R.sup.1 represents
##STR00008##
[0067] In another preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) is
characterized in that the compound of general formula (I) has
general formula (Ia)
##STR00009##
wherein [0068] X represents O or S; [0069] Z represents N(R.sup.3b)
or C(R.sup.4aR.sup.4b); [0070] n is 0, 1 or 2; [0071] R.sup.2
represents CH.sub.3, CFH.sub.2, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3, [0072]
R.sup.3b represents H, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl or
C.sub.1-4-alkoxy-C.sub.1-4-alkyl; [0073] R.sup.4a and R.sup.4b each
independently represent H, F, Cl or C.sub.1-4-alkyl; [0074] R.sup.5
represents F, Cl, Br, CN, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
[0075] each R.sup.6 independently is selected from the group
consisting of F, Cl, Br, CN, OH, C.sub.1-4-alkyl, CF.sub.3,
hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy, C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
C.sub.1-4-alkylS(O), C.sub.1-4-alkylS(O).sub.2, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (C.sub.1-4-alkyl).sub.2N, H.sub.2NC(O),
(C.sub.1-4-alkyl)(H)NC(O) and (C.sub.1-4-alkyl).sub.2NC(O); and
[0076] Ar represents aryl or heteroaryl, [0077] wherein said aryl
or heteroaryl may be condensed with an aromatic or aliphatic ring
to form a bicycle, [0078] and wherein said aryl or heteroaryl and
said condensed aromatic or aliphatic ring each independently may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from the group consisting of F, Cl, Br,
CN, OH, .dbd.O, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy,
hydroxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.1-4-alkylS(O),
hydroxy-C.sub.1-4-alkylS(O), halo-C.sub.1-4-alkylS(O),
cyano-C.sub.1-4-alkylS(O), C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O),
C.sub.1-4-alkylS(O).sub.2, hydroxy-C.sub.1-4-alkylS(O).sub.2,
halo-C.sub.1-4-alkylS(O).sub.2, cyano-C.sub.1-4-alkylS(O).sub.2,
C.sub.1-4-alkoxy-C.sub.1-4-alkylS(O).sub.2,
C.sub.1-4-alkylS(O)C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkylS(O)C.sub.1-4-alkyl,
C.sub.1-4-alkylS(O).sub.2C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkyl-S(O).sub.2C.sub.1-4-alkyl, H.sub.2N,
(C.sub.1-4-alkyl)(H)N, (hydroxy-C.sub.1-4-alkyl)(H)N,
(halo-C.sub.1-4-alkyl)(H)N, (cyano-C.sub.1-4-alkyl)(H)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N, (C.sub.3-6-cycloalkyl)(H)N,
(C.sub.3-7-heterocycloalkyl)(H)N, (C.sub.1-4-alkyl).sub.2N,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N,
(hydroxy-C.sub.1-4-alkyl).sub.2N,
(C.sub.3-6-cyclo-alkyl)(hydroxy-C.sub.1-4-alkyl)N,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N,
(H).sub.2NC.sub.1-4-alkyl,
[(C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(H)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(hydroxy-C.sub.1-4-alkyl).sub.2N](C.sub.1-4-alkyl),
[(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl),
[(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)N](C.sub.1-4-alkyl)-
, H.sub.2NC(O), (C.sub.1-4-alkyl)(H)NC(O),
(hydroxy-C.sub.1-4-alkyl)(H)NC(O), (halo-C.sub.1-4-alkyl)(H)NC(O),
(cyano-C.sub.1-4-alkyl)(H)NC(O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)NC(O),
(C.sub.3-6-cyclo-alkyl)(H)NC(O),
(C.sub.3-7-heterocycloalkyl)(H)NC(O), (C.sub.1-4-alkyl).sub.2NC(O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NC(O),
(C.sub.3-7-heterocycloalkyl)(C.sub.1-4-alkyl)NC(O),
(hydroxy-C.sub.1-4-alkyl).sub.2NC(O),
(C.sub.3-6-cycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(O),
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NC(O),
H.sub.2NS(O).sub.2, (C.sub.1-4-alkyl)(H)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(halo-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(cyano-C.sub.1-4-alkyl)(H)NS(O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(H)--NS(O).sub.2,
(C.sub.3-6-cycloalkyl)(H)N S(O).sub.2,
(C.sub.3-7-heterocycloalkyl)(H)NS(O).sub.2,
(C.sub.1-4-alkyl).sub.2NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(halo-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(cyano-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.1-4-alkoxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-6-cycloalkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-7-hetero-cycloalkyl)(C.sub.1-4-alkyl)NS(O).sub.2,
(hydroxy-C.sub.1-4-alkyl).sub.2NS(O).sub.2,
(C.sub.3-6-cycloalkyl)-(hydroxy-C.sub.1-4-alkyl)NS(O).sub.2,
(C.sub.3-7-heterocycloalkyl)(hydroxy-C.sub.1-4-alkyl)NS(O).sub.2,
H.sub.2NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)(H)NS(O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)(H)NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl).sub.2NS(O).sub.2N(H)C.sub.1-4-alkyl,
(C.sub.1-4-alkyl)S(O).sub.2N(H)C.sub.1-4-alkyl,
(hydroxy-C.sub.1-4-alkyl)S(O).sub.2N(H)C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, (C.sub.3-6-cycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-6-cycloalkyl)-C.sub.1-4-alkoxy,
C.sub.3-7-heterocycloalkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkyl,
(C.sub.3-7-heterocycloalkyl)-C.sub.1-4-alkoxy, [0079] wherein said
C.sub.3-6-cycloalkyl or C.sub.3-7-heterocycloalkyl may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from H, F, Cl, Br, CN, OH, .dbd.O,
C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl,
cyano-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
cyano-C.sub.1-4-alkoxy and C.sub.1-4-alkoxy-C.sub.1-4-alkoxy;
[0080] aryl, heteroaryl, (aryl)C.sub.1-4-alkyl or
(heteroaryl)C.sub.1-4-alkyl, [0081] wherein said aryl or heteroaryl
may be unsubstituted or mono- or independently polysubstituted by
one or more substituents, selected from the group consisting of H,
F, Cl, Br, CN, OH, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkoxy,
halo-C.sub.1-4-alkoxy, cyano-C.sub.1-4-alkoxy and
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy; optionally in the form of a
single stereoisomer or a mixture of stereoisomers, in the form of
the free compound and/or a physiologically acceptable salt or a
solvate thereof.
[0082] In one preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) or
according to general formula (Ia) is characterized in that X is
O.
[0083] In another preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) or
according to general formula (Ia) is characterized in that X is
S.
[0084] In another preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) is
characterized in that the compound has general formula (Ia),
wherein n is 0.
[0085] In another preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) is
characterized in that the compound has general formula (Ia),
wherein R.sup.5 is F, Cl, CN, CH.sub.3, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, OCF.sub.3, OCHF.sub.2 or
CH.sub.2OCH.sub.3.
[0086] Preferably, the compound according to general formula (I) is
characterized in that the compound has general formula (Ia),
wherein R.sup.5 is F, Cl, CN, CH.sub.3, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, OCF.sub.3, OCHF.sub.2 or
CH.sub.2OCH.sub.3 and n is 0.
[0087] In yet another embodiment of the first aspect of the
invention, the compound according to general formula (I) or general
formula (Ia) is characterized in that
Ar is selected from phenyl or pyridinyl, wherein said phenyl or
pyridinyl may be condensed with an aromatic or aliphatic ring to
form a bicycle, and wherein said phenyl or pyridinyl and said
condensed aromatic or aliphatic ring each independently may be
unsubstituted or mono- or independently polysubstituted by one or
more substituents, selected from the group consisting of F, Cl, Br,
CN, OH, .dbd.O, C.sub.1-4-alkyl, hydroxy-C.sub.1-4-alkyl,
halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
hydroxy-C.sub.1-4-alkoxy, halo-C.sub.1-4-alkoxy,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy, H.sub.2N, (C.sub.1-4-alkyl)(H)N,
(hydroxy-C.sub.1-4-alkyl)(H)N, H.sub.2NC(O),
(C.sub.1-4-alkyl)(H)NC(O), (hydroxy-C.sub.1-4-alkyl)(H)NC(O),
(C.sub.1-4-alkyl).sub.2NC(O),
(hydroxy-C.sub.1-4-alkyl)(C.sub.1-4-alkyl)NC(O) and
C.sub.3-6-cycloalkyl.
[0088] In a preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) or general
formula (Ia) is characterized in that Ar is selected from phenyl or
pyridinyl, wherein said phenyl or said pyridinyl is condensed with
an aromatic or aliphatic ring to form a bicycle.
[0089] Preferably, the compound according to general formula (I) or
general formula (Ia) is characterized in that
Ar is selected from
##STR00010## ##STR00011##
each unsubstituted or mono- or independently polysubstituted by one
or more substituents, wherein said substituent(s) are selected from
the group consisting of F, Cl, Br, CN, .dbd.O, OH, CH.sub.3,
CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3,
CH(CH.sub.3).sub.2, (CH.sub.2).sub.3CH.sub.3,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
C(CH.sub.3).sub.3, OCH.sub.3, OCF.sub.3, OCHF.sub.2,
CH.sub.2OCH.sub.3, CH.sub.2OCF.sub.3, CH.sub.2OH,
CH.sub.2CH.sub.2OH, OCH.sub.2CH.sub.2OH, N(H)CH.sub.2CH.sub.2OH,
N(CH.sub.3)CH.sub.2CH.sub.2OH, CH.sub.2OCH.sub.2CH.sub.2OH,
CH.sub.2N(H)CH.sub.2CH.sub.2OH,
CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2N(H)CH.sub.3,
CH.sub.2N(H)S(O).sub.2NH.sub.2, CH.sub.2N(H)S(O).sub.2CH.sub.3,
##STR00012##
[0090] In a preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) or general
formula (Ia) is characterized in that Ar is selected from
1-naphthyl, 2-naphthyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl,
8-quinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl,
8-isoquinolinyl, 5-quinoxalinyl, 6-quinoxalinyl, 5-phthalazinyl,
6-phthalazinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,
8-quinazolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl,
8-cinnolinyl, 5-indazolyl, 5-(1-methyl)-indazolyl, 4-indazolyl,
4-(1-methyl)-indazolyl, 1-(5,6,7,8-tetrahydro)-naphthyl,
2-(5,6,7,8-tetrahydro)-naphthyl, 4-(2,3-dihydro)-1H-indenyl,
5-(2,3-dihydro)-1H-indenyl, 4-benzo[d][1,3]dioxolyl,
5-benzo[d][1,3]dioxolyl, 5-(2,3-dihydro)-benzo[b][1,4]dioxinyl,
6-(2,3-dihydro)-benzo[b][1,4]dioxinyl.
[0091] In a preferred embodiment of the first aspect of the
invention, the compound according to general formula (I) or general
formula (Ia) is characterized in that Ar is selected from
##STR00013## ##STR00014##
wherein G is CH or CF.
[0092] Particularly preferred are compounds according to the
invention from the group
TABLE-US-00001 1
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-flu-
oro- EX-01 4-(2-hydroxyethyl)phenyl)-propanamide 2
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluor-
o- EX-02 4-(2-hydroxyethyl)-phenyl)propanamide 3
N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-
EX-03 (methylsulfonamido-methyl)phenyl)propanamide 4
N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-
EX-04 (methylsulfonamidomethyl)phenyl)propanamide 5
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-
EX-05 ((sulfamoylamino)methyl)-phenyl)propanamide 6
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-
EX-06 ((sulfamoylamino)methyl)-phenyl)propanamide 7
N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-
EX-07 (hydroxymethyl)phenyl)propanamide 8
N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-
EX-08 (hydroxymethyl)phenyl)propanamide 9
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-(3-
EX-09 hydroxyoxetan-3-yl)phenyl)propanamide 10
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-(3-
EX-10 hydroxyoxetan-3-yl)phenyl)propanamide 11
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluo-
ro- EX-11 6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide 12
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-flu-
oro- EX-12 6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide 13
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-
EX-13 hydroxyethyl)amino)pyridin-3-yl)propanamide 14
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-
- EX-14 hydroxyethyl)amino)pyridin-3-yl)propanamide 15
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-
- EX-15 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 1)
16
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-
- EX-16 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 2)
17
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-
EX-17 hydroxyethyl)amino)pyridin-3-yl)propanamide (nenatiomer 1) 18
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-
EX-18 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 2) 19
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluo-
ro- EX-19 6-(hydroxymethyl)pyridin-3-yl)propanamide 20
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-flu-
oro- EX-20 6-(hydroxymethyl)pyridin-3-yl)propanamide (enantiomer 1)
21
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluo-
ro- EX-21 6-(hydroxymethyl)pyridin-3-yl)propanamide 22
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluo-
ro- EX-22 6-(hydroxymethyl)pyridin-3-yl)propanamide (enantiomer 2)
23
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluo-
ro- EX-23 4-((sulfamoylamino)methyl)phenyl)propanamide 24
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-flu-
oro- EX-24 4-((sulfamoylamino)methyl)phenyl)propanamide 25
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-
EX-25 (hydroxymethyl)pyridin-3-yl)urea 26
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-
EX-26 (hydroxymethyl)pyridin-3-yl)urea 27
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-
EX-27 (hydroxymethyl)pyridin-3-yl)urea 28
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
EX-28 (hydroxymethyl)pyridin-3-yl)urea 29
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-
EX-29 methoxypyrimidin-5-yl)urea 30
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-
EX-30 (methylsulfonyl)ethyl)pyridin-3-yl)urea 31
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-
EX-31 (methylsulfonyl)ethyl)pyridin-3-yl)urea 32
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(3-
EX-32 hydroxyazetidin-1-yl)pyridin-3-yl)urea 33
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(3-
EX-33 hydroxyazetidin-1-yl)pyridin-3-yl)urea 34
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-
EX-34 hydroxyethyl)pyridin-3-yl)urea 35
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-
EX-35 hydroxyethyl)pyridin-3-yl)urea 36
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-
EX-36 hydroxyethyl)pyridin-3-yl)urea 37
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-
EX-37 hydroxyethyl)pyridin-3-yl)urea 38
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5- EX-38
yl)methyl)ureido)benzyl)methanesulfonamide 39
N-(4-(3-((2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5- EX-39
yl)methyl)ureido)benzyl)methanesulfonamide 40
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-
EX-40 hydroxyethoxy)pyridin-3-yl)urea 41
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-
EX-41 hydroxyethoxy)pyridin-3-yl)urea 42
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-
EX-42 hydroxyethoxy)pyridin-3-yl)urea 43
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-
EX-43 hydroxyethoxy)pyridin-3-yl)urea 44
N-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-4-yl)methyl)-N'-(4-
EX-44 ((sulfamoylamino)methyl)phenyl)urea 45
N-((5-(3-chlorophenyl)-2-(tertbutyl)thiazol-5-yl)methyl)-N'-(4-
EX-45 ((sulfamoylamino)methyl)phenyl)urea 46
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-
EX-46 hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 47
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-((2-
EX-47 hydroxyethoxy)-methyl)pyridin-3-yl)urea dihydrochloride 48
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-((2-
EX-48 hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 49
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-((2-
- EX-49 hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 50
1-(benzo[d][1,3]dioxol-5-yl)-3-((2-(tert-butyl)-4-(3-chlorophenyl)thiaz-
ol-5- EX-50 yl)methyl)urea 51
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydr-
o-1H- EX-51 inden-4-yl)urea 52
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinoli-
n-6- EX-52 yl)urea 53
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(quinolin-5-
- EX-53 yl)urea 54
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-
EX-54 dihydrobenzo[b][1,4]dioxin-6-yl)urea 55
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydr-
o-1H- EX-55 inden-5-yl)urea 56
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinoli-
n-5- EX-56 yl)urea 57
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)ureido)--
2- EX-57 fluorobenzyl)methanesulfonamide 58
N-(4-(3-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)ureido)-2-
EX-58 fluorobenzyl)methanesulfonamide 59
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-
- EX-59 (hydroxymethyl)phenyl)urea 60
1-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-
EX-60 (hydroxymethyl)phenyl)urea 61
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-
EX-61 methoxypyridin-4-yl)urea 62
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyrimidin--
5- EX-62 yl)urea 63
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(5-
EX-63 methylpyridin-2-yl)urea 64
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-4-
EX-64 yl)urea 65
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-2-
EX-65 yl)urea 66
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-3-
EX-66 yl)urea 67
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-
EX-67 methylpyridin-4-yl)urea 68
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-
EX-68 methylpyridin-4-yl)urea 69
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-fluoropy-
ridin- EX-69 3-yl)urea 70
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-
EX-70 methylpyridin-3-yl)urea 71
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-
EX-71 methylpyrimidin-5-yl)urea
in the form of the free compound and/or a physiologically
acceptable salt thereof.
[0093] Furthermore, preference may be given to compounds according
to the first aspect of the invention that cause a 50% displacement
of capsaicin, which is present at a concentration of 100 nM, in a
FLIPR assay with CHO K1 cells which were transfected with the human
VR1 gene at a concentration of less than 2 000 nM, preferably less
than 1 000 nM, particularly preferably less than 300 nM, most
particularly preferably less than 100 nM, even more preferably less
than 75 nM, additionally preferably less than 50 nM, most
preferably less than 10 nM. In the process, the Ca.sup.2+ influx is
quantified in the FLIPR assay with the aid of a Ca.sup.2+-sensitive
dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the
Netherlands) in a fluorescent imaging plate reader (FLIPR,
Molecular Devices, Sunnyvale, USA), as described hereinafter.
[0094] The compounds according to the first aspect of the invention
and corresponding stereoisomers and also the respective
corresponding acids, bases, salts and solvates are toxicologically
safe and are therefore suitable as pharmaceutical active
ingredients in pharmaceutical compositions.
[0095] In second aspect of the invention, the invention therefore
further relates to a pharmaceutical composition containing at least
one compound according to the first aspect of the invention, in
each case if appropriate in the form of one of its pure
stereoisomers, in particular enantiomers or diastereomers, its
racemates or in the form of a mixture of stereoisomers, in
particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or respectively in the form of a corresponding salt,
or respectively in the form of a corresponding solvate, and also if
appropriate one or more pharmaceutically compatible
auxiliaries.
[0096] These pharmaceutical compositions according to the invention
are suitable in particular for vanilloid receptor 1-(VR1/TRPV1)
regulation, preferably for vanilloid receptor 1-(VR1/TRPV1)
inhibition and/or for vanilloid receptor 1-(VR1/TRPV1) stimulation,
i.e. they exert an agonistic or antagonistic effect. Likewise, the
pharmaceutical compositions according to the invention are
preferably suitable for the prophylaxis and/or treatment of
disorders or diseases which are mediated, at least in part, by
vanilloid receptors 1. The pharmaceutical composition according to
the invention is suitable for administration to adults and
children, including toddlers and babies. The pharmaceutical
composition according to the invention may be found as a liquid,
semisolid or solid pharmaceutical form, for example in the form of
injection solutions, drops, juices, syrups, sprays, suspensions,
tablets, patches, capsules, plasters, suppositories, ointments,
creams, lotions, gels, emulsions, aerosols or in multiparticulate
form, for example in the form of pellets or granules, if
appropriate pressed into tablets, decanted in capsules or suspended
in a liquid, and also be administered as much.
[0097] In a preferred embodiment of the second aspect of the
invention, the pharmaceutical composition according to the
invention is suitable for the treatment and/or prophylaxis of pain,
preferably of pain selected from the group consisting of acute
pain, chronic pain, neuropathic pain and visceral pain.
[0098] In a third aspect of the invention, the present invention
further relates to a compound according to the first aspect of the
invention for use in vanilloid receptor 1-(VR1/TRPV1) regulation,
preferably for use in vanilloid receptor 1-(VR1/TRPV1) inhibition
and/or vanilloid receptor 1-(VR1/TRPV1) stimulation.
[0099] The present invention therefore further relates to a
compound according to the first aspect of the invention and also
for use in the prophylaxis and/or treatment of disorders and/or
diseases which are mediated, at least in part, by vanilloid
receptors 1.
[0100] In particular, the present invention therefore further
relates to a compound according to the first aspect of the
invention for use in the prophylaxis and/or treatment of disorders
and/or diseases selected from the group consisting of pain,
preferably pain selected from the group consisting of acute pain,
chronic pain, neuropathic pain, visceral pain and joint pain;
hyperalgesia; allodynia; causalgia; migraine; depression; nervous
affection; axonal injuries; neurodegenerative diseases, preferably
selected from the group consisting of multiple sclerosis,
Alzheimer's disease, Parkinson's disease and Huntington's disease;
cognitive dysfunctions, preferably cognitive deficiency states,
particularly preferably memory disorders; epilepsy; respiratory
diseases, preferably selected from the group consisting of asthma,
bronchitis and pulmonary inflammation; coughs; urinary
incontinence; overactive bladder (OAB); disorders and/or injuries
of the gastrointestinal tract; duodenal ulcers; gastric ulcers;
irritable bowel syndrome; strokes; eye irritations; skin
irritations; neurotic skin diseases; allergic skin diseases;
psoriasis; vitiligo; herpes simplex; inflammations, preferably
inflammations of the intestine, the eyes, the bladder, the skin or
the nasal mucous membrane; diarrhoea; pruritus; osteoporosis;
arthritis; osteoarthritis; rheumatic diseases; eating disorders,
preferably selected from the group consisting of bulimia, cachexia,
anorexia and obesity; medication dependency; misuse of medication;
withdrawal symptoms in medication dependency; development of
tolerance to medication, preferably to natural or synthetic
opioids; drug dependency; misuse of drugs; withdrawal symptoms in
drug dependency; alcohol dependency; misuse of alcohol and
withdrawal symptoms in alcohol dependency; for diuresis; for
antinatriuresis; for influencing the cardiovascular system; for
increasing vigilance; for the treatment of wounds and/or burns; for
the treatment of severed nerves; for increasing libido; for
modulating movement activity; for anxiolysis; for local anaesthesia
and/or for inhibiting undesirable side effects, preferably selected
from the group consisting of hyperthermia, hypertension and
bronchoconstriction, triggered by the administration of vanilloid
receptor 1 (VR1/TRPV1 receptor) agonists.
[0101] A preferred embodiment of the third aspect of the invention
is a compound according to the first aspect of the invention for
use in the prophylaxis and/or treatment of pain, preferably of pain
selected from the group consisting of acute pain, chronic pain,
neuropathic pain and visceral pain.
[0102] In a fourth aspect of the invention, the present invention
further relates to the use of at least one compound according to
the first aspect of the present invention for the preparation of a
pharmaceutical composition for the prophylaxis and/or treatment of
disorders and/or diseases which are mediated, at least in part, by
vanilloid receptors 1.
[0103] A fifth aspect of the present invention is a method for
vanilloid receptor 1-(VR1/TRPV1) regulation, preferably for
vanilloid receptor 1-(VR1/TRPV1) inhibition and/or for vanilloid
receptor 1-(VR1/TRPV1) stimulation, and, further, a method of
treatment and/or prophylaxis of disorders and/or diseases, which
are mediated, at least in part, by vanilloid receptors 1, in a
mammal, which comprises administering an effective amount of at
least one compound according to the first aspect of the invention
to the mammal.
[0104] A preferred embodiment of the fifth aspect of the invention
is hence a method of treatment and/or prophylaxis of pain,
preferably of pain selected from the group consisting of acute
pain, chronic pain, neuropathic pain, visceral pain and joint pain,
which comprises administering an effective amount of at least one
compound according to the first aspect of the invention to the
mammal.
[0105] The effectiveness against pain can be shown, for example, in
the Bennett or Chung model (Bennett, G. J. and Xie, Y. K., Pain
1988, 33(1), 87-107; Kim, S. H. and Chung, J. M., Pain 1992, 50(3),
355-363), by tail flick experiments (e.g. D'Amour und Smith, J.
Pharm. Exp. Ther. 1941, 72, 74-79) or by the formalin test (e.g. D.
Dubuisson et al., Pain 1977, 4, 161-174).
EXAMPLES
[0106] The indication "equivalents" ("eq." or "eq" or "equiv." or
"equiv") means molar equivalents, "RT" or "rt" means room
temperature (23.+-.7.degree. C.), "M" are indications of
concentration in mol/l, "aq." means aqueous, "sol." means
solution.
[0107] Further abbreviations: conc.: concentrated; DBU:
1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane;
DIBAL:diisobylaluminiumhydride; DMAP: 4-dimethyaminopyridine; DMS:
dimethylsulfide; DMF: dimethylformamide; DPPA: diphenylphosphoryl
azide; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride; Et.sub.2O: diethyl ether; EtOAc: ethyl acetate;
EtOH: ethanol; h: hour(s); HOBt: hydroxybenzotriazole; KO.sup.tBu:
potassium tert.-butanolate; LAH: lithium aluminium hydride; MeOH:
methanol; MCPBA:m-chloroperbenzoic acid; min: minutes; PE:
petroleum ether; PPh.sub.3: triphenylphosphine; RM: reaction
mixture; sat.: saturated; TBDMSCl: tert-butyldimethylsilylchloirde;
TEA: triethylamine; TFA: trifluoroacetic acid; THF:
tetrahydrofuran; TLC: thin layer chromatography.
[0108] The yields of the compounds prepared were not optimized. All
temperatures are uncorrected. All starting materials which are not
explicitly described were either commercially available (the
details of suppliers such as for example Acros, Avocado, Aldrich,
Apollo, Bachem, Fluka, FluoroChem, Lancaster, Manchester Organics,
MatrixScientific, Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood,
etc. can be found in the Symyx.RTM. Available Chemicals Database of
MDL, San Ramon, US or the SciFinder.RTM. Database of the ACS,
Washington D.C., US, respectively, for example) or the synthesis
thereof has already been described precisely in the specialist
literature (experimental guidelines can be found in the Reaxys.RTM.
Database of Elsevier, Amsterdam, NL or the SciFinder.RTM. Database
of the ACS, Washington D.C., US, respectively, for example) or can
be prepared using the conventional methods known to the person
skilled in the art.
[0109] The stationary phase used for the column chromatography was
silica gel 60 (0.04-0.063 mm) from E. Merck, Darmstadt. The mixing
ratios of solvents or eluents for chromatography are specified in
v/v. All the intermediate products and exemplary compounds were
analytically characterized by means of .sup.1H-NMR spectroscopy. In
addition, mass spectrometry tests (MS, m/z for [M+H].sup.+) were
carried out for all the exemplary compounds and selected
intermediate products.
Synthesis of Exemplary Compounds
[0110] In general, the 5-methylamino azoles INT-10 can be
synthesized according to Scheme 1. In brief, thioamides INT-2a,b
required for thiazole synthesis can be prepared by reacting the
corresponding amides INT-1a,b with Lawesson's reagent.
[0111] Phenylethanone (INT-3) is reacted with dimethyl carbonate
(4) to yield 3-oxopropanoates (INT-5). Oxidation of INT-5 with
Dess-Martin periodinane in the presence of p-TsOH gives rise to
methyl 3-oxo-2-(tosyloxy)propanoates (INT-6). Reaction of INT-6
with the amides INT-1 or thioamides INT-2 resulted in the oxazoles
INT-7a,b-i and thiazoles INT-7-ab-ii, respectively. Reduction of
the various INT-7 with LiAlH.sub.4 yields the alcohols INT-8, which
can be converted to the azides INT-9. Finally, Staudinger reduction
with TPP in aqueous THF yields the 5-methylamino azoles INT-10,
which were isolated as their hydrochlorides.
##STR00015## ##STR00016## ##STR00017##
Synthesis Azole Methylamine Hydrochlorides INT-10
Synthesis of
(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanamine
hydrochloride (INT-10a-ii)
Synthesis of 2,2-dimethylpropanethioamide (INT-2a)
[0112] To a stirred solution of pivalamide (INT-1a, 5.0 g, 49.43
mmol, 1.0 eq) in THF (150 mL) was added Lawesson's reagents (29.9
g, 74.1 mmol, 1.5 eq) and the RM was stirred at 70.degree. C. for 4
h. The RM was concentrated, diluted with Et.sub.2O (30 mL) and
washed with NaHCO.sub.3 solution (30 mL), the organic layer was
dried over MgSO.sub.4 and concentrated under reduced pressure. The
crude was washed with hexane (25 mL) to get
2,2-dimethylpropanethioamide (INT-2a, 4.0 g, 70%) which was used
without further purification. TLC system: EtOAc/PE (7:3), R.sub.f:
0.6
Synthesis of methyl 3-(3-chlorophenyl)-3-oxopropanoate (INT-5a)
[0113] To a stirred suspension of NaH (170 mg, 7.11 mmol, 1.1 eq)
in THF (30 mL) at 0.degree. C. was added 1-(3-chlorophenyl)ethanone
(INT-3a, 1.00 g, 6.46 mmol, 1.0 eq) followed by dimethyl carbonate
(4, 1.17 g, 12.9 mmol, 2.0 eq) and the RM was heated to reflux for
3 h. The RM was quenched with water (10 ml) and extracted with
EtOAC (20 mL), the organic layer was dried over Na.sub.2SO.sub.4
filtered and evaporated to get methyl
3-(3-chlorophenyl)-3-oxopropanoate (INT-5a, 700 mg, 73%) which was
used without further purification. TLC system: EtOAc/PE (3:2)
Synthesis of methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)propanoate
(INT-6a)
[0114] To a stirred solution of DMP (6.2 g, 14.1 mmol, 1.5 eq) in
ACN (20 mL) was added p-TsOH (3.57 g, 18.8 mmol, 2.0 eq) followed
by methyl 3-(3-chlorophenyl)-3-oxopropanoate (5, 2.0 g, 9.4 mmol,
1.0 eq) and the RM heated to reflux for 6 h. The RM was filtered,
the filtrate was diluted with water (50 mL) and extracted with
EtOAc (70 mL). The organic layer was washed with NaHCO.sub.3
solution(30 mL), dried over anhydrous Na.sub.2SO.sub.4,
concentrated and the resulting crude was purified by silica gel
(100-200 mesh) column chromatography using EtOAc/PE (1:9) as an
eluent to get methyl
3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)propanoate (INT-6a, 1.0 g,
28%). TLC system: EtOAc/PE (2:3), R.sub.f: 0.55
Synthesis of methyl
2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate
(INT-7a-ii)
[0115] To a stirred solution of methyl
3-(3-chlorophenyl)-3-oxo-2-(tosyloxy) (INT-6, 1.0 g, 2.6 mmol, 1.0
eq) in MeOH (10 mL) was 2,2-dimethylpropanethioamide (INT-2a, 0.367
g, 3.1 mmol, 1.2 eq) and the RM was heated to reflux for 16 h. The
RM was concentrated under reduced pressure and the crude was
purified by silica gel (100-200 mesh) column chromatography using
EtOAc/PE (1:9) as eluent to get methyl
2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii,
0.450 g, 55%). TLC system: PE (2:3), R.sub.f: 0.55
Synthesis of (2-(tert-butyl)-4-(3-chlorophenyl)
thiazol-5-yl)methanol (INT-8a-ii)
[0116] To a stirred solution of methyl
2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii,
450 mg, 1.4 mmol, 1.0 eq) in THF (10 mL) was added LiAlH.sub.4
(0.055 g, 1.4 mmol, 1.0 eq) at 0.degree. C. and the RM was stirred
at same temperature for 2 h. The RM was quenched with MeOH (2 mL),
filtered through a pad of celite and concentrated under reduced to
get (2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanol
(INT-8a-ii, 400 mg, 90%) as colorless liquid which was used without
further purification. TLC system: EtOAc/PE (2:3), R.sub.f: 0.4
Synthesis of
5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole
(INT-9a-ii)
[0117] To a stirred solution of
(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanol (INT-8a-ii,
400 mg, 1.36 mmol, 1.0 eq) in THF (10 mL) was added DBU (620 mg,
4.08 mmol, 3.0 eq) followed by DPPA (748 mg, 2.72 mmol, 2.0 eq) and
the RM was stirred at RT for 16 h. The RM was concentrated and
diluted with EtOAc (20 mL), washed with water (30 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
was purified by silica gel column chromatography (100-200 mesh)
using EtOAc/PE (1:9) as eluent to get
5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole
(INT-9a-ii, 400 mg, 90%) as yellow liquid. TLC system: EtOAc/PE
(2:8), R.sub.f: 0.6
Synthesis (2-(tert-butyl)-4-(3-chlorophenyl)
thiazol-5-yl)methanamine hydrochloride (INT-10a-ii)
[0118] To a stirred solution of
5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole
(INT-9a-ii, 400 mg, 1.3 mmol, 1.0 eq) in THF (10 mL) was added TPP
(685 mg, 2.6 mmol, 2.0 eq) followed by water (1.0 mL) and the RM
was stirred at RT for 16 h. The RM was concentrated and the
resulting crude was dissolved in toluene (10 mL) and extracted with
2N HCl (2.times.10 mL). The aqueous layer was basified with 2N NaOH
and extracted with ether (3.times.10 mL). The organic layers were
dried over Na.sub.2SO.sub.4 and HCl in ether was added to get
(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanamine
hydrochloride (INT-10a-ii, 300 mg, 80%) as a white solid. TLC
system: MeOH/DCM (1:9), R.sub.f: 0.4
[0119] The following azole methylamine hydrochlorides INT-10 were
prepared according to the procedure described above.
TABLE-US-00002 TABLE 1 List of INT-10 prepared according to the
procedure described for INT-10a-ii.
(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5- INT-10a-i Using INT-1a
yl)methanamine hydrochloride instead of INT-2a
(4-(3-chlorophenyl)-2-(trifluorometh- INT-10b-i Using INT-1b
yl)oxazol-5- instead of yl)methanamine hydrochloride INT-2a
(4-(3-chlorophenyl)-2-(trifluorometh- INT-10b-ii Using INT-2b
yl)thiazol-5- instead of yl)methanamine hydrochloride INT-2a
(2-(tert-butyl)-4-(m-tolyl)thiazol-5- INT-10a-iii Using INT-3b
yl)methanaminium chloride instead of INT-3a
(2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5- INT-10a-iv Using
INT-3c yl)methanaminium chloride instead of INT-3a
[0120] Hydrochlorides INT-10 could be converted to the azole amides
by coupling with the acids INT-11 in the presence of EDCI.HCl
(Scheme 2).
##STR00018##
[0121] The acids INT-10 used in this invention are summarized in
Table 2.
TABLE-US-00003 TABLE 2 List of acids
2-(3-fluoro-4-(2-hydroxyethyl)phe- INT-11a Synthesis see below
nyl)propanoic acid 2-(3-fluoro-4- INT-11b Synthesized as
(methylsulfonamidomethyl)phe- described in nyl)propanoic acid
US20130079373, pp. 15 2-(4-(((N-(tert- INT-11c Synthesized as
butoxycarbonyl)sulfamoyl)amino)- described in
methyl)phenyl)propanoic acid US20130079377, pp. 39
2-(3-fluoro-4-(hydroxymethyl)phe- INT-11d Synthesis see below
nyl)propanoic acid 2-(4-(3-hydroxyoxetan-3-yl)phe- INT-11e
Synthesis see below nyl)propanoic acid 2-(5-fluoro-6-(2-(meth-
INT-11f Synthesis see below ylsulfonyl)ethyl)pyridin-3-
yl)propanoic acid 2-(6-((2-methoxyethyl)ami- INT-11g Synthesized as
no)pyridin-3- described in yl)propanoic acid WO2013013817, pp. 115
2-(5-fluoro-6-(hydroxymeth- INT-11h Synthesis see below
yl)pyridin-3- yl)propanoic acid 2-(4-(((N-(tert- INT-11i Synthesis
see below butoxycarbonyl)sulfamoyl)ami- no)methyl)-3-
fluorophenyl)propanoic acid
Synthesis of 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid
(INT-11a)
Synthesis of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate
[0122] To a stirred solution of KO.sup.tBu (1.5 g, 7 mmol, 2 eq) in
DMF (10 mL) was added a solution of 1-fluoro-2-nitrobenzene (1.0 g,
7.00 mmol, 1 eq) and ethyl 2-chloropropanoate (0.952 g, 7.00 mmol,
1 eq) dropwise at 0.degree. C. The mixture was stirred for 30 min
at 0.degree. C. The RM was quenched with 1N HCl and extracted with
Et.sub.2O, dried (MgSO.sub.4), and concentrated. The crude was
purified by silica gel column chromatography (100-200 Mesh) using
EtOAc/PE (1:19) to get ethyl 2-(3-fluoro-4-nitrophenyl)propanoate
(800 mg, 47%) system: EtOAc/PE (1:9), R.sub.f: 0.25
Synthesis of ethyl 2-(4-amino-3-fluorophenyl)propanoate
[0123] To a stirred solution of ethyl
2-(3-fluoro-4-nitrophenyl)propanoate (0.80 g, 3.3 mmol, 1.0 eq) in
MeOH (20 mL) was added 10% Pd--C(0.2 g) and stirred under hydrogen
atmosphere at RT for 1 h. The RM was filtered through celite pad
and filtrate was concentrated under reduced pressure to get ethyl
2-(4-amino-3-fluorophenyl)propanoate (0.62 g, 88%) as a pale brown
liquid. TLC system: EtOAc/PE (2:8), R.sub.f: 0.2
Synthesis of ethyl 2-(3-fluoro-4-iodophenyl)propanoate
[0124] To a stirred solution of ethyl
2-(4-amino-3-fluorophenyl)propanoate (0.12 g, 0.56 mmol, 1.0 eq)
and in conc.HCl (3 mL) was added NaNO.sub.2 (0.078 g, 1.1 mmol, 2
eq) in water (5 mL) and stirred at -5.degree. C. for 30 min. Then
KI (0.466 g, 2.80 mmol, 5 eq), I.sub.2 (0.576 g, 2.20 mmol, 4 eq)
in water (5 mL) was added and stirred at same temperature for
another 30 min. The RM was diluted with EtOAc, and washed with
NaOCl solution, dried over Na.sub.2SO.sub.4 and concentrated to get
ethyl 2-(3-fluoro-4-iodophenyl)propanoate (0.3 g, 43%). TLC system:
EtOAc/PE (1:9), R.sub.f: 0.5.
Synthesis of ethyl 2-(3-fluoro-4-vinylphenyl)propanoate
[0125] LiCl (490 mg, 11.6 mmol, 1.5 eq), Pd (PPh.sub.3).sub.4 (444
mg, 0.38 mmol, 0.05 eq), were suspended in DMF (10 mL) and argon
gas was purged into the solution for 15 min. The tributylvinyltin
(3.6 g, 11.6 mmol, and 1.5 eq) and ethyl
2-(3-fluoro-4-iodophenyl)propanoate were added and heated to
55.degree. C. for 16 h. The RM was filtered through a pad of celite
and washed with EtOAc. The organic layer was washed with water,
dried and concentrated. The crude was purified by column
chromatography using 10% EtOAc in PE as an eluent to get ethyl
2-(3-fluoro-4-vinylphenyl)propanoate (1.1 g, 64%). TLC system:
EtOAc/PE (1:9), R.sub.f: 0.5
Synthesis of ethyl
2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate
[0126] To a stirred solution of ethyl
2-(3-fluoro-4-vinylphenyl)propanoate (150 mg, 0.9 mmol, 1.0 eq) in
THF (2.5 mL) was added BH.sub.3.DMS (0.18 mL, 1.6 mmol, 1.78 eq) at
0.degree. C. and stirred at RT for 1 h. The RM was cooled to
0.degree. C. the 1N NaOH (3 mL) and 30% H.sub.2O.sub.2(2 mL) added
and stirred for 30 min and at RT for another 30 min and extracted
with EtOAc, dried over Na.sub.2SO.sub.4 and concentrated to get
ethyl 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (240 mg
crude). This crude was purified by column chromatography using
100-200 silica gel and 20% EtOAc in PE as an eluent to get ethyl
2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (100 mg, 46%) as a
colourless liquid. TLC system: EtOAc/PE (2:8), R.sub.f: 0.25
Synthesis of 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid
(INT-11a)
[0127] To a stirred solution of ethyl
2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (0.4 g, 1.6 mmol,
1.0 eq) in MeOH and H.sub.2O (6 mL, 1:1) was added LiOH.H.sub.2O
(349 mg, 8.3 mmol, 5.0 eq) and stirred at RT for 2 h. The RM was
concentrated and acidified with 2N HCl to get
2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid (INT-10a, 150
mg, 42%) as a colorless liquid. TLC system: EtOAc/PE (1:1),
R.sub.f: 0.2
Synthesis of 2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid
(INT-11d)
Synthesis of (4-bromo-2-fluorophenyl)methanol
[0128] To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15
g, 79.4 mmol) in MeOH (100 mL) at -5.degree. C. to 0.degree. C. was
added NaBH.sub.4 (6.0 g, 9 mmol) in portions and stirred at RT for
1 h until the starting material was completely consumed, as
evidenced by TLC analysis. The RM was then diluted with ice cold
water (100 mL) and concentrated under reduced pressure. The residue
obtained on concentration was extracted with EtOAc (2.times.200 mL)
and separated. The EtOAc layer was washed with brine (50 mL), dried
over anhydrous NaSO.sub.4, filtered and concentrated to afford
(4-bromo-2-fluorophenyl)methanol (29 g, from 2 batches each of 15 g
of 4-bromo-2-fluoro benzaldehyde, 95%) as colorless oil. TLC
system: EtOAcPE (3:7), R.sub.f: 0.3
Synthesis of ((4-bromo-2-fluorobenzyl)oxy)
(tert-butyl)dimethylsilane
[0129] A stirred solution of 4-bromo-2-fluoro benzaldehyde (49 g,
239 mmol, 1 eq) in DCM (400 mL) was treated with imidazole (32.5 g,
478 mmol, 2 eq) followed by TBDMS chloride (39.6 g, 263 mmol, 1.1
eq). The resulting solution was stirred at RT for 1 h, quenched
with water (100 mL) and the layers were separated. The aqueous
layer was extracted with DCM (2.times.100 mL). The combined organic
layer was washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The residue upon purification by column
chromatography (silica gel 100-200, EtOAc/PE; 10:90) afforded
((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (53 g, 70%)
as a brown liquid. TLC system: EtOAc/PE (1:9), R.sub.f: 0.6
Synthesis of
tert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzy-
l)oxy)dimethylsilane
[0130] To a stirred solution of
((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (1.2 g, 3.7
mmol, 1 eq) in 1,4-dioxane (10 mL) was treated with bis-pinacolato
diboron (1.05 g, 4.15 mmol, 1.1 eq) and KOAc (0.74 g, 7.5 mmol, 2
eq) at RT. The RM was purged with Ar for 20 min.
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.26 g, 0.37 mmol, 0.1 eq) was then
added and the RM was again purged with Ar for an additional 15 min.
The RM was heated to 100.degree. C. for 3 h until complete
consumption of starting material, as evidenced by TLC analysis. The
RM was concentrated and the obtained crude compound was purified by
column chromatography (60-120 mesh) using PE as eluent to afford
tert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzy-
l)oxy)dimethylsilane (1 g, 74%;) as a pale yellow oil. TLC solvent
system: EtOAc/PE (1:9), Rf: 0.7
Synthesis of benzyl 2-bromoacrylate
[0131] A suspension of 2-bromoacrylic acid (25.0 g, 167 mmol), BnBr
(21.8 mL, 183 mmol) and K.sub.2CO.sub.3 (46 g, 0.33 mol) in
acetonitrile (250 mL) was stirred at 80.degree. C. for 3 h until
complete consumption of starting material, as evidenced by TLC
analysis. The RM was filtered and concentrated. The obtained crude
compound was purified by column chromatography (100-200 mesh silica
gel) using EtOAc/PE (5:95) as eluent to afford benzyl
2-bromoacrylate (22 g, 53%) as a yellow liquid. (TLC solvent
system: EtOAc/PE (5:95), Rf: 0.7
Synthesis of benzyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate
[0132] A suspension of
tert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzy-
l)oxy)dimethylsilane (500 mg, 1.36 mmol, 1 eq), Cs.sub.2CO.sub.3
(1.3 g, 4.1 mmol, 3 eq) in DMF (5 mL) was deoxygenated by purging
Ar for 30 min at RT. Pd(dppf)Cl.sub.2 (55.6 mg, 0.068 mmol, 0.04
eq) was added and purging continued. After 10 min, benzyl
2-bromoacrylate (497 mg, 2.05 mmol, 1.5 eq) was added and stirred
at 100.degree. C. for 2 h until complete consumption boronate, as
evidenced by TLC analysis. The RM was diluted with EtOAc (10 mL),
filtered through celite and washed with EtOAc (20 mL). The combined
filtrate was washed with water (3.times.20 mL), brine (50 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
The obtained crude compound was purified by column chromatography
(100-200 mesh silica gel) using 5% EtOAc in PE as eluent to afford
benzyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate
(200 mg, 42%) as a pale brown oil. TLC system: EtOAc/PE (1:9), Rf:
0.65
Synthesis of 2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid
(INT-11d)
[0133] A suspension of benzyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate
(20 mg, 0.050 mmol), 10% Pd(OH).sub.2 (4 mg) and 10% Pd--C(4 mg) in
EtOH (1 mL) was hydrogenated (balloon pressure) at RT for 16 h
until complete consumption of starting material, as evidenced by
TLC analysis. The RM was filtered through Celite, washed with MeOH
(2.times.10 mL). The combined filtrate was concentrated and the
obtained crude compound was purified by dissolving in EtOAc (20 mL)
and shaken with aq 10% NaHCO.sub.3 solution (15 mL). The EtOAc
layer was separated; the aq layer was acidified with aq citric acid
solution (pH 5) and extracted with EtOAc (2.times.20 mL). The
combined EtOAc layer was washed with water (15 mL), brine (15 mL)
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to
afford 2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid (INT-11d,
6.7 mg, 69%; colorless oil). TLC solvent system: EtOAc/PE (6:4),
Rf: 0.2
Synthesis of 2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid
(INT-11e)
Synthesis of 3-(4-bromophenyl)oxetan-3-ol
[0134] To a stirred solution of 1,4-dibromobenzene (5.00 g, 21.4
mmol) in THF (40 mL) at -78.degree. C. was added n-BuLi (8.5 mL,
21.4 mmol, 2.5 M solution in hexane), stirred for 30 min and added
a solution of oxetan-3-one (1.25 mL, 21.4 mmol) in THF (10 mL) over
a period of 15 min. The resultant RM was allowed to warm to RT and
stirred for 3 h. The RM was cooled to 0.degree. C., quenched with
aq.NH.sub.4Cl solution, diluted with water (30 mL) and extracted
with EtOAc (2.times.50 mL), washed with brine (20 mL), dried over
Na.sub.2SO.sub.4 and evaporated to get the crude compound. The
crude was purified by silica gel (100-200 mesh) column
chromatography using EtOAc/PE (1:9) as an eluent to get
3-(4-bromophenyl)oxetan-3-ol (3.0 g, 60%). TLC system: EtOAc/PE
(1:4), R.sub.f: 0.2
Synthesis of
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol
[0135] To a degassed solution of 3-(4-bromophenyl)oxetan-3-ol
(0.500 g, 2.20 mmol), bis(pinacolato)diboron (0.61 g, 2.41 mmol) in
1,4-dioxane (10 mL) under Ar was added KOAc (0.65 g, 6.60 mmol)
followed by PdCl.sub.2(dppf).DCM complex (0.09 g, 0.11 mmol) and
degassed for 30 min. The resultant RM was heated at 100.degree. C.
for 2 h. The RM was evaporated under reduced pressure and the crude
was triturated with EtOAc/PE (3:7), filtered hot through a pad of
neutral alumina and evaporated to get crude compound. The crude was
triturated with pentane, filtered and dried under vacuum to get
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol
(0.42 g, 70%). TLC system: EtOAc/hexane (1:1), R.sub.f: 0.4
Synthesis of benzyl 2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate
[0136] To a degassed solution of cesium carbonate (0.94 g, 2.9
mmol) in 1,4-dioxane (10 mL), water (1 mL) under Ar was added
benzyl 2-bromoacrylate (0.35 g, 1.5 mmol, synthesis: see above),
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol
(0.40 g, 1.5 mmol) followed by Pd(PPh.sub.3).sub.4(0.085 g, 0.073
mmol), degassed for 30 min and heated at 100.degree. C. for 4 h.
The RM was evaporated under reduced pressure and the crude was
diluted with water (10 mL), extracted with EtOAc (2.times.20 mL),
washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and
evaporated the solvent to get crude compound. The crude was
purified by silica gel column chromatography (100-200 mesh) using
EtOAc/PE (3:7) as eluent to get benzyl
2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate (0.36 g, 80%). TLC
system: EtOAc/PE (1:1), R.sub.f: 0.3
Synthesis of 2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid
(INT-11e)
[0137] A solution of benzyl
2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate (0.35 g, 1.1 mmol) in
EtOH (5 mL) was hydrogenated under hydrogen balloon atmosphere with
10% Pd/C (70 mg) at RT for 4 h. The RM was filtered through celite
pad, washed with EtOH and the solvent was evaporated under reduced
pressure. The residue was dried under vacuum to get crude
2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid (INT-11e, 0.25 g)
which was used without further purification. TLC system: 100%
EtOAc, R.sub.f: 0.05
Synthesis of
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid
(INT-11f)
Synthesis of 5-bromo-3-fluoro-2-vinylpyridine
[0138] To a degassed solution of 2,5-dibromo-3-fluoropyridine
(0.500 g, 1.97 mmol), tributyl (vinyl) tin (0.70 mL, 2.4 mmol) in
anhydrous DMF (5 mL) under Ar was added LiCl (0.12 g, 2.95 mmol),
followed by Pd(PPh.sub.3).sub.4(0.12 g, 0.098 mmol). The mixture
was degassed for 30 min and heated at 60.degree. C. for 16 h. The
RM was filtered through celite pad, diluted with water (10 mL) and
extracted with Et.sub.2O (2.times.20 mL), washed with brine (10
mL), dried over Na.sub.2SO.sub.4 and evaporated to get the crude
compound. The crude was purified by silica gel (100-200 mesh)
column chromatography using 2% EtOAc/PE as an eluent to get crude
5-bromo-3-fluoro-2-vinylpyridine (0.30 g) which was used without
further purification. TLC system: EtOAc/PE (1:9), R.sub.f: 0.8
Synthesis of
5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine
[0139] To a stirred solution of 5-bromo-3-fluoro-2-vinylpyridine
(0.30 g, 1.5 mmol) in EtOH (5 mL) was added sodium methanesulfinate
(0.46 g, 4.5 mmol) followed by trifluoroacetic acid (0.33 mL, 4.5
mmol) and heated at 60.degree. C. for 2 h. The RM was cooled,
diluted with water (10 mL) and basified with 10% NaHCO.sub.3,
extracted with DCM (2.times.25 mL), washed with brine (10 mL),
dried over Na.sub.2SO.sub.4 and evaporated to get crude compound.
The crude was triturated with pentane, filtered and dried under
vacuum to get 5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine
(130 mg, 23% over 2 steps). TLC system: EtOAc/PE (1:1), R.sub.f:
0.3
Synthesis of
3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)pyridine
[0140] To a degassed solution of
5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine (0.25 g, 0.89
mmol), bis(pinacolato)diboron (0.23 g, 0.89 mmol) in 1,4-dioxane
(10 mL) under Ar was added KOAc (0.26 g, 2.7 mmol) followed by
PdCl.sub.2(dppf).DCM complex (0.075 g, 0.089 mmol). The RM was
degassed for 30 min and heated at 100.degree. C. for 2 h. The RM
was concentrated under reduced pressure and the crude was
triturated with EtOAc/PE (3:7), filtered through a pad of neutral
alumina and evaporated. The crude product was triturated with
pentane, filtered the solid and dried under vacuum to get
3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)pyridine (0.15 g, 51%). TLC system: EtOAc/hexane (3:7),
R.sub.f: 0.05
Synthesis of benzyl
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate
[0141] To a degassed solution of cesium carbonate (0.54 g, 1.7
mmol) in 1,4-dioxane (5 mL) and water (1 mL) under Ar was added
benzyl 2-bromoacrylate (0.20 g, 0.83 mmol, synthesis: see above),
3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)pyridine (0.30 g, 0.91 mmol) followed by
Pd(PPh.sub.3).sub.4 (0.050 g, 0.040 mmol), degassed for 30 min and
heated at 100.degree. C. for 2 h. The RM was filtered through a pad
of celite, the solvent was evaporated under reduced pressure and
the crude was diluted with water (10 mL), extracted with EtOAc
(2.times.20 mL), washed with brine (10 mL), dried over
Na.sub.2SO.sub.4 and evaporated. The crude was purified by silica
gel column chromatography (100-200 mesh) using EtOAc/PE (1:1) as
eluent to get benzyl
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate (0.21
g, 70%). TLC system: EtOAc/PE (1:1), R.sub.f: 0.2
Synthesis of
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid
(INT-11f)
[0142] A solution of
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate (0.20
g, 0.55 mmol), 10% Pd/C (50 mg) in EtOH (5 mL) was hydrogenated
under hydrogen ballon atmosphere at RT for 3 h. The RM was filtered
through celite pad, washed with EtOH and the solvent was evaporated
under reduced pressure and dried under vacuum to get crude
2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid
(INT-11f, 0.10 g). The compound was used without further
purification. TLC system: MeOH/DCM (1:9), R.sub.f: 0.05
Synthesis of 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic
acid (INT-11h)
Synthesis of ethyl 2,6-dichloro-5-fluoronicotinate
[0143] Thionyl chloride (50.0 mL, 655 mmol) was added to a stirred
solution of 2,6-dichloro,5-fluoro,3-nicotinic acid (55.0 g, 262
mmol) in EtOH (300 mL) at 0.degree. C. The resulting RM was stirred
at reflux for 16 h. The RM was cooled to RT. EtOH was evaporated in
vacuo; crude compound was dissolved in sat NaHCO.sub.3 solution
(300 mL) and extracted with EtOAc (3.times.200 mL). Combined
organic layers were washed with water, brine (200 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give ethyl
2,6-dichloro-5-fluoronicotinate (61 g, 98%) as a light brown oil
which was used without further purification. TLC System: EtOAc/PE
(1:1), R.sub.f: 0.6).
Synthesis of diethyl
2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate
[0144] Diethyl malonate (48.0 mL, 311 mmol) was added drop wise to
a suspension of NaH (60% in mineral oil; 10.3 g, 259 mmol) in DMF
(150 mL) at 0.degree. C., stirred at RT for 1 h. A solution of
ethyl 2,6-dichloro-5-fluoronicotinate (62.0 g, 259. mmol) in DMF
(100 mL) was added at 0.degree. C. and the whole stirred at
50.degree. C. for 16 h. The RM was quenched with sat NH.sub.4Cl
(200 mL) solution and extracted with EtOAc (3.times.300 mL).
Combined organic layer was washed successively with water, brine
(200 mL), dried (Na.sub.2SO.sub.4) and concentrated to give crude
compound, which was purified by silica gel column chromatography
eluting 5% EtOAc in PE to give diethyl
2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate (90.0
g, 96%) as light yellow oil. TLC system: EtOAc/PE (1:9); R.sub.f:
0.4
Synthesis of diethyl
2-(5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate
[0145] 10% palladium hydroxide (9.0 g) was added to a degassed
solution of diethyl
2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate (90.0
g, 249 mmol) and triethyl amine (70.0 mL, 499 mmol) in EtOH (450
mL) at RT. The RM was hydrogenated at RT and 20 psi for 2 h. RM was
filtered through celite bed, washed with excess EtOH, concentrated
to give crude compound, which was dissolved in water and extracted
with EtOAc (2.times.100 mL). Combined organic layer was washed with
water (100 mL), brine (50 mL), dried (Na.sub.2SO.sub.4) and
concentrated to give diethyl
2-(5-(ethoxy-carbonyl)-3-fluoropyridin-2-yl)malonate (80.0 g, 98%)
as light yellow oil. TLC system: EtOAc/PE (1:9), R.sub.f: 0.4)
Synthesis of 5-fluoro-6-methylnicotinic acid hydrochloride
[0146] Conc. HCl (400 mL) was added to diethyl
2-(5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate (80.0 g, 245
mmol) at 0.degree. C. The resulting RM was stirred at 120.degree.
C. for 24 h. The RM was cooled to RT and aqueous layer was
evaporated under reduced pressure, azeotropically dried with
toluene to give 5-fluoro-6-methylnicotinic acid hydrochloride (45
g, 96%) as light yellow solid. TLC System: MeOH/DCM (1:9), R.sub.f:
0.5
Synthesis of ethyl 5-fluoro-6-methylnicotinate
[0147] Thionyl chloride (53.0 mL, 711 mmoles) was added to a
stirred solution of 5-fluoro-6-methylnicotinic acid hydrochloride
(45.0 g, 237 mmol) in EtOH (250 mL) at 0.degree. C. The resulting
RM was stirred at reflux for 16 h. The RM was cooled to RT, EtOH
was evaporated, crude compound was dissolved in sat NaHCO.sub.3
solution (200 mL) and extracted with EtOAc (3.times.200 mL).
Combined organic layers were washed with water, brine (200 mL),
dried (Na.sub.2SO.sub.4) and concentrated to give ethyl
5-fluoro-6-methyl-nicotinate (40.0 g, 92%) as a light brown oil
which was used in next without further purification. TLC System:
EtOAc/PE (1:1), R.sub.f: 0.6
Synthesis of (5-fluoro-6-methylpyridin-3-yl)methanol
[0148] NaBH.sub.4 (24.9 g, 655.73 mmoles) was added to a stirred
solution of ethyl 5-fluoro-6-methylnicotinate (40.0 g, 219 mmol) in
EtOH (400 mL) at 0.degree. C. The resulting RM was stirred at RT
for 16 h, EtOH was evaporated, crude compound was dissolved in
water (200 mL) and extracted with EtOAc (3.times.200 mL). Combined
organic layers were washed with water, brine (200 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give
(5-fluoro-6-methylpyridin-3-yl)methanol (30 g, 96%) as a light
brown oil which was used without further purification. TLC System:
EtOAc/PE (1:1), R.sub.f: 0.2
Synthesis of 5-(chloromethyl)-3-fluoro-2-methylpyridine
[0149] Thionyl chloride (150 mL) was added to
(5-fluoro-6-methylpyridin-3-yl)methanol (30.0 g, 213 mmol) at
0.degree. C. The resulting RM was stirred at reflux for 6 h.
Thionyl chloride was evaporated in vacuo; the residue was dissolved
in sat NaHCO.sub.3 solution (200 mL) and extracted with EtOAc
(3.times.200 mL). Combined organic layers were washed with brine
(200 mL), dried (Na.sub.2SO.sub.4) and concentrated to give
5-(chloro-methyl)-3-fluoro-2-methylpyridine (28 g, 82%) as a brown
oil which was used without further purification. TLC System:
EtOAc/PE (1:1), R.sub.f: 0.5
Synthesis of 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile
[0150] Sodium cyanide (18.0 g, 352 mmoles) was added to a stirred
solution of 5-(chloromethyl)-3-fluoro-2-methylpyridine (28.0 g, 176
mmol) in mixture of EtOH/water (200/20 mL) at 0.degree. C. The
resulting RM was stirred at reflux for 6 h. The RM was cooled to
RT, quenched with ice cold water (300 mL) and extracted with EtOAc
(3.times.500 mL). Combined organic layers were washed with water,
brine (300 mL), dried (Na.sub.2SO.sub.4) and concentrated to give
crude 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile (24.0 g, 90%)
as a brown oil which was used without further purification. TLC
system: EtOAc/PE (1:1), R.sub.f: 0.35
Synthesis of Methyl 2-(5-fluoro-6-methylpyridin-3-yl)acetate
[0151] Trimethylsilyl chloride (100 mL, 800 mmol) was added to a
stirred solution of 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile
(24.0 g, 160 mmol) in MeOH (300 mL) at 0.degree. C. The resulting
RM was stirred at 90.degree. C. for 8 h in a sealed tube. The RM
was cooled to RT. MeOH was evaporated; crude compound was dissolved
in sat NaHCO.sub.3 solution (200 mL) and extracted with EtOAc
(3.times.200 mL). Combined organic layers were washed with water,
brine (200 mL), dried (Na.sub.2SO.sub.4) and concentrated to get
crude, which was purified by silica gel column chromatography
eluting with 20% EtOAc in PE to get methyl
2-(5-fluoro-6-methylpyridin-3-yl)acetate (22.0 g, 75%) as light
yellow oil. TLC system: EtOAc/PE (1:1), R.sub.f: 0.50)
Synthesis of methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate
[0152] A solution of methyl
2-(5-fluoro-6-methylpyridin-3-yl)acetate (22.0 g, 120 mmol) in THF
(200 mL) was added drop wise to a suspension of 60% NaH (4.80 g,
120 mmol) in THF (150 mL) at 0.degree. C., stirred at same
temperature for 15 min and then a solution of methyl iodide (7.75
mL, 120 mmol) in THF (100 mL) was added at 0.degree. C. and the RM
was stirred at 0.degree. C. for 2 h. The RM was quenched with sat
NH.sub.4Cl (100 mL) and extracted with EtOAc (3.times.200 mL).
Combined organic layers were washed with water, brine (200 mL),
dried (Na.sub.2SO.sub.4) and concentrated to give crude, which was
purified by silica gel column chromatography eluting 5% EtOAc in PE
to give methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate (10.0 g,
44%) as a light yellow oil. TLC system: EtOAc/PE (1:1), R.sub.f:
0.68
Synthesis of methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate
N-oxide
[0153] MCPBA (10.4 g, 60.9 mmol) was added to a stirred solution of
methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate (10.0 g, 50.8
mmol) in chloroform (200 mL) at 0.degree. C. The resulting RM was
stirred at RT for 4 h. The RM was diluted with chloroform and
successively washed with sat NaHCO.sub.3 solution (200 mL), water,
brine (200 mL), dried (Na.sub.2SO.sub.4) and concentrated to give
methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate N-oxide (11.0 g)
as a light yellow oil which was used without further purification.
TLC system: EtOAc/PE (1:1), R.sub.f: 0.1
Synthesis of methyl
2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate
[0154] Acetic anhydride (110 mL) was added to
2-(5-fluoro-6-methylpyridin-3-yl)propanoate N-oxide (11.0 g, 51.6
mmol) at 0.degree. C. The resulting RM was stirred at reflux for 4
h, cooled to RT and quenched with ice cold water. Basified with
solid NaHCO.sub.3 and extracted with EtOAc (3.times.200 mL).
Combined organic layers were washed with water, brine (200 mL),
dried (Na.sub.2SO.sub.4) and concentrated to get crude, which was
purified by neutral alumina eluting with 5% EtOAc in PE to get
methyl 2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate (5.5 g,
42% over 2 steps) as a light yellow oil. TLC system: EtOAc/PE
(1:1), R.sub.f: 0.58
Synthesis of 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic
acid (INT-11h)
[0155] Conc. HCl (60.0 mL) was added to
2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate (5.5 g, 21.6
mmol) at 0.degree. C. The resulting RM was stirred at RT for 5 h.
The water was evaporated under reduced pressure. Resulting crude
was redissolved in conc. HCl (60 mL) and stirred at RT for 10 h.
The solvent was evaporated under reduced pressure and
azeotropically dried with toluene to give
2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid (INT-11h,
3.5 g, 83%) as an off white sticky solid which was used without
further purification. TLC System: (MeOH/DCM (15:85), R.sub.f:
0.33
Synthesis of
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoic acid (INT-11i)
Synthesis of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate
[0156] To a stirred solution of KOtBu (16.0 g, 142 mmol, 2 eq) in
DMF (100 mL) were added a mixture of 1-fluoro-2-nitrobenzene (10.0
g, 70.9 mmol, 1.0 eq) and ethyl 2-chloropropanoate (9.0 mL, 70.9
mmol, 1.0 eq) at -50.degree. C. and stirred for 10 min at 0.degree.
C. The RM was cooled to -40.degree. C. and quenched with 2N HCl,
diluted with water (100 mL), extracted into EtOAc (2.times.200 mL),
dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure.
The crude was purified by silica gel (60-120 mesh) column
chromatography using 2-5% EtOAc in PE as eluent to get ethyl
2-(3-fluoro-4-nitrophenyl)propanoate (10 g, 58%) as a yellow
liquid. TLC system: 10% EtOAc in PE, R.sub.f: 0.4
Synthesis of ethyl 2-(4-amino-3-fluorophenyl)propanoate
[0157] To a stirred solution of ethyl
2-(3-fluoro-4-nitrophenyl)propanoate (9.00 g, 37.3 mmol, 1.0 eq) in
MeOH (70 mL) was added 10% Pd--C(4.0 g) and the RM was stirred for
1 h at RT under hydrogen atmosphere (50 psi). The RM filtered
through celite bed and evaporated to get ethyl
2-(4-amino-3-fluorophenyl)propanoate (7.0 g, 88%) as a light brown
liquid which was used without further purification. TLC system: 10%
EtOAc in PE, R.sub.f: 0.1
Synthesis of ethyl 2-(3-fluoro-4-iodophenyl)propanoate
[0158] To a stirred solution of p-TsOH (20.2 g, 106 mmol, 3 eq) in
ACN (100 mL) was added ethyl 2-(4-amino-3-fluorophenyl)propanoate
(7.50 g, 35.5 mmol, 1.0 eq) at 0.degree. C., stirred for 10 min and
added a mixture of KI (14.8 g, 88.9 mmol, 2.5 eq.), NaNO.sub.2
(4.90 g, 71.1 mmol, 2 eq) in water (20 mL). The RM was stirred for
2 h at RT, diluted with water (200 mL), neutralized with sat.
NaHCO.sub.3 and extracted with EtOAc (2.times.30 mL). The organic
layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4
and evaporated under reduced pressure. The crude compound was
purified by silica gel (60-120 mesh) column chromatography using
2-3% EtOAc in PE as eluent to get ethyl
2-(3-fluoro-4-iodophenyl)propanoate (6.5 g, 65%) as a pale yellow
liquid. TLC system: 10% EtOAc in PE R.sub.f: 0.6
Synthesis of ethyl 2-(4-cyano-3-fluorophenyl)propanoate
[0159] To a stirred solution of ethyl
2-(3-fluoro-4-iodophenyl)propanoate (6.8 g, 21.1 mmol, 1.0 eq) in
NMP (50 mL) was added CuCN (1.84 g, 21.1 mmol, 1.0 eq) and stirred
for 3 h at 180.degree. C. The RM was diluted with water (100 mL)
and extracted into EtOAc (2.times.50 mL). The organic layer was
washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude was purified by
silica gel (60-120) column chromatography using 5-10% EtOAc in PE
as eluent to get ethyl 2-(4-cyano-3-fluorophenyl)propanoate (4.5 g,
90%) as a black colour liquid. TLC system: 10% EtOAc in PE,
R.sub.f: 0.4
Synthesis of ethyl 2-(4-(aminomethyl)-3-fluorophenyl)propanoate
[0160] To a stirred solution of ethyl
2-(4-cyano-3-fluorophenyl)propanoate (4.50 g, 20.4 mmol, 1.0 eq) in
EtOH (40 mL) were added Raney-Ni (2.0 g) followed by aq. NH.sub.3
(2 mL) and the mixture was stirred for 2 h at RT under hydrogen
atmosphere (50 psi). The RM was filtered through celite pad and the
filtrate was evaporated under reduced pressure. The crude product
was co-distilled twice with toluene to get ethyl
2-(4-(aminomethyl)-3-fluorophenyl)propanoate (3.0 g, 75%) as a pale
green liquid. TLC system: EtOAc/PE (1:5), R.sub.f: 0.05
Synthesis of ethyl
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoate
[0161] To a stirred solution of t-BuOH (4.27 mL, 44.4 mmol, 2.5 eq)
in DCM (10 mL) at RT was added Sulfuryl chloride isocyanate (3.13
mL, 35.4 mmol, 2.0 eq) and stirred at RT for 1 h. This RM was added
to a solution of ethyl 2-(4-(aminomethyl)-3-fluorophenyl)propanoate
(4.00 g, 17.7 mmol, 1.0 eq), TEA (7.4 mL, 53 mmol, 3.0 eq) in DCM
at 50.degree. C. and refluxed for 2 h. The RM was diluted with
water (50 mL), extracted with DCM (2.times.50 mL), dried over
Na.sub.2SO.sub.4 and evaporated to get crude ethyl
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoate (2.0 g) as an off white solid which was used without
further purification. TLC system: EtOAc/PE (1:1), R.sub.f: 0.6
Synthesis of
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoic acid (INT-11i)
[0162] To a stirred solution of ethyl
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoate (4.0 g, 9.9 mmol, 1.0 eq) in MeOH (20 mL) and H.sub.2O (20
mL) was added LiOH.H.sub.2O (2.0 g, 50 mmol, 5.0 eq) and the
mixture was stirred for 16 h at RT. The RM was evaporated,
acidified with 10% citric acid solution (.about.pH 5), extracted
with EtOAc (2.times.50 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude
was washed with n-pentane to get
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)pro-
panoic acid (INT-11i, 1.5 g, 39%) as white solid. TLC system:
EtOAc/PE (1:1), R.sub.f: 0.25
Synthesis of azole amides
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluor-
o-4-(2-hydroxyethyl)phenyl)propanamide (EX-1)
[0163] To a stirred solution of
2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid (INT-11a, 100
mg, 0.36 mmol, 1.0 eq) in DCM at 0.degree. C. were added EDC HCl
(107 mg, 0.56 mmol, 1.2 eq), HOBT (76 mg, 0.56 mmol, 1.2 eq), TEA
(0.203 mL, 1.4 mmol, 3.0 eq) and
(4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methanamine
hydrochloride (INT-10b-ii, 154 mg, 0.47 mmol, 1.0 eq) and stirred
at RT for 12 h. The RM was diluted with water (10 mL) and extracted
with DCM (10 mL), dried (Na.sub.2SO.sub.4) and evaporated. The
resulting crude was purified by silica gel column chromatography
(100-200) using EtOAc/PE (3:7) to get
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluor-
o-4-(2-hydroxyethyl)phenyl)propanamide (EX-1, 72 mg, 33%) as a pale
yellow solid. TLC system: EtOAc/PE (1:1), R.sub.f: 0.65; ESI (m/z,
MH.sup.+): 487.0
[0164] According to the procedure described for EX-1, the following
amides were prepared:
[0165]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3--
fluoro-4-(2-hydroxyethyl)phenyl)propanamide (EX-2) from INT-10b-i
and INT-11a. TLC system: EtOAc/PE (1:1), R.sub.f: 0.65; ESI (m/z,
MH.sup.+): 471.0
[0166]
N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluo-
ro-4-(methylsulfonamidomethyl)phenyl)propanamide (EX-3) from
INT-10a-ii and INT-11b.
[0167]
N-((2-(tert-butyl)-4-(3-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(m-
ethylsulfonamidomethyl)-phenyl)propanamide (EX-4) from INT-10a-iii
and INT-11b. ESI (m/z, MH.sup.+): 518.1
[0168]
N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluo-
ro-4-(hydroxymethyl)phenyl)propanamide (EX-7) from INT-10a-ii and
INT-11d.
[0169]
N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(h-
ydroxymethyl)phenyl)propanamide (EX-8) from INT-10a-iii and
INT-11d. ESI (m/z, MH.sup.+): 441.3
[0170]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4--
(3-hydroxyoxetan-3-yl)phenyl)propanamide (EX-9) from INT-10b-i and
INT-11e. TLC system: EtOAc/PE (1:1), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 479.1
[0171]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-
-(3-hydroxyoxetan-3-yl)phenyl)propanamide (EX-10) from INT-10b-ii
and INT-11e. TLC system: EtOAc/PE (1:1), R.sub.f; ESI (m/z,
MH.sup.+): 497.0
[0172]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5--
fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide (EX-11)
from INT-10b-i and INT-11f. TLC system: EtOAc, R.sub.f: 0.4; ESI
(m/z, MH.sup.+): 534.1
[0173]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-
-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide (EX-12)
from INT-10b-ii and INT-11f. TLC system: EtOAc, R.sub.f: 0.4; ESI
(m/z, MH.sup.+): 550.1
[0174]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5--
fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamide (EX-19) from
INT-10b-i and INT-11h. TLC system: EtOAc/PE (1:1), R.sub.f: 0.25;
ESI (m/z, MH.sup.+): 458.2
[0175]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-
-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamide (EX-20) from
INT-10b-ii and INT-11h. TLC system: EtOAc, R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 474.1
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulf-
amoylamino)methyl)phenyl)propanamide (EX-5)
Synthesis of tert-butyl
N-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino-
)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate
[0176] To a stirred solution of
2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)phenyl)propanoic
acid (INT-11c, 200 mg, 0.550 mmol, 1.0 eq) in DCM (10 mL) under
inert atmosphere was added EDC-HCl (126 mg, 0.660 mmol, 1.2 eq)
followed by HOBT (89 mg, 0.66 mmol, 1.2 eq), TEA (0.23 mL, 1.7
mmol, 3.0 eq) at RT and stirred for 15 min, then added
(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanamine
hydrochloride (INT-10b-i, 174 mg, 0.550 mmol, 1.0 eq) and stirred
at RT for 12 h. The RM was diluted with water (50 mL) and extracted
into DCM (100 mL), dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure to get tert-butyl
N-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino-
)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate (300 mg, 87%) as a
pale yellow solid. TLC system: EtOAc/PE (1:1), R.sub.f: 0.6
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulf-
amoylamino)methyl)phenyl)propanamide (EX-5)
[0177] To a stirred solution of tert-butyl
N-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino-
)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate (300 mg, 0.480 mmol,
1.0 eq) in DCM (10 mL) was slowly added TFA (4.0 mL) at 0.degree.
C. and the RM was stirred for 3 h at RT. The RM was diluted with
water (30 mL) and basified (pH 8) with sat. NaHCO.sub.3 solution
and extracted into DCM (50 mL), washed with brine, dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude
compound. The crude was washed with Et.sub.2O to get
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulf-
amoylamino)methyl)phenyl)propanamide (EX-5, 125 mg, 49%) as a white
solid. TLC system: EtOAc/PE (1:1), R.sub.f: 0.4; ESI (m/z;
MH.sup.+): 515.1
[0178] According to the procedure described for EX-5, the following
amides were prepared:
[0179]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-
-((sulfamoylamino)methyl)phenyl)propanamide (EX-6) from INT-10b-ii
and INT-11c. TLC system: EtOAc/PE (1:1), R.sub.f: 0.4; ESI (m/z,
MH.sup.+): 533.1
[0180]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3--
fluoro-4-((sulfamoylamino)methyl)phenyl)propanamide (EX-23) from
INT-10b-i and INT-11ii. TLC system: EtOAc/PE (1:1), R.sub.f: 0.25;
ESI (m/z, MH.sup.+): 535.4
[0181]
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-
-fluoro-4-((sulfamoylamino)methyl)phenyl)propanamide (EX-24) from
INT-10b-ii and INT-11i. TLC system: EtOAc/PE (1:1), R.sub.f: 0.05;
ESI (m/z, MH.sup.+): 551.3
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hy-
droxyethyl)amino)pyridin-3-yl)propanamide (EX-13)
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-me-
thoxyethyl)amino)pyridin-3-yl)propanamide
[0182] To a stirred solution of
2-(6-((2-methoxyethyl)amino)pyridin-3-yl)propanoic acid (INT-11g,
200 mg, 0.890 mmol, 1.0 eq) in DCM at 0.degree. C. were added
EDC.HCl (203 mg, 1.06 mmol, 1.2 eq), HOBt (144 mg, 1.06 mmol, 1.2
eq), TEA (0.38 mL, 2.67 mmol, 3.0 eq) and
(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanamine
hydrochloride (INT-10b-i, 278 mg, 0.89 mmol, 1.0 eq) and the RM was
stirred at RT for 16 h. The RM was diluted with water (10 mL) and
extracted with DCM (10 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude was purified by silica gel column
chromatography (60-120 mesh) using EtOAc/PE(1:1) as eluent to get
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-me-
thoxyethyl)amino)pyridin-3-yl)propanamide (200 mg, 46%) as a pale
yellow solid. TLC system: EtOAc (100%), R.sub.f: 0.5
Synthesis of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hy-
droxyethyl)amino)pyridin-3-yl)propanamide (EX-13)
[0183] To a stirred solution of
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-me-
thoxyethyl)amino)pyridin-3-yl)propanamide (150 mg, 0.310 mmol, 1.0
eq) in isopropanethiol (5 mL) was added BF.sub.3.Et.sub.2O (5 mL)
at RT and the RM was refluxed for 12 h. The RM was quenched with
aq. NaHCO.sub.3 solution and extracted with DCM (15 mL), dried over
Na.sub.2SO.sub.4 and evaporated. The crude was purified by
preparative TLC using EtOAc as eluent and was further washed with
Et.sub.2O/pentane (1:9) (2.times.10 mL) to get
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hy-
droxyethyl)amino)pyridin-3-yl)propanamide (EX-13, 110 mg, 75%) as a
colorless solid. TLC system: EtOAc, R.sub.f: 0.15; ESI (m/z;
MH.sup.+): 469.4
[0184] According to the procedure described for EX-13,
N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-h-
ydroxyethyl)amino)pyridin-3-yl)propanamide (EX-14) was prepared
from INT-10b-ii and INT-11g. TLC system: EtOAc/PE (9:1), R.sub.f:
0.2; ESI (m/z, MH.sup.+): 485.1
Chiral Separation of Amides
[0185] Racemic EX-14 was subjected to chiral preparative SFC.
Column: Chiralpak-ASH (250.times.30 mm); eluent CO.sub.2/MeOH 3/1;
flow 70 g/min; pressure 100 bar; loading per injection: 35 mg.
[0186] First eluting enantiomer (EX-15): ESI (m/z, MH.sup.+):
485.2
[0187] Second eluting enantiomer: (EX-16): ESI (m/z, MH.sup.+):
485.3
[0188] Racemic EX-13 was subjected to chiral preparative HPLC.
Column: Chiralpak-IB (250.times.20 mm); eluent
hexane/DCM/EtOH/diethylamine 80/10/10/0.1; flow 22 mL/min; loading
per injection: 5 mg.
[0189] First eluting enantiomer (EX-17): ESI (m/z, MH.sup.+):
468.8
[0190] Second eluting enantiomer: (EX-18): ESI (m/z, MH.sup.+):
468.9
[0191] Racemic EX-19 was subjected to chiral preparative HPLC.
Column: Chiralpak-AY-H (250.times.30 mm); eluent
hexane/isopropanol/EtOH/trifluoroacetic acid 80/20/2/0.1; flow 30
mL/min; loading per injection: 30 mg.
[0192] First eluting enantiomer (EX-21): ESI (m/z, MH.sup.+):
457.9
[0193] Second eluting enantiomer: (EX-22): ESI (m/z, MH.sup.+):
457.8
[0194] Azole ureas can be synthesized from azole methylamines
hydrochlorides INT-10 and the carbamates INT-14. These carbamates
can be prepared by reacting the amines INT-12 with
phenylchloroformate 13 (Scheme 3)
##STR00019##
Synthesis of Phenyl Carbamates INT-14
[0195] Table 3 summarizes the phenyl carbamates INT-14 which
syntheses has already been described in literature.
TABLE-US-00004 TABLE 3 Literature described phenyl carbamates
INT-14. phenyl (6-(((tert- INT-14a WO2013013815,
butyldimethylsilyl)oxy)methyl)pyridin-3- pp. 230 yl)carbamate
phenyl (6-(2-((tert- INT-14b WO2013013815,
butyldimethylsilyl)oxy)ethyl)pyridin-3- pp. 141 yl)carbamate phenyl
(4- INT-14c WO2013068462, (methylsulfonamidometh- pp. 72
yl)phenyl)carbamate tert-butyl INT-14e WO2013068462,
N-(4-(phenyloxycarbonylamino)- pp. 78 benzyl)sulfamoylcarbamate
phenyl (3-fluoro-4- INT-14n WO2013068462, (methylsulfonamidometh-
pp. 76 yl)phenyl)carbamate phenyl (3-fluoro-4- INT-14o
WO2013068467, (hydroxymethyl)phenyl)carbamate pp. 65
Synthesis of phenyl
(6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate (INT-14f)
Synthesis of 5-bromopicolinaldehyde
[0196] To a stirred solution of 5-bromopicolinonitrile (5.00 g,
27.3 mmol, 1 eq) in THF (50 mL) was added 1M DIBAL (41 mL, 40.98
mmol, 1 eq) slowly dropwise at -78.degree. C. and the RM was
stirred for 6 h at same temperature. The RM was quenched with 1N
HCl at -78.degree. C. and neutralized with saturated NaHCO.sub.3
solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), and
concentrated to get 5-bromopicolinaldehyde (3.00 g, 59%), which was
used without further purification. TLC system: EtOAc/PE (2:3),
R.sub.f: 0.5
Synthesis of (5-bromopyridin-2-yl)methanol
[0197] To a stirred solution of 5-bromopicolinaldehyde (3.0 g, 16
mmol, 1.0 eq) in MeOH (30 mL) at 0.degree. C. was added NaBH.sub.4
(1.16 g, 32.0 mmol, 2.0 eq) and the RM was stirred for 1 h at
0.degree. C., warmed to RT and stirred for 1 h. The RM was
concentrated, diluted with water and extracted with EtOAc, dried
(Na.sub.2SO.sub.4) and evaporated to get
(5-bromopyridin-2-yl)methanol (1.5 g, 49%), which was used without
further purification. TLC system: EtOAc/PE (2:3), R.sub.f: 0.55
Synthesis of 5-bromo-2-((2-methoxyethoxy)methyl)pyridine
[0198] To a stirred solution of (5-bromopyridin-2-yl)methanol
(0.100 g, 0.531 mmol, 1.0 eq) in THF (10 mL) was added NaH (38 mg,
1.5 mmol, 3.0 eq) at 0.degree. C. and stirred for 10 min, then
1-bromo-2-methoxyethane (0.1 mL, 1.0 mmol, 2.0 eq) was added and
the RM was stirred at RT for 16 h. The RM was quenched with ice
cold water, extracted with EtOAc, dried (Na.sub.2SO.sub.4) and
evaporated to get 5-bromo-2-((2-methoxyethoxy)methyl)pyridine (0.1
g, crude). TLC system: EtOAc/PE (1:9), R.sub.f: 0.5
Synthesis of
N-(diphenylmethylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine
[0199] To a stirred solution of
5-bromo-2-((2-methoxyethoxy)methyl)pyridine (0.15 g, 0.61 mmol, 1.0
eq) in toluene (5 mL) were added benzophenoneimine (0.12 mL, 0.73
mmol, 1.2 eq), Pd.sub.2dba.sub.3 (56 mg, 0.061 mmol, 0.1 eq)
Cs.sub.2CO.sub.3 (0.3 g, 0.92 mmol, 1.5 eq), under N.sub.2. The RM
was refluxed for 16 h, diluted with water (5 mL) and extracted with
EtOAc (10 mL), dried over Na.sub.2SO.sub.4 and evaporated to get
N-(diphenyl-methylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine
(200 mg, crude). The crude was used directly for next step without
further purification.
Synthesis of 6-((2-methoxyethoxy)methyl)pyridin-3-amine
[0200] To a solution of
N-(diphenylmethylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine
(200 mg) in MeOH was added conc HCl (2 mL) and the RM was stirred
at RT for 30 min. The RM was diluted with water (5 mL), neutralized
with TEA and extracted with EtOAc (10 mL) and evaporated under
reduced pressure. The crude obtained was washed with Et.sub.2O (10
mL) to get 6-((2-methoxyethoxy)methyl)pyridin-3-amine (100 mg),
which was used without further purification. TLC system: MeOH/DCM
(1:19), R.sub.f: 0.2
Synthesis of phenyl
(6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate (INT-14f)
[0201] To a stirred solution of
6-((2-methoxyethoxy)methyl)pyridin-3-amine (450 mg, 2.48 mmol, 1.0
eq) in acetone (5 mL) were added phenyl chloroformate (13, 0.313
mL, 2.48 mmol, 1.0 eq), and pyridine (0.6 mL, 7.5 mmol, 3.0 eq) at
0.degree. C. The RM was stirred at same temperature for 2 h. The RM
was concentrated under reduced pressure, the residue was diluted
with DCM (20 mL and washed with water (8 mL). The aqueous phase was
extracted with DCM, the combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
was purified by silica gel (100-200 mesh) column chromatography
using EtOAc/PE (4:1) as eluent to get to get phenyl
(6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate (INT-14f, 400
mg, 53%) as a colorless solid. TLC system MeOH/DCM (1:19), R.sub.f:
0.4
Synthesis of phenyl
(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate
(INT-14d)
Synthesis of 2-((5-nitropyridin-2-yl)oxy)ethanol
[0202] To a stirred solution of 60% NaH in mineral oil (302 mg,
12.6 mmol, 2.0 eq) in THF (10 mL) was added ethylene glycol (783
mg, 12.6 mmol, 2.0 eq.) at 0.degree. C. and stirred for 15 min.
2-chloro-5-nitropyridine (1.00 g, 6.31 mmol, 1.0 eq.) in DMF (3 mL)
was added, the RM was allowed to warm to RT and heated to
50.degree. C. for 3 h. The RM was cooled and quenched with ice cold
water (10 mL), extracted with EtOAc (2.times.15 mL), washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, evaporated and dried
under vacuum to get crude. The crude was purified by silica gel
column chromatography (100-200 mesh) using EtOAc/PE (1:4) as eluent
to get 2-((5-nitropyridin-2-yl)oxy)ethanol (900 mg, 77%) as a
colourless liquid. TLC system: EtOAc/PE (7:3), R.sub.f: 0.5
Synthesis of
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine
[0203] To a stirred solution of 2-((5-nitropyridin-2-yl)oxy)ethanol
(900 mg, 4.89 mmol, 1.0 eq.) in DCM (10 mL) was added imidazole
(665 mg, 9.78 mmol, 2 eq.), the RM was cooled to 0.degree. C. and
TBDMSCl (820 mg, 5.40 mmol, 1.1 eq.) was added. The RM was stirred
for 2 h at RT, diluted with water (20 mL), extracted with DCM
(2.times.25 mL), washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated to get
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine (1.26 g,
87%) which was used without further purification. TLC system:
EtOAc/PE (1:1), R.sub.f: 0.5.
Synthesis of
6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-amine
[0204] To a stirred solution of
2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine (1.25 g,
4.36 mmol, 1.0 eq.) in MeOH (20 mL) was added 10% Pd/C (200 mg) and
the mixture was hydrogenated using H.sub.2 balloon at RT for 2 h.
The RM was filtered through celite bed and concentrated under
reduced pressure to get crude. The crude was purified by
preparative HPLC to get
6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-pyridin-3-amine (820 mg,
72%) as a brown solid. TLC system: EtOAC/PE (9:1), R.sub.f: 0.2
Synthesis of phenyl
(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate
(INT-14d)
[0205] To a stirred solution of
6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-amine (150 mg,
0.600 mmol, 1.0 eq.) in acetone (5 mL) were added PhOCOCl (0.078
mL, 0.67 mmol, 1.1 eq.) and pyridine (0.14 mL, 1.8 mmol, 3 eq.) at
0.degree. C. The RM was stirred at same temperature for 1 h. The
solvent was evaporated and the residue was diluted with DCM (10
mL), washed with water (10 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude was washed with
Et.sub.2O (5 mL) to get phenyl
(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate
(INT-14d, 125 mg, 56%) as a white solid. TLC system: EtOAC/PE
(3:7), R.sub.f: 0.6.
Synthesis of phenyl
(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-yl)carbamate
(INT-14ac)
Synthesis of 1-(5-nitropyridin-2-yl)azetidin-3-ol
[0206] A mixture of 2-chloro-5-nitropyridine (1.00 g, 6.32 mmol),
azetidin-3-ol hydrochloride (1.04 g, 9.50 mmol) and TEA (1.3 mL,
9.5 mmol) in DMF (33 mL) was heated at 100.degree. C. for 20 h. The
RM was cooled to RT, diluted with water (30 mL), extracted with
EtOAc (2.times.30 mL), washed with water (30 mL) and brine (20 mL),
dried over Na.sub.2SO.sub.4 and evaporated the solvent to get
1-(5-nitropyridin-2-yl)azetidin-3-ol (0.52 g, 42%) which was used
without further purification. TLC system: EtOAc/PE (1:9), R.sub.f:
0.2
Synthesis of
2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine
[0207] To a stirred solution of
1-(5-nitropyridin-2-yl)azetidin-3-ol (0.52 g, 2.7 mmol) in DCM (10
mL) at 0.degree. C. was added imidazole (0.32 g, 5.3 mmol) followed
by TBDMSCl (0.80 g, 5.3 mmol) and stirred at RT for 16 h. The RM
was diluted with water (10 mL), extracted with DCM (2.times.20 mL),
washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and
evaporated to get crude compound. The crude was purified by silica
gel column chromatography (100-200 mesh) using 6% EtOAc/PE as
eluent to get
2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine
(0.60 g, 75%). TLC system: EtOAc/PE (3:7), R.sub.f: 0.6
Synthesis of
6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine
[0208] A solution of
2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine
(0.60 g, 1.94 mmol), 10% Pd/C (300 mg) in EtOH (20 mL) was
hydrogenated under hydrogen balloon at RT for 14 h. The RM was
filtered through a celite pad, washed with EtOH and the solvent was
evaporated under reduced pressure to get
6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine
(0.41 g, 76%). TLC system: EtOAc/PE (3:7), R.sub.f: 0.6
Synthesis of phenyl
(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-yl)carbamate
(INT-14ac)
[0209] To a stirred solution
6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine
(0.40 g, 1.4 mmol) in acetone (10 mL) at 0.degree. C. was added
pyridine (0.17 mL, 2.1 mmol) followed by phenyl chloroformate (0.22
mL, 1.7 mmol) and the RM was stirred for 2 h. The RM was evaporated
under reduced pressure and the crude residue was diluted with water
(10 mL), extracted with EtOAc (2.times.20 mL), washed with brine
(10 mL), dried over Na.sub.2SO.sub.4 and evaporated to get phenyl
(6-(3-((tert-butyldimethylsilyl)oxy)-azetidin-1-yl)pyridin-3-yl)carbamate
(INT-14ac, 0.30 g, 52%). TLC system: EtOAc/PE (3:7), R.sub.f:
0.7
[0210] Table 4 summarizes the phenyl carbamates INT-14 which were
obtained from commercially available amines INT-12 and phenyl
chloroformiate (13) as described for INT-14f.
TABLE-US-00005 TABLE 4 phenyl carbamates from commercially
available amines phenyl benzo[d][1,3]dioxol-5-ylcarbamate INT-14g
phenyl (2,3-dihydro-1H-inden-4-yl)carbamate INT-14h phenyl
isoquinolin-6-ylcarbamate INT-14i phenyl quinolin-5-ylcarbamate
INT-14j phenyl (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate
INT-14k phenyl (2,3-dihydro-1H-inden-5-yl)carbamate INT-14l phenyl
isoquinolin-5-ylcarbamate INT-14m phenyl
(3-methoxypyridin-4-yl)carbamate INT-14p phenyl
pyrimidin-5-ylcarbamate INT-14q phenyl
(5-methylpyridin-2-yl)carbamate INT-14r phenyl
pyridin-4-ylcarbamate INT-14s phenyl pyridin-2-ylcarbamate INT-14t
phenyl pyridin-3-ylcarbamate INT-14u phenyl
(3-methylpyridin-4-yl)carbamate INT-14v phenyl
(2-methylpyridin-4-yl)carbamate INT-14w phenyl
(6-fluoropyridin-3-yl)carbamate INT-14x phenyl
(6-methylpyridin-3-yl)carbamate INT-14y phenyl
(2-methylpyrimidin-5-yl)carbamate INT-14z phenyl
(2-methoxypyrimidin-5-yl)carbamate INT-14aa
[0211] Phenyl (6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)carbamate
(INT-14ab) was synthesized from
6-(2-(methylsulfonyl)ethyl)pyridin-3-amine (synthesis: see
WO20130131815, pp. 129) and phenyl chloroformiate (13) as described
for INT-14f.
Synthesis of Azole Ureas
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydroxymet-
hyl)pyridin-3-yl)urea (EX-25)
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-but-
yldimethylsilyl)oxy)methyl)pyridin-3-yl) urea
[0212] To a stirred solution of
(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine
hydrochloride (INT-10a-i, 200 mg, 0.600 mmol, 1.0 eq) in DCM (5 mL)
were added TEA (192 mg, 1.800 mmol, 3 eq) and phenyl
(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)carbamate
(INT-14a, 245 mg, 0.600 mmol, 1.0 eq) at 0.degree. C. and the
mixture was stirred at RT for 16 h. The RM was diluted with DCM,
washed with water and extracted with DCM. Organic layer was dried
over Na.sub.2SO.sub.4, concentrated under reduced pressure to get
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-but-
yldimethylsilyl)oxy)methyl)pyridin-3-yl)urea (300 mg, 85%) as a
brown liquid. TLC system: EtOAc/PE (1:1), R.sub.f: 0.4
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydroxymet-
hyl)pyridin-3-yl)urea (EX-25)
[0213] To a stirred solution of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-but-
yldimethylsilyl)oxy)methyl)pyridin-3-yl)urea (300 mg, 0.568 mmol,
1.0 eq) in THF (20 mL) was added 2N HCl (10 mL) at 0.degree. C. and
the RM was stirred at RT for 4 h. Then the RM was concentrated,
diluted with EtOAc (20 mL) and washed with water (20 mL), dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
crude was purified by silica gel column chromatography (100-200
mesh) using MeOH/DCM (1:9) as eluent to get
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydrox-
ymethyl)pyridin-3-yl)urea (EX-25, 110 mg, 46%) as pale yellow
solid. TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 415.0
[0214] According to the procedure described for EX-25, the
following ureas were prepared:
[0215]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(hyd-
roxymethyl)pyridin-3-yl)urea (EX-26) from INT-10a-ii and INT-14a.
TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z, MH.sup.+):
431.0
[0216]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6--
(hydroxymethyl)pyridin-3-yl)urea (EX-27) from INT-10b-i and
INT-14a. TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 427.3
[0217]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-(hydroxymethyl)pyridin-3-yl)urea (EX-28) from INT-10b-ii and
INT-14a. TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 443.3
[0218]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6--
(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea (EX-32) from INT-10b-i
and INT-14ac. TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 451.2
[0219]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea (EX-33) from INT-10b-ii
and INT-14ac. TLC system: MeOH/DCM (1:9), R.sub.f: 0.1; ESI (m/z,
MH.sup.+): 484.2
[0220]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-(2-hydroxyethyl)pyridin-3-yl)urea (EX-34) from INT-10b-ii and
INT-14b. TLC system: EtOAc, R.sub.f: 0.2; ESI (m/z, MH.sup.+):
457.3
[0221]
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-hy-
droxyethyl)pyridin-3-yl)urea (EX-35) from INT-10a-i and INT-14b.
TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z, MH.sup.+):
429.0
[0222]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-h-
ydroxyethyl)pyridin-3-yl)urea (EX-36) from INT-10a-ii and INT-14b.
TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z, MH.sup.+):
445.0
[0223]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6--
(2-hydroxyethyl)pyridin-3-yl)urea (EX-37) from INT-10b-i and
INT-14b. TLC system: EtOAc, R.sub.f: 0.2; ESI (m/z, MH.sup.+):
441.3
[0224]
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-hy-
droxyethoxy)pyridin-3-yl)urea (EX-40) from INT-10a-i and INT-14d.
TLC system: EtOAc/PE (1:1), R.sub.f: 0.4; ESI (m/z, MH.sup.+):
445.0
[0225]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-h-
ydroxyethoxy)pyridin-3-yl)urea (EX-41) from INT-10a-ii and INT-14d.
TLC system: EtOAc/PE (1:1), R.sub.f: 0.4; ESI (m/z, MH.sup.+):
460.8
[0226]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6--
(2-hydroxyethoxy)pyridin-3-yl)urea (EX-42) from INT-10b-i and
INT-14d. TLC system: EtOAc/PE (1:1), R.sub.f: 0.a; ESI (m/z,
MH.sup.+): 457.3
[0227]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-(2-hydroxyethoxy)pyridin-3-yl)urea (EX-43) from INT-10b-ii and
INT-14d. TLC system: MeOH/DCM (1:9), R.sub.f: 0.2; ESI (m/z,
MH.sup.+): 473.1
Synthesis of
N-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-4-yl)methyl)-N'-(4-((sulfamoyl-
-amino)methyl)phenyl)urea (EX-44)
Synthesis of tert-butyl
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benz-
yl)sulfamoylcarbamate
[0228] To a stirred solution of
(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine
hydrochloride (INT-10a-i, 160 mg, 0.530 mmol, 1.0 eq) in DCM (20
mL) was added TEA (0.38 mL, 2.7 mmol, 5.0 eq) and stirred at RT for
10 min. Then tert-butyl
N-(4-(phenyloxycarbonylamino)-benzyl)sulfamoylcarbamate (INT-14e,
224 mg, 0.53 mmol, 1.0 eq) was added and the mixture was stirred at
RT for 16 h. The RM was diluted with DCM (10 mL) and washed with
water, dried and evaporated to get crude tert-butyl
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benz-
yl)-sulfamoylcarbamate (300 mg) as thick brown liquid which was
used without further purification. TLC system: EtOAc/PE (1:1),
R.sub.f: 0.4.
Synthesis of
N-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-5-yl)methyl)-N'-(4-((sulfamoyl-
amino)methyl)phenyl)urea (EX-44)
[0229] To a stirred solution of
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benz-
yl)sulfamoylcarbamate (0.30 g, 0.50 mmol, 1.0 eq) in DCM (10 mL)
was added TFA (2 mL) at 0.degree. C., stirred for 30 min and then
at RT for another 2 h. The RM was slowly quenched with saturated
NaHCO.sub.3 solution (pH 8) and extracted with DCM (20 mL), dried
(Na.sub.2SO.sub.4) and evaporated under reduced pressure. This
crude was purified by preparative TLC to get
N-((5-(3-chlorophenyl)-2-(tert-butyl)oxazol-5-yl)methyl)-N'-(4-((sulfamoy-
lamino)methyl)phenyl)urea (EX-44, 75 mg, 28% over 2 steps) as
off-white solid. TLC system: EtOAc, R.sub.f: 0.25; ESI (m/z
MH.sup.+): 491.8
[0230] According to the procedure described for EX-44,
N-((5-(3-chlorophenyl)-2-(tertbutyl)thiazol-5-yl)methyl)-N'-(4-((sulfamoy-
lamino)methyl)phenyl)urea (EX-45) from INT-10aii and INT-14e. TLC
system: EtOAc/PE (1:1), R.sub.f: 0.15; ESI (m/z, MH.sup.+):
507.8
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxy-
ethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-46)
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxy-
ethoxy)methyl)pyridin-3-yl)urea
[0231] To a stirred solution of
(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine
hydrochloride (INT-10a-i, 150 mg, 0.500 mmol, 1.0 eq) in DCM (5 mL)
were added TEA (151 mg, 1.50 mmol, 3 eq) and phenyl
(6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate (INT-14f, 151
mg, 0.500 mmol, 1.0 eq) at 0.degree. C. and stirred at RT for 12 h.
Then the RM was diluted with DCM (10 mL), washed with water (20 mL)
and dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to get
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxy-
ethoxy)methyl)pyridin-3-yl)urea (200 mg, 85%) as a yellow liquid
which was used without further purification. TLC system: EtOAc/PE
(7:3), R.sub.f: 0.5
Synthesis of
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxy-
ethoxy)methyl)pyridin-3-yl) urea dihydrochloride (EX-46)
[0232] To a stirred solution of get
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxy-
ethoxy)methyl)pyridin-3-yl)urea (200 mg, 0.423 mmol, 1.0 eq) in DCM
(20 mL) was added 1 M BBr.sub.3 solution in DCM (0.85 mL, 0.87
mmol, 2.0 eq), at -78.degree. C. and stirred at RT for 2 h. The RM
was quenched with saturated NaHCO.sub.3 solution (10 mL), diluted
with DCM (10 mL), washed with water (20 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
was purified by preparative HPLC, dissolved in Et.sub.2O (5 mL) and
precipitated with HCl in Et.sub.2O to get
1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxy-
ethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-46, 60 mg, 30%)
as off white solid. TLC system: EtOAC/PE (9:1), R.sub.f: 0.4; ESI
(m/z MH.sup.+): 459.2
[0233] According to the procedure described for EX-46, the
following ureas were prepared:
[0234]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-((2--
hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-47) from
INT-10a-ii and INT-14f. TLC system: EtOAc/PE (9:1), R.sub.f: 0.4;
ESI (m/z, MH.sup.+): 475.4
[0235]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6--
((2-hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-48)
from INT-10b-i and INT-14f. TLC system: EtOAc/PE (9:1), R.sub.f:
0.4; ESI (m/z, MH.sup.+): 471.1
[0236]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-((2-hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-49)
from INT-10b-ii and INT-14f. TLC system: EtOAc/PE (9:1), R.sub.f:
0.2; ESI (m/z, MH.sup.+): 487.2
Synthesis of
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-(me-
thylsulfonyl)ethyl)pyridin-3-yl)urea (EX-30)
[0237] To a stirred solution of
(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanamine
hydrochloride (INT-10b-i, 0.15 g, 0.48 mmol) in DCM (10 mL) at
0.degree. C. was added TEA (0.21 mL, 1.44 mmol) followed by phenyl
(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)carbamate (INT-14ab, 0.15
g, 0.48 mmol) and stirred at rt for 16 h. The RM was diluted with
water (10 mL), extracted with DCM (2.times.20 mL), washed with
brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated
the solvent to get the crude compound. The crude was purified by
silica gel column chromatography (60-120 mesh) using 5% MeOH in DCM
as eluent to get
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-(me-
thylsulfonyl)ethyl)pyridin-3-yl)urea (EX-30, 0.16 g, 66%). TLC
system: EtOAc, R.sub.f: 0.2, ESI (m/z MH.sup.+): 503.3
[0238] According to the procedure described for EX-30, the
following ureas were prepared:
[0239]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-meth-
oxypyrimidin-5-yl)urea (EX-29) from INT-10a-ii and INT-14a. ESI
(m/z, MH.sup.+): 432.2
[0240]
1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-
-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea (EX-31) from INT-10b-ii
and INT-14ab. TLC system: EtOAc/hexane (7:3), R.sub.f: 0.2; ESI
(m/z, MH.sup.+): 518.9
[0241]
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureid-
o)benzyl)methanesulfonamide (EX-38) from INT-10a-i and INT-14c. TLC
system: MeOH/DCM (1:9), R.sub.f: 0.4; ESI (m/z, MH.sup.+):
491.0
[0242]
N-(4-(3-((2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5-yl)methyl)urei-
do)benzyl)methanesulfonamide (EX-39) from INT-10a-iv and INT-14c.
TLC system: EtOAc/PE (7:3), R.sub.f: 0.4; ESI (m/z, MH.sup.+):
507.0
[0243]
1-(benzo[d][1,3]dioxol-5-yl)-3-((2-(tert-butyl)-4-(3-chlorophenyl)t-
hiazol-5-yl)methyl)urea (EX-50) from INT-10a-ii and INT-14g.
[0244]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-di-
hydro-1H-inden-4-yl)urea (EX-51) from INT-10a-ii and INT-14h.
[0245]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoqui-
nolin-6-yl)urea (EX-52) from INT-10a-ii and INT-14i.
[0246]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(quinol-
in-5-yl)urea (EX-53) from INT-10a-ii and INT-14j.
[0247]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-di-
hydrobenzo[b][1,4]dioxin-6-yl)urea (EX-54) from INT-10a-ii and
INT-14k.
[0248]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-di-
hydro-1H-inden-5-yl)urea (EX-55) from INT-10a-ii and INT-14l. ESI
(m/z, MH.sup.+): 440.2
[0249]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoqui-
nolin-5-yl)urea (EX-56) from INT-10a-ii and INT-14m. ESI (m/z,
MH.sup.+): 451.2
[0250]
N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)urei-
do)-2-fluorobenzyl)methanesulfonamide (EX-57) from INT-10a-ii and
INT-14n.
[0251]
N-(4-(3-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)ureido)-2-f-
luorobenzyl)methanesulfonamide (EX-58) from INT-10a-iii and
INT-14n.
[0252]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-fluo-
ro-4-(hydroxymethyl)phenyl)urea (EX-59) from INT-10a-ii and
INT-14o. ESI (m/z, MH.sup.+): 448.1
[0253]
1-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-(h-
ydroxymethyl)phenyl)urea (EX-60) from INT-10a-iii and INT-14o.
[0254]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-meth-
oxypyridin-4-yl)urea (EX-61) from INT-10a-ii and INT-14p. ESI (m/z,
MH.sup.+): 431.2
[0255]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyrimi-
din-5-yl)urea (EX-62) from INT-10a-ii and INT-14q. ESI (m/z,
MH.sup.+): 402.1
[0256]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(5-meth-
ylpyridin-2-yl)urea (EX-63) from INT-10a-ii and INT-14r. ESI (m/z,
MH.sup.+): 415.2
[0257]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridi-
n-4-yl)urea (EX-64) from INT-10a-ii and INT-14s. ESI (m/z,
MH.sup.+): 401.1
[0258]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridi-
n-2-yl)urea (EX-65) from INT-10a-ii and INT-14t. ESI (m/z,
MH.sup.+): 401.1
[0259]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridi-
n-3-yl)urea (EX-66) from INT-10a-ii and INT-14u. ESI (m/z,
MH.sup.+): 401.1
[0260]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-meth-
ylpyridin-4-yl)urea (EX-67) from INT-10a-ii and INT-14v. ESI (m/z,
MH.sup.+): 415.1
[0261]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-meth-
ylpyridin-4-yl)urea (EX-68) from INT-10a-ii and INT-14w. ESI (m/z,
MH.sup.+): 415.1
[0262]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-fluo-
ropyridin-3-yl)urea (EX-69) from INT-10a-ii and INT-14x. ESI (m/z,
MH.sup.+): 419.1
[0263]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-meth-
ylpyridin-3-yl)urea (EX-70) from INT-10a-ii and INT-14y. ESI (m/z,
MH.sup.+): 415.1
[0264]
1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-meth-
ylpyrimidin-5-yl)urea (EX-71) from INT-10a-ii and INT-14z. ESI
(m/z, MH.sup.+): 416.2
Pharmacological Methods
FLIPR Assay:
[0265] The FLIPR protocol consists of 2 substance additions during
a kinetic measurement. First the compounds to be tested (5 .mu.M)
are pipetted onto the cells and the Ca.sup.2+ influx is determined
in comparison to the control (capsaicin 10 .mu.M), providing the
result as % activation and representing the compound-alone effect
(calculation at peak signal related to baseline). A Ca.sup.2+
influx of 10%-60% reveals a partial agonist (pAG), a Ca.sup.2+
influx of >60% relates to a pure agonist (AG). After 5 min
incubation, the Ca.sup.2+ influx is related to an injection of 100
nM of capsaicin and thereby the antagonistic effect of the test
compounds detected.
[0266] Desensitising agonists and antagonists lead to suppression
of the Ca.sup.2+ influx. The % inhibition is calculated compared to
the maximum achievable inhibition with 10 .mu.M of capsaicin.
Triple analyses (n=3) are carried out and repeated in at least 3
independent experiments.
[0267] Starting from the percentage displacement caused by
different concentrations of the compounds to be tested of general
formula I, IC.sub.50 inhibitory concentrations which cause a 50-%
displacement of capsaicin were calculated. K.sub.i values for the
test substances were obtained by conversion by means of the
Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22,
3099-3108, 1973).
Method:
[0268] Chinese hamster ovary cells (CHO K1 cells, European
Collection of Cell Cultures (ECACC) United Kingdom) are stably
transfected with the VR1 gene. For functional testing, these cells
are plated out on poly-D-lysine-coated black 96-well plates having
a clear base (BD Biosciences, Heidelberg, Germany) at a density of
25,000 cells/well. The cells are incubated overnight at 37.degree.
C. and 5% CO.sub.2 in a culture medium (Ham's F12 nutrient mixture,
10% by volume of FCS (foetal calf serum), 18 .mu.g/ml of
L-proline). The next day the cells are incubated with Fluo-4
(Fluo-4 2 .mu.M, 0.01% by volume of Pluronic F127, Molecular Probes
in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH,
Karlsruhe, Germany) for 30 min at 37.degree. C. Subsequently, the
plates are washed three times with HBSS buffer and after further
incubation for 15 min at RT used for Ca.sup.2+ measurement in a
FLIPR assay. The Ca.sup.2+-dependent fluorescence is measured
before and after the addition of the substances to be tested
(.lamda.ex wavelength=488 nm, .lamda.em=540 nm). Quantification is
carried out by measuring the highest fluorescence intensity (FC,
fluorescence counts) over time.
Pharmacological Data
[0269] The affinity of the compounds according to the invention for
the vanilloid receptor 1 was determined as described hereinbefore
(pharmacological method I or II). The compounds according to the
invention display affinity to the VR1/TRPV1 receptor (Table 5).
[0270] In Table 5 the abbreviations below have the following
meanings: Cap=capsaicin; AG=agonist; pAG=partial agonist; ne=no
effect (<10% @ 5 .mu.M); nd=not determined; The value after the
"@" symbol indicates the concentration at which the inhibition (as
a percentage) was respectively determined.
TABLE-US-00006 TABLE 5 (f) Ki Exemplary (human) [nM] Compound Cap
EX-01 1.4 EX-02 28.4 EX-03 0.6 EX-04 pAG (1.0) EX-05 7.5 EX-06 0.7
EX-07 AG EX-08 AG EX-09 pAG (73.8) EX-10 pAG (8.8) EX-11 53.1 EX-12
1.1 EX-13 5.2 EX-14 0.7 EX-15 0.4 EX-16 41.9 EX-17 0.7 EX-18 96.7
EX-19 13.8 EX-20 0.3 EX-21 ne EX-22 ne EX-23 4.7 EX-24 2.35 EX-25
pAG (73.1) EX-26 pAG (10.2) EX-27 62.5 EX-28 19.4 EX-29 nd EX-30
41%@5 .mu.M EX-31 48.8 EX-32 60.82225 EX-33 24.6 EX-34 pAG (30.2)
EX-35 78.4 EX-36 AG EX-37 46%@5 .mu.M EX-38 52.6 EX-39 17.6 EX-40
43.6 EX-41 27.5 EX-42 103.4 EX-43 29.8 EX-44 29.9 EX-45 9.1 EX-46
55%@5 .mu.M EX-47 33.3 EX-48 31%@5 .mu.M EX-49 35 EX-50 pAG (5.6)
EX-51 pAG (2.9) EX-52 AG EX-53 AG EX-54 5.9 EX-55 12.3 EX-56 0.1
EX-57 6.6 EX-58 2.3 EX-59 pAG (1.1) EX-60 pAG (3.2) EX-61 nd EX-62
nd EX-63 nd EX-64 nd EX-65 nd EX-66 nd EX-67 nd EX-68 nd EX-69 nd
EX-70 nd EX-71 nd
[0271] Having now fully described the present invention in some
detail by way of illustration and examples for purposes of clarity
of understanding, it will be obvious to one of ordinary skill in
the art that the same can be performed by modifying or changing the
invention within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any specific embodiment thereof, and that such
modifications or changes are intended to be encompassed within the
scope of the appended claims.
[0272] When a group of materials, compositions, components or
compounds is disclosed herein, it is understood that all individual
members of those groups and all subgroups thereof are disclosed
separately. Every formulation or combination of components
described or exemplified herein can be used to practice the
invention, unless otherwise stated. Whenever a range is given in
the specification, for example, a temperature range, a time range,
or a composition range, all intermediate ranges and subranges, as
well as all individual values included in the ranges given are
intended to be included in the disclosure. Additionally, the end
points in a given range are to be included within the range. In the
disclosure and the claims, "and/or" means additionally or
alternatively. Moreover, any use of a term in the singular also
encompasses plural forms.
[0273] As used herein, "comprising" is synonymous with "including,"
"containing," or "characterized by," and is inclusive or open-ended
and does not exclude additional, unrecited elements or method
steps. As used herein, "consisting of" excludes any element, step,
or ingredient not specified in the claim element. As used herein,
"consisting essentially of" does not exclude materials or steps
that do not materially affect the basic and novel characteristics
of the claim. Any recitation herein of the term "comprising",
particularly in a description of components of a composition or in
a description of elements of a device, is understood to encompass
those compositions and methods consisting essentially of and
consisting of the recited components or elements.
[0274] One of ordinary skill in the art will appreciate that
starting materials, device elements, analytical methods, mixtures
and combinations of components other than those specifically
exemplified can be employed in the practice of the invention
without resort to undue experimentation. All art-known functional
equivalents, of any such materials and methods are intended to be
included in this invention. The terms and expressions which have
been employed are used as terms of description and not of
limitation, and there is no intention that in the use of such terms
and expressions of excluding any equivalents of the features shown
and described or portions thereof, but it is recognized that
various modifications are possible within the scope of the
invention claimed. The invention illustratively described herein
suitably may be practiced in the absence of any element or
elements, limitation or limitations which is not specifically
disclosed herein. Headings are used herein for convenience
only.
[0275] All publications referred to herein are incorporated herein
to the extent not inconsistent herewith. Some references provided
herein are incorporated by reference to provide details of
additional uses of the invention. All patents and publications
mentioned in the specification are indicative of the levels of
skill of those skilled in the art to which the invention pertains.
References cited herein are incorporated by reference herein in
their entirety to indicate the state of the art as of their filing
date and it is intended that this information can be employed
herein, if needed, to exclude specific embodiments that are in the
prior art.
* * * * *