U.S. patent application number 09/797083 was filed with the patent office on 2002-06-06 for pde iv inhibiting amides, compositions and methods of treatment.
Invention is credited to Labelle, Marc, Lachance, Nicolas, Macdonald, Dwight, Sturino, Claudio.
Application Number | 20020068756 09/797083 |
Document ID | / |
Family ID | 22685460 |
Filed Date | 2002-06-06 |
United States Patent
Application |
20020068756 |
Kind Code |
A1 |
Labelle, Marc ; et
al. |
June 6, 2002 |
PDE IV inhibiting amides, compositions and methods of treatment
Abstract
Compounds represented by formula I: 1 as well as
pharmaceutically acceptable salts and hydrates thereof are
disclosed as useful for treating or preventing diseases and
conditions mediated by PDE-IV. Pharmaceutical compositions and
methods of treatment are also included.
Inventors: |
Labelle, Marc; (St. Lazare,
CA) ; Sturino, Claudio; (Dorval, CA) ;
Lachance, Nicolas; (Pierrefonds, CA) ; Macdonald,
Dwight; (L'ile Bizard, CA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
22685460 |
Appl. No.: |
09/797083 |
Filed: |
March 1, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60186571 |
Mar 2, 2000 |
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Current U.S.
Class: |
514/339 ;
514/419; 546/277.4; 548/483 |
Current CPC
Class: |
C07D 401/14 20130101;
A61P 21/00 20180101; A61P 25/28 20180101; A61P 27/14 20180101; C07D
401/12 20130101; A61P 35/00 20180101; A61P 25/08 20180101; A61P
25/24 20180101; A61P 19/10 20180101; C07D 403/12 20130101; A61P
9/10 20180101; A61P 17/06 20180101; C07D 209/42 20130101; A61P
37/08 20180101; A61P 11/00 20180101; A61P 43/00 20180101; A61P
11/06 20180101; A61P 19/02 20180101; A61P 29/00 20180101; A61P
15/00 20180101 |
Class at
Publication: |
514/339 ;
514/419; 546/277.4; 548/483 |
International
Class: |
C07D 29/40; C07D
213/00 |
Claims
What is claimed is:
1. A compound represented by formula I: 11or a pharmaceutically
acceptable salt or hydrate thereof wherein: one of Z.sup.1,
Z.sup.2, Z.sup.3 and Z.sup.4 represents N or CR.sup.2 and the
others represent CR.sup.2; a represents 0 or 1; b represents 0, 1
or 2; d represents 0, 1 or 2; R.sup.1 represents H, C.sub.1-4alkyl
or hydroxyC.sub.1-4alkyl; each R.sup.2 is independently selected
from the group consisting of: H, halo, C.sub.1- 8alkyl,
haloC.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CN, Het, OR.sup.a,
OC(O)N(R.sup.b).sub.2, NR.sup.bC(O)R.sup.a,
C(R.sup.a).sub.2CO.sub.2R.sup.a, C.sub.1-8alkylN(R.sup.b).sub.2,
haloC.sub.1-8alkylN(R.sup.b).sub.2, CO.sub.2R.sup.a,
C(O)N(R.sup.b).sub.2, SO.sub.2N(R.sup.b).sub.2, S(O).sub.bR.sup.d
and NR.sup.bSO.sub.2R.sup.d; each R.sup.a is independently selected
from H, C.sub.1-4alkyl, C.sub.1-4alkylNHC.sub.1-4alkyl, and
C.sub.1-4alkylN(C.sub.1-4alkyl).sub.2, the alkyl portions of which
are optionally substituted with 1-3 halo groups; each R.sup.b is
selected from H and C1-7 alkyl, and when two R.sup.b's are present,
they can be taken together and represent a fused ring system having
5-10 members, said ring system being saturated or containing 1-4
double bonds, and optionally including 1-3 heteroatoms selected
from O, S and NR.sup.e; R.sup.d and R.sup.e are independently
selected from Het, C.sub.1-7alkyl, C.sub.2-7alkenyl,
C.sub.2-7alkynyl, and C.sub.1-7alkyl-Het; Het represents a 5-10
membered aromatic, partially aromatic or non- aromatic ring system
containing 1-4 heteroatoms selected from O, S and N, optionally
substituted on any available position with oxo, C.sub.1-4 alkyl,
halo, amino, hydroxyC.sub.1-4 alkyl, haloC.sub.1-4 alkyl and
aminoC.sub.1-4 alkyl; X represents C.sub.3-7cycloalkyl or Ar; and
each Ar is independently selected from the group consisting of:
phenyl, thienyl, thiazolyl, pyridyl, oxazolyl, tetrazolyl,
pyrimidinyl, pyrazinyl and pyridazinyl, said Ar being optionally
substituted with 1-4 members selected from: halo, hydroxy, CN,
C.sub.1-4alkyl, C.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl,
OC.sub.1-6alkyl, OC.sub.1-6haloalkyl, OC.sub.1-6hydroxyalkyl,
C.sub.1-6alkylOC.sub.1-6alkyl, C.sub.1-6alkylOC.sub.1-6haloalkyl,
C(O)NH.sub.2, C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6 alkylOC.sub.1-6alkylC(O)NH.sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl,
NHC(O)OC.sub.1-6alkyl, and SO.sub.2C.sub.1-6alkyl.
2. A compound in accordance with claim 1 wherein Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 represent CR.sup.2.
3. A compound in accordance with claim 1 wherein b represents 0 or
1.
4. A compound in accordance with claim 1 wherein d represents
1.
5. A compound in accordance with claim 1 wherein R.sup.1 represents
H or CH.sub.3.
6. A compound in accordance with claim 1 wherein each R.sup.2 is
independently selected from the group consisting of H,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2 and C(O)N(R.sup.b).sub.2; and
R.sup.b is selected from H and C.sub.1-3 alkyl.
7. A compound in accordance with claim 1 wherein X represents Ar
and Ar is independently selected from the group consisting of:
phenyl, pyridyl and tetrazolyl, said Ar being optionally
substituted with 1-4 members selected from: halo, CN,
C.sub.1-4alkyl, C.sub.1-6haloalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, C(O)NH.sub.2,
C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl, NHC(O)OC.sub.1-6alkyl
and SO.sub.2C.sub.1-6alkyl.
8. A compound in accordance with claim 1 wherein: Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 represent CR.sup.2; each R.sup.2 is
independently selected from the group consisting of H,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2 and C(O)N(R.sup.b).sub.2 wherein
R.sup.b is selected from H and C.sub.1-3 alkyl; b represents 0 or
1; d represents 1; R.sup.1 represents H or CH.sub.3; X represents
Ar and Ar is independently selected from the group consisting of:
phenyl, pyridyl and tetrazolyl, said Ar being optionally
substituted with 1-4 members selected from: halo, CN,
C.sub.1-4alkyl, C.sub.1-6haloalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, C(O)NH.sub.2,
C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl, NHC(O)OC.sub.1-6alkyl
and SO.sub.2C.sub.1-6alkyl.
9. A compound represented by Formula Ia: 12wherein all variables
are as defined in claim 1.
10. A compound in accordance with claim 9 wherein Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 represent CR.sup.2.
11. A compound in accordance with claim 9 wherein each R.sup.2 is
independently selected from the group consisting of H,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2 and C(O)N(R.sup.b).sub.2 wherein
R.sup.a is independently selected and C.sub.1-4alkyl, and R.sup.b
is selected from H and C.sub.1-3 alkyl.
12. A compound in accordance with claim 9 wherein each Ar is
selected from phenyl, pyridyl and tetrazolyl, optionally
substituted with 1-4 members selected from: halo, CN,
C.sub.1-4alkyl, C.sub.1-6haloalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, C(O)NH.sub.2,
C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl, NHC(O)OC.sub.1-6alkyl
and SO.sub.2C.sub.1-6alkyl.
13. A compound in accordance with claim 1 in accordance with the
following table:
3 I 13 Cpd Z's (CH.sub.2).sub.b--(O).sub.a--(CH.sub.2).sub.b-X
N(R.sup.1)(CH.sub.2).sub.- a--Ar (CH.sub.2).sub.d--Ar 1 CH
OCH.sub.2-Phe-4-F N(Me)-3-Pyr Bnzl 2 CH OCH.sub.2-Phe-4-F
N(Me)-3-Pyr Bnzl 3 CH OCH.sub.2-Phe-4-F N(Me)-Phe-3,4-di- Bnzl OMe
4 CH OCH.sub.2-Phe-4-F N(Me)-Phe-3,4-di- Bnzl F 5 CH
OCH.sub.2-Phe-4-F N(Me)-5-Pyr-2- Bnzl OMe 6 CH OCH.sub.2-Phe-4-F
N(Me)-5-tetrazolyl Bnzl 7 CH OCH.sub.2-Phe-4-F N(Me)-4-Pyr-2- Bnzl
OMe 8 CH OCH.sub.2-Phe-4-F N(Me)-5-Pyr-2-CN Bnzl 9 CH
OCH.sub.2-Phe-4-F N(Me)-4-Pyr-2- Bnzl OMe 10 CH O-Bnzl
NH-Phe-3,4-di- Bnzl-4-F OMe 11 CH O-Bnzl NH-3-Pyr Bnzl-4-F 12 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-3-Pyr Bnzl-3- OCF.sub.2H 13 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-4-Pyr Bnzl-3- OCF.sub.2H 14 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-Phe-3,4-di- Bnzl-3- OMe OCF.sub.2H 15
CH OCH.sub.2-Phe-3-OCF.sub.2H NH-Phe-3,4-di-F Bnzl-3- OCF.sub.2H 16
CH O-Bnzl NH-3-Pyr Bnzl-4- OCF.sub.2H 17 CH OCH.sub.2-Phe-3-OMe
NH-3-Pyr Bnzl-4- OCF.sub.2H 18 CH OCH.sub.2-Phe-3-OMe
NH-5-tetrazolyl Bnzl-4- OCF.sub.2H 19 CH OCH.sub.2-Phe-3-OMe
NH-4-Pyr-2-OMe Bnzl-4- OCF.sub.2H 20 CH OCH.sub.2-Phe-3-OMe
NH-4-Pyr Bnzl-4- OCF.sub.2H 21 CH OCH.sub.2-Phe-3-OMe NH-4-Pyr-2-
Bnzl-4- NHC(O)Me OCF.sub.2H 22 CH OCH.sub.2-Phe-3-OMe NH-3-Pyr
Bnzl-4-F 23 CH OCH.sub.2-Phe-3-OMe NH-5-tetrazolyl Bnzl-4-F 24 CH
OCH.sub.2-Phe-3-OMe NH-4-Pyr-2-OMe Bnzl-4-F 25 CH
OCH.sub.2-Phe-3-OMe NH-4-Pyr Bnzl-4-F 26 CH OCH.sub.2-Phe-3-OMe
NH-4-Pyr-2- Bnzl-4-F NHC(O)Me 27 CH OCH.sub.2-Phe-3-OMe
NH-5-pyrimidinyl Bnzl-4-F 28 CH O-Bnzl NH-3-Pyr Bnzl-3 ,4-di- F 29
CH O-Bnzl NH-4-Pyr Bnzl-3,4-di- F 30 CH O-Bnzl NH-Phe-3,4-di-
Bnzl-3,4-di- OMe F 31 CH O-Bnzl NH-Phe-3,4-di-F Bnzl-3,4-di- F 32
CH O-Bnzl NH-5-Pyr-2-OMe Bnzl-3,4-di- F 33 CH O-Bnzl
NH-5-tetrazolyl Bnzl-3,4-di- F 34 CH O-Bnzl NH-4-Pyr-2-OMe
Bnzl-3,4-di- F 35 CH O-Bnzl NH-5-Pyr-2-CN Bnzl-3,4-di- F 36 CH
O-Bnzl NH-5-Pyr-2- Bnzl-3,4-di- NHC(O)Me F 37 CH OCH.sub.2-4-Pyr
NH-3-Pyr Bnzl-4-CF.sub.3 38 CH OCH.sub.2-4-Pyr NH-4-Pyr
Bnzl-4-CF.sub.3 39 CH OCH.sub.2-4-Pyr NR-Phe-3,4-di-
Bnzl-4-CF.sub.3 OMe 40 CH OCH.sub.2-4-Pyr NH-Phe-3,4-di-F
Bnzl-4-CF.sub.3 41 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe
Bnzl-4-CF.sub.3 42 CH OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF.sub.3 43 CH OCH.sub.2-4-Pyr NH-4-Pyr-2-OMe
Bnzl-4-CF.sub.3 44 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN Bnzl-4-CF.sub.3
45 CH OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl-4-CF.sub.3 NHC(O)Me 46 CH
OCH.sub.2-4-Pyr NH-3-Pyr Bnzl 47 CH OCH.sub.2-4-Pyr NH-4-Pyr Bnzl
48 CH OCH.sub.2-4-Pyr NH-Phe-3,4-di- Bnzl OMe 49 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-di-F Bnzl 50 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl 51
CH OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl 52 CH OCH.sub.2-4-Pyr
NH-4-Pyr-2-OMe Bnzl 53 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN Bnzl 54 CH
OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl NHC(O)Me 55 CH OCH.sub.2-4-Pyr
NH-4-Pyr-2- Bnzl NHC(O)OEt 56 CH O-Bnzl NH-3-Pyr Bnzl 57 CH O-Bnzl
NH-4-Pr Bnzl 58 CH O-Bnzl NH-Phe-3,4-di- Bnzl OMe 59 Z.sup.l = N,
all O-Bnzl NH-Phe-3,4-di-F Bnzl others = CH 60 Z.sup.1 = N, all
O-Bnzl NH-5-Pyr-2-OMe Bnzl others = CH 61 CH O-Bnzl NH-5-tetrazolyl
Bnzl 62 CH O-Bnzl NH-4-Pyr-2-OMe Bnzl 63 CH O-Bnzl NH-5-Pyr-2-CN
Bnzl 64 CH O-Bnzl NH-5-Pyr-2- Bnzl NHC(O)Me 65 CH O-Bnzl
NH-4-Pyr-2- Bnzl NHC(O)OEt 66 CH OCH.sub.2-4-Pyr NH-3-Pyr Bnzl-4-
OCF.sub.2H 67 CH OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4- OCF.sub.2H 68 CH
OCH.sub.2-4-Pyr NH-Phe-3,4-di- Bnzl-4- OMe OCF.sub.2H 69 CH
OCH.sub.2-4-Pyr NH-Phe-3,4-di-F Bnzl-4- OCF.sub.2H 70 Z.sup.1 = 2N,
all OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl-4- others = CH OCF.sub.2H
71 Z.sup.1 = N, all OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4- others
= CH OCF.sub.2H 72 Z.sup.1 = N, all OCH.sub.2-4-Pyr NH-4-Pyr-2-OMe
Bnzl-4- others = CH OCF.sub.2H 73 CH O-Bnzl NH-3-Pyr Bnzl-4-Me 74
CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN Bnzl-4- OCF.sub.2H 75 CH
OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl-4- NHC(O)Me OCF.sub.2H 76 Z.sup.4
= OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3 CC(Me).sub.2OH
all others = CH 77 Z.sup.4 = OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF.sub.3 CCO.sub.2H all others = CH 78 Z.sup.4 =
OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3 CCH.sub.2NMe.sub.2
all others = CH 79 Z.sup.4 = OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF.sub.3 CC(O)NMe.sub.2 all others = CH 80 Z.sup.4 = CBr
OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3 all others = CH 81
Z.sup.4 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3
CSO.sub.2NH.sub.2 all others = CH 82 Z.sup.1 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF.sub.3 CC(Me).sub.2OH all others = CH 83
Z.sup.1 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3
CCO.sub.2H all others = CH 84 Z.sup.1 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF.sub.3 CCH.sub.2NMe.sub.2 all others = CH
85 Z.sup.1 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF.sub.3
CC(O)NMe.sub.2 all others = CH 87 Z.sup.1 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF.sub.3 CSO.sub.2NH.sub.2 all others = CH
88 Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CC(Me).sub.2OH all others = CH 89 Z.sup.1 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF.sub.3 CCO.sub.2H all others = CH 90 Z.sup.1 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CCH.sub.2NMe.sub.2 all
others = CH 91 Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CC(O)NMe.sub.2 all others = CH 92 Z.sup.1 = CBr OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF.sub.3 all others = CH 93 Z.sup.1 = OCH.sub.24Pyr
NH-4-Pyr Bnzl-4-CF.sub.3 CSO.sub.2NH.sub.2 all others = CH 94
Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(Me).sub.2OH all others = CH
95 Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F CCO.sub.2H all others = CH 96
Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F CCH.sub.2NMe.sub.2 all others =
CH 97 Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(O)NMe.sub.2 all others
= CH 98 Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F all others = CH 99
Z.sup.1 = O-Bnzl NH-3-Pyr Bnzl-4-F CSO.sub.2NH.sub.2 all others =
CH 100 Z.sup.4 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CC(Me).sub.2OH all others = CH 101 Z.sup.4 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF.sub.3 CCO.sub.2H all others = CH 102 Z.sup.4 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CCH.sub.2NMe all others =
CH 103 Z.sup.4 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CC(O)NMe.sub.2 all others = CH 104 Z.sup.4 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF.sub.3 all others = CH 105 Z.sup.4 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CSO.sub.2NH.sub.2 all
others = CH 106 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(Me).sub.2OH
all others = CH 107 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F CCO.sub.2H
all others = CH 108 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F
CCH.sub.2NMe.sub.2 all others = CH 109 Z.sup.4 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(O)NMe.sub.2 all others = CH 110 Z.sup.4 = CBr O-Bnzl
NH-3-Pyr Bnzl-4-F all others = CH 111 Z.sup.4= O-Bnzl NH-3-Pyr
Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 112 Z.sup.3 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CC(Me).sub.2OH all others
= CH 113 Z.sup.3 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CCO.sub.2H all others = CH 114 Z.sup.3 = OCH.sub.2-4-Pyr NH-4-Pyr
Bnzl-4-CF.sub.3 CCH.sub.2NMe.sub.2 all others = CH 115 Z.sup.3 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CC(O)NMe.sub.2 all others
= CH 116 Z.sup.3 = CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 all
others = CH 117 Z.sup.3 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CSO.sub.2NH.sub.2 all others = CH 118 Z.sup.3 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(Me).sub.2OH all others = CH 119 Z.sup.3 = O-Bnzl
NH-3-Pyr Bnzl-4-F CCO.sub.2H all others = CH 120 Z.sup.3 = O-Bnzl
NH-3-Pyr Bnzl-4-F CCH.sub.2NMe.sub.2 all others = CH 121 Z.sup.3 =
O-Bnzl NH-3-Pyr Bnzl-4-F CC(O)NMe.sub.2 all others = CH 122 Z.sup.3
= CBr O-Bnzl NH-3-Pyr Bnzl-4-F all others = CH 123 Z.sup.3 = O-Bnzl
NH-3-Pyr Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 124 Z.sup.2 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CC(Me).sub.2OH all others
= CH 125 Z.sup.2 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CCO.sub.2H all others = CH 126 Z.sup.2 = OCH.sub.2-4-Pyr NH-4-Pyr
Bnzl-4-CF.sub.3 CCH.sub.2NMe.sub.2 all others = CH 127 Z.sup.2 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 CC(O)NMe.sub.2 all others
= CH 128 Z.sup.2 = CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3 all
others = CH 129 Z.sup.2 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF.sub.3
CSO.sub.2NH.sub.2 all others = CH 130 Z.sup.2 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(Me).sub.2OH all others = CH 131 Z.sup.2 = O-Bnzl
NH-3-Pyr Bnzl-4-F CCO.sub.2H all others = CH 132 Z.sup.2 = O-Bnzl
NH-3-Pyr Bnzl-4-F CCH.sub.2NMe.sub.2 all others = CH 133 Z.sup.2 =
O-Bnzl NH-3-Pyr Bnzl-4-F CC(O)NMe.sub.2 all others = CH 134 Z.sup.2
= CBr O-Bnzl NH-3-Pyr Bnzl-4-F all others = CH 135 Z.sup.2 = O-Bnzl
NH-3-Pyr Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 136 CH O-Bnzl
NH-3-Pyr Bnzl-4- C(Me).sub.2-OH 137 CH OCH.sub.2-3-Pyr NH-3-Pyr
Bnzl-4-F 138 CH OCH.sub.2-3-Pyr NH-4-Pyr Bnzl-4-F 139 CH
OCH.sub.2-3-Pyr NH-Phe-3,4-di- Bnzl-4-F OMe 140 CH OCH.sub.2-3-Pyr
NH-Phe-3,4-di-F Bnzl-4-F 141 CH OCH.sub.2-3-Pyr NH-5-Pyr-2-OMe
Bnzl-4-F 142 CH O-Bnzl NH-3-Pyr Bnzl-4- CO.sub.2Me 143 CH
OCH.sub.2-3-Pyr NH-5-tetrazolyl Bnzl-4-F 144 CH OCH.sub.2-3-Pyr
NH-4-Pyr-2-OMe Bnzl-4-F 145 CH OCH.sub.2-3-Pyr NH-5-Pyr-2-CN
Bnzl-4-F 146 CH OCH.sub.2-3-Pyr NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 147
CH O-Bnzl NH-Phe-3-SO.sub.2Me Bnzl-4-F 148 CH O-Bnzl NH-3-Pyr
Bnzl-4-CF.sub.3 149 CH O--CH.sub.2-cPr NH-Phe-3,4-di- Bnzl-4-t-Bu
OMe 150 CH O--CH.sub.2-cPr NH-5-tetrazolyl Bnzl-4-t-Bu 151 CH
O--CH.sub.2-cPr NH-4-Pyr-2-OMe Bnzl-4-t-Bu 152 CH O--CH.sub.2-cPr
NH-5-Pyr-2-OMe Bnzl-4-t-Bu 153 CH O--CH.sub.2-cPr NH-4-Pyr-2-
Bnzl-4-t-Bu NHC(O)OEt 154 CH O--CH.sub.2-cPr NH-3-Pyr Bnzl-4-F 155
CH O--CH.sub.2-cPr NH-4-Pyr Bnzl-4-F 156 CH O--CH.sub.2-cPr
NH-Phe-3,4-di- Bnzl-4-F OMe 157 CH O--CH.sub.2-cPr NH-Phe-3,4-di-F
Bnzl-4-F 158 CH O--CH.sub.2-cPr NH-5-Pyr-2-OMe Bnzl-4-F 159 CH
O--CH.sub.2-cPr NH-5-tetrazolyl Bnzl-4-F 160 CH O--CH.sub.2-cPr
NH-4-Pyr-2-OMe Bnzl-4-F 161 CH O--CH.sub.2-cPr NH-5-Pyr-2- Bnzl-4-F
NHC(O)Me 162 CH OCH.sub.2-4-Pyr NH-3-Pyr Bnzl-4-F 163 CH
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-F 164 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-di- Bnzl-4-F OMe 165 CH OCH.sub.2-4-Pyr NHI-Phe-3,4-di-F
Bnzl-4-F 166 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl-4-F 167 CH
OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-F 168 CH OCH.sub.2-4-Pyr
NH-4-Pyr-2-OMe Bnzl-4-F 169 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN
Bnzl-4-F 170 CH OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 171
CH OCH.sub.2-4-Pyr NH-4-Pyr-2- Bnzl-4-F NHC(O)OEt 172 CH O-Bnzl
NH-3-Pyr Bnzl-4-t-Bu 173 CH O-Bnzl NH-3-Pyr Bnzl-4-F 174 CH O-Bnzl
NH-4-Pyr Bnzl-4-F 175 CH O-Bnzl NH-Phe-3,4-di- Bnzl-4-F OMe 176 CH
O-Bnzl NH-Phe-3,4-di-F Bnzl-4-F 177 CH O-Bnzl NH-5-Pyr-2-OMe
Bnzl-4-F 178 CH O-Bnzl NH-5-tetrazolyl Bnzl-4-F 179 CH O-Bnzl
NH-4-Pyr-2-OMe Bnzl-4-F 180 CH O-Bnzl NH-5-Pyr-2-CN Bnzl-4-F 181 CH
O-Bnzl NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 182 CH O-Bnzl NH-4-Pyr-2-
Bnzl-4-F NHC(O)OEt 183 CH O-Bnzl N(Me)-3-Pyr Bnzl-4-F 184 CH O-Bnzl
N(Me)-3-Pyr Bnzl-4-CF.sub.3 185 CH O-Bnzl 3-pyridylmethyl Bnzl-4-F
186 CH O-Bnzl 4-pyridylmethyl Bnzl-4-F Phe = phenyl, Bzyl = benzyl,
Pyr = pyridyl
or a pharmaceutically acceptable salt or hydrate thereof.
14. A compound selected from the group consisting of:
{1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)indol-2-yl}-N-(3-pyridyl)for-
mamide;
{1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)indol-2-yl}-N-[3-(met-
hylsulfonyl) formamide;
{1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)
indol-2-yl}-N-(3-pyridylmethyl) formamide;
{1-[(4-Fluorophenyl)methyl]-3-- (phenylmethoxy)
indol-2-yl}-N-(4-pyridylmethyl) formamide; Methyl
4-{[3-(phenylmethoxy)-2-(N-(3-pyridyl)carbamoyl]methyl}benzoate;
1-{[4-(1-Hydroxyisopropyl)phenyl]methyl]-3-(phenylmethoxy)
indol-2-yl}-N-(3-pyridyl)formamide;
{1-[(4-Methylphenyl)methyl]-3-(phenyl- methoxy)
indol-2-yl}-N-(3-pyridyl) formamide; (1-{[4-(tert-Butyl)phenyl)me-
thyl}-3-(phenylmethoxy) indol-2-yl}-N-(3-pyridyl) formamide; (1-
{[4-(Trifluormethyl)phenyl]methyl}-3-(phenylmethoxy)indol-2-yl)-N-(3-pyri-
dyl) formamide;
(1-{[4-(Difluoromethoxy)phenyl]methyl}-3-(phenylmethoxy)in-
dol-2-yl)-N-(3-pyridyl) formamide;
{3-(Cyclopropylmethoxy)-1-[(4-fluorophe-
nyl)methyl]indol-2-yl}-N-(3-pyridyl)formamide;
{1-[(4-Fluorophenyl)methyl]-
-3-(4-pyridylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide;
{1-[(4-Fluorophenyl)methyl]-3-[(3-methoxyphenyl)methoxy]indol-2-yl}-N-(3--
pyridyl)formamide;
{5-Bromo-1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)in-
dol-2-yl}-N-(3-pyridyl) formamide;
{1-[(4-Fluorophenyl)methyl]-5-(1-hydrox-
y-isopropyl)-3-(phenylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide;
1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)-2-(N-(3-pyridyl)carbamoyl)in-
dole-5-carboxylic acid;
{1-[(4-Fluorophenyl)methyl]-4-(1-hydroxy-isopropyl-
)-3-(phenylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide; and
{1-[(4-Fluorophenyl)methyl]-6-(1-hydroxy-isopropyl)-3-(phenylmethoxy)indo-
l-2-yl}-N-(3-pyridyl)formamide, or a pharmaceutically acceptable
salt or hydrate thereof.
15. A pharmaceutical composition comprised of a compound in
accordance with claim 1 in combination with a pharmaceutically
acceptable carrier.
16. A method of treating or preventing a PDE-IV mediated disease or
condition in a mammalian patient in need thereof, comprising
administering said patient an amount of a compound in accordance
with claim 1 that is effective for treating or preventing said
PDE-IV mediated disease or condition.
17. A method in accordance with claim 16 wherein the disease or
condition is selected from the group consisting of: inflammatory
response or muscular spasm; bladder or alimentary smooth muscle
spasm; asthma;inflamed lung associated with asthma; cystic
fibrosis; chronic bronchitis; eosinophilic granuloma; psoriasis;
other benign and malignant proliferative skin diseases; endotoxic
shock; septic shock; ulcerative colitis; Crohn's disease;
reperfusion injury of the myocardium or brain; inflammatory
arthritis; osteoporosis, chronic glomerulonephritis; atopic
dermatitis; urticaria; adult or infant respiratory distress
syndrome; diabetes; diabetes insipidus; allergic rhinitis; allergic
conjunctivitis; vernal conjunctivitis; arterial restenosis and
atherosclerosis.
18. A method in accordance with claim 16 wherein the disease or
condition is selected from the group consisting of: pain; cough;
fever; rheumatoid arthritis; osteoarthritis; ankylosing
spondylitis; transplant rejection; graft versus host disease;
hypersecretion of gastric acid; bacterial, fungal or viral induced
infection or sepsis; septic shock; cachexia and muscle wasting;
depression; memory impairment; and prevention of tumor growth and
invasion of normal tissues.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to compounds and pharmaceutical
compositions for the treatment of diseases by raising the level of
cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition
of phosphodiesterase IV (PDE IV).
[0002] Many hormones and neurotransmitters modulate tissue function
by elevating intracellular levels of 3', 5'-cyclic adenosine
monophosphate (cAMP). The cellular levels of cAMP are regulated by
mechanisms which control synthesis and breakdown. The synthesis of
cAMP is controlled by adenyl cyclase which may be directly
activated by agents such as forskolin or indirectly activated by
the binding of specific agonists to cell surface receptors which
are coupled to adenyl cyclase. The breakdown of cAMP is controlled
by a family of phosphodiesterase (PDE) isoenzymes, which also
control the breakdown of guanosine 3', 5'-cyclic monophosphate
(cGMP). At least seven members of the family have been described
(PDE I-VII), the distribution of which varies from tissue to
tissue. This suggests that specific inhibitors of PDE isoenzymes
could achieve differential elevation of cAMP in different tissues
[for reviews of PDE distribution, structure, function and
regulation, see Beavo & Reifsnyder (1990) TIPS, 11: 150-155,
Nicholson et. al. (1991) TIPS, 12: 19-27, and Torphy and Undem
(1991) Thorax, 46: 512-523].
[0003] The availability of PDE isotype selective inhibitors has
enabled the role of PDEs in a variety of cell types to be
investigated. In particular it has been established that PDE IV
controls the breakdown of cAMP in many inflammatory cells, for
example, basophils (Peachell P. T. et al., (1992) J. Immunol., 148:
2503-2510) and eosinophils (Dent G. et al., (1991) Br. J.
Pharmacol., 103: 1339-1346) and that inhibition of this isotype is
associated with the inhibition of cell activation. Furthermore,
elevation of cAMP in airway smooth muscle has a spasmolytic effect.
Consequently PDE IV inhibitors are currently being developed as
potential anti-inflammatory drugs particularly for the prophylaxis
and treatment of asthma, by achieving both anti-inflammatory and
bronchodilator effects.
[0004] The application of molecular cloning to the study of PDEs
has revealed that for each isotype there may be one or more
isoforms. PDE IV has been shown to exist in four isoforms (A, B, C
and D) to date, each coded for by a separate gene in both rodents
(Swinnen J. V. et al., (1989) Proc. Natl. Acad. Sci. USA, 86:
5325-5329) and man (Bolger G. et al., (1993) Mol. Cell Biol., 13:
6558-6571).
[0005] The existence of multiple PDE IVs raises the prospect of
obtaining inhibitors that are selective for individual isoforms,
thus increasing the specificity of action of such inhibitors. This
assumes that the different PDE IV isoforms are functionally
distinct. Indirect evidence in support of this comes from the
selective distribution of these isoforms in different tissues
(Swinnen et al., 1989; Bolger et al., 1993; Obernolte R. et al.,
(1993) Gene, 129: 239-247, ibid) and the high degree of sequence
conservation amongst isoforms of different species.
[0006] To date, full length cDNAs for human PDE IVA, B and D
(Bolger et al., 1993 ibid; Obernolte et al., 1993 ibid; Mclaughlin
M. et al., (1993) J. Biol. Chem., 268: 6470-6476) and rat PDE IVA,
B and D (Davis R. et al., (1989) Proc. Natl. Acad. Sci. USA, 86:
3604-3608; Swinnen J. V. et al., (1991) J. Biol. Chem., 266:
18370-18377), have been reported, enabling functional recombinant
enzymes to be produced by expression of the cDNAs in an appropriate
host cell. These cDNAs have been isolated by conventional
hybridization methods. However using this approach, only partial
cDNAs for both human and rat PDE IVC have been obtained. (Bolger et
al., ibid. 1993 and Swinnen et al., ibid. 1989 and International
Patent Specification No. WO 91/16457.)
[0007] The design of PDE IV inhibitors for the treatment of
inflammatory diseases such as asthma, has met with limited success
to date. Many of the PDE IV inhibitors which have been synthesised
have lacked potency and/or inhibit more than one type of PDE
isoenzyme in a non-selective manner. PDE IV inhibitors that are
relatively potent and selective for PDE IV, are reported to be
emetic as well. Indeed this side effect has been so universal that
experts have expressed their belief that the emesis experienced
upon administration of a PDE IV inhibitor may be mechanism
based.
[0008] The compounds described herein are potent inhibitors of PDE
IV at concentrations that exhibit little or no inhibitory action on
other PDE isoenzymes. These compounds inhibit the human recombinant
PDE IV enzyme and also elevate cAMP in isolated leukocytes. Certain
compounds prevent inflammation in the lungs induced by carrageenan,
platelet-activating factor (PAF), interleukin-5 (IL-5) or antigen
challenge. These compounds also suppress the hyperresponsiveness of
airway smooth muscle seen in inflamed lungs. Advantageously,
compounds according to the invention have good oral activity, and
at orally effective doses exhibit little or none of the
side-effects associated with known PDE IV inhibitors, such as
rolipram. The compounds of the invention are therefore of use in
medicine, especially in the prophylaxis and treatment of asthma and
other inflammatory conditions.
SUMMARY OF THE INVENTION
[0009] A compound represented by formula I: 2
[0010] or a pharmaceutically acceptable salt or hydrate thereof
wherein: one of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 represents N
or CR.sup.2 and the others represent CR.sup.2;
[0011] a represents 0 or 1;
[0012] b represents 0, 1 or 2;
[0013] d represents 0, 1 or 2;
[0014] R.sup.1 represents H, C.sub.1-4alkyl or
hydroxyC.sub.1-4alkyl;
[0015] each R.sup.2 is independently selected from the group
consisting of: H, halo, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, CN, Het, OR.sup.a, OC(O)N(R.sup.b).sub.2,
NR.sup.bC(O)R.sup.a, C(R.sup.a).sub.2CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2, haloC.sub.1-8alkylN(R.sup.b).sub.2,
CO.sub.2R.sup.a, C(O)N(R.sup.b).sub.2, SO.sub.2N(R.sup.b).sub.2,
S(O).sub.2R.sup.d and NR.sup.bSO.sub.2R.sup.d;
[0016] each R.sup.a is independently selected from H,
C.sub.1-4alkyl, C.sub.1-4alkylNHC.sub.1-4alkyl, and
C.sub.1-4alkylN(C.sub.1-4alkyl).sub.2- , the alkyl portions of
which are optionally substituted with 1-3 halo groups;
[0017] each R.sup.b is selected from H and C1-7 alkyl, and when two
R.sup.b's are present, they can be taken together and represent a
fused ring system having 5-10 members, said ring system being
saturated or containing 1-4 double bonds, and optionally including
1-3 heteroatoms selected from O, S and NR.sup.e;
[0018] R.sup.d and R.sup.e are independently selected from Het,
C.sub.1-7alkyl, C.sub.2-7alkenyl, C.sub.2-7alkynyl, and
C.sub.1-7alkyl-Het;
[0019] Het represents a 5-10 membered aromatic, partially aromatic
or non-aromatic ring system containing 1-4 heteroatoms selected
from O, S and N, optionally substituted on any available position
with oxo, C.sub.1-4 alkyl, halo, amino, hydroxyC.sub.1-4 alkyl,
haloC.sub.1-4 alkyl and aminoC.sub.1-4 alkyl;
[0020] X represents C.sub.3-7cycloalkyl or Ar;
[0021] and each Ar is independently selected from the group
consisting of: phenyl, thienyl, thiazolyl, pyridyl, oxazolyl,
tetrazolyl, pyrimidinyl, pyrazinyl and pyridazinyl,
[0022] said Ar being optionally substituted with 1-4 members
selected from: halo, hydroxy, CN, C.sub.1-4alkyl,
C.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, OC.sub.1-6hydroxyalkyl,
C.sub.1-6alkylOC.sub.1-6alkyl, C.sub.1-6alkylOC.sub.1-6haloalkyl,
C(O)NH.sub.2, C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6 alkylOC.sub.1-6alkylC(O)NH.sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl,
NHC(O)OC.sub.1-6alkyl, and SO.sub.2C.sub.1-6alkyl.
[0023] Pharmaceutical compositions and methods of treatment are
also included.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The invention encompasses compounds represented by formula
I: 3
[0025] as well as pharmaceutically acceptable salts and hydrates
thereof wherein: one of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4
represents N or CR.sup.2 and the others represent CR.sup.2;
[0026] a represents 0 or 1;
[0027] b represents 0, 1 or 2;
[0028] d represents 0, 1 or 2;
[0029] R.sup.1 represents H, C.sub.1-4alkyl or
hydroxyC.sub.1-4alkyl;
[0030] each R.sup.2 is independently selected from the group
consisting of: H, halo, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, CN, Het, OR.sup.a, OC(O)N(R.sup.b).sub.2,
NR.sup.bC(O)R.sup.a, C(R.sup.a).sub.2CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2, haloC.sub.1-8alkylN(R.sup.b).sub.2,
CO.sub.2R.sup.a, C(O)N(R.sup.b).sub.2, SO.sub.2N(R.sup.b).sub.2,
S(O).sub.bR.sup.d and NR.sup.bSO.sub.2R.sup.d;
[0031] each R.sup.a is independently selected from H,
C.sub.1-4alkyl, C.sub.1-4alkylNHC.sub.1-4alkyl, and
C.sub.1-4alkylN(C.sub.1-4alkyl).sub.2- , the alkyl portions of
which are optionally substituted with 1-3 halo groups;
[0032] each R.sup.b is selected from H and C1-7 alkyl, and when two
R.sup.b's are present, they can be taken together and represent a
fused ring system having 5-10 members, said ring system being
saturated or containing 1-4 double bonds, and optionally including
1-3 heteroatoms selected from O, S and NR.sup.e;
[0033] R.sup.d and R.sup.e are independently selected from Het,
C.sub.1-7alkyl, C.sub.2-7alkenyl, C.sub.2-7alkynyl, and
C.sub.1-7alkyl-Het;
[0034] Het represents a 5-10 membered aromatic, partially aromatic
or non-aromatic ring system containing 1-4 heteroatoms selected
from O, S and N, optionally substituted on any available position
with oxo, C.sub.1-4 alkyl, halo, amino, hydroxyC.sub.1-4 alkyl,
haloC.sub.1-4 alkyl and aminoC.sub.1-4 alkyl;
[0035] X represents C.sub.3-7cycloalkyl or Ar;
[0036] and each Ar is independently selected from the group
consisting of: phenyl, thienyl, thiazolyl, pyridyl, oxazolyl,
tetrazolyl, pyrimidinyl, pyrazinyl and pyridazinyl,
[0037] said Ar being optionally substituted with 1-4 members
selected from: halo, hydroxy, CN, C.sub.1-4alkyl,
C.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, OC.sub.1-6hydroxyalkyl,
C.sub.1-6alkylOC.sub.1-6alkyl, C.sub.1-6alkylOC.sub.1-6haloalkyl,
C(O)NH.sub.2, C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6 alkylOC.sub.1-6alkylC(O)NH.sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl,
NHC(O)OC.sub.1-6alkyl, and SO.sub.2C.sub.1-6alkyl.
[0038] As used herein, the following terms and definitions
apply.
[0039] Alkyl includes straight, branched and cyclic groups
containing the indicated number of carbon atoms. If no number is
specified, C.sub.1-6alkyl is appropriate.
[0040] Alkenyl refers to a carbon containing group having from 2-7
carbon atoms unless otherwise indicated, and 1-3 carbon-carbon
double bonds. It can be straight, branched or cyclic as
appropriate.
[0041] Alkynyl refers to a carbon containing group having from 2-7
carbon atoms, and 1-3 carbon-carbon triple bonds. It can be
straight, branched or cyclic.
[0042] Halo includes F, I, Br and Cl. When haloalkyl is indicated,
this includes monohalogenated alkyl groups containing the indicated
number of carbon atoms, dihalo, trihalo, etc. up to perhaloalkyl
groups.
[0043] Het represents a 5-10 membered aromatic, partially aromatic
or non-aromatic ring system containing 1-4 heteroatoms selected
from O, S and N, optionally substituted on any available position
with oxo, C.sub.1-4 alkyl, halo, amino, hydroxyC.sub.1-4 alkyl,
haloC.sub.1-4 alkyl and aminoC.sub.1-4 alkyl. Thus, examples of Het
include well known heteroaryl rings, such as pyridine, pyrrole,
pyrimidine, imidazole, triazole, tetrazole, and the like, as well
as non-aromatic rings, such as piperidine, pyrrolidine and the
like.
[0044] Ar is an aromatic ring and is selected from the group
consisting of: phenyl, thienyl, thiazolyl, pyridyl, oxazolyl,
tetrazolyl, pyrimidinyl, pyrazinyl and pyridazinyl. The Ar moiety
is optionally substituted with 1-4 members selected from: halo,
hydroxy, CN, C.sub.1-4alkyl, C.sub.1-6haloalkyl,
C.sub.1-6hydroxyalkyl, OC.sub.1-6alkyl, OC.sub.1-6haloalkyl,
OC.sub.1-6hydroxyalkyl, C.sub.1-6alkylOC.sub.1-6alkyl,
C.sub.1-6alkylOC.sub.1-6haloalkyl, CN, C(O)NH.sub.2,
C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2, C.sub.1-6
alkylOC.sub.1-6alkylC(O)NH.sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl, C.sub.1-6alkylOC(O)NH
and SO.sub.2C.sub.1-6alkyl.
[0045] The following abbreviations have the indicated meanings:
1 Ac = acetyl Bn = benzyl cAMP = cyclic
adenosine-3',5'-monophosphate DBU = 1,8-diazabicyclo[5.4.0]undec-7-
-ene DIBAL = diisobutylaluminum hydride DMAP =
4-(dimethylamino)pyridine DMZF = N,N-dimethylformamide Et3N =
triethylamine GST = glutathione transferase LDA = lithium
diisopropylamide m-CPBA = metachloroperbenzoic acid MMPP =
monoperoxyphthalic acid MPPM = monoperoxyphthalic acid, magnesium
salt 61120 Ms = methanesulfonyl = mesyl = SO.sub.2Me MsO =
methanesulfonate = mesylate NSAID = non-steroidal anti-inflammatory
drug o-Tol = ortho-tolyl OXONE .RTM. =
2RHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4 PCC = pyridinium
chlorochromate PDC = pyridinium dichromate PDE = phosphodiesterase
Ph = phenyl Phe = benzenediyl PMB = para-methoxybenzyl Pye =
pyridinediyl r.t. = room temperature rac. = raceinic SAM =
aminosulfonyl or sulfonamide or SO.sub.2NH.sub.2 SEM =
2-(trimethylsilyl)ethoxymeth- oxy SPA = scintillation proximity
assay TBAF = tetra-n-butylammonium fluoride Th = 2- or 3-thienyl
TFA = trifluoroacetic acid TFAA = trifluoroacetic acid anhydride
THF = tetrahydrofuran Thi = thiophenedlyl TLC = thin layer
chromatography TMS-CF.sub.3 = trimethyl(trifluoromethyl)silane
TMS-CN = trimethylsilyl cyanide Tz = 1H (or 2H)-tetrazol-5-yl
C.sub.3H.sub.5 = allyl Alkyl Group Abbreviations Me = methyl Et =
ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl
i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr =
cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex =
cyclohexyl
[0046] In one aspect of the invention that is of interest, all four
of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 represent CR.sup.2. Within
this aspect of the invention, all other variables are as originally
defined.
[0047] In another aspect of the invention that is of interest, b
represents 0 or 1. Within this aspect of the invention, all other
variables are as originally defined.
[0048] In another aspect of the invention, d represents 1. Within
this aspect of the invention, all other variables are as originally
defined.
[0049] In another aspect of the invention, R.sup.1 represents H or
CH.sub.3. Within this aspect of the invention, all other variables
are as originally defined.
[0050] In another aspect of the invention, each R.sup.2 is
independently selected from the group consisting of H,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2 and C(O)N(R.sup.b).sub.2. R.sup.b is
selected from H and C.sub.1-3 alkyl. Within this aspect of the
invention, all other variables are as originally defined.
[0051] In another aspect of the invention, X represents Ar and Ar
is independently selected from the group consisting of: phenyl,
pyridyl and tetrazolyl,
[0052] said Ar being optionally substituted with 1-4 members
selected from: halo, CN, C.sub.1-4alkyl, C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, OC.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl,
C(O)NH.sub.2, C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2,
CO.sub.2H, CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl,
NHC(O)OC.sub.1-6alkyl and SO.sub.2C.sub.1-6alkyl. Within this
aspect of the invention, all other variables are as originally
defined.
[0053] A subset of compounds that is of particular interest relates
to compounds of formula I wherein:
[0054] Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 represent
CR.sup.2;
[0055] each R.sup.2 is independently selected from the group
consisting of H, C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl,
CO.sub.2R.sup.a, C.sub.1-8alkylN(R.sup.b).sub.2 and
C(O)N(R.sup.b).sub.2 wherein R.sup.b is selected from H and
C.sub.1-3 alkyl;
[0056] b represents 0 or 1;
[0057] d represents 1;
[0058] R.sup.1 represents H or CH.sub.3;
[0059] X represents Ar and
[0060] Ar is independently selected from the group consisting of:
phenyl, pyridyl and tetrazolyl, said Ar being optionally
substituted with 1-4 members selected from: halo, CN,
C.sub.1-4alkyl, C.sub.1-6haloalkyl, OC.sub.1-6alkyl,
OC.sub.1-6haloalkyl, C.sub.1-6hydroxyalkyl, C(O)NH.sub.2,
C(O)NHC.sub.1-6alkyl, C(O)N(C.sub.1-6alkyl).sub.2, CO.sub.2H,
CO.sub.2C.sub.1-6alkyl, NHC(O)C.sub.1-6alkyl, NHC(O)OC.sub.1-6alkyl
and SO.sub.2C.sub.1-6alkyl. Within this aspect of the invention,
all other variables are as originally defined.
[0061] A further subset of compounds of the invention that is of
interest is represented by Formula Ia: 4
[0062] Within this subset, all variables are as originally
defined.
[0063] More particularly, a subset of compounds that is of interest
relates to compounds of formula Ia wherein Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 represent CR.sup.2. Within this subset, all
variables are as originally defined.
[0064] More particularly, a subset of compounds that is of interest
relates to compounds of formula Ia wherein each R.sup.2 is
independently selected from the group consisting of H,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, CO.sub.2R.sup.a,
C.sub.1-8alkylN(R.sup.b).sub.2 and C(O)N(R.sup.b).sub.2 wherein
R.sup.a is independently selected from H and C.sub.1-4alkyl, and
R.sup.b is selected from H and C.sub.1-3 alkyl.
[0065] More particularly, a subset of compounds that is of interest
relates to compounds of formula Ia wherein each Ar is selected from
phenyl, pyridyl and tetrazolyl, optionally substituted with 1-4
members selected from: halo, CN, C.sub.1-4alkyl,
C.sub.1-6haloalkyl, OC.sub.1-6alkyl, OC.sub.1-6haloalkyl,
C.sub.1-6hydroxyalkyl, C(O)NH.sub.2, C(O)NHC.sub.1-6alkyl,
C(O)N(C.sub.1-6alkyl).sub.2, CO.sub.2H, CO.sub.2C.sub.1-6alkyl,
NHC(O)C.sub.1-6alkyl, NHC(O)OC.sub.1-6alkyl and
SO.sub.2C.sub.1-6alkyl. Within this aspect of the invention, all
other variables are as originally defined.
[0066] Examples of compounds falling within the present invention
include the following:
2 5 Cpd Z's (CH.sub.2).sub.b--(O).s- ub.a(CH.sub.2).sub.b-X
N(R.sup.1(CH.sub.2).sub.a--Ar (CH.sub.2).sub.d--Ar 1 CH
OCH.sub.2-Phe-4-F N(Me)-3-Pyr Bnzl 2 CH OCH.sub.2-Phe-4-F
N(Me)-4-Pyr Bnzl 3 CH OCH.sub.2-Phe-4-F N(Me)-Phe-3,4-di- Bnzl OMe
4 CH OCH.sub.2-Phe-4-F N(Me)-Phe-3,4-di- Bnzl F 5 CH
OCH.sub.2-Phe-4-F N(Me)-5-Pyr-2- Bnzl OMe 6 CH OCH.sub.2-Phe-4-F
N(Me)-5-tetrazolyl Bnzl 7 CH OCH.sub.2-Phe-4-F N(Me)-4-Pyr-2- Bnzl
OMe 8 CH OCH.sub.2-Phe-4-F N(Me)-5-Pyr-2-CN Bnzl 9 CH
OCH.sub.2-Phe-4-F N(Me)-4-Pyr-2- Bnzl OMe 10 CH O-Bnzl
NH-Phe-3,4-di- Bnzl-4-F OMe 11 CH O-Bnzl NH-3-Pyr Bnzl-4-F 12 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-3-Pyr Bnzl-3- OCF.sub.2H 13 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-4-Pyr Bnzl-3- OCF.sub.2H 14 CH
OCH.sub.2-Phe-3-OCF.sub.2H NH-Phe-3,4-di- Bnzl-3- OMe OCF.sub.2H 15
CH OCH.sub.2-Phe-3-OCF.sub.2H NH-Phe-3,4-di-F Bnzl-3- OCF.sub.2H 16
CH O-Bnzl NH-3-Pyr Bnzl-4- OCF.sub.2H 17 CH OCH.sub.2-Phe-3-OMe
NH-3-Pyr Bnzl-4- OCF.sub.2H 18 CH OCH.sub.2-Phe-3-OMe
NH-5-tetrazolyl Bnzl-4- OCF.sub.2H 19 CH OCH.sub.2-Phe-3-OMe
NH-4-Pyr-2-OMe Bnzl-4- OCF.sub.2H 20 CH OCH.sub.2-Phe-3-OMe
NH-4-Pyr Bnzl-4- 21 CH OCH.sub.2-Phe-3-OMe NH-4-Pyr-2- Bnzl-4- 22
CH OCH.sub.2-Phe-3-OMe NH-3-Pyr Bnzl-4-F 23 CH OCH.sub.2-Phe-3-OMe
NH-5-tetrazolyl Bnzl-4-F 24 CH OCH.sub.2-Phe-3-OMe NH-4-Pyr-2-OMe
Bnzl-4-F 25 CH OCH.sub.2-Phe-3-OMe NH-4-Pyr Bnzl-4-F 26 CH
OCH.sub.2-Phe-3-OMe NH-4-Pyr-2- Bnzl-4-F NHC(O)Me 27 CH
OCH.sub.2-Phe-3-OMe NH-5-pyrimidinyl Bnzl-4-F 28 CH O-Bnzl NH-3-Pyr
Bnzl-3,4-di- F 29 CH O-Bnzl NH-4-Pyr Bnzl-3,4-di- F 30 CH O-Bnzl
NH-Phe-3,4-di- Bnzl-3,4-di- OMe F 31 CH O-Bnzl NH-Phe-3,4-di-F
Bnzl-3,4-di- F 32 CH O-Bnzl NH-5-Pyr-2-OMe Bnzl-3,4-di- F 33 CH
O-Bnzl NH-5-tetrazolyl Bnzl-3,4-di- F 34 CH O-Bnzl NH-4-Pyr-2-OMe
Bnzl-3,4-di- F 35 CH O-Bnzl NH-5-Pyr-2-CN Bnzl-3,4-di- F 36 CH
O-Bnzl NH-5-Pyr-2- Bnzl-3,4-di- NHC(O)Me F 37 CH OCH.sub.2-4-Pyr
NH-3-Pyr Bnzl-4-CF3 38 CH OCH.sub.2-4-Pyr Bnzl-4-CF3 39 CH
OCH.sub.2-4-Pyr NH-Phe-3,4-di- Bnzl-4-CF3 40 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-diF Bnzl-4-CF3 41 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe
Bnzl-4-CF.sub.3 42 CH OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3 43
CH OCH.sub.2-4-Pyr NH-4-Pyr-2-OMe Bnzl-4-CF3 44 CH OCH.sub.2-4-Pyr
NH-5-Pyr-2-CN Bnzl-4-CF3 45 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-
Bnzl-4-CF3 NHC(O)Me 46 CH OCH.sub.2-4-Pyr NH-3-Pyr Bnzl 47 CH
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl 48 CH OCH.sub.2-4-Pyr NH-Phe-3,4-di-
Bnzl OMe 49 CH OCH.sub.2-4-Pyr NH-Phe-3,4-di-F Bnzl 50 CH
OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl 51 CH OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl 52 CH OCH.sub.2-4-Pyr NH-4-Pyr-2-OMe Bnzl 53
CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN Bnzl 54 CH OCH.sub.2-4-Pyr
NH-5-Pyr-2- Bnzl NHC(O)Me 55 CH OCH.sub.2-4-Pyr NH-4-Pyr-2- Bnzl
NHC(O)OEt 56 CH O-Bnzl NH-3-Pyr Bnzl 57 CH O-Bnzl NH-4-Pyr Bnzl 58
CH O-Bnzl NH-Phe-3,4-di- Bnzl OMe 59 Z.sup.1 = N, all O-Bnzl
NH-Phe-3,4-di-F Bnzl others = CH 60 Z.sup.1 = 2N, all O-Bnzl
NH-5-Pyr-2-OMe Bnzl others = CH 61 CH O-Bnzl NH-5-tetrazolyl Bnzl
62 CH O-Buzl NH-4-Pyr-2-OMe Bnzl 63 CH O-Bnzl NH-5-Pyr-2-CN Bnzl 64
CH O-Bnzl NH-5-Pyr-2- Bnzl NHC(O)Me 65 CH O-Bnzl NH-4-Pyr-2- Bnzl
NHC(O)OEt 66 CH OCH.sub.2-4-Pyr NH-3-Pyr Bnzl-4- OCF.sub.2H 67 CH
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4- OCF.sub.2H 68 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-di- Bnzl-4- OMe OCF.sub.2H 69 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-di-F Bnzl-4- OCF.sub.2H 70 Z.sup.1 = N, all
OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl-4- others = CH OCF.sub.2H 71
Z.sup.1 = N, all OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4- others =
CH OCF.sub.2H 72 Z.sup.1 = N, all OCH.sub.2-4-Pyr NH-4-Pyr-2-OMe
Bnzl-4- others = CH OCF.sub.2H 73 CH O-Bnzl NH-3-Pyr Bnzl-4-Me 74
CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN Bnzl-4- OCF.sub.2H 75 CH
OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl-4- NHC(O)Me OCF.sub.2H 76 Z.sup.4
= OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3 CC(Me).sub.2OH all
others = CH 77 Z.sup.4 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3
CCO.sub.2H all others = CH 78 Z.sup.4 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF3 CCH.sub.2NMe.sub.2 all others = 79
Z.sup.4 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3 CC(O)NMe.sub.2
all others = CH 80 Z.sup.4 = CBr OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF3 all others = CH 81 Z.sup.4 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF3 CSO.sub.2NH.sub.2 all others = CH 82
Z.sup.1 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3 CC(Me).sub.2OH
all others = CH 83 Z.sup.1 = OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF3 CCO.sub.2H all others = CH 84 Z.sup.1 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF3 CCH.sub.2NMe.sub.2 all others = CH 85
Z.sup.1 = OCH.sub.2-4-Pyr NH-5-tetrazolyl Bnzl-4-CF3 CC(O)NMe.sub.2
all others = CH 86 Z.sup.1 = CBr OCH.sub.2-4-Pyr NH-5-tetrazolyl
Bnzl-4-CF3 all others = CH 87 Z.sup.1 = OCH.sub.2-4-Pyr
NH-5-tetrazolyl Bnzl-4-CF3 CSO.sub.2NH.sub.2 all others = CH 88
Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CC(Me).sub.2OH all
others = CH 89 Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3
CCO.sub.2H all others = CH 90 Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr
Bnzl-4-CF3 CCH.sub.2NMe.sub.2 all others = CH 91 Z.sup.1 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CC(O)NMe.sub.2 all others = CH
92 Z.sup.1 = CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 all others =
CH 93 Z.sup.1 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3
CSO.sub.2NH.sub.2 all others = CH 94 Z.sup.1 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(Me).sub.2OH all others = CH 95 Z.sup.1 = O-Bnzl
NH-3-Pyr Bnzl-4-F CCO.sub.2H all others = CH 96 Z.sup.1 = O-Bnzl
NN-3-Pyr Bnzl-4-F CCH.sub.2NMe.sub.2 all others = CH 97 Z.sup.1 =
O-Bnzl NH-3-Pyr Bnzl-4-F CC(O)NMe.sub.2 all others = CH 98 Z.sup.1
= CBr O-Bnzl NH-3-Pyr Bnzl-4-F all others = CH 99 Z.sup.1 = O-Bnzl
NH-3-Pyr Bnzl-4-F CSO.sub.2NH.sub.2 all other = CH 100 Z.sup.4 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CC(Me).sub.2OH all others = CH
101 Z.sup.4 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CCO.sub.2H all
others = CH 102 Z.sup.4 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3
CCH.sub.2NMe.sub.2 all others = CH 103 Z.sup.4 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF3 CC(O)NMe.sub.2 all others = CH 104 Z.sup.4 =
CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 all others = CH 105 Z.sup.4
= OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CSO.sub.2NH.sub.2 all others
= CH 106 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(Me).sub.2OH all
others = CH 107 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F CCO.sub.2H all
others = CH 108 Z.sup.4 = O-Bnzl NH-3-Pyr Bnzl-4-F
CCH.sub.2NMe.sub.2 all others = CH 109 Z.sup.4 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(O)NMe.sub.2 all others = CH 110 Z.sup.4 = CBr O-Bnzl
NH-3-Pyr Bnzl-4-F all others = CH 111 Z.sup.4 = O-Bnzl NH-3-Pyr
Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 112 Z.sup.3 =
OCH.sub.2-4-Pyr NH-4-Pyrz Bnzl-4-CF3 CC(Me).sub.2OH all others = CH
113 Z.sup.3 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CCO.sub.2H all
others = CH 114 Z.sup.3 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3
CCH.sub.2NMe.sub.2 all others = CH 115 Z.sup.3 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF3 CC(O)NMe.sub.2 all others = CH 116 Z.sup.3 =
CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 all others = CH 117 Z.sup.3
= OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CSO.sub.2NH.sub.2 all others
= CH 118 Z.sup.3 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(Me).sub.2OH all
others = CH 119 Z.sup.3 = O-Bnzl NH-3-Pyr Bnzl-4-F CCO.sub.2H all
others = CH 120 Z.sup.3 = O-Bnzl NH-3-Pyr Bnzl-4-F
CCH.sub.2NMe.sub.2 all others = CH 121 Z.sup.3 = O-Bnzl NH-3-Pyr
Bnzl-4-F CC(O)NMe.sub.2 all others = CH 122 Z.sup.3 = CBr O-Bnzl
NH-3-Pyr Bnzl-4-F all others = CH 123 Z.sup.3 = O-Bnzl NH-3-Pyr
Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 124 Z.sup.2 =
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CC(Me).sub.2OH all others = CH
125 Z.sup.2 = OCH.sub.2-4-PYr NH-4-Pyr Bnzl-4-CF3 CCO.sub.2H all
others = CH 126 Z.sup.2 = OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3
CCH.sub.2NMe.sub.2 all others = CH 127 Z.sup.2 = OCH.sub.2-4-Pyr
NH-4-Pyr Bnzl-4-CF3 CC(O)NMe.sub.2 all others = CH 128 Z.sup.2 =
CBr OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 all others = CH 129 Z.sup.2
= OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-CF3 CSO.sub.2NH.sub.2 all others
= CH 130 Z.sup.2 = O-Bnzl NH-3-Pyr Bnzl-4-F CC(Me).sub.2OH all
others = CH 131 Z.sup.2 = O-Bnzl NH-3-Pyr Bnzl-4-F CCO.sub.2H all
others = CH 132 Z.sup.2 = O-Bnzl NH-3-Pyr Bnzl-4-F
CCH.sub.2NMe.sub.2 all others = CH 133 Z.sup.2= O-Bnzl NH-3-Pyr
Bnzl-4-F CC(O)NMe.sub.2 all others = CH 134 Z.sup.2 = CBr O-Bnzl
NH-3-Pyr Bnzl-4-F all others = CH 135 Z.sup.2 = O-Bnzl NH-3-Pyr
Bnzl-4-F CSO.sub.2NH.sub.2 all others = CH 136 CH O-Bnzl NH-3-Pyr
Bnzl-4- C(Me).sub.2-OH 137 CH OCH.sub.2-3-PYr NH-3-Pyr Bnzl-4-F 138
CH OCH.sub.2-3-Pyr NH-4-Pyr Bnzl-4-F 139 CH OCH.sub.2-3-Pyr
NH-Phe-3,4-di- Bnzl-4-F OMe 140 CH OCH.sub.2-3-Pyr NH-Phe-3,4-di-F
Bnzl-4-F 141 CH OCH.sub.2-3-Pyr NH-5-Pyr-2-OMe Bnzl-4-F 142 CH
O-Bnzl NH-3-Pyr Bnzl-4- CO.sub.2Me 143 CH OCH.sub.2-3-Pyr
NH-5-tetrazolyl Bnzl-4-F 144 CH OCH.sub.2-3-Pyr NH-4-Pyr-2-OMe
Bnzl-4-F 145 CH OCH.sub.2-3-Pyr NH-5-Pyr-2-CN Bnzl-4-F 146 CH
OCH.sub.2-3-Pyr NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 147 CH O-Bnzl
NH-Phe-3-SO.sub.2Me Bnzl-4-F 148 CH O-Bnzl NH-3-Pyr Bnzl-4-CF3 149
CH O--CH.sub.2-cPr NH-Phe-3,4-di- Bnzl-4-t-Bu OMe 150 CH
O--CH.sub.2-cPr NH-5-tetrazolyl Bnzl-4-t-Bu 151 CH O--CH.sub.2-cPr
NH-4-Pyr-2-OMe Bnzl-4-t-Bu 152 CH O--CH.sub.2-cPr NH-5-Pyr-2-OMe
Bnzl-4-t-Bu 153 CH O--CH.sub.2-cPr NH-4-Pyr-2- Bnzl-4-t-Bu
NHC(O)OEt 154 CH O--CH.sub.2-cPr NH-3-Pyr Bnzl-4-F 155 CH
O--CH.sub.2-cPr NH-4-Pyr Bnzl-4-F 156 CH O--CH.sub.2-cPr
NH-Phe-3,4-di- Bnzl-4-F OMe 157 CH O--CH.sub.2-cPr NH-Phe-3,4-di-F
Bnzl-4-F 158 CH O--CH.sub.2-cPr NH-5-Pyr-2-OMe Bnzl-4-F 159 CH
O--CH.sub.2-cPr NH-5-tetrazolyl Bnzl-4-F 160 CH O--CH.sub.2-cPr
NH-4-Pyr-2-OMe Bnzl-4-F 161 CH O--CH.sub.2-cPr NH-5-Pyr-2- Bnzl-4-F
NHC(O)Me 162 CH OCH.sub.2-4-Pyr NH-3-Pyr Bnzl-4-F 163 CH
OCH.sub.2-4-Pyr NH-4-Pyr Bnzl-4-F 164 CH OCH.sub.2-4-Pyr
NH-Phe-3,4-di- Bnzl-4-F OMe 165 CH OCH.sub.2-4-Pyr NH-Phe-3,4-di-F
Bnzl-4-F 166 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-OMe Bnzl-4-F 167 CH
OCH.sub.2-4-Pyr NH-5-tetrazol Bnzl-4-F 168 CH OCH.sub.2-4-Pyr
NH-4-Pr-2-OMe Bnzl-4-F 169 CH OCH.sub.2-4-Pyr NH-5-Pyr-2-CN
Bnzl-4-F 170 CH OCH.sub.2-4-Pyr NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 171
CH OCH.sub.2-4-Pyr NH-4-Pyr-2- Bnzl-4-F NHC(O)OEt 172 CH O-Bnzl
NH-3-Pyr Bnzl-4-t-Bu 173 CH O-Bnzl NH-3-Pyr Bnzl-4-F 174 CH O-Bnzl
NH-4-Pyr Bnzl-4-F 175 CH O-Bnzl NH-Phe-3,4-di- Bnzl-4-F OMe 176 CH
O-Bnzl NH-Phe-3,4-di-F Bnzl-4-F 177 CH O-Bnzl NH-5-Pyr-2-OMe
Bnzl-4-F 178 CH O-Bnzl NH-5-tetrazolyl Bnzl-4-F 179 CH O-Bnzl
NH-4-Pyr-2-OMe Bnzl-4-F 180 CH O-Bnzl NH-5-Pyr-2-CN Bnzl-4.-F 181
CH O-Bnzl NH-5-Pyr-2- Bnzl-4-F NHC(O)Me 182 CH O-Bnzl NH-4-Pyr-2-
Bnzl-4-F NHC(O)OEt 183 CH O-Bnzl N(Me)-3-Pyr Bnzl-4-F 184 CH O-Bnzl
N(Me)-3-Pyr Bnzl-4-CF3 185 CH O-Bnzl 3-pyridylmethyl Bnzl-4--F 186
CH O-Bnzl 4-pyridylmethyl Bnzl-4-F Phe = phenyl, Bzyl = benzyl, Pyr
= pyridyl
[0067] In another embodiment, the invention encompasses a
pharmaceutical composition comprised of a compound of formula I in
combination with a pharmaceutically acceptable carrier.
[0068] Within this embodiment, the invention encompasses
pharmaceutical compositions for the treatment or prevention of
diseases or conditions benefited by the inhibition of PDE IV,
resulting in an elevation of cAMP, comprising a pharmaceutically
acceptable carrier and a non-toxic therapeutically effective amount
of compound of Formula I as described above.
[0069] The pharmaceutical compositions of the present invention
comprise a compound of Formula I as an active ingredient or a
pharmaceutically acceptable salt, thereof, and also contain a
pharmaceutically acceptable carrier and optionally other
therapeutic ingredients.
[0070] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases. Salts derived from inorganic
bases include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic salts, manganous, potassium, sodium,
zinc, and the like. Particularly preferred are the ammonium,
calcium, magnesium, potassium, and sodium salts. Salts derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines,
and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N_-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like.
[0071] The compounds described herein contain one or more
asymmetric centers and thus give rise to diastereomers and optical
isomers. The present invention includes all such possible
diastereomers as well as their racemic and resolved,
enantiomerically pure forms and pharmaceutically acceptable salts
thereof.
[0072] It will be understood that in the discussion of methods of
treatment which follows, references to the compounds of Formula I
is meant to include pharmaceutically acceptable salts.
[0073] Compounds according to the invention are selective and
potent inhibitors of PDE IV. The ability of the compounds to act in
this way may be determined by the tests described in the Examples
hereinafter.
[0074] The compounds according to the invention are thus of
particular use in the prophylaxis and treatment of human diseases
where an unwanted inflammatory response or muscular spasm (for
example bladder or alimentary smooth muscle spasm) is present and
where the elevation of cAMP levels may be expected to prevent or
alleviate the inflammation and relax muscle.
[0075] Particular uses to which the compounds of the invention may
be put include the prophylaxis and treatment of asthma, especially
inflamed lung associated with asthma, cystic fibrosis, or in the
treatment of inflammatory airway disease, chronic bronchitis,
eosinophilic granuloma, psoriasis and other benign and malignant
proliferative skin diseases, endotoxic shock, septic shock,
ulcerative colitis, Crohn's disease, reperfusion injury of the
myocardium and brain, inflammatory arthritis, osteoporosis, chronic
glomerulonephritis, atopic dermatitis, urticaria, adult and infant
respiratory distress syndrome, diabetes, diabetes insipidus,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
arterial restenosis and atherosclerosis.
[0076] Compounds of the invention also suppress neurogenic
inflammation through elevation of cAMP in sensory neurons. They
are, therefore, analgesic, antitussive and anti-hyperalgesic in
inflammatory diseases associated with irritation and pain.
[0077] Compounds of the invention also elevate cAMP in lymphocytes
and thereby suppress unwanted lymphocyte activation in immune-based
diseases such as rheumatoid arthritis, ankylosing spondylitis,
transplant rejection and graft versus host disease.
[0078] Compounds of the invention also reduce gastric acid
secretion and therefore can be used to treat conditions associated
with hypersecretion of gastric acid.
[0079] Compounds of the invention suppress cytokine synthesis by
inflammatory cells in response to immune or infectious stimulation.
They are, therefore, useful in the treatment of bacterial, fungal
or viral induced sepsis and septic shock in which cytokines such as
tumour necrosis factor (TNF) are key mediators. Also compounds of
the invention suppress inflammation and pyrexia due to cytokines
and are, therefore, useful in the treatment of inflammation and
cytokine-mediated chronic tissue degeneration which occurs in
diseases such as rheumatoid or osteoarthritis.
[0080] Over-production of cytokines such as TNF in bacterial,
fungal or viral infections, or in diseases such as cancer, leads to
cachexia and muscle wasting. Compounds of the invention ameliorate
these symptoms with a consequent enhancement of quality of
life.
[0081] Compounds of the invention also elevate cAMP in certain
areas of the brain and thereby counteract depression and memory
impairment.
[0082] Compounds of the invention suppress cell proliferation in
certain tumor cells and can be used, therefore, to prevent tumor
growth and invasion of normal tissues.
[0083] For the prevention, prophylaxis or treatment of disease, the
compounds may be administered to a mammalian patient in need of
such prevention, prophylaxis or treatment, in an amount that is
effective for preventing, controlling or treating the disease. In
addition to the treatment of warm-blooded animals such as mice,
rats, horses, cattle sheep, dogs, cats, etc., the compounds of the
invention are effective in the treatment of humans.
[0084] The compounds of Formula I may be administered orally,
topically, parenterally, by inhalation spray or rectally in the
form of a pharmaceutical composition as described herein.
[0085] The term parenteral as used herein includes subcutaneous,
intravenous, intramuscular or intrasternal injection or infusion
techniques.
[0086] The pharmaceutical composition containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known in the art for the
manufacture of pharmaceutical compositions, and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the technique described in the
U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic
therapeutic tablets for control release.
[0087] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredients is mixed with water or an oil medium, for example
peanut oil, liquid paraffin or olive oil.
[0088] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethyl-cellulose, methylcellulose,
hydroxy-propylmethycellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0089] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0090] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0091] The pharmaceutical compositions of the invention may also be
in the form of an oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and
flavouring agents.
[0092] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleagenous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0093] Compounds of Formula I may also be administered in the form
of a suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Examples of such materials include
cocoa butter and polyethylene glycols.
[0094] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compound of Formula I are
employed. (For purposes of this application, topical application
shall include mouth washes and gargles.)
[0095] Combined therapy to
[0096] The compounds of formula I can also be used in combination
with another active ingredient or ingredients. For example, for the
treatment or prevention of inflammation, the present compounds may
be used in conjunction with an antiinflammatory or analgesic agent
such as an opiate agonist, a lipoxygenase inhibitor, such as an
inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a
cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an
interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric
oxide or an inhibitor of the synthesis of nitric oxide, a
non-steroidal antiinflammatory agent, or a cytokine-suppressing
antiinflammatory agent, for example with a compound such as
acetaminophen, asprin, codeine, fentanyl, ibuprofen, indomethacin,
ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal
analgesic, sufentanyl, sunlindac, tenidap and the like. Similarly,
the instant compounds may be administered with a pain reliever; a
potentiator such as caffeine, an H2-antagonist, simethicone,
aluminum or magnesium hydroxide; a decongestant such as
phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,
ephinephrine, naphazoline, xylometazoline, propylhexedrine, or
levo-desoxyephedrine; an antiitussive such as codeine, hydrocodone,
caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a
sedating or non-sedating antihistamine such as loratidine.
[0097] Likewise, compounds of the present invention may be used in
combination with other drugs that are used in the
treatment/prevention/su- ppression or amelioration of the diseases
or conditions for which compounds of the present invention are
useful. Such other drugs may be administered, by a route and in an
amount commonly used therefor, contemporaneously or sequentially
with a compound of the present invention. When a compound of the
present invention is used contemporaneously with one or more other
drugs, a pharmaceutical composition containing such other drugs in
addition to the compound of the present invention is preferred.
Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active
ingredients, in addition to a compound of the present
invention.
[0098] Examples of other active ingredients that may be combined
with a compound of the present invention, either administered
separately or in the same pharmaceutical compositions, include, but
are not limited to: (a) VLA-4 antagonists such as those described
in U.S. Pat. No. 5,510,332, WO95/15973, WO96/01644, WO96/06108,
WO96/20216, WO96/22966, WO96/31206, WO96/40781, WO97/03094,
WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818,
WO98/54207, and WO98/58902; (b) steroids such as beclomethasone,
methylprednisolone, betamethasone, prednisone, dexamethasone, and
hydrocortisone; (c) immunosuppressants such as cyclosporin,
tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d)
antihistamines (H1-histamine antagonists) such as bromopheniramine,
chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,
diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,
methdilazine, promethazine, trimeprazine, azatadine,
cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,
terfenadine, loratadine, cetirizine, fexofenadine,
descarboethoxyloratadine, and the like; (e) non-steroidal
anti-asthmatics such as .beta.2-agonists (terbutaline,
metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and
pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium
bromide, leukotriene antagonists (zafirlukast, montelukast,
pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene
biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal
antiinflammatory agents (NSAIDs) such as propionic acid derivatives
(alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,
fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen,
ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,
pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic
acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,
diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,
ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin,
zidometacin, and zomepirac), fenamic acid derivatives (flufenamic
acid, meclofenamic acid, mefenamic acid, niflumic acid and
tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal
and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and
tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and
the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone,
oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2)
inhibitors; (h) (h) antagonists of the chemokine receptors,
especially CCR-1, CCR-2, CCR-3, CXCR-3 and CCR-5; (i) cholesterol
lowering agents such as HMG-CoA reductase inhibitors (lovastatin,
simvastatin and pravastatin, fluvastatin, atorvastatin, and other
statins), sequestrants (cholestyramine and colestipol), nicotinic
acid, fenofibric acid derivatives (gemfibrozil, clofibrat,
fenofibrate and benzafibrate), and probucol; (j) anti-diabetic
agents such as insulin, sulfonylureas, biguanides (metformin),
.alpha.-glucosidase inhibitors (acarbose) and glitazones
(troglitazone and pioglitazone); (k) preparations of interferon
beta (interferon beta-1.alpha., interferon beta-1.beta.); (1) other
compounds such as 5-aminosalicylic acid and prodrugs thereof,
antimetabolites such as azathioprine and 6-mercaptopurine, and
cytotoxic cancer chemotherapeutic agents.
[0099] Dosage levels of the order of from about 0.01 mg to about
140 mg/kg of body weight per day are useful in the treatment of the
above-indicated conditions, or alternatively about 0.5 mg to about
7 g per patient per day. For example, inflammation may be
effectively treated by the administration of from about 0.01 to 50
mg of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
[0100] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration to humans may contain from about 0.5 mg to about 5 g
of active agent compounded with an appropriate and convenient
amount of carrier material which may vary from about 5 to about 95
percent of the total composition. Unit dosage forms will generally
contain between from as low as about 1 mg to as high as about 1500
mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg,
300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
[0101] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0102] Methods of Synthesis
[0103] The compounds of Formula I of the present invention can be
prepared according to the synthetic routes outlined in Schemes I to
IV and by following the methods described herein.
Scheme 1
[0104] Compounds of Formula I may be prepared by the method
presented in Scheme 1 from an appropriately substituted anthranilic
acid or Z=Nitrogen equivalent (II). Addition of an appropriate
electrophile such as a E.sup.1Br or E.sup.1Cl (wherein E.sup.1
represents (CH.sub.2).sub.d-Ar in the presence of a base, followed
by alkaline saponification of the ester group leads to III.
Reaction of III with methyl bromoacetate, followed by
esterification with diazomethane yields IV. Reaction with methoxide
in methanol leads to the cyclization product V. Alkylation of the
indanol with the appropriate electrophile such as E.sup.2Br
(wherein E.sup.2 represents (CH.sub.2).sub.b-X in the presence of a
base and in a suitable solvent such as DMF gives VI. Reaction of VI
with an alkaline metal (such as Li, Mg or Al) derivative of the
appropriate NH.sub.2-Ar.sup.1 in a suitable solvent such as TBF
yields VII. Alternatively, VI can be first saponified with
conditions such as alcoholic NaOH, and then reacted with the
NH.sub.2-Ar.sup.1 in the presence of an amide coupling reagent such
as DCC in an appropriate solvent to give VII.
[0105] Following the same sequence of events but starting with an
anthranitrile or its Z=N equivalent (VII), one has access to the
X=CNR.sup.4R.sup.4, X=CNAr.sup.1H and X=CNR.sup.4CH.sub.2Ar.sup.1
series. 6
Scheme 2
[0106] Compounds of Formula I may alternatively be prepared by the
method presented in Scheme 2 from an appropriately substituted
indole or Z=Nitrogen equivalent (IX). Formylation in
Vilsmeier-Haack or similar conditions gives X, which in turn can be
oxidized under Baeyer-Villiger conditions to give XI. Successive
reactions with electrophiles such as bromides, chlorides or iodides
in the presence of bases and in a polar solvent gives XII, and then
XIII. The ester group of XIII is transformed in the amide as
described above in Scheme 1.
[0107] Alternatively, the reaction with the E.sup.1 electrophile
may be conducted on IX to give XV, and the E.sup.1 group carried
through the same sequence to give the same product XIV. 7
Scheme 3
[0108] Compounds of Formula I may alternatively be prepared by the
method presented in Scheme 3 from an appropriately substituted
indole or Z=Nitrogen equivalent (X). Grignard or other
organometallic reagents may be added to X or to the XVI to yield
the alcohol XVII, which in turn can be oxidized to the ketone
XVIII. The rest of the sequence to compounds of Formula I is shown
in Schemes 1 and 2.
[0109] In the case where W is H, with such reagents such as
NaBH.sub.4, the resulting primary alcohol may further be
transformed by a Mitsunobu type reaction to give XIX, which can
undergo the rest of the sequence to give compounds of Formula I.
8
Scheme 4
[0110] Compounds of Formula IX may be prepared by the method
presented in Scheme 4 from an appropriately substituted aldehyde
(XX). Ethyl azidoacetate is condensed onto the aldehyde in a strong
base such as ethoxide, and the resulting cinnamate is pyrolysed to
yield the indole compound. 9
Scheme 5
[0111] Compounds of Formula IX may also be prepared by the method
presented in Scheme 5 from an appropriately substituted methylated
nitroaromatic (XXI). This compound is treated with a strong base
such as ethoxide in ethanol, and condensed onto ethyl oxalate to
give, after saponification, the pyruvic acid XXII. This acid is
then esterified with diazomethane, for example, and then treated
with a reagent such as iron in acetic acid to give the compound IX
(Methyl ester).
Scheme 6
[0112] Compounds of formule I may be prepared by reaction of XIV
first with a suitable metallation agent, such as n-BuLi, followed
by trapping with an electrophile such as DMF to produce the
aldehyde, acetone to produce the t-alcohol, CO.sub.2 to produce the
carboxylic acid. 10
[0113] Assays for Determining Biological Activity
[0114] Measurement of whole-cell cAMP content
[0115] CHO-K1 cells were plated at a density of 10.sup.6 cells/175
cm.sup.2 containing complete media with 500 .mu.g/ml hygromycin.
The flasks were maintained in an incubator at 37.degree. C. with
5.0% CO.sub.2 for 72 hr. The media was changed and the cells were
allowed to grow overnight. The cells were washed and dissociated
from the plate with PBS containing 0.5 mM EDTA. Cellular cAMP
content was measured by centrifuging the cell suspension at 150
g.times.10 min. And resuspending the cells in a Hanks buffered salt
solution at a density of 0.2.times.10.sup.6 cells/ml. The cells
were preincubated at room temperature for 15 min. and then
incubated with 10 .mu.M prostaglandin I.sub.2 (PGI.sub.2) and the
indicated compound for an additional 10 min. Basal cAMP levels were
determined by incubating the cells in 0.1% DMSO. The incubations
were terminated by the addition of HCl (0.1N final) and the cells
measured for cAMP as described below.
[0116] Determinations of whole-cell cAMP content were performed by
incubating 100 .mu.l reconstituted rabbit anti-succinyl cAMP serum
with 100 .mu.l of the whole-cell reaction or known cAMP standard
and 30 pmol of .sup.125I-cAMP TME in a ScintiStrip.TM. well (300
.mu.l final volume) at room temperature for 18 h. Total cpm
(B.sub.O) was determined in the absence of sample of cAMP standard.
The reaction mixture was then aspirated out of the well, and the
individual wells were counted in a Beckman L S 6000SC with the
window open from 10-999 for 1 min. The data were expressed as
%B/B.sub.O=[(standard or sample cpm - non-specific cpm)/(B.sub.O
cpm - non-specific cpm)].times.100. Non-specific cpm were
determined by incubating only the .sup.125I-cAMP TME with assay
buffer (50 mM acetate; pH 5.8) in the ScintiStrip.TM. well. All
determinations were performed in triplicate.
[0117] Phosphodiesterase Scintillation Proximity Assay
[0118] CHO-K1 cells were lysed by sonication for 10 secs at a power
setting of 50% (Braunsonic Model 2000) in an ice cold solution
containing 50 mM Tris, pH 7.5; 1 mM EDTA; and 200 .mu.M
.beta.-mercaptoethanol. The soluble and particulate fractions of
the cell were obtained by centrifuging the sonicate for 90 min. at
100,000.times.g at 4.degree. C. PDE activity was measured in a
solution containing 50 mM Tris, pH 7.5; 10 mM MgCl.sub.2; 1 mM
EDTA; and 100 nM (or indicated) .sup.3H-cAMP (100 .mu.l final
volume) in the presence of varying concentrations of inhibitor. The
reaction mixture containing enzyme was incubated for 10 min. at
30.degree. C. in 96-well View Plates (Packard), and terminated by
the addition of 50 .mu.l Phosphodiesterase Scintillation Proximity
Assay (SPA) Beads (Amersham) containing 18 mM ZnSO.sub.4. The
amount of .sup.3H-cAMP hydrolysis was determined by counting the
plates in a Wallac 1450 .mu.Beta LSC counter.
[0119] The Elevation of cAMP in Leukocytes
[0120] The effect of compounds of the invention on intracellular
cAMP was investigated using human neutrophils or guinea pig
eosinophils. Human neutrophils were separated from peripheral
blood, incubated with dihydrocytochalasin B and the test compound
for 10 min and then stimulated with FMLP. Guinea pig eosinophils
were harvested by peritoneal lavage of animals previously treated
with intra-peritoneal injections of human serum. Eosinophils were
separated from the peritoneal exudate and incubated with
isoprenaline and test compound. With both cell types, suspensions
were centrifuged at the end of the incubation, the cell pellets
were resuspended in buffer and boiled for 10 min prior to
measurement of cAMP by specific radioimmunoassay (DuPont).
[0121] The most potent compounds according to the Examples induced
a concentration-dependent elevation of cAMP in neutrophils and/or
eosinophils at concentrations of 0.1 nM to 1 .mu.M.
[0122] Anti-allergic Activity in vivo
[0123] Compounds of the invention were tested for effects on an
IgE-mediated allergic pulmonary inflammation induced by inhalation
of antigen by sensitised guinea pigs. Guinea pigs were initially
sensitised to ovalbumin under mild cyclophosphamide-induced
immunosuppression, by intraperitoneal injection of antigen in
combinations with aluminium hydroxide and pertussis vaccine.
Booster doses of antigen were given two and four weeks later and at
six weeks, animals were challenged with aerosolised ovalbumin
whilst under cover of an intraperitoneally administered
anti-histamine agent (mepyramine). After a further 48 h, bronchial
alveolar ravages (BAL) were performed and the numbers of
eosinophils and other leukocytes in the BAL fluids were counted.
The lungs were also removed for histological examination for
inflammatory damage. Administration of compounds of the Examples
(0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h
following antigen challenge, lead to a significant reduction in the
eosinophilia and the accumulation of other inflammatory leukocytes.
There was also less inflammatory damage in the lungs of animals
treated with compounds of the Examples.
[0124] SPA based PDE activity assay protocol
[0125] Compounds which inhibit the hydrolysis of cAMP to AMP by the
type-IV cAMP-specific phosphodiesterases were screened in 96-well
plate format as follows:
[0126] In a 96 well-plate at 30.degree. C. was added the test
compound (dissolved in 2 ul DMSO), 188 .mu.l of substrate buffer
containing [2,8-.sup.3H] adenosine 3', 5'-cyclic phosphate (cAMP,
100 nM to 50 .mu.M), 10 mM MgCl.sub.2, 1 mM EDTA, 50 mM Tris, pH
7.5. The reaction was initiated by the addition of 10 .mu.l of
human recombinant PDE-IV (the amount was controlled so that 10%
product was formed in 10 min. at 30.degree. C.). The reaction was
stopped after 10 min. by the addition of 1 mg of PDE-SPA beads
(Amersham). The product AMP generated was quantified on a Microbeta
96-well plate counter. The signal in the absence of enzyme was
defined as the background. 100% activity was defined as the signal
detected in the presence of enzyme and DMSO with the background
subtracted. Percentage of inhibition was calculated accordingly.
IC.sub.50 value was approximated with a non-linear regression fit
of the standard 4-parameter/multiple binding sites equation from a
ten point titration.
[0127] LPS and fMLP-Induced TNF-.alpha. and LTB.sub.4 Assays in
Human Whole Blood
[0128] Whole blood provides a protein and cell-rich milieu
appropriate for the study of biochemical efficacy of
anti-inflammatory compounds such as PDE IV-selective inhibitors.
Normal non-stimulated human blood does not contain detectable
levels of TNF-.alpha. and LTB.sub.4. Upon stimulation with LPS,
activated monocytes expresss and secrete TNF-.alpha. up to 8 hours
and plasma levels remain stable for 24 hours. Published studies
have shown that inhibition of TNF-.alpha. by increasing
intracellular cAMP via PDE IV inhibition and/or enhanced adenylyl
cyclase activity occurs at the transcriptional level. LTB.sub.4
synthesis is also sensitive to levels of intracellular cAMP and can
be completely inhibited by PDE IV-selective inhibitors. As there is
little LTB.sub.4 produced during a 24 hour LPS stimulation of whole
blood, an additional LPS stimulation followed by fMLP challenge of
human whole blood is necessary for LTB.sub.4 synthesis by activated
neutrophils. Thus, using the same blood sample it is possible to
evaluate the potency of a compound on two surrogate markers of PDE
IV activity in the whole blood.
[0129] Fresh blood was collected in heparinized tubes by
venipuncture from healthy human volunteers (male and female). These
subjects had no apparent inflammatory conditions and had not taken
any NSAIDs for at least 4 days prior to blood collection. Five
hundred .mu.L aliquots of blood were pre-incubated with either 2
.mu.L of vehicle (DMSO) or 2 .mu.L test compound at varying
concentrations for 15 minutes at 37.degree. C. This was followed by
the addition of either 10 .mu.L vehicle (PBS) as blanks or 10 .mu.L
LPS (1 .mu.g/ml final concentration, Sigma Chem, #L-2630 from E.
coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24
hours of incubation at 37.degree. C., another 10 .mu.L of PBS
(blank) or 10 .mu.L of LPS (1 .mu.g/ml final concentration) was
added to blood and incubated for 30 minutes at 37.degree. C. The
blood was then challenged with either 10 .mu.L of PBS (blank) or 10
.mu.L of fMLP (1 .mu.M final concentration, Sigma Chem #F-3506;
diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37.degree. C. The
blood samples were centrifuged at 1500.times.g for 10 minutes at
4.degree. C. to obtain plasma. A 50 .mu.L aliquot of plasma was
mixed with 200 .mu.L methanol for protein precipitation and
centrifuged as above. The supernatant was assayed for LTB.sub.4
using an enzyme immunoassay kit (Cayman Chemicals #520111)
according to the manufacturer's procedure. TNF-.alpha. was assayed
in diluted plasma (in PBS) using an ELISA kit (Cistron
Biotechnology) according to manufacturer's procedure.
[0130] Assays for Determining Biological Activity
[0131] Measurement of whole-cell cAMP content
[0132] CHO-K1 cells were plated at a density of 10.sup.6 cells/175
cm.sup.2 containing complete media with 500 .mu.g/ml hygromycin.
The flasks were maintained in an incubator at 37.degree. C. with
5.0% CO.sub.2 for 72 hr. The media was changed and the cells were
allowed to grow overnight. The cells were washed and dissociated
from the plate with PBS containing 0.5 mM EDTA. Cellular cAMP
content was measured by centrifuging the cell suspension at 150
g.times.10 min. And resuspending the cells in a Hanks buffered salt
solution at a density of 0.2.times.10.sup.6 cells/ml. The cells
were preincubated at room temperature for 15 min. and then
incubated with 10 .mu.M prostaglandin I.sub.2 (PGI.sub.2) and the
indicated compound for an additional 10 min. Basal cAMP levels were
determined by incubating the cells in 0.1% DMSO. The incubations
were terminated by the addition of HCl (0.1N final) and the cells
measured for cAMP as described below.
[0133] Determinations of whole-cell cAMP content were performed by
incubating 100 .mu.l reconstituted rabbit anti-succinyl cAMP serum
with 100 .mu.l of the whole-cell reaction or known cAMP standard
and 30 pmol of .sup.125I-cAMP TME in a ScintiStrip.TM. well (300
.mu.l final volume) at room temperature for 18 h. Total cpm
(B.sub.O) was determined in the absence of sample of cAMP standard.
The reaction mixture was then aspirated out of the well, and the
individual wells were counted in a Beckman LS 6000SC with the
window open from 10-999 for 1 min. The data were expressed as
%B/B.sub.O=[(standard or sample cpm - non-specific cpm) / (B.sub.O
cpm - non-specific cpm)].times.100. Non-specific cpm were
determined by incubating only the .sup.125I-cAMP TME with assay
buffer (50 mM acetate; pH 5.8) in the ScintiStrip.TM. well. All
determinations were performed in triplicate.
[0134] Phosphodiesterase Scintillation Proximity Assay
[0135] CHO-K1 cells were lysed by sonication for 10 secs at a power
setting of 50% (Braunsonic Model 2000) in an ice cold solution
containing 50 mM Tris, pH 7.5; 1 mM EDTA; and 200 .mu.M
.beta.-mercaptoethanol. The soluble and particulate fractions of
the cell were obtained by centrifuging the sonicate for 90 min. at
100,000.times.g at 4.degree. C. PDE activity was measured in a
solution containing 50 mM Tris, pH 7.5; 10 mM MgCl.sub.2; 1 mM
EDTA; and 100 nM (or indicated) .sup.3H-cAMP (100 .mu.l final
volume) in the presence of varying concentrations of inhibitor. The
reaction mixture containing enzyme was incubated for 10 min. at
30.degree. C. in 96-well View Plates (Packard), and terminated by
the addition of 50 .mu.l Phosphodiesterase Scintillation Proximity
Assay (SPA) Beads (Amersham) containing 18 mM ZnSO.sub.4. The
amount of .sup.3H-cAMP hydrolysis was determined by counting the
plates in a Wallac 1450 .mu.Beta LSC counter.
[0136] The Elevation of cAMP in Leukocytes
[0137] The effect of compounds of the invention on intracellular
cAMP was investigated using human neutrophils or guinea pig
eosinophils. Human neutrophils were separated from peripheral
blood, incubated with dihydrocytochalasin B and the test compound
for 10 min and then stimulated with FMLP. Guinea pig eosinophils
were harvested by peritoneal lavage of animals previously treated
with intra-peritoneal injections of human serum. Eosinophils were
separated from the peritoneal exudate and incubated with
isoprenaline and test compound. With both cell types, suspensions
were centrifuged at the end of the incubation, the cell pellets
were resuspended in buffer and boiled for 10 min prior to
measurement of cAMP by specific radioimmunoassay (DuPont).
[0138] The most potent compounds according to the Examples induced
a concentration-dependent elevation of cAMP in neutrophils and/or
eosinophils at concentrations of 0.1 nM to 1 .mu.M.
[0139] Anti-allergic Activity in vivo
[0140] Compounds of the invention were tested for effects on an
IgE-mediated allergic pulmonary inflammation induced by inhalation
of antigen by sensitised guinea pigs. Guinea pigs were initially
sensitised to ovalbumin under mild cyclophosphamide-induced
immunosuppression, by intraperitoneal injection of antigen in
combinations with aluminium hydroxide and pertussis vaccine.
Booster doses of antigen were given two and four weeks later and at
six weeks, animals were challenged with aerosolised ovalbumin
whilst under cover of an intraperitoneally administered
anti-histamine agent (mepyramine). After a further 48 h, bronchial
alveolar lavages (BAL) were performed and the numbers of
eosinophils and other leukocytes in the BAL fluids were counted.
The lungs were also removed for histological examination for
inflammatory damage. Administration of compounds of the Examples
(0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h
following antigen challenge, lead to a significant reduction in the
eosinophilia and the accumulation of other inflammatory leukocytes.
There was also less inflammatory damage in the lungs of animals
treated with compounds of the Examples.
[0141] SPA based PDE activity assay protocol
[0142] Compounds which inhibit the hydrolysis of cAMP to AMP by the
type-IV cAMP-specific phosphodiesterases were screened in 96-well
plate format as follows:
[0143] In a 96 well-plate at 30.degree. C. was added the test
compound (dissolved in 2 ul DMSO), 188 .mu.l of substrate buffer
containing [2,8-.sup.3H] adenosine 3', 5'-cyclic phosphate (cAMP,
100 nM to 50 .mu.M), 10 mM MgCl.sub.2, 1 mM EDTA, 50 mM Tris, pH
7.5. The reaction was initiated by the addition of 10 .mu.l of
human recombinant PDE-IV (the amount was controlled so that
.about.10% product was formed in 10 min. at 30.degree. C.). The
reaction was stopped after 10 min. by the addition of 1 mg of
PDE-SPA beads (Amersham). The product AMP generated was quantified
on a Microbeta 96-well plate counter. The signal in the absence of
enzyme was defined as the background. 100% activity was defined as
the signal detected in the presence of enzyme and DMSO with the
background subtracted. Percentage of inhibition was calculated
accordingly. IC.sub.50 value was approximated with a non-linear
regression fit of the standard 4-parameter/multiple binding sites
equation from a ten point titration.
[0144] LPS and fMLP-Induced TNF-.alpha. and LTB.sub.4 Assays in
Human Whole Blood
[0145] Whole blood provides a protein and cell-rich milieu
appropriate for the study of biochemical efficacy of
anti-inflammatory compounds such as PDE IV-selective inhibitors.
Normal non-stimulated human blood does not contain detectable
levels of TNF-.alpha. and LTB.sub.4. Upon stimulation with LPS,
activated monocytes expresss and secrete TNF-.alpha. up to 8 hours
and plasma levels remain stable for 24 hours. Published studies
have shown that inhibition of TNF-.alpha. by increasing
intracellular cAMP via PDE IV inhibition and/or enhanced adenylyl
cyclase activity occurs at the transcriptional level. LTB.sub.4
synthesis is also sensitive to levels of intracellular cAMP and can
be completely inhibited by PDE IV-selective inhibitors. As there is
little LTB.sub.4 produced during a 24 hour LPS stimulation of whole
blood, an additional LPS stimulation followed by fMLP challenge of
human whole blood is necessary for LTB.sub.4 synthesis by activated
neutrophils. Thus, using the same blood sample it is possible to
evaluate the potency of a compound on two surrogate markers of PDE
IV activity in the whole blood.
[0146] Fresh blood was collected in heparinized tubes by
venipuncture from healthy human volunteers (male and female). These
subjects had no apparent inflammatory conditions and had not taken
any NSAIDs for at least 4 days prior to blood collection. Five
hundred .mu.L aliquots of blood were pre-incubated with either 2
.mu.L of vehicle (DMSO) or 2 .mu.L test compound at varying
concentrations for 15 minutes at 37.degree. C. This was followed by
the addition of either 10 .mu.L vehicle (PBS) as blanks or 10 .mu.L
LPS (1 .mu.g/ml final concentration, Sigma Chem, #L-2630 from E.
coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24
hours of incubation at 37.degree. C., another 10 .mu.L of PBS
(blank) or 10 .mu.L of LPS (1 .mu.g/ml final concentration) was
added to blood and incubated for 30 minutes at 37.degree. C. The
blood was then challenged with either 10 .mu.L of PBS (blank) or 10
.mu.L of fMLP (1 .mu.M final concentration, Sigma Chem #F-3506;
diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37.degree. C. The
blood samples were centrifuged at 1500.times.g for 10 minutes at
4.degree. C. to obtain plasma. A 50 .mu.L aliquot of plasma was
mixed with 200 .mu.L methanol for protein precipitation and
centrifuged as above. The supernatant was assayed for LTB.sub.4
using an enzyme immunoassay kit (Cayman Chemicals #520111)
according to the manufacturer's procedure. TNF-.alpha. was assayed
in diluted plasma (in PBS) using an ELISA kit (Cistron
Biotechnology) according to manufacturer's procedure.
EXAMPLES
[0147] The invention will now be illustrated in the following
non-limiting Examples in which, unless otherwise stated:
[0148] 1. All the end products of the formula I were analyzed by
NMR, TLC and elementary analysis or mass spectroscopy.
[0149] 2. Intermediates were analyzed by NMR and TLC.
[0150] 3. Most compounds were purified by flash chromatography on
silica gel, recrystallization and/or swish (suspension in a solvent
followed by filtration of the solid).
[0151] 4. The course of reactions was followed by thin layer
chromatography (TLC) and reaction times are given for illustration
only.
[0152] The following intermediates were prepared according to
literature procedures, or purchased from the following vendor:
[0153] 1. 4-Bromo-2-nitro-phenylpyruvic acid: Kosuge, T.; Ishida,
H.; Inaba, A.; Nukaya, H. Chem. Pharm. Bull. 1985, 33,
1414-1419.
[0154] 2. Ethyl 3-aminoindole-2-carboxylate: Unangst, P. C. J.
Heterocyclic Chem. 1983, 20, 495-499.
[0155] 3. Ethyl 5-bromoindole-2-carboxylate: BIOSYNTH AG.
[0156] 4. Lithium 3-pyridylamide has been prepared such as lithium
N-isopropylcyclohexylamide: Paquette, L. A.; Ewing, G. D. J. Org.
Chem. 1975, 40, 2965-2966.
Example 1
{1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)INDOL-2-YL}-N-(3-PYRIDYL)FORM-
AMIDE (COMPOUND 173)
[0157] Step 1: Methyl 2-{[(4-fluorophenyl)methyl]amino}benzoate
[0158] A suspension of 77 g of potassium carbonate in a mixture of
100 mL of methyl ethyl ketone, 50 g of 4-fluorobenzyl bromide and
26 mL of the methyl 2-aminobenzoate was refluxed for 8 h, cooled to
room temperature, filtered and concentrated. Filtration on 600 mL
of silica gel and washing with 10% ethyl acetate in hexane afforded
the desired material as a yellow oil (41 g, 85% purity). This
material was used as such for the next step.
[0159] Step 2: Methyl
1-[(4-fluorophenyl)methyl]-3-hydroxyindole-2-carboxy- late
[0160] A solution of the previous ester (36 g) in 90 mL of MeOH, 27
mL of 10N aqueous NaOH and 225 mL of THF was refluxed for 2 h. The
reaction mixture was poured into 550 mL of 1N HCl and extracted
three times with ethyl acetate. The organic phase was washed with
brine and dried over MgSO.sub.4. After evaporation, the solid was
swished in 10% ether in hexane.
[0161] This solid was then combined with 28 mL of methyl
bromoacetate and 37 g of K.sub.2CO.sub.3, in solution in 225 mL of
MeOH and 450 mL H.sub.2O. The mixture was refluxed for 18 h. The
cooled reaction mixture was poured onto 65 mL of concentrated HCl
in 700 mL of ice, and extracted with ethyl acetate. The organic
extracts were dried over MgSO.sub.4, titrated with an ether
solution of CH.sub.2N.sub.2 and the solvents were evaporated under
vacuum to give the crude diester.
[0162] This crude diester was dissolved in 450 mL of MeOH
containing 20 g of sodium methoxide, and refluxed for 30 min. This
mixture is then cooled and acidified with 2N HCl and extracted with
ethyl acetate. The organic phase was dried over MgSO.sub.4 and
evaporated to dryness. The solid is swished in 200 mL of 5% ethyl
acetate in hexane to give the title compound as a white solid.
[0163] .sup.1H NMR (acetone-d.sub.6) .delta. 3.91 (s, 3H), 5.69 (s,
2H), 7.04 (t, 2H), 7.10 (m, 3H), 7.37 (t, 1H), 7.51 (d, 1H), 7.72
(d, 1H), 8.7 (s, 1H).
[0164] Step 3:
1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)indole-2-carbox- ylic
acid
[0165] To a solution 5.3 g of the previous ester and 2.53 mL of
benzyl bromide in 17 mL of methyl ethyl ketone was added 3.18 g of
K.sub.2CO.sub.3. The mixture was refluxed for 2 h and then cooled
to room temperature. It was then filtered, the solids were washed
with toluene and the combined liquid phases evaporated. Flash
chromatography (toluene) yielded the methyl ester of the title
compound as an orange solid. This ester was dissolved in 23 mL of
ethanol and 5 mL water, and 2.3 mL of 10N NaOH was added. The
mixture was heated for 40 min at 90.degree. C. and then cooled.
Acidification with 1N HCl and extraction with ethyl acetate
yielded, after evaporation, an off-white solid.
[0166] .sup.1H NMR (CDCl.sub.3) .delta. 5.48 (s, 2H), 5.75 (s, 2H),
6.93 (t, 2H), 7.02 (t, 2H), 7.16 (m, 1H), 7.39 (m, 7H), 7.76 (d,
1H).
[0167] Step 4: {1-[(4-Fluorophenyl)methyl]-3-(phenylmethoxy)
indol-2-yl}-N-(3-pyridyl) formamide
[0168] Into a dry 25 mL round bottom flask was placed
1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy) indole-2-carboxylic
acid (50 mg) along with benzene (2.0 mL), i-Pr.sub.2NEt (0.2 mL)
followed by SOCl.sub.2 (20 .mu.L) and allowed to stir at room
temperature for 0.5 hours. To the resulting mixture was then added
3-aminopyridine (20 mg) and stirred for an additional 4 hours. At
this time, the reaction mixture was poured into a separatory funnel
containing 25 mL H.sub.2O/25 mL EtOAc, the layers were seperated
and the aqueous layer was extracted with EtOAc (2.times.25 mL). The
combined organic layers were dried over anhydrous MgSO.sub.4,
concentrated and the resulting material was purified by flash
chromatography eluting with 50% EtOAc/hexanes to provide the title
amide (14.1 mg) as a light yellow solid.
[0169] .sup.1H NMR (CDCl.sub.3) .delta. 5.45 (s, 2H), 5.90 (s, 2H),
6.92 (m, 2H), 7.08 (m, 2H), 7.20 (m, 2H), 7.40 (m, 7H), 7.82 (m,
1H), 8.02 (m, 1H), 8.04 (s, 1H), 8.28 (s, 1H), 9.55 (s, 1H). MS
(+APCI) m/z 452.2 (M+H).sup.+
Example 2
{1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)INDOL-2-YL}-N-[3-(METHYLSULFO-
NYL) PHENYL]FORMAMIDE (COMPOUND 147)
[0170] Into a dry 50 mL round bottom flask was placed
1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy) indole-2-carboxylic
acid (50 mg) along with dry THF (5.0 mL), i-Pr.sub.2NEt (0.1 mL),
cooled to 0.degree. C., added MsCl (10 .mu.L) and allowed to stir
for 0.5 hours. To this cold stirred solution
3-(methylsulfonyl)aniline (65 mg) was added and allowed to stir at
room temperature for 2 hours. The resulting reaction mixture was
poured into a separatory funnel containing 50 mL H.sub.2O/50 mL
EtOAc, the layers were separated, the aqueous layer was extracted
with EtOAc (2.times.50 mL), the combined organic layers were washed
with brine, dried over anhydrous MgSO.sub.4 and concentrated. The
resulting material was further purified by flash chromatography
eluting with 50% EtOAc/hexanes to provide 42.4 mg of the title
amide as an off-white solid.
[0171] .sup.1H NMR (acetone-d.sub.6) .delta. 3.10 (s, 2H), 5.59 (s,
2H), 5.96 (s, 2H), 7.00 (m, 2H), 7.17 (m, 3H), 7.43 (m, 4H), 7.56
(m, 6H), 7.98 (d, 1H), 8.27 (m, 1H), 9.82 (s, 1H).
Example 3
{1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)
INDOL-2-YL}-N-(3-PYRIDYLMETH- YL) FORMAMIDE (COMPOUND 185)
[0172] Following the procedure describing the preparation of
example 166, 1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)
indole-2-carboxylic acid (50 mg) in THF (3.0 mL) at 0.degree. C.
was treated with i-Pr.sub.2NEt (0.1 mL), MsCl (10 .mu.L), stirred
for 0.5 hours and then added 3-(aminomethyl)pyridine (20 mg). After
work-up and purification by flash chromatography eluting with 30%
EtOAc/hexanes the title amide (27.4 mg) was isolated as a light
yellow oil.
[0173] .sup.1H NMR (acetone-d.sub.6) .delta. 4.52 (d, 2H), 5.37 (s,
2H), 6.97 (m, 2H), 7.07 (m, 3H), 7.30 (m, 7H), 7.58 (m, 1H), 7.61
(m, 1H), 7.82 (m, 1H), 8.18 (m, 1H), 8.46 (m, 1H), 8.54 (m, 1H). MS
(+APCI) m/z 466.4 (M+H).sup.+.
Example 4
{1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)
INDOL-2-YL}-N-(4-PYRIDYLMETH- YL) FORMAMIDE (COMPOUND 186)
[0174] Following the procedure describing the preparation of
example 166, 1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)
indole-2-carboxylic acid (50 mg) in THF (5.0 mL) at 0.degree. C.
was treated with i-Pr.sub.2NEt (0.1 mL), MsCl (10 .mu.L) and after
0.5 hours 4-aminomethylpyridine (20 mg) was added to the reaction
mixture. After work-up and purification by flash chromatography
eluting with 20% EtOAc/hexanes the title amide (15 mg) was obtained
as a light yellow oil.
[0175] .sup.1H NMR (acetone-d.sub.6) .delta. 4.50 (m, 2H), 5.46 (s,
2H), 5.95 (s, 2H), 7.00 (m, 2H), 7.16 (m, 5H), 7.35 (m, 4H), 7.40
(m, 2H), 7.52 (m, 1H), 7.85 (m, 1H), 8.16 (m, 1H), 8.46 (m,
2H).
Example 5
METHY
4-{[3-(PHENYLMETHOXY)-2-(N-(3-PYRIDYL)CARBAMOYL]METHYL}BENZOATE
(COMPOUND 142)
[0176] Into a 100 mL round bottom flask was placed methyl
3-(phenylmethoxy)indole-2-carboxylate (1.0 g) along with TBF (20
mL). To this stirred solution at room temperature was added lithium
3-pyridylamide (0.3M in TBF) until TLC indicated the consumption of
starting material. The resulting reaction mixture was poured into a
separatory funnel containing 50 mL H.sub.2O/100 mL EtOAc, the
layers were separated and the organic layer was washed with a 5%
aqueous AcOH solution (2.times.50 mL). The organic layer was washed
with brine, dried over anhydrous MgSO.sub.4, concentrated and the
residue was purified by flash chromatography eluting with 50%
EtOAc/hexanes to provide 550 mg of the corresponding amide. To a
flask containing the above amide (300 mg) in DMF (5.0 mL) at
0.degree. C. was added 80 mg of a NaH suspension (60% in oil) and
allowed to stir at room temperature for 0.5 hours. To this mixture
was then added methyl 4-(bromomethyl)benzoate (225 mg) and the
reaction was allowed to stir at room temperature overnight. At this
time, the reaction mixture was poured into a separatory funnel
containing 50 mL H.sub.2O/50 mL EtOAc, the layers were separated
and the aqueous layer was extracted with EtOAc (2.times.25 mL). The
combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4, concentrated and purified by flash
chromatography eluting with 30% EtOAc/hexanes. The title amide (175
mg) was obtained as an off-white solid.
[0177] .sup.1H NMR (acetone-d.sub.6) .delta. 3.82 (s, 3H), 5.62 (s,
2H), 6.06 (s, 2H), 7.23 (m, 4H), 7.36 (m, 4H), 7.55 (m, 3H), 7.90
(m, 2H), 7.98 (m, 2H), 8.42 (m, 1H), 8.46 (d, 1H), 9.66 (s, 1H). MS
(+APCI) m/z 492.4 (M+H).sup.+.
Example 6
(1-{[4-(1-HYDROXY-ISOPROPYL)PHENYL]METHYL]-3-(PHENYLMETHOXY)
INDOL-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 136)
[0178] Into a 50 mL round bottom flask was placed the above
benzoate (example 5) (100 mg) along with THF (10 mL) and, to this
stirred solution, was added MeMgCl (0.4 mL, 3.0M solution in THF)
and allowed to stir at room temperature for four hours. At this
time, the reaction mixture was quenched by the addition of 10 mL of
a saturated aqueous NH.sub.4Cl solution and this mixture was poured
into a separatory funnel containing 50 mL H.sub.2O/50 mL EtOAc. The
layers were separated, the aqueous layer was extracted with EtOAc
(50 mL) and the combined organic layers were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated. The collected
material was further purified by flash chromatography eluting with
50% EtOAc/hexanes to provide the title alcohol (30 mg) as a light
yellow solid.
[0179] .sup.1H NMR (acetone-d.sub.6) .delta. 1.42 (s, 6H), 5.60 (s,
2H), 5.97 (s, 2H), 7.05 (d, 2H), 7.18 (m, 1H), 7.25 (m, 1H), 7.57
(m, 31), 7.97 (m, 2H), 8.24 (m, 1H), 8.49 (d, 1H), 9.67 (s, 1H). MS
(+APCI) m/z 492.5 (M+H).sup.+.
Example 7
{1-[(4-METHYLPHENYL)METHYL]-3-(PHENYLMETHOXY)
INDOL-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 73)
[0180] Following the procedure describing the preparation of
example 6, methyl 3-(phenylmethoxy)indole-2-carboxylate (100 mg) in
DMF (5.0 mL) was treated with 12 mg of a NaH suspension (60% in
oil) followed by 4-methybenzyl bromide (100 mL). After work-up the
crude alkylated material was taken up in dry THF (10 mL) and
treated with the lithium 3-pyridylamide (0.3M in TBF) solution as
described previously. Following work-up and purification by flash
chromatography the title indole (58.7 mg) was obtained as a white
solid.
[0181] .sup.1H NMR (acetone-d.sub.6) .delta. 2.22 (s, 3H), 5.59 (s,
2H), 5.94 (s, 2H), 7.01 (m, 4H), 7.16 (m, 1H), 7.25 (m, 1H), 7.38
(m, 1H), 7.53 (m, 3H), 7.99 (m, 2H), 8.23 (m, 1H), 8.49 (d, 1H),
9.65 (s, 1H).
Example 8
(1-{[4-(TERT-BUTYL)PHENYL)METHYL}-3-(PHENYLMETHOXY)
INDOL-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 172)
[0182] Into a round bottom flask was placed methyl
3-(phenylmethoxy)indole- -2-carboxylate (50 mg) along with DMF (1.0
mL), THF (1.0 mL) and 10 mg of a NaH suspension (60% in oil). To
this stirred mixture was added 4-tert-butylbenzyl bromide and
allowed to stir at room temperature overnight. At this time, the
reaction mixture was diluted with H.sub.2O, poured into a teflon
fritted cartridge and extracted with CH.sub.2Cl.sub.2. The filtrate
was concentrated and then treated with THF/H.sub.2O(5.0 mL, 1:1),
MeOH (2.0 mL), NaOH (1 mL of a 1N aq. solution) and allowed to stir
at room temperature overnight. At this time, the reaction mixture
was acidified to pH 4 with an aqueous 1N HCl solution, diluted with
2 mL H.sub.2O, extracted with CH.sub.2Cl.sub.2 through a teflon
fritted cartridge as above and the filtrate was concentrated. The
resulting crude carboxylic acid was taken up in THF (2.0 mL) and
treated with i-Pr.sub.2NEt (0.1 mL), MsCl (10 .mu.L) followed by
3-aminopyridine (50 mg) as described previously for the preparation
of example 166. After work-up and purification by flash
chromatography 10.6 mg of the title amide was isolated.
[0183] .sup.1H NMR (acetone-d.sub.6) .delta. 1.22 (s, 9H), 5.59 (s,
2H), 5.96 (s, 2H), 7.05 (m, 2H), 7.17 (m, 1H), 7.32 (m, 7H), 7.57
(m, 3H), 7.97 (m, 2H), 8.24 (m, 1H), 8.49 (d, 1H), 9.68 (s, 1H). MS
(+APCI) m/z 490.6 (M+H).sup.+.
Example 9
(1-{[4-(TRIFLUORMETHYL)PHENYL]METHYL}-3-(PHENYL
METHOXY)INDOL-2-YL)-N-(3-P- YRIDYL) FORMAMIDE (COMPOUND 148)
[0184] Following the experimental procedure describing the
preparation of example 193, 9.8 mg of the title amide was
isolated.
[0185] .sup.1H NMR (acetone-d.sub.6) .delta. 5.63 (s, 2H), 6.08 (s,
2H), 7.24 (m, 4H), 7.36 (m, 4H), 7.57 (m, 5H), 7.97 (m, 1H), 8.23
(d, 1H), 8.25 (d, 1H), 8.46 (d, 1H), 9.67 (s, 1H). MS (+APCI) m/z
502.4 (M+H).sup.+.
Example 10
(1- {[4-(DIFLUOROMETHOXY)PHENYL]METHYL}-3-(PHENYL
METHOXY)INDOL-2-YL)-N-(3- -PYRIDYL) FORMAMIDE (COMPOUND 16)
[0186] Following the general procedure describing the preparation
of example 8, 3-(phenylmethoxy)indole-2-carboxylate (100 mg) in DMF
(2.0 mL) was treated with 10 mg of a NaH suspension (60% in oil)
followed by 4-(difluoromethoxy)benzyl bromide (120 mL). After
work-up the crude alkylated material was taken up in THF (5.0 mL)
and treated with excess lithium 3-pyridylamide (0.3M in THF).
Following the usual work-up and purification as described
previously, the title amide (50.6 mg) was obtained as a white
solid.
[0187] .sup.1H NMR (acetone-d.sub.6) .delta. 5.59 (s, 2H), 5.96 (s,
2H), 7.06-6.70 (m, 3H), 7.17 (m, 3H), 7.25 (m, 1H), 7.35 (m, 4H),
7.55 (m, 3H), 7.96 (m, 2H), 8.24 (m, 1H), 8.48 (d, 1H), 9.66 (s,
11H). MS (+APCI) m/z 500.5 (M+H).sup.+.
Example 11
{3-(CYCLOPROPYLMETHOXY)-1-[(4-FLUOROPHENYL)METHYL]INDOL-2-YL}-N-(3-PYRIDYL-
)FORMAMIDE (COMPOUND 154)
[0188] Step 1:
{1-[(4-Fluorophenyl)methyl]-3-methoxyindol-2-yl}-N-(3-pyrid-
yl)formamide
[0189] A solution containing 102 mg of methyl
1-[(4-fluorophenyl)methyl]-3- -hydroxyindole-2-carboxylate, 74 mg
of MeOH and 152 mg of di-tert-butyl azodicarboxylate in 1.2 mL of
THF and 0.6 mL of CH.sub.2Cl.sub.2 was treated dropwise with a
solution containing 171 mg of triphenylphosphine in 0.6 mL of
CH.sub.2Cl.sub.2. The resulting reaction mixture was stirred
overnight at room temperature. The organic solvents were removed
under vacuum and the crude mixture was treated with 11 mL of a
solution of lithium 3-pyridylamide (0.3M in THF). The organic
solvents were removed under vacuum, CH.sub.2Cl.sub.2 was added and
the organic phase was washed 3 times with aqueous acetic acid
(0.05M). The desired material was extracted with a cartridge filled
with 500 mg of sulphonic acid resin (Varian SCX). The resin was
washed with MeOH and the desired material was recovered by
neutralizing the resin with 5% NH.sub.4OH in MeOH. The organic
phase was concentrated and filtered over a pad of silica gel
eluting with ethyl acetate. The filtrate was concentrated to
dryness and the resulting solid was recrystallized with a ethyl
acetate/hexane mixture to give 54 mg of the title compound as
off-white solid.
[0190] .sup.1H NMR (acetone-d.sub.6) .delta. 4.37 (s, 3H), 5.97 (s,
2H), 7.00 (t, 2H), 7.15 (t, 1H), 7.21 (dd, 2H), 7.34 (m, 2H), 7.57
(d, 1H), 7.92 (d, 1H), 8.25 (dd, 1H), 8.30 (dd, 1H), 8.86 (dd, 1H),
9.79 (s, 1H). MS (+APCI) m/z 377.4 (M+H).sup.+.
[0191] Step 2:
[0192] The title compound was prepared from 102 mg of methyl
1-[(4-fluorophenyl)methyl]-3-hydroxyindole-2-carboxylate and 50 mg
of cyclopropanemethanol according to example 164 to yield 111 mg of
a yellow solid.
[0193] .sup.1H NMR (acetone-d.sub.6) .delta. 0.43 (m, 2H), 0.65 (m,
2H), 1.46 (m, 1H), 4.41 (d, 2H), 5.98 (s, 2H), 7.00 (t, 2H), 7.14
(t, 1H), 7.21 (dd, 2H), 7.34 (m, 2H), 7.56 (d, 1H), 7.85 (d, 1H),
8.29 (m, 2H), 8.88 (d, 1H), 10.08 (s, 1H). MS (+APCI) m/z 416.4
(M+H).sup.+.
Example 12
{1-[(4-FLUOROPHENYL)METHYL]-3-(4-PYRIDYLMETHOXY)INDOL-2-YL}-N-(3-PYRIDYL)F-
ORMAMIDE (COMPOUND 162)
[0194] The title compound was prepared from 102 mg of methyl
1-[(4-fluorophenyl)methyl]-3-hydroxyindole-2-carboxylate and 59 mg
of 4-pyridyl carbinol according to example 11, step 1, to yield 56
mg of a red solid.
[0195] .sup.1H 1NMR (acetone-d.sub.6) .delta. 5.63 (s, 2H), 5.94
(s, 2H), 7.01 (t, 2H), 7.18 (m, 3H), 7.30 (dd, 1H), 7.35 (t, 1H),
7.54 (d, 2H), 7.59 (d, 1H), 7.89 (d, 1H), 8.08 (dt, 1H), 8.28 (dd,
1H), 8.60 (dd, 2H), 8.65 (d, 1H), 9.62 (s, 1H). MS (+APCI) m/z
453.3 (M+H).sup.+.
Example 13
{1-[(4-FLUOROPHENYL)METHYL]-3-[(3-METHOXYPHENYL)METHOXY]INDOL-2-YL}-N-(3-P-
YRIDYL) FORMAMIDE (COMPOUND 22)
[0196] The title compound was prepared from 102 mg of methyl
1-[(4-fluorophenyl)methyl]-3-hydroxyindole-2-carboxylate and 94 mg
of 3-methoxybenzyl alcohol according to example 164 to yield 63 mg
of a white solid.
[0197] .sup.1H NMR (acetone-d.sub.6) .delta. 5.57 (s, 2H), 5.96 (s,
2H), 6.94 (dd, 1H), 7.00 (t, 2H), 7.05-7.25 (m, 5H), 7.28 (m, 2H),
7.35 (t, 1H), 7.58 (d, 1H), 7.98 (t, 2H), 8.25 (dd, 1H), 8.52 (d,
1H), 9.66 (s, 1H). MS (+APCI) m/z 482.3 (M+H).sup.+.
Example 14
{5-BROMO-1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)INDOL-2-YL}-N-(3-PYRI-
DYL) FORMAMIDE (COMPOUND 134)
[0198] Step 1: Ethyl 5-bromo-3-formlindole-2-carboxylate
[0199] In a 1 L round bottom flask 10.5 mL of phosphorus
oxychloride was added to 15.5 g of N-methylformanilide at room
temperature that resulted in a yellow solid after 15 min. At this
time, 170 mL of 1,2-dichloroethane and 20.1 g of ethyl
5-bromoindole-2-carboxylate were added. The resulting suspension
was heated under reflux for 4 hours and then concentrated to remove
the organic solvent. 75 g of sodium acetate in 750 mL of water were
added and the solid suspension was stirred for 30 min at room
temperature, filtered and washed 3 times with water. The crude
material was dried under vacuum for 1 hour and swished with 500 mL
of EtOH to yield 21.2 g of the title compound as off-white
solid.
[0200] .sup.1H NMR (acetone-d.sub.6) .delta. 1.43 (t, 3H), 5.50 (q,
2H), 7.52 (dd, 1H), 7.58 (d, 1H), 8.52 (d, 1H), 10.68 (s, 1H),
11.86 (s, 1H).
[0201] Step 2: Ethyl 5-bromo-3-hydroxyindole-2-carboxylate
[0202] A mixture of 21.24 g of the previous aldehyde and 14.42 g of
p-toluenesuphonic acid monohydrate in 1 L of CH.sub.2Cl.sub.2 was
maintained at 12-13.degree. C. and treated portionwise with 17.01 g
of dried 3-chloroperoxybenzoic acid (87% purity). The reaction
mixture was stirred at this temperature for 2.5 hours (reaction was
monitored by TLC), quenched with 3 mL of dimethyl sulfide and
poured 30 min later into a saturated aqueous bicarbonate solution.
The product was extracted with CH.sub.2Cl.sub.2, washed twice with
saturated aqueous bicarbonate, brine and dried over anhydrous
Na.sub.2SO.sub.4. The organic solvent was removed under vacuum and
the crude material was hydrolyzed by treatment with 10 mL of
Et.sub.3N in 300 mL of EtOH and heating to 70.degree. C. for 30
min. The organic solvent was removed under vacuum and the crude
material was dissolved in ethyl acetate and washed twice with 0.5 N
HCl, brine and dried over anhydrous Na.sub.2SO.sub.4. The organic
phase was concentrated and filtered over a pad of silica gel
eluting with hot toluene. The organic phase was concentrated to
dryness and the solid was swished with ethyl acetate and hexane to
give 18.14 g of the title compound as a grey solid (>97%
purity).
[0203] .sup.1H NMR (acetone-d.sub.6) .delta. 1.35 (t, 3H), 4.39 (q,
2H), 7.35 (dd, 1H), 7.39 (dd, 1H), 7.79 (t, 1H), 8.24 (s, 1H),
10.23 (s, 1H).
[0204] Step 3: Ethyl
5-bromo-3-(phenylmethoxy)indole-2-carboxylate
[0205] To a solution containing 2.04 g of ethyl
5-bromo-3-hydroxyindole-2-- carboxylate, 3.94 g of benzyl alcohol
and 3.34 g of di-tert-butyl azodicarboxylate in 30 mL of THF and 15
mL of CH.sub.2Cl.sub.2 at -78.degree. C. was treated dropwise with
a solution containing 3.81 g of triphenylphosphine in 15 mL of
CH.sub.2Cl.sub.2. The resulting reaction mixture was warmed slowly
to 0.degree. C. upon consumption of the starting material
(monitored by TLC). 800 .mu.L of acetic acid was added and after 30
min the solvents were removed under vacuum and the excess of acetic
acid was removed by coevaporation with toluene. The crude product
was filtered over a pad of silica gel eluting with
CH.sub.2Cl.sub.2. The organic phase was concentrated to dryness and
the solid was swished with hexane to give 2.13 g of the title
compound as a white solid.
[0206] .sup.1H NMR (acetone-d.sub.6) .delta. 1.36 (t, 3H), 4.38 (q,
2H), 5.30 (s, 2H), 7.30-7.40 (m, 5H), 7.56 (d, 2H), 7.76 (d, 1H),
10.56 (s, 1H). MS (+APCI) m/z 376.2, 374.1 (M+H).sup.+.
[0207] Step 4: Ethyl
5-bromo-1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)i-
ndole-2-carboxylate
[0208] To a mixture of 5.57 g of ethyl
5-bromo-3-(phenylmethoxy)indole-2-c- arboxylate and 2.9 mL of
4-fluorobenzyl bromide in 40 mL of DMF at 0.degree. C. was added
887 mg of a NaH suspension (60% in oil) and the resulting reaction
mixture was warmed slowly to room temperature with continuous
stirring. After 0.5 hour, the reaction was quenched with saturated
aqueous NH.sub.4Cl and extracted twice with ethyl acetate/ether
1:1. The organic phase was washed with water (4 x), brine and dried
over anhydrous Na.sub.2SO.sub.4. Flash chromatography (toluene) and
recrystallization from hexane yielded 5.99 g of the title compound
as a white solid.
[0209] .sup.1H NMR (acetone-d.sub.6) .delta. 1.29 (t, 3H), 4.33 (q,
2H), 5.26 (s, 2H), 5.79 (s, 2H), 7.00-7.10 (m, 4H), 7.30-7.40 (m,
4H), 7.51 (m, 3H), 7.78 (s, 1H). MS (+APCI) m/z 484.3, 482.2
(M+H).sup.+.
[0210] Step 5:
{5-Bromo-1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)indol--
2-yl}-N-(3-pyridyl)formamide
[0211] To a solution of 1.06 g of the above ester in 5 mL of THF 40
mL of a solution of lithium 3-pyridylamide (0.3M in THF) was added
and allowed to stir at room temperature. After consumption of the
starting ester, the organic solvents were removed under vacuum,
aqueous acetic acid (0.05M) was added and the product was extracted
with ethyl acetate. The organic layer was washed 3 times with
aqueous acetic acid (0.05M), water (3 x), brine and dried over
anhydrous Na.sub.2SO.sub.4. The organic phase was concentrated and
filtered over a pad of silica gel eluting with ethyl acetate. The
organic phase was concentrated to dryness and the solid was swished
with ethyl acetate and hexane to give 1.16 g of the title compound
as a white solid.
[0212] .sup.1H NMR (acetone-d.sub.6) .delta. 5.58 (s, 2H), 5.95 (s,
2H), 7.01 (td, 2H), 7.17 (dd, 2H), 7.27 (dd, 1H), 7.38 (m, 3H),
7.44 (dd, 1H), 7.55 (m, 3H), 7.97 (m, 1H), 8.11 (d, 1H), 8.27 (dd,
1H), 8.50 (d, 1H), 9.62 (s, 1H). MS (+APCI) m/z 532.3, 530.2
(M+H).sup.+. Anal. Calcd for C.sub.28H.sub.21BrFN.sub.3O.sub.2: C,
63.41; H, 3.99; N, 7.92. Found: C, 63.12; H, 4.31; N, 7.98.
Example 15
{1-[(4-FLUOROPHENYL)METHYL]-5-(1-HYDROXY-ISOPROPYL)-3-(PHENYLMETHOXY)INDOL-
-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 130)
[0213] To a solution of 201 mg of
{5-Bromo-1-[(4-fluorophenyl)methyl]-3-(p-
henylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide in 10 mL of THF at
-100.degree. C. was added 0.5 mL of n-BuLi (1.6M in hexanes) and
the mixture was stirred at -100.degree. C. for 30 min. To this cold
solution, 190 .mu.L of acetone was added and the reaction mixture
was allowed to warm to room temperature. At this time, aqueous
NH.sub.4Cl was added, the product was extracted with ethyl acetate
and the organic phase was washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. Flash chromatography (100% hexane to
hexane/ethyl acetate 1:2) and swish with CH.sub.2Cl.sub.2/hexane
yielded 61 mg of the title compound as a yellow solid.
[0214] .sup.1HNMR (acetone-d.sub.6) .delta. 1.58 (s, 6H), 4.14 (s,
1H), 5.59 (s, 2H), 5.93 (s, 2H), 7.00 (t, 2H), 7.18 (m, 2H), 7.24
(dd, 1H), 7.38 (m, 3H), 7.45-7.55 (m, 4H), 7,95 (d, 1H), 8.08 (dd,
1H), 8.24 (dd, 1H), 8.46 (d, 1H), 9.65 (s, 1H). MS (+APCI) m/z
510.4 (M+H).sup.+.
Example 16
1-[(4-FLUOROPHENYL)METHYL]-3-(PHENYLMETHOXY)-2-(N-(3-PYRIDYL)CARBAMOYL)IND-
OLE-5-CARBOXYLIC ACID (COMPOUND 131)
[0215] To a solution of 201 mg of
{5-Bromo-1-[(4-fluorophenyl)methyl]-3-(p-
henylmethoxy)indol-2-yl}-N-(3-pyridyl)formamide in 10 mL of THF at
-100.degree. C. was added 0.5 mL of n-BuLi (1.6M in hexanes) and
the mixture was stirred at -100.degree. C. for 30 min. CO.sub.2 was
introduced to the reaction mixture and warmed to room temperature.
The reaction was quenched with 150 .mu.L of acetic acid and poured
into a saturated aqueous NH.sub.4Cl solution. The product was
extracted with ethyl acetate and the organic phase was washed with
brine and dried over anhydrous Na.sub.2SO.sub.4. The organic phase
was concentrated and the crude solid was swished with ethyl acetate
to give 75 mg of the title compound as a white solid (>95%
purity).
[0216] .sup.1H NMR (dmso-d.sub.6) .delta. 5.42 (s, 2H), 5.76 (s,
2H), 7.08 (m, 4H), 7.25-7.35 (m, 4H), 7.40 (d, 2H), 7.69 (d, 1H),
7.87 (d, 1H), 7.98 (d, 1H), 8.28 (d, 1H), 8.46 (s, 1H), 8.61 (s,
1H), 10.12 (s, 1H), 12.76 (s, 11). MS (+APCI) m/z 496.5
(M+H).sup.+.
Example 17
{1-[(4-FLUOROPHENYL)METHYL]-4-(1-HYDROXY-ISOPROPYL)-3-(PHENYLMETHOXY)INDOL-
-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 94)
[0217] Step 1: Ethyl 4-bromo-indolecarboxylate
[0218] A solution of 23 mL of ethyl azidoacetate and 7.6 mL of
2-bromobenzaldehyde in 40 mL ethanol was added dropwise to a
solution of 4.5 g sodium in 180 mL ethanol, in a bath at
-10.degree. C., at a rate such that the reaction temperature does
not rise above 8.degree. C. After the addition is complete, the
mixture is stirred at 5-10.degree. C. for 30 min. The reaction
mixture is then poured into a mixture of 28 g of NH.sub.4Cl in 1 L
ice, and extracted with 1:4 CH.sub.2Cl.sub.2/hexane. The organic
phase is filtered through 150 mL silica gel, which is rinsed with
200 mL of the same solvent. This is evaporated to near dryness,
diluted with 300 mL xylene, and stabilised with 60 mg of
2,5-di-t-butylhydroquinone. This mixture is heated with a
distillation head until 50 mL of xylene has distilled. The mixture
is cooled and evaporated in vacuo to a volume of 80 mL, which is
diluted with 80 mL of hexane. A white solid forms upon cooling to
0.degree. C., which is filtered off.
[0219] .sup.1H NNR (acetone-d.sub.6) .delta. 1.37 (t, 3H), 4.37 (q,
2H), 7.13 (t, 1H), 7.21 (t, 1H), 7.33 (d, 1H), 7.55 (d, 1H), 11.3
(s, 1H).
Example 18
{1-[(4-FLUOROPHENYL)METHYL]-6-(1-HYDROXY-ISOPROPYL)-3-(PHENYLMETHOXY)INDOL-
-2-YL}-N-(3-PYRIDYL) FORMAMIDE (COMPOUND 118)
[0220] Step 1: Ethyl 6-bromo-indolecarboxylate
[0221] Using the method described in example 17, Step 1, starting
with 4-bromobenzaldehyde, the title compound is obtained as a white
solid.
[0222] .sup.1H NMR (acetone-d.sub.6) .delta. 1.35 (t, 3H), 4.35 (q,
2H), 7.18 (s, 1H), 7.24 (d, 1H), 7.64 (d, 1H), 7.73 (s, 1H), 11.10
(s, 1H).
* * * * *