U.S. patent application number 11/808122 was filed with the patent office on 2007-10-25 for new amidino derivatives and their use as thrombin inhibitors.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Tord Inghardt, Olle Karlsson, Marcel Linschoten, Jan-Erik Nystrom.
Application Number | 20070249578 11/808122 |
Document ID | / |
Family ID | 20413647 |
Filed Date | 2007-10-25 |
United States Patent
Application |
20070249578 |
Kind Code |
A1 |
Inghardt; Tord ; et
al. |
October 25, 2007 |
New amidino derivatives and their use as thrombin inhibitors
Abstract
There is provided compounds of formula I ##STR1## wherein
R.sup.1, R.sub.x, Y, R.sup.y, n and B have meanings given in the
description which are useful as competitive inhibitors of
trypsin-like proteases, such as thrombin, and in particular in the
treatment of conditions where inhibition of thrombin is required
(e.g. thrombosis) or as anticoagulants.
Inventors: |
Inghardt; Tord; (Frillesas,
SE) ; Karlsson; Olle; (Molndal, SE) ;
Linschoten; Marcel; (Vastra Frolunda, SE) ; Nystrom;
Jan-Erik; (Ronninge, SE) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
20413647 |
Appl. No.: |
11/808122 |
Filed: |
June 6, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10815954 |
Apr 2, 2004 |
7241757 |
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11808122 |
Jun 6, 2007 |
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09509032 |
Mar 21, 2000 |
6750243 |
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10815954 |
Apr 2, 2004 |
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Current U.S.
Class: |
514/210.18 ;
514/210.17; 544/224; 546/268.1; 548/953 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
43/00 20180101; C07D 207/16 20130101; C07D 205/04 20130101; C07D
405/06 20130101 |
Class at
Publication: |
514/210.18 ;
514/210.17; 544/224; 546/268.1; 548/953 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/4427 20060101 A61K031/4427; A61K 31/497
20060101 A61K031/497; A61K 31/53 20060101 A61K031/53; C07D 205/04
20060101 C07D205/04; C07D 237/02 20060101 C07D237/02; C07D 239/02
20060101 C07D239/02; C07D 241/02 20060101 C07D241/02; C07D 251/02
20060101 C07D251/02; C07D 253/04 20060101 C07D253/04; C07D 253/06
20060101 C07D253/06; C07D 257/02 20060101 C07D257/02; C07D 401/12
20060101 C07D401/12 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 1998 |
SE |
9804313-6 |
Dec 10, 1999 |
SE |
PCT/SE99/02316 |
Claims
1. A compound of formula I, ##STR31## wherein R.sup.1 represents H,
C.sub.1-4 alkyl (optionally substituted by one or more substituents
selected from cyano, halo, OH, C(O)OR.sup.1a or
C(O)N(R.sup.1b)R.sup.1c) or OR.sup.1d; R.sup.1d represents H,
C(O)R.sup.11, SiR.sup.12R.sup.13R.sup.14 or C.sub.1-6 alkyl, which
latter group is optionally substituted or terminated by one or more
substitutent selected from OR.sup.15 or (CH.sub.2).sub.qR.sup.16;
R.sup.12, R.sup.13 and R.sup.14 independently represent H, phenyl
or C.sub.1-6 alkyl; R.sup.16 represents C.sub.1-4 alkyl, phenyl,
OH, C(O)OR.sup.17 or C(O)N(H)R.sup.18; R.sup.18 represents H,
C.sub.1-4 alkyl or CH.sub.2C(O)OR.sup.19; R.sup.15 and R.sup.17
independently represent H, C.sub.1-6 alkyl or C.sub.1-3
alkylphenyl; R.sup.1a, R.sup.1b, R.sup.1c, R.sup.11 and R.sup.19
independently represent H or C.sub.1-4 alkyl; and q represents 0, 1
or 2; R.sub.x represents a structural fragment of formula IIa, IIb
or IIc, ##STR32## wherein the dotted lines independently represent
optional bonds; A and E independently represent O or S, CH or
CH.sub.2 (as appropriate), or N or N(R.sup.21) (as appropriate); D
represents --CH.sub.2--, O, S, N(R.sup.22), --(CH.sub.2).sub.2--,
--CH.dbd.CH--, --CH.sub.2N(R.sup.22)--, --N(R.sup.22)CH.sub.2--,
--CH.dbd.N--, --N.dbd.CH--, --CH.sub.2O--, --OCH.sub.2--,
--CH.sub.2S-- or --SCH.sub.2--; X.sub.1 represents C.sub.2-4
alkylene; C.sub.2-3 alkylene interrupted by Z; --C(O)-Z-A.sup.1-;
-Z-C(O)-A.sup.1-; --CH.sub.2--C(O)-A.sup.1-; -Z-C(O)-Z-A.sup.2-;
--CH.sub.2-Z-C(O)-A.sup.2-; -Z-CH.sub.2--C(O)-A.sup.2-;
-Z-CH.sub.2--S(O).sub.m-A.sup.2-; --C(O)-A.sup.3; -Z-A.sup.3-; or
-A.sup.3-Z-; X.sub.2 represents C.sub.2-3 alkylene, --C(O)-A.sup.4-
or -A.sup.4-C(O)--; X.sub.3 represents CH or N; X.sub.4 represents
a single bond, O, S, C(O), N(R.sup.23), --CH(R.sup.23)--,
--CH(R.sup.23)--CH(R.sup.24)-- or --C(R.sup.23).dbd.C(R.sup.24)--;
A.sup.1 represents a single bond or C.sub.1-2 alkylene; A.sup.2
represents a single bond or --CH.sub.2--; A.sup.3 represents
C.sub.1-3 alkylene; A.sup.4 represents C(O) or C.sub.1-2 alkylene;
Z represents, at each occurrence, O, S(O).sub.m or N(R.sup.25);
R.sup.2 and R.sup.4 independently represent one or more optional
substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy (which
latter two groups are optionally substituted by one or more halo
substituent), methylenedioxy, halo, hydroxy, cyano, nitro,
S(O).sub.2NH.sub.2, C(O)OR.sup.26, SR.sup.26, S(O)R.sup.26a,
S(O).sub.2R.sup.26a or N(R.sup.27)R.sup.28; R.sup.3 represents one
or more optional substituents selected from OH, C.sub.1-4 alkoxy,
C.sub.1-6 alkyl (optionally substituted by one or more halo group),
or N(R.sup.29a)R.sup.29b; R.sup.25, R.sup.29a and R.sup.29b
independently represent H, C.sub.1-4 alkyl or C(O)R.sup.30;
R.sup.26 represents H or C.sub.1-4 alkyl; R.sup.26a represents
C.sub.1-4 alkyl; R.sup.27 and R.sup.23 independently represent H,
C.sub.1-4 alkyl or C(O)R.sup.30, or together represent C.sub.3-6
alkylene, thus forming a 4- to 7-membered ring, which ring is
optionally substituted, on a carbon atom that is .alpha. to the
nitrogen atom, with an .dbd.O group; R.sup.21, R.sup.22, R.sup.23,
R.sup.24 and R.sup.30 independently represent, at each occurrence,
H or C.sub.1-4 alkyl; Y represents CH.sub.2, (CH.sub.2).sub.2,
CH.dbd.CH (which latter group is optionally substituted by
C.sub.1-4 alkyl), (CH.sub.2).sub.3, CH.sub.2CH.dbd.CH or
CH.dbd.CHCH.sub.2 (which latter three groups are optionally
substituted by C.sub.1-4 alkyl, methylene, .dbd.O or hydroxy);
R.sup.y represents H or C.sub.1-4 alkyl; n represents 0, 1, 2, 3 or
4; and B represents a structural fragment of formula IIIa, IIIb or
IIIc ##STR33## wherein X.sup.5, X.sup.6, X.sup.7 and X.sup.8
independently represent CH, N or N--O; X.sup.9 and X.sup.10
independently represent a single bond or CH.sub.2; R.sup.31
represents an optional substituent selected from halo, C.sub.1-4
alkyl (which group is optionally substituted by one or more halo
group), N(R.sup.32)R.sup.33, OR.sup.34 or SR.sup.35; R.sup.32 and
R.sup.33 independently represent H, C.sub.1-4 alkyl or
C(O)R.sup.36; R.sup.34, R.sup.35 and R.sup.36 independently
represent H or C.sub.1-4 alkyl; and one of D.sup.1 and D.sup.2
represents H, and the other represents H, OR.sup.a, NHR.sup.a,
C(.dbd.X.sup.11)X.sup.12R.sup.b, or D.sup.1 and D.sup.2 together
represent a structural fragment of formula IVa:-- ##STR34## R.sup.a
represents H or -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e;
R.sup.b represents -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e;
A.sup.5 represents, at each occurrence, a single bond or C.sub.1-12
alkylene (which alkylene group is optionally interrupted by one or
more O, S(O).sub.m and/or N(R.sup.f) group, and is optionally
substituted by one or more of halo, OH, N(H)C(O)R.sup.g,
C(O)N(R.sup.g)R.sup.h, C.sub.3-7-cycloalkyl (which cycloalkyl group
is optionally interrupted by one or more O, S(O).sub.m and/or
N(R.sup.f) group and/or is optionally substituted by one or more
substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo,
.dbd.O or .dbd.S), Het and C.sub.6-10 aryl (which aryl and Het
groups are themselves optionally substituted by one or more
substituents selected from C.sub.1-6 alkyl (optionally substituted
by one or more halo substituent), C.sub.1-6 alkoxy, halo, cyano,
C(O)OR.sup.9, C(O)N(R.sup.9)R.sup.h and N(R.sup.f)R.sup.g));
R.sup.c and R.sup.d both represent H; or one of R.sup.c and R.sup.d
represents H or C.sub.1-7 alkoxy and the other represents C.sub.1-7
alkyl (which alkyl group is optionally interrupted by one or more O
atoms); or R.sup.c and R.sup.d together represent C.sub.3-8
cycloalkyl, which cycloalkyl group is interrupted by one or more O,
S(O).sub.m and/or N(R.sup.f) group; R.sup.e represents, at each
occurrence, H, C.sub.1-12 alkyl (which alkyl group is optionally
interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group,
and/or is optionally substituted by one or more substituents
selected from halo, OH, N(H)C(O)R.sup.g and C(O)N(R.sup.g)R.sup.h),
A.sup.7-C.sub.3-7-cycloalkyl (which cycloalkyl group is optionally
interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group
and/or is substituted by one or more substituents selected from
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, .dbd.O and .dbd.S),
A.sup.7-C.sub.6-10 aryl or A.sup.7-Het (which aryl and Het groups
are optionally substituted by one or more substituents selected
from C.sub.1-6 alkyl (optionally substituted by one or more halo
substituent), C.sub.1-6 alkoxy, halo, cyano, C(O)OR.sup.9,
C(O)N(R.sup.9)R.sup.h and N(R.sup.f)R.sup.g); A.sup.7 represents a
single bond or C.sub.1-7 alkylene (which alkylene group is
optionally interrupted by one or more O, S(O).sub.m and/or
N(R.sup.f) group, and/or are optionally substituted by one or more
of halo, OH, N(H)COR.sup.9 and CON(R.sup.g)R.sup.h); Het
represents, at each occurrence, a five- to ten-membered heteroaryl
group, which may be aromatic in character, containing one or more
nitrogen, oxygen or sulphur atoms in the ring system; n and r
independently represent 0 or 1; X.sup.11, X.sup.12 and X.sup.14
independently represent O or S; X.sup.13 represents O or
N(R.sup.f); R.sup.f represents, at each occurrence, H, C.sub.1-4
alkyl or C(O)R.sup.g; R.sup.g and R.sup.h independently represent,
at each occurrence, H or C.sub.1-4 alkyl; and m represents, at each
occurrence, 0, 1 or 2; or a pharmaceutically acceptable salt
thereof; provided that: (a) A and E do not both represent O or S;
(b) E and D do not both represent O or S; (c) when R.sup.1
represents OR.sup.1d and X.sub.1 represents --C(O)-Z-A.sup.1,
-Z-CH.sub.2--S(O).sub.m-A.sup.2- or -Z-C(O)-Z-A.sup.2, then A.sup.1
or A.sup.2 (as appropriate) do not represent a single bond; (f)
when X.sub.4 represents --CH(R.sup.23)--, R.sup.1 does not
represent OH; (g) when A.sup.5 represents a single bond, then n and
r both represent 0; (f) when A.sup.5 represents C.sub.1-12
alkylene, then n represents 1; (g) when A.sup.5 represents
--CH.sub.2--, n is 1 and r is 0, then R.sup.e does not represent H;
and (h) the compound is not:-- (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab; (R)- or
(S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab; (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc; (R)-
or (S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab;
1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
1-hydroxy-5,7-dimethyltetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
1-hydroxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc; (R)- or
(S)-7-methoxy-1-methyltetralin-1-yl-C(O)-Aze-Pab;
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab.times.OAc; (S)- or
(R)-1-hydroxy-4-methoxyindan-1-yl-C(O)-Aze-Pab;
1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab(OH); (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(OH);
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OH);
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OMe); (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH.sub.2CC1.sub.3-
); (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH.sub.2CH.sub.3)-
; 7-methoxy-1-allyltetralin-1-yl-C(O)-Aze-Pab.times.HOAc; (S)- or
(R)-1-hydroxy-7-chlorotetralin-1-yl-C(O)-Pro-Pab;
1-n-propyl-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
6,8-dichloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
6-fluoro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
4-hydroxy-6-methylchroman-4-yl-C(O)-Aze-Pab.times.HOAc;
8-chloro-4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
6-chloro-4-hydroxy-8-methylchroman-4-yl-C(O)-Aze-Pab.times.HOAc;
(S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O)-i-Pr);
(S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O-Et); (S)-
or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O)--Ch);
(S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-allyl);
(S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Bzl);
(S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(CO--O-methallyl);
1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab(OH); (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Val); (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-(Me)Pab; or
9-hydroxyfluoren-9-yl-C(O)-Aze-Pab.times.HOAc.
2. A compound as claimed in claim 1 wherein R.sup.1 represents OH
or C.sub.1-4 alkyl (which latter group is optionally substituted by
cyano or OH).
3. A compound as claimed in claim 1 wherein R.sub.x represents a
structural fragment of formula IIa or IIb.
4. A compound as claimed in claim 1 wherein, when R.sub.x
represents a structural fragment of formula IIa, then the dotted
lines represent bonds, A and E both represent CH and D represents
--CH.dbd.CH--;
5. A compound as claimed in claim 1 wherein, when R.sub.x
represents a structural fragment of formula IIa, X, represents
optionally unsaturated C.sub.2- or C.sub.3-alkylene, or -Z-A.sup.3
(in which Z represents O, S(O).sub.m or N(R.sup.25) (in which
R.sup.25 is as defined in claim 1 or represents C.sub.1-4 alkyl or
C(O)R.sup.30 and m and R.sup.30 are as defined in claim 1) and
A.sup.3 represents C.sub.1- or C.sub.2-alkylene (which latter group
is optionally unsaturated)).
6. A compound as claimed in claim 1 wherein Y represents CH.sub.2,
(CH.sub.2).sub.2 or (CH.sub.2).sub.3.
7. A compound as claimed in claim 1 wherein B represents a
structural fragment of formula IIIa in which X.sup.5, X.sup.6,
X.sup.7 and X.sup.8 all represent CH.
8. A compound as claimed in claim 1 wherein, when D.sup.1 and
D.sup.2 together represent a structural fragment of formula IVa, in
which X.sup.13 is O, then one of R.sup.c and R.sup.d represents H
or C.sub.1-7 alkoxy and the other represents C.sub.1-7 alkyl.
9. A compound as claimed in claim 1, wherein, when D.sup.1 or
D.sup.2 represents OR.sup.a and R.sup.a represents
-A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, and (i) A.sup.5 is a
single bond, then R.sup.e is:-- (1) A.sup.7-aryl, optionally
substituted by one or more halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl
or halo-C.sub.1-6-alkyl substituents; or (2) H or linear, branched,
optionally unsaturated, and/or cyclic, C.sub.1-12 alkyl, which
cyclic alkyl group is optionally interrupted by an O atom and,
optionally, a further atom or S(O).sub.m group; or when (ii)
A.sup.5 is linear or branched C.sub.1-12 alkylene, X.sup.14 is O
and r is 0, then R.sup.e is C.sub.1-3 alkyl or A.sup.7-aryl, in
which A.sup.7 is a single bond.
10. A compound as claimed in claim 1, wherein, when D.sup.1 or
D.sup.2 represents OR.sup.a, then R.sup.a is H or C.sub.1-4
alkyl.
11. A compound as claimed in claim 1, wherein, when D.sup.1 or
D.sup.2 represents --C(.dbd.X.sup.11)X.sup.12R.sup.b, in which
X.sup.11 represents O and X.sup.12 represents O or S, and, in which
R.sup.b group, A.sup.5 represents a single bond then R.sup.e
represents optionally unsaturated C.sub.1-6 alkyl,
A.sup.7-C.sub.6-10-aryl (in which A.sup.7 represents a single bond
or C.sub.1-2 alkylene, and which A.sup.7-C.sub.6-10-aryl group is
optionally substituted by one or more halo, C.sub.1-4 alkyl and/or
C.sub.1-4 alkoxy groups), or A.sup.7-C.sub.3-7-cycloalkyl, in which
A.sup.7 represents a single bond or linear or branched C.sub.1-7
alkylene, and which cycloalkyl group is optionally substituted by
C.sub.1-3 alkyl.
12. A compound of formula I, as defined in claim 1, wherein the
fragment ##STR35## is in the S-configuration.
13. A pharmaceutical formulation including a compound as defined in
claim 1, or a pharmaceutically acceptable salt thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier.
14. A compound as defined in claim 1, or a pharmaceutically
acceptable salt thereof, for use as a pharmaceutical.
15. A compound as defined in claim 1, or a pharmaceutically
acceptable salt thereof, for use in the treatment of a condition
where inhibition of thrombin is required.
16. A compound as defined in claim 1, or a pharmaceutically
acceptable salt thereof, for use in the treatment of
thrombosis.
17. A compound as defined in claim 1, or a pharmaceutically
acceptable salt thereof, for use as an anticoagulant.
18. The use of a compound as defined in claim 1, or a
pharmaceutically acceptable salt thereof, as active ingredient in
the manufacture of a medicament for the treatment of a condition
where inhibition of thrombin is required.
19. The use as claim in claim 18, wherein the condition is
thrombosis.
20. The use of a compound as defined in claim 1, or a
pharmaceutically acceptable salt thereof, as active ingredient in
the manufacture of an anticoagulant.
21. A method of treatment of a condition where inhibition of
thrombin is required which method comprises administration of a
therapeutically effective amount of a compound as defined in claim
1, or a pharmaceutically acceptable salt thereof, to a person
suffering from, or susceptible to, such a condition.
22. A method as claimed in claim 21, wherein the condition is
thrombosis.
23. A method as claimed in claim 21, wherein the condition is
hypercoagulability in blood tissues.
24. A process for the preparation of compounds of formula I which
comprises: (i) the coupling of a compound of formula IV, ##STR36##
wherein R.sup.1 and R.sub.x are as defined in claim 1 with a
compound of formula V, ##STR37## wherein R.sup.y, Y, n and B are as
defined in claim 1; (ii) the coupling of a compound of formula VI,
##STR38## wherein R.sup.1, R.sub.x and Y are as defined in claim 1
with a compound of formula VII, H(R.sup.y)N--(CH.sub.2).sub.n--B
VII wherein R.sup.y, n and B are as defined in claim 1; (iii) for
compounds of formula I in which D.sup.1 or D.sup.2 represents
OR.sup.a or NHR.sup.a, reaction of a compound of formula VIII,
##STR39## wherein B.sup.1 represents a structural fragment of
formula IIId, IIIe or IIIf ##STR40## and R.sup.1, R.sub.x, Y,
R.sup.y, n, R.sup.31, X.sup.5, X.sup.6, X.sup.7, X.sup.8, X.sup.9
and X.sup.10 are as defined in claim 1 with a compound of formula
IX, H.sub.2NX.sup.aR.sup.a IX wherein X.sup.a represents O or NH
and R.sup.a is as defined in claim 1; (iv) for compounds of formula
I in which D.sup.1 or D.sup.2 represents OR.sup.a or NHR.sup.a,
reaction of a compound of formula I in which D.sup.1 or D.sup.2 (as
appropriate) represents C(O)OR.sup.b1, in which R.sup.b1 represents
a protecting group with a compound of formula IX as defined above;
(v) for compounds of formula I in which D.sup.1 or D.sup.2
represents OR.sup.a or NHR.sup.a, R.sup.a represents -A.sup.5
[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5 does not
represent a single bond, and n represent 1, reaction of a compound
of formula I in which D.sup.1 or D.sup.2 (as appropriate)
represents OH or NH.sub.2, with a compound of formula X,
L.sup.1A.sup.5a[X.sup.14][C(O)].sub.rR.sup.e X wherein L.sup.1
represents a suitable leaving group, A.sup.5a represents A.sup.5,
as defined in claim 1 except that it does not represent a single
bond, and X.sup.14, r and R.sup.e are as defined in claim 1; (vi)
for compounds of formula I in which D.sup.1 or D.sup.2 represents
OR.sup.a or NHR.sup.a, R.sup.a represents
-A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5
represents C.sub.2-12 alkylene, which alkylene group is branched at
the carbon atom that is .alpha. to the O or N atom of OR.sup.a or
NHR.sup.a (as appropriate, and which group is optionally branched
at the carbon atom that is .beta. to that atom, n represents 1, r
represents 0 and R.sup.e is as defined in claim 1, reaction of a
compound of formula I in which D.sup.1 or D.sup.2 (as appropriate)
represents OH or NH.sub.2, with a compound of formula XI, ##STR41##
or a geometrical isomer thereof, or a mixture of such geometrical
isomers, in which R.sup.b1 and R.sup.b3 each represent H or an
alkyl group, provided that the total number of carbon atoms
provided by R.sup.b1 and R.sup.b3 does not exceed 10, and wherein
X.sup.14 and R.sup.e are as defined in claim 1; (vii) for compounds
of formula I in which D.sup.1 or D.sup.2 represents OR.sup.a or
NHR.sup.a, R.sup.a represents -A.sup.5
[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5 represents a
single bond, and R.sup.e represents A.sup.7-C.sub.3-6-cycloalkyl,
in which A.sup.7 represents a single bond, and the cycloalkyl group
is interrupted by at least one O or S atom, which atom is between
the carbon atom at the point of attachment to the O or NH group of
OR.sup.a or NHR.sup.a, and a carbon atom that is .alpha. to that
point of attachment, and which cycloalkyl group is optionally
interrupted by one or more O or S(O).sub.m group and/or optionally
substituted by one or more .dbd.O group, reaction of a compound of
formula I, in which D.sup.1 or D.sup.2 (as appropriate) represents
OH or NH.sub.2, with a compound of formula XII, ##STR42## wherein
X.sup.15 represents O or S and X.sup.16 represents C.sub.1-4
alkylene (which alkylene groups is optionally interrupted by one or
more O or S(O).sub.m group and/or optionally substituted by one or
more .dbd.O group); (viii) for compounds of formula I in which
D.sup.1 or D.sup.2 represents C(X.sup.11)X.sup.12R.sup.b, reaction
of a compound of formula I in which D.sup.1 and D.sup.2 both
represent H with a compound of formula XIII,
L.sup.2-C(X.sup.11)X.sup.12R.sup.b XIII wherein L.sup.2 represents
a suitable leaving group, and X.sup.11, X.sup.12 and R.sup.b are as
defined in claim 1; (ix) for compounds of formula I in which
D.sup.1 and D.sup.2 together represent a structural fragment of
formula IVa, reaction of a corresponding compound of formula I in
which D.sup.1 or D.sup.2 represents OH or NHR.sup.f (in which
R.sup.f is as defined in claim 1), with a compound of formula XV,
(R.sup.c)(R.sup.d)C(R.sup.c1)(R.sup.c2) XV wherein R.sup.c1 and
R.sup.c2 both represent --OR.sup.c3, in which R.sup.c3 represents
C.sub.1-3 alkyl, or together represent .dbd.O, and R.sup.c and
R.sup.d are as defined in claim 1; (x) for compounds of formula I
in which one or more of X.sup.5, X.sup.1, X.sup.7 and X.sup.8
represent N--O, oxidation of a corresponding compound of formula I
in which X.sup.5, X.sup.6, X.sup.7 and/or X.sup.8 (as appropriate)
represent(s) N; or (xi) for compounds of formula I in which any one
of Z, X.sup.1, R.sup.2, R.sup.4, A.sup.5, A.sup.7, R.sup.c, R.sup.d
and/or R.sup.e comprises or includes a S(O) or a S(O).sub.2 group,
oxidation of a corresponding compound of formula I (or a compound
corresponding to a compound of formula I) wherein Z, X.sub.1,
R.sup.2, R.sup.4, A.sup.5, A.sup.7, R.sup.c, R.sup.d and/or R.sup.e
(as appropriate comprise(s) or include(s) a S group; (xii) for
compounds of formula I in which D.sup.1 and D.sup.2 both represent
H, removal of a OR.sup.a, NHR.sup.a or
C(.dbd.X.sup.11)X.sup.12R.sup.b group (in which R.sup.a, R.sup.b,
X.sup.11 and X.sup.12 are as defined in claim 1), or removal of a
structural fragment of formula IVa as defined in claim 1, from a
corresponding compound of formula I; or (xiii) introduction and/or
interconversion of a substituent on an aromatic and/or
non-aromatic, carbocyclic and/or heterocyclic ring in a
corresponding of compound of formula I.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel pharmaceutically useful
compounds, in particular compounds that are, or are prodrugs of,
competitive inhibitors of trypsin-like serine proteases, especially
thrombin, their use as medicamnents, pharmaceutical compositions
containing them and synthetic routes to their production.
BACKGROUND
[0002] Blood coagulation is the key process involved in both
hemostasis (i.e. the prevention of blood loss from a damaged
vessel) and thrombosis (i.e. the formation of a blood clot in a
blood vessel, sometimes leading to vessel obstruction).
[0003] Coagulation is the result of a complex series of enzymatic
reactions. One of the ultimate steps in this series of reactions is
the conversion of the proenzyme prothrombin to the active enzyme
thrombin.
[0004] Thrombin is known to play a central role in coagulation. It
activates platelets, leading to platelet aggregation, converts
fibrinogen into fibrin monomers, which polymerise spontaneously
into fibrin polymers, and activates factor XIII, which in turn
crosslinks the polymers to form insoluble fibrin. Furthermore,
thrombin activates factor V and factor VIII leading to a "positive
feedback" generation of thrombin from prothrombin.
[0005] By inhibiting the aggregation of platelets and the formation
and crosslinking of fibrin, effective inhibitors of thrombin would
be expected to exhibit antithrombotic activity. In addition,
antithrombotic activity would be expected to be enhanced by
effective inhibition of the positive feedback mechanism.
[0006] Further, it is known that administration of prodrugs of
thrombin inhibitors may give rise to improvements in: [0007] (a)
certain pharmacokinetic properties after administration of; and
[0008] (b) the prevalence of certain side effects associated with,
those inhibitors.
PRIOR ART
[0009] The early development of low molecular weight inhibitors of
thrombin has been described by Claesson in Blood Coagul. Fibrinol.
(1994) 5, 411.
[0010] Blomback et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59,
(1969)) reported thrombin inhibitors based on the amino acid
sequence situated around the cleavage site for the fibrinogen
A.alpha. chain. Of the amino acid sequences discussed, these
authors suggested the tripeptide sequence Phe-Val-Arg (P9-P2-P1,
hereinafter referred to as the P3-P2-P1 sequence) would be the most
effective inhibitor.
[0011] Thrombin inhibitors based on dipeptidyl derivatives with an
.alpha.,.omega.-aminoalkyl guanidine in the PI-position are known
from U.S. Pat. No. 4,346,078 and International Patent Application
WO 93/11152. Similar, structurally related, dipeptidyl derivatives
have also been reported. For example International Patent
Application WO 94/29336 discloses compounds with, for example,
aminomethyl benzamidines, cyclic aminoalkyl amidines and cyclic
aminoalkyl guanidines in the P1-position (International Patent
Application WO 97/23499 discloses prodrugs of certain of these
compounds); European Patent Application 0 649 780, discloses
compounds with, for example, cyclic aminoalkyl guanidines in the
P1-position.
[0012] Thrombin inhibitors based on peptidyl derivatives, also
having cyclic aminoalkyl guanidines (e.g. either 3- or
4-aminomethyl-1-amidinopiperidine) in the P1-position are known
from European Patent Applications 0 468 231, 0 559 046 and 0 641
779.
[0013] Thrombin inhibitors based on tripeptidyl derivatives with
arginine aldehyde in the P1-position were first disclosed in
European Patent Application 0 185 390.
[0014] More recently, arginine aldehyde-based peptidyl derivatives,
modified in the P3-position, have been reported. For example,
International Patent Application WO 93/18060 discloses hydroxy
acids, European Patent Application 0 526 877 des-amino acids, and
European Patent Application 0 542 525 0-methyl mandelic acids in
the P3-position.
[0015] Inhibitors of serine proteases (e.g. thrombin) based on
electrophilic ketones in the P1-position are also known. For
example, European Patent Application 0 195 212 discloses peptidyl
.alpha.-keto esters and amides, European Patent Application 0 362
002 fluoroalkylamide ketones, European Patent Application 0 364 344
.alpha.,.beta.,.delta.-triketocompounds, and European Patent
Application 0 530 167 .alpha.-alkoxy ketone derivatives of arginine
in the P1-position.
[0016] Other, structurally different, inhibitors of trypsin-like
serine proteases based on C-terminal boronic acid derivatives of
arginine and isothiouronium analogues thereof are known from
European Patent Application 0 293 881.
[0017] More recently, thrombin inhibitors based on peptidyl
derivatives have been disclosed in European Patent Application 0
669 317 and International Patent Applications WO 95/35309, WO
95/23609, WO 96/03374, WO 96/25426, WO 96/31504, WO 97/02284, WO
97/46577, WO 96/32110, WO 98/06740, WO 97/49404 and WO
98/57932.
[0018] However, there remains a need for effective inhibitors of
trypsin-like serine proteases, such as thrombin. There is a
particular need for compounds which are both orally bioavailable
and selective in inhibiting thrombin over other serine proteases.
Compounds which exhibit competitive inhibitory activity towards
thrombin would be expected to be especially useful as
anticoagulants and therefore in the therapeutic treatment of
thrombosis and related disorders.
DISCLOSURE OF THE INVENTION
[0019] According to the invention there is provided a compound of
formula I, ##STR2## wherein R.sup.1 represents H, C.sub.1-4 alkyl
(optionally substituted by one or more substituents selected from
cyano, halo, OH, C(O)OR.sup.1a or C(O)N(R.sup.1b)R.sup.1c) or
OR.sup.1d; R.sup.1d represents H, C(O)R.sup.11,
SiR.sup.12R.sup.13R.sup.14 or C.sub.1-6 alkyl, which latter group
is optionally substituted or terminated by one or more substituent
selected from OR.sup.15 or (CH.sub.2).sub.qR.sup.16; R.sup.12,
R.sup.13 and R.sup.14 independently represent H, phenyl or
C.sub.1-6 alkyl; R.sup.16 represents C.sub.1-4 alkyl, phenyl, OH,
C(O)OR.sup.17 or C(O)N(H)R.sup.18; R.sup.18 represents H, C.sub.1-4
alkyl or CH.sub.2C(O)OR.sup.19; R.sup.15 and R.sup.17 independently
represent H, C.sub.1-6 alkyl or C.sub.1-3 alkylphenyl; R.sup.1a,
R.sup.1b, R.sup.1c, R.sup.11 and R.sup.19 independently represent H
or C.sub.1-4 alkyl; and q represents 0, 1 or 2;
[0020] R.sub.x represents a structural fragment of formula IIa, IIb
or IIc, ##STR3## wherein the dotted lines independently represent
optional bonds; A and E independently represent O or S, CH or
CH.sub.2 (as appropriate), or N or N(R.sup.21) (as appropriate); D
represents --CH.sub.2--, O, S, N(R.sup.22), --(CH.sub.2).sub.2--,
--CH.dbd.CH--, --CH.sub.2N(R.sup.22)--, --N(R.sup.22)CH.sub.2--,
--CH.dbd.N--, --N.dbd.CH--, --CH.sub.2O--, --OCH.sub.2--,
--CH.sub.2S-- or --SCH.sub.2--; X.sub.1 represents C.sub.2-4
alkylene; C.sub.2-3 alkylene interrupted by Z; --C(O)-Z-A.sup.1-;
-Z-C(O)-A.sup.1-; --CH.sub.2--C(O)-A.sup.1-; -Z-C(O)-Z-A.sup.2-;
--CH.sub.2-Z-C(O)-A.sup.2-; -Z-CH.sub.2--C(O)-A.sup.2-;
-Z-CH.sub.2--S(O).sub.m-A.sup.2-; --C(O)-A.sup.3; -Z-A.sup.3-; or
-A.sup.3-Z-; X.sub.2 represents C.sub.2-3 alkylene, --C(O)-A.sup.4-
or -A.sup.4-C(O)--; X.sub.3 represents CH or N; X.sub.4 represents
a single bond, O, S, C(O), N(R.sup.23), --CH(R.sup.23)--,
--CH(R.sup.23)--CH(R.sup.24)-- or --C(R.sup.23).dbd.C(24); A.sup.1
represents a single bond or C.sub.1-2 alkylene; A.sup.2 represents
a single bond or --CH.sub.2--; A.sup.3 represents C.sub.1-3
alkylene; A.sup.4 represents C(O) or C.sub.1-2 alkylene; Z
represents, at each occurrence, O, S(O).sub.m or N(R.sup.25);
R.sup.2 and R.sup.4 independently represent one or more optional
substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy (which
latter two groups are optionally substituted by one or more halo
substituent), methylenedioxy, halo, hydroxy, cyano, nitro,
S(O).sub.2NH.sub.2, C(O)OR.sup.26, SR.sup.26, S(O)R.sup.26a,
S(O).sub.2R.sup.26a or N(R.sup.27)R.sup.2s; R.sup.3 represents one
or more optional substituents selected from OH, C.sub.1-4 alkoxy,
C.sub.1-6 alkyl (optionally substituted by one or more halo group),
or N(R.sup.29a)R.sup.29b; R.sup.25, R.sup.29a and R.sup.29b
independently represent H, C.sub.1 alkyl or C(O)R.sup.30; R.sup.26
represents H or C.sub.1-4 alkyl; R.sup.26a represents C.sub.1-4
alkyl; R.sup.27 and R.sup.28 independently represent H, C.sub.1-4
alkyl or C(O)R.sup.30, or together represent C.sub.3-6 alkylene,
thus forming a 4- to 7-membered ring, which ring is optionally
substituted, on a carbon atom .alpha. to the nitrogen atom, with an
.dbd.O group; R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.30
independently represent, at each occurrence, H or C.sub.1-4 alkyl;
Y represents CH.sub.2, (CH.sub.2).sub.2, CH.dbd.CH (which latter
group is optionally substituted by C.sub.1-4 alkyl), (CH).sub.3,
CH.sub.2CH.dbd.CH or CH.dbd.CHCH.sub.2 (which latter three groups
are optionally substituted by C.sub.1-4 alkyl, methylene, .dbd.O or
hydroxy); R.sup.y represents H or C.sub.1-4 alkyl; n represents 0,
1, 2, 3 or 4; and B represents a structural fragment of formula
IIIa, IIIb or IIIc ##STR4## wherein X.sup.5, X.sup.6, X.sup.7 and
X.sup.8 independently represent CH, N or N--O; X.sup.9 and X.sup.10
independently represent a single bond or CH.sub.2; R.sup.31
represents an optional substituent selected from halo, C.sub.1-4
alkyl (which group is optionally substituted by one or more halo
group), N(R.sup.32)R.sup.33, OR.sup.34 or SR.sup.35; R.sup.32 and
R.sup.33 independently represent H, C.sub.1-4 alkyl or
C(O)R.sup.36; R.sup.34, R.sup.35 and R.sup.36 independently
represent H or C.sub.1-4 alkyl; and one of D.sup.1 and D.sup.2
represents H, and the other represents H, OR.sup.a, NHR.sup.a,
C(.dbd.X.sup.11)X.sup.12R.sup.b, or D.sup.1 and D.sup.2 together
represent a structural fragment of formula IVa:-- ##STR5## R.sup.a
represents H or -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e;
R.sup.b represents -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e;
A.sup.5 represents, at each occurrence, a single bond or C.sub.1-12
alkylene (which alkylene group is optionally interrupted by one or
more O, S(O).sub.m and/or N(R.sup.f) group, and is optionally
substituted by one or more of halo. OH, N(H)C(O)R.sup.g,
C(O)N(R.sup.g)R.sup.h, C.sub.3-7-cycloalkyl (which cycloalkyl group
is optionally interrupted by one or more O, S(O).sub.m and/or
N(R.sup.f) group and/or is optionally substituted by one or more
substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo,
.dbd.O or .dbd.S), Het and C.sub.6-10 aryl (which aryl and Het
groups are themselves optionally substituted by one or more
substituents selected from C.sub.1-6 alkyl (optionally substituted
by one or more halo substituent), C.sub.1-6 alkoxy, halo, cyano,
C(O)OR.sup.g, C(O)N(R.sup.g)R.sup.h and N(R.sup.f)R.sup.g));
R.sup.c and R.sup.d both represent H; or one of R.sup.c and R.sup.d
represents H or C.sub.1-7 alkoxy and the other represents C.sub.1-7
alkyl (which alkyl group is optionally interrupted by one or more O
atoms); or R.sup.c and R.sup.d together represent C.sub.3-8
cycloalkyl, which cycloalkyl group is interrupted by one or more O,
S(O).sub.m and/or N(R.sup.f) group; R.sup.e represents, at each
occurrence, H, C.sub.1-12 alkyl (which alkyl group is optionally
interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group,
and/or is optionally substituted by one or more substituents
selected from halo, OH, N(H)C(O)R.sup.g and C(O)N(R.sup.g)R.sup.h),
A.sup.7-C.sub.3-7-cycloalkyl (which cycloalkyl group is optionally
interrupted by one or more O, S(O).sub.m and/or N(R.sup.f) group
and/or is substituted by one or more substituents selected from
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, .dbd.O and .dbd.S),
A.sup.7-C.sub.6-10 aryl or A.sup.7-Het (which aryl and Het groups
are optionally substituted by one or more substituents selected
from C.sub.1-- alkyl (optionally substituted by one or more halo
substituent), C.sub.1-6 alkoxy, halo, cyano, C(O)OR.sup.g,
C(O)N(R.sup.g)R.sup.h and N(R.sup.f)R.sup.g); A.sup.7 represents a
single bond or C.sub.1-7 alkylene (which alkylene group is
optionally interrupted by one or more O, S(O).sub.m and/or
N(R.sup.f) group, and/or are optionally substituted by one or more
of halo, OH, N(H)COR.sup.g and CON(R.sup.g)R.sup.h); Het
represents, at each occurrence, a five- to ten-membered heteroaryl
group, which may be aromatic in character, containing one or more
nitrogen, oxygen or sulphur atoms in the ring system; n and r
independently represent 0 or 1; X.sup.11, X.sup.12 and X.sup.14
independently represent O or S; X.sup.13 represents O or
N(R.sup.f); R.sup.f represents, at each occurrence, H, C.sub.1-4
alkyl or C(O)R.sup.g;
[0021] R.sup.g and R.sup.h independently represent, at each
occurrence, H or C.sub.1-4 alkyl; and
m represents, at each occurrence, 0, 1 or 2;
or a pharmaceutically acceptable salt thereof;
provided that:
(a) A and E do not both represent O or S;
(a) E and D do not both represent O or S;
(c) when R.sup.1 represents OR.sup.1d and X.sub.1 represents
--C(O)-Z-A.sup.1, -Z-CH.sub.2--S(O).sub.m-A.sup.2- or
-Z-C(O)-Z-A.sup.2, then A.sup.7 or A.sup.2 (as appropriate) do not
represent a single bond;
(d) when X.sub.4 represents --CH(R.sup.23)--, R.sup.1 does not
represent OH;
(e) when A.sup.5 represents a single bond, then n and r both
represent 0;
(f) when A.sup.5 represents C.sub.1-12 alkylene, then n represents
1;
(g) when A.sup.5 represents --CH.sub.2--, n is 1 and r is 0, then
R.sup.e does not represent H; and
(h) the compound is not:--
[0022] (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab;
[0023] (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab;
[0024] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0025] (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab;
[0026] 1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0027] 1-hydroxy-5,7-dimethyltetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0028] 1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0029] 1-hydroxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc; [0030]
7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc; [0031] (R)- or
(S)-7-methoxy-1-methyltetralin-1-yl-C(O)-Aze-Pab; [0032]
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab.times.OAc; [0033] (S)-
or (R)-1-hydroxy-4-methoxyindan-1-yl-C(O)-Aze-Pab; [0034]
1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab(OH); [0035] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(OH); [0036]
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OH); [0037]
4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OMe); [0038] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH.sub.2CCl.sub.3-
); [0039] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH.sub.2CH.sub.3)-
; [0040] 7-methoxy-1-allyltetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0041] (S)- or (R)-1-hydroxy-7-chlorotetralin-1-yl-C(O)-Pro-Pab;
[0042] 1-n-propyl-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc;
[0043] 6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
[0044] 4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc; [0045]
6,8-dichloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc; [0046]
6-fluoro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc; [0047]
4-hydroxy-6-methylchroman-4-yl-C(O)-Aze-Pab.times.HOAc; [0048]
8-chloro-4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab.times.HOAc;
[0049]
6-chloro-4-hydroxy-8-methylchroman-4-yl-C(O)-Aze-Pab.times.HOAc;
[0050] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O)-i-Pr);
[0051] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O)-Et);
[0052] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--C(O)--Ch);
[0053] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-allyl); [0054]
(S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Bzl);
[0055] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(CO--O-methally-
l); [0056] 1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab(OH); [0057]
(S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Val);
[0058] (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-(Me)Pab; or [0059]
9-hydroxyfluoren-9-yl-C(O)-Aze-Pab.times.HOAc, which compounds are
referred to hereinafter as "the compounds of the invention".
[0060] The compounds of the invention may exhibit tautomerism. All
tautomeric forms and mixtures thereof are included within the scope
of the invention. Particular tautomeric forms of compounds of the
invention that may be mentioned include those connected with the
position of the double bond in the amidine functionality in the
structural fragment B, and the position of D.sup.1 and D.sup.2,
when one of these does not represent H. Further, it will be
appreciated by those skilled in the art that, in the structural
fragment of formula IIa, the optional double bonds, may, in
conjunction with certain identities of substituent D, render the
ring bearing A, E and D aromatic in character.
[0061] The compounds of formula I may also contain one or more
asymmetric carbon atoms and may therefore exhibit optical and/or
diastereoisomerism. All diastereoisomers may be separated using
conventional techniques, e.g. chromatography or fractional
crystallisation. The various stereoisomers may be isolated by
separation of a racemic or other mixture of the compounds using
conventional, e.g. fractional crystallisation or HPLC, techniques.
Alternatively the desired optical isomers may be made by reaction
of the appropriate optically active starting materials under
conditions which will not cause racemisation or epimerisation, or
by derivatisation, for example with a homochiral acid followed by
separation of the diastereomeric derivatives by conventional means
(e.g. HPLC, chromatography over silica). All stereoisomers are
included within the scope of the invention.
[0062] The term "aryl" includes phenyl, naphthyl and the like. Aryl
groups may also be fused to cycloalkyl groups to form e.g.
benzo-(C.sub.3-7)-cycloalkyl units (e.g. indanyl, indenyl,
tetralinyl, and the like). The term "Het" includes groups such as
pyridinyl, thiophenyl, furanyl, pyrrolidinyl, imidazolyl, indolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl,
thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl,
quinolinyl, isoquinolinyl, piperidinyl, piperazinyl, chromanyl,
thiochromanyl and the like.
[0063] Alkyl groups which R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c,
R.sup.1d, R.sup.2, R.sup.3, R.sup.4, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26,
R.sup.26a, R.sup.27, R.sup.28, R.sup.29a, R.sup.29b, R.sup.30,
R.sup.31, R.sup.32, R.sup.33, R.sup.34, R.sup.35, R.sup.36,
R.sup.y, R.sup.f, R.sup.g and R.sup.h may represent, and with which
Y, A.sup.5 and R.sup.e may be substituted; the alkyl part of
alkylphenyl groups which R.sup.15 and R.sup.17 may represent; and
alkoxy groups which R.sup.2, R.sup.3, R.sup.4, R.sup.c and R.sup.d
may represent, and with which A.sup.5 and R.sup.e may be
substituted, may, when there is a sufficient number of carbon
atoms, be linear or branched, saturated or unsaturated, and/or
cyclic, acyclic or part cyclic/acyclic. Alkyl groups which R.sup.c,
R.sup.d and R.sup.1 may represent, and alkylene groups which
R.sup.27 and R.sup.28 (together), X.sub.1, X.sub.2, A.sup.1,
A.sup.3, A.sup.4 and A.sup.7 may represent may, when there is a
sufficient number of carbon atoms, be linear or branched, and/or
saturated or unsaturated. Cycloalkyl groups which R.sup.c and
R.sup.d may together represent, and which R.sup.1 may include, may
be branched and/or may be saturated or unsaturated.
[0064] Alkylene groups which A.sup.5 may represent may, when there
is a sufficient number of carbon atoms, be linear or branched, be
saturated or unsaturated, and/or be cyclic, acyclic or part
cyclic/acyclic. The C.sub.3-7 cycloalkyl group with which A.sup.5
may be substituted, may be branched, saturated or unsaturated,
and/or part cyclic/acyclic. This cycloalkyl group may also be
attached to A.sup.5 via a carbon-carbon bond or may be attached
directly to the alkylene chain (i.e. to give a "Spiro"
compound).
[0065] Halo groups, which R.sup.2, R.sup.4 and R.sup.31 may
represent, and with which R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.31, A.sup.5, R.sup.e and A.sup.7 may be substituted, include
fluoro, chloro, bromo and iodo.
[0066] In the structural fragments of formulae IIa, IIb and IIc,
the dots indicate the carbon atom which is bonded to the --C(O)--
group and to R.sup.1 in a compound of formula I (for the avoidance
of doubt, there is no further H atom bonded to the carbon atom so
indicated).
[0067] The wavy lines on the bond in the fragments of formulae
IIIa, IIIb, IIIc, IVa and Ar (below) signify the bond position of
the fragment.
[0068] Abbreviations are listed at the end of this
specification.
[0069] Preferred compounds of the invention include those in which,
when:
[0070] R.sup.2 and R.sup.4 do not independently represent C.sub.1-4
alkoxy substituted by one or more halo substituent, SR.sup.26,
S(O)R.sup.26a, S(O).sub.2R.sup.26a or N(R.sup.27)R.sup.28, in which
R.sup.27 and R.sup.28 independently represent C(O)R.sup.30, or
together represent C.sub.3-6 alkylene, thus forming a 4- to
7-membered ring, which ring is optionally substituted, on a carbon
atom that is .alpha. to the nitrogen atom, with a .dbd.O group, and
R.sup.26, R.sup.26a and R.sup.30 are as hereinbefore defined;
R.sup.3 does not represent one or more optional substituents
selected from C.sub.3-6 alkyl (optionally substituted by one or
more halo group) or N(R.sup.29a)R.sup.29b, in which R.sup.29a and
R.sup.29b are as hereinbefore defined;
R.sup.25 does not represent C(O)R.sup.30, in which R.sup.30 is as
hereinbefore defined;
Y does not represent CH.dbd.CH substituted by C.sub.1-4 alkyl;
and/or
R.sup.31 does not represent C.sub.1-4 alkyl (substituted by one or
more halo group),
N(R.sup.32)R.sup.33, OR.sup.34 or SR.sup.35, in which R.sup.32,
R.sup.33, R.sup.34 and R.sup.35 are as hereinbefore defined,
(i.e. when the values of R.sup.2, R.sup.4, R.sup.3 R.sup.25, Y and
R.sup.31 are other than those listed immediately above)
then
(i) D.sup.1 and D.sup.2 do not both represent H;
(ii) when D.sup.1 or D.sup.2 represents OR.sup.a, then R.sup.a does
not represent H, phenyl, benzyl or C.sub.1-7 alkyl (which latter
group is optionally interrupted by O or is optionally substituted
by halo);
[0071] (iii) when D.sup.1 or D.sup.2 represents
C(X.sup.11)X.sup.12R.sup.b and X.sup.11 and X.sup.12 both represent
O, then R.sup.b does not represent 2-naphthyl, phenyl, C.sub.1-3
alkylphenyl (which latter three groups are optionally substituted
by C.sub.1-6 alkyl, C.sub.1-6 alkoxy or halo); C.sub.1-12 alkyl
(which latter group is optionally substituted by C.sub.1-6 alkoxy,
C.sub.1-6 acyloxy or halo);
--[C(R.sup.q)(R.sup.r)].sub.pOC(O)R.sup.s, in which p is 1, 2 or 3,
R.sup.q and R.sup.r independently represent H or C.sub.1-6 alkyl
(provided that the total number of carbon atoms in
[C(R.sup.q)(R.sup.r)].sub.p does not exceed 12), and R.sup.s
represents C.sub.1-6 alkyl (optionally substituted by C.sub.1-6
alkoxy), C.sub.1-12 alkyl (optionally substituted by halo),
C.sub.3-7 cycloalkyl, phenyl, naphthyl or C.sub.1-3 alkylphenyl
(which latter four groups are optionally substituted by C.sub.1-6
alkyl or halo); or --CH.sub.2--Ar, in which Ar represents the
structural fragment: ##STR6##
[0072] Compounds of the invention which may be mentioned include
those in which:
R.sup.2 and R.sup.4 independently represent C.sub.1-4 alkoxy
substituted by one or more halo substituents, SR.sup.26,
S(O)R.sup.26a, S(O).sub.2R.sup.26a or N(R.sup.27)R.sup.28, in which
R.sup.27 and
[0073] R.sup.28 independently represent C(O)R.sup.30, or together
represent C.sub.3-6 alkylene, thus forming a 4- to 7-membered ring,
which ring is optionally substituted, on a carbon atom that is
.alpha. to the nitrogen atom, with a .dbd.O group, and R.sup.26,
R.sup.26a and R.sup.30 are as hereinbefore defined; (R.sup.3
represents one or more optional substituents selected from
C.sub.1-6 alkyl (optionally substituted by one or more halo group)
or N(R.sup.29a)R.sup.29b, in which R.sup.29a and R.sup.29b are as
hereinbefore defined;
R.sup.25 represents C(O)R.sup.30, in which R.sup.30 is as
hereinbefore defined;
Y represents CH.dbd.CH substituted by C.sub.1-4 alkyl;
R.sup.31 represents C.sub.1-4 alkyl (substituted by one or more
halo group), N(R.sup.32)R.sup.33, OR.sup.34 or SR.sup.35, wherein
R.sup.32, R.sup.33, R.sup.34 and R.sup.35 are as hereinbefore
defined.
[0074] Further compounds of the invention which may be mentioned
include those in which:
(i) when one of D.sup.1 or D.sup.2 represents OR.sup.a, then
R.sup.a does not represent H, phenyl, benzyl or C.sub.1-7 alkyl
(which latter group is optionally interrupted by O or is optionally
substituted by halo);
[0075] (ii) when one of D.sup.1 or D.sup.2 represents
C(X.sup.11)X.sup.12R.sup.b and X.sup.11 and X.sup.12 both represent
O, then R.sup.b does not represent 2-naphthyl, phenyl, C.sub.1-3
alkylphenyl (which latter three groups are optionally substituted
by C.sub.1-6 alkyl, C.sub.1-6 alkoxy or halo); C.sub.1-12 alkyl
(which latter group is optionally substituted by C.sub.1-6 alkoxy,
C.sub.1-6 acyloxy or halo);
--[C(R.sup.q)(R.sup.r)].sub.pOC(O)R.sup.s, in which p is 1, 2 or 3,
R.sup.q and R.sup.r independently represent H or C.sub.1-6 alkyl
(provided that the total number of carbon atoms in
[C(R.sup.q)(R.sup.r)].sub.p does not exceed 12), and R.sup.s
represents C.sub.1-6 alkyl (optionally substituted by C.sub.1-6
alkoxy), C.sub.1-12 alkyl (optionally substituted by halo),
C.sub.3-7 cycloalkyl, phenyl, naphthyl or C.sub.1-3 alkylphenyl
(which latter four groups are optionally substituted by C.sub.1--
alkyl or halo); or --CH.sub.2--Ar, in which Ar represents the
structural fragment: ##STR7##
[0076] When n represents 2 and B represents a structural fragment
of formula IIIb, preferred compounds of the invention include those
wherein X.sup.9 and X.sup.10 do not both represent CH.sub.2.
[0077] Preferred compounds of formula I include those wherein:
R.sup.1 represents OH or C.sub.1-4 alkyl (which latter group is
optionally substituted by cyano or OH);
R.sub.x represents a structural fragment of formula IIb or,
especially, IIa;
[0078] when R.sub.x represents a structural fragment of formula
IIa, the dotted lines represent bonds, A and E both represent CH
and D represents --CH.dbd.CH--;
[0079] when R.sub.x represents a structural fragment of formula
IIa, X.sub.1 represents optionally unsaturated C.sub.2- or
C.sub.3-alkylene, or -Z-A.sup.3 (in which Z represents O,
S(O).sub.m or N(R.sup.25) (in which R.sup.25 is as hereinbefore
defied or represents C.sub.1 alkyl or C(O)R.sup.30 and m and
R.sup.30 are as hereinbefore defined) and A.sup.3 represents
C.sub.1- or C.sub.2-alkylene (which latter group is optionally
unsaturated));
Y represents (CH.sub.2).sub.3, preferably (CH.sub.2).sub.2 and more
preferably CH.sub.1;
B represents a structural fragment of formula IIIa in which
X.sup.5, X.sup.6, X.sup.7 and
X.sup.8 all represent CH.
[0080] Particularly preferred compounds of the invention include
those wherein, when R.sub.x represents a structural fragment of
formula IIa, X.sub.1 represents C.sub.3-alkylene or
-Z(CH.sub.2).sub.2--, in which Z represents S(O).sub.m, N(R.sup.25)
(in which R.sup.25 is as hereinbefore defined) or, especially,
O.
[0081] When R.sub.x represents a structural fragment of formula
IIa, and R.sup.2 represents at least one substituent, a preferred
point of substitution is at the carbon atom which is at position E.
It is preferred that at least one (and preferably two) substituents
R.sup.2 are present in a structural fragment of formula IIa.
[0082] When R.sub.x represents a structural fragment of formula
IIa, the dotted lines represent bonds, A and E both represent CH
and D represents --CH.dbd.CH--(i.e. the ring bearing R.sup.2 is a
benzo group), and R.sup.2 represents at least one substituent, the
ring is preferably substituted either at the carbon atom in the
--CH.dbd.CH-- group (position D) which is adjacent to the ring
junction, or at the carbon atom which is at position E, or
preferably at both of these sites. For example, when the fragment
IIa represents a tetralin-1-yl group (i.e. the dotted lines
represent bonds, A and E both represent CH, D represents
--CH.dbd.CH-- and X.sub.1 represents saturated C.sub.3-alkylene),
preferred substitution positions are the 5- and 7-positions, or,
preferably, di-substitution at both of these positions.
Correspondingly, when the fragment IIa represents a chroman-4-yl, a
thiochroman-4-yl, or a quinolin-4-yl, group (i.e. the dotted lines
represent bonds, A and E both represent CH, D represents
--CH.dbd.CH--, and X.sub.1 represents -Z(CH.sub.2).sub.2--, in
which Z represents O, S(O).sub.m or N(R.sup.25)), preferred
substitution positions are the 8- and 6-positions, or, preferably,
di-substitution at both of these positions.
[0083] Preferred optional substituents R.sup.2 include halo,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy (which latter two groups are
optionally substituted by one or more halo groups) or
N(R.sup.2)R.sup.28.
[0084] When R.sup.1 represents OH, R.sub.x represents an
unsubstituted (by R.sup.2 and R.sup.4) structural fragment of
formula IIc, in which X.sub.4 represents a single bond, CH.sub.2 or
O, Y represents CH.sub.2 or (CH.sub.2).sub.2, R.sup.y represents H
and n represents 1, preferred compounds of the invention include
those in which B does not represent a structural fragment of
formula IIIb in which X.sup.9 and X.sup.10 are both CH.sub.2 and
D.sup.1 and D.sup.2 are both H.
[0085] When D.sup.1 and D.sup.2 together represent a structural
fragment of formula IVa, in which X.sup.13 is O, preferred
compounds of the invention include those in which one of R.sup.c
and R.sup.d represents H or C.sub.1-7 alkoxy and the other
represents C.sub.1-7 alkyl (e.g. C.sub.1-4 alkyl, including linear,
saturated, unsubstituted, and uninterrupted, C.sub.1-4 alkyl).
[0086] When D.sup.1 or D.sup.2 represents OR.sup.a and R.sup.a
represents -A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, and:
(i) A.sup.5 is a single bond (and thus n and r both represent 0),
preferred compounds of the invention include those in which R.sup.e
is:--
[0087] (1) optionally substituted A.sup.7-aryl, in which A.sup.7 is
preferably a single bond or C.sub.1-3 alkylene (e.g.
C.sub.1-2-alkylene) and aryl is preferably C.sub.6-10-aryl, (e.g.
phenyl), which A.sup.7-aryl group is optionally substituted by one
or more halo, C.sub.1-6alkoxy (e.g. C.sub.1-4 alkoxy, such as
methoxy), C.sub.1-6 alkyl (e.g. C.sub.1-4 alkyl) or a haloalkyl
(e.g. CF.sub.3) substituent); [0088] (2) H or linear, branched,
optionally unsaturated, and/or cyclic, C.sub.1-12 alkyl (e.g.
C.sub.3-7 alkyl), which cyclic alkyl group is optionally
interrupted by an O atom and, optionally, a further O atom or
S(O).sub.m group; (ii) A.sup.5 is linear or branched C.sub.1-12
alkylene, X.sup.14 is O and r is 0, preferred compounds of the
invention include those in which R.sup.e is C.sub.1-3 alkyl or
A.sup.7-aryl, in which A.sup.7 is a single bond and the aryl group
is preferably optionally substituted phenyl.
[0089] When D.sup.1 or D.sup.2 represents OR.sup.a, preferred
compounds of the invention include those in which R.sup.a is H or
C.sub.1-4 alkyl.
[0090] When D.sup.1 or D.sup.2 represents
--C(.dbd.X.sup.11)X.sup.12R.sup.b, in which X.sup.11 represents O
and X.sup.12 represents O or S, and, in which R.sup.b group,
A.sup.5 represents a single bond (and thus n and r both represent
0), preferred compounds of the invention include those in which
R.sup.e represents optionally unsaturated C.sub.1-6 (e.g.
C.sub.1-4) alkyl, A.sup.7-C.sub.6-10-aryl (in which A.sup.7
represents a single bond or C.sub.1-2 alkylene and the C.sub.6-10
aryl group is preferably phenyl, which A.sup.7-C.sub.6-10-aryl
group is optionally substituted by one or more halo, C.sub.1-4
alkyl and/or C.sub.1-4 alkoxy groups), or
A.sup.7-C.sub.3-7-cycloalkyl (especially A.sup.7-C.sub.1-5
cycloalkyl), in which A.sup.7 represents a single bond or linear or
branched C.sub.1-7 alkylene, and which cycloalkyl group is
optionally substituted by C.sub.1-3 alkyl.
[0091] Compounds of formula I in which the fragment ##STR8## is in
the S-configuration are preferred. The wavy lines on the bonds in
the above fragment signify the bond position of the fragment.
[0092] Preferred compounds of formula I include the compounds of
the Examples described hereinafter.
Preparation
[0093] According to the invention there is also provided a process
for the preparation of compounds of formula I which comprises: (i)
the coupling of a compound of formula IV, ##STR9## wherein R.sup.1
and R.sub.x are as hereinbefore defined with a compound of formula
V, ##STR10## wherein R.sup.y, Y, n and B are as hereinbefore
defined, for example in the presence of a coupling agent (e.g.
oxalyl chloride in DMF PyBOP, EDC, DCC, HBTU, HATU or TBTU), an
appropriate base (e.g. pyridine, 2,4,6,-trimethylpyridine,
2,4,6-collidine, DMAP, TEA or DIPEA) and a suitable organic solvent
(e.g. dichloromethane, acetonitrile or DMF); (ii) the coupling of a
compound of formula VI, ##STR11## wherein R.sup.1, R.sub.x and Y
are as hereinbefore defined with a compound of formula VII,
H(R.sup.y)N--(CH.sub.2).sub.n--B VII wherein R.sup.y, n and B are
as hereinbefore defined, for example in the presence of a coupling
agent (e.g. oxalyl chloride in DMF, PyBOP, EDC, DCC, HBTU, HATU or
TBTU), an appropriate base (e.g. pyridine,
2,4,6,-trimethylpyridine, 2,4,6-collidine, DMAP, TEA or DIPEA) and
a suitable organic solvent (e.g. dichloromethane, acetonitrile or
DMF); (iii) for compounds of formula I in which D.sup.1 or D.sup.2
represents OR.sup.a or NHR.sup.a, reaction of a compound of formula
VIII, ##STR12## wherein B.sup.1 represents a structural fragment of
formula IIId, IIIe or IIIf ##STR13## and R.sup.1, R.sub.x, Y,
R.sup.y, n, R.sup.31, X.sup.5, X.sup.6, X.sup.7, X.sup.8, X.sup.9
and X.sup.10 are as hereinbefore defined with a compound of formula
IX, H.sub.2NX.sup.aR.sup.a IX wherein X.sup.a represents O or NH
and R.sup.a is as hereinbefore defined, for example at between 40
and 70.degree. C. (e.g. 60.degree. 0), in the presence (optionally)
of a suitable base (e.g. TEA), and an appropriate organic solvent
(e.g. THF, CH.sub.3CN, DMF or DMSO), and, optionally, wherein the
compound of formula VIII is first treated with gaseous HCl, in the
presence of a lower alkyl alcohol (e.g. ethanol) at, for example,
0.degree. C.; (iv) for compounds of formula I in which D.sup.1 or
D.sup.2 represents OR.sup.a or NHR.sup.a, reaction of a compound of
formula I in which D.sup.1 or D.sup.2 (as appropriate) represents
C(O)OR.sup.b1, in which R.sup.b1 represents a protecting group
(such as a 2-trimethylsilylethyl, a suitable alkyl (e.g. C.sub.1-6
alkyl), or alkylphenyl (e.g. benzyl), group) with a compound of
formula IX as hereinbefore defined, for example under similar
reaction conditions to those described hereinbefore for preparation
of compounds of formula I (step (iii)) (the skilled person will
appreciate that in such a reaction the deprotected (i.e.
C(O)OR.sup.b1 and OR.sup.a/NHR.sup.a protected) derivative may, in
some cases, be isolated if desired, and the C(O)OR.sup.b1 group
then removed using conventional techniques); (v) for compounds of
formula I in which D.sup.1 or D.sup.2 represents OR.sup.a or
NHR.sup.a, R.sup.a represents
-A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5 does
not represent a single bond, and n represent 1, reaction of a
compound of formula I in which D.sup.1 or D.sup.2 (as appropriate)
represents OH or NH.sub.2, with a compound of formula X,
L.sup.1A.sup.5a[X.sup.14][C(O)].sub.rR.sup.e X wherein L.sup.1
represents a suitable leaving group, such as lower alkoxy or halo,
A.sup.5a represents A.sup.5, as hereinbefore defined except that it
does not represent a single bond, and X.sup.14, r and R.sup.e are
as hereinbefore defined, for example under conditions that are well
known to those skilled in the art (see e.g. U.S. Pat. No.
3,822,283); (vi) for compounds of formula I in which D.sup.1 or
D.sup.2 represents OR.sup.a or NHR.sup.a, R.sup.a represents
-A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5
represents C.sub.2--,2 alkylene, which alkylene group is branched
at the carbon atom that is .alpha. to the O or N atom of OR.sup.a
or NHR.sup.a (as appropriate), and which group is optionally
branched at the carbon atom that is .beta. to that atom, n
represents 1, r represents 0 and R.sup.e is as hereinbefore
defined, reaction of a compound of formula I in which D.sup.1 or
D.sup.2 (as appropriate) represents OH or NH.sub.2, with a compound
of formula XI, ##STR14## or a geometrical isomer thereof, or a
mixture of such geometrical isomers, in which R.sup.b1 and R.sup.b3
each represent H or an alkyl group, provided that the total number
of carbon atoms provided by R.sup.b1 and R.sup.b3 does not exceed
10, and wherein X.sup.14 and R.sup.e are as hereinbefore defined,
for example under conditions that are well known to those skilled
in the art; (vii) for compounds of formula I in which D.sup.1 or
D.sup.2 represents OR.sup.a or NHR.sup.a, R.sup.a represents
-A.sup.5[X.sup.14].sub.n[C(O)].sub.rR.sup.e, in which A.sup.5
represents a single bond (and thus n and r both represent 0), and
R.sup.e represents A.sup.7-C.sub.3-6-cycloalkyl, in which A.sup.7
represents a single bond, and the cycloalkyl group is interrupted
by at least one O or S atom, which atom is between the carbon atom
at the point of attachment to the O or NH group of OR.sup.a or
NHR.sup.a, and a carbon atom that is .alpha. to that point of
attachment, and which cycloalkyl group is optionally interrupted by
one or more O or S(O).sub.m group and/or optionally substituted by
one or more .dbd.O group, reaction of a compound of formula I, in
which D.sup.1 or D.sup.2 (as appropriate) represents OH or
NH.sub.2, with a compound of formula XII, ##STR15## wherein
X.sup.15 represents O or S and X.sup.16 represents C.sub.1-4
alkylene (which alkylene group is optionally interrupted by one or
more O or S(O).sub.m group and/or optionally substituted by one or
more .dbd.O group), for example under conditions that are well
known to those skilled in the art; (viii) for compounds of formula
I in which D.sup.1 or D.sup.2 represents
C(X.sup.11)X.sup.12R.sup.b, reaction of a compound of formula I in
which D.sup.1 and D.sup.2 both represent H with a compound of
formula XIII, L.sup.2-C(X.sup.11)X.sup.12R.sup.b XIII wherein
L.sup.2 represents a suitable leaving group, such as halo or
p-nitrophenoxy, and X.sup.11, X.sup.12 and R.sup.b are as
hereinbefore defined, for example 0.degree. C. in the presence of a
suitable base (e.g. NaOH) and an appropriate organic solvent (e.g.
THF) or water; (ix) for compounds of formula I in which D.sup.1 and
D.sup.2 together represent a structural fragment of formula IVa,
reaction of a corresponding compound of formula I in which D.sup.1
or D.sup.2 represents OH or NHR.sup.f (in which R.sup.f is as
hereinbefore defined), with a compound of formula XV,
(R.sup.c)(R.sup.d)C(R.sup.c1)(R.sup.c2) XV wherein R.sup.c1 and
R.sup.c2 both represent --OR.sup.c3, in which R.sup.c3 represents
C.sub.1-3 alkyl, or together represent .dbd.O, and R.sup.c and
R.sup.d are as hereinbefore defined, for example by using the
compound of formula XV as solvent and HCl as a catalyst, at between
room temperature and reflux (see e.g. J. Org. Chem. USSR, 21, 177
(1985)); (x) for compounds of formula I in which one or more of
X.sup.5, X.sup.6, X.sup.7 and X.sup.8 represent N--O, oxidation of
a corresponding compound of formula I in which X.sup.5, X.sup.6,
X.sup.7 and/or X.sup.8 (as appropriate) represent(s) N under
conditions that are well known to those skilled in the art (for
example in the presence of a suitable oxidising agent (e.g. MCPBA),
at an appropriate temperature (e.g. 0.degree. C.), and in the
presence of a suitable organic solvent (e.g. DCM)); (xi) for
compounds of formula I in which any one of Z, X.sup.1, R.sup.2,
R.sup.4, A.sup.5, A.sup.7, R.sup.c, R.sup.d and/or R.sup.e
comprises or includes a S(O) or a S(O).sub.2 group, oxidation of a
corresponding compound of formula I (or a compound corresponding to
a compound of formula I) wherein Z, X.sup.1, R.sup.2, R.sup.4,
A.sup.5, A.sup.7, R.sup.c, R.sup.d and/or R.sup.e (as appropriate)
comprise(s) or include(s) a S group, in the presence of an
appropriate amount of a suitable oxidising agent (e.g. mCPBA) and
an appropriate organic solvent; or (xii) for compounds of formula I
in which D.sup.1 and D.sup.2 both represent H, removal of a
OR.sup.a, NHR.sup.a or C(.dbd.X.sup.11)X.sup.12R.sup.b group (in
which R.sup.a, R.sup.b, X.sup.11 and X.sup.12 are as hereinbefore
defined), or removal of a structural fragment of formula IVa as
hereinbefore defined, from a corresponding compound of formula I
(i.e. deprotection) under conditions known to those skilled in the
art.
[0094] Compounds of formula IV are commercially available, are well
known in the literature, or are available using known and/or
standard techniques. For example, compounds of formula IV in which
R.sup.1 represents OH may be prepared by reaction of a compound of
formula XVI, R.sub.x=O XVI wherein R.sub.x is as hereinbefore
defined, with: (a) KCN, for example at 20.degree. C. in the
presence of sodium bisulphite in water, followed by hydrolysis in
the presence of aqueous acid (e.g. HCl), for example at 20.degree.
C. in the presence of a suitable solvent (e.g. alcohol and/or
water); (b) CHCl.sub.3, in the presence of aqueous base (e.g.
NaOH); (c) TMSCN, for example at 20.degree. C. in the presence of a
suitable organic solvent (e.g. CH.sub.2Cl.sub.2), followed by
hydrolysis in the presence of acid (e.g. HCl or H.sub.2SO.sub.4),
for example at 20.degree. C. (e.g. according, or analogously, to
the method described by Bigge et al in J. Med. Chem. (1993) 36,
1977), followed by alkaline hydrolysis to give the free acid.
[0095] Compounds of formula IV in which R.sup.1 represents OH may
alternatively be prepared by way of a Sharpless stereoselective
dihydroxylation of a compound of formula XVIA, R.sub.x.dbd.CH.sub.2
XVIA wherein R.sub.x is as hereinbefore defined, under conditions
known to those skilled in the art (e.g. at low temperature (e.g.
0.degree. C.), using, for example, the commercial reagent
AD-mix-.beta..TM. in the presence of suitable solvent (e.g.
t-butanol), followed by oxidation of the resultant intermediate
(e.g. at elevated temperature (e.g. 75.degree. C.) in the presence
of a stream of air and Pt/C (5%) in acetone/water).
[0096] Compounds of formula IV in which R.sup.1 represents H may be
prepared from corresponding compounds of formula IV in which
R.sup.1 represents OH (or a lower alkyl ester of the acid), for
example by elimination of water, followed by hydrogenation of the
resultant alkene using techniques which are well known to those
skilled in the art, followed by, if necessary, hydrolysis to give
the free acid.
[0097] Compounds of formula IV in which R.sup.1 represents
C.sub.1-4 alkyl may be prepared from corresponding compounds of
formula IV in which R.sup.1 represents H (or a lower alkyl ester of
the acid), for example by reaction with an appropriate alkyl halide
using techniques which are well known to those skilled in the art,
followed by, if necessary, hydrolysis to give the free acid.
[0098] Compounds of formula IV in which R.sup.1 represents
OR.sup.1d and R.sup.1d represents C(O)R.sup.11,
SiR.sup.12R.sup.13R.sup.14 or C.sub.1-6 alkyl may be prepared by
acylation, silylation or alkylation (as appropriate) of a
corresponding compound of formula IV in which R.sup.1 represents OH
(or a lower alkyl ester of the acid) under conditions which are
well known to those skilled in the art, followed by, if necessary,
hydrolysis to give the free acid.
[0099] Compounds of formula V may be prepared by reaction of a
compound of formula XVII ##STR16## wherein Y is as hereinbefore
defined with a compound of formula VII as hereinbefore defined, for
example under conditions such as those described hereinbefore for
synthesis of compounds of formula I.
[0100] Compounds of formulae V and VII in which R.sup.y represents
C.sub.1-4 alkyl may be prepared by reaction of a corresponding
compound of formula V or formula VII, as appropriate, in which
R.sup.y represents H with a compound of formula XVIII, R.sup.yHal
XVIII to wherein Hal represents halo (e.g. Cl, Br or I) and R.sup.y
is as hereinbefore defined, for example under conditions which are
well known to those skilled in the art.
[0101] Compounds of formula VI are readily available using known
techniques. For example, compounds of formula VI may be prepared by
reaction of a compound of formula IV as hereinbefore defined with a
compound of formula XVII as hereinbefore defined, for example under
conditions such as those described hereinbefore for synthesis of
compounds of formula I.
[0102] Compounds of formula VIII may be prepared in accordance with
peptide coupling techniques, for example in analogous fashion to
the methods described hereinbefore for compounds of formula I.
[0103] Compounds of formula XVI are commercially available, are
well known in the literature, or may be prepared in accordance with
known techniques. For example compounds of formula XVI may be
prepared as follows: (a) Compounds of formula XVI in which R.sub.x
represents a structural fragment of formula IIa, in which the
dotted lines represent bonds, A and E both represent CH and D
represents --CH.dbd.CH--; X.sub.1 represents C.sub.2-4 alkylene,
-Z-A.sup.3- or --C(O)-A.sup.3-, in which Z and A.sup.3 are as
hereinbefore defined; and R.sup.3 is absent, may be prepared by
cyclisation of a compound of formula XIX, ##STR17## wherein
X.sub.1a represents C.sub.2-4 alkylene, -Z-A.sup.3- or
--C(O)-A.sup.3-, and Z, A.sup.3 and R.sup.2 are as hereinbefore
defined, using an appropriate acylating agent, for example at
100.degree. C. in the presence of polyphosphoric acid or using
PCl.sub.5 followed by AlCl.sub.3, or at low temperature (e.g.
5.degree. C.) in the presence of boron trifluoride dimethyl
etherate and/or trifluoroacetic anhydride and an appropriate
solvent (e.g. CH.sub.2Cl.sub.2). Compounds of formula XIX in which
X.sub.1a represents C.sub.3-alkylene or --C(O)-A.sup.3-, in which
A.sup.3 represents C.sub.2-alkylene, may be prepared in accordance
with known techniques, for example by reaction of succinic
anhydride with the corresponding phenyl lithium and, for compounds
of formula XIX in which X.sub.1a represents C.sub.3-alkylene,
selective reduction of the resultant ketone, under conditions which
are well known to those skilled in the art. Compounds of formula
XIX in which X.sub.1a represents -Z-A.sup.3- and A.sup.3 represents
C.sub.2-3 alkylene may be prepared as described hereinafter. (b)
Compounds of formula XVI in which R.sub.x represents a structural
fragment of formula IIa, in which the dotted lines represent bonds,
A and E both represent CH and D represents --CH.dbd.CH--; X.sub.1
represents C.sub.1-4 alkylene or --C(O)-A.sup.3-, in which A.sup.3
is as hereinbefore defined; and R.sup.3 is absent, may
alternatively be prepared by cyclisation of a compound of formula
XX, ##STR18## wherein R represents C.sub.1-6 alkyl and X.sub.13 and
R.sup.2 are as hereinbefore defined, for example at 20.degree. C.
in the presence of a suitable base (e.g. an alkali metal alkoxide)
and an appropriate organic solvent (e.g. lower alkyl alcohol)
followed by hydrolysis and decarboxylation. Compounds of formula XX
may be prepared in accordance with known techniques. For example,
compounds of formula XX in which X.sub.1a represents
C.sub.3-alkylene or --C(O)-A.sup.3- in which A.sup.3 represents
C.sub.2-alkylene may be prepared by reaction of succinic anhydride
with a compound of formula XXI, ##STR19## wherein R' represents
C.sub.1-6 alkyl and R and R.sup.2 are as hereinbefore defined and,
for compounds of formula XX in which X.sub.1a represents
C.sub.3-alkylene, selective reduction of the resultant ketone,
followed by functional group transformations of the amide and the
acid to ester groups, under conditions which are well known to
those skilled in the art. (c) Compounds of formula XVI in which
R.sub.x represents a structural fragment of formula IIa, in which
the dotted lines represent bonds, A and E both represent CH and D
represents --CH.dbd.CH--; X, represents -Z-A.sup.3- in which
A.sup.3 represents C.sub.2 alkylene and Z represents O or S; and
R.sup.3 is absent, may be prepared by cyclisation of a compound of
formula XXII, ##STR20## wherein Z.sup.a represents O or S and Hal
and R.sup.2 are as hereinbefore defined, for example at 20.degree.
C. in the presence of aqueous-ethanolic NaOH. For corresponding
compounds of formula XVI in which X.sub.1 represents -Z-A.sup.3-
and Z represents S(O).sub.m in which m is 1 or 2, this
above-mentioned cyclisation should be followed by carrying out an
oxidation reaction on the cyclised product comprising an S atom,
for example using m-chloroperbenzoic acid. (d) Compounds of formula
XVI in which R.sub.x represents a structural fragment of formula
IIa, in which the dotted lines represent bonds, A and E both
represent CH and D represents --CH.dbd.CH--; X.sub.1 represents
-Z-A.sup.3- (in which A.sup.3 represents C.sub.2-alkylene) or
-Z-C(O)-A.sup.1 (in which A.sup.1 represents C.sub.1-alkylene); and
R.sup.3 is absent, may be prepared by reaction of a compound of
formula XXIII, ##STR21## wherein R.sup.2 and Z are as hereinbefore
defined, with either:-- (1) for compounds of formula XVI in which
X, represents -Z-A.sup.3- in which A.sup.3 represents
C.sub.1-alkylene, a compound of formula XXIV,
H.sub.2C.dbd.CH--CO.sub.2R XXIV wherein R is as hereinbefore
defined, for example at 20.degree. C. in the presence of a suitable
base (e.g. triethylamine or sodium ethoxide) and an appropriate
organic solvent (e.g. ethanol or DMF); or
[0104] (2) a compound of formula XXV, L.sup.1-G-CH.sub.2--CO.sub.2R
XXV wherein L.sup.1 represents a suitable leaving group (such as
Cl, Br, I, mesylate or tosylate), G represents CH.sub.2 or C(O) and
R is as hereinbefore defined, for example at 20.degree. C. in the
presence of a suitable base (e.g. triethylamine) and an appropriate
organic solvent (e.g. THF); followed by cyclisation under
appropriate conditions (e.g. those described hereinbefore). (e)
Compounds of formula XVI in which R.sub.1 represents a structural
fragment of formula IIa, in which the ring bearing A, E and D is a
carbocyclic aromatic, or heterocyclic aromatic, ring as defined
hereinbefore in respect of compounds of formula I; X.sub.1
represents --CH.sub.2-Z-C.sub.1-2 alkylene-, in which Z is as
hereinbefore defined; and R.sup.3 is absent, may be prepared by
reaction of a compound of formula XXVI, ##STR22## wherein the ring
bearing A.sup.a, E.sup.a and D.sup.a is a carbocyclic aromatic, or
heterocyclic aromatic, ring as defined hereinbefore in respect of
compounds of formula I, and Z and R.sup.2 are as hereinbefore
defined, with a compound of formula XXVII, -- L.sup.1-Alk-CO.sub.2H
XXVII wherein Alk represents C.sub.1-2 alkylene and L.sup.1 is as
hereinbefore defined, for example at 20.degree. C. in the presence
of a suitable base (e.g. sodium methoxide) and an appropriate
organic solvent (e.g. THF). (f) Compounds of formula XVI in which
R.sub.x represents a structural fragment of formulae IIb, IIc or
IIa, in which latter case the ring bearing A, E and D is a
carbocyclic aromatic, or heterocyclic aromatic, ring as defined
hereinbefore in respect of compounds of formula I; and, in the
cases when R.sub.1 represents a structural fragment of formulae IIa
or IIb, R.sup.3 is absent, may be prepared by cyclisation of a
compound of formula XXIX, R.sub.xa--CO.sub.2H XXIX wherein R.sub.xa
represents a structural fragment of formula XXIXa, XXIXb or XXIXc
##STR23## wherein, in XXIXa, the ring bearing A.sup.a, E.sup.a and
D.sup.a is a carbocyclic aromatic, or heterocyclic aromatic, ring
as defined hereinbefore in respect of compounds of formula I, and
R.sup.2, R.sup.4, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are as
hereinbefore defined, in the presence of polyphosphoric acid, for
example at 100.degree. C. The dots adjacent to the carbon atoms in
fragments of formula XXIXa, XXIXb and XXIXc signify the point of
attachment of the fragments to the CO.sub.2H group of the compound
of formula XXIX. Compounds of formula XXIX may be prepared by
hydrolysis of a corresponding compound of formula XXX,
R.sub.xa--CO.sub.2R XXX wherein R.sub.xa and R are as hereinbefore
defined (and in which the CO.sub.2H in the fragments of formulae
XXIXa, XXIXb and XXIXc in R.sub.xa may also be replaced by
CO.sub.2R), for example under reaction conditions which are well
known to those skilled in the art. (g) Compounds of formula XVI in
which R.sub.x represents a structural fragment of formula IIa in
which the ring bearing A, E and D is a carbocyclic aromatic, or
heterocyclic aromatic, ring as defined hereinbefore in respect of
compounds of formula I; X.sub.1 represents --OCH.sub.2--; and
R.sup.3 is absent, may be prepared by reaction of a compound of
formula XXXI, ##STR24## wherein the ring bearing A.sup.a, E.sup.a
and D.sup.a is a carbocyclic aromatic, or heterocyclic aromatic,
ring as defined hereinbefore in respect of compounds of formula I,
and R.sup.2, Hal and R are as hereinbefore defined, with
diazomethane, for example at 20.degree. C. in the presence of a
suitable organic solvent (e.g. diethyl ether). (h) Compounds of
formula XVI in which R.sub.x represents a structural fragment of
formula IIa, in which the dotted lines represent bonds, A and E
both represent CH and D represents --CH.dbd.CH--; X, represents
--C(O)--O--CH.sub.2--; and R.sup.3 is absent, may be prepared by
cyclisation of a compound of formula XXXII, ##STR25## wherein
R.sup.2 and R are as hereinbefore defined, for example at
-20.degree. C. in the presence of sulphuric acid and an appropriate
organic solvent (e.g. methanol). Compounds of formula XXXI may be
prepared by reacting a corresponding acid halide with diazomethane,
for example at 20.degree. C. in the presence of a suitable organic
solvent (e.g. diethyl ether).
[0105] (i) Compounds of formula XVI in which R.sub.x represents a
structural fragment of formula IIa, in which X.sub.1 includes
N(R.sup.25), or IIc, in which X.sub.4 represent N(R.sup.23), (as
appropriate), and R.sup.23 and R.sup.25 (as appropriate) represent
C.sub.1-4 alkyl, may be prepared by reaction of a corresponding
compound of formula XVI in which X.sub.1 includes, or X.sub.4
represents, (as appropriate) NH with a compound of formula XXXIII
R.sup.a-Hal XXXIII wherein R.sup.a represents C.sub.1-4 alkyl and
Hal is as hereinbefore defined, for example under conditions which
are well known to those skilled in the art. (j) Compounds of
formula XVI in which R.sub.x represents a structural fragment of
formula IIa, in which the dotted lines represent bonds, A and E
both represent CH and D represents --CH.dbd.CH--; X.sub.1
represents --C(O)--N(H)--CH.sub.2--; and R.sup.3 is absent, may be
prepared by catalytic hydrogenation of an hydroxamic acid of
formula XXXIV, ##STR26## wherein R.sup.2 is as hereinbefore
defined, using an appropriate catalyst system (e.g. Pd/C) in the
presence of a suitable organic solvent (e.g. methanol). Compounds
of formula XXXIV may be prepared by cyclisation of a corresponding
compound of formula XXXV, ##STR27## wherein R.sup.2 is as
hereinbefore defined, for example at 20.degree. C. in the presence
of fuming HCl and tin dichloride. (k) Selective oxidation of a
compound of formula XXXVI, H--R.sub.x--H XXXVI wherein R.sub.x is
as hereinbefore defined, for example in the presence of a suitable
oxidising agent (e.g. CrO.sub.3 or KMnO.sub.4) and an appropriate
solvent (e.g. water). (l) Selective oxidation of a compound of
formula XXXVII, H--R.sup.y--OH XXXVII wherein R.sup.x is as
hereinbefore defined, for example in the presence of a suitable
oxidising agent (e.g. MnO.sub.2) in an appropriate organic solvent
(e.g. CH.sub.2Cl.sub.2). (m) Hydrolysis of an oxime formula
XXXVIII, R.sub.x.dbd.N--OH XXXVIII wherein R.sub.x is as
hereinbefore defied, for example by heating in the presence of acid
(e.g. HCl) and an appropriate organic solvent. Compounds of formula
XXXVIII may be prepared by reaction of a corresponding compound of
formula XXXVI, as hereinbefore defined, with propyl nitrite, for
example in the presence of HCl in ethanol. (n) Compounds of formula
XVI in which R.sub.x represents a structural fragment of formula
IIa and X.sub.1 represents --CH.sub.2--CH.dbd.CH--, may be prepared
by elimination of a compound of formula XXXIX, ##STR28## wherein
L.sup.3 represents a suitable leaving group (e.g. Br or SePh) and
the dotted lines, A, E, D, R.sup.2 and R.sup.3 are as hereinbefore
defined, under appropriate reaction conditions, for example in the
presence of aqueous ethanolic NaOH or hydrogen peroxide, and an
appropriate organic solvent (e.g. THF). (o) Compounds of formula
XVI in which R.sub.x represents a structural fragment of formula
IIb, X.sub.2 represents --C(O)-A.sup.4- and A.sup.4 is as
hereinbefore defined, may be prepared by cyclisation of a compound
of formula XL, ##STR29## wherein R.sup.b represents OH, C.sub.1-6
alkoxy or Hal and R.sup.2, R.sup.3, A.sup.4, X.sub.3 and Hal are as
hereinbefore defined, for example in the presence of polyphosphoric
acid, as described hereinbefore or, in the case where R.sup.b
represents Hal, in the presence of AlCl.sub.3 in nitromethane at,
for example, 20.degree. C. (p) Compounds of formula XVI in which
R.sub.x represents a structural fragment of formula IIb and X.sub.2
represents -A.sup.4-C(O)-- and A.sup.4 represents C.sub.1-2
alkylene may be prepared by cyclisation of a compound of formula
XLI, ##STR30## wherein A.sup.4a represents C.sub.1-2 alkylene and
Hal, R.sup.2, R.sup.3 and X.sub.3 are as hereinbefore defined.
[0106] Compounds of formulae VII, IX, X, XI, XII, XIII, XV, XVIA,
XVII, XVIII, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXX, XXXI,
XXXIII, XXXV, XXXVI, XXXVII, XXXIX, XL and XLI, and derivatives
thereof, are either commercially available, are known in the
literature, or may be obtained either by analogy with the processes
described herein, or by conventional synthetic procedures, in
accordance with standard techniques, from readily available
starting materials using appropriate reagents and reaction
conditions (e.g. as described hereinafter).
[0107] Substituents on the aromatic and/or non-aromatic,
carbocyclic and/or heterocyclic ring(s) in compounds of formulae I,
IV, V, VI, VII, VIII, IX, X, XI, XIII, XVI, XVIA, XIX, XX, XII,
XXII, XXIII, XXVI, XXIX, XXX, XXXI, XXXII, XXXIV, XXXV, XXXVI,
XXXVII, XXXVIII, XXXIX, XL and XLI may be introduced Blur
interconverted using techniques well known to those skilled in the
art. For example, nitro may be reduced to amino, hydroxy may be
alkylated to give alkoxy, alkoxy may be hydrolysed to hydroxy,
alkenes may be hydrogenated to alkanes, halo may be hydrogenated to
H, etc.
[0108] The compounds of formula I may be isolated from their
reaction mixtures using conventional techniques.
[0109] It will be appreciated by those skilled in the art that in
the process described above the functional groups of intermediate
compounds may need to be protected by protecting groups.
[0110] Functional groups which it is desirable to protect include
hydroxy, amino and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl groups (e.g.
t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and
tetrahydropyranyl. Suitable protecting groups for carboxylic acid
include C.sub.1-6 alkyl or benzyl esters. Suitable protecting
groups for amino, amidino and guanidino include t-butyloxycarbonyl,
benzyloxycarbonyl or 2-trimethylsilylethoxycarbonyl (Teoc). Amidino
and guanidino nitrogens may also be protected by hydroxy or -alkoxy
groups, and may be either mono- or deprotected.
[0111] The protection and deprotection of functional groups may
take place before or after coupling, or before or after any other
reaction in the abovementioned schemes.
[0112] Protecting groups may be removed in accordance with
techniques which are well known to those skilled in the art and as
described hereinafter.
[0113] Persons skilled in the art will appreciate that, in order to
obtain compounds of formula I in an alternative, and, on some
occasions, more convenient, manner, the individual process steps
mentioned hereinbefore may be performed in a different order,
and/or the individual reactions may be performed at a different
stage in the overall route (i.e. substituents may be added to
and/or chemical transformations performed upon, different
intermediates to those mentioned hereinbefore in conjunction with a
particular reaction). This may negate, or render necessary, the
need for protecting groups.
[0114] For example, this is particularly true in respect of the
synthesis of compounds of formula I in which D.sup.1 or D.sup.2 (as
appropriate) does not represent H. In this case, OR.sup.a and/or
C(.dbd.X.sup.11)X.sup.12R.sup.b groups may be introduced at an
earlier stage in the overall synthesis using the process steps
described hereinbefore.
[0115] Accordingly, the order and type of chemistry involved will
dictate the need, and type, of protecting groups as well as the
sequence for accomplishing the synthesis.
[0116] The use of protecting groups is fully described in
"Protective Groups in Organic Chemistry", edited by J W F McOmie,
Plenum Press (1973), and "Protective Groups in Organic Synthesis",
2nd edition, T W Greene & P G M Wutz, Wiley-Interscience
(1991).
[0117] The protected derivatives of compounds of formula I may be
converted chemically to compounds of formula I using standard
deprotection techniques (e.g. hydrogenation). The skilled person
will appreciate that certain compounds of the invention may be
regarded as protected derivatives of other compounds of the
invention.
Medical and Pharmaceutical Use
[0118] Compounds of the invention may possess pharmacological
activity as such. Compounds of the invention that may possess such
activity include, but are not limited to, those with a free amidine
functionality as part of the structural fragment B.
[0119] However, other compounds of formula I (including those that
do not possess such a free amidine functionality) may not possess
such activity, but may be administered parenterally or orally, and
thereafter metabolised in the body to form compounds that are
pharmacologically active (including, but not limited to,
corresponding free amidine compounds). Such compounds (which also
include compounds that may possess some pharmacological activity,
but that activity is appreciably lower than that of the active
compounds to which they are metabolised to), may therefore be
described as "prodrugs" of the active compounds.
[0120] Thus, the compounds of the invention are useful because they
possess pharmacological activity, and/or are metabolised in the
body following oral or parenteral administration to form compounds
which possess pharmacological activity. The compounds of the
invention are therefore indicated as pharmaceuticals.
[0121] According to a further aspect of the invention there is thus
provided the compounds of the invention for use as
pharmaceuticals.
[0122] In particular, the compounds of the invention are potent
inhibitors of thrombin either as such and/or (e.g. in the case of
prodrugs), are metabolised following administration to form potent
inhibitors of thrombin, for example as demonstrated in the tests
described below.
[0123] By "prodrug of a thrombin inhibitor", we include compounds
that form a thrombin inhibitor, in an experimentally-detectable
amount, and within a predetermined time (e.g. about 1 hour),
following oral or parenteral administration.
[0124] The compounds of the invention are thus expected to be
useful in those conditions where inhibition of thrombin is
required.
[0125] The compounds of the invention are thus indicated in the
treatment and/or prophylaxis of thrombosis and hypercoagulability
in blood and tissues of animals including man.
[0126] It is known that hypercoagulability may lead to
thrombo-embolic diseases. Conditions associated with
hypercoagulability and thrombo-embolic diseases which may be
mentioned include inherited or acquired activated protein C
resistance, such as the factor V-mutation (factor V Leiden), and
inherited or acquired deficiencies in antithrombin III, protein C,
protein S, heparin cofactor II. Other conditions known to be
associated with hypercoagulability and thrombo-embolic disease
include circulating antiphospholipid antibodies (Lupus
anticoagulant), homocysteinemi, heparin induced thrombocytopenia
and defects in fibrinolysis. The compounds of the invention are
thus indicated both in the therapeutic and/or prophylactic
treatment of these conditions.
[0127] The compounds of the invention are further indicated in the
treatment of conditions where there is an undesirable excess of
thrombin without signs of hypercoagulability, for example in
neurodegenerative diseases such as Alzheimer's disease.
[0128] Particular disease states which may be mentioned include the
therapeutic and/or prophylactic treatment of venous thrombosis and
pulmonary embolism, arterial thrombosis (eg in myocardial
infarction, unstable angina, thrombosis-based stroke and peripheral
arterial thrombosis) and systemic embolism usually from the atrium
during arterial fibrillation or from the left ventricle after
transmural myocardial infarction.
[0129] Moreover, the compounds of the invention are expected to
have utility in prophylaxis of re-occlusion (ie thrombosis) after
thrombolysis, percutaneous trans-luminal angioplasty (PTA) and
coronary bypass operations; the prevention of re-thrombosis after
microsurgery and vascular surgery in general.
[0130] Further indications include the therapeutic and/or
prophylactic treatment of disseminated intravascular coagulation
caused by bacteria, multiple trauma, intoxication or any other
mechanism; anticoagulant treatment when blood is in contact with
foreign surfaces in the body such as vascular grafts, vascular
stents, vascular catheters, mechanical and biological prosthetic
valves or any other medical device; and anticoagulant treatment
when blood is in contact with medical devices outside the body such
as during cardiovascular surgery using a heart-lung machine or in
hemodialysis.
[0131] In addition to its effects on the coagulation process,
thrombin is known to activate a large number of cells (such as
neutrophils, fibroblasts, endothelial cells and smooth muscle
cells). Therefore, the compounds of the invention may also be
useful for the therapeutic and/or prophylactic treatment of
idiopathic and adult respiratory distress syndrome, pulmonary
fibrosis following treatment with radiation or chemotherapy, septic
shock, septicemia, inflammatory responses, which include, but are
not limited to, edema, acute or chronic atherosclerosis such as
coronary arterial disease, cerebral arterial disease, peripheral
arterial disease, reperfusion damage, and restenosis after
percutaneous trans-luminal angioplasty (PTA).
[0132] Compounds of the invention that inhibit trypsin and/or
thrombin may also be useful in the treatment of pancreatitis.
[0133] According to a further aspect of the present invention,
there is provided a method of treatment of a condition where
inhibition of thrombin is required which method comprises
administration of a therapeutically effective amount of a compound
of the invention, or a pharmaceutically acceptable salt thereof, to
a person suffering from, or susceptible to such a condition.
[0134] The compounds of the invention will normally be administered
orally, intravenously, subcutaneously, buccally, rectally,
dermally, nasally, tracheally, bronchially, by any other parenteral
route or via inhalation, in the form of pharmaceutical preparations
comprising active compound either as a free base, or a
pharmaceutical acceptable non-toxic organic or inorganic acid
addition salt, in a pharmaceutically acceptable dosage form.
Depending upon the disorder and patient to be treated and the route
of administration, the compositions may be administered at varying
doses.
[0135] The compounds of the invention may also be combined and/or
co-administered with any antithrombotic agent with a different
mechanism of action, such as the antiplatelet agents
acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane
receptor and/or synthetase inhibitors, fibrinogen receptor
antagonists, prostacyclin mimetics and phosphodiesterase inhibitors
and ADP-receptor (P.sub.2T) antagonists.
[0136] The compounds of the invention may further be combined
and/or co-administered with thrombolytics such as tissue
plasminogen activator (natural, recombinant or modified),
streptokinase, urokinase, prourokinase, anisoylated
plasminogen-streptokinase activator complex (APSAC), animal
salivary gland plasminogen activators, and the like, in the
treatment of thrombotic diseases, in particular myocardial
infarction.
[0137] According to a further aspect of the invention there is thus
provided a pharmaceutical formulation including a compound of the
invention, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0138] Suitable daily doses of the compounds of the invention in
therapeutical treatment of humans are about 0.001-100 mg/kg body
weight at peroral administration and 0.001-50 mg/kg body weight at
parenteral administration.
[0139] The compounds of the invention have the advantage that the
may be, or may be metabolised to compounds that may be, more
efficacious, be less toxic, be longer acting, have a broader range
of activity, be more potent, produce fewer side effects, be more
easily absorbed than, or that they may have other useful
pharmacological, physical, or chemical, properties-over, compounds
known in the prior art.
Biological Tests
Test A
Determination of Thrombin Clotting Time (TT)
[0140] The inhibitor solution (25 .mu.L) was incubated with plasma
(25 .mu.L) for three minutes. Human thrombin (T 6769; Sigma Chem.
Co) in buffer solution, pH 7.4 (25 .mu.L) was then added and the
clotting time measured in an automatic device (KC 10; Amelung).
[0141] The clotting time in seconds was plotted against the
inhibitor concentration, and the IC.sub.50TT was determined by
interpolation.
[0142] IC.sub.50TT is the concentration of inhibitor in the test
that doubles the thrombin clotting time for human plasma.
Test B
Determination of Thrombin Inhibition with a Chromogenic, Robotic
Assay
[0143] The thrombin inhibitor potency was measured with a
chromogenic substrate method, in a Plato 3300 robotic microplate
processor (Rosys AG, CH-8634 Hombrechtikon, Switzerland), using
96-well, half volume microtitre plates (Costar, Cambridge, Mass.,
USA; Cat No 3690). Stock solutions of test substance in DMSO (72
.mu.L), 1 mmol/L, were diluted serially 1:3 (24+48 .mu.L) with DMSO
to obtain ten different concentrations, which were analysed as
samples in the assay. 2 .mu.L of test sample was diluted with 124
.mu.l assay buffer, 12 .mu.L of chromogenic substrate solution
(S-2366, Chromogenix, Molndal, Sweden) in assay buffer and finally
12 .mu.L of .alpha.-thrombin solution, (Human .alpha.-thrombin,
Sigma Chemical Co.) both in assay buffer, were added, and the
samples mixed. The final assay concentrations were: test substance
0.00068-13.3 .mu.mol/L, S-2366 0.30 mmol/L, .alpha.-thrombin 0.020
NIHU/mL. The linear absorbance increment during 40 minutes
incubation at 37.degree. C. was used for calculation of percentage
inhibition for the test samples, as compared to blanks without
inhibitor. The IC.sub.50-robotic value, corresponding to the
inhibitor concentration which caused 50% inhibition of the thrombin
activity, was calculated from a log concentration vs. % inhibition
curve.
Test C
Determination of the Inhibition Constant K, for Human Thrombin
[0144] K.sub.i-determinations were made using a chromogenic
substrate method, performed at 37.degree. C. on a Cobas Bio
centrifugal analyser (Roche, Basel, Switzerland). Residual enzyme
activity after incubation of human .alpha.-thrombin with various
concentrations of test compound was determined at three different
substrate concentrations, and was measured as the change in optical
absorbance at 405 nm.
[0145] Test compound solutions (100 .mu.L; normally in buffer or
saline containing BSA 10 g/L) were mixed with 200 .mu.L of human
.alpha.-thrombin (Sigma Chemical Co) in assay buffer (0.05 mol/L
Tris-HCl pH 7.4, ionic strength 0.15 adjusted with NaCl) containing
BSA (10 g/L), and analysed as samples in the Cobas Bio. A 60 .mu.L
sample, together with 20 .mu.L of water, was added to 320 .mu.L of
the substrate S-2238 (Chromogenix AB, Molndal, Sweden) in assay
buffer, and the absorbance change (AA/min) was monitored. The final
concentrations of S-2238 were 16, 24 and 50 .mu.mol/L and of
thrombin 0.125 NIH U/mL.
[0146] The steady state reaction rate was used to construct Dixon
plots, i.e. diagrams of inhibitor concentration vs.
1/(.DELTA.A/min). For reversible, competitive inhibitors, the data
points for the different substrate concentrations typically form
straight lines which intercept at x=--K.sub.i.
Test D
Determination of Activated Partial Thromboplastin Time (APTT)
[0147] APTT was determined in pooled normal human citrated plasma
with the reagent PTT Automated 5 manufactured by Stago. The
inhibitors were added to the plasma (10 .mu.L inhibitor solution to
90 .mu.L plasma) and incubated with the APTT reagent for 3 minutes
followed by the addition of 100 .mu.L of calcium chloride solution
(0.025M) and APTT was determined in the mixture by use of the
coagulation analyser KC10 (Amelung) according to the instructions
of the reagent producer. The clotting time in seconds was plotted
against the inhibitor concentration in plasma and the IC.sub.50APTT
was determined by interpolation.
[0148] IC.sub.50APTT is defined as the concentration of inhibitor
in human plasma that doubled the Activated Partial Thromboplastin
Time.
Test E
Determination of Thrombin Time Ex Vivo
[0149] The inhibition of thrombin after oral or parenteral
administration of the compounds of formula I, dissolved in
ethanol:Solutol.TM.:water (5:5:90), were examined in conscious rats
which, one or two days prior to the experiment, were equipped with
a catheter for blood sampling from the carotid artery. On the
experimental day blood samples were withdrawn at fixed times after
the administration of the compound into plastic tubes containing 1
part sodium citrate solution (0.13 mol per L) and 9 parts of blood.
The tubes were centrifuged to obtain platelet poor plasma. The
plasma was used for determination of thrombin time as described
below.
[0150] The citrated rat plasma, 100 .mu.L, was diluted with a
saline solution, 0.9%, 100 .mu.L, and plasma coagulation was
started by the addition of human thrombin (T 6769, Sigma Chem Co,
USA) in a buffer solution, pH 7.4, 100 .mu.L. The clotting time was
measured in an automatic device (KC 10, Amelumg, Germany).
[0151] Where a "prodrug" compound of formula I was administered,
concentrations of the appropriate active thrombin inhibitor of
formula I (e.g. the free amidine or guanidine compound) in the rat
plasma were estimated by the use of standard curves relating the
thrombin time in the pooled citrated rat plasma to known
concentrations of the corresponding "active" thrombin inhibitor
dissolved in saline.
[0152] Based on the estimated plasma concentrations of the active
thrombin inhibitor (which assumes that thrombin time prolongation
is caused by the aforementioned compound) in the rat, the area
under the curve after oral and/or parenteral administration of the
corresponding prodrug compound of formula I was calculated (AUCpd)
using the trapezoidal rule and extrapolation of data to
infinity.
[0153] The bioavailability of the active thrombin inhibitor after
oral or parenteral administration of the prodrug was calculated as
below: [(AUCpd/dose)/(AUCactive,parenteral/dose].times.100 where
AUCactive,parenteral represents the AUC obtained after parenteral
administration of the corresponding active thrombin inhibitor to
conscious rats as described above. Test F Determination of Thrombin
Time in Urine Ex Vivo
[0154] The amount of the "active" thrombin inhibitor that was
excreted in urine after oral or parenteral administration of
"prodrug" compounds of the invention, dissolved in
ethanol:Solutol.TM.:water (5:5:90), was estimated by determination
of the thrombin time in urine ex vivo (assuming that thrombin time
prolongation is caused by the aforementioned compound).
[0155] Conscious rats were placed in metabolism cages, allowing
separate collection of urine and faeces, for 24 hours following
oral administration of compounds of the invention. The thrombin
time was determined on the collected urine as described below.
[0156] Pooled normal citrated human plasma (100 .mu.L) was
incubated with the concentrated rat urine, or saline dilutions
thereof, for one minute. Plasma coagulation was then initiated by
the administration of human thrombin (T 6769, Sigma Chem Company)
in buffer solution (pH 7.4; 100 .mu.L). The clotting time was
measured in an automatic device (KC 10; Amelung).
[0157] The concentrations of the active thrombin inhibitor in the
rat urine were estimated by the use of standard curves relating the
thrombin time in the pooled normal citrated human plasma to known
concentrations of the aforementioned active thrombin inhibitor
dissolved in concentrated rat urine (or saline dilutions thereof).
By multiplying the total rat urine production over the 24 hour
period with the estimated mean concentration of the aforementioned
active inhibitor in the urine, the amount of the active inhibitor
excreted in the urine (AMOUNTpd) could be calculated.
[0158] The bioavailability of the active thrombin inhibitor after
oral or parenteral administration of the prodrug was calculated as
below: [(AMOUNTpd/dose)/(AMOUNTactive,parenteral/dose].times.100
where AMOUNTactive,parenteral represents the amount excreted in the
urine after parenteral administration of the corresponding active
thrombin inhibitor to conscious rats as described above. Test G
[0159] Metabolic Activation of Prodrug Compounds In Vitro
[0160] Prodrug compounds of formula I were incubated at 37.degree.
C. with liver microsomes or 10 000 g (referring to the centrifuge
speed) supernatant fractions (i.e. s9 fraction) prepared from human
or rat liver homogenate. The total protein concentration in the
incubations were 1 or 3 mg/mL dissolved in 0.05 mol/L TRIS buffer
(pH 7.4), and with the cofactors NADH (2.5 mmol/L) and NADPH (0.8
mmol/L) present. The total volume of the incubate was 1.2 mL. The
initial prodrug concentrations were 5 or 10 .mu.mol/L. Samples were
collected from the incubate at regular intervals more than 60
minutes after the start of the incubations. Samples (25 .mu.L) from
the incubate were mixed with an equal volume of human or rat plasma
and an appropriate amount of thrombin, and the clotting time (i.e.
thrombin time) was measured on a coagulometer (KC 10; Amelumg). The
amount of "active" thrombin inhibitor formed was estimated by the
use of standard curves relating the thrombin time in pooled
citrated human or rat plasma to known concentrations of the
corresponding "active thrombin inhibitor".
EXAMPLES
[0161] The invention is illustrated by way of the following
examples. The amino acids Pro and Aze are defined as the S-isomers
if not otherwise specified. The examples were obtained as
diastereoisomers if not otherwise specified.
Example 1
(S) or
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO--O--CH.sub.2-c-
yclopropyl)
(i) 1-Hydroxy-7-methoxytetralin-1-yl-carboxylic acid, methyl
ester
[0162] The sub-title compound was prepared according to the method
described by C. F. Bigge et al in J. Med. Chem., (1993), 36, 1977
using 7-methoxytetralone (1.0 g; 5.67 nmol) and methanol instead of
ethanol.
[0163] Yield: 1.22 g (90%).
[0164] .sup.1H-NMR (300 MHz; CDCl.sub.3): .delta. 7.05 (d, 1H),
6.80 (d, 1H), 6.65 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.85-2.65
(m, 2H), 2.25-1.90 (m, 4H)
(ii) 1-Hydroxy-7-methoxytetralin-1-yl-carboxylic acid
[0165] LiOH.H.sub.2O (0.41 g; 9.8 nmol) and water (4 mL) were added
to a solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid,
methyl ester (1.16 g; 4.9 mmol; from step (i) above) in THF (10
mL). The reaction mixture was stirred at room temperature for 3 h,
the THF was evaporated, and the water phase washed with methylene
chloride. The reaction mixture was acidified with HCl (2M) and some
NaCl was added. After extraction with methylene chloride, the
organic phase was dried and concentrated.
[0166] Yield: 765 mg (70%).
[0167] .sup.1H-NM (400 MHz; CDCl.sub.3): .delta. 7.07 (d, 1H), 6.82
(dd, 1H), 6.77 (d, 1H), 3.76 (s, 3H), 2.83-2.71 (m, 2H), 2.32-2.21
(m, 1H), 2.12-1.88 (m, 3H)
[0168] LC-MS (m/z) 221 (M-1).sup.-
(iii) (S)- and
(R)-1-Hydroxy-7-methoxytetraline-1-yl-C(O)-Aze-Pab(Z)
[0169] TBTU (0.584 g; 1.7 mmol) and DIPEA (0.200 g; 1.55 mmol) were
added, in that order, to an ice-cold solution of
1-hydroxy-7-methoxytetraline-1-yl-carboxylic acid (0.345 g; 1.55
mmol, from step (ii) above) in DMF (10 mL). After stirring at
0.degree. C. for 15 minutes, H-Aze-Pab(Z).times.2HCl (0.750 g; 1.7
mmol; see international patent application WO 97/02284) and DIPEA
(0.603 g; 4.65 mmol) were added and the mixture was stirred at RT
for 4 days. The DMF was evaporated, and the resulting material was
partitioned between water and EtOAc. The organic layer was
separated, the water phase was extracted 3 times with EtOAc, and
the combined organic layer was dried (Na.sub.2SO.sub.4) and
concentrated. The product, a white powder, was further purified
using HPLC (CH.sub.3CN:0.1M ammonium acetate; 46:54), yielding 122
mg (28%) of a faster moving fraction (Compound 1A) and 63 me (14%)
of a slower moving fraction (Compound 1B).
[0170] Compound 1A:
[0171] .sup.1H-NMR (400 MHz; CDCl.sub.3): (complex due to
diastereomers/rotamers) .delta. 8.22 (t, 0.5H, rotamer); 7.94 (t,
0.5H, rotamer); 7.83 (t, 1H); 7.45-7.3 (m, 9H); 7.4 (t, 1H); 6.80
(m, 1H); 4.93 (m, 1H); 4.55 (m, 5H); 3.76 (s, 3H); 3.07-2.94 (m,
2H); 2.81 (m, 2H); 2.60 (m, 2H); 2.50 (m, 1H); 2.38 (m, 1H); 2.25
(m, 1H); 2.0-1.8 (m, 9H)
[0172] LC-MS (m/z) 571 (M+1).sup.+
(iv) (S)- or
(R)-1-Hydroxy-7-methoxytetraline-1-yl-C(O)-Aze-Pab.times.HOAc
[0173] Pd/C (5%; 50 mg) was added to a solution of (S) or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Z) (58 mg; 0.01
mmol; Compound 1A from step (iii) above) in EtOH (5 mL) and HOAc
(5.8 .mu.L; 0.1 mmol), and the mixture was hydrogenated for 3 hours
at room temperature and atmospheric pressure. The resulting mixture
was filtered through Celite, the solution was concentrated, water
was added and the solution was freeze dried, yielding 10 mg (98%)
of the title compound. Yield 15 mg (59%).
[0174] .sup.1H-NMR (400 MHz; D.sub.2O): .delta. 7.65 (d, 2H); 7.47
(d, 2H); 7.16 (d, 1H); 6.90 (d, 1H); 6.71 (d, 1H); 4.91 (dd, 1H);
4.40 (m, 1H); 4.15 (m, 1H); 3.94 (m, 1H); 3.60 (s, 3H); 2.75 (m,
3H); 2.53 (m, 1H); 2.1 (m, 2H); 2.0-1.75 (m, 7H)
[0175] .sup.13C-NMR (100 MHz; CDCl.sub.3) .delta. 182.5; 178.3;
174.0
[0176] LC-MS (m/z) 437 (M+1).sup.+
(v) p-Nitrophenyl-cyclopropylmethyl carbonate
[0177] Pyridine (0.43 g; 5.5 mmol) was added to an ice-cold
solution of cyclopropylmethanol (0.36 g; 5.0 mmol) and
p-nitrophenyl chloroformate (1.06 g; 5.3 mmol) in methylene
chloride (10 mL), and the resultant mixture was stirred at RT
overnight, whereafter the solution washed with KHSO.sub.4
(3.times.) and brine, dried (Na.sub.2SO.sub.4), and concentrated,
yielding 1.2 g (97%) of the sub-title compound.
[0178] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 8.29 (m, 2H);
7.41 (m, 2H); 4.14 (d, 2H); 1.35-1.2 (m, 1H); 0.69 (m, 2H); 0.41
(m, 2H)
(vi) (S) or
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO--O--CH.sub.2-cyclopr-
opyl)
[0179] NaOH (aq; 1.5M; 1.2 mL; 1.8 mmol) was added to a vigorously
stirred solution of (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc. (40
mg; 80 .mu.mol; from step (iv) above) and
p-nitrophenyl-cyclopropylmethyl carbonate (17 mg; 71 .mu.mol; from
step (v) above) in methylene chloride (5 mL) and the solution was
stirred at RT for 2 hours, whereafter the organic layer washed 3
times with NaOH (aq, 1.5M). The crude product was purified using
flash chromatography (silica gel; methylene chloride.fwdarw.EtOAc).
The fractions of interest were concentrated, dissolved in water and
freeze dried, yielding 33 mg (77%) of the title compound.
[0180] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.96 (t, 1H);
7.85 (d, 2H); 7.31 (d, 2H); 7.05 (d, 1H); 6.83 (dd, 1H); 6.66 (d,
1H); 4.92 (dd, 1H); 4.6-4.4 (m, 3H); 3.99 (d, 2H); 3.83 (m, 1H);
3.75 (s, 3H); 3.04 (m, 1H); 2.80 (m, 1H); 2.5-2.7 (m, 2H); 2.25 (m,
1H); 1.8-1.2 (m, 4H); 1.24 (m, 1H); 0.59 (m, 2H); 0.33 (m, 2H)
[0181] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons): .delta. 178.8; 171.4; 168.6; 165.0.
[0182] LC-MS (m/z) 536 (M+1).sup.+
Example 2
(S)- or
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO--O-cyclopenty-
l)
[0183] NaOH (aq; 1.5M; 0.44 mL; 0.66 mmol) was added to a solution
of (S)- or [0184]
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc (30
mg; 60 mmol; see Example 1 (iv) above) and cyclopentyl
chloroformate (9.9 mg; 66 .mu.mol) in methylene chloride, and the
mixture was stirred at RT for 3 hours, whereafter it was diluted
with water, and the resultant mixture was extracted with methylene
chloride (4.times.). The combined organic layer was dried
(Na.sub.2SO.sub.4) and evaporated. The crude product was purified
using flash chromatography (silica gel; methylene chloride 4
EtOAc). The fractions of interest were concentrated, yielding 16.7
mg (50%) of the title compound.
[0185] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.95 (t, 1H);
7.83 (d, 2H); 7.32 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.67 (d,
1H); 5.16 (m, 1H); 4.93 (dd, 1H); 4.6-4.45 (m, 3H); 3.84 (m, 1H);
3.77 (s, 3H); 3.04 (m, 1H); 2.82 (m, 1H); 2.7-2.55 (m, 2H); 2.26
(m, 1H); 2.0-1.7 (m, 10H); 1.65-1.55 (m, 2H)
[0186] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons): .delta. 178.8; 171.4; 168.5; 165.9
[0187] LC-MS (m/z) 549 (M+1).sup.+
Example 3
(S)- or
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO--cyclobutyl)
(i) p-Nitrophenyl-cyclobutyl carbonate
[0188] Pyridine (0.43 g; 5.5 mmol) was added to an ice-cold
solution of cyclobutanol (0.36 g; 5.0 mmol) and p-nitrophenyl
chloroformate (1.0 g; 5.0 mmol) in methylene chloride (10 mL), and
the resultant mixture was stirred at RT overnight. The crude
product was purified using flash chromatography (silica gel;
heptane.fwdarw.heptane:EtOAc (90:10)). The fractions of interest
were concentrated yielding 0.86 g (73%) of the sub-title
compound.
[0189] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 8.29 (m, 2H);
7.39 (m, 2H); 5.07 (m, 1H); 2.45 (m, 2H); 2.25 (m, 2H); 1.89 (m,
1H); 1.68 (m, 1H)
(ii) (S)- or
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO--O-cyclobutyl)
[0190] NaOH (aq; 1.5M; 1 mL; 1.5 mmol) was added to a vigorously
stirred solution of (S)- or
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab.times.HOAc (30
mg; 60 .mu.mol; see Example 1 (iv) above) and
p-nitrophenyl-cyclobutyl carbonate (36 mg; 150 .mu.mol; from step
(i) above) in methylene chloride (5 mL), whereafter the solution
was stirred at RT for 2.5 hours. The resultant mixture washed 3
times with NaOH (aq; 1.5M) and 2 times with brine. The crude
product was purified using flash chromatography (silica gel;
methylene chloride:EtOAc (3:10)). The fractions of interest were
concentrated yielding 24 mg (74%) of the title compound.
[0191] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 9.6 (br, 1H);
7.96 (t, 1H); 7.84 (d, 2H); 7.31 (d, 2H); 7.05 (d, 1H); 6.82 (dd,
1H); 6.67 (d, 1H); 5.00 (p, 1H); 4.92 (dd, 1H); 4.54 (br, 1H); 4.50
(m, 1H); 3.83 (m, 1H); 3.04 (m, 1H); 2.81 (d, 1H); 2.65-2.5 (m,
2H); 2.45-2.3 (m, 2H); 2.3-2.15 (m, 3H); 2.0-1.8 (m, 5H); 1.64 (m,
1H)
[0192] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 178.8; 171.4; 168.7; 165.3
[0193] LC-MS (m/z) 536 (M+1).sup.+
Example 4
(R,S)-4-Hydroxy-6-chlorochroman-4-yl-C(O)-Aze-Pab(CO--O--CH.sub.1-cyclopro-
pyl)
(i) 6-Chloro-4-hydroxychroman-4-yl-carboxylic acid
[0194] The sub-title compound was prepared analogously to the
methods described in Example 1, steps (i) and (ii), starting from
6-chlorochromanone (2.45 g; 13.4 mmol), Me.sub.3SiCN (1.51 g; 15.2
mmol), and ZnI.sub.2 (40 mg; cat.). Yield: 490 mg (93%).
[0195] LC-MS (m/z) 228 (M-1).sup.-
(ii) Boc-Aze-Pab.times.HCOOH
[0196] Ammonium formate (3.0 g; 50 mmol) and Pd/C (5%; 1.0 g) were
added to a solution of Boc-Aze-Pab(Z) (4.7 g; 10 mmol; see
international patent application WO 94/29336) in 50 mL of MeOH.
Formic acid (1.0 g; 22 mmol) was added and the mixture was stirred
for 30 minutes. The reaction mixture was filtered through Hyflo and
the solution was concentrated. The crude product was suspended in
CH.sub.2Cl.sub.2 (50 mL), filtered and washed with more
CH.sub.2Cl.sub.2. The solid material was dried and used in the
following step without further purification.
(iii) Boc-Aze-Pab(Teoc)
[0197] Teoc-p-nitrophenyl carbonate (3.5 g; 12.3 mmol) was added to
a solution of Boc-Aze-Pab.times.HCOOH (3.7 g; 10 mmol; from step
(ii) above) in THF (100 mL) whereafter a solution of
K.sub.2CO.sub.3 (1.8 g; 13 mmol) in water (20 mL) was added over 2
minutes. The resultant solution was stirred for 3 days,
concentrated, and the remainder was taken up in EtOAc (150 mL) and
NaOH (aq.; 0.5M; 50 mL). The organic layer washed with brine
(2.times.50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was purified using flash chromatography (Si-gel;
methylene chloride:acetone; 4:1).
[0198] Yield 4.6 g (96%).
[0199] .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 7.86 (d, 2H);
7.39 (d, 2H); 4.72 (bt, 1H); 4.7-4.5 (br, 2H); 3.93 (m, 1H); 3.81
(m, 1H); 2.48 (br, 2H); 1.43 (s, 9H); 0.09 (s, 9H)
(iv) H-Aze-Pab(Teoc).times.HCl
[0200] A solution of Boc-Aze-Pab(Teoc) (4.6 g; 9.6 mmol; from step
(iii) above) in methylene chloride (150 mL) was saturated with dry
HCl. The solution was kept at RT in a stoppered flask for 10
minutes, whereafter it was concentrated. Yield 4.2 g (97%).
[0201] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.80 (d, 2H);
7.60 (d, 2H); 5.10 (m, 1H); 4.60 (bs, 2H); 4.15 (m, 1H); 3.97 (q,
1H); 2.86 (m, 1H); 2.57 (m, 1H); 0.11 (s, 9H)
(v) 6-Chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab(Teoc)
[0202] A solution of 6-chloro-4-hydroxychroman-4-yl-carboxylic acid
(222 mg; 1.00 mmol; from step (i) above) and HATU (370 mg 0.97
mmol) in DMF (5 mL) was stirred at 0.degree. C. for 1.5 h, and a
mixture of H-Aze-Pab(Teoc).times.HCl (440 mg, 0.98 mmol; from step
(iv) above) and 2,4,6-trimethylpyridine (0.48 g; 3.9 mmol) in DMF
(5 mL) was added at 0.degree. C. After stirring 3 h at 0.degree. C.
the reaction mixture was concentrated, and the crude product was
purified using preparative RPLC(CH.sub.3CN:0.1M ammonium acetate;
55:45). The fractions of interest were partly concentrated and
extracted with methylene chloride. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated, yielding 350 mg (67%) of a
diastereomeric mixture.
[0203] .sup.1H-NMR (400 MHz; CDCl.sub.3) (complex due to
diasteromers/rotamers): .delta. 7.96 (m, 0.5H); 7.87 (bd, 1H); 7.82
(bd, 1H); 7.73 (m, 0.5H); 7.31 (m, 1H); 7.19 (dt, 1H); 7.09 (bd,
0.5H); 7.00 (bd, 0.5H); 6.88 (dd, 1H); 4.93 (m, 1H); 4.9-4.4 (m,
4H); 4.36 (m, 1H); 4.15 (bt, 1H); 3.89 (m, 0.5H); 3.74 (m, 0.5H);
3.09 (m, 1H); 2.65-2.25 (m, 4H); 1.96 (bt, 1H); 0.06 (s, 9H)
[0204] LC-MS (m/z) 588 (M+1).sup.+
[0205] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 176.9; 171.5; 171.3; 169.8; 155.4; 155.2
(vi)
(R,S)-6-Chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc
[0206] Bu.sub.4NF (1.0M in THF; 0.35 mL) was added to a solution of
6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab(Teoc) (190 mg; 0.32
nmol; from step (v) above) in THF (20 mL) at 0.degree. C. The
solution was stirred for two days at 40.degree. C. The solution was
concentrated and the crude material was purified using preparative
RPLC(CH.sub.3CN:0.1M ammonium acetate; 25:75). Yield 115 mg
(71%).
[0207] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.73 (m, 2H);
7.55 (m, 2H); 7.28 (dd, 1H); 7.15 (m, 1H); 6.79 (m, 1H); 4.7-4.0
(m, 6H); 2.8-2.0 (m, 4H); 1.90 (s, 3H)
[0208] LC-MS (m/z) 444 (M+1).sup.+
[0209] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 175.9; 175.6; 174.4; 173.1; 173.0
(vii)
(R,S)-4-Hydroxy-6-chlorochroman-4-yl-C(O)-Aze-Pab(CO--O--CH.sub.1-cy-
clopropyl)
[0210] NaOH (aq; 2M; 1.0 mL; 2.0 mmol) was added to a vigorously
stirred solution of
(R,S)-6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab.times.HOAc (31
mg; 62 .mu.mol; from step (vi) above) and
p-nitrophenyl-cyclopropylmethyl carbonate (39 mg, 160 .mu.mol, see
Example 1 (v) above) in methylene chloride (5 mL), and the solution
was stirred at RT for 2 hours. The resultant mixture washed 3 times
with NaOH (aq.; 1.5M). The crude product was purified using flash
chromatography (silica gel; methylene chloride.fwdarw.EtOAc). The
fractions of interest were concentrated yielding 25 mg (75%) of the
title compound.
[0211] .sup.1H-NMR (400 MHz; CDCl.sub.3): (complex due to
diastereoisomers) .delta. 7.95 (t, 0.5H); 7.85 (d, 1H); 7.80 (m,
1.5H); 7.33 (d, 1H); 7.27 (d, 1H); 7.17 (m, 2H); 7.08 (d, 0.5H);
6.82 (m, 1H); 4.90 (m, 1H); 4.6-4.4 (m, 3H); 4.14 (m, 1H); 3.96 (d,
2H); 3.90 (m, 0.5H); 3.75 (m, 0.5H); 3.11 (m, 1H); 2.51 (m, 1H);
2.40 (m, 0.5H); 2.30 (m, 0.5H); 2.22 (m, 1H); 1.95 (m, 1H); 0.56
(m, 2H); 0.31 (m, 2H)
[0212] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 175.2; 175.1; 171.1; 170.0; 169.9; 167.5
[0213] LC-MS (m/z) 541 (M+1).sup.+
Example 5
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--CH.sub.2-Ph(4-OMe))
(i) (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Teoc)
[0214] The sub-title compound was prepared according to the method
described in Example 4 (v) above from
1-hydroxy-7-methoxytetraline-1-carboxylic acid (0.44 g; 2.0 mmol;
see Example 1 (ii) above), HATU (0.80 g; 2.1 mmol), H-Aze-Pab(Teoc)
.times.HCl (1.17 g; 2.6 mmol; see Example 4 (iv) above), and
2,4,6-trimethylpyridine (1.2 g; 10 mmol). The crude product (1.73
g) was purified using preparative RPLC(CH.sub.3CN:0.1M ammonium
acetate 55:45). The fractions of interest were partly concentrated
and extracted with methylene chloride. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated yielding 0.32 g (28%) of a
diastereomeric mixture. Preparative RPLC(CH.sub.3CN:0.1M ammonium
acetate; 46:54) yielded two diastereomers: Compound 5A (faster
moving diastereomer; 0.16 g; 28%) and Compound 5B (slower moving
diastereomer; 0.16 g; 28%).
Compound 5A:
[0215] .sup.1H-NMR (400 MHz; CDCl.sub.3) .delta. 7.96 (t, 1H); 7.86
(dd, 2H); 7.36 (dd, 2H); 7.07 (d, 1H); 6.87 (dd, 1H); 6.68 (d, 1H);
4.95 (dd, 1H); 4.54 (m, 3H); 4.26 (m, 2H); 3.84 (m, 1H); 3.78 (s,
3H); 3.04 (q, 1H); 2.83 (d, 1H); 2.63 (m, 2H); 2.28 (m, 1H);
2.02-1.85 (m, 4H); 1.15 (dt, 2H); 0.08 (s, 9H)
[0216] LC-MS (m/z) 581 (M+1).sup.+
(ii)
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Teoc)(O--CH.sub.2-P-
h(4-OMe))
[0217] O-(4-methoxybenzyl)-hydroxylamine.times.HCl (78 mg; 0.41
mmol) was added to a solution of
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Teoc) (40 mg; 69
mmol; from step (i) above) in THF (3 mL), and the mixture was
stirred at 60.degree. C. overnight. The solution was concentrated,
and the crude product was purified using preparative RPLC (65%
CH.sub.3CN/0.1M ammonium acetate). The fractions of interest were
concentrated, and the remaining mixture was extracted with
methylene chloride. The organic layer washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated, yielding 35 mg (71%) of the
sub-title compound.
[0218] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.79 (bt, 1H);
7.55 (s, 1H); 7.45 (d, 2H); 7.34 (m, 2H); 7.28 (s, 2H); 7.04 (d,
1H); 6.91 (m, 2H); 6.82 (dd, 1H); 6.65 (d, 1H); 5.09 (s, 2H); 4.91
(dd, 1H); 4.65 (br, 1H); 4.49 (m, 2H); 4.11 (m, 2H); 3.83 (s, 3H);
3.76 (s, 3H); 2.95 (m, 1H); 2.80 (bd, 1H); 2.60 (m, 2H); 2.25 (m,
1H); 2.0-1.8 (m, 4H); 0.94 (m, 2H); 0.00 (s, 9H)
[0219] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 177.3; 170.6; 161.3; 156.6
[0220] LC-MS (m/z) 717 (M+1).sup.+
(iii)
(R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O--CH.sub.1-Ph(4-O-
Me))
[0221] Bu.sub.4NF (1M in THF; 0.1 mL; 0.1 mmol) was added to a
solution of
(R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Teoc)(O--CH.sub.2-Ph-
(4-OMe)) (34 mg; 44 mmol; from step (ii) above) in CH.sub.3CN (2
mL) and the solution was stirred at 60.degree. C. overnight. The
crude product (21.3 mg) was purified using HPLC (65%
CH.sub.3CN/0.1M ammonium acetate, yielding 10 mg (46%) of the title
compound.
[0222] .sup.1H-NMR (400 MHz; CDCl.sub.3) .delta. 7.87 (br, 1H);
7.61 (d, 2H); 7.39 (d, 2H); 7.29 (d, 2H); 7.07 (d, 2H); 6.91 (d,
2H); 6.83 (dd, 1H); 6.67 (d, 1H); 15.07 (s, 2H); 4.93 (dd, 1H);
4.84 (br, 1H); 4.59 (br, 1H); 4.49 (m, 2H); 3.82 (s, 3H); 3.77 (s,
3H); 3.02 (m, 1H); 2.82 (bd, 1H); 2.68-2.55 (m, 2H); 2.26 (m, 1H);
2.0-1.8 (m, 5H)
[0223] .sup.13C-NMR (100 MHz; CDCl.sub.3): (carbonyl and/or amidine
carbons) .delta. 177.9; 170.4; 158.8
[0224] LC-MS (m/z) 573 (M+1).sup.+
Example 6
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab
(i) O--CF.sub.3--O'-allyl-catechol
[0225] A solution of O--CF.sub.3-catechol (10 g, 56.2 mmol) and
allyl bromide (13.6 g, 112.3 mmol) and Cs.sub.2CO.sub.3 (36.6 g,
112.3 mmol) in acetone (100 mL) was refluxed overnight, and the
solvent was removed using a rotary evaporator. The remainder was
dissolved in ether, and the resultant mixture washed with
NaOH/H.sub.2O (2M) and water. The product (10.9 g, 89%) was pure
enough to use without further purification.
[0226] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.26 (m, 2H); 6.96
(m, 2H); 6.06 (m, 1H); 5.47 (d, 1H); 5.33 (d, 1H); 4.65 (s, 2H)
(ii) O--CF.sub.3-O'-3-hydroxy-n-propyl-catechol
[0227] To a cold (ice-bath) solution of
O--CF.sub.3--O'-allyl-catechol (8.9 g, 40.8 mmol, from step (i)
above) in dry THF (100 mL) under N.sub.2 was added
borane-dimethylsulphide complex (2M, 59 mL, 118.3 mmol). The
temperature of the mixture was kept below 5.degree. C. and,
following addition, was stirred in an ice-bath for 2 h and at
ambient temperature for 1 h. The mixture was cooled and water (45
mL) was added. The mixture was stirred for a few minutes and then
NaOH/H.sub.2O (3M, 40 mL) and H.sub.2O.sub.2 (35%, 12.5 mL) were
added. The mixture was stirred at RT for 1 h, K.sub.2CO.sub.3 was
added and the solution was stirred for another 5 minutes. The
organic layer was separated, the THF was evaporated and ether was
added. The ether solution was dried (Na.sub.2SO.sub.4) and
evaporated, yielding 7.30 g (76%) of crude product, which was used
without further purification.
[0228] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.26 (m, 2H); 7.03
(d, 1H); 6.96 (m, 1H); 4.20 (m, 2H); 3.90 (m, 2H); 2.10 (m, 2H)
(iii) 3-(2-OCF.sub.3-phenoxy)propionic acid
[0229] To a solution of CrO.sub.3 (11.3 g, 112.6 mmol) and
H.sub.2SO.sub.4 (conc., 9.5 mL) in water:acetone (21:250) was added
a solution of O--CF.sub.3-O'-3-hydroxy-n-propyl-catechol (7.0 g,
29.6 mmol, from step (ii) above) in acetone (140 mL), and the
resultant mixture was stirred at RT for 2 h. iso-Propanol was added
to destroy the remaining CrO.sub.3, the precipitate was removed by
filtration, and the acetone was evaporated. The residue was
dissolved in methylene chloride and water, the organic layer was
separated, and the aqueous layer was extracted twice with methylene
chloride. The combined organic layer washed with water and
extracted with NaOH/H.sub.2O (2M) whereafter the aqueous phase
washed with methylene chloride, acidified (HCl) and extracted with
ether. After evaporation of the combined ethereal phase, the
product, a yellow solid, was obtained (yield 4.37 g (59%)).
[0230] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.21 (m, 2H); 6.99
(d, 1H); 6.94 (m, 1H); 4.28 (t, 2H); 2.87 (t, 2H)
(iv) 8-Trifluoromethoxychroman-4-one
[0231] To a cold solution of 3-(2-OCF.sub.3-phenoxy)propionic acid
(4.56 g, 18.2 mmol; from step (iii) above) in methylene chloride
was added PCI, (6.45 g; 31.0 mmol) in portions, and the resultant
mixture was stirred at 0.degree. C. for 1 h. To the cold solution
was added AlCl.sub.3 (7.29 g, 54.7 mmol) and the mixture was
stirred at 0.degree. C. for 1 h, and then at RT overnight. The
mixture was cooled and water (50 mL) was added cautiously. After
addition of further methylene chloride the organic layer was
separated and the aqueous layer was extracted twice with methylene
chloride. The combined organic layer washed with water, dried
(Na.sub.2SO.sub.4) and concentrated, yielding 4.10 g (97%) of the
sub-title compound.
[0232] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.83 (d, 1H); 7.41
(d, 1H); 6.99 (t, 1H); 4.61 (t, 2H); 2.84 (t, 2H)
(v) 6-Chloro-8-trifluoromethoxychroman-4-one
[0233] To a solution of calcium hypochlorite (15.4 g, 72.4 mmol) in
water:acetic:acid (65:5) was added a solution of
8-trifluoromethoxychroman-4-one (4.2 g, 18.1 mmol; from step (iv)
above) in acetonitrile (20 mL), whereafter the reaction mixture was
stirred overnight. The mixture was diluted with water and extracted
with ether (3 times) and EtOAc (once). The combined organic layer
washed with water, dried (Na.sub.2SO.sub.4) and evaporated,
yielding 4.2 g (87%) of the sub-title compound.
[0234] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (m, 1H); 7.43
(m, 1H); 4.64 (t, 2H); 2.90 (t, 2H)
(vi) 4-Cyano-4-OTMS-6-chloro-8-trifluoromethoxychromane
[0235] A solution of 6-chloro-8-trifluoromethoxychroman-4-one (2.0
g, 7.5 mmol, from step (v) above), TMSCN (0.8 g, 8.3 mmol) and
ZnI.sub.2 (cat.) in methylene chloride (50 mL) was stirred at RT
for 2 days, whereafter the crude product was used directly for the
next step.
[0236] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.50 (d, 1H); 7.28
(sh, 1H); 4.52-4.38 (m, 2H); 2.52-2.38 (m, 2H); 0.26 (s, 9H)
(vii) 4-Hydroxy-6-chloro-8-trifluoromethoxy-4-carbimidic acid,
methyl ester
[0237] The product solution from the step (vi) above was added
drop-wise to an ice cold saturated solution of HCl in MeOH,
whereafter the resultant mixture was stirred overnight. The solvent
was removed in vacuo, and the resultant material was used directly
to the next step.
(viii) 4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl carboxylic
acid, methyl ester
[0238] The crude product from step (vii) above was dissolved in THF
(100 mL), and H.sub.2SO.sub.4 (0.5M, 100 mL) was added, whereafter
the mixture was left standing at RT for 3 days. The solution was
partially concentrated and the aqueous solution was extracted with
ether (3.times.). The combined organic phase was dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was used
directly in the next step.
(ix) 4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl carboxylic
acid
[0239] A solution of
4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl carboxylic acid,
methyl ester in iso-propanol (50 mL) was added to KOH/H.sub.2O
(20%, 60 mL) and the mixture was refluxed overnight. The resultant
solution was partially concentrated, and the remainder was
acidified with H.sub.2SO.sub.4 (10%). The very turbid mixture was
extracted with ether (3.times.), and the combined organic phase was
dried (Na.sub.2SO.sub.4) and concentrated. The crude product was
purified via prep-HPLC (CH.sub.3CN:0.1M ammonium acetate (30:60)).
The fractions of interest were partly concentrated and extracted
with ether. The combined organic layers were washed with water,
dried (Na.sub.2SO.sub.4), and concentrated, yielding 0.24 g (10%
over steps (vi)-(ix)).
[0240] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.18 (s, 1H); 7.11
(s, 1H); 4.51 (m, 1H); 4.27 (m, 1H); 2.47 (m, 1H); 2.15 (m, 1H)
(x)
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(Teoc)
[0241] To a solution of
4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl carboxylic acid
(0.24 g, 0.77 mmol; from step (ix) above), was added
H-Aze-Pab(Teoc) (0.38 g, 0.84 mmol, see Example 4 (iv) above),
PyBOP (0.44 g, 0.84 mmol) in DMF (7 mL), and DIPEA (0.40 g, 3.07
mmol). The resultant mixture was stirred overnight, poured into
water and then extracted with EtOAc (3.times.). The combined
organic layer washed with water, dried (Na.sub.2SO.sub.4) and
concentrated. The crude product was purified by flash
chromatography (methylene chloride:THF (7:3)) to yield 0.22 g (43%)
of the sub-title product as a diastereomeric mixture.
[0242] .sup.1H NMR (600 MHz, CDCl.sub.3) (complex due to
diastereomers/rotamers) .delta. 7.79 (d, 1H); 7.76 (d, 1H); 7.67
(t, 1H); 7.31 (d, 1H); 7.25 (d, 1H); 7.18 (s, 1H); 7.04 (d, 0.5H);
7.00 (d, 0.5H); 4.87 (m, 1H); 4.60-4.36 (m, 3H); 4.22-4.13 (m, 3H);
3.91 (m, 0.5H); 3.76 (m, 0.5H); 3.14 (m, 1H); 2.55-2.20 (m, 3H);
1.98 (m, 1H); 1.07 (m, 2H); 0.03 (s, 9H)
[0243] LC-MS (m/z) 671 (M+1).sup.+
(xi)
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab
[0244] A solution of
4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(Teoc)
(106 mg, 0.16 mmol; from step (x) above) in TFA (2 mL) was left at
RT for 30 min, whereafter the solution was concentrated in vacuo.
The product was dissolved in a minimal amount of water and freeze
dried overnight, yielding 100 mg (99%) of the title compound with a
purity of 96%.
[0245] .sup.1H NMR (400 MHz, CD.sub.3OD) (complex due to
diastereomers/rotamers) .delta. 7.74 (m, 2H); 7.60-7.50 (m, 2H);
7.38 (d, 0.5H); 7.30 (d, 0.5H); 7.24 (m, 1H); 4.87 (sh, 1H);
4.65-4.40 (m, 4H); 4.35-4.00 (m, 2H); 2.75 (m, 0.5H); 2.60 (m, 1H);
2.42 (m, 1H); 2.37-2.05 (m, 2.5H)
[0246] LC-MS (m/z) 527 (M+1).sup.+
[0247] .sup.13C NMR (carbonyl and/or amidine carbons; 100 MHz,
CD.sub.3OD) .delta. 174.1; 173.7; 172.0; 171.9; 166.9
Example 7
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(OMe)
(i)
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(OMe)(Te-
oc)
[0248] A solution of
4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(Teoc)
(40 mg, 0.06 mmol; see Example 6 (x) above) and
O-methylhydroxylamine (30 mg, 0.36 mmol) in THF (5 mL) was heated
at 65.degree. C. for 2 days, whereafter the solvent was removed in
vacuo and the crude product was purified by
prep-HPLC(CH.sub.3CN:0.1M ammonium acetate 50:50-70:30). The
fractions of interest were partly concentrated and extracted with
EtOAc. The combined organic phase was dried (Na.sub.2SO.sub.4) and
concentrated to dryness, giving the sub-title compound (22 mg,
53%).
[0249] .sup.1H NMR (600 MHz, CDCl.sub.3) (complex due to
diastereomers/rotamers) 57.64 (bt, 0.5H); 7.57 (d, 1H); 7.52 (d,
1H); 7.48 (d, 1H); 7.43 (bt, 0.5H); 7.34 (d, 1H); 7.29 (d, 1H);
7.23 (s, 1H); 7.09 (d, 0.5H); 7.06 (d, 0.5H); 4.90 (m, 1H); 4.75
(b, 1H); 4.61-4.44 (m, 3H); 4.22-4.12 (m, 3H); 3.96 (s, 3H); 3.90
(m, 0.5H); 3.76 (m, 0.5H); 3.15 (q, 0.5H); 3.05 (m, 0.5H); 2.59 (m,
1H); 2.44 (m, 0.5H); 2.36 (m, 0.5H); 2.25 (m, 1H); 2.02 (dd, 1H);
1.67 (b, 1H); 0.97 (m, 1H); 0.02 (d, 9H)
(ii)
4-Hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(OMe)
[0250] A solution of
4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl-C(O)-Aze-Pab(OMe)(Teoc)
(22 mg, 0.03 mmol, from step (i) above) in TFA (3.0 mL) was stirred
for 15 minutes, whereafter the solution was concentrated. The crude
product was dissolved in water, and the product was freeze dried,
yielding 20 mg (95%) of the title compound.
[0251] .sup.1H NMR (600 MHz, CD.sub.3OD) (complex due to
diastereomers/rotamers) .delta. 7.63 (m, 2H); 7.53 (m, 2H); 7.36
(m, 0.5H); 7.28 (m, 0.5H); 7.22 (m, 1H); 4.82 (dd, 1H); 4.62-4.00
(m, 6H); 3.92 (s, 3H); 2.71 (m, 0.5H); 2.55 (m, 0.5H); 2.40 (m,
1H); 2.27 (m, 0.5H); 2.20 (m, 0.5H); 2.10 (m, 1H)
[0252] LC-MS (m/z) 557 (M+1).sup.+
[0253] .sup.13C NMR (carbonyl and/or amidine carbons; 100 MHz,
CD.sub.3OD) .delta. 173.9; 173.6; 171.8; 160.6
Example 8
(S)- or
(R)-4-Hydroxy-6-chloro-8-difluoromethoxychroman-4-yl-C(O)-Aze-Pab.-
times.HOAc
(i) O--CHF, --O'-allyl-catechol
[0254] To a solution of iso-propanol (120 mL) and KOH/H.sub.2O
(30%, 120 mL) was added O-allyl-catechol (26 g, 173 mmol). The
resultant mixture was warmed to 70.degree. C., and a stream of
chlorodifluoromethane was bubbled through the solution for 45
minutes. The mixture was stirred for 30 minutes at 70.degree. C.
and then at room temperature overnight. The mixture was diluted
with water (1000 mL), and extracted with ether (3.times.). The
combined organic phases were washed with NaOH/H.sub.2O (2M) and
water, then dried (Na.sub.2SO.sub.4) and concentrated, yielding
20.5 g (59%) of the sub-title compound, which was used without
further purification.
[0255] --H-NMR (400 MHz; CDCl.sub.3): .delta. 7.15 (m, 2H); 6.93
(m, 2H); 6.30-6.80 (t, 1H); 5.95-6.10 (m, 1H); 5.25-5.45 (dd, 2H);
4.55-4.60 (d, 2H)
(ii) O--CHF.sub.2--O'-3-hydroxy-n-propyl-catechol
[0256] To a cold (ice-bath) solution of
O--CHF.sub.2--O'-allyl-catechol (20.5 g, 102.4 mmol, from step (i)
above) in dry THF (200 mL) under N.sub.2 was added
borane-dimethylsulphide complex (2M, 149 mL, 298 mmol). The
temperature of the mixture was kept at 5.degree. C. and, following
addition, was stirred at this temperature for 2 h, and then at room
temperature for 1 h. The mixture was cooled and water (111 mL) was
added. The mixture was stirred for a few minutes and then
NaOH/H.sub.2O (3M, 102 mL) and H.sub.2O.sub.2 (35%, 31 mL) were
added. The mixture was stirred (ice-bath) for a few minutes and
then at room temperature for 1 h. K.sub.2CO.sub.3 (77 g, 557 mmol)
was added and the mixture was stirred for a few minutes. The
organic layer was separated, the THF was evaporated and ether was
added. The ether solution washed with water (3.times.), then dried
(Na.sub.2SO.sub.4) and concentrated, yielding 16.2 g (72%) of the
sub-title compound, which was used without further
purification.
[0257] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.10-7.17 (m,
2H); 6.86-6.98 (m. 2H); 6.32-6.71 (t, 1H); 4.11 (t, 2H); 3.81 (t,
2H); 2.86 (s, 1H); 2.1 (m, 2H)
(iii) 3-(2-OCHF.sub.2-phenoxy)propionic acid
[0258] To a cold (ice-bath) solution of CrO.sub.3 (27.8 g, 278
mmol) in water (53 mL) was added H.sub.2SO.sub.4 (conc., 23.5 mL).
The mixture was cautiously (ice-bath) added to acetone (500 mL). To
the resultant mixture was added, dropwise over 2 h, a solution of
O--CHF.sub.2--O'-3-hydroxy-n-propyl-catechol (16.0 g, 73 mmol, from
step (ii) above) in acetone (350 mL), whereafter the reaction
mixture was stirred at room temperature overnight. The precipitate
was removed by filtration and the filter cake washed with acetone.
The filtrate was concentrated in vacuo, the residue was dissolved
in methylene chloride, and washed with water (3.times.). The
filter-cake was dissolved in the combined water solutions, and the
resultant solution was extracted with methylene chloride
(2.times.). The combined methylene chloride phases were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford 15.2 g (89%)
of the sub-title compound.
[0259] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 9.64 (s, 1H);
7.12-7.20 (m, 2H); 6.91-7.02 (m, 2H) 6.30-6.70 (t, 1H); 4.29 (t,
2H); 2.88 (t, 2H)
(iv) 8-Difluoromethoxychroman-4-one
[0260] To a cold (ice-bath) solution of
3-(2-OCHF.sub.2-phenoxy)propionic acid (12.5 g, 53.8 mmol, from
step (iii) above) in methylene chloride (175 mL) under N.sub.2 was
added, dropwise, boron trifluoride dimethyl etherate (12.5 mL, 136
mmol) and then trifluoroacetic anhydride (20.0 mL, 143.8 (mmol).
The reaction mixture was stirred at 5.degree. C. for 1 h. The
mixture was cooled and water (175 mL) was added cautiously. The
organic layer was separated, washed with NaHCO.sub.3/aq, dried
(Na.sub.2SO.sub.4) and evaporated. The crude product was
chromatographed on silica gel, eluting with methylene chloride, to
afford 6.3 g (55%) of the sub-title compound.
[0261] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.70-7.74 (dd,
1H); 7.32-7.37 (dd, 1H); 6.93-7.00 (t, 1H); 6.41-6.81 (t, 1H);
4.58-4.64 (t, 2H); 2.80-2.85 (t, 2H)
(v) 6-Chloro-8-difluoromethoxychroman-4-one
[0262] To a solution of calcium hypochlorite (29.4 g, 137.8 mmol)
in water:acetic acid (125:9.5) was added a solution of
8-difluoromethoxychroman-4-one (7.4 g, 34.6 mmol, see step (iv)
above) in acetonitrile (20 mL), whereafter the reaction mixture was
stirred overnight. The mixture was diluted with water and extracted
with ether (3.times.) and with EtOAc (1.times.). The combined
organic layers were washed with water (3.times.), dried
(Na.sub.2SO.sub.4) and evaporated, yielding 8.0 g (93%) of the
sub-title compound.
[0263] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.70-7.73 (d,
1H); 7.33-7.37 (d, 1H); 6.40-6.80 (t, 1H); 4.63 (t, 2H); 2.86 (t,
2H)
(vi) 4-Methylene-6-chloro-8-difluoromethoxychromane
[0264] To a solution of dimethyl methylphosphonate (8.9 g, 71.1
mmol) in dry THF (55 mL) under N.sub.2 was added, dropwise over 1 h
at -70.degree. C., n-butyllithium in hexane (1.6M, 49.2 mL). The
mixture was stirred for 30 minutes at -70.degree. C., whereafter a
solution of 6-chloro-8-difluoromethoxychroman-4-one (6.8 g, 27.35
mmol, from step (v) above) in dry THF (15 mL) was added, dropwise
over 30 minutes at -70.degree. C. The reaction mixture was stirred
for 2 h at -70.degree. C., whereafter NH.sub.4Cl (aq., sat., 110
mL) was added, and then water (50 mL). The layers were separated
and the aqueous phase was extracted with EtOAc. The combined
organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated. The residue was dissolved in DMF (85 mL). To the
solution was added anhydrous potassium carbonate (27.4 g, 201.0
mmol) and water (3.6 ml). The mixture was warmed for 2 h at
120.degree. C. (oil-bath). After the mixture had reached room
temperature water (80 mL) was added. The mixture was extracted with
EtOAc. The combined organic layers were washed with citric acid
(aq., 10%) and with brine, dried (Na.sub.2SO.sub.4) and evaporated.
The crude product was chromatographed on silica gel, eluting with
heptane:methylene chloride (8:2), to afford 3.2 g (47%) of the
sub-title compound.
[0265] .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 7.38 (d, 1H);
7.03 (d, 1H); 6.33-6.74 (t, 1H); 6.52 (s, 1H); 4.99 (s, 1H); 4.27
(t, 2H); 2.66 (t, 2H)
(vii) (S)- or
(R)-4-Hydroxy-4-hydroxymethyl-6-chloro-8-difluoromethoxychromane
[0266] To a mixture of tert-butanol (46 mL) and water (46 mL) was
added AD-mix-.beta. (18.6 g). The mixture was cooled to 0.degree.
C. 4-Methylene-6-chloro-8-difluoromethoxychromane (3.2 g 12.97
mmol, see step (vi) above) in tert-butanol (11 mL) and water (1 mL)
was added. The mixture was stirred at 0.degree. C. for 24 h. Sodium
sulfite (19.0 g, 150.74 mmol) was added, and the mixture was
allowed to warm to room temperature and stirred for 1 h. The layers
were separated and the aqueous phase was extracted with EtOAc
(2.times.). The combined ethyl acetate phases were dried
(Na.sub.2SO.sub.4) and evaporated. The crude product was
chromatographed on silica gel, eluting with methylene
chloride:ethyl acetate (4:6), to afford 3.2 g (88%) of the
sub-title compound.
[0267] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.38 (d, 1H);
7.07 (d, 1H); 6.51-6.74 (t, 1H); 4.86 (s, 2H); 4.3 (m, 2H); 3.70
(dd, 2H); 2.25-2.35 (m, 1H); 1.91-2.02 (m, 1H)
(viii) (S)- or (R)-4-Hydroxy-6-chloro-8-difluoromethoxychroman-4-yl
carboxylic acid
[0268] To a solution of (S)- or
(R)-4-hydroxy-4-hydroxymethyl-6-chloro-8-difluoromethoxychromane
(3.2 g, 11.4 mmol, from step (vii) above) in acetone (25 mL) was
added non-ionized water (110 mL), then sodium hydrogencarbonate
(2.13 g, 22.2 mmol) and Pt/C.sub.5%, 58% water (2.13 g). A stream
of air was bubbled through the solution with stirring at 75.degree.
C. (oil-bath) overnight. The solution was filtered through Celite
and the filter-cake washed with water. The acetone-water solution
was acidified (HCl, 2M) to pH 2, saturated with NaCl and extracted
with EtOAc (3.times.). The combined ethyl acetate phases were
washed with water (2.times.) and with brine, then dried
(Na.sub.2SO.sub.4) and concentrated. The residue was dissolved in
ether. The ether solution washed with water (3.times.) and
concentrated, yielding 2.4 g (71%) of the sub-title compound.
[0269] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.19 (d, 1H);
7.11 (d, 1H); 6.54-6.75 (t, 1H); 4.90-5.30 (s, 2H); 4.43-4.52 (m,
1H); 4.22-4.32 (dt, 1H); 2.44-2.55 (dt, 1H); 2.06-2.16 (dd, 1H)
[.alpha.].sub.D.sup.20=-20.degree. C. (c=1%, MeOH)
(ix) (S)- or
(R)-4-Hydroxy-6-chloro-8-difluoromethoxychroman-4-yl-C(O)-Aze-Pab(Teoc)
[0270] To ethyl acetate (20 mL) saturated with HCl was added
Boc-Aze-Pab(Teoc) (0.33 g, 0.66 mmol, see Example 4 (iii) above).
The mixture was kept at room temperature for 15 minutes, whereafter
it was concentrated. To the residue dissolved in DMF (4.5 mL) was
added (S)- or (R)-4-hydroxy-6-chloro-8-difluoromethoxychroman-4-yl
carboxylic acid (0.195 g, 0.66 mmol, from step (viii) above), then
PyBOP (0.36 g, 0.68 mmol) and DIPEA (0.33 g, 0.68 mmol). The
mixture was stirred at room temperature for 2 h, diluted with water
(175 mL) and sodium hydrogencarbonate was added to give a pH of 9.
The mixture was then extracted with EtOAc (3.times.). The combined
ethyl acetate phases were washed with water and with brine, and
then dried (Na.sub.2SO.sub.4) and concentrated. The crude product
was further purified using preparative HPLC(CH.sub.3CN:0.1 M
ammonium acetate, 60:40). The fractions of interest were
concentrated. The residue was dissolved in water. The aqueous phase
was extracted with EtOAc (3.times.). The combined ethyl acetate
phases were washed with water and with brine, and then dried
(Na.sub.2SO.sub.4) and concentrated, yielding 0.3 g (68%) of the
sub-title compound.
[0271] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.80 (m, 2H);
7.09-7.44 (m, 3H); 6.52-7.00 (dt, 1H); 5.48 (m, 1H); 4.86 (s, 4H);
3.80-4.60 (m, 8H)); 1.80-2.80 (m, 4H); 1.22 (t, 1H); 1.08 (t, 2H);
0.07 (s, 9H)
(x) (S)- or
(R)-4-Hydroxy-6-chloro-8-difluoromethoxychroman-4-yl-C(O)-Aze-Pab.times.H-
OAc
[0272] To a cold solution of (S)- or
(R)-4-hydroxy-6-chloro-8-difluoromethoxychroman-4-yl-C(O)-Aze-Pab(Teoc)
(0.30 g, 0.459 n-mol, from step (ix) above) in methylene chloride
(1 mL) was added TFA (10 mL). The mixture was stirred for 1 h, and
then concentrated carefully in vacuo. The crude product was further
purified using preparative HPLC (CH.sub.3CN:0.1 M ammonium acetate,
30:70). The fractions of interest were concentrated. The product
was dissolved in a minimal amount of CH.sub.3CN/water and freeze
dried (2.times.), yielding 0.24 g (92%) of the title compound.
[0273] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.68-7.78 (dd,
2H); 7.49-7.57 (dd, 2H); 7.27 (d, 1H); 7.09-7.15 (dd, 1H);
6.56-6.94 (t, 1H); 5.51-5.54 (m, 1H); 4.90-5.02 (m, 8H); 3.98-4.62
(m, 6H); 2.08-2.80 (m, 5H); 1.91 (s, 3H). .sup.13C NMR (400 MHz;
CD.sub.3OD): carbonyl and/or amidine carbons 179.30; 175.93;
175.37; 174.31; 173.04; 168.11.
[0274] MS (m/z) 509 (M+1).sup.+
Example 9
(S)- or
(R)-4-Hydroxy-6-chloro-8-difluoromethoxychroman-4-yl-C(O)-Aze-Pab(-
OMe)
[0275] To a solution of (S)- or
(R)-4-hydroxy-6-chloro-8-difluoromethoxychroman-4-yl carboxylic
acid (0.065 g, 0.22 mmol, see Example 8 (viii) above) in DMF (1.5
mL) was added H-Aze-Pab(OMe).times.2HCl (0.060 g, 0.23 mmol, see
international patent application WO 98/57932), then PyBOP (0.12 g,
0.23 mmol) and DIPEA (0.11 g, 0.85 mmol). The mixture was stirred
at room temperature for 1.5 h and then evaporated. The residue was
dissolved in water (50 mL) and sodium hydrogencarbonate was added
to give a pH of 9. The mixture was extracted with EtOAc (3.times.).
The combined ethyl acetate phases were washed with NaHCO.sub.3/aq
(2.times.) and with water, dried (Na.sub.2SO.sub.4) and
concentrated. The crude product was further purified using
preparative HPLC(CH.sub.3CN:0.1 M ammonium acetate, 50:50). The
fractions of interest were concentrated. The product was dissolved
in a minimal amount of CH.sub.3CN/water and freeze dried
(2.times.), yielding 0.080 g (67%) of the title compound.
[0276] .sup.1H-NMR (400 MHz; CD.sub.3OD): .delta. 7.44 (d, 1H);
7.10-7.26 (m, 2H); 6.91-7.01 (d, 1H); 6.40-6.80 (t, 1H); 5.31 (m,
1H); 4.67 (s, 2H); 4.20-4.40 (m, 2H); 3.80-4.15 (m, 2H); 3.66 (s,
1H); 2.97-3.01 (m, 4H); 2.50-2.64 (m, 1H); 1.87-2.41 (m, 4H);
1.67-1.71 (t, 3H)
[0277] .sup.13C NMR (400 MHz; CD.sub.3OD): carbonyl and/or amidine
carbons 175.87; 175.31; 174.04; 172.73 MS (m/z) 539 (M+1).sup.+
Example 10
[0278] The title compounds of Examples 6 and 8 were tested in Test
A above and were found to exhibit an IC.sub.50TT value of less than
0.1 .mu.M.
Example 11
[0279] The title compounds of Examples 1 to 5, 7 and 9 were tested
in Test E above and were all found to exhibit oral and/or
parenteral bioavailability in the rat as the corresponding active
inhibitor (free amidine).
Example 12
[0280] The title compounds of Examples 1 to 5 were tested in Test G
above and all exhibited formation of the corresponding active
inhibitor (free amidine).
Abbreviations
[0281] Ac=acetyl [0282] AcOH=acetic acid [0283]
Aze=azetidine-2-carboxylate [0284] AzeOH=azetidine-2-carboxylic
acid [0285] Bzl=benzyl [0286] DIPEA=diisopropylethylamine [0287]
DMAP=4-(N,N-dimethyl amino) pyridine [0288] DMF=dimethylformamide
[0289] DMSO=dimethylsulphoxide [0290]
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
[0291] Et=ethyl [0292] ether=diethyl ether [0293] EtOAc=ethyl
acetate [0294] EtOH=ethanol [0295] h=hours [0296]
HATU=O-(azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0297]
HBTU=[N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
hexafluorophosphate] [0298] HCl(g)=hydrogen chloride gas [0299]
HOAc=acetic acid [0300] LC=liquid chromatography [0301] Me=methyl
[0302] MeOH=methanol [0303] Pab=para-amidinobenzylamino [0304]
H-Pab=para-amidinobenzylamine [0305]
PyBOP=(benzotriazole-1-yl-oxy)tripyrrolidinophosphonium
hexafluorophosphate [0306] RPLC=reverse phase high performance
liquid chromatography [0307] RT=room temperature [0308]
TBTU=[N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate] [0309] TEA=triethylamine [0310]
Teoc=2-(trimethylsilyl)ethoxycarbonyl [0311] THF=tetrahydrofuran
[0312] TLC=thin layer chromatography [0313] Val=L-valine [0314]
Z=benzyloxycarbonyl
[0315] Prefixes n, s, i and t have their usual meanings: normal,
secondary, iso and tertiary.
* * * * *