U.S. patent application number 10/817960 was filed with the patent office on 2004-12-30 for heterocyclic derivatives which inhibit factor xa.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Caulkett, Peter W.R., James, Roger, Pearson, Stuart E., Slater, Anthony M., Walker, Rolf P..
Application Number | 20040266759 10/817960 |
Document ID | / |
Family ID | 26313572 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040266759 |
Kind Code |
A1 |
Caulkett, Peter W.R. ; et
al. |
December 30, 2004 |
Heterocyclic derivatives which inhibit factor Xa
Abstract
The invention relates to heterocyclic derivatives of formula
(I), or pharmaceutically-acceptable salts thereof, which possess
antithrombotic and anticoagulant properties and are accordingly
useful in methods of treatment of humans or animals. The invention
also relates to processes for the preparation of the heterocyclic
derivatives, to pharmaceutical compositions containing them and to
their use in the manufacture of medicaments for use in the
production of an antithrombotic or anticoagulant effect. 1
Inventors: |
Caulkett, Peter W.R.;
(Macclesfield, GB) ; James, Roger; (Macclesfield,
GB) ; Pearson, Stuart E.; (Macclesfield, GB) ;
Slater, Anthony M.; (Macclesfield, GB) ; Walker, Rolf
P.; (Macclesfield, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
AstraZeneca AB
|
Family ID: |
26313572 |
Appl. No.: |
10/817960 |
Filed: |
April 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10817960 |
Apr 6, 2004 |
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09674559 |
Jan 4, 2001 |
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6753331 |
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09674559 |
Jan 4, 2001 |
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PCT/GB99/01308 |
Apr 27, 1999 |
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Current U.S.
Class: |
514/227.5 ;
514/235.5; 514/252.14; 514/253.01; 514/254.01; 514/254.02;
514/254.05; 544/114; 544/295; 544/360; 544/369; 544/370;
544/60 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
43/00 20180101; C07D 403/12 20130101; A61P 9/00 20180101; C07D
405/12 20130101; C07D 401/12 20130101; A61P 7/02 20180101 |
Class at
Publication: |
514/227.5 ;
514/235.5; 514/253.01; 514/254.01; 514/254.02; 514/254.05;
514/252.14; 544/060; 544/114; 544/360; 544/295; 544/370;
544/369 |
International
Class: |
A61K 031/541; A61K
031/5377; A61K 031/496; C07D 417/02; C07D 413/02; C07D 43/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 1998 |
GB |
9809351.1 |
Feb 16, 1999 |
GB |
9903337.5 |
Claims
1. A compound of formula (I) 9wherein: A is a 5- or 6-membered
monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms
selected from nitrogen, oxygen and sulphur atoms and is
unsubstituted or is substituted by one, two or three atoms or
groups selected from halo, oxo, carboxy, trifluoromethyl, cyano,
amino, hydroxy, nitro, C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino or aminoC.sub.1-4alkyl; B is N; D is
2-benzimidazolyl, or 2-benzo[b]furanyl, and is unsubstituted or is
substituted by one, two or three substituents selected from halo or
a pharmaceutically-acceptable salts thereof.
2. A compound of formula (I) as claimed in claim 1 wherein A is a
pyridyl, pyrimidinyl, imidazolyl or pyridazinyl ring; or a
pharmaceutically-accept- able salt thereof.
3. A compound of formula (I) as claimed in claim 2 wherein A is
2-pyridyl, 3-pyridyl, 4-pyridyl 3-pyradazinyl, 4-pyridazinyl,
4-pyrimidinyl, 5-pyrimidinyl, 1-imidazolyl, 2-imidazolyl or
4-imidazolyl; or a pharmaceutically-acceptable salt thereof.
4. A compound of formula (I) as claimed in claim 1 wherein A is
substituted by C.sub.1-4alkyl, amino and halo; or a
pharmaceutically-acceptable salt thereof.
5. A compound of formula (I) as claimed in claim 1 wherein A is
unsubstituted; or a pharmaceutically-acceptable salt thereof.
6-9. (cancelled).
10. A compound of formula (I) as claimed in claim 1 wherein D is
substituted by halo; or a pharmaceutically-acceptable salt
thereof.
11. A compound of formula (I) as claimed in claim 1 wherein D is
substituted by bromo or chloro; or a pharmaceutically-acceptable
salt thereof.
12. A compound of formula (I) as claimed in claim 1 wherein: A is
pyridyl, pyrimidinyl, imidazolyl or pyridazinyl; B is N; D is
2-benzo[b]furanyl optionally substituted by fluoro, chloro or
bromo; or a pharmaceutically-acceptable salt thereof.
13-15. (cancelled).
16. A pharmaceutical composition comprising a compound of formula
(I), or a pharmaceutically-acceptable salt thereof, as defined in
any one of claims 1-5 or 10-12, with a pharmaceutically-acceptable
diluent or carrier.
17. (cancelled).
18. A method of treating a Factor Xa mediated disease or condition
in a warm-blooded animal comprising administering an effective
amount of a compound of formula (I), as defined in any one of
claims 1-5 or 10-12, or a pharmaceutically-acceptable salt thereof.
Description
[0001] The invention relates to heterocyclic derivatives, or
pharmaceutically-acceptable salts thereof, which possess
antithrombotic and anticoagulant properties and are accordingly
useful in methods of treatment of humans or animals. The invention
also relates to processes for the preparation of the heterocyclic
derivatives, to pharmaceutical compositions containing them and to
their use in the manufacture of medicaments for use in the
production of an antithrombotic or anticoagulant effect.
[0002] The antithrombotic and anticoagulant effect produced by the
compounds of the invention is believed to be attributable to their
strong inhibitory effect against the activated coagulation protease
known as Factor Xa. Factor Xa is one of a cascade of proteases
involved in the complex process of blood coagulation. The protease
known as thrombin is the final protease in the cascade and Factor
Xa is the preceding protease which cleaves prothrombin to generate
thrombin.
[0003] Certain compounds are known to possess Factor Xa inhibitory
properties and the field has been reviewed by R. B. Wallis, Current
Opinion in Therapeutic Patents, 1993, 1173-1179. Thus it is known
that two proteins, one known as antistatin and the other known as
tick anticoagulant protein (TAP), are specific Factor Xa inhibitors
which possess antithrombotic properties in various animal models of
thrombotic disease.
[0004] It is also known that certain non-peptidic compounds possess
Factor Xa inhibitory properties. Of the low molecular weight
inhibitors mentioned in the review by R. B. Wallis, all possessed a
strongly basic group such as an amidinophenyl or amidinonaphthyl
group.
[0005] We have now found that certain heterocyclic derivatives
possess Factor Xa inhibitory activity. Many of the compounds of the
present invention also possess the advantage of being selective
Factor Xa inhibitors, that is the enzyme Factor Xa is inhibited
strongly at concentrations of test compound which do not inhibit or
which inhibit to a lesser extent the enzyme thrombin which is also
a member of the blood coagulation enzymatic cascade.
[0006] The compounds of the present invention possess activity in
the treatment or prevention of a variety of medical disorders where
anticoagulant therapy is indicated, for example in the treatment or
prevention of thrombotic conditions such as coronary artery and
cerebro-vascular disease. Further examples of such medical
disorders include various cardiovascular and cerebrovascular
conditions such as myocardial infarction, the formation of
atherosclerotic plaques, venous or arterial thrombosis, coagulation
syndromes, vascular injury including reocclusion and restenosis
following angioplasty and coronary artery bypass surgery, thrombus
formation after the application of blood vessel operative
techniques or after general surgery such as hip replacement
surgery, the introduction of artificial heart valves or on the
recirculation of blood, cerebral infarction, cerebral thrombosis,
stroke, cerebral embolism, pulmonary embolism, ischaemia and angina
(including unstable angina).
[0007] The compounds of the invention are also useful as inhibitors
of blood coagulation in an ex-vivo situation such as, for example,
the storage of whole blood or other biological samples suspected to
contain Factor Xa and in which coagulation is detrimental.
[0008] The compound
1-(5-chlorobenzofuran-2-ylsulphonyl)-4-[4-(4-pyridyl)b-
enzoyl]piperazine is disclosed as a Factor Xa inhibitor in PCT
Application No.97/03033, which published after the two priority
dates claimed in this application.
[0009] Accordingly in one aspect the present invention provides
compounds of formula (I) 2
[0010] wherein:
[0011] A is a 5- or 6-membered monocyclic aromatic ring containing
1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and
sulphur atoms and is unsubstituted or is substituted by one, two or
three atoms or groups selected from halo (for example fluoro,
chloro or bromo), oxo, carboxy, trifluoromethyl, cyano, amino,
hydroxy, nitro, C.sub.1-4alkyl (for example methyl or ethyl),
C.sub.1-4alkoxy (for example methoxy or ethoxy),
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylamino (for example
methylamino or ethylamino), di-C.sub.1-4alkylamino (for example
dimethylamino or diethylamino) or aminoC.sub.1-4alkyl (for example
aminomethyl or aminoethyl);
[0012] the 1,4-phenylene ring of a compound of formula (I) is
either unsubstituted or is substituted by one or two substituents
selected from halo, trifluoromethyl, trifluoromethoxy, cyano,
nitro, C.sub.1-4alkyl, C.sub.2-4alkenyl and C.sub.2-4alkynyl, from
the substituent --(CH.sub.2).sub.nY.sup.1 wherein n is 0-4 and
Y.sup.1 is selected from hydroxy, amino, carboxy, C.sub.1-4alkoxy,
C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, pyrrolidin-1-yl, piperidino, morpholino,
thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino,
piperazin-1-yl, 4-C.sub.4alkylpiperazin-1-yl, C.sub.1-4alkylthio,
C.sub.1-4alkylsulphinyl- , C.sub.1-4alkylsulphonyl,
C.sub.2-4alkanoylamino, benzamido, C.sub.1-4alkylsulphonamido and
phenylsulphonamido, from the substituent --(CH.sub.2)Y.sup.2
wherein n is 0-4 and Y.sup.2 is selected from carboxy, carbamoyl,
C.sub.1-4alkoxycarbonyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di-C.sub.4alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl,
1-oxothiomorpholinocarbonyl, 1,1-dioxothiomorpholinocarbonyl,
piperazin-1-ylcarbonyl, 4-C.sub.1-4alkylpiperazin-1-ylcarbonyl,
C.sub.1-4alkylsulphonamidocarbonyl, phenylsulphonamidocarbonyl and
benzylsulphonamidocarbonyl, from a substituent of the formula
--X.sup.3-L.sup.2-Y.sup.2 wherein X.sup.3 is a group of the formula
CON(R.sup.5), CON(L.sup.2-Y.sup.2), C(R.sup.5).sub.2O, O,N(R.sup.5)
or N(L.sup.2-Y.sup.2), L.sup.2 is C.sub.1-4alkylene, Y.sup.2 has
any of the meanings defined immediately hereinbefore and each
R.sup.5 is independently hydrogen or C.sub.1-4alkyl, and from a
substituent of the formula --X.sup.3-L.sup.3-Y.sup.1 wherein
X.sup.3 is a group of the formula CON(R.sup.5),
CON(L.sup.3-Y.sup.1), C(R.sup.5).sub.2O, O,N(R) or
N(L.sup.3-Y.sup.1), L.sup.3 is C.sub.2-4alkylene, Y.sup.1 has any
of the meanings defined immediately hereinbefore and each R.sup.5
is independently hydrogen or C.sub.1-4alkyl, and wherein any
heterocyclic group in a substituent of the 1,4-phenylene ring of
compounds of formula (I) optionally bears 1 or 2 substituents
selected from carboxy, carbamoyl, C.sub.1-4alkyl,
C.sub.1-4alkoxycarbonyl, N--C.sub.1-4alkylcarbamoyl and
N,N-di-C.sub.1-4alkylcarbamoyl, and wherein any phenyl group in a
substituent of the 1,4-phenylene ring of compounds of formula I
optionally bears 1 or 2 substituents selected from halo,
trifluoromethyl, cyano, C.sub.1-4alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, C.sub.1-4alkoxy, C.sub.2-4alkenyloxy and
C.sub.2-4alkynyloxy;
[0013] B is CH or N;
[0014] the heterocyclic ring containing B is either unsubstituted
or is substituted by one or two substituents selected from hydroxy,
oxo, carboxy and C.sub.1-4alkoxycarbonyl; or one of the
following:
[0015] --(CH.sub.2).sub.n--R, --(CH.sub.2).sub.n--NRR.sup.1,
--CO--R, --CO--NRR.sup.1, --(CH.sub.2).sub.n--CO--R and
--(CH.sub.2).sub.n--CO--NR- R.sup.1;
[0016] wherein n is 0, 1 or 2, preferably n is 1 or 2;
[0017] R and R.sup.1 are independently selected from hydrogen,
C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
hydroxyC.sub.1-4alkyl, carboxyC.sub.1-4alkyl and
C.sub.1-4alkoxycarbonylC- .sub.1-4alkyl or where possible R and
R.sup.1 may together form a 5- or 6-membered optionally substituted
saturated or partially unsaturated (preferably unsaturated)
heterocyclic ring which may include in addition to the nitrogen to
which R and R.sup.1 are attached 1 or 2 additional heteroatoms
selected from nitrogen, oxygen and sulphur;
[0018] D is 2-indolyl, 2-benzimidazolyl, 2-benzo[b]furanyl,
2-pyrrolo[2,3-b]pyridyl, 2-furo[2,3-b]pyridyl or
6-7H-cyclopenta[b]pyridy- l and is unsubstituted or is substituted
by one, two or three substituents selected from halo,
trifluromethyl, trifluoromethoxy, cyano, hydroxy, oxo, amino,
nitro, trifluoromethylsulphonyl, carboxy, carbamoyl,
C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.1-4alkoxy, C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy,
C.sub.1-4alkylthio, C.sub.1-4alkylsulphinyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.1-4-alkoxycarbonyl,
N--C.sub.1-4ylcarbamoyl- , N,N-di-C.sub.1-4alkylcarbamoyl,
C.sub.2-4alkanoyl, C.sub.2-4alkanoylamino, hydroxyC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4al- kyl, carboxyC.sub.1-4alkyl,
C.sub.1-4alkoxycarbonylC.sub.1-4alkyl, carbamoylC.sub.1-4alkyl,
N--C.sub.1-4alkylcarbamoylC.sub.1-4alkyl,
N,N-di-C.sub.1-4alkylcarbamoylC.sub.1-4alkyl, phenyl, heteroaryl,
phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl,
benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and
heteroarylsulphonyl, and wherein said heteroaryl substituent or the
heteroaryl group in a heteroaryl-containing substituent is a 5- or
6-membered monocyclic heteroaryl ring containing up to 3
heteroatoms selected from nitrogen, oxygen and sulphur, and wherein
said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,
phenylsulphonyl, heteroaryloxy, heteroarylthio,
heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl
substituent optionally bears 1, 2 or 3 substituents selected from
halo, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy,
carbamoyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.1-4alkoxycarbonyl,
N--C.sub.1-4alkylcarbamo- yl, N,N-di-C.sub.1-4alkylcarbamoyl and
C.sub.2-4alkanoylamino;
[0019] and excluding the compound
1-(5-chlorobenzofuran-2-ylsulphonyl)-4-[-
4-(4pyridyl)benzoyl]piperazine;
[0020] and pharmaceutically acceptable salts thereof.
[0021] For the avoidance of doubt substituents D are drawn below:
3
[0022] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups but references to
individual alkyl groups such as "propyl" are specific for the
straight chain version only. An analogous convention applies to
other generic terms.
[0023] It is to be understood that certain heterocyclic derivatives
of the present invention can exist in solvated as well as
unsolvated forms such as, for example, hydrated forms. It is to be
understood that the invention encompasses all such solvated forms
which possess Factor Xa inhibitory activity.
[0024] It is further to be understood that, insofar as certain of
the compounds of the formula defined above may exist in optically
active or racemic forms by virtue of one or more asymmetric carbon
atoms, the invention encompasses any such optically active or
racemic form which possesses Factor Xa inhibitory activity. The
synthesis of optically active forms may be carried out by standard
techniques of organic chemistry well known in the art, for example
by synthesis from optically active starting materials or by
resolution of a racemic form.
[0025] For the avoidance "oxo" as used herein defines the
substituent ".dbd.O". For the avoidance of doubt susbstituents on A
may also be present, where possible, on the heteroatom of the ring,
such as, for example, N-oxides.
[0026] Preferably A is an optionally substituted 5- or 6-membered
monocyclic aromatic ring containing 1, 2 or 3 ring nitrogen atoms.
Preferably A is a pyridyl, pyrimidinyl, imidazolyl or pyridazinyl
ring for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl,
4-pyridazinyl, 4-pyrimidinyl, 5-pyrimidinyl, 1-imidazolyl,
2-imidazolyl or 4-imidazolyl. Of these 4-pyrimidinyl,
4-pyridazinyl, 1-imidazolyl, 4-imidazolyl and 4-pyridyl are
preferred.
[0027] Preferred substituents of A are C.sub.1-4alkyl, oxo, amino
and halo. Preferably substituents are C.sub.1-4alkyl, amino and
halo. Preferably A is unsubstituted.
[0028] Preferably the 1,4-phenylene ring of a compound of formula I
is substituted by carboxy, C.sub.1-4alkoxy or
C.sub.1-4alkoxycarbonyl. Preferably the 1,4-phenylene ring of a
compound of formula I is unsubstituted.
[0029] In a particular aspect the heterocyclic ring formed by R and
R.sup.1 on a substituent on the heterocyclic ring containing B is
preferably selected from 1-pyrrolidinyl, 1-imidazolinyl,
1-piperidino, 1-piperazinyl, 4-morpholino and 4-thiomorpholino. In
a particular aspect the heterocyclic ring formed by R and R.sup.1
may be unsubstituted. In an alternative aspect the ring formed by R
and R.sup.1 is substituted by 1 or 2 substituents selected from
oxo, hydroxy and carboxy. Preferably the heterocyclic ring
containing B is substituted by oxo, carboxy, C.sub.1-4alkoxy or
C.sub.1-4alkoxycarbonyl. Preferably the heterocyclic ring
containing B is unsubstituted.
[0030] Preferably D is substituted by halo. Preferably the halo
substituent is bromo or chloro and preferably at a position
equivalent to the 5-position as numbered on the indole ring.
[0031] Suitable values for optional substituents for the
1,4-phenylene ring and D of compounds of formula I are:
[0032] for C.sub.1-4alkyl: methyl, ethyl and propyl;
[0033] for C.sub.4alkoxycarbonyl: methoxycarbonyl,
ethoxycarbonyl,
[0034] propoxycarbonyl and tert-butoxycarbonyl;
[0035] for N--C.sub.1-4alkylcarbamoyl: N-methylcarbamoyl,
N-ethylcarbamoyl
[0036] and N-propylcarbamoyl;
[0037] for N,N-di-C.sub.1-4alkylcarbamoyl:
N,N-dimethylcarbamoyl,
[0038] N-ethyl-N-methylcarbamoyl and
[0039] N,N-diethylcarbamoyl;
[0040] for hydroxyC.sub.1-4alkyl: hydroxymethyl,
1-hydroxyethyl,
[0041] 2-hydroxyethyl and 3-hydroxypropyl;
[0042] for C.sub.1-4alkoxyC.sub.1-4alkyl: methoxymethyl,
ethoxymethyl,
[0043] 1-methoxymethyl, 2-methoxyethyl,
[0044] 2-ethoxyethyl and 3-methoxypropyl;
[0045] for carboxyC.sub.1-4alkyl: carboxymethyl,
1-carboxyethyl,
[0046] 2-carboxyethyl and 3-carboxypropyl;
[0047] for C.sub.1-4alkoxycarbonylC.sub.1-4alkyl:
methoxycarbonylmethyl,
[0048] ethoxycarbonylmethyl, tert-butoxy-carbonylmethyl,
[0049] 1-methoxycarbonylethyl,
[0050] 1-ethoxycarbonylethyl,
[0051] 2-methoxycarbonylethyl,
[0052] 2-ethoxycarbonylethyl,
[0053] 3-methoxycarbonylpropyl and
[0054] 3-ethoxycarbonylpropyl;
[0055] for carbamoylC.sub.1-4alkyl: carbamoylmethyl,
1-carbamoyethyl,
[0056] 2-carbamoylethyl and 3-carbamoylpropyl;
[0057] for N--C.sub.1-4alkylcarbamoylC.sub.1-4alkyl:
N-methylcarbamoylmethyl,
[0058] N-ethylcarbamoylmethyl,
[0059] N-propylcarbamoylmethyl,
[0060] 1-(N-methylcarbamoyl)ethyl,
[0061] 1-(N-ethylcarbamoyl)ethyl,
[0062] 2-(N-methylcarbamoyl)ethyl,
[0063] 2-(N-ethylcarbamoyl)ethyl and
[0064] 3 -(N-methylcarbamoyl)propyl;
[0065] for N,N-di-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkyl:
N,N-dimethylcarbamoylmethyl,
[0066] N-ethyl-N-methylcarbamoylmethyl,
[0067] N,N-diethylcarbamoylmethyl,
[0068] 1-(N,N-dimethylcarbamoyl)ethyl,
[0069] 1-(N,N-diethylcarbamoyl)ethyl,
[0070] 2-(N,N-dimethylcarbamoyl)ethyl,
[0071] 2-(N,N-diethylcarbamoyl)ethyl and
[0072] 3-(N,N-dimethylcarbamoyl)propyl;
[0073] for halo: fluoro, chloro, bromo;
[0074] for C.sub.1-4alkoxy: methoxy, ethoxy;
[0075] for C.sub.1-4alkylamino: methylamino, ethylamino;
[0076] for di-C.sub.1-4alkylamino: dimethylamino, diethylamino;
[0077] for C.sub.1-4alkenyl: vinyl and allyl;
[0078] for C.sub.2-4alkynyl: ethynyl and prop-2-ynyl;
[0079] for C.sub.2-4alkenyloxy: vinyloxy and allyloxy;
[0080] for C.sub.2-4alkynyloxy: ethynyloxy and prop-2-ynyloxy;
[0081] for C.sub.1-4alkylthio: methylthio, ethylthio and
propylthio;
[0082] for C.sub.1-4alkylsulphinyl: methylsulphinyl, ethylsulphinyl
and
[0083] propylsulphinyl;
[0084] for C.sub.1-4alkylsulphonyl: methylsulphonyl, ethylsulphonyl
and
[0085] propylsulphonyl;
[0086] for C.sub.2-4alkanoyl; formyl, acetyl, proprionyl or
butyryl;
[0087] for C.sub.2-4alkanoylamino: acetamido, propionamido and
butyramido;
[0088] A preferred class of compounds of the present invention is
that wherein:
[0089] A is pyridyl, pyrimidinyl, imidazolyl or pyridazinyl;
[0090] B is N;
[0091] D is 2-indolyl, or 2-benzo[b]furanyl optionally substituted
by fluoro, chloro or bromo;
[0092] and pharmaceutically-acceptable salts thereof.
[0093] Particular compounds of the invention include the Examples
described below.
[0094] A heterocyclic derivative of formula I, or
pharmaceutically-accepta- ble salt thereof, may be prepared by any
process known to be applicable to the preparation of related
compounds. Such procedures are provided as a further feature of the
invention and are illustrated by the following representative
processes in which, unless otherwise stated A, B, and D have any of
the meanings defined hereinbefore wherein any functional group, for
example amino, alkylamino, carboxy hydroxy, is optionally protected
by a protecting group which may be removed when necessary.
[0095] Necessary starting materials may be obtained by standard
procedures of organic chemistry and by reference to the processes
used in the Examples.
[0096] According to another aspect, the present invention provides
a process for preparing a compound of formula (I) or a
pharmaceutically acceptable salt thereof, which comprises:
[0097] (a) For the production of those compounds of the formula (I)
wherein B is N, the reaction, conveniently in the presence of a
suitable base, of an amine of formula (II) 4
[0098] with an acid of the formula (III) 5
[0099] or a reactive derivative thereof.
[0100] A suitable reactive derivative of an acid of the formula
(III) is, for example, an acyl halide, for example an acyl chloride
formed by the reaction of the acid and an inorganic acid chloride,
for example thionyl chloride; a mixed anhydride, for example an
anhydride formed by the reaction of the acid with a chloroformate
such as isobutyl chloroformate or with an activated amide such as
1,1'-carbonyldiimidazole; an active ester, for example an ester
formed by the reaction of the acid and a phenol such as
pentafluorophenol, an ester such as pentafluorophenyl
trifluoroacetate or an alcohol such as N-hydroxybenzotriazole or
N-hydroxysuccinimide; an acyl azide, for example an azide formed by
the reaction of the acid and an azide such as diphenylphosphoryl
azide; an acyl cyanide, for example a cyanide formed by the
reaction of an acid and a cyanide such as diethylphosphoryl
cyanide; or the product of the reaction of the acid and a
carbodiimide such as N,N'-dicyclohexylcarbodii- mide or
N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide.
[0101] The reaction is conveniently carried out in the presence of
a suitable base such as, for example, an alkali or alkaline earth
metal carbonate, also preferably carried out in a suitable inert
solvent or diluent, for example methylene chloride, and at a
temperature in the range, for example, -78' to 150.degree. C.,
conveniently at or near ambient temperature.
[0102] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a tert-butoxycarbonyl group may be removed,
for example, by treatment with a suitable acid such as
hydrochloric, sulphuric, phosphoric acid or trifluoroacetic acid
and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-carbon, or by treatment with a Lewis acid for
example boron tris(trifluoroacetate). A suitable alternative
protecting group for a primary amino group is, for example, a
phthaloyl group which may be removed by treatment with an
alkylamine, for example dimethylaminopropylamine, or with
hydrazine.
[0103] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. An arylmethyl group such
as a benzyl group may be removed, for example, by hydrogenation
over a catalyst such as palladium-on-carbon.
[0104] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a tert-butyl group which
may be removed, for example, by treatment with an acid, for example
an organic acid such as trifluoroacetic acid, or for example a
benzyl group which may be removed, for example, by hydrogenation
over a catalyst such as palladium-on-carbon.
[0105] (b) The reaction of a compound of the formula (IV): 6
[0106] wherein Z is a displaceable group such as halo, with an
activated derivative of ring A. Suitable activated derivatives
include metalised derivatives, such as with zinc or tin, and borane
derivatives. The activated derivative of ring A is reacted with a
compound of the formula (IV) to effect cross coupling where Z is
triflate or a halo group, such as iodo, bromo or chloro. Suitably
the reaction is catalysed by use of a transition state metal
catalyst, such as palladium, for example tetrakis
(triphenylphosphine) palladium (0).
[0107] Alternatively it is possible that ring A contains the
displaceable group Z and the phenyl ring is activated, and the
reaction performed as described above.
[0108] Compounds of the formula (IV) not suitable for this method
are those which contain a halo substituent on any of the rings.
[0109] (c) By forming A ring on compounds of formula (IV), wherein
Z is a functional group capable of cyclisation. Suitable reagents
and conditions are described in Bredereck H. Chem. Ber.; 96 1505,
(1963); Fuchigami, T., Bull. Chem. Soc. Jpn., 49, p3607, (1976);
Huffman, K. R., J. Org. Chem., 2, p1812, (1963); Palusso, G., Gazz.
Chim. Ital., 90 p1290, (1960) and Ainsworth C., J. Het. Chem., 3.
p470, (1966). Such reactions are particularly suited to the
formation of 5-membered A rings. Processes suitable for synthesis
of starting materials in such cyclisation reactions are described,
for example, in Zhang M. Q. et.al; J. Heterocyclic. Chem.; 2, 673,
(1991) and Kosugi, M. et al., Bull. Chem. Soc. Jpn., 60 767-768
(1987).
[0110] (d) The reaction of a compound of the formula (V): 7
[0111] with a compound of the formula (VI):
z-SO.sub.2-D (VI)
[0112] wherein Z is a displaceable group for example chloro, under
conditions similar to those of process (a) above.
[0113] When a pharmaceutically-acceptable salt of a compound of the
formula (I) is required, it may be obtained, for example, by
reaction of said compound with a suitable acid or base using a
conventional procedure.
[0114] When an optically active form of a compound of the formula
(I) is required, it may be obtained, for example, by carrying out
one of the aforesaid procedures using an optically active starting
material or by resolution of a racemic form of said compound using
a conventional procedure, for example by the formation of
diastereomeric salts, use of chromatographic techniques, conversion
using chirally specific enzymatic processes, or by additon of
temporary extra chiral group to aid separation.
[0115] As stated previously, the compounds of the formula (I) are
inhibitors of the enzyme Factor Xa. The effects of this inhibition
may be demonstrated using one or more of the standard procedures
set out hereinafter:--
[0116] a) Measurement of Factor Xa Inhibition
[0117] An in vitro assay system based on the method of Kettner et
al., J. Biol. Chem., 1990, 265 18289-18297, whereby various
concentrations of a test compound are dissolved in a pH7.5 buffer
containing 0.5% of a polyethylene glycol (PEG 6000) and incubated
at 37.degree. C. with human Factor Xa (0.001 Units/ml, 0.3 ml) for
15 minutes. The chromogenic substrate S-2765 (KabiVitrum AB, 20
.mu.M) is added and the mixture is incubated at 37.degree. C. for
20 minutes whilst the absorbance at 405 nm is measured. The maximum
reaction velocity (Vmax) is determined and compared with that of a
control sample containing no test compound. Inhibitor potency is
expressed as an IC.sub.50 value.
[0118] b) Measurement of Thrombin Inhibition
[0119] The procedure of method a) is repeated except that human
thrombin (0.005 Units/ml) and the chromogenic substrate S-2238
(KabiVitrum AB, 7 .mu.M) are employed.
[0120] c) Measurement of Anticoagulant Activity
[0121] An in vitro assay whereby human, rat or rabbit venous blood
is collected and added directly to a sodium citrate solution (3.2
g/100 ml, 9 parts blood to 1 part citrate solution). Blood plasma
is prepared by centrifugation (1000 g, 15 minutes) and stored at
2-4.degree. C. Conventional prothrombin time (PT) tests are carried
out in the presence of various concentrations of a test compound
and the concentration of test compound required to double the
clotting time, hereinafter referred to as CT2, is determined. In
the PT test, the test compound and blood plasma are incubated at
37.degree. C. for 10 minutes. Tissue thromboplastin with calcium
(Sigma Limited, Poole, England) is added and fibrin formation and
the time required for a clot to form are determined.
[0122] d) Rat Disseminated Intravascular Coagulation In Vivo
Activity Test:
[0123] Fasted male Alderley Park rats (300-450 g) are pre-dosed by
oral gavage (5 mls/kg) with compound or vehicle (5% DMSO/PEG200) at
various times before being anaesthetised with Intraval.RTM. (120
mg/kg i.p.). The left jugular vein and the right carotid artery are
exposed and cannulated. A 1 mL blood sample is taken from the
carotid canular into 3.2% trisodium citrate. 0.5 mL of the whole
blood is then treated with EDTA and used for platelet count
determination whilst the remainder is centrifuged (5 mins, 20000 g)
and the resultant plasma frozen for subsequent drug level,
fibrinogen or thrombin antithrombin (TAT) complex determinations.
Recombinant human tissue factor (Dade Innovin Cat.B4212-50),
reconstituted to the manufacturers specification, is infused (2
mL/kg/hr) into the venous canular for 60 minutes. Immediately after
the infusion is stopped a 2 mL blood sample is taken and platelet
count, drug level, plasma fibrinogen concentration and TAT complex
are determined as before. Platelet counting is performed using at
Coulter T540 blood analyser. Plasma fibrinogen and TAT levels are
determining using a clotting assay (Sigma Cat. 880-B) and TAT ELISA
(Behring) respectively. The plasma concentration of the compound is
bioassayed using human Factor Xa and a chromogenic substrate S2765
(Kabi), extrapolated from a standard curve (Fragmin) and expressed
in Anti-Factor Xa units. The data is analysed as follows; tissue
factor-induced reductions in platelet count are normalised with
respect to pre-dose platelet count and drug activity expressed as a
percent inhibition of tissue factor-induced thrombocytopenia when
compared to vehicle treated animals. Compounds are active if there
is statistically significant (p<0.05) inhibition of TF-induced
thrombocytopenia.
[0124] e) An Ex Vivo Assay of Anticoagulant Activity
[0125] The test compound is administered intravenously or orally to
a group of Alderley Park Wistar rats. At various times thereafter
animals are anaesthetised, blood is collected and PT coagulation
assays analogous to those described hereinbefore are conducted.
[0126] f) An In Vivo Measurement of Antithrombotic Activity
[0127] Thrombus formation is induced using an analogous method to
that described by Vogel et al., Thromb. Research, 1989, 54, 399410.
A group of Alderley Park Wistar rats is anaesthetised and surgery
is performed to expose the vena cava. Collateral veins are ligated
and two loose sutures are located, 0.7 cm apart, round the inferior
vena cava. Test compound is administered intravenously or orally.
At an appropriate time thereafter tissue thromboplastin (30
.mu.l/kg) is administered via the jugular vein and, after 10
seconds, the two sutures are tightened to induce stasis within the
ligated portion of vena cava. After 10 minutes the ligated tissue
is excised and the thrombus therein is isolated, blotted and
weighed.
[0128] Example 1 showed an IC.sub.50 in test a) of 0.005 .mu.M and
in test b) a CT2 (PT) against human thrombin of 15 .mu.M.
[0129] A feature of the invention is a compound of formula (I), or
a pharmaceutically acceptable salt thereof, for use in medical
therapy.
[0130] According to a further feature of the invention there is
provided a pharmaceutical composition which comprises a
heterocyclic derivative of formula (I), or a
pharmaceutically-acceptable salt thereof, in association with a
pharmaceutically-acceptable diluent or carrier.
[0131] The composition may be in a form suitable for oral use, for
example a tablet, capsule, aqueous or oily solution, suspension or
emulsion; for topical use, for example a cream, ointment, gel or
aqueous or oily solution or suspension; for nasal use, for example
a snuff, nasal spray or nasal drops; for vaginal or rectal use, for
example a suppository; for administration by inhalation, for
example as a finely divided powder such as a dry powder, a
microcrystalline form or a liquid aerosol; for sub-lingual or
buccal use, for example a tablet or capsule; or for parenteral use
(including intravenous, subcutaneous, intramuscular, intravascular
or infusion), for example a sterile aqueous or oily-solution or
suspension. In general the above compositions may be prepared in a
conventional manner using conventional excipients.
[0132] The amount of active ingredient (that is a heterocyclic
derivative of the formula (I),
[0133] or a pharmaceutically-acceptable salt thereof) that is
combined with one or more excipients to produce a single dosage
form will necessarily vary depending upon the host treated and the
particular route of administration. For example, a formulation
intended for oral administration to humans will generally contain,
for example, from 0.5 mg to 2 g of active agent compounded with an
appropriate and convenient amount of excipients which may vary from
about 5 to about 98 percent by weight of the total composition.
Dosage unit forms will generally contain about 1 mg to about 500 mg
of an active ingredient.
[0134] According to a further feature of the invention there is
provided a heterocyclic derivative of formula (I), or a
pharmaceutically-acceptable salt thereof, for use in a method of
treatment of the human or animal body by therapy.
[0135] The invention also includes the use of such an active
ingredient in the production of a medicament for use in:--
[0136] (i) producing a Factor Xa inhibitory effect;
[0137] (ii) producing an anticoagulant effect;
[0138] (iii) producing an antithrombotic effect;
[0139] (iv) treating a Factor Xa mediated disease or medical
condition;
[0140] (v) treating a thrombosis mediated disease or medical
condition;
[0141] (vi) treating coagulation disorders; and/or
[0142] (vii) treating thrombosis or embolism involving Factor Xa
mediated coagulation.
[0143] The invention also includes a method of producing an effect
as defined hereinbefore or treating a disease or disorder as
defined hereinbefore which comprises administering to a
warm-blooded animal requiring such treatment an effective amount of
an active ingredient as defined hereinbefore.
[0144] The size of the dose for therapeutic or prophylactic
purposes of a compound of the formula (I) will naturally vary
according to the nature and severity of the medical condition, the
age and sex of the animal or patient being treated and the route of
administration, according to well known principles of medicine. As
mentioned above, compounds of the formula (I) are useful in the
treatment or prevention of a variety of medical disorders where
anticoagulant therapy is indicated. In using a compound of the
formula (I) for such a purpose, it will generally be administered
so that a daily oral dose in the range, for example, 0.5 to 100
mg/kg body weight/day is received, given if required in divided
doses. In general lower doses will be administered when a
parenteral route is employed, for example a dose for intravenous
administration in the range, for example, 0.01 to 10 mg/kg body
weight/day will generally be used. For preferred and especially
preferred compounds of the invention, in general, lower doses will
be employed, for example a daily dose in the range, for example,
0.1 to 10 mg/kg body weight/day. In general a preferred dose range
for either oral or parenteral administration would be 0.01 to 10
mg/kg body weight/day.
[0145] Although the compounds of formula (I) are primarily of value
as therapeutic or prophylactic agents for use in warm-blooded
animals including man, they are also useful whenever it is required
to produce an anticoagulant effect, for example during the ex-vivo
storage of whole blood or in the development of biological tests
for compounds having anticoagulant properties.
[0146] The compounds of the invention may be administered as a sole
therapy or they may be administered in conjunction with other
pharmacologically active agents such as a thrombolytic agent, for
example tissue plasminogen activator or derivatives thereof or
streptokinase. The compounds of the invention may also be
administered with, for example, a known platelet aggregation
inhibitor (for example aspirin, a thromboxane antagonist or a
thromboxane synthase inhibitor), a known hypolipidaemic agent or a
known anti-hypertensive agent.
[0147] The invention will now be illustrated in the following
Examples in which, unless otherwise stated:--
[0148] (i) yields are given for illustration only and are not
necessarily the maximum attainable;
[0149] (ii) the end-products have satisfactory microanalyses and
their structures were confirmed by nuclear magnetic resonance (NMR)
and mass spectral techniques (MS). Chemical shift values were
measured on the delta scale; the following abbreviations have been
used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet;
[0150] (iii) intermediates were not generally fully characterised
and purity was assessed by thin layer chromatographic, infra-red
(IR) or NMR analysis; and
[0151] (iv) melting points were determined using a Mettler SP62
automatic melting point apparatus or an oil-bath apparatus; melting
points for the end-products of the formula I were generally
determined after crystallisation from a conventional organic
solvent such as ethanol, methanol, acetone, ether or hexane, alone
or in admixture.
EXAMPLE 1
[0152]
1-(5-Chlorobenzo[b]furan-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]pip-
erazine
[0153] A stirred suspension of 4-(4-pyridyl)benzoic acid (133 mg,
0.67 mmol) in dimethylformamide (5 ml) was treated sequentially
with 1-hydroxybenzotriazole hydrate (HOBT, 108 mg, 0.8 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC,
153 mg, 0.8 mmol) and
1-(5-chlorobenzo[b]furan-2-ylsulphonyl)piperazine (201 mg, 0.67
mmol). After stirring overnight the solvent was removed in vacuo
and the residue chromatographed (Merck Art 9385 silica, eluting
with dichloromethane containing 2% v/v of methanol) to yield
1-(5-chlorobenzo[b]furan-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazin-
e as a colourless solid (40 mg), .sup.1H NMR (CDCl.sub.3) 3.2-3.4
ppm (broad s, 4H), 3.6-4.0 ppm (broad s, 4H), 7.35 ppm (s, 1H), 7.5
ppm (m, 6H), 7.7 ppm (m, 3H), 8.7 ppm (d, 2H), MS (M+H).sup.+
482/484.
[0154] The requisite
1-(5-chlorobenzo[b]furan-2-ylsulphonyl)piperazine starting material
was prepared as follows. A stirred solution of piperazine (1.15 g,
13.4 mmol) and triethylamine (4.7 ml, 46.5 mmol) in dichloromethane
(30 ml) was cooled to 5.degree. C., and a solution of
[0155] 5-chlorobenzo[b]furan-2-sulphonyl chloride (1.69 g, 7.8
mmol) in dichloromethane (10 ml) was added. Stirring was continued
for 15 mins, and the reaction mixture then allowed to warm to
ambient temperature over 2 hrs with stirring. Water was added to
the reaction mixture, and the organic layer separated; this was
washed with water (twice), brine (once), then dried (MgSO.sub.4),
filtered and evaporated to give a yellow gum. This was
chromatographed (Merck Art 9385 silica, eluting with
dichloromethane containing increasing amounts of methanol, up to
10% v/v) to give a yellow solid; trituration with diethyl ether
gave 5-chlorobenzo[b]furan-2-ylsulphonyl piperazine as a colourless
solid (1.11 g) which was used without further purification, .sup.1H
NMR (CDCl.sub.3) 2.8-3.0 ppm (t, 4H), 3.2-3.4 ppm (t, 4H), 7.3 ppm
(s, 1H), 7.45 ppm (dd, 2H), 7.7 ppm (s, 1H); MS (M+H).sup.+
301/303.
[0156] The requisite 5-chlorobenzo[b]furan-2-sulphonyl chloride
starting material was prepared as described in European Patent
Application 0 355 827 (Mochida, Hydantoin derivatives).
EXAMPLE 2
[0157]
1-(5-Chlorobenzo[b]furan-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]-
piperazine
[0158] To a suspension of 4-(1-imidazolyl)benzoic acid
hydrochloride (225 mg, 1 mmol.) in dimethylformamide (6 ml) was
added 1-(5-chlorobenzo[b]furan-2-ylsulphonyl)piperazine (315 mg,
1.05 mmol), 1-hydroxybenzotriazole hydrate (150 mg, 1 mmol),
triethylamine (0.2 ml, 1.5 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (EDAC,
210 mg, 1.1 mmol), and the resultant suspension stirred overnight.
The reaction mixture was poured into water, and the precipitated
solid filtered off and washed with water to give (after drying) 550
mg of colourless solid.
[0159] This was purified by flash chromatography using an ISOLUTE
20 g silica column, eluting with dichloromethane containing
methanol (2.5%), giving 330 mg of essentially pure product. This
was crystallised from 2-propanol to give (220 mg, 47% yield)
1-(5-chlorobenzo[b]furan-2-ylsulph-
onyl)-4-[4-(1-imidazolyl)benzoyl]piperazine as colourless prisms,
m.p. 175-177.degree. C., .sup.1H NMR (d.sub.6DMSO) 3.3 ppm (sharp
s, 4H), 3.4-3.8 ppm (broad s, 4H), 7.1 ppm (s, 1H), 7.55 ppm (d,
2H), 7.6 ppm (dd, 1H), 7.7 ppm (m, 3H), 7.8 ppm (m, 2H), 7.9 ppm
(d, 1H), 8.3 ppm (s, 1H); MS (M+H).sup.+ 470/472.
[0160] The requisite 4-(1-imidazolyl)benzoic acid starting material
may prepared as described in J. Med. Chem. 33 1091 (1990).
EXAMPLE 3
[0161]
1-(5-Chloroindol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
[0162] A stirred suspension of 4-(4-pyridyl)benzoic acid (252 mg,
1.27 mmol) in dimethylformamide (10 ml) was treated sequentially
with 1-(5-chloroindol-2-ylsulphonyl) piperazine (380 mg, 1.27
mmol), 1-hydroxybenzotriazole hydrate (HOBT, 271 mg, 1.77 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (EDAC,
291 mg, 1.52 mmol). After stirring overnight the solvent was
removed in vacuo and the residue taken up in dichloromethane (50
ml). This was washed sequentially with water, saturated sodium
bicarbonate solution, water and brine. Evaporation of the solvent
gave a residue which was chromatographed (MPLC on Merck Art 9385
silica, gradient eluting with dichloromethane containing 0-3.5% v/v
of methanol) to yield, after crystallisation from acetone,
1-(5-chloroindol-2-ylsulphonyl)-4-[4-(4-pyr-
idyl)benzoyl]piperazine as colourless crystals (244 mg), m.p.
185-188.degree. C., .sup.1H NMR (d.sub.6DMSO) 3.0-3.2 ppm (broad s,
4H), 3.4-3.8 ppm (broad s, 4H), 7.0 ppm (s, 1H), 7.3 ppm (dd, 1H),
7.5 ppm (m, 3H), 7.7 ppm (m, 2H), 7.8 ppm (m, 3H), 8.6 ppm (m, 2H),
12.4 ppm (broad s, 1H), the spectrum also contained a signal due to
acetone, ca 0.5 mol. eq.; Microanalysis, found: C, 59.9; H, 4.4; N,
10.6; S, 6.1%; C.sub.24H.sub.21N.sub.4O.sub.3ClS.
0.5C.sub.3H.sub.6O requires: C, 60.1; H, 4.7; N, 11.0; S. 6.3%; MS
(M+H).sup.+481/483.
[0163] The requisite 1-(5-chloroindol-2-ylsulphonyl)piperazine
starting material was prepared as follows
1-(1-Benzenesulphonyl-5-chloroindol-2-yl- sulphonyl)piperazine
(4.15 g, 9.44 mmol) was treated with sodium hydroxide solution (32
ml of 2.5M), giving a yellow suspension. This was warmed to
80.degree. C. with vigorous stirring and stirred for 45 mins,
giving complete solution. The solution was cooled to ambient
temperature and carefully treated with concentrated hydrochloric
acid to pH 8; the resultant precipitate was filtered off, washed
with water and dried to give
1-(5-chloroindol-2-ylsulphonyl)piperazine as a pale yellow
solid,
[0164] .sup.1H NMR (d.sub.6DMSO) 2.75 ppm (m, 4H), 2.9 ppm (m, 4H),
7.0 ppm (s, 1H), 7.3 ppm (dd, 1H), 7.5 ppm (d, 1H), 7.8 ppm (d,
1H); MS (M+H).sup.+ 300/302.
[0165] The requisite 1-(1-benzene
sulphonyl-5-chloroindol-2-ylsulphonyl)pi- perazine starting
material was prepared as follows. A solution of 1-benzene
sulphonyl-5-chloroindol-2-ylsulphonyl chloride (10.0 g, 25.6 mmol)
in dichloromethane (100 ml) was added dropwise to a stirred
solution of piperazine (13.23 g, 6eq.) in dichloromethane (200 ml),
and the mixture stirred for a further 2 hrs. The reaction mixture
was then washed with water (3.times.200 ml), dried
(Phase-Separating paper) and evaporated to give a red oil which was
purified by flash chromatography using Merck silica (Art 9385),
eluting with dichloromethane containing methanol (0-6%), to give
1-(1-benzene sulphonyl-5-chloroindol-2-ylsulphon- yl)piperazine as
a colourless solid, .sup.1H NMR (CDCl.sub.3) 2.95 ppm (m, 4H), 3.4
ppm (m, 4H), 7.4 ppm (m, 4H), 7.55 ppm (m, 2H), 8.0 ppm (d, 2H),
8.0 ppm (d, 1H); MS (M+H).sup.+ 440/442.
[0166] The requisite 1-benzene
sulphonyl-5-chloroindol-2-ylsulphonyl chloride starting material
may be prepared by a method analagous to that reported in J. Med.
Chem. 33 749 (1990), starting from 5-chloroindole.
EXAMPLE 4
[0167]
1-(5-Chloroindol-2-ylsulphonyl)-4-[4-(4-pyrimidyl)benzoyl]piperazin-
e
[0168] By an exactly analogous method, starting from
4-(4-pyrimidyl)benzoic acid, was prepared
1-(5-chloroindol-2-ylsulphonyl)-
-4-[4-(4-pyrimidyl)benzoyl]piperazine as colourless crystals (230
mg) from acetone, m.p. 229-230.degree. C., .sup.1H NMR
(d.sub.6DMSO) 3.0-3.2 ppm (broad s, 4H), 3.4-3.8 ppm (broad s, 4H),
7.0 ppm (s, 1H), 7.3 ppm (dd, 1H), 7.5 ppm (m, 3H), 7.8 ppm (s,
1H), 8.1 ppm (d, 1H), 8.2 ppm (d, 2H), 8.9 ppm (d, 1H), 9.3 ppm (s,
1H), 12.4 ppm (broad s, 1H), the spectrum also contained a signal
due to acetone, ca 0.2 mol. eq.; microanalysis, found: C, 56.7; H,
4.2; N, 14.2; S, 6.5%; C.sub.23H.sub.20N.sub.5O.sub.3C- lS. 0.2
C.sub.3H.sub.6O requires: C, 57.1; H, 4.2; N, 14.1; S, 6.5%; MS
(M+H).sup.+ 482/484.
EXAMPLE 5
[0169]
1-(5-Chloroindol-2-ylsulphonyl)-4-[4-(4-pyridazinyl)benzoyl]piperaz-
ine
[0170] By an exactly analogous method, starting from
4-(4-pyridazinyl)benzoic acid, was prepared
1-(5-chloroindol-2-ylsulphony-
l)-4-[4-(4-pyridazinyl)benzoyl]piperazine as colourless crystals
(370 mg) from acetone, m.p. 170-172.degree. C., .sup.1H NMR
(d.sub.6DMSO) 3.0-3.2 ppm (broad s,4H), 3.4-3.8 ppm (broad s,4H),
7.0 ppm (s,1H), 7.3 ppm (d,1H), 7.5 ppm (m,3H), 7.8 ppm (s,1H),
7.95 ppm (d, 2H), 8.0 ppm (dd,1H), 9.3 ppm (d,1H), 9.6 ppm (s,1H),
12.4 ppm (broad s,1H), the spectrum also contained a signal due to
acetone, ca 1.0 mol. eq.; MS (M+H).sup.+482/484.
EXAMPLE 6
[0171]
1-(5-Chloroindol-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazi-
ne
[0172] By an analogous method, starting from
4-(1-imidazolyl)benzoic acid hydrochloride and
1-(5-chloroindol-2-ylsulphonyl)piperazine, was prepared
1-(5-chloroindol-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazine
(375 mg, 60% yield) as colourless crystals from acetone; m.p.
155-165.degree. C., .sup.1H NMR (d.sub.6DMSO) 3.0-3.2 ppm (broad s,
4H), 3.4-3.8 ppm (broad s, 4H), 7.0 ppm (s,1H), 7.1 ppm (s,1H), 7.3
ppm (dd, 1H), 7.5 ppm (m, 3H), 7.7 ppm (d, 2H), 7.8 ppm (m, 2H),
8.3 ppm (s,1H),12.4 ppm (broad s,1H), the spectrum also contained a
signal due to acetone, ca 0.05 mol. eq.; MS (M+H).sup.+
470/472.
EXAMPLE 7
[0173]
1-(6-Chloroindol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
[0174] By an exactly analogous method, starting from
4-(4-pyridyl)benzoic acid and
1-(6-chloroindol-2-ylsulphonyl)piperazine, was prepared
1-(6-chloroindol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
as colourless crystals (145 mg) from acetone, m.p. 231-234.degree.
C., .sup.1H NMR (d.sub.6DMSO) 3.0-3.2 ppm (broad s, 4H), 3.4-3.8
ppm (broad s, 4H), 7.1 ppm (s, 1H), 7.2 ppm (dd, 1H), 7.5 ppm (m,
3H), 7.7 ppm (m, 3H), 7.8 ppm (d, 2H), 8.6 ppm (d, 2H), 12.4 ppm
(broad s, 1H), the spectrum also contained a signal due to acetone,
ca 0.25 mol. eq.; MS (M+H).sup.+ 481/483.
[0175] The requisite 1-(6-chloroindol-2-ylsulphonyl)piperazine
starting material was prepared as follows.
1-(1-Benzenesulphonyl-6-chloroindol-2-y- lsulphonyl)piperazine (500
mg, 1.18 mmol) was treated with sodium hydroxide solution (4 ml of
10M), and the suspension refluxed for 2 hrs. The reaction mixture
was cooled to ambient temperature and carefully treated with
concentrated hydrochloric acid to pH 8; the resultant precipitate
was filtered off, washed with water and dried to give
1-(6-chloroindol-2-ylsulphonyl)piperazine as a pale yellow solid
which was used without further purification; .sup.1H NMR
(d.sub.6DMSO) 3.1 ppm (m, 4H), 3.2 ppm (m, 4H), 7.1 ppm (s, 1H),
7.2 ppm (dd, 1H), 7.5 ppm (s, 1H), 7.7 ppm (d, 1H); the spectrum
also contained signals due to benzene sulphonic acid (ca 25 mol %);
MS (h+H).sup.+300/302.
[0176] The requisite 1-(1-benzene
sulphonyl-6-chloroindol-2-ylsulphonyl)pi- perazine starting
material was prepared as follows. A solution of 1-benzene
sulphonyl-6-chloroindol-2-ylsulphonyl chloride (5.0 g, 12.8 mmol)
in dichloromethane (50 ml) was added dropwise to a stirred solution
of piperazine (6.62 g, 6eq.) in dichloromethane (100 ml), and the
mixture stirred for a further 4 hrs. giving a yellow solution. This
was then evaporated and dried overnight under high vacuum. The
residue was purified by flash chromatography using Merck silica
(Art. 9385), eluting with dichloromethane containing methanol
(0-6%), to give 1-(1-benzene
sulphonyl-6-chloroindol-2-ylsulphonyl)piperazine as an off-white
solid (3.68 g, 68% yield); .sup.1H NMR (CDCl.sub.3) 2.75 ppm (m,
4H), 3.3 ppm (m, 4H), 7.45 ppm (d, 1H), 7.6 ppm (m, 3H), 7.7 ppm
(m, 1H), 7.75 ppm (d, 1H), 8.0 ppm (d, 2H), 8.15 ppm (s, 1H); MS
(M+H).sup.+440/442.
[0177] The requisite 1-benzene
sulphonyl-6-chloroindol-2-ylsulphonyl chloride starting material
may be prepared by a method analagous to that reported in J. Med.
Chem. 33 749 (1990), starting from 6-chloroindole.
EXAMPLE 8
[0178]
1-(5-Chlorobenzimidazol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]pipe-
razine
[0179] A solution of
1-(5-chlorobenzimidazol-2-ylsulphonyl)-4-(t-butyloxyc- arbonyl)
piperazine (860 mg, 2.15 mmol) in dichloromethane/methanol (15 ml
of 1:1) was treated with an excess of hydrogen chloride gas as a
saturated solution in ethyl acetate. After stirring for 4 hrs. the
solvent was removed in vacuo and the residue dried under high
vacuum. This was then suspended in DMF and treated sequentially
with 44-pyridyl)benzoic acid (428 mg, 2.15 mmol), triethylamine
(0.6 ml, 4.3 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (EDAC,
495 mg, 2.68 mmol). After stirring overnight the solvent was
removed in vacuo and the residue taken up in dichloromethane (50
ml). This was washed sequentially with water, saturated sodium
bicarbonate solution, water and brine. Evaporation of the solvent
gave a residue which was purified by chromatography (MPLC on Merck
Art 9385 silica, gradient eluting with ethyl acetate containing
0-8.0% methanol) to give
1-(5-chlorobenzimidazol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
as colourless crystals (370 mg) from ethanol, m.p. 242-244.degree.
C., .sup.1H NMR (d.sub.6DMSO) 3.0-3.4 ppm (broad s, 4H), 3.4-3.8
ppm (broad s, 4H), 7.4 ppm (d, 1H), 7.5 ppm (d, 2H), 7.6-7.8 ppm
(m, 4H), 7.85 ppm (d, 2H), 8.6 ppm (d, 2H), 14.0 ppm (broad s, 1H);
MS (M+H).sup.+ 482/484.
[0180] The requisite
1-(5-chlorobenzimidazol-2-ylsulphonyl)-4-(t-butyloxyc- arbonyl)
piperazine starting material was prepared as follows. A suspension
of 5-chloro-2-thiolbenzimidazole (500 mg, 2.71 mmol) in acetic acid
(2.5 ml) and water (10 ml) was cooled to 5.degree. C. and chlorine
gas bubbled in slowly, keeping the temperature below 7.degree. C.
The flow of chlorine was maintained until no more was absorbed, and
then for a further 15 mins., after which time the reaction was
purged with argon. The suspension was filtered off, washed quickly
with water and then added in small portions to a stirred, cooled
(5.degree. C.) solution of N-Boc piperazine (1.26 g, 6.78 mmol) in
dichloromethane (20 ml). After stirring for 1 hr. At ambient
temperature, the reaction mixture was diluted with more
dichloromethane (30 ml) and washed sequentially with citric acid
solution (30 ml, 1M), sat brine (30 ml), water (2.times.30 ml) and
sat. brine (30 ml). The solution was dried (Phase-Sep paper) and
evaporated to give 1-(5-chlorobenzimidazol-2-ylsulphonyl)
4-(t-butyloxycarbonyl)piperaz- ine as a brown foam (880 mg, 81%
yield), which was used without further purification; .sup.1H NMR
(CDCl.sub.3)1.4 ppm (s, 9H), 3.4 ppm (m, 4H), 3.6 ppm (m, 4H), 7.4
ppm (d, 1H), 7.4-7.6 ppm (broad s, 1H), 7.7-7.9 ppm (broad s, 1H);
MS (M+H).sup.+ 401/403 (w), (M+H-56).sup.+ 345/347 (s).
EXAMPLE 9
[0181]
1-(5-Bromoindol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
[0182] By a method analogous to that described in Example 3
starting from 4-(4-pyridyl)benzoic acid (199 mg, 1 mmol) and
1-(5-bromoindol-2-ylsulpho- nyl)piperazine (344 mg, 1 mmol, 1 mol
eq.), was prepared
1-(5-bromoindol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
methane sulphonic acid salt, (155 mg), .sup.1H NMR (d.sub.6-DMSO)
2.3 (s,3H), 3.0-3.3 (broad d,4H), 3.4-3.8 (broad d,4H), 7.0 (d,1H),
7.45 (s,2H), 7.6 (d,2H), 7.95 (s,1H), 8.0 (d,2H), 8.25 (d,2H), 8.9
(d,2H), 12.4 (s,1H), signals were also present due to ethanol (0.15
mol equiv.); MS (M+H).sup.+ 525/527.
EXAMPLE 10
[0183]
1-(5-Chloroindol-2-ylsulphonyl)-4-[4-(6-oxo-1H-pyridazin-3-yl)benzo-
yl]piperazine
[0184] By a method analogous to that described in Example 3
starting from 4-(6-oxo-1H-pyridazin-3-yl)benzoic acid (302 mg, 1.4
mmol) and 1-(5-chloroindol-2-ylsulphonyl)-piperazine (419 mg, 1.4
mmol, 1.0 mol eq.) was prepared
1-(5-chloroindol-2-ylsulphonyl)-4-[4-(6-oxo-1H-pyridazi-
n-3-yl)benzoyl]piperazine(234 mg) as an off white solid. .sup.1H
NMR (300 MHz, d.sub.6-DMSO) 3.1 (s, 4H, under H.sub.2O),3.6 (bs,
4H), 6.9 (d, 1H), 7.0 (s, 1H), 7.3 (dd, 1H), 7.4 (d, 2H), 7.5 (d,
1H), 7.8 (s, 1H), 7.9 (d, 2H), 8.0 (d, 1H), 12.2 (bs, 1H), 13.1
(bs, 1H), signals were also present due to dichloromethane (1 mol
equ.); MS (MH)-496/498. 4-(3-1H-pyrazin-6-onyl)-benzoic acid was
prepared by the method described by: Coates, W. J.; McKillop, A.,
Synthesis, 1993, 334-342.
EXAMPLE 11
[0185] Method A:
[0186] The reaction is performed in a manner analogous to that
described in Example 2, using the appropriate starting
materials.
[0187] Method B:
[0188] In a typical example excess methylamine gas (or other
appropriate amine) was added to a solution of
1-(5-chloroindol-2-ylsulphonyl)-4-[(6-m-
ethylsulfonylpyrimidin-4-yl)benzoyl]piperazine (or the
2-methylsulfonylpyrimidinyl isomer) in THF or similar appropriate
solvent. The solution was stirred at ambient or elevated
temperature until TLC analysis indicated that the starting material
had been consumed. The solution was concentrated in vacuo and the
residue purified by column chromatography on silica. Where
appropriate, he resultant free base was dissolved in 2:1
dichloromethane/methanol (20 mL) and treated with excess methanolic
hydrogen chloride. The mixture was concentrated in vacuo to give
the product as a near colourless foam, which could be crystallised,
typically from aqueous ethanol.
[0189] Method C:
[0190] To a solution of
1-(5-chloroindol-2-ylsulphonyl)-4-[(2-tert-butylox-
ypyrimidin-4-yl)benzoyl]piperazine (200 mg, 0.361 mmol) in
dichloromethane and methanol (10 ml of a 4:1 mixture) was added a
solution of hydrogen chloride in methanol (0.40 ml of .about.4.5 M,
1.8 mmol), and the reaction stirred at ambient temperature for 1
hr. The solvent was removed in vacuo and the residue crystallised
from ethanol to give
1-(5-chloroindol-2-ylsulphonyl)-4-[(2-hydroxypyrimidin-4-yl)benzoyl]piper-
azine as a colourless solid.
[0191] From the above methods the following examples were prepared:
8
1 MS: No A D Method m/z .sup.1H NMR (NMR, solvent) 1 4-pyridyl
5-fluoro-2-indolyl A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO)
3.0-3.2ppm(broad s, 4H), 465. 3.4-3.7ppm(broad s, 4H), 7.0ppm(s,
1H), 7.2ppm(t of d, 1H), 7.5ppm(m, 4H), 7.7ppm(d, 2H), 7.8ppm(d,
2H), 8.6ppm(d, 2H), 12.3ppm(broad s, 1H); the spectrum also
contained signals due to acetone (0.33 mol eq). 2 4-pyridyl
5-bromo-2- A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO) 2.3ppm(s, 3H),
3.3-3.5ppm(broad s, 4H), 3.5-3.8ppm(broad s, indolyl 525/527. 4H),
7.0ppm(s, 1H), 7.4ppm(s, 2H), 7.6ppm(d, 2H), 7.9ppm(s, 1H),
8.0ppm(d, 2H), 8.3ppm(d, 2H), 8.9ppm(d, 2H), 12.3ppm(broad s, 1H);
the spectrum also contained signals due to ethanol (0.15 mol eq). 3
2-pyridyl 5-chloro-2-indolyl A (M+H).sup.+ .sup.1H NMR
(d.sub.6DMSO) 3.0-3.2ppm(broad s, 4H), 481/483 3.4-3.8ppm(broad s,
4H), 7.0ppm(s, 1H), 7.3ppm(m, 2H), 7.5ppm(m, 3H), 7.8ppm(s, 1H),
7.9ppm(m, 1H), 8.0ppm(d, 1H), 8.1ppm(d, 2H), 8.7ppm(d, 1H),
12.4ppm(broad s, 1H); the spectrum also contained signals due to
ethanol (1 mol eq). 4 1-imidazolyl 5-bromo-2- A (M+H).sup.+ .sup.1H
NMR (d.sub.6DMSO) 2.9-3.2ppm(broad s, 4H), 3.2-3.8ppm(broad indolyl
514/516 s, 4H), 7.0ppm(s, 1H), 7.4ppm(dd, 2H), 7.6ppm(d, 2H),
7.8ppm(s, 1H and d, 2H), 7.9ppm(s, 1H), 8.3ppm(s, 1H), 9.6ppm(s,
1H), 12.4ppm(broad s, 1H); the spectrum also contained signals due
to ethanol (0.15 mol eq). 5 2-methyl-1- 5-chloro-2-indolyl A
(MH).sup.+ .sup.1H NMR (d.sub.6DMSO) 2.54ppm(s, 3H), 3.14ppm(s,
4H), 3.56ppm(s, imidazolyl 484/486 4H), 7.01ppm(s, 1H), 7.29ppm(d,
1H), 7.52ppm(d, 1H), 7.61ppm(m, (1 .times. Cl) 6H), 7.74ppm(s, 2H).
6 2-imidazolyl 5-chloro-2-indolyl A (MH).sup.+ .sup.1H
NMR(d.sub.6-DMSO)2.54-3.19ppm(broad s, 4H), 3.67ppm(broad 470/472
s, 4H), 7.01ppm(s, 1H), 7.31ppm(d .times. d, 1H), 7.50ppm(d, 1H),
7.60ppm(d, 2H), (.times.Cl) 7.78ppm(d, 2H), 7.80ppm(s, 1H),
8.14ppm(d, 2H), 12.41 (broad s, 1H). 7 4-imidazolyl
5-chloro-2-indolyl A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO)
3.05-3.15ppm(broad s, 4H), 3.5-3.7ppm(broad s, 470/472. 4H),
7.0ppm(s, 1H), 7.3ppm(dd, 2H), 7.5ppm(m, 3H), 7.8ppm(m, 3H),
8.15ppm(s, 1H), 9.0ppm(s, 1H), 12.4ppm(broad s, 1H). 8 4-imidazolyl
5-bromo-2- A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO) 2.3ppm(s, 3H),
3.2-3.8ppm(broad s, 8H), 7.0ppm(s, indolyl 514/516. 1H), 7.45ppm(d,
2H), 7.5ppm(d, 2H), 7.8ppm(d, 2H), 7.9ppm(s, 1H), 8.2ppm(s, 1H),
9.2ppm(s, 1H), 12.4ppm(broad s, 1H). 9 1-methyl-4- 5-chloro-2- A
(M+H).sup.+ .sup.1H NMR (d.sub.6DMSO) 3.0-3.2ppm(broad s, 4H),
3.3-3.8ppm(broad s, imidazolyl indolyl 484/486. 4H), 3.9ppm(s, 3H),
7.0ppm(s, 1H), 7.3ppm(dd, 1H), 7.5ppm(m, 3H), 7.8ppm(s, 1H),
7.9ppm(d, 2H), 8.2ppm(s, 1H), 9.15ppm(s, 1H), 12.4ppm(broad s, 1H);
the spectrum also contained signals due to acetone (0.5 mol eq). 10
2-methyl-4- 5-chloro-2- A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO)
2.6ppm(s, 3H), .about.3ppm(broad s, 4H), 3.4-3.8ppm(broad s,
imidazolyl benzofuranyl 485/487. 4H), 7.5ppm(d, 2H), 7.6ppm(dd,
1H), 7.65ppm(s, 1H), 7.8ppm(m, 3H), 7.9ppm(d, 1H), 8.1ppm(s, 1H).
11 2-methyl-4- 5-chloro-2- A (M+H).sup.+ .sup.1H NMR (d.sub.6DMSO)
2.3ppm(s, 3H), 3.0-3.1ppm(broad s, 4H), 3.5-3.7ppm(broad s,
imidazolyl indolyl 484/486. 4H), 7.0ppm(s, 1H), .about.7.3ppm(m,
3H), 7.5ppm(d, 2H), 7.7ppm(br d, 2H), 7.8ppm(d, 1H), 11.85ppm(broad
s, 1H), 12.4ppm(broad s, 1H). 12 2-methyl-4- 5-bromo-2- A
(M+H).sup.+ .sup.1H NMR (d.sub.6DMSO) 2.6ppm(s, 3H),
3.0-3.2ppm(broad s, 4H), 3.6-3.9ppm(broad s, imidazolyl indolyl
528/530. 4H), 7.0ppm(s, 1H), 7.4-7.5ppm(m, 4H), 7.85ppm(d, 2H),
7.95ppm(s, 1H), 8.1ppm(s, 1H), 12.4ppm(s, 1H), 14.3-15.0ppm(broad
s, 1H); the spectrum also contained signals due to ethanol (0.5 mol
eq). 13 2-amino-4- 5-chloro-2- A (MH).sup.- .sup.1H NMR
(d.sub.6-DMSO) 3.10ppm(s, 4H), 3.55ppm(broad s, 4H), 7.02ppm(s,
imidazolyl indolyl 485/487 1H), 7.32ppm(d .times. d, 1H),
7.42ppm(d, 2H), 7.48ppm(m, 2H), (1 .times. Cl) 7.65ppm(m, 4H),
7.80ppm(d, 1H), 12.21ppm(broad s, 1H), 12.43ppm(d, 1H),
12.92ppm(broad s, 1H). 14 6-hydroxy-3- 5-chloro-2- A (MH).sup.-
.sup.1H NMR (d.sub.6-DMSO) 3.10ppm(s, 4H, under H.sub.20),
3.57ppm(broad s, pyridazinyl indolyl 496/498 4H), 6.95ppm(d, 1H),
7.02ppm(s, 1H), 7.31ppm(d .times. d, 1H), 7.43ppm(d, (1 .times. Cl)
2H), 7.49ppm(d, 1H), 7.75ppm(s, 1H), 7.85ppm(d, 2H), 7.98ppm(d,
1H), 12.23ppm(s, 1H), 13.08ppm(s, 1H). Signal also present
consistent with dichloromethane (1 mol). 15 6-hydroxy-3-
5-chloro-2- A (MH).sup.+ .sup.1H NMR (d.sub.6-DMSO) 3.21ppm(s, 4H,
under H.sub.20), 3.46ppm(broad s, pyridazinyl benzofuranyl 499/501
4H), 6.92ppm(d, 1H), 7.42ppm(d, 2H), 7.53ppm(d, 1H), 7.59ppm(d, (1
.times. Cl) 1H), 7.76ppm(s, 1H), 7.81ppm(m, 3H), 7.96ppm(d, 1H),
13.14ppm(s, 1H)ppm 16 6-hydroxy-3- 5-chloro-2- A (MH).sup.+ .sup.1H
NMR (d.sub.6-DMSO) 3.42ppm(s, 4H, under H.sub.20), 3.64ppm(s, 4H),
pyridazinyl benzimidazolyl 499/501 6.98ppm(d, 1H), 7.39ppm(d, 1H),
7.50ppm(d, 2H), 7.75ppm(m, 2H), (1 .times. Cl) 7.89ppm(d, 2H),
7.96ppm(d, 1H), 12.92ppm(s, 1H). 17 6- 5-chloro-2- A (MH).sup.+
.sup.1H NMR (d.sub.6-DMSO) 3.12ppm(s, 4H), 3.25ppm(s, 6H),
3.59ppm(broad s, dimethylamino- indolyl 525/527 4H, under water),
7.01ppm(s, 1H), 7.32ppm(d .times. d, 1H), 3-pyridazinyl (1 .times.
Cl) 7.50ppm(m, 3H), 7.70ppm(d, 1H), 7.78ppm(s, 1AH), 8.04ppm(d,
2H), 8.28ppm(d, 1H), 12.42ppm(s, 1H). 18 6-chloro-3- 5-chloro-2- A
(MH).sup.+ .sup.1H NMR (d.sub.6-DMSO) 1.43ppm(m, 2H), 1.60ppm(m,
2H), 2.89ppm(m, pyridazinyl indolyl 523/525 3H), 2.97ppm(s, 4H),
3.52ppm(s, 2H), 3.62ppm(s, 2H), 4.23ppm(d, (1 .times. Cl) 2H),
7.00ppm(s, 1H), 7.30ppm(m, 2H), 7.45ppm(t, 2H), 7.76ppm(d, 1H). 19
6-amino-3- 5-chloro-2- A (MH).sup.+ .sup.1H NMR (d.sub.6-DMSO)
3.13ppm(s, 4H), 3.59ppm(broad s, 4H under pyridazinyl indolyl
497/499 water), 7.03ppm(s, 1H), 7.33ppm(d, 1H), 7.40ppm(d, 1H),
7.49ppm(m, (1 .times. Cl) 3H), 7.79ppm(s, 1H), 7.96ppm(d, 2H),
8.19ppm(broad s, 2H), 8.27ppm(d, 1H) 12.41ppm(s, 1H). 20
6-methylamino- 5-chloro-2- A (MH).sup.+ .sup.1H NMR (d.sub.6-DMSO)
2.38ppm(s, 3H), 3.17ppm(m, 4H), 3.58ppm(m, 3-pyridazinyl indolyl
522/524 4H under water), 7.00ppm(s, 1H), 7.28ppm(d .times. d, 1H),
7.53ppm(t, (1 .times. Cl) 4H), 7.73ppm(s, 1H), 7.97ppm(d, 2H),
8.21ppm(d, 1H), 12.10ppm(broad s, 1H). 21 6- 5-chloro-2- B
525.2/527.1 .sup.1H NMR (d.sub.6DMSO) 2.95-3.25ppm(m, 5H),
3.32ppm(s, 6H), 3.32-3.85ppm(m, dimethylamino- indolyl (M+H).sup.+
4H under water), 7.00ppm(s, 1H), 7.25-7.35ppm(m, 2H), 4-pyrimidinyl
7.45-7.55ppm(d, 1H), 7.55-7.62ppm(d, 2H), 7.80 (s, 1H),
8.00-8.10ppm(d, 2H), 8.80ppm(s, 1H), 12.5ppm(s, 1H) spectrum
contains iso-propanol. 22 6-amino-4- 5-chloro-2- B (MH).sup.+
.sup.1H NMR (d.sub.6DMSO) 2.9-3.3ppm(broad s, 4H), 3.5-4.0ppm(broad
s, pyrimidinyl indolyl 497/499 4H), 7.0ppm(s, 1H and s, 1H),
7.3ppm(dd, 1H), 7.5ppm(d, 1H), 7.6ppm(d, (1 .times. Cl) 2H),
7.8ppm(s, 1H), 7.9ppm(d, 2H), 8.7ppm(s, 1H), 8.8ppm(br s, 2H),
12.4ppm(s, 1H). 23 6-methylamino- 5-chloro-2- B (MH).sup.+ .sup.1H
NMR (300 MHz, d.sub.6-DMSO) 2.32 (s, 3H), 3.05 (broad s, 4H),
3.30-3.85(m, 4-pyrimidinyl indolyl 511/513 4H), 6.94-7.05 (m,
1.7H), 7.14 (s, 0.3H), 7.32 (dd, 1H), 7.50(d, (1 .times. Cl) 1H),
7.62 (d, 2H), 7.75-7.91 (m, 2.3H), 7.95-8.07 (m, 0.7H), 8.70 (s,
0.3H), 8.86 (s, 0.7H), 9.37 (s, 1H), 12.38 (s, 1H)ppm. 24
2-hydroxy-5- 5-chloro-2- C (MH).sup.+ .sup.1H NMR (d.sub.6DMSO)
3.0-3.2ppm(broad s, 4H), 3.4-3.7ppm(broad s, pyrimidinyl indolyl
498/500 4H), 7.0ppm(d, 1H), 7.3ppm(dd, 1H), 7.4ppm(d, 2H),
7.5ppm(d, (1 .times. Cl) 1H), 7.65ppm(d, 2H), 7.8ppm(s, 1H),
8.6ppm(br s, 2H), 12.4ppm(s, 1H); the spectrum also contained
signals due to ethanol (0.5 mol eq).
* * * * *