U.S. patent application number 12/141179 was filed with the patent office on 2009-03-19 for phthalazine derivatives with angiogenesis inhibiting activity.
This patent application is currently assigned to Novartis AG. Invention is credited to Guido Bold, Paul William Manley.
Application Number | 20090076003 12/141179 |
Document ID | / |
Family ID | 9914117 |
Filed Date | 2009-03-19 |
United States Patent
Application |
20090076003 |
Kind Code |
A1 |
Bold; Guido ; et
al. |
March 19, 2009 |
Phthalazine Derivatives with Angiogenesis Inhibiting Activity
Abstract
The invention relates to new phthalazine derivatives, processes
for the preparation thereof, the application thereof in a process
for the treatment of the human or animal body, the use thereof
alone or in combination with one or more other pharmaceutically
active compounds for the treatment of a disease, especially of a
disease that responds to the inhibition of tyrosine kinases, more
especially the inhibition of the vascular endothelial growth factor
(VEGF) receptor kinase, preferably the treatment of a proliferative
disease, such as a tumour disease.
Inventors: |
Bold; Guido;
(Gipf-Oberfrick, CH) ; Manley; Paul William;
(Arlesheim, CH) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
400 TECHNOLOGY SQUARE
CAMBRIDGE
MA
02139
US
|
Assignee: |
Novartis AG
|
Family ID: |
9914117 |
Appl. No.: |
12/141179 |
Filed: |
June 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10475419 |
Mar 29, 2004 |
7399761 |
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PCT/EP2002/004892 |
May 3, 2002 |
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12141179 |
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Current U.S.
Class: |
514/234.5 ;
514/249; 544/116; 544/237 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 27/02 20180101; C07D 405/12 20130101; A61P 29/00 20180101;
C07D 401/06 20130101; C07D 409/12 20130101; A61P 43/00 20180101;
A61P 35/00 20180101; A61P 25/02 20180101 |
Class at
Publication: |
514/234.5 ;
544/237; 514/249; 544/116 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 237/30 20060101 C07D237/30; A61K 31/498 20060101
A61K031/498; A61P 29/00 20060101 A61P029/00; A61P 35/00 20060101
A61P035/00; C07D 413/14 20060101 C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2001 |
GB |
0111078.2 |
Claims
1. A compound of the formula I, ##STR00033## wherein r is 1 or 2, n
is 0-3, t is 0, 1 or 2, R1 and R2 a) are independently in each case
a lower alkyl; or b) together form a bridge of subformula 1**,
##STR00034## wherein one or two of the ring members T.sub.1,
T.sub.2, T.sub.3 and T.sub.4 are nitrogen, and the others are in
each case CH, and the bond is achieved via atoms T.sub.1 and
T.sub.4; G is --C(.dbd.O)--, --CHF--, --CFr, lower alkylene,
.about.6alkenylene, lower alkylene or C.sub.3-C.sub.6alkenylene
substituted by acyloxy or hydroxy, --CH.sub.2O--, --CH.sub.2S--,
--CH.sub.2--NH--, --CH.sub.2O--CH.sub.2, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--, oxa (--O--), thia (--S--), imino
(--NH--), --CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2NH--CH.sub.2--,
--(C(R.sub.4).sub.2).sub.t--S(O).sub.p-(5-membered
heteroaryl)-(C(R.sub.4).sub.2).sub.s--,
--(C(R.sub.4).sub.2).sub.t--C(G.sub.1)(R.sub.4)(C(R.sub.4).sub.2).sub.s---
, --O--CH.sub.2--, --S(O)--, --S(O.sub.2)--, --SCH.sub.2,
--S(O)CH.sub.2--, --CH.sub.2S(O)-- or --CH.sub.2S(O).sub.2, wherein
each of p, sand t, independently of the other, is 0, 1 or 2;
R.sub.4 is hydrogen, halogen or lower alkyl; and G.sub.1 is --CN,
--CO.sub.2R.sub.3, --CON(R.sub.6).sub.2 or
CH.sub.2N(R.sub.6).sub.2, wherein R.sub.3 is hydrogen or lower
alkyl and R.sub.6 is hydrogen, alkyl, aryl or aryl-lower alkyl; A,
B, D, E and T are independents N or CH subject to the proviso that
at least one and not more than three of these radicals are N; Q is
either lower alkoxy or O (oxo), with the proviso that if Q is lower
alkoxy, the waved line representing the bonding of Q is a single
bond and the ring carrying Q has three double bonds, and if Q is O,
the waved line representing the bonding of Q is a double bond and
for each Q=O, one of the double bonds in the ring is changed to a
single bond; and with the proviso that any Q is bonded to a ring C
atom; Q' is halogen, NHR.sup.Q, NR.sup.Q.sub.2, OR.sup.Q, SR.sup.Q,
alkyl, aryl-alkyl, cycloalkyl-alkyl, perfluoroalkyl, acyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
hetaryl, wherein R.sup.Q represents acyl, alkyl, or alkyl
substituted by hydroxy, halogen, substituted or unsubstituted aryl,
substituted or unsubstituted cycloalkyl or substituted or
unsubstituted heterocyclyl; R.sub.a and R.sub.a' are each
independently H, halogen or lower alkyl; X is imino, oxa, or thia;
Y is hydrogen, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or unsubstituted or substituted
cycloalkyl; and with the proviso that when two groups R.sub.6 are
each alkyl and located on the same nitrogen atom, they may be
linked by a bond, an O, an S or NR.sub.3 with R.sub.3 as defined
above to form a N-containing heterocycle of 5 to 7 ring atoms; or
an N-oxide of a compound of formula I, wherein 1 or more N atoms
carry an oxygen atom; or a tautomer or mixture of tautomers of a
compound of formula I or an N-oxide thereof; or a pharmaceutically
acceptable salt of a compound of formula I, of an N-oxide or of a
tautomer or mixture of tautomers thereof.
2. A compound of the formula I according to claim 1, wherein r is 1
or 2, n is 0 to 3, t is 0, R1 and R2 a) are independents in each
case a lower alkyl; or b) together form a bridge of subformula 1
**, wherein one or two of the ring members T.sub.1, T.sub.2,
T.sub.3 and T.sub.4 are nitrogen, and the others are in each case
CH, and the bond is achieved via atoms T.sub.1 and T.sub.4; G is
--C(.dbd.O)--, --CHF--, --CF.sub.2--, lower alkylene,
C.sub.2-C.sub.6alkenylene, lower alkylene or
C.sub.3-C.sub.6alkenylene substituted by acyloxy or hydroxy,
--CH.sub.2--O--, --CH.sub.2--S--, --CH.sub.2NH--,
--CH.sub.2--O--CH.sub.2--, --CH.sub.2S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--, oxa (--O--), thia (--S--), imino
(--NH--), --CH.sub.2O--CH.sub.2--, --CH.sub.2S--CH.sub.2--,
--CH.sub.2NH--CH.sub.2--,
--(C(R.sub.4).sub.2).sub.tS(O).sub.p-(5-membered
heteroaryl)-(C(R.sub.4).sub.2).sub.s--,
--(C(R.sub.4).sub.2).sub.t--C(G.sub.1)(R.sub.4)--(C(R.sub.4).sub.2).sub.s-
--, --O--CH.sub.2--, --S(O)--, --S(O.sub.2)--, --SCH.sub.2,
--S(O)CH.sub.2--, --CH.sub.2S(O)-- or --CH.sub.2S(O).sub.2--,
wherein each of p, s and t, independently of the other, is 0, 1 or
2; R.sub.4 is hydrogen, halogen or lower alkyl; and G.sub.1 is
--CN, --CO.sub.2R.sub.3, --CON(R.sub.6).sub.2 or
CH.sub.2N(R.sub.6).sub.2, wherein R.sub.3 is hydrogen or lower
alkyl and R.sub.6 is hydrogen, alkyl, aryl or aryl-lower alkyl; A,
B, D, E and T are independently N or CH subject to the proviso that
at least one and not more than three of these radicals are N; Q is
either lower alkoxy or O (oxo), with the proviso that if Q is lower
alkoxy, the waved line representing the bonding of Q is a single
bond and the ring carrying Q has three double bonds, and if Q is O,
the waved line representing the bonding of Q is a double bond and
for each Q=O, one of the double bonds in the ring is changed to a
single bond; and with the proviso that any Q is bonded to a ring C
atom; R.sub.a and R.sub.a' are each independently H, halogen or
lower alkyl; X is imino, oxa, or thia; Y is hydrogen, aryl,
heteroaryl, or unsubstituted or substituted cycloalkyl; and with
the proviso that when two groups R.sub.6 are each alkyl and located
on the same nitrogen atom, they may be linked by a bond, an O, an S
or NR.sub.3 with R.sub.3 as defined above b form a N-containing
heterocycle of 5 to 7 ring atoms; or an N-oxide of a compound of
formula I, wherein 1 or more N atoms carry an oxygen atom; or a
tautomer or mixture of tautomers of a compound of formula I or an
N-oxide thereof; or a pharmaceutically acceptable salt of a
compound of formula I, of an N-oxide or of a tautomer or mixture of
tautomers thereof.
3. A compound of formula I according to claim 1, wherein Q is O,
with the proviso that the waved line representing the bonding of Q
is a double bond and for each Q=O, one of the double bonds in the
ring is changed to a single bond; and with the proviso that any Q
is bonded to a ring C atom; and the other symbols have the meaning
described in claim 1; an N-oxide of said compound of formula I,
wherein 1 or more N atoms carry an oxygen atom; or a tautomer or
mixture of tautomers of said compound of formula I or an N-oxide
thereof; or a pharmaceutically acceptable salt of said compound of
formula I, of an N-oxide or of a tautomer or mixture of tautomers
thereof.
4. A compound of formula I according to claim 1 wherein r is 1 and
either T is NH, each of B, D and E is CH, A is C and Q is O bonded
at A via a double bond, with the proviso that the double bond
between A and T is absent; or A is NH, each of B, D and E is CH and
T is C and Q is O bonded at T via a double bond; and the remaining
radicals and symbols are as defined in each of claims 1 to 5; or a
tautomer or mixture of tautomers of said compound of formula I; or
a pharmaceutically acceptable salt of said compound of formula I,
or of a tautomer or mixture of tautomers thereof.
5. A compound of formula I according to claim 1 wherein r is 1 and
A is NH, each of B, D and E is CH and T is C and Q is O bonded at T
via a double bond; and the remaining radicals and symbols are as
defined in each of claims 1 to 5; or a tautomer or mixture of
tautomers of said compound of formula I; or a pharmaceutically
acceptable salt of said compound of formula I, or of a tautomer or
mixture of tautomers thereof.
6. A compound of the formula I, an N-oxide thereof, a tautomer or
mixture of tautomers of said compound of formula I or an N-oxide
thereof; or a pharmaceutically acceptable salt of said compound of
formula I, of an N-oxide or of a tautomer or mixture of tautomers
thereof according to claim 1 for use in the therapeutic or
diagnostic treatment of the animal or human body.
7. A pharmaceutical preparation comprising a compound of the
formula I, an N-oxide thereof, a tautomer or mixture of tautomers
of said compound of formula I or an N-oxide thereof; or a
pharmaceutically acceptable salt of said compound of formula I, of
an N-oxide or of a tautomer or mixture of tautomers thereof
according to claim 1 and a pharmaceutically acceptable carrier.
8. The use of a compound of the formula I, an N-oxide thereof, a
tautomer or mixture of tautomers of said compound of formula I or
an N-oxide thereof; or a pharmaceutically acceptable salt of said
compound of formula I, of an N-oxide or of a tautomer or mixture of
tautomers thereof according to claim 1, for the preparation of a
pharmaceutical preparation for the treatment of VEGF receptor
tyrosine kinase inhibiting activity, of cell proliferation, of
inflammatory rheumatic or rheumatoid diseases, or pain.
9. A method for treating a warm-blooded animal, including a human,
in which an antitumourally effective dose of a compound of formula
I, an N-oxide thereof, a tautomer or mixture of tautomers of said
compound of formula I or an N-oxide thereof; or a pharmaceutically
acceptable salt of said compound of formula I, of an N-oxide or of
a tautomer or mixture of tautomers thereof according to claim 1 is
administered to a warm-blooded animal suffering from a tumour
disease, of inflammatory rheumatic or rheumatoid diseases, or
pain.
10.-15. (canceled)
Description
[0001] The invention relates to new phthalazine derivatives,
processes for the preparation thereof, the application thereof in a
process for the treatment of the human or animal body, the use
thereof alone or in combination with one or more other
pharmaceutically active compounds for the treatment of a disease,
especially of a disease that responds to the inhibition of tyrosine
kinases, more especially the inhibition of the vascular endothelial
growth factor (VEGF) receptor kinase, preferably the treatment of a
proliferative disease, such as a tumour disease or a disease caused
by ocular neovascularisation, such as age-related macula
degeneration or diabetic retinopathy, or the treatment of
inflammatory rheumatic or rheumatoid arthritis and/or pain; a
method for the treatment of such disease in an animal, especially
in a human, and the use of such a compound alone or in combination
with one or more other pharmaceutically active compounds for the
manufacture of a pharmaceutical preparation for the treatment of
said diseases in an animal, especially in humans.
[0002] The angiogenic factor known as "Vascular Endothelial Growth
Factor" (VGEF), along with its cellular receptors, lies at the
centre of the network regulating the growth and differentiation of
the vascular system and its components, both during embryonic
development and normal growth and in a wide number of pathological
anomalies and diseases (see Breier, G., et al., Trends in Cell
Biology 6, 454-6 [1996] and references cited therein). A number of
isoforms of VEGF are known which show comparable biological
activity, but differ in the type cells that secrete them and in
their heparin-binding capacity. The receptors for VEGF are
trans-membranous receptor tyrosine kinases and have an
extracellular domain and an intracellular tyrosine kinase domain.
Various types are known, e.g. VEGFR-1, VEGFR-2, and VEGFR-3.
[0003] Angiogenesis is regarded as an absolute prerequisite for
those tumours which grow beyond a maximum diameter of about 1-2 mm;
up to this limit, oxygen and nutrients may be supplied to the
tumour cells by diffusion. Every tumour, regardless of its origin
and its cause, is thus dependent on angiogenesis for its growth
after it has reached a certain size. A number of publications and
patent applications, e.g. WO 98/35958, WO 00/59509 and WO 01/10859,
disclose certain phthalazine derivatives that are capable of VEGF
receptor inhibition.
[0004] One class of metabolising enzymes that are especially
important in the metabolism of xenobiotics, such as drugs, is
represented by the Cytochrome P 450-dependent family of isoenzymes
(CyP 450 hereinafter). CyP 450-dependent monoxygenases are a
supergene family of enzymes that catalyse the oxidation of mainly
lipophilic chemicals through the insertion of one atom from
molecular oxygen into the substrate, resulting, for example, in
aliphatic and aromatic hydroxylations and epoxidations of olefinic
or aromatic double bonds, respectively. They can usually be found
in the microsomal fraction of cell lysates. More than 20 isoenzymes
of CyP 450-depending monoxygenases are known in human, partially
with overlapping, but often defined substrate specificities. In
view of their amino acid sequences and their resulting substrate
specificity and specific inducibility, the different isoenzymes are
classified into different families. For the metabolism of
xenobiotics, the families 1 to 4 are especially important, each of
which is again subclassified into subfamilies (A, B, . . . ).
Examples are CyP1A, CyP2C, CyP2D or CyP3A. Each of these subclasses
is further split into sub-subclasses, e.g. Cyp2C8, Cyp2C9 or
CyP3A4, and polymorphism may be present.
[0005] The group of CyP 450-dependent enzymes has both harmful and
beneficial activities. Metabolic conversion of xenobiotics to
toxic, mutagenic and carcinogenic forms is a harmful activity.
Detoxification of some drugs or the activation of drugs to their
active form are examples of beneficial activities.
[0006] Especially in the field of tumor treatment, but also in
other areas, two or more drugs are combined, for example in order
to take advantage of synergistic effects or in the parallel
treatment of two diseases at the same time. A possible disadvantage
in such combination that the compounds may interfere with each
other by mutual inhibition of metabolising enzymes, such as the Cyp
450 monoxygenases. This can lead to drastical changes in
pharmacokinetics, leading to elevated levels of drugs the
metabolism of which is inhibited by co-administered drugs, and may
thus lead to adverse drug reactions, e.g. due to elevated toxicity
of the unmetabolized drugs, or to inefficiency if only the
metabolised drug is pharmaceutically active, etc. Also when used
alone, drugs may influence normal physiological processes by
inhibiting normal biosynthetic or metabolic enzymes, thus
interfering with biochemical processes in the living being. It is
therefore desirable to design drugs that show no or low inhibition
of CyP 450 hemoproteins.
[0007] With this background, it is the problem of the present
invention to provide a novel advantageous class of phthalazine
derivatives that especially display a low level of inhibition on
enzymes that metabolise xenobiotics, especially drugs, preferably
low inhibition of Cyp 450-dependent enzymes, thus inter alia
allowing for predictably low interactions with other xenobiotics or
substrates present in the body, better pharmacokinetic and
pharmacodynamic behaviour, and/or display superior tyrosine kinase
inhibiting properties, especially regarding the inhibition of VEGF
receptor tyrosine kinase.
[0008] Surprisingly, it has now been found that phthalazine
derivatives of formula I, described hereinafter, have advantageous
pharmacological properties and show advantageous VEGF receptor
tyrosine kinase inhibiting activity, allowing inter alia treatment
of VEGF-dependent cell proliferation, the treatment of especially
inflammatory rheumatic or rheumatoid diseases, such as rheumatoid
arthritis, and/or of pain, or the other diseases mentioned above
and below, especially at the same time showing lower levels of
inhibition on enzymes that metabolise xenobiotics, especially of
CyP 450-dependent enzymes, leading to more predictable
pharmacokinetic and pharmacodynamic behaviour, especially in
combination with xenobiotics present in food or drugs.
[0009] The compounds of formula I permit thus a better therapeutic
approach, especially for diseases in the treatment of which, and
also for the prevention of which, an inhibition of angiogenesis
and/or of the VEGF receptor tyrosine kinase shows beneficial
effects.
[0010] The invention relates to a compound of the formula I, [0011]
A compound of the formula I,
##STR00001##
[0011] wherein [0012] r is 1 or 2, [0013] n is 0 to 3, [0014] t is
0, 1 or 2, [0015] R.sub.1 and R.sub.2 [0016] a) are independently
in each case a lower alkyl; [0017] b) together form a bridge of
subformula I*,
[0017] ##STR00002## [0018] wherein the bond is achieved via the two
terminal C atoms and [0019] m is 0 to 4, or [0020] c) together form
a bridge of subformula I**,
[0020] ##STR00003## [0021] wherein one or two of the ring members
T.sub.1, T.sub.2, T.sub.3 and T.sub.4 are nitrogen, and the others
are in each case CH, and the bond is achieved via atoms T.sub.1 and
T.sub.4; [0022] G is --C(.dbd.O)--, --CHF--, --CF.sub.2--, lower
alkylene, C.sub.2-C.sub.6alkenylene, lower alkylene or
C.sub.3-C.sub.6alkenylene substituted by acyloxy or hydroxy,
--CH.sub.2--O--, --CH.sub.2--S--, --CH.sub.2--NH--,
--CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--, oxa (--O--), thia (--S--), imino
(--NH--), --CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--,
--(C(R.sub.4).sub.2).sub.t--S(O).sub.p-(5-membered
heteroaryl)-(C(R.sub.4).sub.2).sub.s--,
--(C(R.sub.4).sub.2).sub.t--C(G.sub.1)(R.sub.4)--(C(R.sub.4).sub.2).sub.s-
--, --O--CH.sub.2--, --S(O)--, --S(O.sub.2)--, --SCH.sub.2,
--S(O)CH.sub.2--, --CH.sub.2S(O)-- or --CH.sub.2S(O).sub.2--,
wherein each of p, s and t, independently of the other, is 0, 1 or
2; R.sub.4 is hydrogen, halogen or lower alkyl; and G.sub.1 is
--CN, --CO.sub.2R.sub.3, --CON(R.sub.6).sub.2 or
CH.sub.2N(R.sub.6).sub.2, wherein R.sub.3 is hydrogen or lower
alkyl and R.sub.6 is hydrogen, alkyl, aryl or aryl-lower alkyl;
[0023] A, B, D, E and T are independently N or CH subject to the
proviso that at least one and not more than three of these radicals
are N; [0024] Q is either lower alkoxy or O (oxo), with the proviso
that if Q is lower alkoxy, the waved line representing the bonding
of Q is a single bond and the ring carrying Q has three double
bonds, and if Q is O, the waved line representing the bonding of Q
is a double bond and for each Q=O, one of the double bonds in the
ring is changed to a single bond; and with the proviso that any Q
is bonded to a ring C atom; [0025] Q' is halogen, NHR.sup.Q,
NR.sup.Q.sub.2, OR.sup.Q, SR.sup.Q, alkyl, aryl-alkyl,
cyclohexyl-alkyl, perfluoroalkyl, acyl, substituted or
unsubstituted aryl, or substituted or unsubstituted hetaryl,
wherein R.sup.Q represents acyl, alkyl, or alkyl substituted by
hydroxy or halogen; [0026] R.sub.a and R.sub.a' are each
independently H, halogen or lower alkyl; [0027] X is imino, oxa, or
thia; [0028] Y is hydrogen, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or unsubstituted or
substituted cycloalkyl; and [0029] Z is mono- or disubstituted
amino, halogen, alkyl, cycloalkyl, substituted alkyl, hydroxy,
etherified or esterified hydroxy, nitro, cyano, carboxy, esterified
carboxy, --OCOR.sub.6, --CH.sub.2OR.sub.3, --OCO.sub.2R.sub.3,
alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,
amidino, guanidino, mercapto, sulfo, alkylthio, especially lower
alkylthio, halogenated lower alkylthio, arylthio, especially
phenylthio or alkylphenylthio, aryl lower alkylthio, especially
phenyl lower alkylthio, arylsulfinyl, especially phenylsulfinyl or
alkylphenylsulfinyl, aryl-lower alkylsulfinyl, especially
phenyl-lower alkylsulfinyl, alkylsulfonyl, especially lower
alkylsulfonyl, halogeno-lower alkylsulfonyl, arylsulfonyl,
especially phenylsulfonyl or alkylphenylsulfonyl, aryl-lower
alkylsulfonyl, especially phenyl-lower alkylsulfonyl, ureido,
C.sub.2-C.sub.7alkenyl, aryl, heteroaryl, especially pyrazolyl or
lower-alkyl pyrazolyl, optionally substituted saturated
heterocyclyl, heteroarylalkyl, heteroaryloxy,
--S(O).sub.p(heteroaryl) or --S(O).sub.p(heteroarylalkyl) wherein p
is 0, 1 or 2, heteroaryloxy, --CHO or --OCON(R.sub.6).sub.2,
--NR.sub.3CO.sub.2R.sub.6 or --NR.sub.3CON(R.sub.6).sub.2 wherein
R.sub.3 and R.sub.6 are as defined above; wherein--if more than 1
radical Z (m.gtoreq.2) is present--the substituents Z are selected
independently from each other, and wherein R.sub.3 and R.sub.6 are
as defined above; [0030] and wherein the bonds characterized in
subformula I* by a wavy line are either single or double bonds;
[0031] with the proviso that when two groups R.sub.6 are each alkyl
and located on the same nitrogen atom, they may be linked by a
bond, an O, an S or NR.sub.3 with R.sub.3 as defined above to form
a N-containing heterocycle of 5 to 7 ring atoms; and with the
proviso that only compounds other than those wherein r is 1, n is
0, R.sub.1 and R.sub.2 together form a bridge of subformula I*
wherein m is 0 and the waved lines represent double bonds,
respectively, G is --CH.sub.2--, T is N, each of A, B, E and T is
CH, Q is methoxy and Y is 4-methyl-3-bromo-phenyl,
4-ethyl-3-bromo-phenyl, 3-chloro-5-trifluoromethyl-phenyl or
4-isopropyl-3-methyl-phenyl fall under the claim; or an N-oxide of
a compound of formula I, wherein 1 or more N atoms carry an oxygen
atom; or a tautomer or mixture of tautomers of a compound of
formula I or an N-oxide thereof; or a pharmaceutically acceptable
salt of a compound of formula I, of an N-oxide or of a tautomer or
mixture of tautomers thereof.
[0032] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0033] The prefix "lower" denotes a radical having up to and
including a maximum of 7, especially up to and including a maximum
of 4 carbon atoms, the radicals in question being either linear or
branched with single or multiple branching.
[0034] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0035] Any asymmetric carbon atoms (for example in compounds of
formula I [or an N-oxide thereof], wherein n=1 and R is lower
alkyl) may be present in the (R)-, (S)- or (R,S)-configuration,
preferably in the (R)- or (S)-configuration. Substituents at a
double bond or a ring may be present in cis- (=Z-) or trans (=E-)
form. The compounds may thus be present as mixtures of isomers or
as pure isomers, preferably as enantiomer-pure diastereomers.
[0036] The present invention relates also to possible tautomers of
the compounds of formula I. Especially an oxo substituent Q may
display tautomerism of the following kind: Thus, a ring of the
partial formula IA (forming a part of the formula I),
##STR00004##
wherein each of A, B, D and E is CH, T is N, Q is oxo in 2-position
relatively to the N, r is one, and Q' and t are as defined for a
compound of formula I above, may show the following
tautomerism:
##STR00005##
with the form shown on the left (lactam form) prevailing under
normal conditions.
[0037] In analogy, a ring of the partial formula IA wherein each of
A, B, E and T is CH, D is N, Q is oxo in 6-position relatively to
the N and r is one, may show the following tautomerism:
##STR00006##
with the form shown on the left (lactam form) prevailing under
normal conditions.
[0038] Thus, depending on the equilibrium constants and the
conditions, a compound of the formula I may be present in the form
of a pure tautomer or a mixture of tautomers.
[0039] The index r in formula I is preferably 1. Q is preferably
oxo.
[0040] t is preferably 0 or 1. Q' is preferably halogen or
NHR.sup.Q, wherein R.sup.Q represents lower alkyl; thiazolyl or
furyl. Q' is most preferably bound to a carbon atom and located in
.alpha.-position to the radical Q.
[0041] The index n in formula I is preferably 0 or 1, or it is 2 or
3.
[0042] In the preferred embodiment, R.sub.1 and R.sub.2 together
form a bridge of subformula I*. The index m is preferably 0, 1, or
2. In particular, m is preferably 0 or 1, most preferably 0.
[0043] In subformula I**, the ring member T.sub.2 or T.sub.3 is
preferably nitrogen, and each of the other ring members are CH.
[0044] Of ring members A, B, D, E and T in formula I, not more than
3 may be N, and the remainder are CH. Preferably, A, D or T is N,
while the remaining of the ring members A, B, D, E and T are CH,
respectively. Most preferably, each of B, D, E and T is CH, while A
is N.
[0045] In the representation of bivalent groups G, the bond shown
on the left side in each case is bound to the ring with ring
members A, B, D, and E, whereas the bond shown on the right is
bound to the phthalazine ring in formula I.
[0046] Lower alkylene, C.sub.2-C.sub.6alkylene and
C.sub.2-C.sub.6alkenylene G may be branched or, preferably,
unbranched and are in particular methylene (where lower alkylene is
encompassed) or C.sub.2-C.sub.4alkylene or
C.sub.2-C.sub.4alkenylene, above all ethylene
(--CH.sub.2--CH.sub.2--), ethenylene, (--CH.dbd.CH--), propenylene
(--CH.dbd.CH--CH.sub.2--), propylene
(--CH.sub.2--CH.sub.2--CH.sub.2--) or tetramethylene
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--). G is preferably in
particular methylene or in a broader aspect of the invention
ethylene, ethenylene or propylene. In C.sub.2-C.sub.6alkenylene G,
the substituents on the double bond are preferably present in the
E- (=trans-) form.
[0047] Acyl is preferably arylcarbonyl, wherein aryl is as defined
below, in particular benzoyl, or lower alkanoyl, especially
acetyl.
[0048] Lower alkylene substituted by hydroxy is especially
hydroxymethylene; C.sub.2-C.sub.6alkylene substituted by hydroxy is
preferably hydroxyethylene (--CH.sub.2--CH(OH)).
[0049] Lower alkyl is especially C.sub.1-C.sub.4alkyl, e.g.
n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, or especially
methyl or also ethyl.
[0050] Aryl is preferably an aromatic radical having 6 to 14 carbon
atoms, especially phenyl, naphthyl, fluorenyl or phenanthrenyl, the
radicals defined above being unsubstituted or substituted by one or
more, preferably up to three, especially one or two substituents,
especially selected from the group consisting of amino, mono- or
disubstituted amino, halogen, alkyl, alkenyl, such as ethenyl,
cycloalkyl, cycloalkenyl, substituted alkyl, hydroxy, etherified or
esterified hydroxy, nitro, cyano, carboxy, esterified carboxy,
alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,
especially N-methylcarbamoyl or N-tert-butylcarbamoyl; amidino,
guanidino, mercapto, lower alkylthio, such as methylthio, sulfo,
phenylthio, phenyl-lower alkylthio, alkylphenylthio, alkylsulfinyl,
phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl,
phenylsulfonyl, phenyl-lower alkylsulfonyl, phenyl, lower alkanoyl,
such as acetyl, lower alkylmercapto, such as methylmercapto
(--S--CH.sub.3), halogen-lower alkylthio, such as
trifluoromethylthio (--S--CF.sub.3), lower alkylsulfonyl,
halogen-lower alkylsulfonyl, such as especially trifluoromethane
sulfonyl, dihydroxybora (--B(OH).sub.2), heterocyclyl, heterocyclyl
lower alkyl, heteroaryloxy, heteroaryl-lower alkoxy,
--S(O).sub.p(heteroaryl), --S(O).sub.p(heteroarylalkyl), --CHO,
--CH.sub.2OR.sub.3, --O--CON(R.sub.6).sub.2,
--NR.sub.3CO.sub.2R.sub.6 or --NR.sub.3CON(R.sub.6).sub.2, or where
R.sub.6 is H, alkyl, aryl (except substituted by aryl or aryl-lower
alkyl) or aryl-lower alkyl (with aryl except if substituted by aryl
or aryl-lower alkyl), R.sub.3 is H or lower alkyl and p is 0, 1 or
2; lower alkylene dioxy bound at adjacent C-atoms of the ring, such
as methylene dioxy, ureido and sulfamoyl; for example, aryl is
phenyl, which is either unsubstituted or substituted by one or two
substituents selected independently of one another from the group
consisting of amino; lower alkanoylamino, especially acetylamino;
halogen, especially fluorine, chlorine, bromine, or iodine; lower
alkyl, especially methyl or preferably ethyl, further propyl or
t-butyl; halogen-lower alkyl, especially trifluoromethyl; hydroxy;
lower alkoxy, especially methoxy or also ethoxy; phenyl-lower
alkoxy, especially benzyloxy; and cyano, or (as an alternative or
in addition to the previous group of substituents)
C.sub.8-C.sub.12alkoxy, especially n-decyloxy, carbamoyl, lower
alkylcarbamoyl, such as n-methyl- or n-tert-butylcarbamoyl, lower
alkanoyl, such as acetyl, phenyloxy, halogen-lower alkyloxy, such
as trifluoromethoxy or 1,1,2,2-tetrafluoroethyloxy, lower
alkoxycarbonyl, such as methoxy-, tert-butoxy- or ethoxycarbonyl,
lower alkylmercapto, such as methylmercapto, halogen-lower
alkylmercapto, such as trifluoromethylmercapto, hydroxy-lower
alkyl, such as hydroxymethyl or 1-hydroxymethyl, lower
alkylsulfonyl, such as methane sulfonyl, halogen-lower
alkylsulfonyl, such as trifluoromethane sulfonyl, phenylsulfonyl,
dihydroxybora (B(OH).sub.2), 2-methylpyrimidin-4-yl, oxazol-5-yl,
2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, 1-methyl-pyrazol-3-yl
and lower alkylenedioxy bound to two adjacent C-atoms, such as
methylene dioxy or, alternatively or in addition to the previous
group of substitutents, ureido, vinyl, pyrazol-3-yl and
1-methyl-pyrazol-3-yl, especially preferred are (especially with
regard to a novel compound of the formula I as described
hereinbefore and hereinafter) one or two substituents independently
selected from lower alkyl, especially methyl, halogen, especially
chlorine or bromine, and halogen lower alkyl, especially
trifluoromethyl. In the cases where Y is aryl, it is in particular
preferred that aryl is phenyl preferably substituted by one or two
substituents independently selected from the group consisting of
lower alkyl, in particular methyl, ethyl, n-propyl, i-propyl or
t-butyl; halogen, in particular fluorine, chlorine, bromine or
iodine; lower alkoxy, in particular ethoxy; and halogen lower
alkyl, in particular trifluoromethyl; special preference being for
substitution by one or two substitutents independently selected
from the group consisting of lower alkyl, in particular methyl or
t-butyl; halogen, in particular chlorine; and halogen lower alkyl,
in particular trifluoromethyl; or that (especially in a novel
compound of the formula I) aryl is napthyl, especially
2-naphthyl.
[0051] Heteroaryl is preferably a heterocyclic radical unsaturated
in the bonding ring and is preferably monocyclic or in a broader
sense bicyclic or tricyclic; wherein at least in the ring bonding
to the radical of the molecule of formula I one or more, preferably
one to four, especially one or two carbon atoms of a corresponding
aryl radical are substituted by a heteroatom selected from the
group consisting of nitrogen, oxygen and sulfur, the bonding ring
preferably having 4 to 12, especially 5 to 7 ring atoms; or is a
saturated analogue of such an unsaturated heteroaryl; heteroaryl
being unsubstituted or substituted by one or more, especially 1 to
3, independently selected from the group consisting of the
substituents defined above as substituents of aryl; and especially
being a heteroaryl radical selected from the group consisting of
imidazolyl, thienyl, furyl, pyranyl, thianthrenyl, isobenzofuranyl,
benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, lower
alkyl-substituted imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,
indolyl, indazolyl, triazolyl, tetrazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl,
carbazolyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl and furazanyl, or a saturated analogue thereof,
especially dioxanyl, preferably [1,3]dioxan-5-yl; each of these
radicals being bonded to at least one heteroatom and the radical of
the molecule of formula I via a ring and each of these radicals
being unsubstituted or substituted by one to two radicals selected
from the group consisting of lower alkyl, especially methyl,
propyl, isopropyl or tert-butyl, lower alkoxy, especially methoxy,
and halo, especially bromo or chloro; pyridyl is especially
preferred; also especially preferred are quinolyl, especially
quinolin-6-yl; lower alkyl-pyridyl, especially
5-methyl-pyridin-2-yl or 6-methyl-pyridin-2-yl; lower
alkylpyrimidinyl, especially 4-methylpyrimidin-2-yl or
6-tert-butyl-pyrimidin-4-yl; halo-lower alkylpyridyl, especially
5-trifluoromethyl-pyridin-2-yl; lower alkoxy-pyridyl, especially
5-methoxy-pyridin-2-yl; di-lower alkylpyridyl, especially
2,6-dimethyl-pyridin-4-yl or 4,6-dimethyl-pyridin-2-yl; di-lower
alkylpyrimidinyl, especially 2,6-dimethyl-pyrimidin-4-yl; or
halo-pyridyl, especially 5-bromo-pyridin-2-yl or
6-chloro-pyridin-3-yl; or lower-alkyl-[1,3]dioxan-5-yl, such as
cis,trans-, cis- or preferably trans-2-isopropyl-[1,3]dioxan-5-yl.
Pyridyl Y is preferably 3- or 4-pyridyl.
[0052] Mono- or disubstituted amino is especially amino substituted
by one or two radicals selected independently of one another from
alkyl, especially lower alkyl, such as methyl; hydroxy-lower alkyl,
such as 2-hydroxyethyl; halogen-lower alkyl; amino-lower alkyl;
N-lower alkylaminoalkyl; N,N-di-lower alkylamino-alkyl,
phenyl-lower alkyl; N-lower alkanoylamino-alkyl; N,N-di-lower
alkanoylamino-alkyl; cyanoalkyl; carboxyalkyl;
lower-alkoxycarbonylalkyl; phenyl-lower alkoxycarbonylalkyl; lower
alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the
phenyl radical is unsubstituted or especially substituted by one or
more, preferably one or two, substituents selected from nitro or
amino, or also from halogen, amino, N-lower alkylamino,
N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower
alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower
alkoxycarbonyl, wherein the phenyl radical is unsubstituted or
especially substituted by one or more, preferably one or two,
substituents selected from nitro or amino, or also from halogen,
amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano,
carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and
is preferably N-lower alkylamino, such as N-methylamino,
hydroxy-lower alkylamino, such as 2-hydroxyethylamino, phenyl-lower
alkylamino, such as benzylamino, N,N-di-lower alkylamino,
N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower
alkylphenylamino, lower alkanoylamino, such as acetylamino, or a
substituent selected from the group consisting of benzoylamino and
phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in
each case is unsubstituted or especially substituted by nitro or
amino, or also by halogen, amino, N-lower alkylamino, N,N-di-lower
alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl or carbamoyl, or as an alternative or in addition to the
previous group of radicals by aminocarbonylamino.
[0053] Halo or halogen is above all fluorine, chlorine, bromine, or
iodine, especially fluorine, chlorine, or bromine.
[0054] Alkyl (alone or as part of radicals, e.g. halogenalkyl or
the like) has preferably up to a maximum of 12 carbon atoms and is
especially lower alkyl, especially methyl, or also ethyl, n-propyl,
isopropyl, or tert-butyl.
[0055] Substituted alkyl is alkyl as last defined, especially lower
alkyl, preferably methyl; where one or more, especially up to
three, substituents may be present, primarily from the group
selected from halogen, especially fluorine, and also from amino,
N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower
alkoxycarbonyl. Trifluoromethyl is especially preferred. In a novel
compound of the formula I, methyl is especially preferred.
[0056] Aryl-lower alkyl is lower alkyl that is substituted
(preferably terminally) by aryl as defined above.
[0057] Heteroaryl-lower alkyl is lower alkyl that is substituted
(preferably terminally) by heteroaryl as defined above.
[0058] Optionally substituted saturated heterocyclyl is preferably
a saturated analogue of heteroaryl as described above which is
unsubstituted or substituted as described for heteroaryl.
[0059] When two groups R.sub.6 are each alkyl and located on the
same nitrogen atom, and they are linked by a bond, an O, an S or
NR.sub.3 with R.sub.3 as defined above to form a N-containing
heterocycle of 5 to 7 ring atoms, preferred examples of such
heterocycles, including the N to which they are attached, are:
##STR00007##
[0060] Etherified hydroxy is especially C.sub.8-C.sub.20alkyloxy,
such as n-decyloxy, lower alkoxy (preferred), such as methoxy,
ethoxy, isopropyloxy, or n-pentyloxy, phenyl-lower alkoxy, such as
benzyloxy, or also phenyloxy, or as an alternative or in addition
to the previous group halogen-lower alkyloxy, such as
trifluoromethyloxy or 1,1,2,2-tetrafluoroethoxy.
[0061] Esterified hydroxy is especially lower alkanoyloxy,
benzoyloxy, lower alkoxycarbonyloxy, such as
tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as
benzyloxycarbonyloxy.
[0062] Esterified carboxy is especially lower alkoxycarbonyl, such
as tert-butoxycarbonyl or ethoxycarbonyl, or further
methoxycarbonyl, phenyl-lower alkoxycarbonyl, or
phenyloxycarbonyl.
[0063] Alkanoyl is above all alkylcarbonyl, especially lower
alkanoyl, e.g. acetyl.
[0064] N-mono- or N,N-disubstituted carbamoyl is especially
substituted by one or two substituents selected from the group
consisting of lower alkyl, especially methyl, phenyl-lower alkyl,
or hydroxy-lower alkyl, at the terminal nitrogen atom.
[0065] Alkylphenylthio is especially lower alkylphenylthio.
[0066] Alkylphenylsulfinyl is especially lower
alkylphenylsulfinyl.
[0067] Halo-lower alkylthio is preferably trifluoromethylthio.
[0068] Halo-lower alkanesulfonyl is preferably
trifluoromethylsulfonyl.
[0069] Pyrazolyl is preferably pyrazol-3-yl, lower alkylpyrazolyl
is preferably 1-methyl-pyrazol-3-yl.
[0070] C.sub.2-C.sub.7-Alkenyl is preferably vinyl.
[0071] Unsubstituted or substituted cycloalkyl has 3 to 12 ring
carbon atoms, and is preferably C.sub.3-C.sub.8cycloalkyl, which is
unsubstituted or substituted in the same way as aryl, especially as
defined for phenyl. Cyclohexyl, in a broader sense cyclopentyl or
cyclopropyl, are preferred.
[0072] Cycloalkenyl is a non-aromatic unsaturated carbocycle that
contains between 3 and 12, preferably 3 to 8, carbon atoms and up
to three double bonds, with the proviso that cycloalkenyl groups
that differ from aromatics by lacking only one double bond (such as
cyclohexadiene) which are not sufficiently non-reactive are not
comprised.
[0073] Z in a compound of the formula I is preferably amino,
hydroxy-lower alkylamino, such as 2-hydroxyethylamino, lower
alkanoylamino, such as acetylamino, nitrobenzoylamino, such as
3-nitrobenzoylamino, aminobenzoylamino, such as
4-aminobenzoylamino, phenyl-lower alkoxycarbonylamino, such as
benzyloxycarbonylamino, or halogen, such as bromine; preferably
only one substituent is present (m=1), especially one of the last
mentioned, especially halogen. A compound of formula I wherein
R.sub.1 and R.sub.2 together form a bridge of the sub-formula I*,
especially a compound of the formula IA wherein Z is absent (m=0),
is quite especially preferred.
[0074] Heterocyclyl is especially a five or six-membered
heterocyclic system with 1 or 2 heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, which may be
unsaturated or wholly or partly saturated, and is unsubstituted or
substituted, especially by lower alkyl, such as methyl; a radical
selected from 2-methylpyrimidin-4-yl, oxazol-5-yl,
2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, and
1-methyl-pyrazol-3-yl is preferred.
[0075] Aryl in the form of phenyl which is substituted by lower
alkylene dioxy bound to two adjacent C-atoms, such as methylene
dioxy, is preferably 3,4-methylene dioxyphenyl.
[0076] If Q is O (oxo), the waved line representing the bonding of
Q is a double bond and for each Q=O, one of the double bonds
(namely the one that would otherwise start from the ring carbon
atom binding Q) in the ring is changed to a single bond;
preferably, the moieties A, B, D, E and T are chosen such that any
carbon A, B, D, E or T binding Q is directly bound to an N or (if Q
is oxo) to an NH.
[0077] Where a substitutent such as Q or Z is present, an H atom of
the binding atom to which these moieties are attached is replaced
by such substituent.
[0078] The bonds in subformula I* characterized by wavy lines are
present either as single or as double bonds. Preferably both at the
same time are either single or double bonds. It is especially
preferred when both are double bonds at the same time.
[0079] The bridges formed from R.sub.1 and R.sub.2 in formula I and
formula IA which are of subformula I* or I** form, together with
the carbon atoms bonding R.sub.1 and R.sub.2, a ring with 6 ring
atoms.
[0080] An N-oxide of a compound of formula I is preferably an
N-oxide in which a phthalazine-ring nitrogen or a nitrogen in the
ring with ring members A, B, D, and E carries an oxygen atom, or
several of said nitrogen atoms carry an oxygen atom. Preferred are
compounds without N-oxide moiety.
[0081] Salts are especially the pharmaceutically acceptable salts
of compounds of formula I (or an N-oxide or tautomer or mixture of
tautomers thereof).
[0082] Such salts are formed, for example, as acid addition salts,
preferably with organic or inorganic acids, from compounds of
formula I (or an N-oxide or tautomer or mixture of tautomers
thereof) with a basic nitrogen atom, especially the
pharmaceutically acceptable salts. Suitable inorganic acids are,
for example, halogen acids, such as hydrochloric acid; sulfuric
acid; or phosphoric acid. Suitable organic acids are, for example,
carboxylic, phosphonic, sulfonic or sulfamic acids, for example
acetic acid, propionic acid, octanoic acid, decanoic acid,
dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid,
gluconic acid, glucosemono-carboxylic acid, fumaric acid, succinic
acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic
acid, tartaric acid, citric acid, glucaric acid, galactaric acid,
amino acids, such as glutamic acid, aspartic acid, N-methylglycine,
acetylaminoacetic acid, N-acetylasparagine or N-acetylcysteine,
pyruvic acid, acetoacetic acid, phosphoserine, 2- or
3-glycerophosphoric acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, benzoic acid,
salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid,
3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid,
2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid,
phenylacetic acid, glucuronic acid, galacturonic acid, methane- or
ethanesulfonic acid, 2-hydroxyethanesulfonic acid,
ethane-1,2-disulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid,
N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propylsulfamic
acid, or other organic protonic acids, such as ascorbic acid.
[0083] In the presence of negatively charged radicals, such as
carboxy or sulfo, salts may also be formed with bases, e.g. metal
or ammonium salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium, magnesium or calcium salts,
or ammonium salts with ammonia or suitable organic amines, such as
tertiary monoamines, for example triethylamine or
tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
N-ethyl-piperidine or N,N'-dimethylpiperazine.
[0084] In the presence of a basic group and an acid group in the
same molecule, a compound of formula I (or an N-oxide or tautomer
or mixture of tautomers thereof) may also form internal salts.
[0085] For isolation or purification purposes it is also possible
to use pharmaceutically unacceptable salts, for example picrates or
perchlorates. Only the pharmaceutically acceptable salts or free
compounds (if the occasion arises, in the form of pharmaceutical
preparations) attain therapeutic use, and these are therefore
preferred.
[0086] In view of the close relationship between the novel
compounds in free form and in the form of their salts, including
those salts that can be used as intermediates, for example in the
purification or identification of the novel compounds, their
tautomers or tautomeric mixtures and their salts and the N-oxides
or the salts thereof, any reference hereinbefore and hereinafter to
compounds of the formula I is to be understood as referring also to
the corresponding N-oxides, tautomers of compounds of the formula I
or their N-oxides, tautomeric mixtures of compounds of the formula
I or their N-oxides, or salts of any of these, as appropriate and
expedient and if not mentioned otherwise.
[0087] The compounds of formula I have valuable pharmacological
properties, as described hereinbefore and hereinafter.
[0088] The efficacy of the compounds of the formula I as inhibitors
of VEGF-receptor tyrosine kinase activity can be demonstrated as
follows:
[0089] Test for activity against VEGF-receptor tyrosine kinase: the
test is conducted using Flt-1 VEGF-receptor tyrosine kinase. The
detailed procedure is as follows: 30 .mu.l kinase solution (10 ng
of the kinase domain of Flt-1, Shibuya et al., Oncogene 5, 519-24
[1990]) in 20 mM Tris.HCl pH 7.6, 3 mM manganese dichloride
(MnCl.sub.2), 3 mM magnesium chloride (MgCl.sub.2) and 3 .mu.g/ml
poly(Glu,Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 .mu.M
[.sup.33P]-ATP (0.2 .mu.Ci/batch), 1% dimethyl sulfoxide, and 0 to
50 .mu.M of the compound to be tested are incubated together for 15
minutes at room temperature. The reaction is then ended by the
addition of 10 .mu.l 0.25 M ethylenediaminetetraacetate (EDTA) pH
7. Using a multichannel dispenser (LAB SYSTEMS, USA), an aliquot of
20 .mu.l is applied to a PVDF (=polyvinyl difluoride) Immobilon P
membrane (Millipore, USA), which is incorporated into a Millipore
microtitre filter manifold, and connected to a vacuum. Following
complete elimination of the liquid, the membrane is washed 4 times
successively in a bath containing 0.5% phosphoric acid
(H.sub.3PO.sub.4), incubated for 10 minutes each time while
shaking, then mounted in a Hewlett Packard TopCount Manifold and
the radioactivity measured after the addition of 10 .mu.l
Microscint.RTM. (.beta.-scintillation counter liquid; Packard USA).
IC.sub.50-values are determined by linear regression analysis of
the percentages for the inhibition of each compound in three
concentrations (as a rule 0.01, 0.1, and 1 .mu.M). Preferably
inhibitory concentrations (IC.sub.50 with 50% maximum inhibition
versus control without inhibitory substance of formula I) in the
range 10 nmol/litre to 100 .mu.mol/litre are found here, especially
in the range 10 to 2000 nmol/litre.
[0090] The antitumour efficacy of the compounds of formula I can be
demonstrated in vivo as follows:
[0091] In vivo activity in the nude mouse xenotransplant model:
female BALB/c nude mice (8-12 weeks old, for example Novartis
Animal Farm, Sisseln, Switzerland) are kept under sterile
conditions with water and feed ad libitum. Tumours are induced by
subcutaneous injection of tumour cells (human epithelial cell line
A-431; American Type Culture Collection (ATCC), Rockville, Md.,
USA, Catalogue Number ATCC CRL 1555; cell line from an 85-year-old
woman; epidermoid carcinoma cell line) into carrier mice. The
resulting tumours pass through at least three consecutive
transplantations before the start of treatment. Tumour fragments
(about 25 mg) are implanted subcutaneously in the left flank of the
animals using a 13-gauge trocar needle under Forene.RTM.
anaesthesia (Abbott, Switzerland). Treatment with the test compound
is started as soon as the tumour has reached a mean volume of 100
mm.sup.3. Tumour growth is measured two to three times a week and
24 hours after the last treatment by determining the length of two
perpendicular axes. The tumour volumes are calculated in accordance
with published methods (see Evans et al., Brit. J. Cancer 45, 466-8
[1982]). The antitumour efficacy is determined as the mean increase
in tumour volume of the treated animals divided by the mean
increase in tumour volume of the untreated animals (controls) and,
after multiplication by 100, is expressed as T/C %. Tumour
regression (given in %) is reported as the smallest mean tumour
volume in relation to the mean tumour volume at the start of
treatment. The test compound is administered daily by gavage. In
vivo tumor inhibition can e.g. be found at around 10 to 200 mg/kg
and day.
[0092] As an alternative to cell line A-431, other cell lines may
also be used in the same manner, for example the MCF-7 breast
adenocarcinoma cell line, the MDA-MB 468 breast adenocarcinoma cell
line, the MDA-MB 231 breast adenocarcinoma cell line, the Colo 205
colon carcinoma cell line, the HCT 116 colon carcinoma cell line,
the DU145 prostate carcinoma cell line DU 145 or the PC-3 prostate
carcinoma cell line PC-3
[0093] The inhibition of VEGF-induced KDR-receptor
autophosphorylation can be confirmed with a further in vitro
experiment in cells: transfected CHO cells, which permanently
express human VEGF receptor (KDR), are seeded in culture medium
(with 10% fetal calf serum=FCS) in 6-well cell-culture plates and
incubated at 37.degree. C. under 5% CO.sub.2 until they show about
80% confluency. The compounds to be tested are then diluted in
culture medium (without FCS, with 0.1% bovine serum albumin) and
added to the cells. (Controls comprise medium without test
compounds). After two hours' incubation at 37.degree. C.,
recombinant VEGF is added; the final VEGF concentration is 20
ng/ml). After a further five minutes' incubation at 37.degree. C.,
the cells are washed twice with ice-cold PBS (phosphate-buffered
saline) and immediately lysed in 100 .mu.l lysis buffer per well.
The lysates are then centrifuged to remove the cell nuclei, and the
protein concentrations of the supernatants are determined using a
commercial protein assay (BIORAD). The lysates can then either be
immediately used or, if desired, stored at -20.degree. C.
[0094] A sandwich ELISA is carried out to measure the KDR-receptor
phosphorylation: a monoclonal antibody to KDR (for example Mab
1495.12.14; prepared by H. Towbin) is immobilized on black ELISA
plates (OptiPlate.TM. HTRF-96 from Packard). The plates are then
washed and the remaining free protein-binding sites are saturated
with 1% BSA in PBS. The cell lysates (20 .mu.g protein per well)
are then incubated overnight at 4.degree. C. with an
antiphosphotyrosine antibody coupled with alkaline phosphatase
(PY20:AP from Transduction Laboratories). The binding of the
antiphosphotyrosine antibody is then demonstrated using a
luminescent AP substrate (CDP-Star, ready to use, with Emerald II;
TROPIX). The luminescence is measured in a Packard Top Count
Microplate Scintillation Counter (Top Count). The difference
between the signal of the positive control (stimulated with VEGF)
and that of the negative control (not stimulated with VEGF)
corresponds to VEGF-induced KDR-receptor phosphorylation (=100%).
The activity of the tested substances is calculated as % inhibition
of VEGF-induced KDR-receptor phosphorylation, wherein the
concentration of substance that induces half the maximum inhibition
is defined as the ED50 (effective dose for 50% inhibition).
Compounds of formula I here preferably show ED50 values in the
range of 5 nM to 10 .mu.M. Those compounds where r is 1, Q is
4-lower alkoxy, especially lower methoxy, and is bound at A instead
of the H, with A, B, D and E each being CH and T N, or preferably
at T instead of the H, with T, B, D and E each being CH and A being
A, and most especially those compounds wherein Q is oxo and one of
the double bonds in the ring with A, B, D, E and T is a single
bond, and the oxo Q is bound at A which is C if T is NH, while B, D
and E each are CH, or preferably at T which is C if A is NH, while
B, D and E each are CH, show especially advantageous
inhibition.
[0095] Compounds of formula I inhibit to varying degrees also other
tyrosine kinases involved in signal transduction which are mediated
by trophic factors, for example AbI kinase, kinases from the Src
family, especially c-Src kinase, Lck, and Fyn; or in a broader
sense kinases of the EGF family, for example, c-erbB2 kinase
(HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth factor
receptor kinase (IGF-1 kinase), especially members of the
PDGF-receptor tyrosine kinase family, such as PDGF-receptor kinase,
CSF-1-receptor kinase, Kit-receptor kinase and VEGF-receptor
kinase, especially KDR and Flk, and the angiopoetin 1 and 2
receptor Tek; or in a broader sense also serine/threonine kinases,
all of which play a role in growth regulation and transformation in
mammalian cells, including human cells. The respective assays can
be done utilizing the respective tyrosine kinase expressed as
GST-fusion protein using the baculovirus system. The respective
kinases are purified via a glutathione-Sepharose column and
utilized to determine the IC.sub.50s for the compounds.
[0096] The inhibition of c-erbB2 tyrosine kinase (HER-2) can be
measured, for example, in the same way as the inhibition of EGF-R
protein kinase (see House et al., Europ. J. Biochem. 140, 363-7
[1984]). The erbB2 kinase can be isolated, and its activity
determined, using methods known per se (see Akiyama et al., Science
232, 1644 [1986]). In particular, an inhibitory effect can also be
found on PDGF-receptor kinase, which is determined according to the
method described by Trinks et al. (see J. Med. Chem. 37(7): 1015-27
[1994]).
[0097] The usefulness of a compound of the formula I in the
treatment of arthritis as an example of an inflammatory rheumatic
or rheumatoid disease can be demonstrated using the well-known rat
adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol. 91, 95-101
(1956)) to test the anti-arthritic activity of compounds of the
formula I (for details see WO 00/59509).
[0098] The activity of compounds of the formula I against pain can
be shown in the model of nociception (pain) described also in WO
00/59509.
[0099] On the basis of these studies, a compound of formula I is
appropriate for the treatment of inflammatory (especially rheumatic
or rheumatoid) diseases and/or pain. The compounds of the formula I
according to the invention also show therapeutic efficacy
especially against other disorders dependent on protein kinase,
especially proliferative diseases.
[0100] On the basis of their efficacy as inhibitors of
VEGF-receptor tyrosine kinase activity, the compounds according to
the invention primarily inhibit the growth of blood vessels and are
thus, for example, effective against a number of diseases
associated with deregulated angiogenesis, especially diseases
caused by ocular neovascularisation, especially retinopathies, such
as diabetic retinopathy or age-related macula degeneration,
psoriasis, haemangio-blastoma, such as haemangioma, mesangial cell
proliferative disorders, such as chronic or acute renal diseases,
e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic
microangiopathy syndromes or transplant rejection, or especially
inflammatory renal disease, such as glomerulonephritis, especially
mesangioproliferative glomerulonephritis, haemolyticuraemic
syndrome, diabetic nephropathy, hypertensive nephrosclerosis,
atheroma, arterial restenosis, autoimmune diseases, acute
inflammation, fibrotic disorders (e.g. hepatic cirrhosis),
diabetes, neurodegenerative disorders and especially neoplastic
diseases (solid tumours, but also leucemias and other "liquid
tumours", especially those expressing c-kit, KDR or fit-1), such as
especially breast cancer, cancer of the colon, lung cancer
(especially small-cell lung cancer), cancer of the prostate or
Kaposi's sarcoma. A compound of formula I inhibits the growth of
tumours and is especially suited to preventing the metastatic
spread of tumours and the growth of micrometastases.
[0101] A compound of formula I can be administered alone or in
combination with one or more other therapeutic agents, possible
combination therapy taking the form of fixed combinations or the
administration of a compound of the invention and one or more other
therapeutic agents being staggered or given independently of one
another, or the combined administration of fixed combinations and
one or more other therapeutic agents. In particular, a compound of
formula I can besides or in addition be administered for example in
the case of tumour therapy in combination with chemotherapy,
radiotherapy, immunotherapy, surgical intervention, or a
combination of these. Long-term therapy is equally possible as is
adjuvant therapy in the context of other treatment strategies, as
described above. Other possible treatments are therapy to maintain
the patient's status after tumour regression, or even
chemopreventive therapy, for example in patients at risk.
[0102] Therapeutic agents for possible combination are especially
one or more antiproliferative, cytostatic or cytotoxic compounds,
for example a chemotherapeutic agent or several agents selected
from the group which includes, but is not limited to, an inhibitor
of polyamine biosynthesis, an inhibitor of a protein kinase,
especially of a serine/threonine protein kinase, such as protein
kinase C, or of a tyrosine protein kinase, such as the EGF receptor
tyrosine kinase, e.g. PKI166, the VEGF receptor tyrosine kinase,
e.g. PTK787, or the PDGF receptor tyrosine kinase, e.g. STI571, a
cytokine, a negative growth regulator, such as TGF-.beta. or
IFN-.beta., an aromatase inhibitor, e.g. letrozole or anastrozole,
an inhibitor of the interaction of an SH2 domain with a
phosphorylated protein, antiestrogens, topoisomerase I inhibitors,
such as irinotecan, topoisomerase II inhibitors, microtubule active
agents, e.g. paclitaxel, discodermolide or an epothilone,
alkylating agents, antineoplastic antimetabolites, such as
gemcitabine or capecitabine, platin compounds, such as carboplatin
or cisplatin, anti-angiogenic compounds, gonadorelin agonists,
anti-androgens, bisphosphonates, e.g. AREDIA.RTM. or ZOMETA.RTM.,
and trastuzumab. The structure of the active agents identified by
code nos., generic or trade names may be taken from the actual
edition of the standard compendium "The Merck Index" or from
databases, e.g. Patents International (e.g. IMS World
Publications). The corresponding content thereof is hereby
incorporated by reference.
[0103] The compounds of formula I, especially those wherein Q is
oxo and r is preferably one, are especially appropriate for
combination therapy and show especially low interference with other
xenobiotics from e.g. food or especially drug administration as
they display the advantage of low inhibition of metabolising
enzymes, especially monoxygenases, preferably the CyP 450-dependent
monoxygenases.
[0104] This can be shown according to the following test system:
Human liver microsomes or high level expression of cDNAs encoding
Cytochrome P450 in insect cells provide a flexible source of
materials for several in vitro measurement methods. A microtiter
plate-based, direct fluorometric assay for the activities of any
one or more of the principal drug metabolizing enzymes CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6 and/or CYP3A4 is used in order to
assess the potential for drug candidates to inhibit cytochrome
P450.
[0105] Fluorescent marker substrates are incubated at
concentrations close to their Michaelis-Menten affinity constant,
Km. Inhibitors are tested in the 1 to 10 .mu.M concentration range.
50% inhibition concentration (IC50 values) are estimated by
non-linear regression of a two parameter model equation where the
lower data limit is 0, i.e. the data are background corrected, and
the upper data limit is 100, i.e. the data are range corrected. The
equation assumes that y falls with increasing x. A relatively high
standard error associated with IC50 values suggests that the
regression does not fit the data very well. Extrapolation or
interpolation of IC50 values beyond the concentration range studied
are not provided. The potential drug interaction is predicted with
the following criterion: If the estimated apparent IC50 used is
less than 1 .mu.mol/l, the test compound has a potential drug
interaction which should be investigated in more detail, if, on the
other hand, the estimated IC50 is greater than 1 .mu.mol/l, the
test compound has a potential for drug interactions only if human
therapeutic in vivo concentrations are likely to be in the IC50
range.
[0106] Details for the assays and the technology that forms the
basis for the assays are known (see C. L. Crespi et al., Analytical
Biochemistry 248, 188-190 (1997), and C I L. Crespi et al., J.
Pharmacol. Toxicol. Methods 44, 325-331 (2000), and the references
mentioned therein). For example, 3-cyano-7-ethoxycoumarin is used
as fluorescent substrate for CYP1A2, CYP2C9, CYP2C19 and CYP2D6,
7-methoxy-4-trifluoromethylcoumarin is used for CYP2C9, resorufin
benzyl ether for CYP3A4,
3-82-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin
for CYP2D6.
[0107] With this test system, it can be shown that the compound of
formula I, salts, tautomers or tautomer mixtures thereof show lower
inhibition of CyP 450 isoenzymes; e.g. in the case of CyP 3A4,
CyP2C8 and CyP2C9, a compound without substituent Q shows a higher
inhibition by a factor of 2 or more when compared with a compound
bearing an alkoxy or especially an oxo substituent, usually with 1
.mu.M or higher IC50.
[0108] A compound of formula I is not only useful for the
(prophylactic and preferably therapeutic) management of humans, but
also for the treatment of other warm-blooded animals, for example
of commercially useful animals, for example rodents, such as mice,
rabbits or rats, or guinea-pigs. Such a compound may also be used
as a reference standard in the test systems described above to
permit a comparison with other compounds. In general, the invention
relates also to the use of a compound of formula I for the
inhibition of VEGF-receptor tyrosine kinase activity. A compound of
formula I may also be used for diagnostic purposes, for example
with tumours that have been obtained from warm-blooded animal
"hosts", especially humans, and implanted into mice to test them
for decreases in growth after treatment with such a compound, in
order to investigate their sensitivity to said compound and thus to
improve the detection and determination of possible therapeutic
methods for neoplastic diseases in the original host.
[0109] With the groups of preferred compounds of formula I
mentioned hereinafter, definitions of substituents from the general
definitions mentioned hereinbefore may reasonably be used, for
example, to replace more general definitions with more specific
definitions or especially with definitions characterized as being
preferred; in each case, the definitions described hereinbefore as
being preferred or exemplary are preferred.
[0110] The present invention pertains in particular to compounds of
the formula I wherein [0111] r is 1 or 2, [0112] n is 0 to 3,
[0113] t is 0, [0114] R.sub.1 and R.sub.2 [0115] a) are
independently in each case a lower alkyl; [0116] b) together form a
bridge of subformula I*, [0117] wherein the bond is achieved via
the two terminal C atoms and [0118] m is 0 to 4, or [0119] c)
together form a bridge of subformula I**, [0120] wherein one or two
of the ring members T.sub.1, T.sub.2, T.sub.3 and T.sub.4 are
nitrogen, and the others are in each case CH, and the bond is
achieved via atoms T.sub.1 and T.sub.4; [0121] G is --C(.dbd.O)--,
--CHF--, --CF.sub.2--, lower alkylene, C.sub.2-C.sub.6alkenylene,
lower alkylene or C.sub.3-C.sub.6alkenylene substituted by acyloxy
or hydroxy, --CH.sub.2--O--, --CH.sub.2--S--, --CH.sub.2--NH--,
--CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--, oxa (--O--), thia (--S--), imino
(--NH--), --CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--,
--(C(R.sub.4).sub.2).sub.t--S(O).sub.p-(5-membered
heteroaryl)-(C(R.sub.4).sub.2).sub.s--,
--(C(R.sub.4).sub.2).sub.t--C(G.sub.1)(R.sub.4)--(C(R.sub.4).sub.2).sub.s-
--, --O--CH.sub.2--, --S(O)--, --S(O.sub.2)--, --SCH.sub.2,
--S(O)CH.sub.2--, --CH.sub.2S(O)-- or --CH.sub.2S(O).sub.2--,
wherein each of p, s and t, independently of the other, is 0, 1 or
2; R.sub.4 is hydrogen, halogen or lower alkyl; and G.sub.1 is
--CN, --CO.sub.2R.sub.3, --CON(R.sub.6).sub.2 or
CH.sub.2N(R.sub.6).sub.2, wherein R.sub.3 is hydrogen or lower
alkyl and R.sub.6 is hydrogen, alkyl, aryl or aryl-lower alkyl;
[0122] A, B, D, E and T are independently N or CH subject to the
proviso that at least one and not more than three of these radicals
are N; [0123] Q is either lower alkoxy or O (oxo), with the proviso
that if Q is lower alkoxy, the waved line representing the bonding
of Q is a single bond and the ring carrying Q has three double
bonds, and if Q is O, the waved line representing the bonding of Q
is a double bond and for each Q=O, one of the double bonds in the
ring is changed to a single bond; and with the proviso that any Q
is bonded to a ring C atom; [0124] R.sub.a and R.sub.a' are each
independently H, halogen or lower alkyl; [0125] X is imino, oxa, or
thia; [0126] Y is hydrogen, aryl, heteroaryl, or unsubstituted or
substituted cycloalkyl; and [0127] Z is mono- or disubstituted
amino, halogen, alkyl, cycloalkyl, substituted alkyl, hydroxy,
etherified or esterified hydroxy, nitro, cyano, carboxy, esterified
carboxy, --OCOR.sub.6, --CH.sub.2OR.sub.3, --OCO.sub.2R.sub.3,
alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,
amidino, guanidino, mercapto, sulfo, alkylthio, especially lower
alkylthio, halogenated lower alkylthio, arylthio, especially
phenylthio or alkylphenylthio, aryl lower alkylthio, especially
phenyl lower alkylthio, arylsulfinyl, especially phenylsulfinyl or
alkylphenylsulfinyl, aryl-lower alkylsulfinyl, especially
phenyl-lower alkylsulfinyl, alkylsulfonyl, especially lower
alkylsulfonyl, halogeno-lower alkylsulfonyl, arylsulfonyl,
especially phenylsulfonyl or alkylphenylsulfonyl, aryl-lower
alkylsulfonyl, especially phenyl-lower alkylsulfonyl, ureido,
C.sub.2-C.sub.7alkenyl, aryl, heteroaryl, especially pyrazolyl or
lower-alkyl pyrazolyl, optionally substituted saturated
heterocyclyl, heteroarylalkyl, heteroaryloxy,
--S(O).sub.p(heteroaryl) or --S(O).sub.p(heteroarylalkyl) wherein p
is 0, 1 or 2, heteroaryloxy, --CHO or --OCON(R.sub.6).sub.2,
--NR.sub.3CO.sub.2R.sub.6 or --NR.sub.3CON(R.sub.6).sub.2 wherein
R.sub.3 and R.sub.6 are as defined above; wherein--if more than 1
radical Z (m.gtoreq.2) is present--the substituents Z are selected
independently from each other, and wherein R.sub.3 and R.sub.6 are
as defined above; [0128] and wherein the bonds characterized in
subformula I* by a wavy line are either single or double bonds;
[0129] with the proviso that when two groups R.sub.6 are each alkyl
and located on the same nitrogen atom, they may be linked by a
bond, an O, an S or NR.sub.3 with R.sub.3 as defined above to form
a N-containing heterocycle of 5 to 7 ring atoms; and with the
proviso that only compounds other than those wherein r is 1, n is
0, R.sub.1 and R.sub.2 together form a bridge of subformula I*
wherein m is 0 and the waved lines represent double bonds,
respectively, G is --CH.sub.2--, T is N, each of A, B, E and T is
CH, Q is methoxy and Y is 4-methyl-3-bromo-phenyl,
4-ethyl-3-bromo-phenyl, 3-chloro-5-trifluoromethyl-phenyl or
4-isopropyl-3-methyl-phenyl fall under the claim; [0130] to the
N-oxides of such compounds of formula I, wherein 1 or more N atoms
carry an oxygen atom; [0131] to the tautomers or mixtures of
tautomers of such compounds of formula I and the N-oxides thereof;
and to the pharmaceutically acceptable salts of such compounds of
formula I, of an N-oxide and of the tautomers and mixtures of
tautomers thereof.
[0132] Preferred is a compound of formula I, wherein Q is O, with
the proviso that the waved line representing the bonding of Q is a
double bond and for each Q=O, one of the double bonds in the ring
is changed to a single bond; and with the proviso that any Q is
bonded to a ring C atom; and the other symbols have the meaning
described for compounds of formula I above; an N-oxide of said
compound of formula I, wherein 1 or more N atoms carry an oxygen
atom; or a tautomer or mixture of tautomers of said compound of
formula I or an N-oxide thereof; or a pharmaceutically acceptable
salt of said compound of formula I, of an N-oxide or of a tautomer
or mixture of tautomers thereof.
[0133] More preferred is a compound of formula I, wherein [0134] r
is 1 or 2, preferably 1, [0135] t is 0, 1 or 2, [0136] n is 0,
[0137] R.sub.1 and R.sub.2 [0138] together form a bridge of
subformula I*, [0139] wherein the bond is achieved via the two
terminal C atoms and [0140] m is 0, [0141] G is lower alkylene,
especially methylene; [0142] A, B, D, E and T are independently N
or CH subject to the proviso that at least one and not more than
three of these radicals are N; [0143] Q is O, with the proviso that
the waved line representing the bonding of Q is a double bond and
for each Q=O, one of the double bonds in the ring is changed to a
single bond; and with the proviso that any Q is bonded to a ring C
atom; [0144] Q' is halogen, NHR.sup.Q, NR.sup.Q.sub.2, OR.sup.Q,
SR.sup.Q, perfluoroalkyl, acyl, substituted or unsubstituted aryl,
or substituted or unsubstituted hetaryl, wherein R.sup.Q represents
acyl, alkyl, or alkyl substituted by hydroxy or halogen; [0145] X
is imino, oxa, or thia, preferably imino; and [0146] Y is (i)
hydrogen; (ii) phenyl which is either unsubstituted or substituted
by one, two or three substituents selected independently of one
another from the group consisting of halogen, especially fluorine,
chlorine, bromine, or iodine; lower alkyl, especially methyl or
preferably ethyl, further propyl or t-butyl; halogen-lower alkyl,
especially trifluoromethyl; (iii) lower-alkyl-[1,3]dioxan-5-yl,
such as cis,trans-, cis- or preferably
trans-2-isopropyl-[1,3]dioxan-5-yl, heteroaryl, or unsubstituted or
substituted cycloalkyl; or lower alkyl-cyclohexyl in cis,trans-
cis- or preferably trans-form, preferably 4-isopropyl-cyclohexyl,
especially in trans-form; [0147] and wherein the bonds
characterized in subformula I* by a wavy line are either single or
double bonds, preferably both double bonds; [0148] or an N-oxide of
said compound of formula I, wherein 1 or more N atoms carry an
oxygen atom; [0149] or a tautomer or mixture of tautomers of said
compound of formula I or an N-oxide thereof; [0150] or a
pharmaceutically acceptable salt of said compound of formula I, of
an N-oxide or of a tautomer or mixture of tautomers thereof.
[0151] Still more preferred is a compound of formula I according to
the preceding definitions wherein r is 1 and [0152] either T is NH,
each of B, D and E is CH, A is C and Q is O bonded at A via a
double bond, with the proviso that the double bond between A and T
is absent; [0153] or (especially preferably) A is NH, each of B, D
and E is CH and T is C and Q is O bonded at T via a double bond;
and the remaining radicals and symbols are as defined above for
compounds of formula for a tautomer or mixture of tautomers of said
compound of formula I; or a pharmaceutically acceptable salt of
said compound of formula I, of a tautomer or of a mixture of
tautomers thereof.
[0154] One preferred embodiment of the invention relates to a
compound of formula I wherein [0155] r is 1, [0156] n is 0, [0157]
t is 0 or 1, [0158] R.sub.1 and R.sub.2 together form a bridge of
subformula I*, [0159] wherein the bond is achieved via the two
terminal C atoms and [0160] m is 0; [0161] G is lower alkylene;
[0162] A, B, and E are CH; [0163] D is CH and T is N or D is N and
T is CH; [0164] Q is either lower alkoxy or O (oxo), with the
proviso that if Q is lower alkoxy, the waved line representing the
bonding of Q is a single bond and the ring carrying Q has three
double bonds, and if Q is O, the waved line representing the
bonding of Q is a double bond and for each Q=O, one of the double
bonds in the ring is changed to a single bond; and with the proviso
that any Q is bonded to a ring C atom; [0165] Q' is halogen,
NHR.sup.Q, wherein R.sup.Q represents lower alkyl; thiazolyl or
furanyl; [0166] X is imino or oxa; [0167] Y is phenyl substituted
by one or two substituents selected from lower alkyl, halogen and
trifluoromethyl; C.sub.5-7cycloalkyl, wherein up to two methylene
groups are replaced by oxa, substituted by lower alkyl; or indolyl
which is substituted by one or two substituents selected from lower
alkyl and halogen; [0168] and wherein the bonds characterized in
subformula I* by a wavy line are double bonds; [0169] and with the
proviso that only compounds other than those wherein G is
--CH.sub.2--, T is N, each of A, B, E and T is CH, Q is methoxy and
Y is 4-methyl-3-bromo-phenyl, 4-ethyl-3-bromophenyl,
3-chloro-5-trifluoromethyl-phenyl or 4-isopropyl-3-methyl-phenyl
fall under the claim; [0170] a tautomer or mixture of tautomers of
a compound of formula I; [0171] a pharmaceutically acceptable salt
of a compound of formula I, of a tautomer or of a mixture of
tautomers thereof.
[0172] Most preferred are the compounds given in the examples,
especially those wherein Q is oxo (O), tautomers or mixtures of
tautomers thereof; or salts of any of these
[0173] A compound of the formula I may be prepared by processes
known per se for other compounds, especially by or in analogy to
any of the methods described in WO 98/35958, WO 00/59509 or WO
01/10859, which are therefore incorporated by reference herewith,
especially
for the preparation of a compound of formula I, in which G is
--CH.sub.2--, by reacting a compound of formula II,
##STR00008##
wherein Q, Q', A, B, D, E, T, R.sub.1, and R.sub.2 are as defined
for a compound of formula I, G is --CH.sub.2-- and L is a
nucleofugal leaving group, with a compound of formula III
H--X--(CR.sub.aR.sub.a').sub.n--Y (III)
wherein n, R.sub.a, R.sub.a', X, and Y are as defined for a
compound of formula I; wherein in compounds of formulae I, II
and/or III functional groups which shall not participate in the
reaction are present in protected form where necessary, and
removing any protective groups present, whereas said starting
compounds may also be present in the form of salts if a
salt-forming group is present and the reaction in salt form is
possible; and, if so desired, converting an obtainable compound of
formula I into another compound of formula I, converting a free
compound of formula I into a salt, converting an obtainable salt of
a compound of formula into the free compound or another salt,
and/or separating a mixture of isomeric compounds of formula I
thereof into the individual isomers, the term "compound of formula
I" in the present paragraph being understood to be directed to the
compounds of formula I, its N-oxides, and/or tautomers or mixtures
of tautomers of any of these.
DETAILED DESCRIPTION OF METHODS
[0174] In the more detailed description of the process method
below, r, n, t, A, B, D, E, T, G, Q, Q', R.sub.a, R.sub.a',
R.sub.1, R.sub.2, X and Y are as defined for compounds of formula
I, unless otherwise indicated.
[0175] In the compound of formula II, a nucleofugal leaving group L
is especially halogen, above all bromine, especially chlorine or
iodine.
[0176] The reaction between the compound of formula II and the
compound of formula III takes place in suitable, inert polar
solvents, especially alcohols, e.g. lower alcohols, such as
methanol, ethanol, propanol, isopropanol or n-butanol, in the
presence of cyclic ethers, especially dioxane, or in the presence
of mixtures of one or more alcohols with one or more cyclic ether,
e.g. in isopropanol/dioxane mixtures; or in a melt without the
addition of a solvent, especially if one of the reaction partners
is present in liquid form. The reaction takes place at elevated
temperatures, preferably between about 60.degree. C. and the reflux
temperature of the solvent used, for example under reflux
conditions, or at a temperature between approximately 70 and
approximately 150.degree. C. (if necessary in a closed vessel). The
compound of formula III may also be used as a salt, for example as
an acid addition salt with a strong acid, such as a hydrogen
halide, for example as a hydrochloride salt, or the corresponding
acid, for example hydrochloric acid, can be added in a suitable
solvent, for example an ether, such as dioxane. If L is iodine, the
reaction is preferably allowed to proceed in presence or absence of
an inert solvent, such as toluene, in the presence of a base,
especially a nitrogen base, such as tributylamine, or an
alkalimetal carbonate, such as dipotassium carbonate, in the
presence of catalytic amounts of
tetrakis-(triphenylphosphin)-palladium, at elevated temperature,
e.g. at 80 to 115.degree. C.
Additional Process Steps
[0177] In the additional process steps which are carried out as
desired, functional groups of the starting compounds which should
not take part in the reaction may be present in unprotected form or
may be protected for example by one or more of the protecting
groups mentioned hereinabove. The protecting groups are then wholly
or partly removed according to one of the methods described.
[0178] If one or more other functional groups, for example carboxy,
hydroxy, amino, or mercapto, are or need to be protected in a
compound of formulae II or III, because they should not take part
in the reaction, these are such as are usually used in the
synthesis of peptide compounds, cephalosporins or penicillins, as
well as nucleic acid derivatives and sugars. The protecting groups
may already be present in precursors and should protect the
functional groups concerned against unwanted secondary reactions,
such as acylations, etherifications, esterifications, oxidations,
solvolysis, and similar reactions. In certain cases, the protecting
groups may, in addition to this protection, effect a selective,
typically stereoselective, course of reactions. It is a
characteristic of protecting groups that they lend themselves
readily, i.e. without undesired secondary reactions, to removal,
typically by solvolysis, reduction, photolysis or also by enzyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products. A
person skilled in the art knows, or can easily establish, which
protecting groups are suitable with the reactions mentioned
hereinabove and hereinafter.
[0179] The protection of functional groups by such protecting
groups, the protecting groups themselves, and their cleavage
reactions are described for example in standard reference works,
such as J. F. W. McOmie, "Protective Groups in Organic Chemistry",
Plenum Press, London and New York 1973, in T. W. Greene,
"Protective Groups in Organic Synthesis", Wiley, New York 1981, in
"The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer),
Academic Press, London and New York 1981, in "Methoden der
organischen Chemie" (Methods of organic chemistry), Houben Weyl,
4th edition, Volume 15/l, Georg Thieme Verlag, Stuttgart 1974, in
H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine"
(Amino acids, peptides, proteins), Verlag Chemie, Weinheim,
Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der
Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of
carbohydrates: monosaccharides and derivatives), Georg Thieme
Verlag, Stuttgart 1974.
[0180] Salts of a compound of formula I (or an N-oxide, a tautomer
or a mixture of tautomers thereof) with a salt-forming group may be
prepared in a manner known per se. Acid addition salts may thus be
obtained by treatment with an acid or with a suitable anion
exchange reagent. A salt with two acid molecules (for example a
dihalogenide of a compound of formula I (or an N-oxide, a tautomer
or a mixture of tautomers thereof)) may also be converted into a
salt with one acid molecule per compound (for example a
monohalogenide); this may be done by heating to a melt, or for
example by heating as a solid under a high vacuum at elevated
temperature, for example from 130 to 170.degree. C., one molecule
of the acid being expelled per molecule of a compound according to
the invention. Salts can usually be converted to free compounds,
e.g. by treating with suitable basic agents, for example with
alkali metal carbonates, hydrogencarbonates, or hydroxides,
typically potassium carbonate or sodium hydroxide.
[0181] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can
be separated into their corresponding isomers in a manner known per
se by means of suitable separation methods. Diastereomeric mixtures
for example may be separated into their individual diastereomers by
means of fractionated crystallization, chromatography, solvent
distribution, and similar procedures. This separation may take
place either at the level of one of the starting compounds or in a
compound of formula I itself. Enantiomers may be separated through
the formation of diastereomeric salts, for example by salt
formation with an enantiomer-pure chiral acid, or by means of
chromatography, for example by HPLC, using chromatographic
substrates with chiral ligands.
[0182] A compound of formula I wherein Q is oxo is prepared from a
compound wherein Q is lower alkoxy (obtainable by the process shown
above or in analogy to the methods described in WO 98/35958, WO
00/59509 or WO 01/10859) by reacting a tri-lower
alkylsilylhalogenide, especially -iodide, most preferably
trimethylsilyl-iodide, in an appropriate solvent, especially a
halogenated hydrocarbon, such as trichloromethane or
methylenechloride, at elevated temperature, e.g. at a temperature
between 30.degree. C. and the reflux temperature, especially at 55
to 65.degree. C., preferably with subsequent addition of a base,
such as a nitrogen base or especially a metal carbonate or metal
hydrogen carbonate, such as an alkali metal carbonate or -hydrogen
carbonate, in a mixture of water, an alcohol, especially methanol,
and an ester, especially a lower alkyl-alkanoate, preferably ethyl
acetate, preferably at a temperature between 0 and 50.degree. C.,
e.g. at ambient temperature. Other methods of ether cleavage can
make use of Lewis acids, such as BF.sub.3, BCl.sub.3,
(CH.sub.3).sub.2B--Br, BBr.sub.3 or AlCl.sub.3 (see e.g. Jerry
March, "Advanced Organic Chemistry--Reactions, Mechanisms and
Structure", 4.sup.th edition, Wiley-Interscience 1992), page 434,
and references cited therein).
[0183] Other transformations of a compound of the formula I, an
N-oxide, a tautomer or mixture of tautomers of any of these or a
salt of any of these, respectively, can be made in analogy to the
additional process steps described in WO 98/35958, WO 00/59509 or
WO 01/10859, which are therefore incorporated by reference
herewith.
General Process Conditions
[0184] All process steps described here can be carried out under
known reaction conditions, especially those described as General
process conditions in WO 98/35958 and WO 00/59509, which are
therefore incorporated by reference herewith.
[0185] The invention relates also to those forms of the process in
which one starts from a compound obtainable at any stage as an
intermediate and carries out the missing steps, or breaks off the
process at any stage, or forms a starting material under the
reaction conditions, or uses said starting material in the form of
a reactive derivative or salt, or produces a compound obtainable by
means of the process according to the invention and processes said
compound in situ. In the preferred embodiment, one starts from
those starting materials which lead to the compounds described
hereinabove as preferred, particularly as especially preferred,
primarily preferred, and/or preferred above all.
[0186] In the preferred embodiment, a compound of formula I is
prepared according to or in analogy to the processes and process
steps defined in the Examples.
[0187] The compounds according to the invention, including their
salts, are also obtainable in the form of hydrates, or their
crystals can include for example the solvent used for
crystallization (present as solvates).
Pharmaceutical Preparations, Methods, and Uses
[0188] The present invention relates also to pharmaceutical
compositions that comprise a compound of formula I as active
ingredient and that can be used especially in the treatment of the
diseases mentioned at the beginning. Compositions for enteral
administration, such as nasal, buccal, rectal or, especially, oral
administration, and for parenteral administration, such as
intravenous, intramuscular or subcutaneous administration, to
warm-blooded animals, especially humans, are especially preferred.
The compositions comprise the active ingredient (a compound of the
formula I, ist N-oxide, tautomers or tautomer mixtures of any of
these or a pharmaceutically acceptable salt of any of these) alone
or, preferably, together with a pharmaceutically acceptable
carrier. The dosage of the active ingredient depends upon the
disease to be treated and upon the species, its age, weight, and
individual condition, the individual pharmacokinetic data, and the
mode of administration.
[0189] The invention relates also to pharmaceutical compositions
for use in a method for the prophylactic or especially therapeutic
management of the human or animal body, to a process for the
preparation thereof (especially in the form of compositions for the
treatment of tumours) and to a method of treating tumour diseases,
especially those mentioned above, where a compound of the formula I
is used.
[0190] The invention relates also to processes and to the use of
compounds of formula I for the preparation of pharmaceutical
preparations which comprise compounds of formula I as active
component (active ingredient).
[0191] The said pharmaceutical preparations may also, if so
desired, comprise other active components, for example cytostatic
agents, and/or be used in combination with known therapeutic
methods, for example the administration of hormones or
irradiation.
[0192] Preference is for a pharmaceutical preparation which is
suitable for administration to a warm-blooded animal, especially
humans or commercially useful mammals suffering from an
inflammatory rheumatoid or rheumatic disease and/or pain, or a
disease which responds to an inhibition of angiogenesis or of
VEGF-receptor tyrosine kinase, for example psoriasis or especially
a neoplastic disease, comprising an effective quantity of a
compound of formula I for the inhibition of angiogenesis or of
VEGF-receptor tyrosine kinase, or a pharmaceutically acceptable
salt thereof, if salt-forming groups are present, together with at
least one pharmaceutically acceptable carrier.
[0193] A pharmaceutical composition for the prophylactic or
especially therapeutic management of a rheumatoid or rheumatic
inflammatory disease and/or pain, or a neoplastic and other
proliferative disease of a warm-blooded animal, especially a human
or a commercially useful mammal requiring such treatment,
especially suffering from such a disease, comprising as active
ingredient in a quantity that is prophylactically or especially
therapeutically active against said diseases a new compound of
formula I, is likewise preferred.
[0194] The pharmaceutical compositions comprise from approximately
1% to approximately 95% active ingredient, single-dose
administration forms comprising in the preferred embodiment from
approximately 20% to approximately 90% active ingredient and forms
that are not of single-dose type comprising in the preferred
embodiment from approximately 5% to approximately 20% active
ingredient. Unit dose forms are, for example, coated and uncoated
tablets, ampoules, vials, suppositories, or capsules. Examples are
capsules containing from about 0.05 g to about 1.0 g of active
substance.
[0195] The pharmaceutical compositions of the present invention are
prepared in a manner known per se, for example by means of
conventional mixing, granulating, coating, dissolving or
lyophilizing processes.
[0196] Pharmaceutical compositions for oral administration can be
obtained, for example, by combining the active ingredient with one
or more solid carriers, if need be granulating a resulting mixture,
and processing the mixture or granules, if desired, to form tablets
or tablet cores, if need be by the inclusion of additional
excipients.
[0197] Suitable carriers are especially fillers, such as sugars,
cellulose preparations, and/or calcium phosphates, and also
binders, such as starches, methylcellulose, and/or
polyvinylpyrrolidone, and/or disintegrators. Additional excipients
are especially flow conditioners and lubricants, for example
silicic acid, talc, stearic acid or salts thereof and/or
polyethylene glycol, or derivatives thereof.
[0198] Tablet cores may be provided with suitable coatings. Orally
administrable pharmaceutical compositions also include hard
capsules consisting of gelatin, and also soft, sealed capsules
consisting of gelatin and a plasticiser, such as glycerol or
sorbitol. In soft capsules, the active ingredient is preferably
dissolved or suspended in suitable liquid excipients, such as fatty
oils.
[0199] Suitable rectally administrable pharmaceutical compositions
are, for example, suppositories that consist of a combination of
the active ingredient and a suppository base.
[0200] The aqueous solutions suitable for parenteral administration
are especially those of an active ingredient in water-soluble form,
for example in the form of a water-soluble salt, or aqueous
injection suspensions that contain viscosity-increasing substances.
Solutions such as are used for parenteral administration can also
be employed as infusion solutions.
[0201] The invention relates likewise to a process or a method for
the treatment of one of the pathological conditions mentioned
hereinabove, especially an inflammatory rheumatic or rheumatoid
disease and/or pain, or a disease which responds to an inhibition
of the VEGF-receptor tyrosine kinase or an inhibition of
angiogenesis, especially a corresponding neoplastic disease or also
psoriasis. The compounds of formula I can be administered as such
or in the form of pharmaceutical compositions, prophylactically or
therapeutically, preferably in an amount effective against said
diseases, to a warm-blooded animal, for example a human, requiring
such treatment, the compounds especially being used in the form of
pharmaceutical compositions. In the case of an individual having a
body weight of about 70 kg the daily dose administered is from
approximately 0.1 g to approximately 5 g, preferably from
approximately 0.5 g to approximately 2 g, of a compound of formula
I.
[0202] The present invention relates especially also to the use of
a compound of formula I (in this paragraph meaning the compound of
formula I, an N-oxide thereof, or a tautomer or tautomeric mixture
of any of these), or a pharmaceutically acceptable salt thereof,
especially a compound of formula I which is said to be preferred,
or a pharmaceutically acceptable salt thereof, as such or in the
form of a pharmaceutical formulation with at least one
pharmaceutically acceptable carrier for the therapeutic and also
prophylactic management of one or more of the diseases mentioned
hereinabove, preferably an inflammatory rheumatic or rheumatoid
disease and/or pain, or especially a disease which responds to an
inhibition of VEGF-receptor tyrosine kinase or an inhibition of
angiogenesis, especially a neoplastic disease or also psoriasis,
above all if said disease responds to an inhibition of
VEGF-receptor tyrosine kinase or angiogenesis.
[0203] The present invention relates especially also to the use of
a compound of formula I as defined in the last paragraph, or a
pharmaceutically acceptable salt thereof, especially a compound of
formula I which is said to be preferred, or a pharmaceutically
acceptable salt thereof, for the preparation of a pharmaceutical
formulation for the therapeutic and also prophylactic management of
one or more of the diseases mentioned hereinabove, especially a
rheumatic or rheumatoid inflammatory disease and/or pain, or
especially a neoplastic disease or also psoriasis, above all if the
disease responds to an inhibition of VEGF-receptor tyrosine kinase
or angiogenesis. The preferred dose quantity, composition, and
preparation of pharmaceutical formulations (medicines) to be used
in each case are described above.
Starting Materials
[0204] New starting materials and/or transients, as well as
processes for the preparation thereof, are likewise the subject of
this invention. In the preferred embodiment, such starting
materials are used and reaction conditions so selected as to enable
the preferred compounds to be obtained.
[0205] The starting materials of formulae II and III are known,
capable of being prepared according to known processes, or
commercially obtainable; in particular, they can be prepared using
processes as described in the Examples.
[0206] In the preparation of starting materials, existing
functional groups which do not participate in the reaction should,
if necessary, be protected. Preferred protecting groups, their
introduction and their removal are described hereinabove or in the
Examples. In place of the respective starting materials and
transients, salts thereof may also be used for the reaction,
provided that salt-forming groups are present and the reaction with
a salt is also possible. Where the term starting materials is used
hereinbefore and hereinafter, the salts thereof are always
included, insofar as reasonable and possible.
[0207] A compound of formula II, wherein G is --CH.sub.2-- and the
remaining symbols are as defined under formula I, can be prepared
for example by reacting an aldehyde of formula IV,
##STR00009##
wherein Q is lower alkoxy and A, B, D, E, Q', T, t and r are as
defined for compounds of formula I, with a
triphenylphosphonium-halide, especially -chloride, of the formula
V,
##STR00010##
wherein R.sub.1 and R.sub.2 are as defined for a compound of
formula I and Hal is halogen, especially Cl, in the presence of an
appropriate solvent, e.g. an ether, especially tetrahydrofurane,
and a tertiary amine, especially triethylamine, preferably at
lowered temperature, e.g. between -10 and 15.degree. C., resulting
in a lactone compound of the formula VI,
##STR00011##
wherein R.sub.1, R.sub.2, A, B, D, E, Q', T, t and r have the
meanings given under formula I and Q is lower alkoxy, which
compound is then converted by reaction with hydrazine (preferably
in the form of ist hydrate), preferably in the presence of a
solvent or solvent mixture, such as a cyclic ether, especially
tetrahydrofuran, and/or water, at an elevated temperature,
preferably between 50.degree. C. and reflux temperature, to the
corresponding phthalazine analogue of the formula VII,
##STR00012##
wherein the symbols are as defined for compounds of the formula VI;
the compound of formula VII is then be converted to the
corresponding compound of formula II, wherein L is halogen,
especially chlorine, G is methylene, and the remaining radicals are
as defined under formula I, by reaction with a phosphoryl halide or
phosphorus pentahalide, especially phosphoryl chloride (POCl.sub.3)
or phosphorus pentachloride without solvent or in a suitable
solvent, for example acetonitrile, at preferred temperatures
between 40.degree. C. and reflux temperature, preferably under
reflux, preferably in the presence of the respective hydrohalic
acid, e.g. HCl. Instead of halogen L, another nucleofugal radical
(e.g. tosyl) can be introduced by substitution under customary
conditions
[0208] The starting materials of formula IV are known, capable of
being prepared according to known processes, or commercially
obtainable; in particular, they can be prepared using processes in
analogy to those described in the Examples.
[0209] Other starting materials are known, capable of being
prepared according to known processes, or commercially available;
in particular, they can be prepared using processes identical or
analogous to those described in the Examples.
EXAMPLES
[0210] The subsequent examples serve for illustrating the invention
without limiting the scope thereof. Temperatures are represented in
degree Celsius (.degree. C.). If not mentioned otherwise, reactions
take place at room temperature.
HPLC-Gradient:
[0211] Grad.sub.20-100 20%.fwdarw.100% a) in b) during 13 min+5 min
100% a). [0212] Grad.sub.5-40 5% 40% a) in b) during 9 min+7 min
40% a). Eluent a): Acetonitrile+0.05% TFA; Eluent b): Water+0.05%
TFA. Column (250.times.4.6 mm) filled with reversed-phase-material
C18-Nucleosil (5 .mu.m mean bead diameter, silicagel covalently
modified with octadecylsilanes, Macherey & Nagel, Duren, BRD).
Detection: UV-absorption at 215 nm. Retention times (t.sub.Ret) are
represented in minutes. Flow rate 1 ml/min.
[0213] The further short names and abbreviations used have the
following meanings:
Ex. example DIPE di-isopropyl-ether DMF dimethylformamide DMSO
dimethylsulfoxide ES-MS "Elektron Spray" mass spectroskopie Ether
diethylether EtOAc ethyl acetate FAB-MS "Fast Atom Bombardement"
mass spectroskopie sat. saturated h hour(s) min minute(s) RT room
temperature RE rotary evaporator m.p. Melting point brine saturated
sodium chloride solution TFA trifluoroacetic acid THF
tetrahydrofurane (dest. over Na/benzophenone)
Example 1
trans
1-(4-Isopropyl-cyclohexylamino)-4-[2-hydroxy-(pyridin-4-yl)-methyl]--
phthalazine
[0214] Under N.sub.2-atmosphere, 0.28 ml (2.05 mMol) Me.sub.3SiI
are added to 400 mg (1.02 mMol) of trans
1-(4-isopropyl-cyclohexylamino)-4-[2-methoxy-(pyridin-4-yl)-methyl]-phtha-
lazine in 10 ml chloroform, and the resulting mixture is stirred
during 20 h at 60.degree. C. After cooling to RT, 5 ml sat.
NaHCO.sub.3-solution, 5 ml water, 20 ml EtOAc and a small amount of
methanol are added, followed by agitation. The resulting white
crystals are filtered off, washed with water and dried, yielding
the title compound: M.p. 266-267.degree. C. (decomposition);
FAB-MS: (M+H).sup.+=377; HPLC (Grad.sub.20-100) t.sub.Ret=10.3).
From the filtrate, by extraction with EtOAc, washing of the organic
phase with water and brine, drying (Na.sub.2SO.sub.4), evaporation
and crystallisation from dichlormethane/methanol under addition of
ether, more product results.
[0215] The starting materials are prepared as follows:
[0216] 1a)
3-[1-(2-Methoxy-pyridin-4-yl)-methyliden]-3.H.-isobenzofuran-1--
one: Under exclusion of air, 4.6 g (10.7 mMol) of
1,3-dihydro-3-oxo-1-isobenzofuranyl-triphenyl-phosphonium chloride
(preparation see J. Organomet. Chem. 1972, 42, 391) and 1.85 ml (13
mMol) triethylamine are added to an ice-cooled solution of 1.75 g
(12.8 mMol) 2-methoxy-pyridin-4-carbaldehyde (preparation see Eur.
J. Med. Chem. 1993, 28, 601) in 29 ml THF. After stirring for 2 h
in the ice bath, the mixture is suction-filtered, the remainder is
washed out with EtOAc and the filtrate is evaporated yielding the
title compound (mixture of the double bond isomers, further
containing triphenyl phosphinoxide): HPLC (Grad.sub.20-100)
t.sub.Ret=12.1/12.6
[0217] 1b) 4-[2-Methoxy-pyridin-4-yl)methyl]phthalazin-1(2H)-one:
4.4 g (17 mMol)
3-[1-(2-methoxypyridin-4-yl)-methyliden]-3.H.-isobenzofuran-1-o- n
in 60 ml THF and 60 ml hydrazine-hydrate are stirred during 75 min
under reflux. After cooling to RT, the mixture is diluted with
water and EtOAc, and the aqueous phase is separated off and
extracted twice with EtOAc. The organic phases are extracted three
times each with 26 ml 1 N HCl, and the acidic aqueous phases are
made alkaline with 1 N NaOH and extracted three times with EtOAc.
The EtOAc extracts are washed twice with water and brine, dried
(Na.sub.2SO.sub.4) and partially evaporated in a RE. Under
agitation, the title compound crystallizes out from the residue and
is filtered off: FAB-MS: (M+H).sup.+=268; HPLC (Grad.sub.20-100)
t.sub.Ret=7.9.
[0218] 1c) 1-Chloro-4-[2-methoxy-pyridin-4-yl)methyl]phthalazine:
Under exclusion of humidity, 1.7 ml (19 mMol) phosphorous
oxychloride and 3.8 ml 4 N HCl in dioxane are added to 2.0 g (7.5
mMol) 4-[2-methoxy-pyridin-4-yl)methyl]phthalazin-1(2H)-one in 40
ml of acetonitrile. After 15 h of agitation at 65.degree. C., the
mixture is cooled, and the precipitate is filtered off and is
washed with acetonitrile*. The residue is dissolved in 25 ml of
water, and 15 ml of 2.5% NH.sub.3 solution are added. The title
compound precipitating in the course of this is filtered off,
washed with water, dried, redissolved in THF and crystallized by
addition of hexane: M.p. 105-106.degree. C.; FAB-MS:
(M+H).sup.+=286. *From the filtrate, by distribution between EtOAc,
2.5% NH.sub.3 solution, water and brine, further product can be
obtained.
[0219] 1d) trans
1-(4-Isopropyl-cyclohexylamino)-4-[2-methoxy-(pyridin-4-yl)-methyl]-phtha-
lazine: Under N.sub.2 atmosphere, in an ampoule 1.73 g (12 mMol) of
trans 4-isopropyl-cyclohexylamine (preparation see Arzneim. Forsch.
1969, 19, 140) and 700 mg (2.4 mMol) of
1-chloro-4-[2-methoxy-pyridin-4-yl)methyl]phthalazine are heated
during 17 h at 140.degree. C. The reaction mixture is suspended in
EtOAc, and 1.5 ml of NH.sub.3 solution (25%) and water are added.
The isolated aqueous phase is extracted another two times with
EtOAc, and the organic phases are washed with water and brine,
dried (Na.sub.2SO.sub.4) and evaporated to dryness. Column
chromatography (SiO.sub.2; hexane/EtOAc 1:1) results in the title
compound: M.p. 65-66.degree. C.; FAB-MS: (M+H).sup.+=391.
Example 2
1-(3-Bromo-4-ethyl-anilino)-4-[2-hydroxy-(pyridin-4-yl)-methyl]-phthalazin-
e
[0220] In analogy to Ex. 1, 500 mg (1.11 mMol) of
1-(3-bromo-4-ethyl-anilino)-4-[2-methoxy-(pyridin-4-yl)-methyl]-phthalazi-
ne in 12 ml of chloroform are reacted with 0.3 ml (2.2 mMol)
Me.sub.3SiI to give the title compound: M.p. 251-252.degree. C.;
FAB-MS: (M+H).sup.+=435/437; HPLC (Grad.sub.20-100)
t.sub.Ret=9.6.
[0221] The starting materials are prepared as follows:
[0222] 2a) 3-Bromo-4-ethyl-aniline: Obtained by hydrogenation of
4.45 g (19 mMol) of 3-bromo-4-ethyl-nitrobenzene (preparation see
Macromolecules 1995, 28, 5618) in 100 ml of ethanol in the presence
of 1 g Raney nickel, filtration, evaporation and column
chromatography (SiO.sub.2; methylenechloride): .sup.1H NMR
(CDCl.sub.3) .delta. 6.94 (d, 1H), 6.82 (s, 1H), 6.50 (d, 1H), 3.50
(s, H.sub.2N), 2.57 (q, 2H), 1.10 (t, 3H).
[0223] 2b)
1-(3-Bromo-4-ethyl-anilino)-4-[2-methoxy-(pyridin-4-yl)-methyl]-
-phthalazine: Under N.sub.2-atmosphere, 0.73 g (3.7 mMol)
3-bromo-4-ethyl-aniline and 0.82 ml 4 N HCl/dioxane are added to
1.00 g (3.5 mMol)
1-chloro-4-[2-methoxy-pyridin-4-yl)methyl]phthalazine in 12 ml
methanol, and the mixture is stirred for 2 h at 70.degree. C. After
cooling, the resulting yellow solution is diluted with EtOAc and
2.5% NH.sub.3 solution, and the aqueous phase is removed and
extracted twice with EtOAct. The organic phases are washed with
water and brine, dried (Na.sub.2SO.sub.4) and evaporated with a RE.
After addition of DIPE to the residue, the title compound
crystallizes out: M.p. 133-135.degree. C.; FAB-MS:
(M+H).sup.+=449/451; HPLC (Grad.sub.20-100) t.sub.Ret=11.4.
Example 3
1-(4-tert-Butyl-anilino)-4-[6-hydroxy-(pyridin-3-yl)-methyl]-phthalazine
[0224] Under protective gas, 0.37 ml (2.6 mMol) of Me.sub.3SiI are
added to 500 mg (1.3 mMol) of
1-(4-tert-butylanilino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-phthalazine
in 15 ml of chloroform, and the mixture is stirred during 6 h at
60.degree. C. After cooling to RT, 20 ml of sat. NaHCO.sub.3
solution, 10 ml of water, 200 ml of EtOAc and a small amount of
methanol are added, followed by agitation until all is dissolved.
The aqueous phase is removed and extracted twice with EtOAc. The
organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and evaporated partially with a RE. During this
procedure, the title compound crystallizes out: M.p.
277-278.degree. C. (decomposition); FAB-MS: (M+H).sup.+=385; HPLC
(Grad.sub.20-100) t.sub.Ret=9.8.
[0225] The starting materials are prepared as follows:
[0226] 3a) 6-Methoxy-pyridin-3-carbaldehyde: 10 g (71.9 mMol) of
2-methoxy-5-hydroxymethylpyridine (preparation see Heterocycl.
Commun. 1999, 5, 257) are dissolved in 160 ml of DMSO and 30 ml
(215 mMol) of triethylamine. At RT (exothermic--cool!), 34.3 g (215
mMol) of sulfur trioxide pyridine complex in 160 ml DMSO are added
dropwise, and the mixture is stirred 1 h at RT. The mixture is
poured into water and extracted three times with EtOAc. The organic
phases are washed with water and brine, dried (Na.sub.2SO.sub.4)
and evaporated to yield the title compound: HPLC (Grad.sub.5-40)
t.sub.Ret=12.9.
[0227] 3b)
3-[1-(6-Methoxy-pyridin-3-yl)-methyliden]-3.H.-isobenzofuran-1--
one: Under exclusion of air, 38.7 g (89.8 mMol) of
1,3-dihydro-3-oxo-1-isobenzofuranyl-triphenyl-phosphonium chloride
(preparation see J. Organomet. Chem. 1972, 42, 391) and 11 ml (79
mMol) of triethylamine are added to an ice-cooled solution of 9.9 g
(72 mMol) of 6-methoxy-pyridin-3-carbaldehyde in 150 ml THF. After
stirring 2 h on the ice bath, the mixture is filtrated, the residue
is washed out with EtOAc and the filtrate is evaporated, yielding
the double bond isomers of the title compound, further containing
triphenyl phosphinoxide): FAB-MS: (M+H).sup.+=254.
[0228] 3c) 4-[6-Methoxy-pyridin-3-yl)methyl]phthalazin-1(2H)-one:
38.9 g of the raw
3-[1-(6-methoxypyridin-3-yl)-methyliden]-3.H.-isobenzofuran-1-one
just mentioned in 400 ml of THF and 400 ml of hydrazine hydrate are
stirred for 90 min at 80.degree. C. After cooling to RT, the
mixture is diluted with 1.5 l of water and 1 l of EtOAc, and the
water phase is removed and extracted a further two times with
EtOAc. The organic phases are washed with water and then extracted
three times each with 400 ml of 1 N HCl, and the acidic aqueous
phases are made alkaline with 4 N NaOH and extracted three times
each with 400 ml EtOAc. The resulting EtOAc extracts are washed
with water and brine, dried (Na.sub.2SO.sub.4) and evaporated
partially using a RE. During that procedure, the title compound
crystallizes out and is obtained by filtration: FAB-MS:
(M+H).sup.+=268; HPLC (Grad.sub.20-100) t.sub.Ret=7.7.
[0229] 3e) 1-Chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine:
Excluding humidity, 13 ml (142 mMol) of phosphorous oxychloride and
20 ml of 4 N HCl in dioxane are added to 10.8 g (40 mMol) of
4-[6-methoxy-pyridin-3-yl)methyl]phthalazin-1(2H)-one in 170 ml of
acetonitrile. After stirring for 24 h at 75.degree. C., the mixture
is cooled, and the precipitate is filtered off and washed out with
acetonitrile *. The residue is dissolved in 150 ml of water, and
170 ml of 2.5% NH.sub.3 solution are added. The precipitate forming
during that procedure is re-dissolved by addition of EtOAc, and the
aqueous phase is removed and extracted twice with EtOAc. The
organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and evaporated partially with a RE. This caused
the title compound to crystallize out, which is filtered off: M.p.
134-135.degree. C.; FAB-MS: (M+H).sup.+=286. *From the filtrate, by
distribution between EtOAc, 2.5% NH.sub.3 solution, water and brine
and column chromatography (SiO.sub.2; methylenechloride,
methylenechloride/EtOAc 9:1.fwdarw.7:3.fwdarw.EtOAc) further
product is obtained.
[0230] 3f)
1-(4-tert-Butyl-anilino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-ph-
thalazine: Under N2 atmosphere, 0.40 g (2.7 mMol) of
4-tert-butyl-aniline and 0.62 ml 4 N HCl/dioxane are added to 750
mg (2.6 mMol) of
1-chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine in 11 ml of
methanol, and the mixture is stirred for 2 h at 65.degree. C. After
cooling, the resulting yellow solution is diluted with EtOAc, 20 ml
of water and 10 ml of 2.5% NH.sub.3 solution, and the aqueous phase
is removed and extracted twice with EtOAc. The organic phases are
washed with water and brine, dried and partially evaporated with a
RE. After addition of DIPE to the remnant, the title compound
crystallizes out: FAB-MS: (M+H).sup.+=399; HPLC (Grad.sub.20-100)
t.sub.Ret=11.9.
Example 4
trans
1-(4-Isopropyl-cyclohexylamino)-4-[6-hydroxy-(pyridin-3-yl)-methyl]--
phthalazine
[0231] Under N.sub.2 atmosphere, 0.35 ml (2.6 mMol) of Me.sub.3SiI
are added to 500 mg (1.3 m Mol) of trans
1-(4-isopropyl-cyclohexylamino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-phtha-
lazine in 15 ml of chloroform, followed by stirring for 16 h at
60.degree. C. After cooling to RT, 15 ml of sat. NaHCO.sub.3
solution, 10 ml of water, EtOAc and a small amount of methanol are
added, followed by agitation. From the resulting solution, the
aqueous phase is removed and extracted twice with EtOAc. The
organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and evaporated to dryness. Crystallization by
partial evaporation of a solution in methanol results in the title
compound: M.p. 271-272.degree. C. (decomposition); FAB-MS:
(M+H).sup.+=377; HPLC (Grad.sub.20-100) t.sub.Ret=10.2.
[0232] The starting materials are prepared as follows:
[0233] 4a) trans
1-(4-Isopropyl-cyclohexylamino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-phtha-
lazine: Under N.sub.2 atmosphere, in an ampoule 1.8 g (12.7 mMol)
of trans 4-isopropyl-cyclohexylamine (preparation see Arzneim.
Forsch. 1969, 19, 140) and 700 mg (2.4 mMol) of
1-chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine are heated
during 14 h at 140.degree. C. The suspension is dissolved by
dilution with EtOAc, 1.5 ml of NH.sub.3 solution (25%) and water,
and the aqueous phase is removed and extracted twice with EtOAc.
The organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and evaporated. Crystallization from
EtOAc/hexane 1:1 results in the title compound: M.p.
124-125.degree. C.; FAB-MS: (M+H).sup.+=391; HPLC (Grad.sub.20-100)
t.sub.Ret=12.4.
Example 5
trans
1-(2-Isopropyl-[1,3]dioxan-5-ylamino)-4-[6-hydroxy-(pyridin-3-yl)-me-
thyl]-phthalazine
[0234] Under N.sub.2 atmosphere, 320 mg (2.2 mMol) of
trans-2-isopropyl-[1,3]dioxan-5-ylamine and 400 mg (1.1 mMol) of
1-iodo-4-[6-hydroxy-pyridin-3-yl)methyl]phthalazine in 4 ml of
tributylamine are heated for 8 h at 85.degree. C. The reaction
mixture is taken up by dilution with EtOAc and a small amount of
methanol and diluted. NaHCO.sub.3 solution, and the aqueous phase
is removed and extracted twice with EtOAc. The organic phases are
washed with water and brine, dried (Na.sub.2SO.sub.4) and
evaporated to dryness. Reversed phase medium-pressure
chromatography (water/acetonitrile/TFA) yields the title compound:
.sup.1H NMR (DMSO-d.sub.6) .delta. 11.4 (s, 1H), 8.28 und 8.12 (2d,
2 HC), 7.87 (m, 2 HC), 7.33 (m, 2 HC), 6.99 (s, HN), 6.24 (d, HC),
4.54 (m, 1H), 4.27 (m, 3H), 4.19 (s, H.sub.2C), 3.59 (t, 2H), 1.79
(m, 1H), 0.92 (d, 2H.sub.3C); FAB-MS: (M+H).sup.+=381; HPLC
(Grad.sub.20-100) t.sub.Ret=7.9.
[0235] The starting materials are obtained as follows:
[0236] 5a) 1-Iodo-4-[6-hydroxy-pyridin-3-yl)methyl]phthalazine:
Excluding humidity, 0.5 ml (3.6 mMol) of Me.sub.3SiI are added to
500 mg (1.7 mMol) of
1-chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine (Ex. 3e) in
20 ml chloroform and stirred at 60.degree. C. After 5 h and 20 h of
agitating, again each time 0.5 ml of Me.sub.3SiI are added. After a
total of 38 h, the mixture is cooled. Suction filtration and
washing with chloroform results in the title compound which is used
directly in Ex. 5: FAB-MS: (M+H).sup.+=364; HPLC (Grad.sub.20-100)
t.sub.Ret=8.3.
[0237] 5b) 2-Benzyloxy-carbonylamino-1,3-propandiole: On an ice
bath, 11.7 g (85 mMol) of K.sub.2CO.sub.3 and 10.5 ml (95%; 71
mMol) of benzyl chloroformate are added to a solution of 5.4 g (59
mMol) of 2-amino-1,3-propandiole in 50 ml of THF and 5 ml of water.
After 1 h at 0.degree. C., the mixture is stirred overnight at RT.
The mixture is then diluted with EtOAc, the water is removed with
solid Na.sub.2SO.sub.4, filtration follows and the residue is
washed with EtOAc. During evaporation of the filtrate, the title
compound is crystallizing out and is filtered off and washed with
hexane: M.p. 108-109.degree. C.; FAB-MS: (M+H).sup.+=226.
[0238] 5c) Benzyl-(2-isopropyl-[1,3]dioxan-5-yl)-carbamate: Under
water separation, a solution of 10.1 g (44.8 mMol) of
2-benzyloxy-carbonylamino-1,3-propandiole, 123 mg of
p-toluene-sulfonic acid and 4.2 ml (46 mMol) of isobutyraldehyde is
boiled in 100 ml of benzene. After 5 h, again 4.2 ml of
isobutyraldehyde are added. After 16 h the mixture is cooled down.
This results in the precipitation of platelets. Filtration and
washing with hexane produces
trans-benzyl-(2-isopropyl-[1,3]dioxan-5-yl)-carbamate: M.p.
152.degree. C.; FAB-MS: (M+H).sup.+=226. Washing of the filtrate
with NaHCO.sub.3 solution, water and brine, drying
(Na.sub.2SO.sub.4) and evaporation yields a cis-/trans mixture of
the title compound from which, by crystallization from boiling
toluene (with a small amount of p-toluenesulfonic acid) more of the
trans isomer is obtained.
[0239] 5e) trans 2-Isopropyl-[1,3]dioxan-5-ylamine: Hydrogenation
of 4.07 g (14.6 mMol) of trans
benzyl-(2-isopropyl-[1,3]dioxan-5-yl)-carbamate in 80 ml of EtOAc
in the presence of 0.4 g of 10% Pd/C, followed by filtration
through Celite and evaporation, yields the title compound: .sup.1H
NMR (CDCl.sub.3) .delta. 4.11 (m, 3H), 3.20 (t, 10.5 Hz, 2H), 3.04
(m, 1H), 1.80 (m, 1H), 1.56 (sb, H.sub.2N), 0.93 (d, 6H).
[0240] In analogy to Ex. 3, the following derivatives of structural
type A are obtained from which by cleavage (Me.sub.3SiI/hydrolysis)
the respective compounds of structural type B are obtained:
TABLE-US-00001 ##STR00013## Structural HPLC t.sub.Ret FAB-MS M.p.
Ex. Y--NH Type (Grad.sub.20-100) (M + H).sup.+ [.degree. C.] 6a6
##STR00014## AB 10.9 8.5 411397 165226-227 7a7* ##STR00015## AB
12.610.5 479465 287-288 8a**8 ##STR00016## AB 12.0 9.3
449/451435/437 171-172273-274 9a9* ##STR00017## AB 425411 183-184
10a***10* ##STR00018## AB 12.610.4 477/479463/465 168-169277-278
11a11 ##STR00019## AB 12a12 ##STR00020## AB *obtained directly as
by-product of the reaction of
chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine with the
respective aniline derivative and separated off by column
chromatography. **preparation of 3-bromo-4-ethyl-aniline see Ex.
2a. ***analogously, 3-bromo-4-(tert-butyl)-aniline is obtained by
hydrogenation of 3-bromo-4-(tert-butyl)-nitrobenzene
(Maybridge).
Example 13
trans-1-(2-Isopropyl-[1,3]dioxan-5-ylamino)-4-[6-methoxy-(pyridin-3-yl)met-
hyl]phthalazin
[0241] In analogy to Example 4a, starting from 408 mg (2.8 mMol) of
trans-2-isopropyl[1,3]dioxan-5-ylamine (Ex. 5e) and 400 mg (1.4
mMol) 1-chloro-4-[6-methoxypyridin-3-yl)methyl]phthalazine, the
title compound is obtained: m.p. 186-187.degree. C.; FAB-MS:
(M+H).sup.+=395; HPLC (Grad.sub.20-100) t.sub.Ret=9.7.
[0242] In analogy to Ex. 2, cleavage of derivatives of structural
type A with Me.sub.3SiI and hydrolysis yields the respective
compounds of structural type B:
TABLE-US-00002 ##STR00021## Struktural HPLC t.sub.Ret FAB-MS Smp.
Expl. Y--NH Type (Grad.sub.20-100) (M + H).sup.+ [.degree. C.] NVP-
14a14 ##STR00022## AB 11.4 435/437 156-157 ABH059 15a15*
##STR00023## AB 12.5 445 151-152 ABH442 16a**16 ##STR00024## AB
12.3 399 273 ABH443
Example 17
1-(4-tert-Butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthal-
azine (a) and
1-(4-tert-butyl-anilino)-4-[5-bromo-6-hydroxy-(pyridin-3-yl)-methyl]phtha-
lazine (b)
[0243] Under N.sub.2 atmosphere, 0.84 ml (5.33 mMol) of
4-tert-butyl-aniline and 1.8 ml 4 N HCl/dioxane are added to 1.80 g
(72%; 3.55 mMol) of
1-chloro-4-[5-bromo-6-methoxy-(pyridin-3-yl)methyl]phthalazine
containing
1-chloro-4-[5-bromo-6-hydroxy-(pyridin-3-yl)methyl]phthalazine in
30 ml of dioxane containing 17 vol % of isopropanol. After stirring
for 25 min at 90.degree. C., the yellow suspension is cooled to RT
and filtered, washed with dioxane and dried in vacuo. Mother
liquors are evaporated, diluted in 5 ml MeOH, EtOAc, and
NaHCO.sub.3 solution. The aqueous phase is removed and extracted
twice with EtOAc. The organic layers are washed with water and
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Column
chromatography of crystals and mother liquors (SiO.sub.2;
CH.sub.2Cl.sub.2/EtOAc 4:1 the CH.sub.2Cl.sub.2/MeOH 9:1) yields a
followed by b. a: ES-MS: (M+H).sup.+=477/479; HPLC
(Grad.sub.20-100) t.sub.Ret=14.1. b: ES-MS: (M+H).sup.+=463/465;
HPLC (Grad.sub.20-100) t.sub.Ret=11.1.
[0244] The starting materials are prepared as follows:
[0245] 17a) 5-Bromo-6-methoxy-pyridin-3-carbaldehyde: (see Eur. J.
Med. Chem.-Chim. Ther. 1977, 12, 531) 54.8 g (400 mMol)
6-methoxy-3-pyridinecarbaldehyde (Aldrich) are dissolved in 180 ml
of acetic acid. 63.8 g (778 mMol) sodium acetate are added
portionwise (slightly exothermic). Then a solution of 30 ml (582
mMol) of bromine in 120 ml of acetic acid is added dropwise during
30 min. The mixture is stirred for 5 h at 90.degree. C., then
cooled to RT and concentrated partially in vacuo. The residue is
diluted with ice water, neutralized to pH 7.5 with 4 N NaOH and
extracted with 4 portions of EtOAc. The organic layers are washed
twice with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Column chromatography (SiO.sub.2;
CH.sub.2Cl.sub.2) of the resulting oil and crystallization from
CH.sub.2Cl.sub.2/hexane gives the title compound: mp: 94-95.degree.
C.
[0246] 17b)
3-[1-(5-Bromo-6-methoxy-pyridin-3-yl)-methyliden]-3.H.-isobenzofuran-1-on-
: Under N.sub.2 atmosphere, 8.0 g (37 mMol)
5-bromo-6-methoxy-pyridin-3-carbaldehyde are dissolved in 200 ml of
THF. To the ice-cooled solution, 17.5 g (40.7 mMol) of
1,3-dihydro-3-oxo-1-isobenzofuranyl-triphenyl-phosphonium chloride
(preparation see J. Organomet Chem. 1972, 42, 391) are added
followed by 5.7 ml (40.8 mMol) of triethylamine. After 18 h at
0.degree. C., the solid [OP(C.sub.6H.sub.5).sub.3] is filtered off,
washed with THF and discarded. The filtrate is concentrated,
re-dissolved in 1 l of EtOAC and washed with water and brine. The
aqueous layers are extracted with EtOAc, the organic phases
combined, dried (Na.sub.2SO.sub.4) and concentrated to the title
compound [E/Z-mixture; containing OP(C.sub.6H.sub.5).sub.3]:
FAB-MS: (M+H).sup.+=332/334; HPLC (Grad.sub.20-100)
t.sub.Ret=15.5/16.7.
[0247] 17c)
4-[5-Bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazin-1(2H)-one: A
solution of 26.6 mMol of the above product in 180 ml of THF is
heated to 70.degree. C. under an atmosphere of nitrogen. Then 3.12
ml (80 mMol; 80% solution in H.sub.2O) of hydrazine hydrate are
added dropwise. After stirring for 90 min at 70.degree. C., the
reaction mixture is cooled to RT and partially concentrated in
vacuo. The crystallized product is filtered off, washed with EtOAc
and recrystallized from EtOAc yielding the title compound: mp:
227-228.degree. C.; FAB-MS: (M+H).sup.+=346/348; HPLC
(Grad.sub.20-100) t.sub.Ret=12.2.
[0248] 17d)
1-Chloro-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine: To
a suspension of 1.38 g (4.00 mMol) of
4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazin-1(2H)-one and
1.33 g (8.0 mMol) of Et.sub.4NCl in 75 ml of acetonitrile under
N.sub.2-atmosphere, 1.01 ml (8.0 mMol) of N,N-dimethyl-aniline and
8.79 ml (96 mMol) of POCl.sub.3 are added. After heating the
mixture for 1 h to 90.degree. C., the resulting solution is cooled
to RT, pored into 400 ml of ice water and 500 ml sat. NaHCO.sub.3
solution and extracted with 3 portions of EtOAc. The organic phases
are washed twice with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated to the title compound containing some
1-chloro-4-[5-bromo-6-hydroxy-(pyridin-3-yl)-methyl]phthalazine:
FAB-MS: (M+H).sup.+=364/366; HPLC (Grad.sub.20-100)
t.sub.Ret=14.5.
Example 18
1-(4-tert-Butyl-anilino)-4-[5-(furan-2-yl)-6-hydroxy-(pyridin-3-yl)methyl]-
phthalazine
[0249] In analogy to Ex. 3, treatment of a solution of
1-(4-tert-butyl-anilino)-4-[5-(furan-2-yl)-6-methoxy-(pyridin-3-yl)-methy-
l]phthalazine in CHCl.sub.3 with Me.sub.3SiI, followed by
hydrolysis gives the title compound. ES-MS: (M+H).sup.+=451; HPLC
(Grad.sub.20-100) t.sub.Ret=12.6.
[0250] The starting material is prepared as follows:
[0251] 18a)
1-(4-tert-Butyl-anilino)-4-[5-(furan-2-yl)-6-methoxy-(pyridin-3-yl)-methy-
l]phthalazine: To a solution of 366 mg (0.76 mMol)
1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phtha-
lazine (Ex. 17: a) in 7 ml degassed DMF under a N.sub.2-atmosphere
are added 174 mg (0.15 mMol) of Pd[P(C.sub.6H.sub.5).sub.3].sub.4
and 0.6 ml (1.9 mMol) of 2-tributylstannyl-furan (Aldrich). After 4
h stirring at 100.degree. C., the reaction mixture is diluted with
EtOAc and washed with NaHCO.sub.3 solution. The aqueous layers are
extracted twice with EtOAc, the organic phases washed with water,
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Column
chromatography (SiO.sub.2; CH.sub.2Cl.sub.2/Et.sub.2O 7:3) and
crystallization from DIPE yields the title compound. mp:
180-182.degree. C.; ES-MS: (M+H).sup.+=465; HPLC (Grad.sub.20-100)
t.sub.Ret=15.0.
Example 19
[0252]
1-(4-tert-Butyl-anilino)-4-[5-(thiazol-2-yl)-6-hydroxy-(pyridin-3-y-
l)-methyl]phthalazine can be obtained analogously to Ex. 18 from
1-(4-tert-butyl-anilino)-4-[5-(thiazol-2-yl)-6-methoxy-(pyridin-3-yl)-met-
hyl]phthalazine by deprotection with Me.sub.3SiI. ES-MS:
(M+H).sup.+=468; HPLC (Grad.sub.20-100) t.sub.Ret=11.9.
[0253] The starting material is prepared as follows:
[0254] 19a)
1-(4-tert-Butyl-anilino)-4-[5-(thiazol-2-yl)-6-methoxy-(pyridin-3-yl)-met-
hyl]phthalazine can be obtained analogously to Ex. 18a from
1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phtha-
lazine and 2-tributylstannyl-thiazol (supplier: Frontier
Scientific; Logan/USA). MS: (M+H).sup.+=482; HPLC (Grad.sub.20-100)
t.sub.Ret=14.6.
Example 20
1-(4-tert-Butyl-anilino)-4-[5-ethylamino-6-hydroxy-(pyridin-3-yl)-methyl]p-
hthalazine
[0255] In analogy to Ex. 3, treatment of a solution of
1-(4-tert-butyl-anilino)-4-[5-ethylamino-6-methoxy-(pyridin-3-yl)-methyl]-
phthalazine in CHCl.sub.3 with Me.sub.3SiI, followed by hydrolysis
gives the title compound. ES-MS: (M+H).sup.+=428; HPLC
(Grad.sub.20-100) t.sub.Ret=11.9.
[0256] The starting material is prepared as follows:
[0257] 20a)
1-(4-tert-Butyl-anilino)-4-[5-ethylamino-6-methoxy-(pyridin-3-yl)-methyl]-
phthalazine: A mixture of 400 mg (0.84 mMol)
1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)methyl]phthal-
azine (Ex. 17: a), 52 mg R(+)-BINAP
[R(+)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalin); 0.08 mMol],
22 mg Pd.sub.2(dba).sub.3CHCl.sub.3
[tris(dibenzylideneacetone)dipalladium (0) chloroform complex; 0.02
mMol] and 161 mg (1.68 mMol) of sodium-tert-butylate is prepared in
10 ml degassed DMF in a sealed tube under a N.sub.2-atmosphere.
Then 2.5 ml (5 mMol) of a 2 N solution of ethylamine in THF are
added. After 58 h stirring at 70.degree. C., the reaction mixture
is diluted with EtOAc and sat. NaHCO.sub.3 solution. The aqueous
layers are extracted twice with EtOAc, the organic phases washed
with sat. NaHCO.sub.3 solution, brine, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Column chromatography (SiO.sub.2;
CH.sub.2Cl.sub.2/Aceton 5:1) yields the title compound, containing
1-(4-tert-butyl-anilino)-4-[6-methoxy-(pyridin-3-yl)-methyl]phthalazine.
The title compound is then isolated by preparative MPLC. ES-MS:
(M+H).sup.+=442; HPLC (Grad.sub.20-100) t.sub.Ret=13.2.
[0258] In analogy to the above described examples, the following
derivatives can be obtained:
TABLE-US-00003 ##STR00025## ##STR00026## Struktural Expl. R R' Type
21a2122a22 23a2324a24 ##STR00027## HHClCl HHn-propyln-propyl ABAB
ABAB ##STR00028## 25a2526a26 27a2728a28 ##STR00029##
HHpropine-3-ylpropine-3-yl HHethylethyl ABAB ABAB ##STR00030##
Example 29
1-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-4-[6-hydroxy-(pyridin-3-yl)methyl]p-
hthalazine
[0259] In analogy to Ex. 3, treatment of a solution of
1-(4-fluoro-2-methyl-1H-indol-5-yloxy)-4-[6-methoxy-(pyridin-3-yl)-methyl-
]phthalazine in CHCl.sub.3 with Me.sub.3SiI, followed by hydrolysis
gives the title compound.
[0260] The starting material is prepared as follows:
[0261] 29a)
1-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-4-[6-methoxy-(pyridin-3-yl)-methyl-
]phthalazine: Heating of a mixture of
1-chloro-4-[6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 3e),
4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212;
Ex. 237) and K.sub.2CO.sub.3 in DMF yields the title compound.
Example 30
Cyp.sub.450-Inhibition
[0262] By the help of recombinant CyP 450 enzymes, the
corresponding IC.sub.50 values for the compounds of formula I are
determined. This allows to demonstrate that the compounds of
formula I, when compared with compounds form the prior art, e.g. as
described in WO 00/59509, have advantageous properties. Description
of the Assay: Fluorescence-labelled substrate compounds are
incubated with different concentrations of test compound of formula
I with recombinant Cytochrome P.sub.450 isoenzymes. From these
data, the concentration is determined at which 50% of the activity
of the enzyme is inhibited when compared to the activity in the
absence of inhibitor (.fwdarw.IC.sub.50). For details see above in
the general description.
TABLE-US-00004 Inhibition ofCytochrome-IC.sub.50 [.mu.M]
##STR00031## ##STR00032## Cyp3A4 <1 2.8 Cyp2C8 5 >10 Cyp2C9
<1 3.5
[0263] This shows that there is an at least more than two-fold
lower inhibition of the three mentioned cytochromes for Example 8
of the present disclosure when compared with Ex. 14 q from WO
00/59509, and that the IC50 is larger than 1 .mu.M.
Example 31
Test for Activity Against Flt-1 VEGF-Receptor Tyrosine Kinase
[0264] The test is conducted using Flt-1 VEGF-receptor tyrosine
kinase, as described hereinabove. The IC.sub.50 values determined
are given below, insofar as they have been accurately
determined:
TABLE-US-00005 Title compound from Example IC.sub.50 (.mu.mol)
Example 1 d) 1.2 Example 2 d) 1.9
Example 32
Soft Capsules
[0265] 5000 soft gelatin capsules, each comprising as active
ingredient 0.05 g of one of the compounds of formula I mentioned in
the preceding Examples, are prepared as follows:
TABLE-US-00006 Composition Active ingredient 250 g Lauroglycol 2
litre
[0266] Preparation process: The pulverized active ingredient is
suspended in Lauroglykol.RTM. (propylene glycol laurate, Gattefosse
S. A., Saint Priest, France) and ground in a wet pulverizer to
produce a particle size of about 1 to 3 .mu.m. Then 0.419 g
portions of the mixture are introduced into soft gelatin capsules
using a capsule-filling machine.
* * * * *