Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-05-09
2004-11-16
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S336000
Reexamination Certificate
active
06818661
ABSTRACT:
The invention relates to substituted anthranylalkyl and -cycloalkyl amides and their use as medicaments in the treatment of diseases caused by persistent angiogenesis.
Persistent angiogenesis may be the cause of various diseases such as psoriasis, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplantation rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferation diseases, artheriosclerosis and injuries to nerve tissue, or may lead to a worsening of these diseases.
The direct or indirect inhibition of the VEGF receptor can be used to treat such diseases and other VEGF-induced pathological angiogenesis and vascular permeable conditions, such as tumour vascularisation. For example, it is known that the growth of tumours can be inhibited by soluble receptors and antibodies to VEGF.
Persistent angiogenesis is induced by the VEGF through its receptor. So that VEGF can display this activity, it is necessary for VEGF to bind to the receptor and for tyrosine phosphorylation to develop.
It has now been found that compounds of general formula I:
in which
A is the group ═NR
7
,
W is oxygen, sulfur, two hydrogen atoms or the group ═NR
8
,
Z is a bond or the group ═NR
10
or ═N—,
R
1
is branched or unbranched C
1-12
-alkyl or C
2-12
-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
; or C
3-10
-cycloalkyl, or C
3-10
-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
,
X is C
1-6
-alkyl;
R
2
signifies monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted once or many times by halogen, C
1-6
-alkyl, C
1-6
-alkoxy and/or hydroxy,
R
3
, R
4
, R
5
and R
6
are hydrogen, halogen; or C
1-6
-alkoxy, C
1-6
-alkyl, C
1-6
-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R
7
is hydrogen, C
1-6
-alkyl or C
1-8
-cycloalkyl,
R
8
, R
9
and R
10
are hydrogen or C
1-6
-alkyl and
R
11
and R
12
are hydrogen or C
1-6
-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C
1-6
-alkyl,
as well as the isomers and salts thereof, stop tyrosine phosphorylation or persistent angiogenesis and thus prevent the growth and spread of tumours.
By alkyl is understood in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert.-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
By cycloalkyl is understood monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl oder cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and also bicyclic rings or tricyclic rings, for example adamantanyl.
By cycloalkenyl is understood in each case cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby linking may take place at the double bond and also at the single bonds.
Halogen is understood to be in each case fluorine, chlorine, bromine or iodine.
The alkenyl substituents are respectively straight-chained or branched and contain 2-6, preferably 2-4 carbon atoms. The following radicals may be mentioned by way of example: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, allyl.
The aryl radical respectively has 6-12 carbon atoms, for example naphthyl, biphenyl and in particular phenyl.
The heteroaryl radical may be respectively benzocondensed. Examples of 5-ring heteroaromatics are: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives, and examples of 6-ring heteroaromatics are pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.
The aryl and the heteroaryl radical may respectively be substituted once, twice or three times by identical or different substituents from hydroxy, halogen, C
1-4
-alkoxy.
If an acidic function is contained therein, suitable salts are the physiologically acceptable salts of organic and inorganic bases, for example the readily soluble alkali and alkaline earth salts, as well as N-methyl-glucamine, dimethyl glucamine, ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tri-hydroxy-methyl-amino-methane, amino-propanediol, Sovak base, 1-amino-2,3,4-butanetriol.
If a basic function is contained therein, suitable salts are the physiologically acceptable salts of organic and inorganic acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, etc.
Of particular interest are those compounds of the general formula I, in which
A is the group ═NR
7
,
W is oxygen,
Z is a bond,
R
1
is branched or unbranched C
1-12
-alkyl or C
2-12
-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
; or C
3-10
-cycloalkyl, or C
3-10
-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
,
X is C
1-6
-alkyl;
R
2
signifies monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted once or many times by halogen, C
1-6
-alkyl, C
1-6
-alkoxy and/or hydroxy,
R
3
, R
4
, R
5
and R
6
are hydrogen, halogen; or C
1-6
-alkoxy, C
1-6
-alkyl, C
1-6
-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R
7
is hydrogen, C
1-6
-alkyl or C
1-8
-cycloalkyl,
R
9
is hydrogen or C
1-6
-alkyl and
R
11
and R
12
are hydrogen or C
1-6
-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C
16
-alkyl,
as well as the isomers and salts thereof.
Of particular interest are those compounds of the general formula I, in which
A is the group ═NR
7
,
W is oxygen,
Z is a bond,
R
1
is branched or unbranched C
1-12
-alkyl or C
2-12
-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
; or C
3-10
-cycloalkyl, or C
3-10
-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
,
X is C
1-6
-alkyl;
R
2
is pyridyl,
R
3
, R
4
, R
5
and R
6
are hydrogen, halogen; or C
1-6
-alkoxy, C
1-6
-alkyl, C
1-6
-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R
7
is hydrogen, C
1-6
-alkyl or C
1-8
-cycloalkyl,
R
9
is hydrogen or C
1-6
-alkyl and
R
11
and R
12
are hydrogen or C
1-6
-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C
1-6
-alkyl,
as well as the isomers and salts thereof.
Of particular value are those compounds of the general formula I, in which
A is the group ═NR
7
,
W is oxygen,
Z is a bond,
R
1
is branched or unbranched C
1-12
-alkyl or C
2-12
-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
; or C
3-10
-cycloalkyl, or C
3-10
-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C
1-6
-alkyloxy, aralkyloxy, C
1-6
-alkyl and/or NR
11
R
12
,
X is C
1-6
-alkyl;
R
2
is pyridyl,
R
3
, R
4
, R
5
and R
6
are hydrogen, halogen; or C
1-6
-alkoxy, C
1-6
-alkyl, C
1-6
-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R
7
is hydrogen, C
1-6
-alkyl or C
1-8
-cycloalkyl,
R
9
is hydrogen or C
1-6
-alkyl and
R
11
and R
12
are hydrogen or C
1-6
-alkyl, or form a ring which may contain oxygen or nitrogen as a further hetero atom a
Haberey Martin
Huth Andreas
Krüger Martin
Menrad Andreas
Ottow Eckhard
Davis Zinna Northington
Dohmann George R.
McNally Lydia T.
Novartis AG
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