Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-05
2003-11-11
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S269000, C514S272000, C514S274000, C514S311000, C514S312000, C514S313000, C514S314000, C514S307000, C514S309000, C514S310000, C544S284000, C544S235000, C546S135000, C546S139000, C546S141000, C546S143000
Reexamination Certificate
active
06645970
ABSTRACT:
The present invention relates to indolylmaleimide derivatives, process for their production and pharmaceutical compositions containing them.
More particularly the present invention provides a compound of formula I
wherein
R
a
is H; C
1-4
alkyl; or C
1-4
alkyl substituted by OH, NH
2
, NHC
1-4
alkyl or N(C
1-4
alkyl)
2
;
R
b
is H; or C
1-4
alkyl;
R is a radical of formula (a), (b), (c), (d), (e) or (f)
wherein
each of R
1
, R
4
, R
7
, R
8
, R
11
and R
14
is OH; SH; a heterocyclic residue; NR
16
R
17
wherein each of R
16
and R
17
, independently, is H or C
1-4
alkyl or R
16
and R
17
form together with the nitrogen atom to which they are bound a heterocyclic residue; or a radical of formula &agr;
—X—R
c
—Y (&agr;)
wherein X is a direct bond, O, S or NR
18
wherein R
18
is H or C
1-4
alkyl,
R
c
is C
1-4
alkylene or C
1-4
alkylene wherein one CH
2
is replaced by CR
x
R
y
wherein one of R
x
and R
y
is H and the other is CH
3
, each of R
x
and R
y
is CH
3
or R
x
and R
y
form together —CH
2
—CH
2
—, and
Y is bound to the terminal carbon atom and is selected from OH, a heterocyclic residue and —NR
19
R
20
wherein each of R
19
and R
20
independently is H, C
3-6
cycloalkyl, C
3-6
cycloalkyl-C
1-4
alkyl, aryl-C
1-4
alkyl or C
1-4
alkyl optionally substituted on the terminal carbon atom by OH, or R
19
and R
20
form together with the nitrogen atom to which they are bound a heterocyclic residue;
each of R
2
, R
3
, R
5
, R
6
, R
9
, R
10
, R
12
, R
13
, R
15
and R′
15
, independently, is H, halogen, C
1-4
alkyl, CF
3
, OH, SH, NH
2
, C
1-4
alkoxy, C
1-4
alkylthio, NHC
1-4
alkyl, N(C
1-4
alkyl)
2
or CN;
either E is —N═ and G is —CH═ or E is —CH═ and G is —N═; and
ring A is optionally substituted.
Any alkyl or alkyl moiety in e.g. alkoxy may be linear or branched. Halogen may be F, Cl, Br or I, preferably F or Cl. Any aryl may be phenyl or naphthyl, preferably phenyl.
By heterocyclic residue as R
1
, R
4
, R
7
, R
8
, R
11
, R
14
or Y or formed, respectively, by NR
16
R
17
or NR
19
R
20
, is meant a three to eight, preferably five to eight, membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S, and optionally substituted. Suitable examples include e.g. pyridyl, e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl, optionally substituted, e.g. mono- or polysubstituted. When the heterocyclic residue is substituted, this may be on one or more ring carbon atoms and/or on a ring nitrogen atom when present. Examples of a substituent on a ring carbon atom include e.g. C
1-4
alkyl e.g. CH
3
;
C
3-6
cycloalkyl e.g. cyclopropyl, optionally further substituted by C
1-4
alkyl;
wherein p is 1,2 or 3, preferably 1; CF
3
; halogen; OH; NH
2
; —CH
2
—NH
2
; —CH
2
—OH; piperidin-1-yl; pyrrolidinyl. Examples of a substituent on a ring nitrogen atom are e.g. C
1-6
alkyl; acyl, e.g. R′
x
-CO wherein R′
x
is H, C
1
alkyl or phenyl optionally substituted by C
1-4
alkyl, C
1-4
alkoxy or amino, e.g formyl; C
3-6
cycloalkyl; C
3-6
cycloalkyl—C
1-4
alkyl; phenyl; phenyl-C
1-4
alkyl e.g. benzyl; a heterocyclic residue, e.g. as disclosed above, e.g. an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms; or a residue of formula &bgr;
—R
21
—Y′ (&bgr;)
wherein R
21
is C
1-4
alkylene or C
2-4
alkylene interrupted by O and Y′ is OH, NH
2
, NH(C
1-4
alkyl) or N(C
1-4
alkyl)
2
.
C
2-4
alkylene interrupted by O may be e.g. —CH
2
—CH
2
—O—CH
2
—CH
2
—.
When the substituent on a cyclic nitrogen is a heterocyclic residue, it may be a five or six membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S. Examples include e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, pyrimidinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl,
When R
a
is substituted C
1-4
alkyl, the substituent is preferably on the terminal carbon atom.
When ring A is substituted, it may be mono- or polysubstituted, preferably monosubstituted, the substituent(s) being selected from the group consisting of e.g. halogen, OH, C
1-4
alkoxy, e.g. OCH
3
, C
1-4
alkyl, e.g. CH
3
, NO
2
, CF
3
, NH
2
, NHC
1-4
alkyl, N(C
1-4
alkyl)
2
and CN. For example, ring A may be a residue of formula
wherein
R
d
is H; C
1-4
alkyl; or halogen; and
R
e
is OH; NO
2
; NH
2
; NHC
1-4
alkyl; or N(C
1-4
alkyl)
2
.
When R
a
has a CH
2
replaced by CR
x
R
Y
, it is preferably the CH
2
bearing Y.
Examples of heterocyclic residue as R
1
, R
4
, R
7
, R
8
, R
11
, R
14
or Y or formed, respectively, by NR
16
R
17
or NR
19
R
20
, include e.g. a residue of formula (&ggr;)
wherein
the ring D is a 5, 6 or 7 membered saturated, unsaturated or aromatic ring;
X
b
is —N—, —C═ or —CH—;
X
c
is —N═, —NR
f
—, —CR
f
′— or —CHR
f
′— wherein R
f
is a substituent as indicated above for a ring nitrogen atom, and R
f
′ is a substituent as indicated above for a ring carbon atom;
the bond between C
1
and C
2
is either saturated or unsaturated;
each of C
1
and C
2
, independently, is a carbon atom which is optionally substituted by one or two substituents selected among those indicated above for a ring carbon atom; and
the line between C
3
and X
b
and between C
1
and X
b
, respectively, represents the number of carbon atoms as required to obtain a 5, 6 or 7 membered ring D.
A preferred residue of formula (&ggr;) is one wherein the ring D forms a 1,4-piperazinyl ring optionally C- and/or N-substituted as indicated.
Representative examples of a residue of formula (&ggr;) are e.g. 3- or 4- pyridyl; piperidin-1-yl; 1-N-(C
1-4
alkyl)- or —(&ohgr;-hydroxy—C
1-4
alkyl)-3-piperidyl; morpholin-4-yl; imidazolyl; pyrrolidinyl; 1-piperazinyl; 2-C
1-4
alkyl- or -C
3-6
cycloalkyl-1-piperazinyl; 3-C
1-4
alkyl- or —C
3-6
cycloalkyl-1-piperazinyl; 2,2- or 3,5- or 2,5- or 2,6-di(C
1-4
alkyl)-1-piperazinyl; 3,4,5-tri-(C
1-4
alkyl)-1-piperazinyl; 4-N-(C
1-4
alkyl)- or —(&ohgr;-hydroxy-C
1-4
alkyl)- or —(&ohgr;-dimethylamino-C
1-4
alkyl)-1-piperazinyl; 4-N-pyridin-4-yl-1-piperazinyl; 4-N-phenyl- or —C
3-6
cycloalkyl-1-piperazinyl; 4-N-(C
1-4
alkyl)- or —(&ohgr;-hydroxy-C
1-4
alkyl)-3-C
1-4
alkyl- or —3,3-di(C
1-4
alkyl)-1-piperazinyl; 4-N-(1-C
1-4
alkyl-C
3-6
cycloalkyl)-1-piperazinyl; 4-N-formyl-1-piperazinyl; 4-N-pyrimidin-2-yl-1-piperazinyl; or 4-N-C
1-4
alkyl-1-homopiperazinyl.
The compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid, acetic acid, when R
1
, R
4
, R
7
, R
8
, R
11
or R
14
and/or R
2
, R
3
, R
5
, R
6
, R
9
, R
10
, R
12
, R
13
or R
15
comprises an optionally substituted amino group or a heterocyclic residue which can form acid addition salts.
It will be appreciated that the compounds of formula I may exist in the form of optical isomers, racemates or diastereoisomers. For example, a ring carbon atom bearing a substituent in the heterocyclic residue as R
1
, R
4
, R
7
, R
8
, R
11
, R
14
or Y or formed, respectively, by NR
16
R
17
or NR
19
R
20
, is asymmetric and may have the D- or L- configuration. It is to be understood that the present invention embraces all enantiomers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms as mentioned.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. R
a
is H or CH
3
;
2. R
b
is H;
3. Ring A is unsubstituted; or is substituted by methyl in position 7;
4. Preferred heterocyclic residue as formed by NR
16
R
17
is e.g. piperazin-1-yl optionally N-substituted, e.g. by C
1-4
aakyl, &ohgr;-hydroxy-C
1-4
alkyl, &ohgr;-dimethylamino-C
1-4
alkyl, C
5-6
cycloalkyl, C
1-4
alkyl-C
5-6
cycloalkyl, an aromatic heterocycl
Albert Rainer
Cooke Nigel Graham
Cottens Sylvain
Ehrhardt Claus
Evenou Jean-Pierre
Anderson Rebecca
Gruenfeld Norbert
McKane Joseph K.
Novartis AG
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