Compounds

Details Compounds Compounds

1999-01-12

2002-01-29

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C514S248000

Reexamination Certificate

active

06342601

ABSTRACT:

The present invention relates to certain pyrrolo-, thieno-, furano- and pyrazolo-[3,4-d]pyridazinones, processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and methods of treatment involving their use.
In accordance with the present invention, there is provided a compound of the general formula
wherein B represents a group CH or a nitrogen (N), sulfur (S) or oxygen (O) atom; D represents a carbon (C) or nitrogen (N) atom; E represents a group CR
3
or a nitrogen (N) atom; when D is a carbon atom, then B is a sulfur or oxygen atom and E is a group CR
3
, and when D is a nitrogen atom, then either B is a group CH and E is a group CR
3
or a nitrogen atom, or B is a nitrogen atom and E is a group CR
3
; R
1
represents a group NR′R″ where R′ represent a hydrogen atom or a C
1
-C
6
alkyl group, R″ represents a C
1
-C
6
alkyl group, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, or R
1
represents a C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
3
-alkyloxyC
1
-C
3
-alkyl, C
3
-C
6
-cycloalkyloxyC
1
-C
3
-alkyl, C
3
-C
6
alkenyl, phenyl, C
3
-C
7
cycloalkyl, C
3
-C
5
cycloalkylmethyl or C
3
-C
7
cycloalkenyl group, each of which may be optionally substituted by one or more halogen atoms; R
2
represents a methyl group, or a C
2
-C
6
alkyl group optionally substituted by a C
1
-C
6
alkoxy group other than in the 1-position; R
3
represents a hydrogen atom or a group X—R
5
or X—Ar
1
; X represents a group —O—, S(O)
n
, SO
2
N(R
6
) or C(═O)N(R
6
); n is 0, 1 or 2; R
5
represents an optionally substituted alkyl or alkenyl group, or, additionally, in the case where X represents SO
2
N(R
6
) or C(═O)N(R
6
), R
5
and R
6
together with the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring; Ar
1
represents an optionally substituted phenyl or pyridyl group; R
6
represents a hydrogen atom, C
1
-C
6
alkyl or is linked to R
5
as defined above; R
4
represents a group CHR
7
Ar
2
or Ar
3
or, additionally, in the case where D represents a carbon atom, a group C(O)Ar
2
or CR
7
(OH)Ar
2
; Ar
2
represents an aryl or heteroaryl group which may be optionally substituted; Ar
3
represents an acenaphthenyl, indanyl or fluorenyl group, each of which may be optionally substituted; and R
7
represents a hydrogen atom or a C
1
-C
4
alkyl group; or a pharmaceutically-acceptable salt or solvate thereof.
In the present specification, unless otherwise indicated, an alkyl or alkenyl substituent or an alkyl moiety in an alkoxy, alkoxycarbonyl, (di)alkylamino, acylamino, alkylsulfonamido, alkylamido or (di)alkylsulfamoyl substituent group may be linear or branched. Furthermore, the alkyl moieties in a dialkylamino or dialkylsulfamoyl substituent group may be the same or different.
R
1
represents a group NR′R″ where R′ represent a hydrogen atom or a C
1
-C
6
alkyl, preferably C
1
-C
4
alkyl, group, R″ represents a C
1
-C
6
alkyl, preferably C
1
-C
4
alkyl, group, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, or R
1
represents a C
1
-C
6
, preferably C
3
-C
5
, alkyl group (e.g. propyl, isopropyl, butyl or isobutyl), a C
1
-C
6
alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy orhexoxy), C
1
-C
3
-alkyloxyC
1
-C
3
-alkyl (e.g. —CH
2
—O—CH
3
), C
3
-C
6
-cycloalkyloxyC
1
-C
3
-alkyl (e.g. —CH
2
—O-cyclopropyl, —CH
2
—O-cyclobutyl or —CH
2
—O-cyclopentyl), a C
3
-C
6
alkenyl group (e.g. propenyl orbutenyl), a phenyl group, a C
3
-C
7
, preferably C
3
-C
5
, cycloalkyl group (e.g. cyclopropyl, cyclobutyl or cyclopentyl), a C
3
-C
5
cycloalkylmethyl group (e.g. cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl), or a C
3
-C
7
, preferably C
3
-C
5
, cycloalkenyl group (e.g. cyclopropenyl, cyclobutenyl or cyclopentenyl, each of which may be optionally substituted by one or more, preferably one to four, e.g. one or two, halogen atoms (e.g. fluorine or chlorine). Where R
1
groups contain a double bond the first carbon atom of the R
1
group cannot be part of the olefin.
R
2
represents a methyl group, or a C
2
-C
6
, preferably C
2
-C
4
, alkyl group optionally substituted by a C
1
-C
6
, preferably C
1
-C
4
, alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy) other than in the 1-position. Thus, the alkoxy substituent, if present, is attached to a carbon atom other than the carbon atom which is directly bonded to the ring nitrogen atom.
R
3
represents a hydrogen atom or a group X—R
5
or X—Ar
1
.
X represents a group —O—, S(O)
n
where n is 0, 1 or 2 or a group SO
2
N(R
6
) or C(═O)NR
6
. Preferably X represents a group —O—, S(O)
n
where n is 0, 1 or 2, or a group C(═O)NR
6
.
The group R
5
represents an optionally substituted alkyl or alkenyl group, or, additionally, in the case where X represents SO
2
N(R
6
) or C(═O)N(R
6
), R
5
and R
6
together with the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring. If R
5
represents an optionally substituted alkyl group, the alkyl group will preferably contain from 2 to 10, particularly from 2 to 6, carbon atoms or if R
5
represents an optionally substituted alkenyl group, the alkenyl group will preferably contain from 3 to 10, particularly from 3 to 6, carbon atoms. R
5
groups cannot form enamines or enol ethers. The alkyl or alkenyl group or heterocyclic ring may be substituted preferably by one or more, e.g. one, two, three or four, substituents independently selected from amido, amino, carboxyl, cyano, hydroxyl, C
1
-C
6
alkoxy (preferably C
1
-C
4
alkoxy), C
1
-C
6
alkylthio (preferably C
1
-C
4
alkylthio), C
1
-C
6
alkylcarbonyl (preferably C
1
-C
4
alkylcarbonyl), C
1
-C
6
alkoxycarbonyl (preferably C
1
-C
4
alkoxycarbonyl), C
3
-C
7
cycloalkyl (preferably C
5
-C
6
cycloalkyl), (di) C
1
-C
6
alkylamino (preferably (di)methylamino or (di)ethylamino), C
2
-C
6
acylamino (preferably C
2
-C
4
acylamino), C
1
-C
6
alkylsulfonamido (preferably C
1
-C
4
alkylsulfonamido), tetrahydrofuranyl, dioxolanyl, imidazolyl, haloC
1
-C
6
alkylsulfonamido and tetrazolyl. Especially preferred substituent groups are hydroxyl, carboxyl, methoxy, methylthio, methylcarbonyl, cyclopentyl, —NHC(O)CH
3
, tetrahydrofuranyl, dioxolanyl and imidazolyl groups.
Ar
1
represents an optionally substituted phenyl or pyridyl group. The phenyl or pyridyl group may be substituted preferably by one or more, e.g. one to four, substituents independently selected from carboxyl, hydroxyl, C
2
-C
6
, preferably C
2
-C
4
, acylamino, C
1
-C
6
, preferably C
1
-C
4
, alkylamido, C
1
-C
6
, preferably C
1
-C
4
, alkylsulfonamido and (di)C
1
-C
6
, preferably C
1
-C
4
, alkylsulfamoyl. The group Ar
1
is preferably a pyridyl, particularly 2-pyridyl, group.
R
4
represents a group CHR
7
Ar
2
or Ar
3
or, additionally, in the case where D represents a carbon atom, a group C(O)Ar
2
or CR
7
(OH)Ar
2
. R
4
is preferably a group CHR
7
Ar
2
, C(O)Ar
2
or CR
7
(OH)Ar
2
.
R
7
represents a C
1
-C
4
alkyl group (e.g. methyl or ethyl) or, most preferably, a hydrogen atom.
Ar
2
represents an aryl or heteroaryl group which may be optionally substituted. Examples of suitable aryl and heteroaryl groups include phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thienyl, benzothienyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, indolyl, indolizinyl, pyrazolyl, indazyl, imidazolyl, benzimidazolyl, imidazopyridyl, triazolyl, benzotriazolyl and triazolopyridyl.
The Ar
2
group may be optionally substituted by one or more, preferably one to four, especially one to three, substituent groups independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, trifluo

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