Respiratory syncytial virus replication inhibitors

Details Respiratory syncytial virus replication inhibitors Respiratory syncytial virus replication inhibitors

2001-12-27

2004-06-08

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252030, C514S252060, C514S252110, C514S252140, C514S252190, C514S256000, C514S316000, C514S318000, C514S320000, C514S322000, C514S364000, C514S365000, C514S372000, C514S374000, C514S339000, C514S378000, C514S394000, C544S295000, C544S238000, C544S364000, C544S357000, C544S370000, C546S193000, C546S199000, C548S306100, C548S304400

Reexamination Certificate

active

06747028

ABSTRACT:

The present invention is concerned with benzimidazoles and imidazopyridines having antiviral activity, in particular, they have an inhibitory activity on the replication of the respiratory syncytial virus. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.
Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumovirinae together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.
Today only three drugs have been approved for use against RSV infection. Ribavirin, a nucleoside analogue, provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam® and palivizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.
Other attempts to develop a safe and effective RSV vaccine have all met with failure thus far. Inactivated vaccines failed to protect against disease, and in fact in some cases enhanced disease during subsequent infection. Life attenuated vaccines have been tried with limited success. Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. EP-A-0,005,138, EP-A-0,099,139, EP-A-0,145,037, EP-A-0,144,101, EP-A-0,151,826, BP-A-0,151,824, EP-A-0,232,937, EP-A-0,295,742, EP 0,297,661, EP-A-0,307,014, WO 92 01697 describe benzimidazole and imidazopyridines substituted piperidine and piperazine derivatives as antihistaminics, antiallergics or serotonine antagonists.
The present invention concerns the compounds of formula (I)
their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein
—a
1
═a
2
—a
3
═a
4
— represents a bivalent radical of formula
—CH═CH—CH═CH—  (a-1);
—N═CH—CH═CH—  (a-2);
—CH═N—CH═CH—  (a-3);
—CH═CH—N═CH—(a-4); or
CH═CH—CH═N—  (a-5);
wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3), (a-4) and (a-5) may optionally be replaced by halo, C
1-6
alkyl, nitro, amino, hydroxy, C
1-6
-alkyl-oxy, polyhaloC
1-6
alkyl, carboxyl, aminoC
1-6
alkyl, mono- or di(C
1-4
alkyl)-aminoC
1-6
alkyl, C
1-6
alkyloxycarbonyl, hydroxyC
1-6
alkyl, or a radical of formula
 wherein ═Z is ═O, ═CH—(═O)—NR
5a
R
5b
, ═CH
2
, ═CH—C
1-6
alkyl, ═N—OH or ═N—O—C
1-6
alkyl;
Q is a radical of formula
wherein Alk is C
1-6
alkanediyl;
Y
1
is a bivalent radical of formula —NR
2
— or —CH(NR
2
R
4
)—;
X
1
is NR
4
, S, S(═O), S(═O)
2
, O, CH
2
, C(═O), C(═CH
2
), CH(OH), CH(CH
3
),
CH(OCH
3
), CH(SCH
3
), CH(NR
5a
R
5b
), CH
2
—NR
4
or NR
4
—CH
2
;
X
2
is a direct bond, CH
2
, C(═O), NR
4
, C
1-4
alkyl-NR
4
, R4—C
1-4
alkyl;
t is 2, 3, 4 or 5;
u is 1, 2, 3,4 or 5;
vis 2or 3; and
whereby each hydrogen atom in Alk and the carbocycles and the heterocycles defined in radicals (b-3), (b-4), (b-5) (b-6), (b-7) and (b-8) may optionally be replaced by R
3
; with the proviso that when R
3
is hydroxy or C
1-6
alkyloxy, then R
3
can not replace a hydrogen atom in the &agr; position relative to a nitrogen atom;
G is C
1-10
alkanediyl substituted with one or more hydroxy, C
1-6
alkyloxy, arylC
1-6
alkyloxy, C
1-6
akylthio, arylC
1-6
alkylthio, HO(—CH
2
—CH
2
—O)
n
—, C
1-6
alkyloxy-(—CH
2
—CH
2
—O)
n
— or arylC
1-6
alkyloxy(—CH
2
CH
2
—O)
n
—;
R
1
is a monocyclic heterocycle or aryl; said heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl; and each heterocycle may optionally be substituted with 1 or where possible more, such as 2, 3 or 4, substituents selected from halo, hydroxy, amino, cyano, carboxy, C
1-6
alkyl , C
1-6
alkyloxy, C
1-6
alkylthio, C
1-6
alkyloxyC
1-6
alkyl, aryl, arylC
1-6
alkyl, arylC
1-6
akyloxy, hydroxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)amino, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, polyhaloC
1-6
alkyl, C
1-6
alkylcarbonylamino, C
1-6
alkyl-SO
2
—NR
5c
—, aryl-SO
2
NR
5c
—, C
1-6
alkyloxycarbonyl, —(═O)—NR
5c
R
5d
, HO(—CH
2
—CH
2
—O)
n
—, halo(—CH
2
—CH
2
—O)
n
—, C
1-6
alkyloxy(—CH
2
CH
2
—O)
n
—, alylC
1-6
alkyloxy(—CH
2
—CH
2
—O)
n
— and mono- or di(C
1-6
alkyl)amino(—CH
2
—CH
2
—O)
n
—; each n independently is 1, 2, 3 or 4;
R
2
is hydrogen, formyl, C
1-6
alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C
3-7
cycyoalkyl substituted with N(R
6
)
2
, or C
1-10
alkyl substituted with N(R
6
)
2
and optionally with a second, third or fourth substituent selected from amino, hydroxy, C
3-7
cycloalkyl, C
2-5
alkanediyl, piperidinyl, mono- or di(C
1-6
alkyl)amino, C
1-6
alkylcarbonylamino, aryl and aryloxy;
R
3
is hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, arylC
1-6
alkyl or arylC
1-6
alkyloxy;
R
4
is hydrogen, C
1-6
alkyl or arylC
1-6
alkyl;
R
5a
, R
5b
, R
5c
and R
5d
each independently are hydrogen or C
1-6
akyl; or
R
5a
and R
5b
, or R
5c
and R
5d
taken together form a bivalent radical of formula —(CH
2
)
s
— wherein s is 4 or 5;
R
6
is hydrogen, C
1-4
alkyl, formyl, hydroxyC
1-6
akyl, C
1-6
alkylcarbonyl or C
1-6
alkyloxycarbonyl;
aryl is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, C
1-6
alkyl, hydroxyC
1-6
alkyl, polyhaloC
1-6
alkyl, and C
1-6
alkyloxy;
Het is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.
The term prodrug as used throughout this text means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8
th
ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15) describing prodrugs generally, is hereby incorporated.
As used herein C
1-3
alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl and the like; C
1-4
alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C
1-3
alkyl and butyl and the like; C
2-4
alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl and the like; C
1-6
alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C
1-4
alkyl and pentyl, hexyl, 2-methylbutyl and the like; C
1-9
alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 9 carbon atoms such a

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