Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-27
2001-12-04
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S397000, C514S399000, C514S400000, C548S335100, C548S336100, C548S338100, C548S340100, C548S342100
Reexamination Certificate
active
06326500
ABSTRACT:
This invention relates to novel substituted imidazoles having therapeutic activity useful in treating conditions associated with inflammation, allergy or aberrant immune reactions, to therapeutic compositions containing these novel compounds and to processes for preparing these novel compounds.
It is believed that, in response to an inflammatory stimulus, phospholipase enzymes are activated leading to the release of arachidonic acid from phospholipids. Existing non-steroidal antiinflammatory agents (NSAIA) are believed to act primarily by blocking the conversion of this released arachidonic acid into prostaglandins via the cyclo-oxygenase pathway of the arachidonic acid cascade. Many existing NSAIA are unsuitable for use by asthmatics. We have found a series of compounds which act to block the release of arachidonic acid from phospholipids. These compounds are indicated as useful antiinflammatory compounds with a potentially broader spectrum of activity than existing NSAIA, and potentially fewer gastro-intestinal side-effects. In addition the compounds may be useful in the treatment of asthma.
Compound A is disclosed in Il Farmaco, 44 (5), 495-502, 1989 as having an inhibitory effect on platelet aggregation in vitro.
Compound B is disclosed as a chemical intermediate in EP 0230035. No pharmacological activity is disclosed for this compound.
GB 2088888 discloses desensitizing compositions for photographic developers comprising imidazoles of formula C
wherein R
1
represents a hydrogen atom, a C
1-20
alkyl group or a C
6-20
aryl group; R
2
represents a hydrogen atom, a C
1-20
alkyl group, a C
6-20
aryl group, an amino group, or a C
1-20
alkylthio group; and R
3
and R
4
, which may be the same or different, each represents a hydrogen atom, a C
1-4
alkyl group, or a C
6-20
aryl group; and R
1
, R
2
, R
3
and R
4
may be substituted. 1-(6-Benzylaminohexyl)-2-methylimidazole is disclosed. No pharmacological activity is disclosed for this compound.
More distantly related compounds of formula D
in which the ring incorporating N and Z represents dialkylamino, morpholino or piperidino are disclosed in the Indian Journal of Pharmacology 1973, 5, 428 and Pfl. Krankh. 1975, 3, 149. These compounds are disclosed as potential central nervous system depressants. N-[2-(4-Morpholino)propyl[-&agr;-ethyl-3,4-dichlorobenzylamine is alleged to have antiinflammatory activity but has a wide range of undesirable side-effects in mice.
Our co-pending application PCT/EP92/02899 (WO 93/13075) discloses compounds of formula E
All compounds disclosed in that application are disclaimed from this present application in the first proviso.
The co-pending application WO 93/14070 discloses the use of compounds of formula F
in which chain A represents inter alia a C
1-6
hydrocarbon chain which is straight or branched; X represents inter alia —NH—; chain B represents an alkylene chain of formula (CH
2
)
n
in which n is a number between 0 and 5 or a branched alkylene chain having from 2 to 8 carbon atoms and Y represents inter alia an aryl group such as an optionally substituted phenyl group; as antagonists of histamine H
3
receptors. There is no disclosure of antiinflammatory or anti-asthmatic activity for these compounds.
EP 0485890 discloses the use of compounds of formula G
in which A is CH or N; X is inter alia —NR
1
R
2
in which R
1
is alkylphenyl (in which the phenyl ring is optionally substituted) inter alia, R
2
is hydrogen or R
1
; and Y is OH inter alia; for the treatment and prophylaxis of systemic mycoses, protozoal, fungal and bacterial infections. All compounds disclosed in that application are disclaimed from this present application in the third proviso.
EP 081324 discloses the use of compounds of formula H
in which
R
1
, R
2
and R
3
which may be the same or different represent hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro;
R
4
is hydrogen or a C
1-7
alkyl group;
R
5
is hydrogen or a C
1-5
alkyl group or phenyl;
R
6
is hydrogen or a C
1-7
alkyl group or a substituted or unsubstituted benzyl group; and
n is 0 or 1;
as diuretic agents which also have antithrombotic and antihypertensive activity. All compounds disclosed in that application are disclaimed from this present application in the second proviso (part a).
Japanese patent application no. 63-141969 (1988) discloses the use of compounds of formula J
in which
R
1
represents lower alkyl;
R
2
and R
3
represent hydrogen, lower alkyl or SR
5
;
R
4
represents substituted phenyl or substituted pyridyl (wherein the substituent is hydrogen, lower alkyl or halogen);
R
5
represents hydrogen or lower alkyl;
X is O, S or imino (optionally substituted by lower alkyl) and
m and n are 0, 1 or 2; as cerebral function improvers.
All compounds disclosed in that application are disclaimed from this present application in the second proviso (part b).
3′-(Imidazol-1-yl)-3-phenyldipropylamine is disclosed in J.A.C.S. 101, 5376 (1979). No biological activity is reported. This compound is disclaimed in the fifth proviso.
U.S. Pat. Nos. 4,404,387 and 4,338,453 disclose the use of compounds of formula K
wherein X
1
is a) CH; or b) C(CH
3
); wherein m is zero, 1, 2 or 3; n is zero, 1 or 2; R
1
is a) 1-piperidinyl substituted at the 3 or 4 position by R
15
; b) —N(CH
3
)—(CH
2
)
p
—R
15
or c) —NH—(CH
2
)
p
—R
15
wherein p is 1, 2 or 3; R
4
is a) hydrogen or b) C
1-3
alkyl inter alia; R
5
and R
15
are the same or different and are a) 2, 3 or 4-pyridinyl or b) phenyl substituted by zero to 2 chloro, fluoro, bromo, C
1-3
alkyl or C
1-3
alkoxy or c) phenyl substituted by one trifluoromethyl and zero to one of the previous phenyl substituents, wherein R
6
is a) hydrogen; b) C
1-3
alkyl or c) hydroxy inter alia; as antiallergic agents. All compounds disclosed in these applications are disclaimed from the present application in the fourth proviso.
The present invention provides novel compounds of formula I
and pharmaceutically acceptable salts thereof in which R
1
represents hydrogen, halo, cyano, a cyano C
1-6
alkyl group, a C
1-12
alkyl group (optionally substituted by one or more hydroxy groups), a C
1-6
alkoxy group, phenoxy (optionally substituted), phenyl (optionally substituted), a C
2-6
alkoxycarbonyl group, an amino group of formula —NR
13
R
14
(in which R
13
and R
14
are independently hydrogen or a C
1-4
alkyl group or R
13
and R
14
together with the nitrogen atom to which they are attached represent a saturated 3-7 membered heterocyclic ring, optionally containing sulphur, oxygen or an additional nitrogen atom, wherein the ring may be optionally substituted by one or more C
1-4
alkyl groups), a group of formula —N(R
15
)SO
2
R
16
(in which R
15
represents hydrogen or C
1-6
alkyl and R
16
represents hydroxy, a C
1-6
alkyl group or optionally substituted phenyl), a halogenated C
1-4
alkoxy group, a halogenated C
1-4
alkyl group, arylalkoxy (optionally substituted), hydroxy, a phenyl C
1-6
alkyl group (optionally substituted), a (C
2-6
alkoxycarbonyl)vinyl group, a group of formula —S(O)
n
R
7
(in which R
7
represents a C
1-6
alkyl group and n is 0, 1 or 2 or n is 2 and R
7
represents a group of formula —N(R
17
)R
18
(in which R
17
and R
18
independently represent hydrogen, a C
1-6
alkyl group, a C
3-6
cycloalkyl group or optionally substituted phenyl or R
17
and R
18
together with the nitrogen atom to which they are attached represent a saturated 3-7 membered heterocyclic ring, optionally containing sulphur, oxygen or an additional nitrogen atom, wherein the ring may be optionally substituted by one or more C
1-4
alkyl groups), a C
2-6
alkoxycarbonyl C
1-6
alkyl group, a carboxy C
1-6
alkyl group, a carbamoyl group of formula —CONR
11
R
12
(in which R
11
and R
12
are independently hydrogen, a C
1-6
alkyl group, a C
3-8
cycloalkyl group or optionally substituted phenyl or R
11
and R
12
together with the nitrogen atom to which they are attached represent a saturated 3-7 membered heterocyclic ring, optionally containing sulphur, o
Calderwood David John
Fisher Adrian John
Jeffery James Edward
Jones Colin Gerhart Pryce
Rafferty Paul
Abbott Laboratories
Higel Floyd D.
Keil & Weinkauf
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