Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-14
2001-02-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S258100, C514S333000, C514S370000, C544S281000, C546S256000, C548S154000, C548S184000, C548S190000, C548S193000
Reexamination Certificate
active
06187802
ABSTRACT:
The present invention relates to certain substituted 4-arylmethylene-2-imino-2,3-dihydrothiazoles which inhibit neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline and/or dopamine, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, Parkinson's disease, obesity, cognitive disorders, seizures, neurological disorders such as epilepsy, and as neuroprotective agents to protect against conditions such as stroke. The invention includes novel arylalkyl- and arylcycloalkyldihydroimidazo[2,1 -b]thiazole, arylalkyl- and arylcycloalkyldihydro-5H-thiazolo[3,2-a]pyrimidine and arylalkyl- and arylcycloalkyldihydrothiazole compounds.
Sharpe C. J and Shadbolt R. S. disclose certain dihydroimidazo[2,1-b]thiazole compounds having antidepressant activity, Journal of Medicinal Chemistry, 1971, Vol 14 No.10, p977-982. However, the document also states that these compounds were generally less active and more toxic than the imidazolines also disclosed in the document. The compounds of the present invention are not disclosed or suggested in this document.
PCT/EP96/02676 discloses substituted benzo[b]thiophen-3-yldihydro-imidazo[2,1-b]thiazole, benzo[b]thiophen-3-yldihydro-5H-thiazolo[3,2-a]pyrimidine, benzo[b]furan-3-yldihydroimidazo[2,1-b]thiazole and benzo[b]furan-3-yldihydro-5H-thiazolo[3,2-a]pyrimidine compounds which have affinity for 5-HT
1A
receptors and which inhibit neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline. These compounds are stated to be useful in the treatment of CNS disorders. The compounds of the present invention are not disclosed or suggested in this document.
EP683,160 discloses inter alia iminothiazoline compounds of Formula A
in which inter alia
R
1
is C
1
-C
6
(halo)alkyl, R
2
is C
1
-C
6
(halo)alkyl, C
7
-C
17
aralkyl which may be substituted with one or more C
1
-C
3
(halo)alkyl groups, C
1
-C
3
(halo)alkoxy groups or halogen atoms, aryl which may be substituted; R
3
is hydrogen, C
1
-C
6
(halo)alkyl or a group of the general formula: CO
2
R
6
; X is hydrogen, chlorine or fluorine; Y is chlorine, fluorine, bromine, nitro or cyano; R
6
is hydrogen or C
1
-C
3
(halo)alkyl; B is nitro, or a group of the general formula: SR
4
, or OR
4
; R
4
is C
1
-C
6
(halo)alkyl, C
3
-C
6
(halo)alkenyl; wherein the term “(halo)” as used in the names of the above substituents means that they may be substituted with one or more halogen atoms; which are herbicides.
EP600,489 discloses a process for preparing compounds of Formula B
wherein R
1
is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R
2
is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and R
3
, R
4
and R
5
are the same or different, each of which is hydrogen, optionally substituted alkyl or optionally substituted aryl.
U.S. Pat. No. 4,347,248 discloses 2,3-disubstitutedthiazolo[3,2-a][1,3]diazacyclenes of Formula C
wherein R
1
is hydrogen, fluoro, chloro, bromo, alkyl having up to 3 carbon atoms or dimethylamino; R
2
is hydrogen, fluoro, chloro, bromo or alkyl having up to 3 carbon atoms; n is zero, one or two; and Q is a divalent moiety of the formula; —CH
2
—, —C(CH
3
)
2
——CH
2
CH
2
— or —CH
2
CH
2
CH
2
—; which are diuretics.
U.S. Pat. No. 4,325,955 discloses 3-benzhydrylthiazolo[3,2-a][1,3]diazacyclenes which are diuretics.
Certain cyclic 2-iminothiazoles are disclosed in J.Chem.Soc. 1995, 2943-2948 and J.Chem.Soc. Perkin Trans. 1, 1989, 643-648.
The present invention provides compounds of Formula I
including pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers,
in which:
Ar is phenyl, naphthyl or benzo[b]thiophenyl, each of which may be optionally substituted by one or more substituents selected from a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) a phenoxy group optionally substituted by one or more halo or f) phenyl optionally substituted by one or more halo;
R
1
and R
2
, which may be the same or different, independently are a) H, b) an alkyl group containing 1 to 6 carbon atoms, c) an alkenyl group containing 3 to 6 carbon atoms, d) a cycloalkyl group containing 3 to 7 carbon atoms, e) a cycloalkylmethyl group in which the ring contains 3 to 7 carbon atoms, f) an aryl or heteroaryl group optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, g) an arylalkyl or heteroarylalkyl group in which the alkyl chain contains 1 to 3 carbon atoms and in which the aryl or heteroaryl group may optionally be substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo; or R
1
and R
2
form an alkylene chain optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms, such that, together with the atoms to which they are attached, they form a 5 or 6 membered ring,
R
3
is a) H, b) an aryl or heteroaryl group optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an arylmethyl group in which the aryl is optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo; or d) an alkoxyalkyl group containing 3 to 6 carbon atoms; and
R
4
and R
5
, which may be the same or different, independently are an alkyl group containing 1 to 3 carbon atoms, or R
4
and R
5
together with the atom to which they are attached form a cycloalkyl ring containing 3 to 6 carbon atoms.
It will be understood that the term halo, when used herein, includes fluoro, chloro, bromo and iodo. It will be understood that in alkyl groups, alkylthio groups and alkoxy groups containing more than two carbon atoms the alkyl group may be straight or branched.
The term aryl as used herein means phenyl or naphthyl preferably phenyl. The term heteroaryl as used herein means aryl in which one or more of the ring carbon atoms is replaced by a heteroatom such as N, S or O and furyl and thienyl. Preferably heteroaryl means furyl, pyridyl or thienyl.
In preferred compounds of Formula I, Ar is naphthyl, benzo[b]thiophenyl or phenyl optionally substituted by one or more substituents selected from halo, an alkylthio group containing 1 to 3 carbon atoms, or a phenoxy group. In more preferred compounds, Ar is naphthyl, benzo[b]thiophenyl or phenyl optionally substituted by one or more substituents selected from chloro, bromo, methylthio, or phenoxy. Most preferably, Ar is 2-naphthyl, benzo[b]thiophen-2-yl
Cheetham Sharon Crawford
Jones Colin Gerhart Pryce
Kerrigan Frank
Keil & Weinkauf
Knoll Aktiengesellschaft
Schroeder Ben
Shah Mukund J.
LandOfFree
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