Tripeptidyl peptidase inhibitors

Details Tripeptidyl peptidase inhibitors Tripeptidyl peptidase inhibitors

2000-09-18

2002-01-01

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S492000

Reexamination Certificate

active

06335360

ABSTRACT:

The present invention relates to inhibitors of a membrane tripeptidyl peptidase responsible for the inactivation of endogenous neuropeptides such as cholecystokinins (CCKs).
Cholecystokinins (CCKs) are a family of hormonal and neuronal peptides which exert pleiotropic biological effects in the gut and brain. For example, CCK-33, the sulphated tritriaconta-peptide is implicated in the control of gall-bladder contraction, gastric emptying and intestinal motility (Dockray, G. J., Gastrointestinal Endocrinology: Receptors and Post-receptors Mechanisms (ed. Thompson, J.) 321-332 (Academic, New York 1990)).
In cerebral neurons, CCK immunoreactivity corresponds mainly to the sulphated carboxy-terminal octapeptide CCK-8 (Vanderhaegen, J. J., Signeau, J. C. and Gepts, W., Nature, 257, 604-605, (1975); Dockray, G. J., Nature 264, 568-570 (1976)). CCK immunoreactivity and dopamine coexist in mesolimbic neurons and may be implicated in psychotic disorders, (Hökfelt, T. et al., Nature, 285, 476-479 (1980)).
The actions of CCK are mediated by CCK
A
and CCK
B
receptors. CCK is known to have a physiological role in the control of food intake, which is enhanced by CCK
A
agonists (Smith, G. P. and Gibbs, J., Ann. N.Y. Acad. Sci., 713, 236-241 (1994)), and the control of anxiety, which is decreased by CCK
B
antagonists (Woodruff, G. and Hughes, J. A., Rev. Pharmac., 31, 469-501 (1991)).
Tripeptidyl peptidase II (TPP II) is a CCK inactivating peptidase. TPP II is found in neurons responding to cholecystokinin as well as in non-neuronal cells. TPP II is considered to be a neuropeptidase responsible for CCK-8 inactivation (Rose, C et al, Nature, 380, 403409, (1996)). TPP II has the following characteristics:
1) in two steps, it rapidly cleaves the neuropeptide CCK-8 into biologically inactive fragments with a reasonably high degree of specificity;
2) it is expressed by CCK-responsive neurons; and
3) its inhibition allows neuronal CCK-8 to escape inactivation and results in CCK-like effects such as satiation in rodents.
TPP II could be involved in CCK-8 inactivation in the gastrointestinal tract. Exogenous CCK reduces food intake and elicits other behavioural concomitants of satiation. Food intake is increased by systemic administration of CCK
A
receptor agonists (Smith, G. P. and Gibb, J., Ann. N.Y. Acad. Sci., 713, 236-241, (1994)). Endogenous CCK-controlling food intake seems to be of neuronal rather than hormonal origin and acts upon peripheral CCK
A
receptors on vagal afferent fibres (Smith, G. P. et al., Am. J. Physiol., 249, R638-R641 (1985)). In addition TPPII, although displaying preference for CCK, is also able to hydrolyse several other peptides with a free N-terminal ammonium group.
Inhibitors of TPP II are useful tools in investigating the functions of CCK neurons and may be useful drugs for the treatment of disorders such as over-eating, problems with gastrointestinal motility and psychotic syndromes.
The present invention relates to compounds which are useful in inhibiting TPP II, processes for producing these compounds, pharmaceutical compositions comprising these compounds and the use of the compounds to inhibit TPP II.
The present invention provides a compound of the following formula I:
wherein: each R
1
may be the same or different, and is chosen from
halogen; OH; C
1
-C
6
alkyl, C
1
-C
6
alkenyl or C
1
-C
6
alkynyl, optionally substituted by at least one halogen, OH or mixtures thereof; X(C
1
-C
6
alkyl), wherein X is S, O or OCO, and the alkyl is optionally substituted by at least one halogen, OH or mixtures thereof; SO
2
(C
1
-C
6
alkyl), optionally substituted by at least one halogen; or YSO
3
H, YSO
2
(C
1
-C
6
alkyl), wherein Y is O or NH and the alkyl is optionally substituted by at least one halogen; a diradical —X
1
—(C
1
-C
2
alkylene)—X
1
— wherein X
1
is O or S; a benzene ring fused to the indoline ring;
n is from 0 to 4;
R
2
is CH
2
R
4
, wherein R
4
is
C
1
-C
6
alkyl substituted by at least one halogen, OH or mixtures thereof; (CH
2
)
p
Z(CH
2
)
q
CH
3
, wherein Z is O or S, p is from 0 to 5 and q is from 0 to 5, provided that p+q is from 0 to 5;
C
2
-C
6
unsaturated alkyl; or C
3
-C
6
cycloalkyl; or R
2
is C
1
-C
6
alkyl or O(C
1
-C
6
alkyl), each optionally substituted by at least one halogen;
R
3
is H; C
1
-C
6
alkyl optionally substituted by at least one halogen; (CH
2
)
p
ZR
5
wherein p is from 1 to 3, Z is O or S and R
5
is H or C
1
-C
3
alkyl; benzyl;
or a pharmaceutically acceptable acid addition salt thereof;
The invention provides in particular a compound of the above formula I wherein: each R
1
may be the same or different, and is chosen from
halogen; OH; C
1
-C
6
alkyl, optionally substituted by at least one halogen, OH or mixtures thereof; X(C
1
-C
6
alkyl), wherein X is S, O or OCO, optionally substituted by at least one halogen, OH or mixtures thereof; SO
2
(C
1
-C
6
alkyl), optionally substituted by at least one halogen; or YSO
3
H, YSO
2
(C
1
-C
6
alkyl), wherein Y is O or NH optionally substituted by at least one halogen;
n is from 0 to 4;
R
2
is CH
2
R
4
, wherein R
4
is
C
1
-C
6
alkyl substituted by at least one halogen, OH or mixtures thereof; (CH
2
)
p
Z(CH
2
)
q
CH
3
, wherein Z is O, S, p is from 0 to 5 and q is from 0 to 5, provided that p+q is from 0 to 5; C
2
-C
6
unsaturated alkyl; or C
3
-C
6
cycloalkyl,
or R
2
is C
1
-C
6
alkyl or O(C
1
-C
6
alkyl), each optionally substituted by at least one halogen;
R
3
is H or C
1
-C
6
alkyl;
or a pharmaceutically acceptable acid addition salt thereof.
Compounds of formula (I) wherein n=0 or when n is not 0 wherein R
1
is a halogen atom, a O(C
1
-C
4
)alkyl, OH or a (C
1
-C
4
)alkyl group, R
2
is CH
2
R
4
with R
4
being (CH
2
)
2
SCH
3
, (CH
2
)
2
OH or cyclohexyl or R
2
is a (C
1
-C
6
)alkyl group, and R
3
is an hydrogen atom or a (C
1
-C
4
)alkyl group, are known from WO 96/35805 and are not included in the present invention.
According to one aspect of the present invention, it is relative to compounds of formula (I) wherein R
2
is CH
2
R
4
, R
4
being C
1
-C
6
alkyl substituted by at least one halogen; (CH
2
)
p
Z(CH
2
)
q
CH
3
wherein Z is O (p and q are as defined above); C
2
-C
6
unsaturated alkyl; or R
2
is O(C
1
-C
6
)alkyl optionally substituted by at least one halogen.
According to another aspect of the present invention, it is relative to compounds of formula (I) wherein n is not 0 and R
1
is C
1
-C
6
alkyl substituted by at least one halogen, OH or mixtures thereof; X(C
1
-C
6
alkyl) wherein X is S or OCO, optionally substituted by at least one halogen, OH or mixtures thereof; O(C
1
-C
6
)alkyl substituted by at least one halogen, OH or mixtures thereof; SO
2
(C
1
-C
6
alkyl), optionally substituted by at least one halogen; or YSO
3
H, YSO
2
(C
1
-C
6
alkyl) wherein Y is O or NH optionally substituted by at least one halogen.
According to another aspect, the present invention is directed to compounds (I) wherein n is not 0 and R
1
represents a C
1
-C
6
alkenyl or C
1
-C
6
alkynyl group.
The alkyl groups may be straight-chain or branched. The alkyl groups have from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. Preferred alkyl groups are C
1-4
straight chain alkyl. Typically a substituted alkyl group has from 1 to 6 substituents and preferably from 1 to 3 substituents. Halogen is typically F,Cl,Br, or I, preferably Cl or F, most preferably F.
The alkenyl or alkynyl groups may be straight-chain or branched. These groups contain from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
Typical alkenyl groups include ethenyl.
Typical alkynyl groups include ethynyl.
Unsaturated alkyl groups (in R
2
) contain one or more double or triple bonds.
According to still another aspect of the invention, it is relative to compounds (I) wherein R
1
is a diradical —X
1
—(C
1
-C
2
alkylene)—X
1
— where X
1
is as defined above. R
1
is typically —OCH
2
O—.
The diradical is preferably attached to the indoline ring a

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