Gastrin and cholecystokinin receptor ligands

Details Gastrin and cholecystokinin receptor ligands Gastrin and cholecystokinin receptor ligands

2001-08-02

2002-11-12

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S398000, C514S399000, C548S314700, C548S326500, C548S331100, C548S335100

Reexamination Certificate

active

06479531

ABSTRACT:

This invention relates to gastrin and cholecystokinin (CCK) receptor ligands. The invention also relates to methods for preparing such ligands and to compounds which are useful intermediates in such methods. The invention further relates to pharmaceutical compositions comprising such ligands and methods for preparing such pharmaceutical compositions.
Gastrin and the cholecystokinins are structurally related neuropeptides which exist in gastrointestinal tissue and the central nervous system (Mutt V.,
Gastrointestinal Hormones,
Glass G. B. J., ed., Raven Press, New York, p. 169; Nisson G., ibid., p. 127).
Gastrin is one of the three primary stimulants of gastric acid secretion. Several forms of gastrin are found including 34-, 17- and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe-NH
2
) which is reported in the literature to have full pharmacological activity (Tracey H. J. and Gregory R. A.,
Nature
(London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH
2
) in an attempt to elucidate the relationship between structure and activity.
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal mobility, gall bladder contraction, pancreatic enzyme secretion and are known to have a trophic action on the pancreas. They also inhibit gastric emptying and have various effects in the central nervous system.
Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as antagonists or partial agonists of the natural peptides.
A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which lower gastrin activity or lower acid secretion is desirable. The hormone has also been shown to have a trophic action on cells and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach and the colon.
Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (for example morphine) analgesia and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCK
B
receptors) have been claimed to possess anxiolytic activity.
According to the present invention, there are provided compounds of formula (I)
wherein
X and Y are independently ═N—, —N(R
5
)—(R
5
being selected from H, Me, Et, Pr, Bn, —OH and —CH
2
COOR
6
, wherein R
6
represents H, Me, Et, Pr or Bn), ═CH—, —S— or —O—;
n is from 1 to 4;
R
1
is H or C
1
to C
15
hydrocarbyl wherein up to three C atoms may optionally be replaced by N, O and/or S atoms and up to three H atoms may optionally be replaced by halogen atoms;
R
2
is selected from H, Me, Et, Pr and OH, each R
2
being independently selected from H, Me, Et, Pr and OH when n is greater than 1;
R
3
(when n is 1) is selected from H, Me, Et and Pr; or (when n is greater than 1) each R
3
is independently selected from H, Me, Et and Pr, or two R
3
groups on neighbouring carbon atoms are linked to form a C
3
to C
6
carbocylic ring, or two R
3
groups are absent from neighbouring carbon atoms which are linked by a double bond; or R
2
and R
3
on the same carbon atom together represent an ═O group;
R
4
is C
1
to C
15
hydrocarbyl wherein up to two C atoms may optionally be replaced by N, O and/or S atoms and up to two H atoms may optionally be replaced by halogen atoms;
Z is —(NR
7
)
a
—CO—(NR
8
)
b
— (wherein a is 0 or 1, b is 0 or 1, and R
7
and R
8
are independently selected from the groups recited above for R
6
), —CO—NR
7
—CH
2
—CO—NR
8
—, CO—O—, —CH
2
—CH
2
—, —CH═CH—, —CH
2
—NR
8
— or a bond;
Q is —R
9
V, or
(wherein R
9
is —CH
2
—; —CH
2
—CH
2
—; or
 or R
9
and R
8
, together with the nitrogen atom to which R
8
is attached, form a piperidine or pyrrolidine ring which is substituted by V;
V is —CO—NH—SO
2
—Ph, —SO
2
—NH—CO—Ph, —CH
2
OH, or a group of the formula —R
10
U, (wherein U is —COOH, tetrazolyl, —CONHOH or —SO
3
H; and
R
10
is a bond; C
1
to C
6
hydrocarbylene, optionally substituted by hydroxy, amino or acetamido; —O—(C
1
to C
3
alkylene)—; —SO
2
NR
11
—CHR
12
—;
—CO—NR
11
—CHR
12
—, R
11
and R
12
being independently selected from H and methyl; or —NH—(CO)
c
—CH
2
—, c being 0 or 1);
T is C
1
to C
6
hydrocarbyl, —NR
6
R
7
(wherein R
6
and R
7
are as defined above), —OMe, —OH, —CH
2
OH, halogen or trihalomethyl;
m is 1 or 2;
p is from 0 to 3; and
q is from 0 to 2, with the proviso that q is 1 or 2 when Z is a bond);
and pharmaceutically acceptable salts thereof.
In certain compounds according to the invention, R
5
is selected from H, Me, Et, Pr and Bn; Z is —(NR
7
)
a
—CO—(NR
8
)
b
—, —CO—NH—CH
2
—CO—NH— or a bond; Q is
V is —CO—NH—SO
2
—Ph, —SO
2
—NH—CO—Ph, —OCH
2
COOH, tetrazolyl or —CH
2
)
s
COOH, wherein s is from 0 to 2; and T is C
1
to C
6
hydrocarbyl, —NR
6
R
7
, —OMe, —OH, —CH
2
OH or halogen. Such compounds are disclosed in U.K. patent application No. 9824536.8, the contents of which are hereby incorporated by reference.
A further group of compounds according to the invention are those in which R
5
is selected from H, Me, Et, Pr and Bn; Z is —(NR
7
)
a
—CO—(NR
8
)
b
—, Q is —(CH
2
)
r
COOH, wherein r is from 1 to 3; and T is C
1
to C
6
hydrocarbyl, —NR
6
R
7
, —OMe, —OH, —CH
2
OH or halogen.
A still further group of compounds according to the invention are those in which R
5
is selected from H, Me, Et, Pr and Bn; —Z—Q is
k is 1 or 2; and T is C
1
to C
6
hydrocarbyl, —NR
6
R
7
, —OMe, —OH, —CH
2
OH or halogen.
Preferably X and Y are independently ═N—, ═CH—, —NH—, —NOH—, —NMe— or —NBn—. Most preferably X is —NH— or —NOH— and Y is ═CH— (or vice versa) or X is ═N— and Y is —NH— or —NOH— (or vice versa).
Preferably R
1
is C
1
to C
12
hydrocarbyl wherein one C atom may optionally be replaced by N or O and up to three H atoms may optionally be replaced by F, Cl or Br. More preferably R
1
is C
3
to C
12
alicyclic; phenyl (optionally substituted with OMe, NMe
2
, CF
3
, Me, F, Cl, Br or I); or C
1
to C
8
alkyl. Alicyclic groups include C
5
to C
8
cycloalkyl, C
7
to C
10
polycycloalkyl, C
5
to C
8
cycloalkenyl and C
7
to C
10
polycycloalkenyl, all optionally substituted with methyl.
Preferably Z is —CO—NH—.
Preferably Q is
and more preferably
p is preferably 0 or 1, and q is preferably 0. If p is greater than 0, then T is preferably C
1
to C
6
hydrocarbyl or halo.
m is preferably 1, and V is preferably —CO
2
H, —CH
2
CO
2
H or tetrazolyl.
Preferably R
2
and R
3
are H; n is 1 to 3; and R
4
is C
3
to C
12
carbocyclic. More preferably, R
4
is adamantyl, cycloheptyl, cyclohexyl or phenyl. Alternatively, R
4
may be —NH—R
13
or —OR
13
, wherein R
13
is C
3
to C
12
carbocyclic, preferably adamantyl, cycloheptyl, cyclohexyl or phenyl.
R
10
is preferably a bond, C
1
or C
2
alkylene (optionally substituted by hydroxy, amino or acetamido), —O—(C
1
to C
3
alkylene)—; —SO
2
NR
11
—CHR
12
—; —CO—NR
11
—CHR
12
—, —NH—(CO)
c
—CH
2
—, or a group of the formula
Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolations from each other as well as mixtures.
Compounds of the invention wherein
(i) X is —NH

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