GB2263639A - Substituted pyrimidinones as neurotensin antagonists - Google Patents
Substituted pyrimidinones as neurotensin antagonists Download PDFInfo
- Publication number
- GB2263639A GB2263639A GB9301047A GB9301047A GB2263639A GB 2263639 A GB2263639 A GB 2263639A GB 9301047 A GB9301047 A GB 9301047A GB 9301047 A GB9301047 A GB 9301047A GB 2263639 A GB2263639 A GB 2263639A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- aryl
- tetrazol
- alkoxy
- single bond
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Treating disease states mediated by neurotensin by administering to a patient in need of treatment of a therapeutically effective amount of a neurotensin antagonist useful for treating certain GI and CNS disorders which is a substituted pyrimidinone of structural formula I as disclosed in EP-041 9048-A2. <IMAGE>
Description
TITLE OF THE INVENTION
SUBSTITUTED PERIMIDINONES AS NEUROTENSIN ANTAGONISTS
INTRODUCTION OF THE INVENTION
This invention is concerned with a method of treating disease states mediated by neurotensin by the administration to a patient in need of treatment of a therapeutically effective amount of a neurotensin antagonist which is a substituted pyrimidinone of structural formula I:
As neurotensin antagonists these compounds find utility in the treatment of CNS dysfunctions such as psychoses, depression, cognitive dysfunction, such as Alzheimer's disease, anxiety, tardive dyskinesia, drug dependency, panic attack and mania.
The neurotensin antagonist property also imparts to the compounds utility in GI disorders such as gastroesophageal reflux disorder (GERD), irritable bowel syndrome, diarrhea, cholic, ulcer, GI tumors, dyspepsia, pancreatitis, esophagitis and gastroparesis. The known ability of neurotensin to release mast cell histamine indicates that antagonists will be useful in the treatment of allergic and inflammatory conditions.
BACKGROUND OF THE INVENTION
Neurotensin (NT) is a tridecapeptide hormone (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro
Tyr-Ile-Leu-OH), originally isolated from the bovine hypothalamus [Carraway, R. and Leeman, S. E., J.
Biol. Chem.,248, 6854 (1973)], has subsequently been shown to be distributed in the brain [Uhl, G. R., ffe al., Proc. Natl. Acad. Sci. USA, 74, 4059-4063 (1977)), gastrointestinal tract [ 1). Kitabgi, P.,
Carraway, R. and Leeman, S. E., J. Biol. Chem., 251, 7053 (1976); 2). Caraway, R., Kitabgi, P., and
Leeman, S. E., J. Biol. Chem., 253, 7996 (1978); 3).
llelmstadler, V., Tadgner, C., Feurle, G. E. and
Frossman, W. G., Histochemistry, 53, 35-41 (1977)] and pancreas [Feurle, G. E. and Niestroj, S.,
Pancreas, 6, 202-207 (1991) and references cited therein] of various animals including human [Mai, J.
K., et al., Neuroscience, 22, 499-524 (1987)1.
Although the physiological role of neurotensin has not yet been clearly understood, this endogenous peptide participates in a wide spectrum of central.
[1). Prange, A. J. and Nemeroff, C. B., Annal. NY
Acad. Sciences, 400, 368-375 (1982); 2). Stowe, Z.
N.and Nemeroff, C. B., Life Sci., 49, 987-1002, (1991); 3) Kitabgi, P., Neurochem. Int., 14, 111-119 (1989); 4). Levant and Nemeroff, C. B., Current topics in Neuroendocrinology, 8, 231-262 (1988)] and peripheral [Leeman, S. E., Aronin, N. and Ferris, C.,
Hormone Res., 38, 93-132 (1982)] biological functions.
Neurotensin is also known to release mast cell histamine, indicating that antagonists will be useful in the treatment of allergic and inflammatory conditions, as well. [See, Rossei, S.S. and Miller,
R.J., Life Sci., 31, 509-516 (1982) and Kurose, M.
and Saeki, K., Eur. J. Pharmacol., 76, 129-136 (1981).]
Neurotensin, like most other peptides, is unable to cross the blood-brain barrier (BBB).
However, certain peripheral effects of neurotensin have been observed after central administration of the peptide [Prange, A. J. and Nemeroff, C. B.,
Annal. NY Acad. Sciences, 400, 368-391 (1982)]. The direct application of neurotensin into the brain causes hypothermia, potentiation of barbiturate induced sedation, catalepsy, antinociception, blockade of psychostSimulant-induced locomotor activity and reduced food consumption. In the central nervous system (CNS), neurotensin behaves as a neurotransmitter or neuromodulator [1) Uhl, G. R.
and Snyder, S. H., Eur. J. Pharmacol., 41,'89-91 (1977); 2) Uhl, G. R., Annal. NY Acad. Sciences, 400, 132-149 (1982)], and has been shown to have close anatomical and biochemical associations with the dopaminergic (DA) system [Nemeroff, C. B.,-et al.
Annal. NY Acad. Sciences, 406, 330-344 (1982)].
Neurotensin increases the synthesis and the turnover of DA in rat brain. Acute and chronic treatment with clinically efficacious antipsychotic drugs (e.g., haloperidol, chloropromazine) have consistently demonstrated an increase in neurotensin concentrations in the nucleus accumbens and striatum while phenothiazines that are not antipsychotics did not produce this increase. Behaviorally, neurotensin, after central administration, mimics the effects of systemically administered neuroletics. However, unlike classical neuroleptics (which primarily act on
D2 receptors), neurotensin fails to bind to dopamine receptors or inhibit cAMP accumulation following DA receptor activation. Neurotensin does not block the stereotypy induced by DA agonists.The post-mortem studies of patients with schizophrenia showed an increase in the level of neurotensin in the Brodman's area 32 of human brain [Nemeroff, C. B., et. al.,
Science., 221, 972-975 (1983) and references cited therein], which suggest possible roles of neurotensin in the pathophysiology of this disease.
Neurotensin receptors have also been implicated in
Parkinsonrs disease and progressive supranuclear palsy [Chinaglia, GS et al., Neuroscience, 39, 351-360 (1990)].
Of the total body neurotensin in many mammalian species, more than 80% is present in the gastrointestinal tract, especially in the distal small' intestine in the endocrine like N-cells. In the gut, neurotensin stimulates pancreatic secretion [Sakamoto, T.,et al, Surgery, 96, 146-53 (1984)], inhibits gastric acid secretion and gastric emptying [ Blackburn, A. M., Lancet, 1, 987-989 (1980)].
Neurotensin also stimulates the growth of small intestinal mucosa in an isolated defunctional loop of jejunum, which suggests a direct systemic effect of neurotensin in the gut. In addition, neurotensin can stimulate pancreatic exocrine secretion in mammals [Iwatsuki, K.,.et al., Clin. Expt. Pharmacol.
Phvsiol., 18, 475-481 (1991) and references cited therein].
From the structural work, it is evident that the biological activity of neurotensin resides within the carboxy terminal five or six amino acid residues.- The C-terminal hexapeptide NT8-13 has displayed full biological activity of the tridecapeptide. In contrast, all amino terminal partial sequences are essentially inactive [Leeman, S. E. and Carraway, R.
E., Annal. NY Acad. Sciences, 400, 1-16 (1982)]. The
C-terminal COOH group and two Arg residues are essential for the biological activity of NT8-13 as well as neurotensin. L-amino acids are required at positions-9,10,11 and 13, and only Arg8 can be replaced by D-Arg without loss of any activity. At the position-ll, an aromatic amino acid is essential.
Similarly, alkyl side-chains of Ilex2 and Leul3 are also necessary for Pull biological activity [Kitabgi,
P., Annal. NY Acad. Sciences, 400, 37-53 (1982)].
Most of the analogues of neurotensin examined generally behaved as agonists. However, two analogues
D-Trpll-NT and Tyr(Me)11-NT have displayed partial antagonist activity tRioux, F. R.,et al., Eur. J.
Pharmacol., 66, 373-379 (1980)).
The compounds useful in the novel method of treatment of this invention are known in the art having been published in European Patent Application
EP 419,048 (Merck & Co., Inc.) on March 27, 1991, where they are alleged to be angiotensin II receptor antagonists useful in the treatment of hypertension and ocular hypertension.
Although there are reports of peptidic neurotensin antagonists, they are unstable and not orally active and none are clinically available.
There are no reports of nolf-peptidic neurotensin antagonists.
Now with this invention there are provided non-peptidic neurotensin antagonists.
DETAILED DESCRIPTION OF THE INVENTION
The compounds useful in the novel method of treatment of this invention have structural formula I:
or a pharmaceutically acceptable salt thereof wherein:
J is -C(=M)- or
K is -C(=M)- or
provided that one and only
one of J and K is -C(=M)- ;
M is O or NR21; one of a and b is a double bond, provided that when J is -C(=M)- b is a double bond and when K is -C(=M)- a is a double bond;
R1 is (a) -NHS02R21, (b) -NHSO2NHCOR21,
(c) -NHCONHS02R21, (d) -SO2NHR21,
(e) -SO2NHCOR21,
(f) -SO2NHCONR9R21,
(g) -SO2NHCOOR21, (h) -S02NHOR21,
(i) -CH2SO2NHCOR21,
(j) -CH2SO2NHCONHR21,
(k) -CO2H, or
(l) -1H-tetrazol-5-yl;
R2a and R2b are each independently
(a) H,
(b) C1, Br, I, F,
(c) CF3,
(d) C1-C4-alkyl, or
(e) C1-C4-alkoxy; R3a is
(a) H,
(b) Cl, Br, I, F, (c) C1-C6-alkyl,
(d) C1-C6-alkoxy, or
(e) C1-C6-alkoxy-C1-C4-alkyl;;
R3b is
(a) H
(b) Cl, Br, I, F,
(c) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl,
(d) C1-C6-acyloxy,
(e) C3-C6-cycloalkyl,
(f) C1-C6-alkoxy, or
(g) perfluoro-C1-C4-alkyl;
R4 is H or C1-C6-alkyl unsubstituted or
substituted with aryl, wherein aryl is
phenyl optionally substituted with one or
two substituents selected from the group consisting of or C1, Br, I, F, or C1-C4-alkyl, optionally substituted with members selected
from the group consisting of N(R4)2, CO2R4,
OH, N(R4)CO2R21, S(O)xR21 wherein x is O to
2; C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio,
OH, NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2,
-CO2H, -CO2-C1-C4-alkyl, N(R4)CO2R21, or
1H-tetrazol-5-yl; or
R4a is C1-C6-alkyl, aryl or aryl-CH2-;
E is a single bond, -NR13(CH2)s-, -S(O)x(CH2)s-
where x is O to 2 and s is O to 5, -CH(OH)-, -O-, CO-;
R6 is
(a) aryl;
(b) Cl-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl
each of which can be unsubstituted or
substituted with a substituent selected from
the group consisting of aryl,
C3-C7-cycloalkyl, C1, Br, I, F -OH, CF3,
-CF2CF3, CC13, -NH2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -NH-SO2R4, -COOR4,
-SO2NHR9, C1-C4-alkoxy, C1-C4-alkyl-S;;
(c) heteroaryl, wherein heteroaryl is defined as
an unsubstituted, monosubstituted or
disubstituted 5 or 6 membered heteroaromatic
ring which can contain one or two members
selected from the group consisting of N, O,
S, and wherein the substituents are members
selected from the group consisting of -OH,
-SH, C1-C4-alkyl, C1-C4-alkyloxy -CF3, C1,
Br, I, F, NO2, -C02H, -CO2-C1-C4-alkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2;
(d) C3-C7-cycloalkyl;;
R7 and R8 are independently
(a) H-,
(b) aryl-C1-C4-alkyl-,
(c) heteroaryl-C1-C4-alkyl-, (d) C1-C6-alkyl unsubstituted or substituted
with a substituent selected from the group
consisting of -OH, '-NH2, guanidino,
C1-C4-alkoxy, -S(O)xR21, C1-C4-alkylaminol,
C1-C4-dialkylamino, -COOR4, -CON(R4)R21, -OCON'(R4)R21, -0-COR4, C3-C5-cycloalkyl,
-N(R4)CON(R4)R21, -N(R4)COOR21, -CONHSO2R21, -N(R4)So2R21;; (e) C2-C4-alkenyl,
(f) -CO-aryl,
(g) C3-C7-cycloalkyl,
(h) C1, Br, I, F,
(i) -OH,
(j) -OR21,
(k) perfluoro-C1-C4-alkyl, (1) -SH,
(m) -S(O)@R21 where x is as defined above,
(n) -CHO,
(o) -CO2R4,
(p) -SO3H, (q) -N(R4)2,
(r) -NR4CO2R21,
(s) -SO2NR9R10,
(t) -CH2OCOR4,
(u) -N(R4)-SO2-C1-C4-alkyl,
(v) 5' or 6 membered saturated heterocycle
containing one nitrogen atom and optionally
containing one other heteroatom selected
from N, O or S, such as pyrrolidine,
morpholine, or piperazine,
(w) aryl,
(x) heteroaryl,
(y) 1H-tetrazol-5-yl,
(z) -NHSO2-perfluoro-C1-C4-alkyl,
(aa) -CONHSO2R21,
(bb) -SO2NHCOR21,
(cc) -SO2NH-heteroaryl,
(dd) -S(O)x-aryl,
(ee) -S(O)xCH2-aryl, or
(ff) -CON(R4)2;
R9 is H, C1-C5-alkyl, phenyl or benzyl;;
R10 is H, C1-C4-alkyl; R11 is H, C1-C6-alkyl, C2-C4-alkenyl, C1-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2 or -CO2R4; R13 is H, C1-C4-acyl, C1-C6-alkyl, allyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, C1-C6-alkyl; R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl or
benzyl;
R17 is -NR9R10, -OR10, -NHCONH2, -NHCSNH2,
R18 and R19 are independently C1-C4-alkyl or taken
together are -(CH2)q- where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3; ; R21 is
(a) aryl,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C8-alkyl wherein alkyl is unsubstituted
or substituted with one or two substituents
selected from the group consisting of aryl,
heteroaryl, -OH, -SH, C1-C4-alkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, Cl,
Br, F, I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, -NR4CO2R22, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -PO3H2,
-PO(OH)(O-C1-C4-alkyl), -PO(OR4)R9,
-NR4COR4a, -CONR4R4a, -OCONR4R4a,
-SO2NR4R4a, -NR4SO2R4a, or
(e) perfluoro-C1-C4-alkyl;; X is
(a) a carbon-carbon single bond,
(b) -CO-,
(c) -O-,
(d) -S-,
(h) -OCH2-, (i) -CH2O-, (j) -SCH2-, (k) -CH2S-, (1) -NHCCR9)CR10), (m) -NR9SO2-, (n) -SO2NR9-, (o) -C(R9)(R10)NH-, (p) -CH=CH-, (q) -CF=CF-, (r) -CH=CF-, (s) -CF=CH-, (t) -CH2CH2-, (u) -CF2CF2-,
r is 1 or 2.
The terms "alkyl", "alkenyl", "alkynyl: and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms in the species permit. Unless otherwise noted, the specific names for these generic terms shall mean the straight chain species. For example, the term "butyl" shall mean the normal butyl substituent, n-butyl.
One embodiment of the compounds of formula (I) are those compounds wherein:
J is
K is
b is a double bond;
R is -NHSO2R21, -NHSO2NHCOR21, -NHCONHSO2R21,
-SO2NHR21, -SO2NHCOR21, -SO2NHCONR9R21,
-SO2NHCOOR21, -SO2NHOR21, -CH2SO2NHCOR21,
-CH2SO2NHCONHR21, -CO2H, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3 or C1-C4-alkyl; R3a is H;
R3b is H, F, C1, CF3, or C1-C6-alkyl; E is a single bond, -0- or -S-;
R6 is
(a) Cl-C5-alkyl unsubstituted or substituted
with a substituent selected from the group
consiting of C1, CF3, CC13, -O-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C1-C5-alkynyl, or
(c) aryl;;
R7 and R8 are independently
(a) H,
(b) C1-C6-alkyl,
(c) C2-C4-alkenyl,
(d) -OH,
(e) -CH2OCOR4,
(f) -NH2,
(h) -C1-C4-alkoxy,
(i) -NH(C1-C4-alkyl),
(j) -N(C1-C4-alkyl)2,
(k) -Cl, -F, -Br,
(1) -CF3,
(m) -CO2R4,
(n) -CH2-OH, (o) 5 or 6 membered saturated heterocycle
containing one nitrogen atom and optionally
containing one other heteratom selected
from N, O, or S, such as pyrrolidine,
morpholine, or piperazine;
(p) -CO-aryl,
(q) -S(O)x-C1-C4-alkyl,
(r) -SO2-NH-C1-C4-alkyl, Cs') -SO2-NH-aryl, -(t) -NH-S02CH3,
(u) aryl, (v) heteroaryl, or
(w) 1H-tetrazol-5-yl;
X is a C-C single bond or -CO-; and, r is one.
In a class of this embodiment are those compunds wherein:
E is a single bond or -S-; r is one,
R is -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21,
-SO2NHOR21, -CH2SO2NHCOR21, or
-lH-tetrazol-5-yl;
R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, iso-propyl, n-butyl, iso-butyl,
-CH3, -CH2CH3, phenyl, or -CH2-S-CH3;
R7 is -NHSO2CF3, -CH2OH, -CH2OCOR4, -CO2R4,
1H-tetrazol-5-yl, -N(CH3)2, -NR4CO2-C1-C4-alkyl, H, -C1-C4-alkyl, aryl,
or a 5- or 6-membered saturated heterocycle;
R8 is H, -Cl-C4-alkyl, aryl, heteroaryl, C1, F,
CF3;
X is a single bond.
In a second embodiment are those compounds of formula (I) wherein:
K is -C(=O)-;
J is
a is a double bond;
R is -NHSO2R21, -NHSO2NHCOR21, -NHCONHSO2R21,
-SO2NHR21, -SO2NHCOR21, -SO2NHCONR9R21,
-SO2NHCOOR21, -SO2NHOR21, -CH2SO2NHCOR21,
-CH2SO2NHCONHR21, -CO2H, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, or C1-C4-alkyl; R3a is H, F or C1;
R3b is H, F, C1, CF3, or C1-C6-alkyl, E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl unsubstituted or substituted
with a substituent selected from the group
consisting of C1, CF3, CC13, -O-CH3, -OC2H5', -S-CH3, -S-C2H5 or phenyl,
C2-C5-alkenyl or C2-C5-alkynyl,
C3-C5-cycloalkyl, or
(b) aryl;;
R7 and R8 are independently
(a) H,
(b) C1-C4-alkyl unsubstituted or substituted
with -N(R4)CO2R21, -S(O)xR21, aryl,
-N(R4)2, -CO2R4, -N(R4)CON(R4)R21, -CON(R4)R21, (c) C2-C4-alkenyl,
(d) -OH,
(e) -CH2OCOR4,
(f) -NH2,
(g) -N(R4)COOR21,
(h) -C1-C4-alkoxy,
(i) -NH(C1-C4-alkyl),
(j) -N(C1-C4-alkyl)2,
(k) -Cl, -F, -Br,
(l) -CF3,
(m) -C02R4,
(n) -CH2-OH, (o) 5 or 6 membered saturated heterocycle, (p)' -CO-aryl,
(q) -S(O)x-C1-C4-alkyl,
(r) -SO2-NH-C1-C4-alkyl,
(s) -SO2-NH-aryl,
(t) -NH-SO2CH3, (u) aryl,
(v) heteroaryl, or
(w) 1H-tetrazl-5-yl; a X is a C-C single bond or -CO-; and, r is one.
In a class of this embodiment are those compounds wherein:
E is a single bond or -S--; R is -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21,
-SO2NHOR21, -CH2SO2NHCOR21, or
-1H-tetrazol-5-yl;
R2a and R2b are E, E, C1, CF3, or C1-C4-alkyl; R3a is H, F, or C1;
R3b is H, E, C1, CF3, C1-C6-alkyl; R6 is n-propyl, iso-propyl, n-butyl, iso-butyl,
-CH2CH3, cyclopropyl, cyclopropylmethyl or
aryl;
X is a single bond.
In a third embodiment are those compounds of formula (I) wherein:
K is -C(=NR21);
J is
a is a double bond;
R is -NHSO2R21, -NHSO2NHCOR21, -NHCONHSO2R21,
-S02NHR21, -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21, -SO2NHOR21, -CH2SO2NHCOR21,
-CH2SO2NHCONHR21, -CO2H, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, or C1-C4-alkyl; R3a is H, F or C1;
R3b is H, F, C1, CF3, or C1-C6-alkyl; E is a single bond, -0- or -S-;
R6 is
(a) Cl-C5-alkyl unsubstituted or substituted
with a substituent selected from the group
consisting of C1, CF3, CC13, -O-CH3,
-OC2H5, -S-CH3, -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C2-C5-alkynyl, or
(c) aryl;;
R7 and R8 are independently
(a) H,
(b) C1-C6-alkyl, (c) C2-C6-alkenyl,
(d) -OH,
(e) -CH2OCOR4,
(f) -NH2,
(h) -C1-C4-alkoxy, (i) -NH(C1-C4-alkyl), (j) -N(C1-C4-alkyl)2, (k) C1, F, Br, (1) -CF3, (m) -CO2R4, (n) -CH2-OH, (o) 5 or 6 membered saturated heterocycle, (p) -CO-aryl, (q) -S(O)x-C1-C4-alkyl (r) -SO2-NH-C1-C4-alkyl, (s) -SO2-NH-aryl, (t) -NH-S02CH3, (u) aryl, (v) heteroaryl, or (w) lH-tetrazol-5-yl;
X is a C-C single bond or -CO-; and r is one.
In a class of this embodiment are those compounds of formula (I) wherein:
E is a single' bond or -S-; r is one;
R is -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21,
-SO2NHOR21, -CH2SO2NHCOR21, or
-lH-tetrazol-5-yl; R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, iso-propyl, n-butyl, iso-butyl,
-CH3, -CH2CH3, or phenyl;
R7 and R8 are independently selected from::
H, C1-C6-alkyl, -Cl, C1-C4-alkoxy, -F,
-CH2OH, NO2, -CO2R4, -NR4-COO-C1-C4-alkyl,
-CF3, -CH2OCOR4, -NH2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, 1H-tetrazol-5-yl, aryl or
a 5 or 6 membered saturated heterocycle; a X is a C-C single bound or -CO-;
The compounds of Formula (I) can be synthesized using the reactions and techniques described in published under the Patent Cooperation
Treaty as International Application WO 9115479 (Merck & Co.). The above mentioned application discloses the compounds of this invention where they are alleged to be angiotensin II receptor antagonists useful in the'treatment of hypertension and ocular hypertension.
The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and in the reactants being employed should be consistent with the chemical transformations being conducted. Depending upon the reactions and techniques employed, optimal yields may require changing the order of synthetic steps or use of protecting groups followed by deprotection.
The compounds useful in the novel method treatment of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkai metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-Dglucamine, salts. with amino acids like arginine,.
lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HC1, HBr,
H2S04, H3P04, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
The salts can be formed by conventional means,such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
Neurotensin is a peptide hormone and the as says described below have been developed to identify neurotensin antagonists and to determine their efficacy in vitro. The following two as says have been employed for that purpose.
RAT FOREBRAIN RECEPTOR ASSAY
Male rats are sacrificed by decapitation following ether anesthetization. Forebrains are homogenized using a polytron in 20 volumes 50 mM Tris
HCl, pH 7.4, and centrifuged at 50,000 x g for 20 min. The final pellet is resuspended at a concentration of 8 mg tissue (wet weight) per 0.750 ml of 50 mM Tris HCl, pH 7.4, which also contains 1 mM EDTA, 4 g/ml bacitracin, 5 M levocabastine HCl, 1 mM phenanthroline, 10 Fg/ml soybean trypsin inhibitor and 100 WM phenyl methyl sulfonyl fluoride. Assay tubes (13 x 100 polypropylene) receive 1) 100 l buffer or 10 M neurotensin (for non-specific binding) 2) 100 > 1 of 60 pM tl25I]neurotensin 3) 20 l test compounds 4) 750 l tissue suspension and 5) enough buffer to bring final volume to 1 ml.After 30 minutes at room temp, the samples are filtered using a Brandel M24 cell harvestor with GF/B filtermats that have been presoaked in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3 x 4 ml of ice cold lOmM Tris buffer (pH 7.4 at room temperature). The filter discs are placed in 12 x 75 mM polypropylene tubes for counting on a Packard Multu-Prias gamma counter.
HUMAN HT-29 CELL MEMBRANE ASSAY
HT-29 cells were routinely grown in 225 cm2
Costar tissue culture flasks at 37 C in a humidified atmosphere of 5% C02/95% air in Dulbecco's modified
Eagle's medium with high glucose containing 50 U/ml penicillin, 50 g/ml streptomycin, 5% fetal bovine serum and 5% newborn calf serum. Cells were subcultured with 0.25% trypsin at a ratio of 1:6 with confluence being reached at 48 to 72 hrs. Cells from confluent flasks (approx. 1 x 108 cells/flask) were harvested by scraping. The cells were pelleted by centrifugation (1000 x g, 5 min), resuspended in 50 mM Tris HCl, pH 7.4, and homogenized with a polytron (setting 7 for 10 sec.). Cell membranes were washed twice by centrifugation (50,000 x g, 15 min) and rehomogenization.The resulting pellet was either frozen at -70 C for future use or run directly in the assay by resuspending at a concentration of 0.5 x 106 cells per 0.750 ml of assay buffer (50 mM Tris HC1, pH 7.4, containing 1 mM EDTA, 40 Fg/ml bacitracin, 1 mM phenanthroline, 10 Fg/ml soybean trypsin inhibitor and 100 WM phenylmethylsulfonyl fluoride).
Assay tubes (13 x 100 polypropylene) receive 1) 100 l buffer or 10 M neurotensin (for non-specific binding) 2) 100 l of 60 pM [1251]neurotensin 3) 20 > 1 test compounds 4a) 750 l cell membrane suspension and 5) enough buffer to bring final volume to 1 ml.
After 30 minutes at room temperature, the samples are filtered using a Brandel M24 cell harvestor with GF/B filtermats that have been presoaked in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3 x 4 ml of ice cold 10 mM Tris buffer CpH 7.4 at room temperature). The filter discs are placed in 12 x 75 mM polypropylene tubes for counting on a
Packard Multi-Prias gamma counter. [The above assay is derived from the assay described in Kitabgi, P. et al., Molecular Pharmacology, 18, 11-19 (1980)].
NEUROTENSIN BINDING ASSAY USING HUMAN FRONTAL CORTEX
Post-mortem human brain is obtained through the National Disease Research Interchange (Philadelphia, PA). The donors were without psychiatric or neurological abnormalities. Frontal cortex is dissected free of white matter and homogenized using a polytron in 20 volumes 50 mM Tris HC1, pH 7.4; and centrifuged at 50,000 x g for 20 min. The resulting pellet is washed twice by rehomogenization and centrifugation as before. The final pellet is resuspended at a concentration of 8 mg tissue (wet weight) per 0.750 ml of 50 mM Tris HC1, pH 7.4, which also contains 1 mM EDTA, 4 Fg/ml bacitracin, 1 mM phenanthroline, 10 Fg/ml soybean trypsin inhibitor and 100 M phenyl methyl sulfonyl fluoride. Assay tubes (13 x 100 polypropylene) receive 1) 100 l buffer or 10 WM neurotensin (for non-specific binding ) 2) 100 > 1 of 60 pM [125I]neurotensin 3Y 20 l test compounds 4) 750 1 tissue suspension and 5) enough buffer to bring final volume to 1 ml. After 30 minutes at room temp, the samples are filtered using a Brandel M24 cell harvestor with GF/D filtermats that have been presoaked.in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3 x 4 ml of ice cold lOmM Tris buffer CpH 7.4 at room temperature). The filter discs are placed in 12 x 75 mM polypropylene tubes for counting on a Packard Multu-Prias gamma counter.
Using the methodology described above, representative compounds of the invention were evaluated and all were found to exhibit an activity of at least IC5o < 50WM thereby demonstrating and confirming the utility of the compounds of the invention as effective neurotensin antagonists.
Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg. of compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegratig agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can beformulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
The compounds listed in the Table below are representative of the compounds of the invention and are prepared according to the procedures described in
EP 419,048 published on March 27, 1991: 2-n-Butyl-3-(2'-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl )methyl-5-ethyl-6-methylpyr imidin-, 4(3H)-one (Example 5) 2-n-Butyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl5-ethyl-6-methylpyrimidin-4(3H)-one (Example 6) 2-n-Butyl-3-(2'-cyanobiphen-4-yl)methyl-5-ethOxy- earbonylpyrimidin-4(3H)-one (Example 7) 2-n-Butyl-3-(2'-(tetrazol-5-yl)biphebnyl-4-yl)methyl-5-ethoxycarbonylpyrimidin-4(3H)-one (Example 8) 2-n-Butyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl5-carboxypyrimidin-4(3H)-one (Example 9) 2-n-Butyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methylpyrimidin-4(3H)-one (Example 10) 2-n-Butyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl6-methylpyrimidin-4(3H)-one (Example 11) 2-n-Butyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl 6-ethoxypyrimidin-4(3E)-one (Example 16) 2-n-Butyl-1-(2'-(N-triphenylmethyl-tetrazol-5-yl)- biphen-4-yl)methyl-5-ethyl-6-methylpyrimidin4(3H)-one (Example 20) 2-n-Butyl-1-(2-(N-triphenylmethyl-tetrazol-5-yl)- biphenyl-4-yl)methyl-5 , 6-dimethylpyrimidin-4(3H)-one (Example 24) 2-n-Butyl-1-(2 '-(tetrazol-5-yl)-biphen-4-yl)methyl- 5,6-dimethylpyrimidin-4(3H)-one (Example 25) 2-Butyl-l-C21 -(N-triphenylmethyl-tetrazol-5-yl)- biphen-4-yl)methyl-6-methylpyrimidin-4(3H)-one (Example 28) 2-n-Butyl-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylmethylpyrimidin-4(3H)-one (Example 29) 2-Butyl-5-(2-'chlorophenyl)-6-methyl-3-(2 1 -(tetrazol-5- yl)-biphen-4-yl)methylpyrimidin-4(3H)-one (Example 30, Step 4)
Claims (9)
1. A method of treating gastrointestinal or CNS disorders which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula CI):
or a pharmaceutically acceptable salt thereof, wherein:
o J is -C(=M)- or
K is -C(=M)- or
provided that one and only
one of J and K is -C(=M)-;
M is O or NR21; one of a and b is a double bond, provided that when J is -C(=M)- b 'is a double bond and when K is -C(=M)- a is a double bond;
R is (a) -NHSO2R21, (b) -NHSO2NHCOR21, (c) -NHCONHSO2R21,
(d) -S02NHR21,
(e) -SO2NHCOR21,
(f) -SO2NHCONR9R21,
(g) -SO2NHCOOR21,
(h) -SO2NHOR21,
(i) -CH2SO2NHCOR21,
(j) -CH2SO2NHCONHR21,
(k) -CO2H, or
(1) -lH-tetrazol-4-yl;
R2a and R2b ar.e each independently
(a) H,
(b) C1, Br, I, F,
(c) CF3,
(d) C1-C4-alkyl, or
(e) C1-C4-alkoxy;
R3a is (a). H,.
(b) C1, Br, I, F,
(c) C1-C6-alkyl, (d) C1-C6-alkoxy, or
(e) C1-C6-alkoxy-C1-C4-alkyl;
R3b is
(a) H
(b) Cl, Br, I, F,
(c) C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,
(d) C1-C6-acyloxy,
(e) C3-C6-cycloalkyl,
(f) C1-C6-alkoxy, or
(g) perfluoro-C1-C4-alkyl;
R4 is H, C1-C6-alkyl unsubstituted or substituted
with aryl, wherein aryl is phenyl optionally
substituted with one or two substituents
selected from the group consisting of C1, Br,
I, F, or C1-C4-alkyl unsubstituted or
substituted with members selected from the
group consisting of N(R4)2, CO2R4, OH,
N(R4)CO2R21, S(O)xR21 where x is O to 2;
C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH,
NH2, -NH(C1-C4-alkyl), -NCC1-C4-alkyl)2, -CO?H, -CO2-C1-C4-alkyl, -N(R4)CO2R21 or
1H-tetrazol-5-yl;; R4a is C1-C6-alkyl, aryl or aryl-CH2-;
E is a single bond, -NR13(CH2)s-, -S(O)x(CH2)s
where x is O to
2 and s is O to 5,
-CH(OH)-, -O-, CO-;
R6 is
(a) aryl,
(b) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be unsubstituted or
substituted with a substituent selected
from the group consisting of aryl, C3-C7-cycloalkyl,-Cl, Br,'I, F,- -OH, CF3,
-CF2CF3, CC13, -NH2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -NH-SO2R4, -COOR4,
-S02NHR9, C1-C4-alkoxy, C1-C4-alkyl-S;; (c) heteroaryl, wherein heteroaryl is defined
as an unsubstituted, monosubstituted or
disubstituted 5 or 6 membered
heteroaromatic ring which can contain one
or two members selected from the group
consisting of N, O, S, and wherein the
substituents are members selected from the
group consisting of -OH, -SH, C1-C4-alkyl, Cl-C4-alkyloxy -CF3, C1, Br, I, F, NO2,
-CO2H, -CO2-C1-C4-alkyl, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2;
(d) C3-C7-cycloalkyl;; a R7 and R8 are independently
(a) H,
(b) aryl-C1-C4-alkyl-,
(c) heteroaryl-C1-C4-'alkyl-, (d) C1-C6-alkyl optionally substituted with a
substituent selected from the group
consisting of -OH, -NH2, guanidino,
C1-C4-alkoxy, -S(O)xR21, C1-C4-alkylamino,
C1-C4-dialkylamino, -COOR4, -CON(R4)R21, -OCON(R4)R21, -O-COR4, C3-C5-cycloalkyl,
-N(R4)CON(R4)R21, -N(R4)COOR21,
-CONHSO2R21, -N(R4)SO2R21;; (e) C2-C4-alkenyl, (f) -CO-aryl, (g) C3-C7-cycloalkyl, (h) Cl, Br, I, F, (i) -OH, (j) -OR21, (k) perfluoro-C1-C4-alkyl, (1) -SH, (m) -S(O)xR21 where x is as defined above, (n) -CHO, (o) -Co2R4, (p) -SO3H, (q) -N(R4)2, (r) -NR4CO2R21, (s) -SO2NR9R10, (t) -CH2OCOR4, (u) -N(R4)-SO2-C1-C4-alkyl, (v) 5 or 6 membered saturated heterocycle
containing one nitrogen atom and
optionally containing one other heteroatom
selected from N, 0 or S, such as
pyrrolidine, morpholine, or piperazine, (w) aryl, (x) heteroaryl, (y) lH-tetrazol-5-yl,
(z) -NHS02-perfluoro-C1-C4-alkyl,
(aa) -CONHS02R21,
(bb) -SO2NHCOR21, (cc) -SO2NH-heteroaryl,
(dd) -S(O)x-aryl,
(ee) -S(O)x-CH2-aryl,
(ff) -CoN(R4)2;
R9 is H, C1-C5-alkyl, phenyl or benzyl;
R10 is. H, or C1-C4-alkyl;; R is H, C1-C6-alkyl, C2-C4-alkenyl,
C1-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2 or -C02R4; R13 is H, C1-C4-acyl, C1-C6-alkyl, allyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, C1-c6-alkyl;
R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl
or benzyl;
R17 is -NR9R10, -OR10, -NHCONH2, -NHCSNH2,
R18 and R19 are independently Cl-C4-alkyl or taken
together are -(CH2)q- where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3;; R21 is
(a) aryl,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C8-alkyl wherein alkyl is unsubstituted
or substituted with one or two substituents
selected from the group consisting of aryl,
heteroaryl, -OH, -SH, C1-C4-alkyl, -O-(C1-C4-alky), -S(C1-C4-alkyl), -CF3, Cl, Br, F, I, -NO2, -CO2H, -C02-C1-C4-alkyl, -NH2, -NR4CO2R22, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -P03H2,
-PO(OH)(O-C1-C4-alkyl), -PO(OR4)R9,
-NR4COR4a, -CONR4R4a, -OCONR4R4a,
-SO2NR4R4a, -NR4SO2R4a, or
(e) perfluoro-C1-C4-alkyl;
X is
(a) a carbon-carbon single bond,
(b) -CO-,
(c) -O-,
(d) -S-, ;;
(h) -OCH2-, (i) -CH2O (j) -SCH2-, (k) -CH2S-, (l) -NHC(R9)(R10), (m) -NR9SO2-, (n) SO2NR9-, (o) -C(R9)(R10)NH-, (p) -CH=CH-, (q) -CF=CF-, (r) -CH=CF-, (s) -CF=CH-, (t) -CH2CH2-, (u) -CF2CF2-,
r is 1 or 2.
.2. The method of Claim 1 wherein:
J is
K is
b is a double bond;
R1 is (a) -NHS02R21,
(b) -NHSO2NHCOR21,
(c) -NHCONHSO2R21,
(d) -SO2NHR21,
(e) -SO2NHCOR21,
(f) -SO2NHCONR9R21,
(g) -SO2NHCOOR21,
(h) -SO2NHOR21,
(i) -CH2SO2NHCOR21,
(j) -CH2SO2NHCONHR21,
(k) -CO2H, or
(1) -1H-tetrazol-4-yl;
R2a and R2b are H, F, C1, CF3 or C1-C4-alkyl; R3a is H; a R3b is H, F, C1, aCF3, or C1--C6-alkyl; E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl optionally substituted with a
substituent selected from the group
consisting of C1, CF3, CC13, -O-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C2-C5-alkynyl, or
(c) aryl; ;
R7 and R8 are independently
(a) H,
(b) Cl-C6-alkyl, (c) C2-C4-alkenyl,
(d) -OH,
(e) -CH2OCOR4,
(f) -NH2,
(h) -C1-C4-alkoxy, (i) -NH(C1-C4-alkyl)2, (j) -N(C1-C4-alkyl)2, (k) C1, F, Br, (1) -CF3, (m) -C02R4, (n) -CH20H, (o) 5 or 6 membered saturated heterocycle
containing one nitrogen atom and optionally
containing one other heteratom selected
from N, 0,1 or S, such as pyrrolidine,
morpholine, or piperazine; (p) -CO-aryl, (q) -S(O)x-C1-C4-alkyl, (r) -SO2-NH-C1-C4-alkyl, (s) -SO2-NH-aryl,
(t) -NH-SO2CH3,
(u) aryl,
(v) heteroaryl, or
(w) lH-tetrazol-5-yl;
X is a C-C single bond or -CO-; and r is one;
3.The method of Claim 2 wherein:
E is a single bond or -S-; r is one,
R is -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21,
-SO2NHOR21, -CH2SO2NHCOR21, or
-1H-tetrazol-5-yl;
R2a R2b, R3a and R3b are each H;
R6 is n-propyl, iso-propyl, n-butyl, iso-butyl,
-CH3, -CH2CH3, phenyl, or -CH2-S-CH3;
R7 is -NHSO2CF3, -CH20H, -CH2OCOR4, C02R4, 1H-tetrazol-5-yl, -N(CH3)2, -NR4CO2-C1-C4
alkyl, H, -C1-C6-alkyl, aryl, or a 5 or 6
membered saturated heterocycle,
R8 is H, -C1-C6-alkyl, aryl, heteroaryl, C1, F,
CF3;
X is a single bond.
4. The method of Claim 1 wherein:
K is -C(=O)-;
J is
a is a double bond;
R1 is
(a) -NHS02R21,
(b) -NHSO2NHCOR21,
(c) -NHCONHSO2R21,
(d) -SO2NHR21,
(e) -SO2NHCOR21,
(f) -SO2NHCONR9R21,
(g) -SO2NHCOOR21,
(h) -SO2NHOR21,
(i) -CH2SO2NHCOR21,
(j) -CH2SO2NHCONHR21,
(k) -CO2H, or
(1) -lH-tetrazol-4-yl;
R2a and R2b are H, F, C1, CF3, C1-C4-alkyl; R3a is H, F or C1; @ R3b is H, F, C1, tF3, or C1-C6-alkyl; E is a single bond, -0- or -S-;
R6 is
(a) Cl-C5-alkyl unsubstituted or
substituted with a substituent selected
from the group consisting of C1, CF3,
CCl3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5
or phenyl, or
(b) aryl;;
R7 and R8 are independently
(a) H,
(b) C1-C6-alkyl unsubstituted or
substituted with -N(R4)CO2R21,
-S(O)xR21, aryl, -N(R4)2, -CO2R4,
-N(R4)CON(R4)R21, -CON(R4)R21; Cc) C2-C4-alkenyl,
(d) -OH,
(e) -CH2OCOR4,
(f) -NH2,
(g) -N(R4)COOR21,
(h) -C1-C4-alkoxy, (i) -NH(C1-C4-alkyl),
(j) -N(C1-C4-alkyl)2,
(k) C1, F, Br; (1) -CF3, (m) -C02R4, (n) -CH2-OH, (o) 5 or 6 membered saturated heterocycle,
(p) -CO-aryl,
(q) -S(O)x-C1-C4-alkyl
(r) -SO2-NH-C1-C4-alkyl,
(s) -SO2-NH-aryl,
(t) -NH-SO2CH3.
(u) aryl,
(v) heteroaryl,
(w) lH-tetrazol-5-yl,
X is a C-C single bond or -CO-; and r is one.
5. The method of Claim 4 wherein:
E is a single bond or -S-; r is one,
R is -SO2NHCOR21, -SO2NHCONR9R21, -SO2NHCOOR21,
-SO2NHOR21, -CH2SO2NHCOR21, or -1H-tetrazol-5-yl; R2a and R2b are H, F, C1, CF3, or C1-C4-alkyl; R3a is H, F, or C1;
R3b is H, F, C1, CF3, or C1-C6-alkyl; R6 is n-propyl, iso-propyl, n-butyl, iso-butyl,
-CH2CH3, cyclopropyl, cyclopropylmethyl or
aryl,
X is a C-C single bond.
6. The method of Claim 1 wherein:
K is -C(=NR21); J is
a is a double bond;
R1 is
(a) -NHS02R21,
(b) -NHSO2NHCOR21,
(c) -NHCONHSO2R21,
(d) -SO2NHR21,
(e) -SO2NHCOR21, (f) -SO2NHCONR9R21,
(g) -SO2NHCOOR21,
(h) -SO2NHOR21, Ci) -CH2S02NHCOR21,
(j) -CH2SO2NHCONHR21,
(k) -CO2H, or
(1) -lH-tetrazol-4-yl;
R2a and R2b are H, F, C1, CF3, or C1-'C4-alkyl;
R3a is H, F or C1; a R3b is H, F, C1, CF3, or C1-C6-alkyl;
E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl unsubstituted or substituted
with a substituent selected from the group
consisting of Cl, CF3, CCl3. -0-CH3, -OC2H5,
-S-CH3, -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C2-C5-alkynyl, or
(c) aryl;
R7 and R8 are independently selected from:H, C1-C6-alkyl, -Cl, C1-C4-alkoxy, -F,
-CH2OH, NO2, -CO2R4 -NR4-COO-C1-C4-alkyl,
-CF3, -CH2OCOR4, -NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2. lH-tetrazol-5-yl, aryl or
5- or 6-membered saturated heterocycle; and
X is a C-C single bond or -CO-; and r is one.
7. The method of Claim 1 wherein the gastrointestinal disorder is selected from the group consisting of gastroesophagal reflux disorder (GER
D), irritable bowel syndrome, diarrhea, cholic, ulcer, GI tumors, dyspepsia, pancreatitis, esophagitis and gastroparesis.
8. A pharmaceutical composition useful in the treatment.of gastrointestinal disorders which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound as recited in Claim 1.
The method of Claim I.' wherein the
central nervous disorder is selected from the group
consisting of psychoses, depression, cognitive
dysfunction, anxiety, tardive dyskinesia, drug
dependency, panic attack and mania.
lo. A pharmaceutical composition useful in
the treatment of cental nervous system disorders
which comprises a pharmaceutically acceptable carrier
and a pharmaceutically acceptable amount of a
compound as recited in Claim 1.
11 The use of a compound as defined in any of claims 1-6 in the preparation of a medicine for the treatment of a condition as defined in any of claims 1, 7 or
9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82670592A | 1992-01-28 | 1992-01-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9301047D0 GB9301047D0 (en) | 1993-03-10 |
| GB2263639A true GB2263639A (en) | 1993-08-04 |
Family
ID=25247301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9301047A Withdrawn GB2263639A (en) | 1992-01-28 | 1993-01-20 | Substituted pyrimidinones as neurotensin antagonists |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2263639A (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5491172A (en) * | 1993-05-14 | 1996-02-13 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
| WO1997000070A1 (en) * | 1995-06-19 | 1997-01-03 | Astra Aktiebolag | Novel medical use |
| US5633287A (en) * | 1993-05-14 | 1997-05-27 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
| US5955474A (en) * | 1994-08-04 | 1999-09-21 | Sanofi | Use of neurotensin antagonists for the treatment of edematous conditions |
| EP1970063A1 (en) * | 2005-12-28 | 2008-09-17 | Takeda Pharmaceutical Company Limited | Therapeutic agent for diabetes |
| US8835449B2 (en) | 2011-11-11 | 2014-09-16 | Pfizer Inc. | 2-thiopyrimidinones |
| US9771332B2 (en) | 2015-05-05 | 2017-09-26 | Pfizer Inc. | 2-thiopyrimidinones |
| US9975886B1 (en) | 2017-01-23 | 2018-05-22 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| US10106528B2 (en) | 2016-03-24 | 2018-10-23 | Bristol-Myers Squibb Company | 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as APJ agonists |
| US10392347B2 (en) | 2015-10-14 | 2019-08-27 | Bristol-Myers Squibb Company | 2,4-dihydroxy-nicotinamides as APJ agonists |
| US10669261B2 (en) | 2015-12-16 | 2020-06-02 | Bristl-Myers Squibb Company | Heteroarylhydroxypyrimidinones as agonists of the APJ receptor |
| US10774064B2 (en) | 2016-06-02 | 2020-09-15 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| US11390616B2 (en) | 2015-12-04 | 2022-07-19 | Bristol-Myers Squibb Company | Apelin receptor agonists and methods of use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0407342A2 (en) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Pyrimidine derivatives |
| EP0419048A2 (en) * | 1989-08-28 | 1991-03-27 | Merck & Co. Inc. | Substituted pyrimidinones as angiotensin II antagonists |
-
1993
- 1993-01-20 GB GB9301047A patent/GB2263639A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0407342A2 (en) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Pyrimidine derivatives |
| EP0419048A2 (en) * | 1989-08-28 | 1991-03-27 | Merck & Co. Inc. | Substituted pyrimidinones as angiotensin II antagonists |
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5491172A (en) * | 1993-05-14 | 1996-02-13 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
| US5633287A (en) * | 1993-05-14 | 1997-05-27 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
| US5955474A (en) * | 1994-08-04 | 1999-09-21 | Sanofi | Use of neurotensin antagonists for the treatment of edematous conditions |
| WO1997000070A1 (en) * | 1995-06-19 | 1997-01-03 | Astra Aktiebolag | Novel medical use |
| AU706660B2 (en) * | 1995-06-19 | 1999-06-17 | Pharmacore Ab | Use of certain angiotensin II type I receptor antagonists for dyspeptic symptons in mammals including man |
| US6096772A (en) * | 1995-06-19 | 2000-08-01 | Astra Aktiebolag | Use of Angiotensin II type 1 receptor antagonists in the treatment of dyspeptic symptoms |
| EP1970063A1 (en) * | 2005-12-28 | 2008-09-17 | Takeda Pharmaceutical Company Limited | Therapeutic agent for diabetes |
| EP1970063A4 (en) * | 2005-12-28 | 2014-05-21 | Takeda Pharmaceutical | Therapeutic agent for diabetes |
| US9399626B2 (en) | 2011-11-11 | 2016-07-26 | Pfizer Inc. | 2-thiopyrimidinones |
| US8835449B2 (en) | 2011-11-11 | 2014-09-16 | Pfizer Inc. | 2-thiopyrimidinones |
| US9873673B2 (en) | 2011-11-11 | 2018-01-23 | Pfizer Inc. | 2-thiopyrimidinones |
| US8841314B2 (en) | 2011-11-11 | 2014-09-23 | Pfizer Inc. | 2-Thiopyrimidinones |
| US9771332B2 (en) | 2015-05-05 | 2017-09-26 | Pfizer Inc. | 2-thiopyrimidinones |
| US10392347B2 (en) | 2015-10-14 | 2019-08-27 | Bristol-Myers Squibb Company | 2,4-dihydroxy-nicotinamides as APJ agonists |
| US11390616B2 (en) | 2015-12-04 | 2022-07-19 | Bristol-Myers Squibb Company | Apelin receptor agonists and methods of use |
| US10669261B2 (en) | 2015-12-16 | 2020-06-02 | Bristl-Myers Squibb Company | Heteroarylhydroxypyrimidinones as agonists of the APJ receptor |
| US10590113B2 (en) | 2016-03-24 | 2020-03-17 | Bristol-Myers Squibb Company | 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as APJ agonists |
| US10106528B2 (en) | 2016-03-24 | 2018-10-23 | Bristol-Myers Squibb Company | 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as APJ agonists |
| US10774064B2 (en) | 2016-06-02 | 2020-09-15 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| US10351553B2 (en) | 2017-01-23 | 2019-07-16 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| US10717728B2 (en) | 2017-01-23 | 2020-07-21 | Cadent Therapeutics, Inc. | Potassium channel modulators |
| US9975886B1 (en) | 2017-01-23 | 2018-05-22 | Cadent Therapeutics, Inc. | Potassium channel modulators |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9301047D0 (en) | 1993-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5204354A (en) | Substituted quinazolinones as neurotensin antagonists useful in the treatment of CNS disorders | |
| EP0760658B1 (en) | Compounds for inhibiting osteoclast-mediated bone resorption | |
| CN102869666B (en) | For the heterocycle inhibitor of the Histamine Receptors of disease treatment | |
| KR100443850B1 (en) | Use of heterocyclic compounds as dopamine-d3 ligans | |
| RU2734261C2 (en) | Optionally condensed heterocyclyl-substituted pyrimidine derivatives suitable for treating inflammatory, metabolic, oncological and autoimmune diseases | |
| US8173643B2 (en) | N-substituted thiomorpholine derivatives as the inhibitors of dipeptidyl peptidase IV and the pharmaceutical uses thereof | |
| GB2263639A (en) | Substituted pyrimidinones as neurotensin antagonists | |
| JP5436462B2 (en) | Piperazine derivatives and methods of use | |
| NO303541B1 (en) | Substituted biphenyl pyridones and their use in the manufacture of drugs | |
| CN114057702A (en) | Novel inhibitor of coronavirus main protease and preparation method and application thereof | |
| JP2008063256A (en) | beta-AMINO ACID DERIVATIVE | |
| CN102159589A (en) | Neuropeptide-2 receptor (y-2r) agonists and uses thereof | |
| TWI824403B (en) | A heterocyclic compound, its intermediates, its preparation method and its application | |
| AU2009330131B2 (en) | Compounds and methods for the treatment of pain and other diseases | |
| WO2024040768A1 (en) | 5-pyridine-1h-indazole compound, pharmaceutical composition, and use | |
| IL171332A (en) | 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine derivative or salt thereof and pharmaceutical compositions comprising them | |
| GB2263637A (en) | Substituted imidazo-fused 6-membered carbocycle or heterocycle as neurotensin antagonists | |
| WO1994010151A1 (en) | Substituted phthalazinones as nerotensin antagonists | |
| GB2263636A (en) | Substituted triazolinones, triazolinethiones, and triazolinimines as neurotensin antagonists | |
| ES2282234T3 (en) | DERIVATIVES OF TYROSINE WITH ANTI-LEUCOTRIEN ACTIVITY. | |
| EP2246347A1 (en) | Dicycloazaalkane derivates, preparation processes and medical uses thereof | |
| GB2263635A (en) | Substitiuted triazoles as neurotensin antagonists | |
| EP0925295A1 (en) | N-benzenesulphonyl-l-proline derivatives as bradykinin b2 agonists | |
| GB2263638A (en) | Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists | |
| JPS62169730A (en) | Treatment for nervous trouble by oligopeptide containing tryptophan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |