GB2263638A - Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists - Google Patents
Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists Download PDFInfo
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- GB2263638A GB2263638A GB9301003A GB9301003A GB2263638A GB 2263638 A GB2263638 A GB 2263638A GB 9301003 A GB9301003 A GB 9301003A GB 9301003 A GB9301003 A GB 9301003A GB 2263638 A GB2263638 A GB 2263638A
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
Abstract
Substituted pyrazoles, isoxazoles and isothiazoles of formula (I) as disclosed in WO91/15479-A1 are neurotensin antagonists which are useful in the treatment of certain CNS and GI disorders. The compounds have the general formula: <IMAGE>
Description
TITLE OF THE INVENTION
SUBSTITUTED PYRAZOLES, ISOXAZOLES AND ISOTHIAZOLES 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 pyrazoles, isoxazoles and isothiazoles 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., et al., Proc. Natl. Acad. Sci. USA, 74, 4059-4063 (1977), gastrointestinal tract C 1). Kitabgi, P.,
Carraway, R. and Leeman, S. E., J. Biol. Chem., 251, 7053 (1976); 2). Carraway, R., Kitabgi, P., and
Leeman, S. E., J. Biol. Chem., 253, 7996 (1978); 3).Helmstadler, V., Taugner, 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)].
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. E, 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 thepeptide (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 psychostimulant-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., .
Annal. NY Acad. Sciences, 400, 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 neuroleptics. However, unlike classical neuroleptics (which primarily acts 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
Parkinson's disease and progressive supranuclear palsy (Chinaglia, G. 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 E 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.
Physiol., 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 NT813 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 Ile12 and Leu13 are also necessary for full 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-Trp11-NT and Tyr(Me)ll-NT have displayed partial antagonist activity (sioux, 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 under the Patent Cooperation
Treaty as International Application number WO 9115479 (Merck & Co., Inc.) 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 non-peptidic neurotensin antagonists.
Now with this invention there are provided non-p-eptidic 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:
K is 0, S or NR7;
R1 is: (a) -NHS02R23,
(b) -NHSO'2NHCOR23, (c) -NHCONHSO2R23, (d) -SO2NHR23-,
(e) -SO2NHCOR23,
(f) -SO2NHCONR9R23,
(g) -SO2NHCOOR23,
(h) -SO2NHOR23,
(i) -=CH2SO2NHCOR23, (j) -CH2SO2NHCONHR23, (k) -CO2H, or
(1) -lH-tetrazol-5-yl;
R2a and R2b are 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,
(d) C2-C6-alkanoyloxy,
(e) C3-C6-cycloalkyl,
(f) Cl-C6-alkoxy, or
(g) CF3;
R4 is H, C1-C6-alkyl, -CH2-aryl, or aryl, wherein
aryl is phenyl or naphthyl either
unsubstituted or substituted with one, two
or three substituents selected from the
group consisting of C1, Br, I, F,
C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3,
C1-C4-alkylthio, OH, NH2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -CO2H, -CO2-C1-C4-alkyl, C1-C4-polyfluoroalkyl, C3-C6-polyfluoro
cycloalkyl, and lH-tetrazol-5-yl;
R4a is C1-C6-alkyl, aryl, or -CH2-aryl; R4 0
R5 is H, or -CH-O-C-R4a;
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) H,
(b) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl
each of which can be substituted with a
substituent selected from the group
consisting of aryl, C3-C7-cycloalkyl, C1,
Br, I, F, -OH, -CF3, -CC13, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2,
-NH-S02R4, -COOR4, -SO2NHR9, C1-C4-alkoxy,
or C1-C4-alkyl-S;
(c) aryl;;
R7 is
(a) -H,
(b) C1-C10-alkyl,
(c) substituted C1-C10-alkyl in which one or
more substituent(s) is selected from
(1) I, Br, C1, or F,
(2) hydroxy,
(3) C1-C10-alkoxy,
(4) C1-C5-alkoxycarbonyl, (5) C1-C4-alkylcarbonyloxy,
(6) C3-C8-cycloalkyl,
(7) aryl,
(8) heteroaryl,
(9) C1-C10-alkyl-S(O)p- in which p
is O to 2,
(10) C3-C8-cycloalkyl-S(O)p-,
(11) aryl-S(O)p-,
(12) oxo,
(13) carboxy,
(14) NR9R9,
(15) C1-C5-alkylaminocarbonyl, (16) di (C1-C5-alkyl)aminocarbonyl, (17) cyano,
(18) -OCONR22R23,
(19) -NR22COR23,
(20) -NR22CO2R23,
(21) -NR22CONR22R23,
(22) -NR22CON(CH2CH2]2L, wherein L is a
single bond, CH2, O, S(O)p or NR9,
(23) -OCON(CH2CH2]2L, (d) C2-C10-alkenyl, (e) C2-C10-alkynyl, (f) C3-C8-cycloalkyl, (g) substituted C3-C8-cycloalkyl or substituted
C3-C8-cycloalkyl-C1-C4
alkyl having one or more substituents
selected from the group:
(1) C1, Br, F, or I
(2) hydroxy,
(3) C1-C6-alkyl, (4)C1-C6-alkoxy,
(5) C1-C4-alkylcarbonyloxy, (6) C1-C5-alkoxycarbonyl,
(7) carboxy,
(8) oxo,
(9) C1-C5-alkylaminocarbonyl,
(10) di(C1-C5-alkyl)aminocarbonyl,
(11) C1-C4-alkylcarbonyl, and
(12) aryl,
(h) aryl, or
(i) heteroaryl, wherein'heteroaryl is an
unsubstituted, monosubstituted or
disubstituted five or six membered aromatic
ring comprising from 1 to 3 heteroatoms
selected from the group consisiting of 0, N
and S and wherein the substitutents are
members selected from the group consisting
of -OH, -SH, C1-C4-alkyl, -C1-C4-alkoxy,
-CF3, Cl, Br, I, F, -NO2, -CO2H,
-CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl, -N(C1-C4-alkyl)2 and a fused benzo group; R8 is
(a) hydrogen,
(b) -OH,
(c) -NH2, (d) -NH(C1-C4-alkyl) wherein the alkyl is
unsubstituted or substituted with C02R4, (e) -N(C1-C4-alkyl)2 wherein one or both of the
alkyl groups can be substituted with C02R4, (f) -NHCO2-C1-C4-alkyl, (g) -NHSO2-aryl, (h) -NHSO2-heteroaryl,
(i) -NHSO2(C1-C4-perfluoroalkyl),
(j) -CO2H, (k) -C02R5, (1) C1, Br, I, F,
(m) -CONHSO2-aryl,
(n) -CONHSO2-heteroaryl,
(o) -CONHSO2-C1-C4-alkyl, either unsubstituted
or substituted with aryl, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2; -OH,
-CO2H, or CO2(C1-C4-alkyl),
(p) -CONHSO2(C1-C4-perfluoroalkyl),
(q) -CH2OH,
(r) -CH2OCOR4, (s) -O-C1-C4-alkyl, (t) -S(O)x-C1-C4-alkyl, either unsubstituted or
substituted with aryl, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -OH,
-CO2H, or CO2(C1-C4-alkyl),
(u) -SO2NHR21,
(v) -CN,
(w) tetrazol-5-yl,
(x) CONH-l-tetrazol-5-yl, or
(y) -CH2CO2R4;
R9 is H, C1-C5-alkyl, aryl or -CH2-aryl;
R10 is H, Cl-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, Cl-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -N02, -C02R4, or -CF3; ;
R13 is H, C2-C4-alkanoyl, 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) -CO-aryl,
(b) -CO-C1-C4-alkyl,
(c) -COCF3,
(d) -CO-heteroaryl, or
(e) heteroaryl;
R22 is
(a) aryl, or
(b) C1-C6-alkyl;; R23 is
(a) aryl,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C8-alkyl either unsubstituted or
substituted with aryl, heteroaryl, -OH,
-SH, C1-C4-alkyl, C3-C7-cycloalkyl,
-O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, Cl,
Br, I, F, -NO2, -CO2H, CO2-C1-C4-alkyl-, -NH2, NHaryl, N(aryl)2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -NR4CO2R22, -NR4COR22,
-CONR4R22, -O-CONR4R22, -SO2R4R22,
-NR4SO2RR22, -PO3H, -PO(OH)(O-C1-C4-alkyl),
or -N(CH2CH2)2L wherein L is single bond,
-CH2- -O-, -S(O)p-, or NR9, or
(e) perfluoro-C1-C4-alkyl;;
X is
(a) a carbon-carbon single bond,
(b) -CO-,
(c) -O-,
(d) -S-,
(e) -N-,
R13
(f) -CON-,
R15
(g) -NCO-,
R15
(h) -OCH2-,
(i) -CH2O
(j) -SCH2-,
(k) -CH2S-,
(1) -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-,
z is 0, NR13 or S; and r is 1 or 2.
The terms "alkyl", "alkenyl", 1?alkyflyl: 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 K is -O-.
A class of compounds within this embodiment is that wherein:
R1 is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, oR
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, Cl-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, C1, CF3, C1-C4-alkyl, C1-C4-alkoxy,
-COOCH3, -COOC2H5, -S02-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-S02CH3;
E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl either 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;
X is a C-C single bond; and r is one.
In a preferred class of this embodiment are those compounds wherein:
E is a single bond or -S-; r is one, R1 is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, or
-1H-tetrazol-5-yl;
R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, phenyl,
or -CH2-S-CH3;
R8 is -C02R5, -CONHS02aryl, -CONHSO2CC1-C4-alkyl), or CONH-SO2-cyclopropyl, -NHSO2(C1-C4- perfluoroalkyl), -S(O)x-(C1-C4-alkyl)-aryl,
-NHSO2aryl, or -NHSO2-heteroaryl; and
X is a single bond.
Another embodiment of the compounds of formula (I) is that wherein K is S.
A class of compounds within that embodiment are those compounds wherein
R is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23,
-SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, C1, CF3, C1-C4-alkyl, C5-C6
cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO,CH3;.
E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl either 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;
X is a C-C single bond; and r is one.
In a preferred class of this 'embodiment are
those compounds wherein:
E is a single bond or -S-;
r is one;
R is -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23,
-SO2NHOR23 -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or
-CH2-S-CH3;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2- (C1-C4-alkyl), -CONHSO2-cyclopropyl,
-NHSO2(C1-C4-perfluoroalkyl), S(O)x
(C1-C4-alkyl)aryl, -NHSO2-aryl, or -NHSO2-heteroaryl; R23 is aryl, perfluoro-Cl-C4 alkyl, C3-C7
cycloalkyl or C1-C4 alkyl(aryl)2; and
X is a single bond.
Another embodiment of the novel compounds of
formula (I) is that wherein K=NR7.
A class of compounds within this embodiment is that wherein:
R is -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23,
-SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, C1, CF3, C1-C4-alkyl, C5-C6
cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-S02CH3;
E is a single bond, -0- or -S-; R6 is
(a) Cl-C5-alkyl either unsubstituted or
substituted with a substituent selected
from the group consisting of C1, CF3, CC13, -O-CH3, -OC2H5, -S-CH31 -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C2-C5-alkynyl,
(c) aryl;
R7 and R8 are as defined above;
X is a C-C single bond; and r is one.
In a preferred class of this embodiment are those compounds wherein:
E is a single bond or -S-; r is one, R1 is -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, or
-1H-tetrazol-5-yl;
R2a R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or
-CH2-S-CH3;
R7 is H, aryl-C1-C10-alkyl, perfluoro-Cl-C4- alkyl, heteroaryl, or aryl either
unsubstituted or substituted with one or
two substituents selected from -C1, -CF3,
-CH3, -OCH3 and -NO2;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2
(C1-C4-alkyl), -CONHSO2-cyclopropyl, -NHSO2
(C1-C4-perfluoroalkyl), -S(O)x-(C1-C4
alkyl)-aryl, or -NHSO2-aryl, or NHSO2- heteroaryl; ;
R23 is aryl, -N(aryl)2, C3-C7-cycloalkyl, C1-C6
alkyl, either unsubstituted or substituted
with 1) C3,-C7 cycloalkyl, 2) perfluoro, or
3) two aryl groups, and
X is a single bond.
Another preferred class of this embodiment are those compounds listed in the table below:
R R6 R7 R8 1H-tetrazol-5-yl n-butyl 2,4-dichlorophenyl -CO2Et 1H-tetrazol-5-yl n-butyl 3,6-dichlorophenyl -CO2Et 1H-tetrazol-5-yl n-butyl 2,4. 6-trichlorophenyl -CO=Et 1H-tetrazol-5-yl n-butyl 3-chiorophenyl -CO2Et 1H-tetrazol-5-yl n-butyl 4-chiorophenyl -CO2Et 1H-tetrazol-5-yl n-butyl 2,3-dichlorophenyl -CO2Et 1H-tetrazol-5-yl n-butyl benzyl -CO2Et
SO2NHCO-cyclopropyl n-butyl 2,6-dichlorophenyl -CO2Me
SO2NHCO-cyclopropyl n-butyl 2,2,2-trifluoroethyl -CO2Et SO2NHCO-cyclopropyl n-butyl 2-trifluoromethylphenyl -CO2Et
SO2NHCO-cyclopropyl n-butyl 2-chlorophenyl -CO2Et SO2NHCO-(CH2)5-NHBoc n-butyl 2-chlorophenyl -CO2Et
SO2NHCO-(CH2)5-NHBoc n-butyl 2,4-dichlorophenyl -CO2Et
SO2NHCO0-(CH2)5NHBoc n-butyl 2, 4, 6, trichlorophenyl -C02Et
SO2NHCO-(CH2)5-NH2 n-butyl 2,4,6-trichlorophenyl -CO2Et
SO2NHCO-(CH2)5-NH2 n-butyl 2, 4-dichlorophenyl -CO2Et
SO2NHCO-(CH2)5-NH2 n-butyl 2-chlorophenyl -CO2Et
SO2NHCO-(CH2)4CH3 n-butyl 2-chlorophenyl -CO2Et
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 assays 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 HCI, 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 HC1, pH 7.4, which also contains 1 mM EDTA, 4 Fg/ml bacitracin, 5 M levocabastine HCl, 1 mM phenanthroline, 10 g/ml soybean trypsin inhibitor and 100 FM 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 l of 60 pM F125I]neurotensin 3) 20 > 1 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 i5 mM polypropylene tubes for counting on as 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 HC1, 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 g/ml soybean trypsin inhibitor and 100 SM phenylmethylsulfonyl 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 (125I]fleurotensin 3) 20 l test compounds 4) 750 l cell membrane suspension an 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 (pH 7.4 at room temperature). The filter discs are placed in 12 x 75 mM polypropylene tubes for counting on as
Packard Multi-Prias gamma counter. EThe 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 g/ml soybean trypsin inhibitor and 100 M 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 E125I]neurotensin 3) 20 > 1 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/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.
Using the methodology described above, representative compounds of the invention were evaluated and all were found to exhibit an activity of at least IC50 < 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 disintegrating 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 preseruatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated 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
WO 9115479 published on October 17, 1991: 5-amino-3-butyl-4-t(2'-tetrazol-5-yl)biphen-4-yl)- methyI]isoxazole (Example 1) 5-amino-3-butyl-1-(2'-chlorophenyl)-4-[(2'-tetrazol- 5-yl)biphen-4-yl)methyl]pyrazole (Example 2)
Ethyl 3-butyl-1-(2-chlorophenyl)-4-[[2'-(5 tetrazolyl)biphenyl-4-yl]methyl]-lH-pyrazole-5- carboxylate (Example 3)
Ethyl 3-butyl-1-phenyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-lH-pyrazole-5-carboxylate (Example 4)
Ethyl 3-butyl-1-(2-chlorophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (Example 6)
Ethyl 3-butyl-1-(2-methylphenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (Example 8)
Ethyl 3-butyl-1-(2,6-dichlorophenyl)-4-[[2'-(5tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole5-carboxylate (Example 10)
Ethyl 3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-[2-(trifluoromethyl)phenyl]-1H pyrazole-5-carboxylate (Example 13)
Ethyl 3-butyl-4-[(2'-(5-tetrazolyl)biphenyl-4-yl]- methyl]-lH-pyrazole-5-carboxylate (Example 14)
Ethyl 3-butyl-4-CC2'-(5-tetrazolyl)biphenyl- 4-yl]methyl]-1-(2,2,2-trifluoroethyl)-lH- pyrazole-5-carboxylate (Example 16)
Ethyl 4-([2 '-(N-benzoylsulfamoyl)biphenyl-4-yl]- methyl]-3-n-butyl-1-(2-chlorophenyl)-1H-pyrazole-5carboxylate (Example 18)
Ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[2'-[N (trifluoroacetyl)sulfamoyl]biphenyl-4-yl]methyl]-lH- pyrazole-5-carboxylate (Example 20)
Ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[(2'-[N (trifluoromethanesulfonyl)amino]biphenyl-4-yl]methyl]lH-pyrazole-5-carboxylate (Example 21) 3-butyl-1-C2-chlorophenyl)-5-( (trifluoromethanesulfon- amido)-4-[(2'-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrazole (Example 22)
Claims (12)
1. A method of treating gastrointestinal disorders or central nervous system disorders which comprises administering to a patient in need of such treatment a therapeutically effective amount of a neurotensin antagonist of structural formula:
CI) or a pharmaceutically acceptable salt thereof, wherein:
K is 0, S, or NR7;
R1 is::
(a) -NHSO2R23, (b) -NHSO2NHCOR23,
(c) -NHCONHSO2R23,
(d) -SO2NHR23, (e) -SO2NHCOR23,
(f) -SO2NHCONR9R23,
(g) -SO2NHCOOR23, (h) -SO2NHOR23, (i) - CH2SO2NHCOR23,
(j) -CH2SO2NHCONHR23,
(k) -CO2H, or
(l) -1H-tetrazol-5-yl;
R2a and R2b are independently
(a) H,
(b) C1, Br, I, F,
(c) CF3,
(d) C1-C4-alkyl, or
(e) C1-C4-alkoxy;
R a 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) C1, Br, I, F,
(c) C1-C6-alkyl,
(d) C2-C6-alkanoyloxy,
(e) C3-C6-cycloalkyl,
(f) C1-C6-alkoxy, or
(g) CF3;;
R4 is H, C1-C6-alkyl, -CH2-aryl, or aryl, wherein
aryl is phenyl or naphthyl either
unsubstituted or substituted with one, two
or three substituents selected from the
group consisting of C1, Br, I, F, C1-C4-alkyl, Cl-C4-alkoxy, NO2, CF3,
C1-C4-alkylthio, OH, NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, -CO2-C1-C4-alkyl,
C1-C4-perfloroalkyl, C3-C6-perfluoro
cycloalkyl, and 1H-tetrazol-5-yl;
R4a is C1-C6-alkyl, aryl, or -CH2-aryl; R5 is H, or
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) H,
(b) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl
each of which can be substituted with a
substituent selected from the group
consisting of aryl, C3-C7-cycloalkyl, C1,
Br, I, F, -OH, -CF3, -CCl3, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2,
-NH-SO2R4, -COOR4, -SO2NHR9, C1-C4-alkoxy,
or C1-C4-alkyl-S;
(c) aryl;;
R7 is
(a) -H,
(b) C1-C10-alkyl, (c) substituted C1-C10-alkyl in which one or
more substituent(s) is selected from
(1) I, Br, C1, or F,
(2) hydroxy,
(3) C1-C10-alkoxy,
(4) C1-C5-alkoxycarbonyl, (5) C1-C4-alkylcarbonyloxy,
(6) C3-C8-cycloalkyl, (7) aryl,
(8) heteroaryl,
(9) C1-C10-alkyl-S(O)p in which p is O to 2,
(10) C3-C8-cycloalkyl-S(O)p,
(11) aryl-S(O)p,
(12) oxo,
(13) carboxy,
(14) NR9R9,
-(15) C1-C5-alkylaminocarbonyl, (16) di(C1-C5-alkyl)aminocarbonyl,
(17) cyano,
(18) -OCONR22R23,
(19) NR22COR23,
(20) -NR22CO2R23,
(21) -NR22CONR22R23,
(22) -NR22CON(CH2CH2]2L, wherein L is a
single bond, CH2, O, S(O)p or NR9,
(23) -OCON(CH2CH2]2L, Cd) C2-C10-alkenyl, (e) C2-C10-alkynyl, (f) C3-C8-cycloalkyl, (g) substituted C3-C8-cycloalkyl or substituted
C3-C8-cycloalkyl-C1-C4
alkyl having one or more substituents
selected from the group:
(1) C1, Br, F, or
(2) hydroxy,
(3) C1-C6-alkyl, (4) Cl-C6-alkoxy, (5) C1-C4-alkylcarbonyloxy,
(6) C1-C5-alkoxycarbonyl,
(7) carboxy,
(8) oxo,
(9) C1-C5-alkylaminocarbonyl,
(10) di(C1-C5-alkyl)aminocarbonyl,
(11) C1-C4-alkylcarbonyl, and
(12) aryl, (h) aryl, or (i) heteroaryl, wherein heteroaryl is an
unsubstituted, monosubstituted or
disubstituted five or six membered aromatic
ring comprising from 1 to 3 heteroatoms
selected from the group consisiting of 0, N
and S and wherein the substitutents are
members selected from the group consisting
of -OH, -SH, C1-C4-alkyl, -C1-C4-alkoxy, -CF3, C1, Br, I, F, -N02, -C02H, -CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl), -N(Cl-C4-alkyl)2 and a fused benzo group;;
R8 is
(a) hydrogen,
(b) -OH,
(c) -NH2,
(d) -NH(C1-C4-alkyl) wherein the' alkyl is
unsubstituted or substituted with CO2R4,
(e) -N(Cl-C4-alkyl)2 wherein one or both of the
alkyl groups can be substituted with Co2R4, (f) -NHCO2-C1-C4-alkyl,
(g) -NHS02-aryl,
(h) -NHSO2-heteroaryl,
(i) -NHSO2(C1-C4-perfluoroalkyl), (j) -CO2H, (k) -CO2R5,
(1) C1, Br, I, F,
(m) -CONHSO2-aryl,
(n) -CONHS02-heteroaryl,
(o) -CONHS02-Cl-C4-alkyl, either unsubstituted
or substituted with aryl, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2; -OH,
-CO2H, or CO2(C1-C4-alkyl),
(p) -CONHSO2(C1-C4-perfluoroalkyl),
(q) -CH2OH,
(r) -CH2OCOR4, (s) -O-C1-C4-alkyl,
(t) -S(O)-C1-C4-alkyl, either unsubstituted or
substituted with aryl, -NH2,
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -OH,
-CO2H, or CO(C1-C4-alkyl),
(u) -SO2NHR21,
(v) -CN,
(w) tetrazol-5-yl,
(x) CONH-1-tetrazol-5-yl, or
(y) -CH2CO2R4;
R9 is H, C1-C5-alkyl, aryl or -CH2-aryl;
R10 is H, or C1-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, Cl-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2, -CO2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, 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, or C1-C6-alkyl;; R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl or
benzyl;
R7 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) -CO-aryl,
(b) -CO-C1-C4-alkyl, (c) -COCF3,
(d) -CO-heteroaryl, or
(e) heteroaryl;
R22 is
(a) aryl, or
(b) C1-C6-alkyl;; R23 is
(a) aryl,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C8-alkyl either unsubstituted or
substituted with aryl, heteroaryl, -OH,
-SH, C1-C4-alkyl, C3-C7-cycloalkyl,
-O-(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, Cl,
Br, I, F, -NO2, -CO2H, CO2-C1-C4-alkyl,
-NH2, NHaryl, N(aryl)2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -NR4CO2R22, -NR4COR22,
-CONR4R22, -O-CONR4R22, -SO2NR4R-PO22,
-NR4SO2R22, -PO3H, -PO(OH)(-O-C1-C4-alkyl),
or -N(CH2CH2)2L wherein L is single bond,
-CH2-, -O-, -S(O)P, or NR9, 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) -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) -CH2-CH2-, (u) -CF2CF2-,
NR17
(y) -C-, or
R18O OR19
(z) -C-; z is o, NR13 or S; r is 1 or 2.
2. The method of Claim 1 wherein
K is O;
R is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, Cl-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy, -COOCH3, -COOC2H5, -S02-CH3, NH2,
-N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -0- or -S-;
R6 is
(a) Cl-C5-alkyl either unsubstituted or
substituted with a substituent selected
from the group consisting of C1, CF3, CCl3,
-O-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl,
(b) C2-C5-alkenyl or C2-C5-alkynyl, or
(c) aryl;
X is a C-C single bond; and r is one.
3. The method of Claim 2 wherein:
E is a single bond or -S-; r is one;
R1 is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, or
-1H-tetrazol-5-yl;
R2a R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, phenyl,
or -CH2-S-CH3; R8 is -CO2R5, -CONHSO2aryl, -CONHS02
(C1-C4-alkyl), -CONHSO2-cyclopropyl, -HNSO2(C1-C4- polyfluoroalkyl),
-S(O)x-(C1-C4- alkyl)-aryl, -NHS02-aryl or
-NHSO2-heteroaryl; and
X is a single bond.
4. The method of Claim 1 wherein:
K is S;
R is : -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23,
-SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, C1, CF3, C1-C4-alkyl, C5-C6-
cycloalkyl, -COOCH3, -COOC2H5, --SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-S02CH3;
E is a single bond, -0- or -S-;
R6 is
(a) Cl-C5-alkyl either 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;
X is a C-C single bond; and r is one.
5. The method of Claim 4 wherein:
E is a single bond or -S-; r is one;
R is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23,
-SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
Rȃ, R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, phenyl, or
-CH2-S-CH3;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2
(C1-C4-alkyl), -CONHSO2-cyclopropyl,
-NHSO2(C1-C4-polyfluoroalkyl)
(S(O)x-(C1-C4- alkyl)aryl, -NHSO2-aryl or
-NHS02-heteroaryl; and
X is @ a single bond.
6. The method of claim 1 wherein:
K is NR7; R1 is: -SO2NHCOR23, -SO2NHCONR9R23, -Sb2NHCOOR23,
-SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a and R2b are H, F, C1, CF3, Cl-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or C1;
R3b is H, F, C1, CF3, C1-C4-alkyl, C5-C6
cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -0- or -S-;
R6 is
(a) C1-C5-alkyl either 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;
X is a C-C single bond; and r is one.
7. The method of Claim 6 wherein:
E is a single bond or -S-; r is one,
R1 is: -SO2NHCOR23, -SO2NHCONR9R23, -SO2NHCOOR23, -SO2NHOR23, -CH2SO2NHCOR23, or
-lH-tetrazol-5-yl;
R2a R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, phenyl, or
-CH2-S-CH3;
R7 is H, aryl-C1-C10-alkyl, polyfluoro-Cl-C4- alkyl, heteroaryl, or aryl either
unsubstituted or substituted with one or two
substituents selected from -Cl, -CF3, -CH3,
-OCH3 and -NO2;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2 (Cl-C4-alkyl), -CONHSO2-cyclopropyl, -NHSO2(C1-C4 polyfluoroalkyl),
-S(O)x-(C1-C4-alkyl-aryl), -NHSO2-aryl or
-NHSO2-heteroaryl; and
X is a single bond.
8. The method of Claim 6 wherein the compound is a member selected from the group consisting of:
R R6 R7 R8
1H-tetrazol-5-yl n-butyl 2, 4-dichiorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl 3,6-dichlorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl 2,4,6-trichlorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl 3-chlorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl 4-chlorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl 2, 3-dichlorophenyl -CO2Et
1H-tetrazol-5-yl n-butyl benzyl -CO2Et
SO2NHCO-cyclopropyl n-butyl 2,6-dichlorophenyl -CO2Me
SO2NHCO-cyclopropyl n-butyl 2,2,2-trifluoroethyl -CO2Et
SO2NHCO-cyclopropyl n-butyl 2-trifluoronethylphenyl -CO2Et
SO2NHCO-cyclopropyl n-butyl 2-chlorophenyl -CO2Et
SO2NHCO-(CH2)5NHBoc n-butyl 2-chlorophenyl -CO2Et
SO2NHCO-(CH2)5NHBoc n-butyl 2, 4- dichlorophenyl -CO2Et
SO2NHCO-(CH2)5NHBoc n-butyl 2,4,6-trichlorophenyl -CO2Et
SO2-NHCO(CH2)5NH2 n-butyl 2,4,6-trichlorophenyl -CO2Et
SO2NHCO-(CH2)5NH2 n-butyl 2,4-dichlorophenyl -CO2Et
SO2NHCO-(CH2)5NH2 n-butyl 2-chlorophenyl -C02Et
SO2NHCO-(CH2)4CH3 n-butyl 2-chlorophenyl -CO2Et
9. The method of claim 1 wherein the
gastrointestinal disorder is selected from the group
consisting of gastroesophagal reflux disorder (GERD),
irritable bowel syndrome, diarrhea, cholic, ulcer, GI
tumors, dyspepsia, pancreatitis, esophagitis and gastroparesis.
10. A pharmaceutical composition useful in
the treatment of gastrointestinal disorders or
central nervous system disorders which comprises a
pharmaceutically acceptable carrier and a
pharmaceutically effective amount of a compound as
recited in Claim 1.
11. The method of Claim 1 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.
12. The use of a compound as defined in any of claims 1 to 8 in the preparation of a medicine for the treatment of a disorder as specified in any of claims 1, 9 or 11.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82712692A | 1992-01-28 | 1992-01-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9301003D0 GB9301003D0 (en) | 1993-03-10 |
| GB2263638A true GB2263638A (en) | 1993-08-04 |
Family
ID=25248370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9301003A Withdrawn GB2263638A (en) | 1992-01-28 | 1993-01-20 | Substituted pyrazoles, isoxazoles and isothiazoles as neurotensin antagonists |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2263638A (en) |
Cited By (6)
| 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 |
| US6297198B1 (en) | 1996-05-14 | 2001-10-02 | Syngenta Participations Ag | Isoxazole derivatives and their use as herbicides |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0446062A1 (en) * | 1990-03-09 | 1991-09-11 | Glaxo Group Limited | C-Linked pyrazole derivatives |
| WO1991015479A1 (en) * | 1990-03-30 | 1991-10-17 | Merck & Co., Inc. | Substituted pyrazoles, isoxazoles and isothiazoles |
-
1993
- 1993-01-20 GB GB9301003A patent/GB2263638A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0446062A1 (en) * | 1990-03-09 | 1991-09-11 | Glaxo Group Limited | C-Linked pyrazole derivatives |
| WO1991015479A1 (en) * | 1990-03-30 | 1991-10-17 | Merck & Co., Inc. | Substituted pyrazoles, isoxazoles and isothiazoles |
Cited By (8)
| 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 |
| US6297198B1 (en) | 1996-05-14 | 2001-10-02 | Syngenta Participations Ag | Isoxazole derivatives and their use as herbicides |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9301003D0 (en) | 1993-03-10 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |