Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-04
2004-08-17
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S495000
Reexamination Certificate
active
06777408
ABSTRACT:
The present invention relates to novel pyrido-thieno-diazepines, their preparation process and the pharmaceutical compositions containing them. These diazepines are particularly useful for treating pathological states or diseases in which one (or more) somatostatin receptors are involved.
Somatostatin (SST) was isolated for the first time as a factor inhibiting the secretion of growth hormone (Brazeau P. et al.,
Science
1973, 179, 77-79). This substance is known in two forms somatostatin 14 and somatostatin 28 and is widely distributed in the animal kingdom and in man. The peptides of this family also operate as neurotransmitters in the brain (hypothalamus, sensitive neurons, cerebral cortex) (Reisine T. et al.,
Neuroscience
1995, 67, 777-790; Reisine et al.,
Endocrinology
1995, 16:427-442) and in the endocrine organs (pancreas, intestine, kidney, salivary glands, thyroid C cells etc.). The bioactivity of somatostatin depends directly on a family of five recently cloned receptors.
Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromgalia, hypophyseal adenomas which do not secrete growth hormones, hypophyseal adenomas which secrete thyreostimulin, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, hypophyseal adenomas without endocrinic action, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastoenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodepression syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastrointestinal hemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumors, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, osteoporosis as well as Alzheimer's disease.
These diazepines have an affinity and a selectivity for the somatostatin receptors. The clinical applications of natural somatostatin and its peptide analogues are often limited. In fact, a poor bioavailability by oral route and low selectivity are often the main cause (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110). Due to their non peptide structure, the compounds of the present invention, agonists or antagonists of somatostatin, appear less susceptible to metabolic degradation than the. natural hormone and its peptide analogues and would thus have a superior duration of action. These compounds can be advantageously used for treating pathological states or the diseases as presented above and in which one (or more) somatostatin receptors are involved.
A subject of the present invention is therefore the compounds of general formula I
under racemic, or enantiomeric or diastereoisomeric form or mixture thereof, and in which
R
1
represents the hydrogen atom or a radical of formula R′
1
—NH—C(Y)—;
R′
1
represents an aryl or heteroaryl radical, the aryl and heteroaryl radicals being optionally substituted;
R
2
represents a lower alkyl, trifluoromethyl radical or the phenyl radical optionally substituted;
X and Y represent independently O or S;
R
3a
represents the hydrogen atom, a lower alkyl, hydroxy radical or the radical of formula —OC(O) R′
3a
;
R′
3a
represents an alkyl radical containing 1 to 10 carbon atoms optionally substituted;
R
3b
represents the hydrogen atom or a lower alkyl radical;
R
4
represents a radical of formula —(CH
2
)
n
—CHR′
4
R″
4
;
n represents the values 0, 1, 2, 3, 4, 5 or 6;
R′
4
and R″
4
represent, independently, the hydrogen atom, a lower alkyl, cycloalkyl, lower cycloaklyl alkyl aryl, lower arylalkyl, beteroaryl, lower heteroarylalkyl, arylcarbonyl or adamantyl, radical, these radicals being optionally substituted;
A—B represents —C═N— or —C—N(R
5
)—;
R
5
represents the hydrogen atom, a lower alkyl, lower alkenyl radical or a radical of formula —C(O)—(CH
2
)
p
—R′
5
;
R′
5
represents the hydrogen atom, the radical amino, lower alkyl amino, di(lower alkyl)amino, cycloalkyl, heterocycloalkyl, guanidyl optionally susbtituted by nitro or cyano, aryl optionally substituted, heteroaryl or a radical of formula —NH—C(O)—(CH
2
)
c
—NH—C(O)—(CH
2
)
d
—NH
2
;
p represents the values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
c and d represent independently the values 0, 1, 2 or 3;
or a salt of these compounds.
A more particular subject of the invention is the compounds of general formula I as defined above in which
the substituents, identical or different,of the aryl or heteroaryl radical represented by R′
1
, are chosen from the following radicals: lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy carbonyl, lower alkyl sulphonyl, halo, trifluoromethyl, trifluoromethyloxy, hydroxy, nitro, cyano, aryl, aryloxy, cycloalkyl or heterocycloalkyl;
the substituents, identical or different, of the phenyl radical represented by R
2
, are chosen from: the hydroxy, halo radical, a lower alkyl or lower alkoxy radical;
the substituents, identical or different, of the alkyl radical represented by R′
3a
, are chosen from the following radicals: cycloalkyl; heterocycloalkyl; aryl; heteroaryl; guanidyl optionally substituted by nitro or cyano; a radical of formula NR″
3a
R′″
3a
in which R″
3a
and R′″
3a
represent, independently, the hydrogen atom, a lower alkyl, aryl, lower arylalkyl, lower heteroarylalkyl, alkylcarbonyl or alkoxycarbonyl radical;
the susbtitents, identical or different, of alkyl, cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcarbonyl or adamantyl radical represented independently by R′
4
and R″
4
, are chosen from: the hydroxy, halo, trifluoromethyl radical, a lower alkyl or lower alkoxy radical;
the substituents, identical or different, of aryl represented by R′
5
, are chosen from the following radicals: alkyl or alkoxyalkyl, these radicals alkyl or alkoxyalkyl being optionally substituted by oxy and amino.
In the definitions indicated above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. The expression lower alkyl preferably represents an alkyl radical having 1 to 6 carbon atoms, linear or branched, and in particular an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl
Bigg Dennis
Liberatore Anne-Marie
Coleman Brenda
Muserlian Lucas and Mercanti
Societe de Conseils de Recherches et d'Applications Scienti
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