Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-23
2004-07-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S310000
Reexamination Certificate
active
06759415
ABSTRACT:
The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones of general formula (I) represented below, their preparation processes and their use as medicaments. These compounds have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to the pharmaceutical compositions containing said compounds and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.
Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al.,
Science
1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al.,
Neuroscience
1995, 67, 777-790; Reisine T. et al.,
Endocrinology
1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.
The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al.,
Proc. Natl. Acad. Sci. U.S.A
, 89, 251-255, 1992; Raynor, K. et al,
Mol. Pharmacol
., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhoea syndrome, diarrhoea associated with AIDS, diarrhoea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumours; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.
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: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours 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 diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage 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 tumours, 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, leukaemia, meningioma, cancerous cachexia, inhibition of
H pylori
, psoriasis, as well as Alzheimer's disease. Osteoporosis can also be mentioned.
The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C.,
Drugs of the Future
, 1994, 19, 992; Reubi, J. C. et al.,
TIPS
, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumours including carcinoid syndrome.
The compounds of the present invention correspond to general formula (I)
in racemic, enantiomeric form or all combinations of these forms, in which:
R1 represents a (C
1
-C
12
)alkyl, (C
0
-C
6
)alkyl-C(O)—O—Z1, (C
0
-C
6
)alkyl-C(O)—NH—(CH
2
)
p
—Z2 or aryl radical optionally substituted,
Z1 represents H, a (C
1
-C
6
)alkyl, —(CH
2
)
p
-aryl radical;
Z2 represents an amino, (C
1
-C
12
)alkylamino, (C
3
-C
8
)cycloalkylamino, N,N-di-(C
1
-C
12
)alkylamino, NH—C(O)—O—(CH
2
)
p
-phenyl, NH—C(O)—O—(CH
2
)
p
—(C
1
-C
6
)alkyl radical, an optionally substituted carbocyclic or heterocyclic aryl radical or an optionally substituted heterocyclic non aromatic radical;
R2 represents H, (C
1
-C
12
)alkyl or aryl optionally substituted;
R3 represents H or (CH
2
)
p
—Z3;
Z3 represents (C
1
-C
12
)alkyl, (C
1
-C
12
)alkenyl, (C
3
-C
8
)cycloalkyl, —Y1—(CH
2
)
p
-phenyl-(X1)
n
, —S—(C
1
-C
12
)alkyl, S—(C
1
-C
12
)alkyl-S—S—(C
1
-C
12
)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, and in particular one of the radicals represented below
an optionally substituted heterocyclic non aromatic radical, a bis-arylalkyl or di-arylalkyl radical or also the radical
Y1 represents O, S, NH or is absent;
R4 represents (CH
2
)
p
—Z4;
Z4 represents amino, (C
1
-C
12
)alkyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
12
)alkylamino, N,N-di-(C
1
-C
12
)alkylamino, amino(C
3
-C
6
)cycloalkyl, amino(C
1
-C
6
)alkyl(C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, carboxylic or heterocyclic aminoaryl, (C
1
-C
12
)alkoxy, (C
1
-C
12
)alkenyl, N—C(O)O(C
1
-C
6
)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below
or also Z4 represents an N(R6)(R7) radical in which R6 and R7 taken together with the nitrogen atom which they carry form together a hete
Brault Valérie
Poitout Lydie
Thurieau Christophe
Muserlian Lucas and Mercanti
Raymond Richard L.
Societe de Conseils de Recherches et d' Applications Scient
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