US 2003/0191134 A1 · Non-peptide somatostatin receptor ligands

Abstract

Non-peptide somatostatin receptor ligands with conformationally restricted side chains exhibiting high binding affinity toward somatostatin receptors are provided. The compounds exhibit a high selectivity and act as agonists at human subtype 2 somatostatin receptors. The compounds are long acting for advantageous use as medicaments in peripheral diseases where somatostatinergic therapy is indicated. Furthermore, many of the compounds are lipophilic and are particularly useful for treating central nervous system and ophthalmic diseases where penetration of the blood brain and blood retinal barriers is required. It is a further object to describe the preferred stereoisomers of these somatostatin agonists and processes for their preparation. Further objects will become apparent from reading the following description.

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Claims59

Dependent claims

A non-peptide, somatostatin receptor ligand represented by Formula IC:

36
or a pharmaceutically acceptable racemate, enantiomer, diastereomer, solvate, salt or prodrug thereof, wherein:
A and B independently are oxygen, or (H,H);
R1 is a group selected from Formula Set A or Formula Set B
37
wherein;
each Ra independently is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, or form together a 3-6 carbon-membered ring;
G is aryloxy, cyano, —CO2Ra, or —C(O)N(Rb)2 wherein Rb is independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, arylalkyl, heterocyclylalkyl, or is optionally joined to a five- or six-membered ring;
Q is a C1-C5 alkyl, alkenyl, or alkynyl linker group that can optionally include oxygen, sulfur, or nitrogen atoms or —N(Ra)— and/or is optionally substituted by hydroxy, alkoxy, alkyl, or aryl;
each E1, E2, and E3 independently is a covalent bond, carbon, oxygen, sulfur, or nitrogen optionally substituted with an alkyl, alkenyl, alkynyl, alkylaryl, or aryl, n is an independently 0, 1, or 2;
and
J is hydrogen, alkyl, heterocyclylalkyl, or CH2N(Ra)2;
R2 is —SO2—Ar or (CHRc)n—Ar wherein
Rc is hydrogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, aryl, aryloxy, cyano, —CO2Ra or —C(O)N(Rb)2;
Ar is phenyl or naphthyl, optionally and independently mono- or di-substituted with hydroxy, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, amino, nitro, trifluoromethyl, aminomethyl, dimethylaminocarbonyl, benzimidazolyloxy, morpholinocarbonyl, or an aromatic group of formula:
38
wherein D is oxygen, sulfur, CH2, or CO;
and each Rd is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy;
trifluoromethyl, amino, halogen, or hydroxy;
R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
and
R4 is either a group of formula —CH2—Y or CHRe—Y if R1 is a group of Formula Set A or a group of formula CHRe—Y if R1 is a group of Formula Set B;
wherein
Re is alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl;
Y is a group of formula
39
wherein Rf is hydrogen, halogen, or alkoxy;
and Rg is hydrogen, alkyl, or benzyl.

25 more elements

A non-peptide, somatostatin receptor ligand represented by Formula IA:

42
wherein
A and B independently are O or (H, H);
R1 is a group of formula
43
wherein the Ra groups are, independently, hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylaryl;
X is aryloxy, cyano, —CO2Rb, or —C(O)N(Rc)2 wherein Rb is H, alkyl or alkylaryl and wherein the Rc groups are, independently, hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaryl, heterocyloalkyl or are optionally joined to form a six membered ring;
Q is an alkyl spacer group optionally interrupted by oxygen, sulfur or nitrogen atoms and optionally substituted by hydroxy, alkoxy, alkyl, or aryl;
Z1, Z2, and Z3 are, independently, carbon, oxygen, sulfur, or nitrogen optionally substituted with an alkyl;
n is an integer from 0 to 2;
and Y is either hydrogen, an alkyl, heterocyloalkyl, or CH2N(Ra)2;
R2 is —CH(Rd)—Ar or —SO2—Ar wherein Rd is alkyl, aryl, cyano, —CO2Rb, or —C(O)N(Rc)2;
Ar is phenyl or naphthyl optionally and independently,
44
mono- or di-substituted by hydroxy, cyano, halogen, alkyl, alkoxy, —N(Ra)2, alkylthio, alkylsulfonyl, arylsulfonyl, nitro, —S(O)2N(Rc)2, trifluoromethyl, —CH2N(Ra)2, —CO2Rb, —C(O)N(Rc)2, or an aromatic group of formula
wherein A is CH2, O, NH, S or CO and the Re groups, independently, are hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, amino, halogen, hydroxy;
R3 is selected from hydrogen, alkyl, aryl, alkylaryl or heteroaryl;
and
R4 is a group of formula:
45
wherein Z1, Z2, and Z3 are, independently, carbon, oxygen, sulfur or nitrogen optionally substituted with an alkyl;
Rf is hydrogen, alkyl or an aryl group;
and Rg is hydrogen, halogen, cyano, trifluoromethyl, aryl, alkyl or alkoxy.

20 more elements

Dependencies are inferred from the claim text.

Description13,566 words

Summary2,139 words

#Somatostatin is an endogenous peptide that performs a variety of important functions within the body. Somatostatin is a highly flexible cyclic peptide with a very short biological half-life. Two known biologically active forms of somatostatin are a 14mer (SRIF-14) and a 28mer N-terminal extended form (SRIF-28). Naturally-occurring somatostatin (also known as somatotropin release inhibiting factor, SRIF) was originally isolated from ovine hypothalamus.

#Somatostatin, originally discovered to act as a classical endocrine hormone of the hypothalamic-pituitary system, has since been shown to act additionally as a paracrine and autocrine signaling factor on a wide variety of cell types. The numerous physiological processes currently recognized to be influenced by somatostatin include hormone and peptide factor secretion, neurotransmission, cell proliferation, smooth muscle contraction, nutrient absorption and inflammation. Hormones and peptides regulated by somatostatin include growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), insulin, and substance P (SP).

#Somatostatin affects the function of many important biological systems such as the endocrine, gastrointestinal, vascular, and immune systems along with the central and peripheral nervous systems. In the endocrine system, somatostatin plays an important role in controlling growth hormone, insulin and glucagon secretion (Koerker et al., Science 1974, 184, 482-484). The effects of somatostatin on the gastrointestinal and vascular biological systems have led to clinical applications for somatostatin therapeutics in both of these areas. In the central nervous system (CNS), somatostatin appears to be an important regulator of cognitive functions (Schettini, Pharmacological Research 1991, 23, 203-215) and, in specific areas of the brain, appears to act as a neurotransmitter or as a neuromodulator regulating the release of neurotransmitters such as acetylcholine (Gray et al., J. of Neuroscience 1990, 10, 2687-2698) and dopamine (Thal et al., Brain Research 1986, 372, 205-209). In the peripheral nervous system (PNS), somatostatin is present in catecholamine containing fibers and in sensory terminals together with substance P (Green et al., Neuroscience 1992, 50, 745-749) and acts to inhibit their release and mediated effects.

Brief description of the drawings2 figures

#FIG. 1 illustrates the binding affinity of Compound Example 15a to human SSTR2 receptors according to the present invention.

#FIG. 2 illustrates the binding affinity of Compound Example 15b to human SSTR2 receptors according to the present invention.

Detailed description11,389 words

#The subject invention provides non-peptide compounds that are capable of binding to somatostatin receptors. In one embodiment of this invention, these compounds bind to, and activate, a somatostatin receptor. Preferred compounds of the subject invention are those compounds which selectively bind to somatostatin receptors, are stable, are readily administered, and in a specific embodiment, are able to penetrate the BBB and the BRB. Particularly preferred compounds are those which selectively bind to and activate somatostatin subtype 2 (SSTR2) receptors. The compounds are useful in the treatment of acromegaly, diarrhea management, diabetic retinopathy, macular degeneration, osteosarcoma, irritable bowel syndrome, and for the treatment of abnormal cellular proliferation, including tumors and cancer, and in particular, neuroendocrine tumors and breast cancer.

#In another embodiment, the compounds may treat certain of these disorders through a mechanism that does not involve a somatostatin receptor.

#One embodiment of the subject invention provides potent, non-peptide somatostatin receptor ligands based on a central imidazolin-2-one, imidazolin-4-one or imidazoline-2,4-dione ring as a core heterocyclic scaffolding structure. Appended to the heterocyclic scaffold are at least three side chains that account for the advantageous activity of the compounds. In a preferred embodiment, at least two groups appended to the core heterocyclic structure include one or more structural elements that restrict the conformational mobility of these appended groups. This ligand structure fixes side chains in the 3-dimensional geometry necessary for biological activity when bound by a somatostatin receptor. Such ligand structures provided herein elicit biological effects similar to somatostatin upon binding to somatostatin receptors.

Non-peptide somatostatin receptor ligands

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Non-peptide somatostatin receptor ligands

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Abstract

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Claims59

Description13,566 words

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Description13,566 words

Classification4 codes

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