WO2014122638A2

WO2014122638A2 - Thalidomide and thalidomide analogues for the stimulation in human/animals of stem cell factor to increase regenerative potential in aging conditions

Info

Publication number: WO2014122638A2
Application number: PCT/IE2014/000001
Authority: WO
Inventors: Thomas Patrick PRENDERGAST
Original assignee: Prendergast Thomas Patrick
Priority date: 2013-02-08
Filing date: 2014-02-10
Publication date: 2014-08-14
Also published as: IE20130078A1; WO2014122638A3

Abstract

The present invention relates to the administration of thalidomide and/or thalidomide analogues to a patient to enhance or maintain endogenous levels of stem cell factor in a patient to prevent and/or treat medical conditions associated with declining endogenous stem cell factor levels also known as mast cell growth factor or kit-ligand.

Description

Title

Thalidomide and thalidomide analogues for the stimulation in human/animals of stem cell factor to increase regenerative potential in aging conditions. Description

The present invention relates to thalidomide and thalidomide analogues and methods for using same to maintain or increase endogenous levels of stem cell factor. In particular the present invention provides compositions and methods to prevent and/or treat declining stem cell factor levels.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting more than 35 million people worldwide. Cognitive decline is an integral part of AD, and AD patients show considerable variations concerning the rate of cognitive decline. The assessment of how rapidly AD is progressing has important implications in clinical practice, since the rate of disease progression may be the most important factor in determining prognosis. The identification of factors associated with the rate of cognitive decline in AD patients could be extremely valuable 1) to better understand the underlying disease mechanisms, 2) to develop new treatment strategies in order to halt or modify disease progression in AD, and 3) because at risk patients could be early targeted for pharmacologic, medical, and psychosocial interventions designed to slow deterioration.

Stem cell factors (SCFs) belongs to the family of hematopoietic growth factors (HGFs) and is involved in the mobilization, survival, proliferation, and differentiation of hematopoietic stem cells (HSCs) and other hematopoietic progenitor cells. However, recent studies have indicated that SCF may also be relevant for neuroprotection and neurogenesis in the central nervous system (CNS). We have recently reported decreased SCF plasma levels in AD patients. However, it is not known whether SCF plasma levels are also associated with the rate of cognitive decline of AD patients. Given the substantial neuroprotective effects of SCF in the CNS and the potential of SCF to transit the blood-brain barrier (BBB), we hypothesized that higher SCF plasma levels may be associated with a slower rate of cognitive decline in AD patients. - -

We have previously reported that brain-derived neurotrophic factor (BDNF) serum levels, amyloid-β (A β)ι^₂ plasma levels and the degree of plateletactivation (activated glycoprotein [GP] llb-llla and P-selectin) are associated with the rate of cognitive decline at the "Pythia" cohort of probable AD patients. In the present study, we examined the possible association of cognitive decline and SCF plasma levels at the "Pythia" cohort in an attempt to further elucidate pathophysiological mechanisms taking place in dementia development and defining possible candidate prognostic markers which could be used in a multimarker approach to predict dementia progression. Moreover, we determined the relative predictive value of SCF in a multimarker approach of a multiple linear regression analysis for fast versus slow cognitive decline including the known biomarkers of dementia progression (BDNF serum levels, A β_1-42 plasma levels and the degree of platelet activation [activated GP llb-llla and P-selectin]) Idiopathic pulmonary fibrosis (IPF) (or cryptogenic fibrosing alveolitis (CFA) or idiopathic fibrosing interstitial pneumonia) is a chronic, progressive form of lung disease characterized by fibrosis of the supporting framework (interstitium) of the lungs. Microscopically, lung tissue from patients shows a characteristic set of histologic/pathologic features known as usual interstitial pneumonia (UIP). UIP is therefore the pathologic counterpart of IPF. In the UK IPF kills about 5,000 people every year. Half of IPF sufferers in the UK die within three years of diagnosis.

Despite extensive investigation, the cause of IPF remains unknown. The condition involves abnormal and excessive deposition of collagen in the pulmonary interstitium (mainly the walls of the alveoli) with minimal associated inflammation. The fibrosis in IPF has been linked to cigarette smoking, gastroesophageal reflux disease and autoimmune disorders, but none of these are present in all patients with IPF, and therefore do not provide a completely satisfactory explanation for the disease. IPF affects both genders and is usually encountered in patients greater than 50 years of age. There are many different statements about average survival time following first diagnosis. Symptoms are gradual in onset. The most common are progressive dyspnea (difficulty breathing), but also include dry cough, clubbing (a disfigurement of the fingers), and rales (a crackling sound in the lungs during inhalation, heard with a stethoscope) It should be noted that these features are not specific for IPF and can occur in a wide variety of other pulmonary disorders. - -

Thalidomide (Ν-α-phthalimidoglutarimide) is a glutamic acid derivative that was introduced onto the market as a sedative hypnotic in 1956, but was withdrawn in 1961 due to the development of severe congenital abnormalities in babies born to mothers using it for morning sickness. Interest in the agent was reawakened after thalidomide was found clinically effective in the treatment of erythema nodosum leprosum (ENL) and in the treatment of HIV wasting syndrome and various cancers. Mechanistic studies of its ENL activity also demonstrated an anti-tumor necrosis factor alpha (anti- TNF-a) action. Specifically, thalidomide enhances the degradation of TNF -a RNA, and thereby lowers its synthesis and secretion. Further studies have defined it to be a co-stimulator of CD8+ and CD4+ T cells, an inhibitor of angiogenesis via its inhibitory actions on basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), and an inhibitor of the transcription factor, NFKB. Overproduction of TNF- a has been implicated in many inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease and Crohn's disease, and it additionally exacerbates ENL, septic shock, AIDS and dementia associated with Alzheimer's disease (AD).

The present invention discloses thalidomide and thalidomide analogues for maintaining and increasing stem cell factor in a subject. The invention also discloses compositions and methods for the prevention and/or treatment of cognitive decline in Alzheimer's by enhancing endogenous levels of stem cell factor. In some embodiments, the disclosed thalidomide analogues are sulfur-analogues of thalidomide, its open-ring metabolites and its derivatives (such as its hydroxylated derivatives) in which one or more carbonyl groups are replaced by thiocarbonyl groups. For example, in some embodiments, thalidomide analogues wherein at least one carbonyl group on the pthaloyl moiety or on the glutaramide moiety (or its open ring form) of a thalidomide or a thalidomide analogue is replaced by a thiocarbonyl group.

A study carried out to perform a comparison study to determine if Thalidomide is equally effective as MMP-9 gene deletion in delaying cardiac sarcopenia. Twenty mice were administered 10Omg/kg/day in 1x phosphate buffered saline by gavage two hours before dark cycle. Survival rates of the twenty untreated mice was 75% and 85% in treated animals (p=0.695 Fisher's exact test) which indicates that survival - - was not affected by thalidomide treatment. Echocardiography results showed improvements in the treated mice in stroke volume, cardiac output and fractional shortening which can be seen in Figure 1. The improved fractional shortenings suggest that thalidomide has a direct effect on cardiac myocyte contractility. 58 plasma analytes were examined during this study, compared to untreated with treated groups only two analytes were statistically different, and these can be seen in Figure 2. Gene array results indicate that a specific portfolio of extracellular matrix, adhesion molecules and cytokines are changing with Thalidomide treatment. The fact that only 21 % of the genes showed changes indicates that the effect of Thalidomide is localized and not a generic response, so potential side effects may be limited (Figure 3). These results show that Thalidomide treatment when started at middle age in mice improved myocardial contractility and left ventricular function without affecting survival, showed anti-inflammatory effects and increased the regenerative potential of the cardiomyocyte. Thalidomide treatment started at middle-age may improve cardiac performance by reducing the rate of cardiac sarcopenia.

Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination [MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score≤ 4 after one year; n = 28) (fast versus slow cognitive decline: mean ± SD: 1051.1 ± 178.7 versus 1237.9 ± 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) llb/llla. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to - - elucidate the value of plasma SCF in a multimarker approach determining AD prognosis.

Taken from the paper - Stem cell factor plasma levels are decreased in alzheimer's disease patients with fast cognitive decline after one-year follow-up period: The Pythia Study. Christoph Laske el

Stem cell factor (SCF) also known as mast cell growth factor or kit-ligand, is a hematopoietic cytokine that mediates its effects through its receptor c-kit (Huang et al. 1990). SCF is encoded by the Steel locus on chromosome 12 (Geissler et al. 1991). Mutations in genes, coding SCF and its receptor, show that SCF plays an essential role during development in utero (Broudy 1997). SCF plays role in hematopoiesis, spermatogenesis and melanogenesis (Broudy 1997). SCF intracellular signalling induces activation of phosphatidylinositol (PI) 3-kinase, which leads to Akt-mediated phosphorylation of Bcl-2 related protein (BAD). SCF-induced phosporylation of BAD suppresses cell apoptosis, promoting cell survival (Blume- Jensen et al. 1998). SCF signals through many other pathways, such as phospholipase C-gamma, Src kinase, Janus kinase, Signal Transducers and Activators of Transcription (STAT), mitogen activated protein (MAP) kinase pathway (Reber et al. 2006). SCF has synergistic activity with other cytokines in megakaryocytopoesis (Briddell et al. 1991).

Additionally, the disclosed compounds can be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. Therefore, also disclosed are pharmaceutical compositions including one or more of any of the compounds disclosed below and a pharmaceutically acceptable carrier. The composition may comprise a unit dosage form of the composition, and may further comprise instructions for administering the composition to a subject to prevent and/or treat sarcopenia.

The disclosed pharmaceutical compositions can be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions (e.g. eye or ear drops, throat or nasal sprays etc), transdermal patches and other forms known in the art. - -

Pharmaceutical compositions can be administered systemically or locally in any manner appropriate to the treatment of a given condition, including orally, parenteral^, rectally, nasally, buccally, vaginally, topically, optically, by inhalation spray, or via an implanted reservoir.

The term 'parenterally' as used herein includes, but is not limited to subcutaneous, intravenous, intramuscular, intrasternal, intrasynovial, intrathecal, intrahepatic, intralesional and intracranial administration, for example, by injection of infusion. Pharmaceutically acceptable carriers include, but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Disclosed are thalidomide analogues that can be used to maintain and increase muscle mass in order to prevent and/or treat sarcopenia. Pharmaceutically acceptable salts, stereoisomers, and metabolites of all of the disclosed compounds also are contemplated. In some embodiments, the thalidomide analogues are thiothalidomide derivatives in which carbonyl groups in corresponding nonsulfur- containing thalidomide derivatives are replaced by one or more thiocarbonyl groups.

In the structures that follow, all valency requirements are understood to be satisfied. Thus, for example, carbon atoms have four bonds to other atoms, even if all such bonds are not shown. As is understood by those of ordinary skill in the art, where all four bonds to a carbon atom are not shown, additional bonds to hydrogen atoms are implied. Further substitution of such implied hydrogen atoms is possible.

In other embodiments, the disclosed compounds include compounds having the chemical formula:

- -

wherein X and Y are independently CH₂, oxygen or sulfur, and at least one of X and Y is sulfur if does not include a sulfur atom; each of R₂-R₅ are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen, nitro or linked to form a five- or six-membered, unsubstituted or substituted, aliphatic, aromatic or heterocyclic ring, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and is an unsubstituted or substituted, aliphatic or aromatic heterocyclic ring, an unsubstituted or substituted cycloalkenyl ring, or

wherein W and Z are each independently oxygen or sulfur, R₆ and R₇ are each independently hydroxyl, alkoxy or substituted alkoxy, and each of R₈- i2 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted ally, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl.

In particular embodiments, is

W - - wherein W and Z are each independently oxygen or sulfur, R ₃ and R_w are each independently hydrogen, alkyl or substituted alkyl; R₂₀ is hydrogen, hydroxyl, alkyl or substituted alkyl such as aryl substituted alkyl; and R15-R19 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl. In some embodiments, at least one of R₂, R₃, R₄, Rs, Re, R9. R10. R11, Ri5, R16, Ri7, R18 and R₍g is hydroxyl. In other embodiments, at least one of X, Y, W and Z is sulfur, at least two of X, Y, W and Z are sulfur, or at least three of X, Y, W and Z are sulfur. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both Wand Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present. Alternatively, where W and Z are present the following are possible: X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. In other particular embodiments X=S and Y=CH₂.

In more particular embodiments, the disclosed compounds have the formula

wherein X, Y, W and Z are independently sulfur or oxygen and at least one of X, Y, W and Z is sulfur, and R2-R12 are as before. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W - - or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present. Alternatively, where W and Z are present the following are possible: X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y =S, W=S, Z=S.

In more particular embodiments, at least one of R₂-R₅ and R₈-Rn is hydroxyl. Specific examples of such compounds include:

In other more particular embodiments, the disclosed compounds have the chemical formula:

- -

wherein W, X, Y and Z each are independently sulfur or oxygen and at least one of W, X, Y and Z is sulfur; and R₂- Rs, and R15-R20 are as before. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur. Alternatively, the following are possible: X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. In more particular embodiments, at least one of R2-R5, and 15-R19 is hydroxyl. Specific examples of such compounds include:

and

The disclosed compounds also include compounds having the formula:

- - wherein T and V are independently oxygen or sulfur, R₂i-R₂5 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R₂e is

wherein W, Z and R13-R₂0 are as before. For example, in more particular embodiments, T or V is sulfur, and both W and Z are oxygen if present; both T and V are sulfur and both W and Z are oxygen if present; T and V are both oxygen and W or Z is sulfur if present; both T and V are sulfur and W or Z is sulfur if present; or T or V are sulfur and both W and Z are sulfur if present. Alternatively, where W and Z are present the following are possible: T =0, V=0, W=0, Z=0; T =S, V=0, W=0, Z=0; T =0, V=S, W=0, Z=0; T =0, V=0, W=S, Z=0; T =0, V=0, W=0, Z=S, T =S, V=S, W=0, Z=0; T =S, V=0, W=S, Z=0; T =S, V=0, W=0, Z=S; T =0, V=0, W=S, Z=S; T =0, V=S, W=0, Z=S; T=0, V=S, W=S, Z=0; T=S, V=S, W=S, Z=0; T =S, V=S, - -

W=0, Z=S; T =S, V=0, W=S, Z=S; T =0, V=S, W=S, Z=S; or T =S, V=S, W=S, Z=S. In some embodiments, at least one of R₁₅-Ri₉ and R22- 26 is hydroxyl.

Still further, the disclosed compounds include compounds having the formula:

wherein X, Y are each independently oxygen or sulfur, W, X and Ri₅-R₂o are as before; R27-R33 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R34 is hydrogen, alkyl or substituted alkyl. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur. Alternatively, the following are possible: X=0, Y=0, W=0, Z=0; X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. - -

In addition, the disclosed compounds include compounds having the formula:

wherein X and Yare each independently oxygen or sulfur; W, Z, R₁₅-R₂o and R34 are as before, R₃₅ is alkyl or substituted alkyl, and R36- 39 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acy- loxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur. Alternatively, the following are possible: X=0, Y=0, W=0, Z=0, X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S.

Other embodiments include compounds having the formula:

- - wherein X and Y each are independently oxygen or sulfur; W, Z and R15-R₂₀ are as before; and R40- 5 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl. For example, in more particular embodiments, X or Y is sulfur, and both and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur. Alternatively, the following are possible: X=0, Y=0, W=0, Z=0; X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S.

The disclosed compounds further include compounds having the formula:

wherein X Y, W and Z are independently oxygen or sulfur, and R₂-R₅ and R13-R16 are as before. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfa and both W and Z are sulfur. Alternatively, the following are possible: X=0, Y=0, W=0, Z=0, X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, - -

W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S.

Also disclosed is a thalidomide analogue compound having the formula:

wherein X, Y and Z are independently oxygen or sulfur, and R₂-R5 , R15-R20 and R34 are as before. For example, in more particular embodiments, X or Y is sulfur, and Z is oxygen; both X and Y are sulfur and Z is oxygen; X and Y are both oxygen and Z is sulfur. Alternatively, the following are possible: X=0, Y=0, Z=0; X=S, Y=0, Z=0; X=0, Y=S, Z=0; X=0, Y=0, Z=S; X=S, Y=S, Z=0; X=S, Y=0, Z=S; X=0, Y=S, Z=S; or X=S, Y=S, Z=S.

Also disclosed is a thalidomide analogue compound having the formula:

wherein X and Y are independently oxygen or sulfur, and R^ R₂, R4 and R₅ are as before. For example, in particular embodiments, Ri is

wherein W, Z, and Ri₃-R₂o are as before. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present. Alternatively, where W and Z are present the following are possible: X=0, Y=0, W=0, Z=0; X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. In more particular embodiments, the compound has the formula:

wherein X, Y are independently oxygen or sulfur, and W, Z, R₂, R4, R₅, and Ri₃-R₁₆ are as before. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur. Alternatively, the following - - are possible: X=0, Y=0, W=0, Z=0; X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. In even more particular embodiments, at least one of R₂, R4, Rs, R15 and R₁₆ is hydroxyl.

Also disclosed is a compound having the formula:

wherein G and D are each independently oxygen or sulfur, R2-R5 are as before, and

wherein W, Z and R13-R20 are as before. For example, in particular embodiments, G or D is sulfur, and both W and Z are oxygen; both G and D are sulfur and both W and Z are oxygen; G and D are both oxygen and W or Z is sulfur; both G and D are sulfur and W or Z is sulfur; or G or D are sulfur and both W and Z are sulfur. Alternatively, the following are possible: G=0, D=0, W=0, Z=0; G=S, D=0, W=0, Z=0; G=0, D=S, W=0, Z=0; G=0, D=0, W=S, Z=0; G=0, D=0, W=0, Z=S; G=S, D=S, W=0, Z=0; G=S, D=0, W=S, Z=0; G=S, D=0, W=0, Z=S; G=0, D=0, W=S, Z=S; G=0, D=S, W=0, Z=S; G=0, D=S, W=S, Z=0; G=S, D=S, W=S, Z=0; G=S, D=S, W=0, Z=S; G=S, D=0, W=S, Z=S; G=0, D=S, W=S, Z=S; or G=S, D=S, W=S, Z=S. - -

A method for preventing and/or treating sarcopenia in a subject is also disclosed. The method includes administering to the subject a therapeutically effective amount of one or more of any of the compounds disclosed above, or a compound having the formula:

where X and Y are independently oxygen or sulfur; W, Z, R₁₅ -R₂₀ are as before; and R47-R52 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; or a compound having the formula:

wherein n=1-5; X is oxygen or sulfur, and R2-R5 and R₁₅ -R₁₉ are as before; - - or a compound having the formula.

wherein each of X and Y are independently oxygen or sulfur, n=1-5, and R₂-R₅ are as before; or a compound having the formula:

wherein R₅₃ and R5 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R₅₅ is hydrogen, alkyl, or substituted alkyl; or a compound having the formula:

wherein R2-R5 are as before and R₅₆ is hydrogen, alkyl or substituted alkyl;

or pharmaceutically acceptable salts or stereoisomers thereof.

- -

Novel thio-substituted analogues having the structures described with respect to the method above also are contemplated. For example, in more particular embodiments, X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present. Alternatively, if W and Z are present, the following are possible: X=0, Y=0, W=0, Z=0; X=S, Y=0, W=0, Z=0; X=0, Y=S, W=0, Z=0; X=0, Y=0, W=S, Z=0; X=0, Y=0, W=0, Z=S; X=S, Y=S, W=0, Z=0; X=S, Y=0, W=S, Z=0; X=S, Y=0, W=0, Z=S; X=0, Y=0, W=S, Z=S; X=0, Y=S, W=0, Z=S; X=0, Y=S, W=S, Z=0; X=S, Y=S, W=S, Z=0; X=S, Y=S, W=0, Z=S; X=S, Y=0, W=S, Z=S; X=0, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S.

Particularly disclosed compounds and compounds that can be used in the disclosed methods include one or more compounds having the following structures:

. -

Claims

1. The method of administering Thalidomide or its analogues to a patient in need of enhancing their endogenous levels of stem cell factor to increase regenerative capacity where deficiency of stem cell factor has been confirmed as a contributing factor to a disease state such as Alzheimer's and other conditions.

2. The method of claim 1 , wherein the patient is considered vulnerable to developing Alzheimers or neurodegenerative disease.

3. The method of claim 1 , wherein the patient is considered vulnerable to developing cognitive decline due to low endogenous levels of stem cell factor.

4. The method of claim 1 , wherein the patient has low endogenous levels of stem cell factor with no evidence of cognitive impairment or pre-Alzheimer symptoms.

5. The method of claim 1 , wherein the patient need enhanced performance of stem cells factor.

6. A method of claim 1 , for treatment of leucopenia in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues

7. A method of claim 1 , for treatment of thrombocytopenia in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues

8. A method of claim 1 , for enhancing engraftment of bone marrow during transplantation in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues

9. A method of claim 1 , for enhancing bone marrow recovery in treatment of radiation, chemical, or chemotherapeutic induced bone marrow aplasia or myelosuppression which comprises treating patients with therapeutically effective doses of thalidomide or its analogues.

10. A method of claim 1 , for treating nerve damage in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues

11. A method of claim 1 , for treating infertility in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues.

12. A method of claim 1 , for treating intestinal damage in a mammal comprising administering a therapeutically effective 20 amount of thalidomide or its analogues.

13. A method of claim 1 , for treating myeloproliferative disorder in a mammal comprising administering a therapeutically effective amount of thalidomide or its analogues

14. The method of claim 1 wherein administration of thalidomide or its analogues produces an effect selected from among stimulation pulsatile growth hormone release; improved bone strength, muscle strength and/or tone; reduced subcutaneous fat in a subject; increased athletic performance; attenuation or reversal of protein catabolic responses following trauma; improved sleep quality; correction of the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency; modification of lipid profile; correction of female androgen deficiency; and correction of male androgen decline.

15. The method of delivering Thalidomide by aerosol delivery to Idiopathic pulmonary fibrosis patients for the treatment of this condition as our current results demonstrate reduction in macrophage-derived-chemokine.

16. The method of administering Thalidomide or its analogues in combination with Granlocyte colony stimulating factor (G-CSF) to a patient in need of enhancing their endogenous levels of stem cell factor to increase regenerative capacity where deficiency of stem cell factor has been confirmed as a contributing factor to a disease state such as Alzheimer's and other conditions.

17. The method of administering Thalidomide or its analogues as per claim 1 , wherein preferentially the thalidomide is administered to the patient one hour prior to the dark cycle commencing to enhance stem cell factor production.