IE20130078A1 - Methods for using thalidomide and thalidomide analogues to maintain or increase muscle mass in treating sarcopenia - Google Patents

Abstract

The present invention relates to thalidomide and/or thalidomide analogues and methods for using same to maintain or increase muscle mass to prevent and/or treat sarcopenia. The invention also provides pharmaceutical compositions comprising thalidomide and thalidomide analogues for the prevention and/or treatment of sarcopenia.

Description

Title Thalidomide ajjid th sarcopenia a ΙΕί 3 ο ο uesj for the prevention and treatment of Id Id pa 111 IC (SBlrnonary fibrosis and for the stimulation in human/animals of stem ceil 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 muscle mass. In particular the present invention provides compositions and methods to prevent and/or treat sarcopenia, Muscle atrophy (also know as muscle wasting) is a debilitating syndrome which slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two conditions, there are currently no widely used, effective treatment options for those suffering from muscle wasting. Rosenberg first coined the term Sarcopenia, from the Greek, which literally means poverty of flesh, to describe age-associated loss of skeletal muscle mass. Sarcopenia is now generally used to describe age-related changes that occur within skeletal muscle and thus encompasses the effects of altered central and peripheral nervous system innervations, altered hormone status, inflammatory effects and altered caloric and protein intake.

Sarcopenia is characterised by the loss of skeletal muscie mass as weii as strength, these morphological and functional modifications result from intrinsic events, such as changes in the muscle fibre type composition, mitochondrial dysfunction and oxidative damage, and from extrinsic factors including reduced physical activities and excessive and/or unbalanced nutritional intake, Sarcopenia has important health consequences for older adults because it is associated with an increased risk of falls, hip fractures, bone mineral loss and physical disability.

Baumgartner et al. (Am J Epidemiol 1998; 147:755-63; 149,111) have defined sarcopenia as appendicular skeletal muscle mass (kg/height2 (m2)) being less than two standard deviations beiow the mean of a young reference group. This is referred 2 IE 1 3 0 0 7 8 'Ί to as a ‘t-score’ hereinafter, Baumgartner et a I used the data from the New Mexico Elder Health Survey 1993-1995, to develop a method for estimating the prevalence of sarcopenia and found that the prevafence increased from 13-24% in persons under 70 years of age to >50% in persons over 80 years of age. The study by Baumgartner et al was one of the first to estimate the extent of the prevalence of sarcopenia.

A t-score is determined by measuring the axial skeletal muscle mass of a patient, typically by dxa (Le. dual energy xray absorptiometry) or a similar and reducible measure. The measurement of axiaE skeletal muscle mass can be used to follow the progress of the patient to determine if treatment is slowing, preventing or reversing muscle mass decline.

Multiple factors appear to be involved in the development of sarcopenia however no primary cause has been identified as yet. Although the overall biological mechanism of sarcopenia is not fuliy understood, observational studies have shown that satellite cells which are involved in muscle regeneration are much lower in older people and therefore, could pi ay a role in sarcopenia . Other factors including hormonal changes, such as growth hormone (GH) and insulin-like growth factor (IGF-1) and androgens which help regulate growth and development of skeletal muscle appear to decrease in old age. It has also been suggested that the renin-angiotensin system may play a roie in modulating muscle function, Sarcopenia is a major public health problem in industrialised nations, placing an increasing burden on public healthcare systems because the ioss of skeletal muscie mass and strength that characterises this indication increases the dependence and the risk of injury caused by sudden falls in elderty people.

It has been estimated that up to 15% of people older than 65 years and as many as 50% of people older than 80 years have sarcopenia. Sarcopenia has a major impact on public health and the cost in the United States aEorte was estimated to be ¢18.5 billion in 2000, With the rising number of older people worldwide, the cost is ever increasing.

IE 1 3 0 0 73 -3Treating sarcopenia includes slowing its progression, stopping its progression and partially reversing it An example of slowing the progression of sarcopenia would be to change the length of time a patient would go from a t-score of -1.5 to -2 (e g. if such a progression would normaily take 5 years, then treating as used herein could slow this change to 10 years). Examples of partial reversal include reducing a t-score 0.1: 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 or more units (e.g. moving from a t-score of -2 to a t-score of -1,9, -1.8, -1.7, -1.6, -1.5, -1.4, -1.3, -1.2, -1.1 etc). Treating sarcopenia also includes delaying the onset of sarcopenia. For example, if a typical male age 50 wouid begin to see signs of sarcopenia by age 55, treatment according to the present invention could delay the onset 1, 2, 3, 4, 5, 6, 7, 8, 9 ,10 or more years Thus, treating sarcopenia would include treating patients who have not yet been diagnosed with sarcopenia, but who would be vulnerable or expected to be vulnerable to developing sarcopenia. Patients who are vulnerable also Include (a) patients using glucocorticoid steroids, (b) patients with chronic infections, (c) patients with chronic inflammatory conditions (e.g. inflammatory bowel disease), and (d) patients with cancer.

Another type of patient that would benefit from the present invention is one that has suffered seme !oss of muscle mass, but who does not suffer from a condition that interferes with acts of daily living and/or prevents the subject from living an independent life (e g, a patient who might soon need assisted living).

In one embodiment, a further decline in t-score is prevented via treatment for at least one year.

In another embodiment, an increase in the t-score of a patient is obtained via treatment for at least one year.

Examples of t-scores include 3, 2.9, 2.8, 2.7, 2,6, 2.5, 2.4, 2.3, 2.2, 2.1,2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0, -0,1, 0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0-9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, 1.8, -1.9, -2.0, -2.1, -2.2, -2,3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9, -3.0, -3,1, -3.2, -3.3, 3.4, -3.5, -3.6, -3.7, -3.8, -3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4,5, -4.6, -4.7, -4.8, -4.9, -4IE * 3 η ο 7 8 .0, “5,1, -5.2, -5.3, -5,4, 5.5, -5.6, -5.7, -5,8, -5.9, and -6 0. Typically patients with negative t-scores are more likely to be treated for sarcopenia. However a patient that is at risk of tosing function or who has a medical need to maintain muscle may also be a subject for treatment in accordance with the present invention even if their t5 score is 0 or greater.

Sn another embodiment, the patient has a t-score selected from (a) <-3, (b) <-2.5, (c) s-2, (d) £-1.5, (e) sS-1.0 and (f) <-0.5.

The age or age range of the patient can vary depending on their susceptibility to SO sarcopenia. Examples of ages and age ranges include (a) 40-45, (b) 45-50, (c) 5055. (d) 55-60, (e) 60-65, (f) 65-70, (g) 70-75, (h) 75-80, (i) 80-85, (j) 85-90 or older.

In another embodiment, the age ofthe patient is selected from at Seast (a) 40, (b) 50, (c) 60, (e) 65 and (f) 70.

Sn another embodiment, the present invention provides a novel method of maintaining and/or increasing muscle mass to treat sarcopenia, comprising; administering to a patient irr need thereof a therapeutically effective amount of a pharmaceutical composition, comprising thalidomide, or an analogue of thalidomide and a pharmaceutically acceptable carrier.

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 histolegic/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 -5ΙΕί 3 Ο Ο 7 8 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 I PF and can occur in a wide variety of other pulmonary disorders.

Thalidomide (N-a-phthalimidogiutarimide) 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 Ieprosum (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-σ) 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- α 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 muscle mass in a subject. The invention also discloses compositions and methods for the prevention and/or treatment of sarcopenia. In some embodiments, the disclosed thairdomide analogues are sulfur-analogues of thalidomide, its open-ring metabolites and its derivatives (such as its hydroxy lated derivatives) in which one or more carbonyl groups are repfaced by thiocarbonyl groups. For example, in some embodiments, thalidomide analogues wherein at least one carbonyl group on the pthaioyl moiety or on the gfutaramide moiety (or its open ring form) of a thalidomide or a thalidomide analogue is replaced by a thiocarbonyl group. -6IE1 3 0 0 7B A study carried out to perform a comparison study to determine if Thalidomide is equally effective as MM P-9 gene deletion in delaying cardiac sarcopenia, Twenty mice were administered 100mg/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 rs 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.

Still further, a method for preventing and/or treating sarcopenia in a subject is disclosed. The method includes administering to the subject a therapeutically effective amount of one or more of any of the disclosed compounds Examples of compounds useful for the method are shown below Additionally, the disclosed compounds can be combined with pharmaceutically acceptable excipients, and optionally sustained-re lease 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 oomprise instructions for administering the composition to a subject to prevent and/or treat sarcopenia.

IE 1 3 Ο Ο 7 3 -7The 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, pa rente rally, re eta I iy, nasally, buccally, vagina ily, topically, optically, by inhalation spray, or via an implanted reservoir.

The term ‘pare ntera Ily' as used herein Includes, but is not limited to subcutaneous, intravenous, intramuscular, intrastern al, intrasynovial, intrathecal, intrahepatlc, intrales ional 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 suifate, dlsodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycot, sodium carboxymethylcellulose, poly acrylates, waxes, poiyethylenepoly oxy propylene-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 nonsulfurcontaining 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 alf 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, additionai bonds to hydrogen atoms are implied. Further substitution of such implied hydrogen atoms is possible. -8J Ο Ο 7 3 In other embodiments, the disclosed compounds include compounds having the chemical formula: wherein X and Y are independently CHa, oxygen or sulfur, and at least one of X and Y is sulfur if Rt does not include a sulfur atom; each of R2-R5 are independently hydrogen, hydroxyl, acyi, substituted acyl, acyioxy, substituted acyioxy, alkyl, substituted aikyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyf, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, haiogen, nitro or linked to form a five- or six-membered, unsubstituted or substituted, aliphatic, aromatic or heterocyclic ring, for example, hydrogen, lower alkyl, acyioxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyioxy or hydroxyl; and Ri is an unsubstituted or substituted, aliphatic or aromatic heterocyclic ring, an unsubstituted or substituted cycioalkenyl ring, or wherein W and Z are each independently oxygen or sulfur, R0 and R7 are each 30 independently hydroxyi, alkoxy or substituted alkoxy, and each of R^-R1;: are independently hydrogen, hydroxyl, acyl, substituted acyl, acyioxy, substituted acyioxy, 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 alkyt, acyioxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyioxy or hydroxyl. -9in particular embodiments, Rd is /Εί 30 o 78 Rid R,i K Rid wherein W and Z are each independently oxygen or suffer, R13 and R|4 are each independently hydrogen, aikyl or substituted alkyl; is hydrogen, hydroxy!, alkyl or substituted alkyl such as aryl substituted aikyl; and R16-R19 are each independently hydrogen, hydroxyl, acyl, substituted acyf, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aikynyl, 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 hydroxy! in some embodiments, at least one of Ra, R3, R4, R6i R3, Rg, Ri0, R- Rir„ R16, R17, R,a and R,9 is hydroxyl in other embodiments, at least one cf 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=O, W=C>, Z=O; X=O, Y=S, W=O, ZO; X“O, Y=O, - 10« ί 3 ο 0 7 δ Χ-Ο 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 5 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-R^ 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 rf 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=O, W~O, Z=O; X=O, Y=$, W=O, Z=O; X=O, Y=O, W-S, Z=O; X=O, Y=O, W=O, Z=S; X=S, Y-S, W=O, Z=O; X=S, Y=O, W=8, Z=O; X-S, Y=O, W=O, Z=S; X=O, Y=O, W=S, Z=S; X=O, Y=S, WO, Z=S; X=O, Y=S, W=S, Z=O; X“S, Y=S, W=S, Z=O; X=8, Y=S, W=O, Z-S, X=S, Y-O, W=S, Z=S X=O, Y-S, W=S, Z-S; orX=Q, Y -S, W=S, Z=S.

In more particular embodiments, at ieast one of RrRs and Re-R,i is hydroxyl. Specific examples of such compounds include: and - 11 fcl 30 0 78 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 suifur; 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=Or W=O, Z=O; X=Or Y=S, W-O, Z=O; X=O, Y=O, W=S, Z=O; X=O, Y=O, W-O, Z=S; X=S, Y=S, W~O, Z=O; X=S, Y=O, W=S, Z=O; X=S, Y=O, W=O, Z=S; X=O, Y=O, W“S, Z~S; X=O, Y=s, W^O, Z=S; X=O, Y=S, W=S, Z=O X=S, Y=S, W=S, Z=Q; X=S, Y^S, W=O, Z=S; X=S, Y=O, W-S, Z-S; X=O, 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 RiS-Ria is hydroxyl Specific examples of such compounds include: and O HO 12The disclosed compounds also include compounds having the formula: wherein T and V are independently oxygen or sulfur, R-rR-s are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyi, substituted alkyl, alkenyl, substituted alkenyl, aikynyl, substituted aikynyl, 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 IEl 3ο ο 78 wherein W, Z and Ri3-R2O 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 -O, V=0, W=0, Z=0; T -S, V=O, W=O, 2=0; T =O, V=S, W=0, Z=O; T -O, V=0, W=S, Z=0; T =0, V=O, W=0, Z=S; T -Q, V“S, W=0, Z=0, T =S, V=O, W=S, Z=O; T =S, V=0, W=O, Z=S, T =O, V=O, W=S, Z=S; T -0, V-S, W=o, Z-S, T-O, V=S, W-S, Z-0 T=S, V-S, W=S, Z-0; T -S, V-S, KJ W=O, Z=S; T =S, V=O W-S, Z=S; Τ -O. V=S, W=S, Z=S; orT =S, V-S. W=S, Z=S. in some embodiments, at least one of R15-Rfg and R22-R2B 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; R2?-R33 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyioxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aikynyl, substituted aikynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyioxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and 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 sutfur 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=O, Y=O, W=0, ZO; X-S, Y=O, W=0, Z=O; X=O, Y=S, - 14IE 1 3 Ο Ο 7 3 W-O, Ζ=; Χ=Ο, Υ^Ο, W~S, Ζ=Ο; Χ=Ο, Υ=Ο, W=O, Z=S; X=S, Y=S, W=O, Z=O; X=S, Y=O, W=S, Z=O; X=S, Y=O, W=O, Z“S; XO, Y=O, W-S, Z-S; X=O, Y=S, W-O, Z=S; X=O, Y-S, W-S, Z=O, X=S, Y=S, W=S, Z=O; X=Q, Y=S, W=O, Z-S; X=S, Y=O, W=S, Z=S; X=O, Y=S, W=S, Z^S; orX^S, Y^S, W-S, Z-S. tn addition, the disclosed compounds include compounds having the formula; wherein X and Yare each independently oxygen or suifur; W, Z, R15-R20 and Ra4 are as before, R35 is alkyi or substituted alkyl, and R3e-R39 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyi, 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 suifur 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=Or Y=O, W-O, Z=O; X=S, Y=O, W=O, Z=O, X=O, Y=S, W=O, ZO; X=O, Y=O, W=S, Z=O; X=O, Y=O, W-O, Z-S; X=S, Y=S, W=O, Z=O; X-S, Y=O, W=S. Z=O; X=S, Y=o, W-O, Z=S; X=O, Y=O, W=S, Z-S; X=O, Y=S, W=O, Z=S; X=O, Y=S, W-S, Z=O; X=S, Y=S, W=S, Z=O; X=S, Y=S, W=O, Z=8; X-S, Y=O, W=S, Z-S; X=O, Y=Q, W=S, Z-S; or X=S, Y=S, W=S, Z=S. - 15ΙΕ ί 30 0 78 Other embodiments include compounds having the formula: wherein X artd Y each are independently oxygen or sulfur; W, Z and Rt5-R20 are as before; and R^-R^ are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyioxy, substituted acyioxy, alkyl, substituted aikyl, aikenyi, substituted alkenyl, alkynyl, substituted alkynyl, aikoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyioxy, haiogen, hydroxyl, amino or nitro such as hydrogen, acyioxy 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=O, Y=O, W=O, Z-O; X=S, Y=O, W=O, Z=O; X=O, Y=S, W-O, 2=0; X=O, Y=O, W=S, Z=O; X=O, Y=O, W=O, Z=S; X=S, Y=S, W=O, Z=O; X=Q, Y=O, W=S, Z=O; X=S, Y=O, W=O, Z=S, X=O, Y=O, W=S, Z=S; X=O, Y=S, W=O, Z=S, X=O, Y=S, W=S, Z-0 X=S, Y=S, W=S, Z=O; X=Q, Y=S, W-O, Z=S; X=S, Y-O, W=S, Z=S; X=O, Y=S, W=S, Z=S; or X=S, Y=S, W=S, Z=S.

The disclosed compounds further include compounds having the formula: Ri3 - 16ί£ ? X λ η / wherein X Υ, W and Ζ are independently oxygen or sulfur, and R2-R5 and R-ryRw are as before. Forexampie, 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 suifur 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-O, Y=O, W=O, Z=O; X=S, Y=O, W=O, Z=O; X-O, Y=S, W=O, Z=O; X=Or Y=O, W=S, Z=O: X-O, Y=O, W=O, Z=S; X=S, Y=S, W=O, Z=O: X=S, YO, W=Sf Z=O; X-S, Y=O, W=O, Z=S, X=O, Y=O, W=S, Z=S; X=o, Y=S, W=O, Z-S, X=Or Y=s, W=S, Z=O; X=S, Y-S, W-S, Z=O; X=S, Y=S, W=O, Z=S; X=S, Y=O, W=S, Z=S; i 0 X=O, 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-R$, R1&-R2D and Ra^ 25 are as before. For example, in more particular embodiments, X or Y is suifur, 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=O, Y-O Z=O; X=S, Y=O, Z-O; X=O, Y=S, Z-0 X=O, Y=Or Z=S; X=S, Y=S, Z=O; X=S, Y-O, Z-S; X=O, Y-S, Z=S; orX=S, Y=S, Z=S.

Also disclosed is a thalidomide analogue compound having the formula: N— ft 1 - 17IE J 30 0 78 wherein X and Y are independently oxygen or sulfur, and R1k R2, R4 and R5 are as 5 before. For exampie, in particular embodiments, Rd is His Rl8 wherein W, Z, and R13-R2fl 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 suifur and both W and Z are sulfur if present. Alternatively, where W and Z are present the following are possible; X=O Y=O W=O, Z=O; X=S, Y=O, W=O, Z=Q; X=O, y=s, W^O, Z=O; X=O, Y=O, W=S, Z=O; X=O, Y=O, W=O, Z=S; X=S, Y=S, W=O, Z=O; X=S, Y=O, W^S, Z=O; X=S, Y=O, W=O, Z=S; X=O, Y=O, W=S, Z=S; X=O, Y=S, W=O, Z=S; X=O, Y=S, W=S, Z=O; X=S, Y=S, W=S, Z=O; X=S, Y=S, W-O, Z=S; X=S, Y=O, W=s, Z=S; X=O, Y~S, W=S, Z=S; or X=S, Y=S, W=S, Z=S. In more particular embodiments, the compound has the formula: -18ΪΕί 30 Ο 78 wherein X, Y are independently oxygen or sulfur, and W, Z, R2, R4, Rs, and R^-R^ 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-O, Y=O, W=O, Z=O; X=S, Y=O, W=O, Z-O; X=O, Y=S, W=O, Z^O; X=O, Y=O, W=S, Z=O; X=O, Y-O, W=O, Z=S; X=S, Y=S, W=O, Z=O; X-S, Y=O, W=S, Z-O; X=S, Y=O, W=O, Z=S; X=O, Y=O, W=S, Z=S; X=O, Y=S, W=O, Z=S; X=O, Y=S, W=S, Z=O; X-S, Y=S, W-S, ZO; X=S, Y=S, W=O, Z=S; X-S, Y=O, W=S, Z=Q; X=O, 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, Ris and RiB is hydroxyl.

Also disclosed is a compound having the formuia: wherein G and D are each independently oxygen or sulfur, R2-R5 are as before, and R4fi iS E-U 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 -19IEl 3 Ο Ο 78 Ζ 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=O, D=O, W=Q, Z=O; G=S, D=O, W=O, Z-0 G=O, D=S, W-O, Z=O, G=O, D-O, W=S, Z=O; G=O, D=Q, W=O, Z=S; G-S, D=S, W“O, Z-0 G=S, D-O, W=Q, Z=O; G^S, D=O, W=O, Z=S; G=O, D=O, W=S, Z=S; G=O, D“S, W=O, Z=S; G=O, D=S, W=S, Z=O; G=S, D=S, W=S, Z=O; G=S, D-S, W=O, Z=S; G=Sr D-O, W=S, Z=S; GO, D=S, W-S, Z=S; or G=3, D=S, W=S, Z=S.

A method for preventing and/or treating sarcopenia in a subject is also disclosed. The 1(1 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, R16 -R-x, are as before; and Re7-R52 are each independently hydrogen, hydroxyl, acyl, substituted acyl, aeyloxy, substituted aeyloxy, 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, aeyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, aeyloxy or hydroxyl; or a compound having the formula: R2 Rs E-19 Ris Rs -20IEl 3 0 0 7 8 wherein η=1-6; X is oxygen or sulfur, and R2-R5 and Rt5 -Rw are as before; or a compound having the formula: wherein each of X and Y are independently oxygen or suifur, n=1 -5, and R-Rs are as before; or a compound having the formula: wherein R6S and Rg4 are independently hydrogen, hydroxyl, acyl, substituted acyl, 30 acyloxy, substituted acyloxy, alky], substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted aikoxy, 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 alky!; or a compound having the formula: -21 IEt 30 Ο 78 wherein R2-R5 are as before and is hydrogen, alkyl or substituted alkyt; or pharmaceuticaliy acceptable saits 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=O, Y=O, W=O, Z=O; X=S, Y=Q, W=O, Z=O; X=O, Y=S, W=O, Z=O; X-O, Y=O, W=S, Z=O; X=O, Y=O, W-O, 2=S; X-S, Y=S, W=O, Z=O; X=S, Y=O, W=S, Z=O; X=S, Y=O, W=O, Z=S; X=O, Y=O, W=S, Z=S; X=O, Y=S, WO, Z=S XO, YO, W=S ZO: X=S, Y=S, W=S, ZO; X=S, Y=S, WO, Z=S; X=S, YO, W=S, Z=S; XO, 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: -22IEl 3 0 0 78 -23iE ί 2 ο β 7 a -24IE ΐ 3 0 0 7 8

Claims (13)

Claims

1. A method of maintaining or increasing muscle mass to treat sarcopenia, comprising: administering to a patient in need thereof a therapeutically effective amount of thalidomide or an analogue of thalidomide.

2. The method of claim 1, wherein the patient has a t-score selected from (a) £-3, (b) £-2.5, (c) £-2, (d) £-1.5, (e) £-1.0 and (f) £-0.5

3. The method of claim 1, wherein the age of the patient is selected from at least (a) 10 40, (b) 50, (c) 55, (d) 60, (e) 65 and (f) 70

4. The method of claiml, wherein the age range of the patient is selected from (a) 40-50, (b) 50-60 and (c) 60-70 15

5. The method of claim 1, wherein the patient s t-score is increased after at least one year of treatment.

6. The method of claim 1, wherein the patient’s t-score is unchanged after at least one year of treatment.

7. The method of ciaim 1, wherein the patient has suffered some loss of muscle mass, but does not suffer from a condition that interferes with acts of daily living and/or prevents the subject from living an independent life. 25

8 The method of claim 1, wherein the patient is considered vulnerable to developing sarcopenia.

9. The method of claim 8, wherein the patient falls into at least one of the following categories (a) uses glucocorticoid steroids, (b) has a chronic infection, (c) has a 30 chronic inflammatory condition and (d) has cancer.

10. A method of maintaining or increasing muscle mass to treat sarcopenia, comprising, administering to a patient in need thereof, a therapeutically effective amount of a pharmaceutical composition, comprising: thalidomide, or an analogue of 35 tha lid om i de and a pha rmaceuticali y a ccepta ble ca rrier. -26IEI 3 0 0 7 8

11. The method of daim 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

5. Subcutaneous fat in a subject; increased athletic performance; attenuation or re versa! of protein cataboiic 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. to

12. 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 of muscle cells in wasting disease and regenerative in aging conditions where deficiency of stem cell factor has been confirmed as a contributing to a 15 disease state such as Alzheimer's and other neurodegenerative conditions.

13. 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.