Methods of treating aging related skin changes and of increasing skin thickness with topical administration of N-acyldipeptide derivatives are described. Compositions comprising N-acyldipeptide derivatives, are therapeutically effective for increasing skin thickness, and for treating extrinsic and intrinsic aging and aging related skin changes, such as fine lines, wrinkles, photoaging, hyperpigmentation, laxity, age spots, lentigines, mottled skin, and cellulite.

Methods of treating aging related skin changes and of increasing skin thickness with topical administration of N-acyldipeptide derivatives and retinol are described. Combinations of retinol and N-acyldipeptide derivatives, are therapeutically effective for increasing skin thickness, and for treating extrinsic and intrinsic aging and aging related skin changes, such as fine lines, wrinkles, photoaging, hyperpigmentation, laxity, age spots, lentigines, mottled skin, and cellulite.

A peptide selected from the group consisting of Ala-Hyp-Gly, Hyp-Gly-Pro, Leu-Hyp, Glu-Hyp, Gly-Pro-Hyp, Pro-Ala, Hyp-Gly and Pro-Hyp, or a pharmaceutically acceptable salt thereof has a myoblast differentiation promoting effect superior to conventional arts.

The present invention concerns a compound of following formula (1): where: R.sub.1 is H or OH, R.sub.2 is a (C.sub.1-C.sub.6)alkyl, COOH, COO((C.sub.1-C.sub.6)alkyl) or thiazolyl group, R.sub.3 is H or a (C.sub.1-C.sub.6)alkyl group, and R.sub.4 is: .square-solid.a straight-chain or branched, saturated or unsaturated hydrocarbon group having 1 to 8 carbon atoms substituted by one or more groups chosen from among OH and NR.sub.5R.sub.6, .square-solid.(CH.sub.2CH.sub.2X.sub.1)(CH.sub.2CH.sub.2X.sub.2).sub.a2(CH.sub.2CH.sub.2X.sub.3).sub.a3(CH.sub.2CH.sub.2X.sub.4).sub.a4(CH.sub.2CH.sub.2X.sub.5).sub.a5R.sub.7, .square-solid.an aryl-(C.sub.1-C.sub.8)alkyl group substituted by one N or more groups chosen from among OH and NR.sub.9R.sub.10 groups, or .square-solid.a heterocycle-(C.sub.1-C.sub.8)alkyl group optionally substituted by one or C more groups chosen from among (C.sub.1-C.sub.6)alkyl, OH and NR.sub.12R.sub.13 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.

##STR00001##

The present disclosure discloses a liquid-phase synthesis method of oxytocin under mild conditions for the first time, which is characterized in that three oxytocin fragments which include Boc-Cys(Acm)-Tyr(tBu)-OH, H-Ile-Gln(Trt)-Asn(Trt)-Cys(Acm)-Pro-OMe and H-Leu-Gly-NH.sub.2 are synthesized for the first time, the fragments are assembled to synthesize an all-protected oxytocin amino acid sequence, iodine is used to remove Acm while cyclization is performed to form a disulfide bond to obtain protected cyclic oxytocin, trifluoroacetic acid is used to remove residual protecting groups to obtain crude oxytocin, ethyl acetate is used to perform recrystallization, and reversed-phase chromatography purification is performed to reach high-purity (crude product purity reaches 95%) and high biological value of oxytocin (588 IU/mg). In the present invention, a Boc-polypeptide synthesis and Fmoc-polypeptide synthesis combined method is provided, wherein, all the reactions are carried out under mild conditions without using the ammonia-sodium-method decapping reaction which is reported by literature referring to oxytocin liquid-phase synthesis domestically and abroad. Furthermore, the liquid-phase synthesis method of oxytocin is first performed without highly toxic reagents and unsafe reaction conditions, thus greatly reducing the cost of oxytocin synthesis and providing access to industrial production of oxytocin.

The proteasome inhibitors of this invention include peptide-based compounds with a short linear sequence of amino acids. An oxo or thio group is attached to the N-terminal amino acid. A protein-reactive electrophilic group such as an epoxyketone, an aziridinylketone, or a beta-lactone is attached to the C-terminal amino acid. Upon contact with a proteasome complex in a target cell, the electrophilic group reacts with a functional group in or near a binding pocket or active site of the proteasome, forming a covalent bond and thereby inactivating the proteasome. These and other proteasome inhibitors can be screened for binding affinity and an ability to selectively eliminate senescent cells or cancer cells. Compounds that selectively remove senescent cells can be developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

The proteasome inhibitors of this invention include peptide-based compounds with a short linear sequence of amino acids. An oxo or thio group is attached to the N-terminal amino acid. A protein-reactive electrophilic group such as an epoxyketone, an aziridinylketone, or a beta-lactone is attached to the C-terminal amino acid. Upon contact with a proteasome complex in a target cell, the electrophilic group reacts with a functional group in or near a binding pocket or active site of the proteasome, forming a covalent bond and thereby inactivating the proteasome. These and other proteasome inhibitors can be screened for binding affinity and an ability to selectively eliminate senescent cells or cancer cells. Compounds that selectively remove senescent cells can be developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

In some embodiments, the present disclosure provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions comprising the compound of Formula (I) or Formula (II), and methods of treating cancer using the compound of Formula (I) or Formula (II) are also provided.

##STR00001##

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

The present disclosure relates to Quinstatin compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.