Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
  • C07C57/32—Phenylacetic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
  • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
  • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings

Definitions

• the present invention relates to the field of medicine. Particular aspects of the invention relates to compounds, pharmaceutical compositions and uses thereof for the tissue self-repair and/or the tissue regeneration of an injured organ, for stimulating the generation of tissue growth, and/or for modulating the expression of tissue self-repair markers and/or tissue regeneration markers such as metalloproteinases and growth factors.
• Tissue regeneration involves known markers such as metalloproteinases and growth factors, including without limitation HGF (hepatocyte growth factor), LOX (lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1 (AAT), Serpin E1 (PAI- 1 ), TIMP3, ILK (integrin-linked kinase).
• HGF hepatocyte growth factor
• LOX lysyl oxidase
• MMP1 hepatocyte growth factor
• MMP2 lysyl oxidase
• MMP13 MMP1 , MMP2, MMP9, MMP13
• PLAT tPA
• PLAU uPA
• Serpin A1 AAT
• Serpin E1 PAI- 1
• TIMP3 integrated kinase
• HGF Hepatocyte Growth factor
• HGF has an anti-inflammatory action and attenuated cellular senescence.
• HGF gene therapy or compound increasing HGF expression and secretion might be an anti-aging therapy in cardiovascular diseases (Nakagami, Morishita, 2009).
• HGF is also known to accelerate would healing (Li ei a/., BioMed Research International, Volume 2013 (2013), Article ID 470418.
• Regeneration enzymes are also very important in repair and regeneration of injured organs.
• a recent publication (abstract presented at Plastic surgery meeting 2014 by Radtke et al. entitled Single treatment With Alpha-1 antitrypsin Enhances Nerve Regeneration After Peripheral Nerve Injury) has demonstrated that AAT improves peripheral nerve regeneration.
• the application of AAT into an acute axotomy model led to the significantly improved axonal regeneration and re-myelination than compared control animals.
• not only histological, but also functional improvement was observed following direct injection of AAT after acute peripheral nerve lesion. Their results indicate that AAT delivered into injured peripheral nerve participate in neural repair.
• Cutaneous aging is a complex phenomenon responsible for progressive changes of the skin. Aging of the skin results from two processes: (1 ) an intrinsic process, corresponding to chronological aging, and (2) an extrinsic process resulting mainly from the deleterious effect of exposure environmental stresses. Genetic, UV exposure, climatic factors (harshness/wind/cold/warm), pollution (chemical, free radicals, contaminant, nitrogen oxide, metals), alcohol consumption or smoking are factors involved in cutaneous aging.
• Exposure to irritants compromises the barrier function of the stratum corneum and decreases its ability to protect the skin against environmental stresses (e.g., ultraviolet irradiation, infections agents, etc.).
• environmental stresses e.g., ultraviolet irradiation, infections agents, etc.
• Repeated and prolonged exposition to environmental irritants results in denatured skin proteins, disorganization of the lipid lamellae layers, removal of the protective intercellular lipids, loss of natural moisturizing factors and decreased cohesion between cells. These damages are also responsible for the loss of function of the enzymes responsible for desquamation of corneocytes.
• An irritant is any agent that is capable of producing cell damage if there exposure for sufficient time and in sufficient concentrations.
• the severity of the damage is dependent of the type and intensity of exposure to these irritating factors.
• Novel compounds and medicaments are needed to stimulate the tissue self-repair and the tissue regeneration in injured organ.
• tissue self-repair and/or the tissue regeneration of an injured organ and/or for modulating the expression of tissue self-repair markers and/or tissue regeneration markers such as metalloproteinases and growth factors, including without limitation HGF, LOX (Lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1 (AAT), Serpin E1 (PAI-1 ), TIMP3, and ILK (integrin-linked kinase).
• tissue self-repair markers and/or tissue regeneration markers such as metalloproteinases and growth factors, including without limitation HGF, LOX (Lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1 (AAT), Serpin E1 (PAI-1 ), TIMP3, and ILK (integrin-linked kinase).
• a method for tissue self-repair or tissue regeneration of an organ in a subject in need thereof comprising the step of administering to a subject in need thereof a compound represented by Formula I or a pharmaceutically acceptable salt thereof :
• the invention relates to a method for tissue self-repair or tissue regeneration of an organ in a subject in need thereof, comprising administering a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein to said subject.
• the invention relates to a method for tissue self- repair of an organ in a subject in need thereof, comprising administering a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein to said subject.
• the invention relates to a method for tissue remodelling of an organ in a subject in need thereof, comprising administering a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein to said subject.
• the invention relates to a method for tissue regeneration of an organ in a subject in need thereof, comprising administering a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein to said subject.
• the invention relates to a method for stimulating the generation of tissue growth, with a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein.
• the invention relates to a method for stimulating the expression of tissue self-repair markers and/or tissue regeneration markers, with a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein.
• said markers includes without limitation metalloproteinases, growth factors, hepatocyte growth factor (HGF), LOX (Lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1 (AAT), Serpin E1 (PAI-1 ), TIMP3, and ILK (integrin-linked kinase).
• the invention relates to a method for increasing HGF level in an organ, comprising the step of administering to said organ, a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein.
• the organ includes without limitation kidney, heart, liver, lung, skin, stomach, intestine, muscle and cartilage.
• the invention relates to a method for increasing AAT level in an organ, comprising the step of administering to said organ, a compound represented by Formula I or a pharmaceutically acceptable salt thereof as defined herein.
• FIG. 1 is an illustration of the effect of Compound I on the increase of mRNA expression of Hepatocyte Growth Factor (HGF), a growth factor involved in tissue self-repair and regeneration.
• HGF Hepatocyte Growth Factor
• Figure 2 is an illustration of the effect of Compound I on the modulation of regeneration markers expressed in injured fibroblast (NHDF) involved in self-repair and regeneration of tissue.
• NHDF injured fibroblast
• Figure 3 is an illustration of the effect of Compound I on the modulation of regeneration markers expressed in injured epithelial cells (HK-2) involved in self-repair and regeneration of tissue.
• Figure 4 demonstrates that Compound I can increase mRNA expression of Serpin A1 (AAT) involved in nerve generation.
• Figure 5 is a representation of the increase in organ function (GFR) observed with Compound I and indicating tissue regeneration of an injured kidney.
• the present discloses compounds of Formula I, pharmaceutically acceptable salts thereof, compositions comprising same and uses thereof.
• Various embodiments of the present invention include:
• the invention concerns the pharmaceutical compounds represented by Formula I, or pharmaceutically acceptable salts thereof:
• A is C 5 alkyl, C 6 alkyl, C 5 alkenyl, C 6 alkenyl, C(0)-(CH 2 )n-CH 3 or CH(OH)-(CH 2 )n-CH 3 wherein n is 3 or 4; or is C 5 alkyl, C 5 alkenyl, C(0)-(CH 2 ) n -CH 3 or CH(OH)-(CH 2 )n-CH 3 wherein n is 3; or is C 6 alkyl, C 6 alkenyl, C(0)-(CH 2 ) n -CH 3 or CH(OH)-(CH 2 ) n -CH 3 wherein n is 4;
• Ri is H, F or OH; or is H or OH;
• R 2 is H, F, OH, C 5 alkyl, C 6 alkyl, C 5 alkenyl, C 6 alkenyl, C(0)-(CH 2 ) n -CH 3 or CH(OH)-(CH 2 ) n - CH 3 wherein n is 3 or 4; or is C 5 alkyl, C 5 alkenyl, C(0)-(CH 2 ) n -CH 3 or CH(OH)-(CH 2 ) n -CH 3 wherein n is 3; or is C 6 alkyl, C 6 alkenyl, C(0)-(CH 2 ) n -CH 3 or CH(OH)-(CH 2 )n-CH 3 wherein n is 4
• R 3 is H, F, OH or CH 2 Ph; or is H, F or OH; or is H or OH; R 4 is H, F or OH; or is H or OH; Q is
• A is C 5 alkyl or Ce alkyl.
• C 5 alkyl is a straight chain C 5 alkyl.
• Ri is H or OH.
• R 2 is H, F, OH, Cs alkyl or C6 alkyl.
• R 3 is H or OH.
• R4 is H or OH.
• Q is:
• Q is (CH2) m C(0)OH where m is 1 or 2.
• the compound is of Formula I, wherein A is Cs alkyl or C 6 alkyl; Ri is H, F or OH; R 2 is H, F, OH, C 5 alkyl or C 6 alkyl; R 3 is H, OH or CH 2 Ph; R 4 is H, F or OH; and Q is (CH 2 ) m C(0)OH where m is 1 or 2.
• the compound is of Formula I; wherein A is Cs alkyl; Ri is H; R 2 is H or C 5 alkyl; R 3 is H; R 4 is H; and Q is (CH 2 ) m C(0)OH where m is 1.
• alkyl is intended to include a straight chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms in a linear arrangement, and a branched chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms in a non-linear arrangement, or a cyclic chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms in a cyclic arrangement.
• alkenyl is intended to mean unsaturated straight chain hydrocarbon groups having the specified number of carbon atoms therein, and in which at least two of the carbon atoms are bonded to each other by a double bond, and having either E or Z regiochemistry and combinations thereof.
• Examples of compounds of Formula I include, but are not limited to, Compounds I to XXXIII and acid form thereof listed in Table 1 hereinbelow.
• the term "pharmaceutically acceptable salt” is intended to mean base addition salts.
• Example of pharmaceutically acceptable salts are also described, for example, in Berge er a/., "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977).
• Pharmaceutically acceptable salts may be synthesized from the parent agent that contains an acidic moiety, by conventional chemical methods. Generally, such salts are prepared by reacting the free acid forms of these agents with a stoichiometric amount of the appropriate base in water or in an organic solvent, or in a mixture of the two. Salts may be prepared in situ, during the final isolation or purification of the agent or by separately reacting a purified compound of the invention in its free acid form with the desired corresponding base, and isolating the salt thus formed.
• the pharmaceutically acceptable salt of the compounds of Formula I may be selected from the group consisting of base addition salts of sodium, potassium, calcium, magnesium, lithium, ammonium, manganese, zinc, iron, or copper.
• the pharmaceutically acceptable salt of the compounds according to the invention may be the sodium, potassium, calcium, magnesium or lithium salt. More preferably the pharmaceutically acceptable salt is sodium.
• the compounds of Formula I disclosed herein may be in any form, including any acid, salt or other ionic and non-ionic forms.
• any acid for example, if a compound is shown as an acid herein, the salt forms of the compound are also included. Likewise, if a compound is shown as a salt and the acid forms are also included.
• the compounds of Formula I disclosed herein, wherein said compounds are present in the free carboxylic acid form may also include all pharmaceutically acceptable salts, isosteric equivalents such as tetrazole and prodrug forms thereof.
• examples of the latter include the pharmaceutically acceptable esters or amides obtained upon reaction of alcohols or amines, including amino acids, with the free acids defined by Formula I.
• the compounds of Formula I disclosed herein, their pharmaceutically acceptable salts, or prodrugs thereof, may contain one or more asymmetric centers, chiral axes and chiral planes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms and may be defined in terms of absolute stereochemistry, such as (R)- or (S)-.
• the present invention is intended to include all such possible isomers, as well as, their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.
• the racemic mixtures may be prepared and thereafter separated into individual optical isomers or these optical isomers may be prepared by chiral synthesis.
• the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may then be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of one enantiomer with an enantiomer specific reagent. It will also be appreciated by those skilled in the art that where the desired enantiomer is converted into another chemical entity by a separation technique, an additional step is then required to form the desired enantiomeric form.
• the compounds of Formula I or pharmaceutically acceptable salts thereof disclosed herein may also exist in hydrated and anhydrous forms.
• the present invention includes the use of hydrates of any of the compounds of Formula I or pharmaceutically acceptable salts thereof described herein, which may exist as a monohydrate or in the form of a polyhydrate.
• the Compounds of Formula I or pharmaceutically acceptable salts thereof (or a composition comprising same) disclosed herein are useful: in the tissue self-repair and/or the tissue regeneration of an injured organ, tissue or cell, in stimulating the generation of new cells in an in vitro cell culture, and/or in modulating the expression of tissue self-repair markers and/or tissue regeneration markers such as metalloproteinases and growth factors.
• the Compounds of Formula I or pharmaceutically acceptable salts thereof disclosed herein are useful for an anti-aging treatment.
• the treatment preferably comprises the administration of a Compound of Formula I or pharmaceutically acceptable salts thereof disclosed herein or a combination thereof, or a pharmaceutical composition comprising a therapeutically effective amount one or more of the compounds of Formula I or pharmaceutically acceptable salts thereof disclosed herein.
• tissue self-repair and “tissue regeneration” used herein may also refer to processes involved in an anti-aging treatment.
• Representative Compounds according to Formula I disclosed herein have been found to stimulate the expression of known markers associated with anti- aging, tissue regeneration and tissue self-repair, and to stimulate the generation of new cells.
• the injured organ, tissue or cell is not an organ, tissue or cell injured by an inflammatory-related disease. In an embodiment, the injured organ, tissue or cell is not an organ, tissue or cell injured by a cancer.
• the organ, tissue or cell injury results from a physical injury (i.e. following an acute exposure to an external agent or stress that results in some form of damage/injury to the organ, tissue or cell), for example an organ, tissue or cell injured by a physical trauma/insult (e.g., cut, bite, shock, tear, puncture, perforation, burn (heat or chemical), freezing, radiations, electrocution, physical overexertion), or a surgery.
• a physical trauma/insult e.g., cut, bite, shock, tear, puncture, perforation, burn (heat or chemical), freezing, radiations, electrocution, physical overexertion
• Physical injury as used herein excludes organ, tissue or cell damages resulting from (i.e.
• an underlying disease for example inflammatory or autoimmune diseases such as inflammatory bowel diseases, glomerulonephritis, vasculitis, psoriatic arthritis, systemic lupus erythematoses (SLE), idiopathic thrombocytopenic purpura (ITP), psoriasis, Crohn's disease, inflammatory bowel disease, ankylosing spondylitis, Sjogren's syndrome, Still's disease (macrophage activation syndrome), uveitis, scleroderma, myositis, Reiter's syndrome, and Wegener's syndrome.
• inflammatory or autoimmune diseases such as inflammatory bowel diseases, glomerulonephritis, vasculitis, psoriatic arthritis, systemic lupus erythematoses (SLE), idiopathic thrombocytopenic purpura (ITP), psoriasis, Crohn's disease, inflammatory bowel disease, ankylosing
• the Compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein may be used to promote tissue self-repair and/or the tissue regeneration to treat secondary tissue damages/injuries that result from the initial physical injury, for example secondary tissue damages/injuries caused by inflammation that may occur following the initial physical injury.
• the present invention provides a method for treating a physical injury in an organ, tissue or cell (e.g., for promoting self-repair and/or tissue regeneration of the injured organ, tissue or cell), the method comprising contacting the organ, tissue or cell with an effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof (or a composition comprising same) disclosed herein.
• the present invention provides the use of the compound of Formula I or pharmaceutically acceptable salt thereof (or a composition comprising same) disclosed herein for treating a physical injury in an organ, tissue or cell (e.g., for promoting self-repair and/or tissue regeneration of the injured organ, tissue or cell).
• the present invention provides the compound of Formula I or pharmaceutically acceptable salt thereof (or a composition comprising same) disclosed herein for use in treating a physical injury in an organ, tissue or cell (e.g., for promoting self-repair and/or tissue regeneration of the injured organ, tissue or cell).
• the (physically) injured organ, tissue or cell is not a kidney or kidney tissue. In another embodiment, the (physically) injured organ, tissue or cell is not a bone or bone tissue. In an embodiment, the (physically) injured organ, tissue or cell is skin, muscle, tendon, ligament, liver, heart, pancreas, an organ/tissue of the digestive/gastrointestinal tract (e.g., mouth, esophagus, stomach, intestines), gallbladder, liver, an organ of the respiratory tract (e.g., lung), spinal cord, spleen, breast, ocular tissue, a blood vessel, a periodontal tissue, mucosa (e.g., oral mucosa, nasal mucosa) and/or cartilage.
• an organ/tissue of the digestive/gastrointestinal tract e.g., mouth, esophagus, stomach, intestines
• gallbladder e.g., an organ of the respiratory tract
• a blood vessel e.g., a period
• the compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein are used/administered acutely, i.e. shortly after the injury.
• the compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein are used/administered to promote tissue self-repair and/or the tissue regeneration prior to the development of fibrosis in the injured organ, tissue or cell, e.g. prior to the development of a fibrotic disease.
• the compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein are useful for promoting wound healing.
• the injured organ, tissue or cell is an organ, tissue or cell of the nervous system (e.g., a neural tissue), for example an organ, tissue or cell of the central nervous system or peripheral nervous system.
• the compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein are useful for tissue self-repair and/or tissue regeneration following neural injury, for example spinal cord injury, peripheral nerve injury, or neural injury associated with multiple sclerosis.
• the compounds of Formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein are useful for tissue self-repair and/or tissue regeneration in the skin, for example following a skin cut, puncture, bruise or burn.
• the injured organ, tissue or cell is an organ, tissue or cell of the respiratory system, for example lungs.
• the injured organ, tissue or cell is liver or a liver tissue.
• the injured organ, tissue or cell is bladder or a bladder tissue.
• the injured organ, tissue or cell is an ovary or an ovarian tissue.
• the injured organ, tissue or cell is prostate or a prostate tissue.
• the injured organ, tissue or cell is spleen or a spleen tissue.
• the injured organ, tissue or cell is breast or a breast tissue.
• the injured organ, tissue or cell is a muscle, for example a muscle injured by muscle strain, muscle tear and/or any other type of physical muscle injury.
• the injured organ, tissue or cell is a blood vessel (e.g., an artery).
• a blood vessel e.g., an artery
• the injured organ, tissue or cell is an organ/tissue of the digestive/gastrointestinal tract (e.g., mouth, esophagus, stomach, intestines)
• the digestive/gastrointestinal tract e.g., mouth, esophagus, stomach, intestines
• the methods and used described herein are not for bone remodelling and/or regeneration of Islets of Langerhans.
• the tissue is not a bone.
• the tissue is not a pancreatic tissue.
• the present invention relates to a cosmetic composition comprising a compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein.
• the present invention relates to a skin care composition comprising a compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein.
• the present invention relates to an anti-aging skin care composition comprising a compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein.
• the present invention relates to the above-mentioned compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) for use in anti-aging skin care.
• the above-mentioned compound of formula I or composition comprising same is for use in stimulating skin repair and/or regeneration following skin damage associated with aging.
• the above- mentioned compound or composition is for use in stimulating skin repair and/or regeneration following skin damage or injury.
• the skin damage or injury results from exposure to UV irradiation, e.g. exposure to sun (e.g., sunburns).
• the methods and uses disclosed herein further comprise identifying a subject having an injured organ, tissue or cell and who is in need of a treatment with the above-mentioned compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) for promoting tissue self-repair and/or tissue regeneration in the injured organ, tissue or cell.
• the method may comprise identifying in a sample from a subject, such as an organ, tissue or cell sample, a decreased level of one or more tissue self- repair and/or tissue regeneration markers, such as metalloproteinases and growth factors, including without limitation HGF, LOX (Lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1 (AAT), Serpin E1 (PAI-1 ), TIMP3, and ILK (integrin-linked kinase), and contacting the organ, tissue or cell with an effective amount of the compound of formula I or pharmaceutically acceptable salts thereof (or composition comprising same) disclosed herein.
• tissue self- repair and/or tissue regeneration markers such as metalloproteinases and growth factors, including without limitation HGF, LOX (Lysyl oxidase), MMP1 , MMP2, MMP9, MMP13, PLAT (tPA), PLAU (uPA), Serpin A1
• the term "subject” includes living organisms in need of a treatment as disclosed herein, for example in which an organ is injured.
• the term “subject” includes animals such as mammals or birds.
• the subject is a mammal, including but not limited to human, horse, dog and cat. In some embodiments, the mammal is not a mouse. More preferably, the subject is a human.
• the compounds of Formula I or pharmaceutically acceptable salts thereof described herein are comprised in pharmaceutical compositions comprising a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof.
• the pharmaceutical compositions may be useful: in the tissue self-repair and/or the tissue regeneration of an injured organ, in stimulating the generation of new cells in an in vitro cell culture, and/or in modulating the expression of tissue self-repair markers and/or tissue regeneration markers such as metalloproteinases and growth factors.
• the term "therapeutically effective amount” means the amount of compound that, when administered to a subject for treating or preventing a particular disorder, disease or condition, or for exerting a biological effect (e.g., to stimulate tissue self-repair and/or the tissue regeneration of an injured organ, to stimulate the generation of new cells in an in vitro cell culture, and/or to modulate (increase) the expression of tissue self-repair markers and/or tissue regeneration markers), is sufficient to effect such treatment or prevention of that disorder, disease or condition, or to exert the biological effect.
• a biological effect e.g., to stimulate tissue self-repair and/or the tissue regeneration of an injured organ, to stimulate the generation of new cells in an in vitro cell culture, and/or to modulate (increase) the expression of tissue self-repair markers and/or tissue regeneration markers
• Dosages and therapeutically effective amounts may vary for example, depending upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination, if applicable, the effect which the practitioner desires the compound to have upon the subject, the properties of the compounds (e.g., bioavailability, stability, potency, toxicity, etc.), and the particular disorders) the subject is suffering from.
• the therapeutically effective amount may depend on the subject's blood parameters (e.g., calcium levels, lipid profile, insulin levels, glycemia), the severity of the disease state, organ function, or underlying disease or complications.
• Such appropriate doses may be determined using any available assays including the assays described herein.
• a physician may for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
• the dose to be administered will ultimately be at the discretion of the health care professionnal.
• the dose for the compounds of Formula I or pharmaceutically acceptable salts thereof disclosed herein may be in the range of about 1 to about 50 mg/kg per day in human. In selected embodiments, the range may be between 1 to 30 mg/kg per day in human. In selected embodiments, the range may be between 1 to 20 mg/kg per day in human. In selected embodiments, the range may be between 5 to 18 mg/kg per day in human. In selected embodiments, the range may be between 1 to 18 mg/kg per day in human.
• composition refers to the presence of at least one compound according to Formula I or pharmaceutically acceptable salts thereof as defined herein and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.
• the term "pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent” or “pharmaceutically acceptable excipient” is intended to mean, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, such as a liposome, cyclodextrins, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in subjects, preferably humans.
• the pharmaceutically acceptable vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• compositions include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
• water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glyco
• antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
• Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
• composition of the present invention may include one or more compounds of Formula I as defined herein or pharmaceutically acceptable derivatives, salts, prodrugs, analogues, isomers or enantiomers thereof.
• Formulations of the active compound may be prepared so as to provide a pharmaceutical composition in a form suitable for enteral, mucosal (including oral, sublingual, ophthalmic, nasal, pulmonary and rectal), parenteral (including intramuscular, intradermal, subcutaneous and intravenous) or topical (including ointments, creams, lotions or drops) administration.
• the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well-known in the art of pharmaceutical formulation.
• All methods include the step of bringing together the active pharmaceutical ingredient with liquid carriers or finely divided solid carriers or both as the need dictates.
• the above-described formulations may be adapted so as to provide sustained release of the active pharmaceutical ingredient.
• Sustained release formulations well-known to the art include the use of a bolus injection, continuous infusion, biocompatible polymers or liposomes.
• the above-mentioned compound or composition may be formulated in a topically applicable cosmetic composition (e.g., a topical formulation).
• Non-limitative examples of such topically applicable compositions include skin care cream, cleansing cream, ointment, skin care lotion, skin care gel, skin care foam, sun care composition, sunscreen skin care, makeup removal cream, make-up removal lotion, foundation cream, liquid foundation, bath and shower preparation, deodorant composition, antiperspirant composition, shaving products composition, after-shave gel or lotion, beauty aids composition, depilatory cream, soap composition, hand cleaner composition, cleansing bar, baby care, hair care, shampoo, setting lotion, treatment lotion, hair cream, hair gel, colouring composition, restructuring composition, permanent composition, or any other composition which is adapted for the use in a topical cosmetic regimen.
• Such compositions may further comprise one or more cosmeceutically acceptable vehicles.
• Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil.
• Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
• the oil phase also called the "internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
• the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
• the emulsifier in a cream formulation is generally a non-ionic, anionic, cationic or amphoteric surfactant.
• Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semi liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
• Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type.
• Lotions are preferred formulations for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided.
• Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.
• Solutions are homogeneous mixtures prepared by dissolving one or more chemical substances (solutes) in a liquid such that the molecules of the dissolved substance are dispersed among those of the solvent.
• the solution may contain other cosmeceutically acceptable chemicals to buffer, stabilize or preserve the solute.
• Common examples of solvents used in preparing solutions are ethanol, water, propylene glycol or any other cosmeceutically acceptable vehicles.
• Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably contain an alcohol, and, optionally, oil.
• Organic macromolecules i.e., gelling agents
• gelling agents are crosslinked acrylic acid polymers such as the "carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under CarbopolTM.
• hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol
• cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose
• gums such as tragacanth and xanthan gum; sodium alginate; and gelatin.
• dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.
• Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
• the specific ointment base to be used is one that will provide for a number of desirable characteristics, e.g., emolliency or the like.
• an ointment base should be inert, stable, no irritating, and no sensitizing.
• ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
• Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
• Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum.
• Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.
• Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, see Remington: The Science and Practice of Pharmacy for further information.
• Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.
• the base in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like.
• the pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.
• Formulations may also be prepared with liposomes, micelles, and microspheres.
• Liposomes are microscopic vesicles having a lipid wall comprising a lipid bilayer, and, in the present context, encapsulate one or more components of the anti-aging formulations.
• Liposomal preparations herein include cationic (positively charged), anionic (negatively charged), and neutral preparations.
• Cationic liposomes are readily available.
• N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are available under the tradename LipofectinTM (GIBCO BRL, Grand Island, N.Y.).
• anionic and neutral liposomes are readily available as well, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials.
• Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with DOTMA in appropriate ratios. Methods for making liposomes using these materials are well known in the art.
• Micelles are known in the art as comprised of surfactant molecules arranged so that their polar head groups form an outer spherical shell, while the hydrophobic, hydrocarbon chains are oriented towards the centre of the sphere, forming a core. Micelles form in an aqueous solution containing surfactant at a high enough concentration so that micelles naturally result.
• Surfactants useful for forming micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride, polyoxyl-8 dodecyl ether, polyoxyl-12 dodecyl ether, nonoxynol 10, and nonoxynol 30.
• Microspheres similarly, may be incorporated into the present formulations. Like liposomes and micelles, microspheres essentially encapsulate one or more components of the present formulations. They are generally although not necessarily formed from lipids, preferably charged lipids such as phospholipids. Preparation of lipidic microspheres is well known in the art and described in the pertinent texts and literature.
• the compound(s) of Formula I or pharmaceutically acceptable salts thereof disclosed herein may be packaged as part of a kit, optionally including a container (e.g., packaging, a box, a vial, etc.).
• the kit may be commercially used according to the methods described herein and may include instructions for use in a method disclosed herein.
• Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
• the additional kit components are present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components optionally further comprise buffers.
• kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of two or more active ingredients to a patient.
• a typical kit of the invention comprises a unit dosage form of at least one compound of Formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a unit dosage form of at least one additional active ingredient.
• additional active ingredients that may be used in conjunction with the compounds of the invention include, but are not limited to, any of the drugs indicated hereinbefore that could be used in combination with the compound(s) Formula I or pharmaceutically acceptable salts thereof as defined herein.
• Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
• the kit can comprise a sealed container or a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
• suitable vehicles are provided hereinbefore.
• Step 3 To ethyl[3-[pentyne-1-yl]phenyl]-acetate (0.23 g, 0.98 mmol) in ethanol (5 mL) under nitrogen atmosphere was added Pd on carbon (10%, 25 mg, 10% w/w). The mixture was vigorously stirred under hydrogen atmosphere at room temperature overnight. The solution was filtered and the palladium/carbon was washed with ethanol (20 mL). The filtrate was concentrated with silica gel. The crude product was purified by flash chromatography using a mixture of 10% hexanes/ ethyl acetate. A clear oil was obtained (0.21 g, 90%).
• aqueous phase was extracted with a further portion of ethyl acetate (50 mL); and the combined extracts were washed with water (2 x 50 mL) and with saturated aqueous sodium chloride (50 mL); dried over sodium sulfate; filtered, and evaporated in vacuo to give the crude product.
• Step 6 A solution of the partially-purified acid (0.28 g, 1.26 mmol) in acetone (5 mL) was treated with potassium carbonate (0.26 g, 1.90 mmol), potassium iodide (0.04 g, 0.25 mmol) and benzyl bromide (0.18 mL, 1.5 mmol), and the reaction was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and 1 M aqueous hydrochloric acid (25 mL).
• the above compound was prepared from ethyl 2-fluoro-2-(3-pentylphenyl)acetate as for Compound I.
• the ester was prepared by reaction of ethyl 2-(3-pentylphenyl)acetate with lithium diisopropylamide and A -fluorobenzenesulfonimide at -78°C in Tetrahydrofuran.
• the reaction was cooled to room temperature and was partitioned between ethyl acetate (200 mL) and 1 M aqueous hydrochloric acid (150 mL). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL), and with saturated aqueous sodium chloride (150 mL); then dried over sodium sulphate; filtered, and evaporated in vacuo to give the crude product.
• Methyl 2-(2-hydroxy-3,5-dipentylphenyl)acetate (0.2 g, 0.53 mmol) was hydrolysed as for Compound I, step 4, to give the crude product mixed with lactonised material. A small portion was purified on a BiotageTM SP1 system (120 g silica cartridge), eluting with 0-100% ethyl acetate in hexanes, to give 2-(2-hydroxy-3,5-dipentylphenyl)acetic acid (13.5 mg).
• Compound XVII Sodium salt of 2-(3,5-Dihexyl-2-hydroxyphenyl)acetic acid
• the tittle compound was prepared from methyl 2-[3-bromophenyl]acetate as for compound XIV, with the additional step of alkylation of the methyl 2-[3-pentylphenyl]acetate intermediate with sodium hydride and methyl iodide; and with the temperature of the ester hydrolysis step being raised to 50°C.
• a suspension of sodium hydride (60% w/w; 0.53 g, 13.3 mmol) in anhydrous THF (16 ml) was cooled to 0°C under argon, and was treated with a solution of diethyl 2-[3- bromophenyljmalonate (3.0 g, 9.52 mmol) in anhydrous THF (20 ml).
• the reaction mixture was stirred at 0°C for 30 min, and was then treated dropwise with methyl iodide (0.8 ml, 13.3 mmol). The reaction mixture was then warmed to room temperature, and was stirred at room temperature, under argon, overnight.
• Step 6 (RS)-2-[3-Pentylphenyl]propanoic acid (0.4 g, 1.8 mmol) was converted to the sodium salt using the method described for compound I, Step 5, to give sodium (RS)-2-[3- pentylphenyl]propanoate (0.44 g, quantitative).
• Step 1 [00162] i) A solution of methyl 2-[3-pentylphenyl]acetate (0.5 g, 2.0 mmol) in acetonitrile (15 ml), under nitrogen, was treated with 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.22 ml, 1.5 mmol) and the reaction was stirred at room temperature for 15 min. The reaction was cooled to 0°C, and 4-acetamidobenzenesulfonyl azide (0.6 g, 2.4 mmol) was added slowly. The reaction was then warmed to room temperature, and was stirred, under nitrogen, for 22.5 h.
• Step 2 Methyl 2-[2-hydroxy-5-pentylphenyl]acetate (2.3 g, 9.6 mmol) was converted to the trifluoromethanesulfonate-derivative as described for Compound VII, Step 2, to give methyl 2- [5-pentyl-2-(trifluoromethylsulfonyloxy)phenyl]acetate (3.4 g, 97%).
• a nitrogen-flushed pressure vessel was charged sequentially with tribasic potassium phosphate (5.4 g, 25.3 mmol), palladium(ll) acetate (74 mg, 0.33 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 '-biphenyl (0.14 g, 0.33 mmol), a solution of methyl 2-[5-pentyl-2-(trifluoromethylsulfonyloxy)phenyl]acetate (3.1 g, 8.3 mmol) in anhydrous tetrahydrofuran (20 ml) and a 0.5M solution of 9-benzyl-9-borabicyclo[3.3.1]nonane in tetrahydrofuran (34 ml, 17 mmol).
• Step 1
• Step 2 [00174] Methyl 2-amino-3,5-di[(E)-pent-1-enyl]benzoate (5.7 g, 19.9 mmol) was hydrogenated as described for compound I to give methyl 2-amino-3,5-dipentylbenzoate (5.50 g, 95%).
• Real-Time PCR was performed as described in the RT 2 Profiler PCR Array handbook on a AB-7900HT real-time cycler. Real-Time PCR data was analyzed using the ⁇ method on the RT 2 Profiler PCR Array Data Analysis Web Portal. All Ct values > 35 or non amplified were changed to the cut-off value of 35.
• the housekeeping genes used for normalization are GAPDH and RPLP0.
• the control group is TGF- ⁇ treated cells.
• Compound I increases the expression of HGF, growth factor associated with tissue repair, regeneration and anti-aging.
• Table 2 shows that HGF expression in NHDF cells (Untreated) is reduced by TGF- ⁇ which is corrected or increased with representative Compounds of formula I disclosed herein(Com pound #).
• LOX, MMP13, PLAU (uPA), serpin E1 , TIMP3 and ILK are all expressed at a normal level, additionally in HK-2 cells ( Figure 3), LOX, MMP1 , MMP2, MMP9, MMP13, TIMP3 and PLAT (tPA) are also all expressed at a level close to the normal level observed in healthy cells.
• Example 3 Effect of compound I on endogenous production of AAT and regeneration of nerve tissue.
• AAT can induce nerve regeneration.
• Compound I has demonstrated an ability to increase AAT mRNA expression ( Figure 4) in injured cells, indicating that Compound I can increase nerve regeneration or other injured tissues.
• Compound I is representative of the compounds of formula I disclosed herein. Therefore, the compounds of formula I disclosed herein may increase regeneration of nerves via the production of endogenous AAT at the site of injury.

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