WO2016020919A1

WO2016020919A1 - Compositions comprising tricyclic compounds, and uses thereof

Info

Publication number: WO2016020919A1
Application number: PCT/IL2015/050798
Authority: WO
Inventors: Shmuel Ben-Sasson
Original assignee: Raziel Therapeutics Ltd.
Priority date: 2014-08-07
Filing date: 2015-08-03
Publication date: 2016-02-11

Abstract

The present invention relates to compositions and formulations comprising tricyclic compounds and uses thereof in the methods of treatment of abnormal fat distribution and related disorders.

Description

COMPOSITIONS COMPRISING TRICYCLIC COMPOUNDS, AND USES THEREOF

TECHNOLOGICAL FIELD

This invention relates to compositions (formulations) comprising tricyclic compounds and uses thereof in the treatment of abnormal fat distribution and related disorders.

BACKGROUND ART

References considered to be relevant as background to the presently disclosed subject matter are listed below:

WO 2013/072915

Farmer SR, Gene&Developmentll, 1269 - 1275 (2008)

Petrovic N, JBC25S, 7153 - 7164 (2010)

Ohno H. et al, Cell MetabolismXS: 395-404 (2012)

Rao RR, Cell 157: 1279-1291 (2014)

Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

BACKGROUND

Fat tissue or adipose tissue is the loose connective tissue composed of adipocytes. Adipose tissue is derived from lipoblasts. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Adipose tissue includes all fat tissue in the body including abdominal fat, epicardial fat and subcutaneous fat.

Adipose tissue has been recognized to participate in endocrine processes, including the production of hormones such as leptin, estrogen, resistin, and cytokineTNFa. Moreover, adipose tissue can affect other organ systems of the body and may lead to disease.

Obesity in humans and most animals does not depend on body weight, but on the amount of adipose tissue.

There are two types of adipose tissue: white adipose tissue (WAT), which primarily stores fat, and brown adipose tissue (BAT), which functions in the process of fat burning for heat production (Farmer SR, Gene&Development22, 1269 - 1275 (2008), Petrovic N, JBC25S, 7153 - 7164 (2010)). The feasibility of WAT to BAT conversion was demonstrated, for example, by application of PPARy agonists (Ohno H. et al., Cell Metabolism 15: 395-404 (2012)). However, from the whole organism point of view, PPARy activation has also other effects on other tissues with the end result of increase in body weight in PPARy agonists treated patients.

One optional strategy for treating obesity and related conditions, diseases and disorders associated with abnormal WAT distribution is to induce the conversion of WAT to BAT. Previous treatment of obesity in such mechanism of action included the use of thiazolidazine compounds which increased the body's sensitivity to insulin. Such compounds showed many adverse effects, including liver toxicity, bone loss, and weight gain.

GENERAL DESCRIPTION

The present invention provides a composition comprising at least one active agent having the ge

(I) wherein

each of Ri-Rs is independently selected from the group consisting of H, OH, SH, halogen, nitro, amino, nitrilo, nitroso, acetyl, acetamido, acylamido, alkylamino, straight or branched C1-C5 alkyl, straight or branched Ci-Csalkenyl, straight or branched Ci-Csalkynyl, straight or branched Ci-Csalkoxy, straight or branched C1-C5 carboxyl, straight or branched C1-C5 ester, straight or branched Ci-Csthioxy, straight or branched Ci-C₅sulfinyl and straight or branched Ci-Csthionyl;

R is selected from null, straight or branched C1-C9 alkyl, straight or branched Ci-C alkenyl, straight or branched Ci-Cgaikynyl, piperazinyl, pyridinyl, piperidinyl, morpholinyl and thiomorpholinyl;

wherein said R is optionally substituted with at least one substituent selected from the group consisting of amino (including quarternary ammonium), phosphonium, straight or branched Ci-Csalkoxy, straight or branched C1-C5 carboxyl, straight or branched C1-C5 ester, straight or branched Ci-Csthioxy, straight or branched Q- Cssulfinyl, straight or branched Ci-Csthionyl; and

wherein said composition comprises at least one pharmaceutically acceptable additive; and the water content in said composition is less than 50% of total composition weight.

In further embodiments, R is a straight or branched C1-C9 alkyl substituted with at least one amino.

In other embodiments, said amino (ammonium) has a general formula (V):

(V)

wherein each of R', R" and R'" is independently selected from a group consisting of straight or branched C1-C9 alkyl, straight or branched Ci-Cgalkenyl, straight or branched Ci-Cgalkynyl. In some embodiments, each of R', R" and R'" is independently a straight or branched C1-C9 alkyl. In further embodiments, R is a straight or branched C₁-C9 alkyl. In other embodiments, said straight or branched C₁-C9 alkyl is substituted with at least one phosphonium group. In other embodiments, said phosphonium group has a general formula (VI):

(VI)

wherein each of R', R" and R'" is independently selected from a group consisting of straight or branched C₁-C9 alkyl, straight or branched Ci-Cgalkenyl, straight or branched Ci-C9alkynyl. In some embodiments, each of R', R" and R'" is independently a straight or branched C₁-C9 alkyl.

In some embodiments at least one of Rj - Rg are different than H. In some other embodiments, at least one of Rj - R4 are different than H. In some further embodiments, at least one of R5 - Rg are different than H.

In other embodiments, at least one of Rj-R4 is a halogen. In further embodiments, at least one of Rs-Rg is a halogen. In yet other embodiments, at least one of Rj-R4 is a halogen and at least one of Rs-Rg is a halogen. In some embodiments said halogen is Br.

In other embodiments, at least one of Rj-R4 is OH. In further embodiments, at least one of Rs-Rg is OH.

In other embodiments, at least one of Rj-R4 is a nitro. In further embodiments, at least one of

is a nitro and at least one of Rs-Rg is a nitro.

The invention also provides a composition comprising at least one active agent selected from the following:

-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-l-aminium(MTK-012)

-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-l-aminium (MTK-013)

5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-l-aminium

5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan-l-aminium

The term "halogen" is meant to encompass any halogen moiety selected from F, CI, Br and I.

The term "nitro" is a -N(¾ moiety.

The term "amino" refers to -NH₂, -NHR, -NRR', wherein R, R' and R" are each independently selected from straight or branched Q-Cio alkyl (also termed "alkylamino"), straight or branched C₂-Cioalkenyl, straight or branched C₂-Cioalkynyl. The term amino also includesquarternary ammonium moietyof the form -⁺NRR'R" wherein R, R' and R" are as defined herein above.

The term "nitrilo " refers to-R-CN, wherein R is selected from straight or branched Ci-Cioalkanyl, straight or branched C₂-Cioalkenylene, straight or branched C₂- Cioalkynylene.

The term "nitroso" refers to a NO moiety, including C-nitrosomoieties (e.g., nitrosoalkanes -R-N=0, wherein R is selected from straight or branched Ci-Cioalkanyl, straight or branched C₂-Cioalkenylene, straight or branched C₂-Cioalkynylene), S- nitrosomoieties (nitrosothiols; -S-N=0 or -RS-N=0 wherein R is selected from straight or branched Cj-Qoalkanyl, straight or branched C₂-C_!oalkenylene, straight or branched C₂-Cioalkynylene), N-nitrosomoieties (e.g., nitrosamines; -N=N=0, RN-N=0, -RR'N- N=0), and O-nitrosomoieties (-0-N=0, -RO-N=0 wherein R is selected from straight or branched Ci-Cioalkanyl, straight or branched C2-Cioalkenylene, straight or branched C2-Cioalkynylene).

The term "acetyl" refers to a -C(=0)CH₃moiety.

The terms "acetamido " and "acylamido " refers to -CH2C(=0)NH2 and CH₃C(=0)NH- respectively.

The term "straight or branched C₁-C5 alkyl" and "straight or branched Cj-Cg alkyl" encompasses a saturated hydrocarbon chain having between 1 to 5 or 1 to 9 carbon atoms.

The term "straight or branched C2-Csalkenyl"and "straight or branched C2- Cgalkenyl" encompasses a hydrocarbon chain having between 1 to 5 or 1 to 9 carbon atoms and at least one double bond.

The term "straight or branched C2-Csalkynyl"and "straight or branched C2- Cgalkynyl" encompasses a hydrocarbon chain having between 1 to 5 or 1 to 9 carbon atoms and at least one triple bond.

The term "straight or branched Cj-Csalkoxy" is meant to encompass an -OR moiety wherein R is selected from a straight or branched C₁-C5 alkyl, straight or branched C2-Csalkenyl and straight or branched C2-Csalkynyl.

The term "straight or branched C₁-C5 carboxyl" refers to a -R-C(=0)OH moiety wherein R is selected from a straight or branched C₁-C5 alkyl, straight or branched C2- Csalkenyl and straight or branched C2-Csalkynyl.

The term "straight or branched C₁-C5 ester" refers to a RC(=0)0- moiety wherein R is selected from a straight or branched C₁-C5 alkyl, straight or branched C2- Csalkenyl and straight or branched C2-Csalkynyl. The term "straight or branched Cj-Csthioxy" refers to a RS- moiety wherein R is selected from a straight or branched C₁-C5 alkyl, straight or branched C2-Csalkenyl and straight or branched C2-Csalkynyl.

The term "straight or branched Cj-CsSulfinyVwd" straight or branched Cj- Csthionyl" refers to a RS(=0)- moiety wherein R is selected from a straight or branched C₁-C5 alkyl, straight or branched C2-Csalkenyl and straight or branched C2-Csalkynyl.

The term " phosphonium" refers to a -P⁺RR'R" moiety wherein R, R' and R" are each selected from a straight or branched C₁-C₁₀ alkyl, straight or branched C₂- Cioalkenyl and straight or branched C2-Cioalkynyl.

The term "piperazinyl" encompasses a moiety selected from:

The term "piperidinyl" :

The term "morpholinyl" encompasses a moiety selected from:

The term "thiomorphol d from:

The compounds defined in the present invention, may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms (^'polymorphs") are within the scope of formulae (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers or as two or more diastereomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Furthermore, the compounds of this invention include mixtures of diastereomers, as well as purified stereoisomers or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the invention, as defined above, as well as any wholly or partially mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

It is also noted that the compounds defined in the present invention may form tautomers. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention, are included within the scope of the compounds of the present invention.

Pharmaceutical compositions of the invention may additionally comprise any other suitable substances such as other therapeutically useful substances, diagnostically useful substances, pharmaceutically acceptable carriers or the like.

In some embodiments a composition of the invention is administered (suitable to be administered) into an adipose tissue of a subject. In some embodiments said compound or composition of the invention is administered directly into an adipose tissue of a subject. In other embodiments said administration is via injection. In other embodiments, said administration is a transdermal administration. Under such embodiments, transdermal admonition can be achieved by any transdermal formulation known in the art and/or via a transdermal delivery device (for example a patch containing a compound or composition of the invention) at a close proximity to the adipose tissue location of said subject (for example the direct skin or mucosal tissue in contact with said adipose tissue).

Pharmaceutical compositions of the invention comprise a compound of the subject invention in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intra-adipose tissue and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, anti-oxidants, and wetting agents.

Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules (including softgel capsules), or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus, liquid formulation or paste. The compositions can further be processed into a suppository or enema for rectal administration.

The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.

For parenteral administration, suitable compositions include aqueous and nonaqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g. gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.

In some embodiments, compositions of the invention include also compositions where the compound of the invention is formulated in a fat emulsion formulation (i.e. formulated in conventional formulation processes to produce an emulation comprising at least one fat component, either from a natural or synthetic source), such as for example Intralipid formulation (in any concentration). The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.

The invention also includes any salt of a compound of the invention, including any pharmaceutically acceptable salt, wherein a compound of the invention has a net charge (either positive or negative) and at least one counter ion (having a counter negative or positive charge) is added thereto to form said salt. The phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the invention that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p- toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Salts of the invention may also include a counter anion being a halogen anion such as for example chloride and bromide anions. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see BERGE ET AL., 66 /. PHARM. SCI. 1-19 (1977), incorporated herein by reference.

In some embodiments a composition of the invention is a cosmetic composition, i.e. it comprises additives and excipients that are suitable for topical delivery and treatment (see Puglia C and Bonina F, Expert Opin drug Deliv 9: 429-441 (2012); Rehman K and Zulfakar MH Drug Dev Ind Pharm 40: 433-440 (2014)).

The tricyclic compounds disclosed as active agent in the present invention are hydrophobic that are substantially water insoluble (i.e. having marginal to no solubility in water). On the other hand, body-fluids are typically hydrophilic and, in general, is incompatible with hydrophobic (organic) solvents, compositions and solutions. The present composition of the invention enable the solubilization of active tricyclic compounds disclosed herein at concentrations that provide effective amounts of said compounds in bodily fluids once administered to a subject (for example therapeutic effective amounts of about -0.1M). In some embodiments formulations/ compositions according to the present invention, are genuine homogenous solutions with a low water content, thus enabling the tricyclic compounds solubilization at high concentrations, yet compatible with the aqueous environment of body fluids.

When referring to a composition of the invention having "water content of less than 50% of total composition weight", it should be understood to relate to said composition comprising at least one active agent having the general formula (I), at least one pharmaceutically acceptable additive and water content that does not exceed about 50% by weight of the total weight of the composition.

In some embodiments said composition of the invention has water content is less than 30% of total composition weight. In some other embodiments, said composition of the invention has water content is less than 10% of total composition weight. In some further embodiments of the invention, said composition has water content is between about 50% to about 0%, of total composition weight. In some further embodiments of the invention, said composition has water content is between about 30% to about 0%, of total composition weight. In some further embodiments of the invention, said composition has water content is between about 10% to about 0%, of total composition weight.

In some embodiments, a composition of the invention comprises at least one pharmaceutically acceptable additive selected from alcohols, including aromatic alcohols such as benzyl alcohol, polyalcohol such as propyleneglycol or glycerol, fatty acids, ionic surfactants, nonionic surfactants (e.g. Lauryl-glucoside, Polysorbate-20, Polysorbate-80 or Polysorbate-85), mono-, di- and Triglycerides,esters (aliphatic and aromatic - such as benzyl-benzoate), antioxidants such as acetyl carnitine HC1, amino- acids and esters thereof and other cosmetically acceptable additives (see: http://www.paulaschoice.com/cosmetic-ingredient-dictionary/).

In some embodiments, a composition of the invention comprises at least 0.1% by weight of said at least one active agent of total composition. In some other embodiments, a composition of the invention comprises between about 0.1% to about 10% by weight of said at least one active agent of total composition. In some further embodiments, a composition of the invention comprises between about 1% to about 5% by weight of said at least one active agent of total composition.

In some embodiments a composition of the invention further comprises at least one agent selected from anti-inflammatory agents such as NSAIDs, anti-fibrotic agents such as silicone gel, prostaglandin E2 (PGE2), retinoic acid or halofuginone and related compounds thereof.

In some embodiments said at least one active agent of a composition of the invention is formulated in a way suitable for oral administration. In some other embodiments, said at least one active agent of a composition of the invention is formulated in a way suitable for topical application. In other embodiments, said at least one active agent of a composition of the invention is formulated in a way suitable for parenteral injection.

In some aspect the invention provides a composition of the invention for use in a method of reducing fat in subcutaneous tissue.

The term "fat in subcutaneous tissue " or "subcutaneous fat" or "subcutaneous adipose tissue " is meant to encompass, also known as hypodermis, hypoderm, subcutis, or superficial fascia. The hypodermis is beneath dermis which is beneath epidermis. It is used mainly for fat storage.

By reducing fat in subcutaneous tissue it is meant to encompass any change in at least one feature of a fat subcutaneous tissue, including but not limited to fat tissue thickness and/or fat tissue composition, fat cell size and/or fat cell molecular features in said subcutaneous tissue. Fat cells are also known as adipocytes and fat tissue is also known as adipose tissue.

In some embodiments, a composition of the invention is being administered to a subject in need thereof at least once in single injection site (i.e. in a single area to be injected to in a body of a treated subject, wherein a professional care taker has identified has having fat in subcutaneous tissue).

In some other embodiments, a composition of the invention is being administered to a subject simultaneously in at least two different injection sites.

The invention further envisages a medical device comprising a composition of the invention. In some embodiments, such a medical device of the invention is selected from an injection, an injection at a fix angel such as 45° with respect to the skin surface, a multiple-needle device or a transdermal patch.

In some embodiments a medical device of the invention is being suitable for subcutaneous-fat delivery.

In other embodiments, said composition is for the treatment of abnormal fat- distribution and conditions or disease associated therewith.

The term "abnormal fat-distribution" is meant to encompass any irregular fat tissue distribution in, near or on an organ of a subject or parts thereof. Fat or adipose tissue includes all fat tissue in the body including abdominal fat, epicardial fat and subcutaneous fat. The term is further meant to encompass any irregular fat tissue distribution as perceived by the affected person and thereby is associated with poor self- image and psychiatric disorders related to it.

The term "obesity" is meant to encompass is a condition in a subject having excess body fat. It is defined by body mass index (BMI) and further evaluated in terms of fat distribution via the waist-hip ratio and total cardiovascular risk factors. Additional parameters measuring extent of obesity are percentage body fat and total body fat. Subjects suffering from obesity have a BMI value of above 25. In some embodiments the term "obesity" includes subjects having BMI values of between about 25.0 to about 29.9 (overweight), in some further embodiments between about 30.0 to about 34.9 (class I obesity), in yet further embodiments between about 35.0 to about 39.9 (class II obesity), in further embodiments above 40.0 (class III obesity), in other embodiments between about 40 to about 49.9 (morbid obesity) and in other embodiments >50 (super obesity).

In some embodiments, conditions or disease associated with obesity,or abnormal fat-distribution include, but are not limited to: diabetes, cardiovascular diseases, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrinologic disease and disorders, reproductive disease and disorders, neurological diseases and disorders, psychiatric diseases and disorders, rheumatological diseases and disorders and orthopedic disease and disorders and any combinations thereof.

The invention further provides a use of a composition of the invention as defined herein above, for the preparation of a composition for the remodeling of white adipose tissue (WAT) to brown- like adipose tissue (BAT).

WAT adipocytes, contain a single lipid droplet. BAT adipocytes contain numerous smaller lipid droplets and a higher number of mitochondria. BAT also contains more blood-capillaries than WAT.

The term "remodeling of white adipose tissue (WAT) to brown-like adipose tissue (BAT)" is meant to encompass any qualitative or quantitative difference or change inthe histology of WAT between the initial WAT condition and the WAT condition after treatment. Said qualitative or quantitative difference may be manifested by a change in WAT adipocytes size, ablation thereof, including macrophage-associated liponecrosis, and in appearance of BAT-like adipocytes.

The invention further provides a use of a composition of the invention for the treatment of a disease, disorder or condition associated with or benefiting from the remodeling of WAT to BAT. The invention also provides a use of a composition of the invention as defined herein above, for the preparation of a composition for reducing the white adipose tissue (WAT) of a subject in need thereof.

It is to be noted that a reduction of WAT may be measured in any way known to a person skilled in the art, such as for example the reduction of tissue thickness, change in tissue density and so forth. Such reduction in WAT in a subject administered with a compound of the invention may be for any known purposes, such as for example cosmetic, medical (i.e. the treatment of conditions and diseases associated with excess or abnormal levels of WAT), or both.

In some embodiments said inhibition is associated with the treatment of at least one disease, disorder or condition selected from obesity, overweight or abnormal fat- distribution and conditions or disease associated therewith.

In another one of its aspects the invention provides a method of treating obesity, and conditions or disease associated therewith in a subject in need thereof, wherein said method comprises the administration of an effective amount of a composition of the invention as defined herein above.

In another one of its aspects the invention provides a method of treating abnormal fat-distribution and conditions or disease associated therewith in a subject in need thereof, wherein said method comprises the administration of an effective amount of a composition of the invention as defined herein above.

In a further aspect the invention provides a method of activating the remodeling of white adipose tissue to brown-like adipose tissue in a subject, comprising administrating to said subject an effective amount of a composition of the invention as defined herein above.

In a further aspect the invention provides a method of treating a disease, disorder or condition associated with or benefiting from the remodeling of white adipose tissue to brown-like adipose tissue in a subject, comprising administrating to said subject an effective amount of a composition of the invention as defined herein above.

The term "treatment" as used herein refers to the administering of a therapeutic amount of a compound and/or a composition of the present invention which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease or condition, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease or condition, to delay the onset of said progressive stage, to lessen the severity or cure the disease or condition, to improve survival rate or more rapid recovery, or to prevent the disease or condition form occurring or a combination of two or more of the above.

The "effective amount" for purposes disclosed herein is determined by such considerations as may be known in the art. The amount must be effective to achieve the desired therapeutic effect as described above, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the compound to its target protein(s), its distribution profile within the body, a variety of pharmacological parameters such as half life in the body, on undesired side effects, if any, on factors such as body-weight, BMI, age and gender, etc.

It must be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Figs. 1A-1B show 80 kg male pig in preparation for MTK-012 composition injection (Fig. 1A) and two clusters, composed of 5 injection site each that are clearly marked. Fig. IB shows measurement of subcutaneous fat thickness between these clusters (3.8cm).

Figs. 2A-2B show the thermogenic response at the injection sites of the pig depicted in Figs. 1A-1B. Fig. 2A shows flank temperature before injection. Fig. 2B shows flank temperature 4 wks after injection of MTK-012 composition. Color-code of the temperature scale is to the right of each. The thermogenic image was obtained via FLIR A-320 IR camera.

Fig. 3 shows the shrinkage of the subcutaneous fat at the sites of MTK-012 composition injection, 10 wks after treatment initiation (marked in red circle).

DETAILED DESCRIPTION OF EMBODIMENTS

Example 1:

MTK-012 composition according to an embodiment of the present invention, suitable for administration to a human being by various routs, including parenteral injection. As specified in Table 1, this composition contains <25 water.

Table 1 provides the w/w% and quantities of the components of a composition of MTK-012 for preparation of lOg sample, containing 5% WAV pure RZL-012 concentration (~ 0.1M; MTK-012 API contains -10% water + chloride) in accordance with the invention. Table 1: Composition of MTK-012 Composition of the Invention

Miilei kil name Contents of lOg composition

, w/w Quantity (g)

MTK-012 API 5.6 0.56

Tween 80 10 1

Propylene glycol 57 5.7

Benzyl alcohol 3 0.3

Water 24.4 2.44

SUM 100 10

Procedure (quantities and w/w/% as shown in Table 1): MTK-012 was weighed, propylene glycol was then added. The mixture was heated to 50°C until dissolution (approximately 15min). Benzyl alcohol was added. Mixture was heated to 50°C to dissolution. Tween-80 was added. Mixture was heated to 50°C to dissolution. Water was added. Mixture was heated to 50°C to dissolution. The solution was stable and could be stored at RT.

Example 2:

Demonstration of subcutaneous-fat treatment with MTK-012, utilizing the composition according to Example 1.

A male domestic pig 7-months old (80kg) was injected at the left flank, according to the pattern illustrated in Fig.l. Two clusters, of 5 injection sites each, are clearly marked. Each injection consists of 0.5ml of said MTK-012 formulation delivered into the subcutaneous fat at a depth of around 1.5cm. Surface temperature of the pig's flank was measured before the injections and 4 weeks after it, utilizing FLIR A-320 IR camera. As can be seen in Fig. 2, there is an outstanding increase in temperature at the injected sites. Moreover, with time, this excessive thermogenesis is translated into a shrinkage of the subcutaneous fat as evident by the concave shape surface contours at the injected site 10 wks after local treatment, as depicted in Fig. 3, as compared to the shape before treatment, shown in Fig. 1.

Claims

CLAIMS:

1. A composition comprising at least one active agent having the general formula

(I)

Wherein

each of Rj-Rgis independently selected from the group consisting of H, OH, SH, halogen, nitro, amino, nitrilo, nitroso, acetyl, acetamido, acylamido, alkylamino, straight or branched C₁-C5 alkyl, straight or branched Ci-Csalkenyl, straight or branched Ci-Csalkynyl, amine, straight or branched Q-Csalkoxy, straight or branched C₁-C5 carboxyl, straight or branched C₁-C5 ester, straight or branched Ci-Csthioxy, straight or branched Ci-Cssulfinyl, straight or branched Ci-Csthionyl;

R₉ is selected from straight or branched C₁-C9 alkyl, straight or branched Q- Cgalkenyl, straight or branched Ci-Cgalkynyl, piperazinyl, pyridinyl,piperidinyl,morpholinyl and thiomorpholinyl;

R is substituted with at least one quaternary amino (ammonium) group or a phophonium group; and

wherein said composition comprises at least one pharmaceutically acceptable additive; and water content in said composition is less than 50% of total composition weight.

2. A composition according to claim 1, wherein R is a straight or branched C₁-C9 alkyl substituted with at least one quaternary amino group.

3. A composition according to claim 1, wherein said at least one quaternary amino group has a general formula (V):

(V)

wherein each of R', R" and R'" is independently selected from a group consisting of straight or branched C₁-C9 alkyl, straight or branched Ci-Cgalkenyl and straight or branched Ci-C9alkynyl.

4. A composition according to claim 3, wherein each of R', R" and R'" is independently a straight or branched C₁-C9 alkyl.

5. A composition according to any one of claims 1 - 4, wherein at least one of Rj- R4 is a halogen.

6. A composition according to any one of claims 1 - 4, wherein at least one of R5- Rg is a halogen.

7. A composition according to any one of claims 1 - 4, wherein at least one of Rj- R4 is a halogen and at least one of R5-R8 is a halogen.

8. A composition according to any one of claims 5 - 8, wherein said halogen is Br.

9. A composition according to any one of claims 1 - 4, wherein at least one of Ri- R4 is OH.

10. A composition according to any one of claims 1 - 4, wherein at least one of R5- R₈ is OH.

11. A composition according to any one of claims 1 - 4, wherein at least one of Rj- R4 is a nitro and at least one of R5-R8 is a nitro.

12. A composition according to any one of claims 1 to 11, wherein said at least one active agent is being selected from:

■ 3-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpropan-l-aminium

■ 5-(9H-carbazol-9-yl)-N,N,N-trimethylpentan-l-aminium

■ 5-(2-hydroxy-9H-carbazol-9-yl)-N,N,N-trimethylpentan- 1 -aminium

■ 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-l-aminium.

13. A composition according to claim 1 , wherein the water content is less than 30% of total composition weight.

14. A composition according to claim 1, wherein the water content is less than 10% of total composition weight.

15. A composition according to claim 1 , wherein the water content is between about 30% to about 0%, of total composition weight.

16. A composition according to any one of the preceding claims, wherein said at least one pharmaceutically acceptable additive is selected from alcohols, fatty acids, ionic surfactants, nonionic surfactants, mono-, di- and triglycerides, esters, antioxidants, amino-acids and esters thereof and other cosmetically acceptable additives.

17. A composition according to any one of the preceding claims wherein the composition comprises at least 0.1 % by weight of said at least one active agent of total composition.

18. A composition according to any one of the preceding claims wherein the composition comprises between about 0.1% to about 10% by weight of said at least one active agent of total composition.

19. A composition according to any one of the preceding claims wherein the composition comprises between about 1% to about 5% by weight of said at least one active agent of total composition.

20. A composition according to any one of the preceding claims, wherein said at least one active agent further comprises at least one agent selected from antiinflammatory agents such as NSAIDs, anti-fibrotic agents such as silicone gel, prostaglandin E2 (PGE2), retinoic acid or halofuginone and related compounds thereof.

21. A composition according to any one of the preceding claims, wherein said at least one active agent is formulated in a way suitable for oral administration.

22. A composition according to any one of the preceding claims, wherein said at least one active agent is formulated for topical administration.

23. A composition according to any one of the preceding claims, wherein said at least one active agent is formulated for parenteral injection.

24. A composition according to any one of the preceding claims for use in a method of reducing fat in subcutaneous tissue.

25. A composition for use according to claim 24, being administered to a subject in need thereof at least once in single injection site.

26. A composition for use according to claim 24, being administered to a subject simultaneously in at least two different injection sites.

27. A medical device comprising a composition according to any one of the preceding claims.

28. A medical device according to claim 27, being suitable for subcutaneous-fat delivery.

29. A medical device according to claim 27, selected from an injection, an injection at a fix angel such as 45° with respect to the skin surface, a multiple-needle device or a transdermal patch.