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  Pharmaceutical Patents  

 

Title:  Lipophilic diesters of chelating agent for inhibition of enzyme activity
United States Patent: 
7,799,831
Issued: 
September 21, 2010

Inventors:
 Striem; Sarina (Rehovot, IL), Friedman; Jonathan Eduard (Rehovot, IL), Reznitsky-Cohen; Dalia (Nes-Ziona, IL), Kozak; Alexander (Rehovot, IL)
Assignee:
  D-Pharm Ltd. (Kiryat Weizmann Science Park Rehovot, IL)
Appl. No.:
 10/529,028
Filed:
 March 16, 2003
PCT Filed:
 March 16, 2003
PCT No.:
 PCT/IL03/00225
371(c)(1),(2),(4) Date:
 March 24, 2005
PCT Pub. No.: 
WO2004/028443
PCT Pub. Date:  April 08, 2004


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The present invention relates to the use of lipophilic diesters of the chelating agent 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) for inhibition of proteolytic activities of certain metalloproteinases and of calpain. The invention further relates to methods for preventing, treating or managing MMP-related and calpain-related diseases or disorders in mammals comprising administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of said lipophilic diesters of the chelating agent BAPTA.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates to the use of lipophilic diesters of the chelating agent 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) for inhibition of proteolytic activities of certain metalloproteinases and of calpain.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are extracellular zinc- and calcium-dependent proteases, which are produced in a latent form and require activation for catalytic activity. Activation occurs at the cell surface and enables MMPs to degrade components of the extracellular matrix (ECM) at specific sites in the membrane surroundings. The most studied MMPs are the gelatinases, which include MMP-2 and MMP-9 that use gelatin, Type IV collagen and fibronectin as preferred substrates. While transcription of MMP-9 genes is transactivated by cytokines and growth factors, MMP-2 is constitutively expressed and unresponsive to phorbol ester and most cytokines. MMP-2 activation is regulated by MT1-MMP, which is a membrane-anchored MMP. MMP-9 activation is regulated by a protease cascade involving plasmin and stromelysin-1 (MMP-3).

Matrix metalloproteinases are responsible for much of the turnover of matrix components and as such are involved in normal as well as in pathological processes. MMPs have an important role in maintenance and remodeling of membranes and ECM, for example, in breaking down the extracellular matrix to allow cell growth and tissue remodeling during development and recovery from injury. They also play a role in processes such as ovulation, modulation of capillary permeability and in enabling cell migration to a site of inflammation.

MMPs are involved in many pathological conditions. For example, they are associated with pathogenic mechanisms in cancer such as invasion, metastasis and angiogenesis [Reviewed by Foda and Zucker (2001) Drug Discovery Today 6: 478-482]. MMPs play a part in progression of inflammatory conditions and diseases involving degradation of extracellular matrix, such as in stroke, hemorrhage, rheumatic diseases (e.g. arthritis), Crohn's disease, asthma, and in cerebrovascular and cardiovascular disorders [Mun-Bryce and Rosenberg (1998) J. Cerebral Blood Flow Metabolism 18:1163-72; Yong et al. (1998) TINS 21:75-80; Lukes et al. (1999) Mol. Neurobiol. 19:267-284]. Members of the MMP family have also been implicated in neurological diseases and conditions as being involved in demyelination and neuro-inflammatory processes. For example, MMPs have been associated with brain damage and ischemia, Guillain-Barre, multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's disease. The current notion is that inflammation leads to the production of cytokines, chemokines, growth factors and hormones that modulate MMPs production. Activation of MMPs and plasminogen activators (PAs) is an important regulatory step in the inflammatory response.

Members of another family of metalloproteinases, identified as "A Disintegrin And Metalloproteases" (ADAM), have, like members of the MMP family, multiple domains including a zinc-dependent catalytic domain and a N-terminus pro-domain that is responsible for maintaining the enzyme in an inactive state [Moss et al. (2001) Drug Discovery Today 6: 417-426]. It was shown that members of the ADAM family are involved in several different processing events including cleavage of substrates off the cell membrane surface (a phenomenon termed "shedding"). One member of the ADAM family is the TNF.alpha.-Converting Enzyme (TACE). TACE is found on the cell surface where it processes the membrane-bound TNF.alpha., a pro-inflammatory cytokine, to its mature soluble form. Soluble TNF.alpha., which is released in inflammatory conditions, can induce apoptosis. For example, TNF induces secretion and activation of MMP-9 in macrophages and glial cells and causes neuronal cell death in neuroinflammatory diseases and following brain injuries. TNF has also been shown to play a role in pathological conditions such as rheumatoid arthritis.

As potentially highly toxic proteolytic enzymes, the matrix metalloproteinases are tightly regulated at multiple stages, as follows:

i) Gene transcription--most MMPs are not constitutively expressed, but their transcription is controlled by various cytokines (e.g. IL-1, TNF) and growth factors (e.g. TGF-.beta., retinoic acid, FGF).

ii) Pro-enzyme activation--MMPs are normally produced in a latent form (pro-MMP) including a propeptide segment that generally must be removed to activate the enzyme.

iii) Inhibition of enzyme activity--There are at least four endogenous MMP-inhibitors known as tissue inhibitors of metalloproteinases (TIMPs), which bind to the enzyme and block its activity. Another known natural inhibitor of MMPs is the serum proteinase inhibitor .alpha.-macroglobulin.

Several synthetic inhibitors of MMPs have been described in various publications in the scientific and patent literature. Currently known inhibitors mainly include synthetic peptides and chelating agents [reviewed by Woessner J F Jr. in Ann N.Y. Acad. Sci. (1999) 30:388-403].

Some synthetic inhibitors of the MMP active site are peptidomimetics based on the sequence of peptides cleaved in collagen [Masui et al. (1977) Biochem Med. 17:215-21). Peptidic agents based on conserved peptide sequence derived from the pro-segment of human collagenase IV are disclosed by Stelter-Stevenson et al. [Am J Med Sci. (1991) 302:163-70] and in U.S. Pat. No. 5,270,447 to Liotta et al. Synthetic peptides isolated from phage display peptide libraries and cyclic peptides with MMP inhibitory activity are described by Koivunen et al. [Nat. Biothechnol (1999) 17: 768-74].

N-hydroxyformamide peptidomimetics useful as TACE and MMPs inhibitors are disclosed by Musso et al. [Bioorg Med Chem Lett (2001) 11: 2147-51].

Other polypeptides and peptoid compounds useful as metalloproteinase inhibitors are disclosed in U.S. Pat. Nos. 4,263,293 and 4,297,275 to Sundeen et al., in U.S. Pat. Nos. 4,371,465, 4,371,466 and 4,374,765 all issued to McGregor, and in U.S. Patent Publication No. 2002/0090654 to Langley et al.

Non-peptidic MMP-inhibitory compounds are disclosed in U.S. Pat. No. 4,950,755 to Witiak et al. and in U.S. Pat. No. 5,866,570 to Liang et al.

MMPs inhibitors comprising targeting moieties and chelators are disclosed in International Patent Publication No. WO 01/60820 of Dupont Pharmaceuticals Company, and in International Patent Publication No. WO 02/053173 to Kimberly-Clark Worldwide, Inc.

Matrix metalloproteinases as well as other members of the ADAM family are inhibited by chelating agents. Most of these chelating agents are natural and synthetic hydroxamate compounds and derivatives thereof such as succinyl hydroxamate, sulfonamide hydroxamate etc. [reviewed by Woessner, J. F. Jr. (1999) in Annals New York Academy of Sciences 30: 388-403]. For example, the synthetic hydroxamates batimastat (BB-94; Invest New Drugs (1996) 14:193-202) and its orally bioavailable analogue marimastat have been shown to inhibit spread and growth of malignant tumors in animals. These compounds are currently examined in advanced clinical trials.

Among the compounds that have been shown as MMPs inhibitors are also antibiotics such as tetracyclines and their chemically modified analogs (Golub et al. (1983) J Periodontal Res. 18:516-26; U.S. Pat. No. 4,704,383 to McNamara et al.; U.S. Pat. No. 5,837,696 to Golub et al.].

Most of the above-mentioned agents are non-specific inhibitors of metalloproteinases and other metal-ion dependent proteases.

Calpains are members of another family of proteases. These are cytosolic enzymes which are calcium-dependent cysteine proteases. Calpains predominantly exist within cells as inactive proenzymes and are converted into their active forms in the presence of elevated intracellular calcium levels. Upon binding of calcium, the precursor enzyme goes through a self-digestion process that results in release of the activated calpain.

A wide range of proteins serves as substrates for calpain including cytoskeletal, membrane and regulatory proteins. Calpain participates in a number of normal cellular signal transduction systems as well as in pathological conditions. For example, calpain activation has been associated with ischemia and neuronal cell death such as those caused by stroke and traumatic brain and spinal cord injuries [Bartus et al. (1995) Neurol. Research 17:249-258]. Calpain proteolytic activity has also been implicated in several neurodegeneration diseases and conditions, including Alzheimer's Disease, Parkinson's disease, Huntington's disease and Pick's disease.

Presently known natural and synthetic calpain inhibitors, including both peptidic and non-peptide molecules, are reviewed by Wang and Yuen ["Calpain inhibition: an overview of its therapeutic potential" in Trends Pharm. Sci. (1994) 15, 412-419] and by Donkor ["A survey of calpain inhibitors" in Curr. Med. Chem. (2000) 7:1171-88]. Known calpain inhibitors include polypeptides which mimic peptide sequences of the natural inhibitors calpastatin and kininogen [for review, see Wang and Yuen (1994) Trends Pharm. Sci. (1994) 15, 412-419].

Compounds which are sulfonamide derivatives and ketone derivatives that possess inhibitory activity against cysteine proteases are disclosed, respectively, in U.S. Pat. Nos. 5,506,243 and 5,639,783 both to Ando et al. Calpain inhibitors which are di-peptide alpha-keto esters, alpha-keto amides and alpha-keto acids are described by Li et al. [J. Med Chem (1993) 36: 3472-80]. Several other classes of calpain inhibitors are disclosed by Bartus et al. in International Patent Publication no. WO 92/11850.

Most commercially available calpain-inhibitors are compounds based on peptide structures that interact with the substrate-binding site of the enzyme. Many of these compounds are non-specific and inhibit a wide variety of proteases in addition to calpain. Moreover, most of the known inhibitors that were active in vitro, were found ineffective in inhibiting calpain in-vivo, in particular in the CNS, as being poor membrane permeants. Furthermore, almost all MMPs-inhibitors tested for treating pathological inflammatory conditions or cancers failed in in-vivo clinical studies.

Thus, there remains a long-felt need for effective, non-toxic agents which are specific inhibitors of critical proteases such as the MMPs and calpain.

BAPTA-Diesters

Stable lipophilic diesters of the divalent metal ion chelator 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) have been disclosed in the International Patent Publication No. WO 99/16741 of the same applicant. Also disclosed in this publication is the use of these compounds in pharmaceutical compositions useful for treating diseases and disorders related to excess of divalent metal ions. Among these diseases and disorders are ischemia, stroke, epilepsy and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

At that time, however, the mechanism by which these chelating agents exert their neuroprotective effects has not been elucidated or disclosed. No indication or suggestion for the cellular targets affected by these chelators has been mentioned in the WO 99/16741 or any other publication.

SUMMARY OF THE INVENTION

It has now been found, in accordance with the present invention, that certain diesters of the chelating agent 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (hereinafter denoted as "DP-BAPTAs") are capable of inhibiting enzymatic activities of the proteases matrix metalloproteinase (MMP), calpain and TNF.alpha.-Converting Enzyme (TACE).

Accordingly, the present invention provides, in one aspect, a method of inhibiting protease activity, said protease being selected from metalloproteinase and calpain, the method comprising exposing cells to inhibiting amount of a compound of the general formula (I) -- see Original Patent.

According to currently preferred embodiments of the invention, the useful compounds for inhibiting the MMP-9 activity are the following compounds and physiologically acceptable salts thereof:

1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-octoxyethyl acetate), N,N'-diacetic acid (denoted herein DP-b99),

1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-octodecyloxyethyl acetate), N,N'-diacetic acid (denoted herein DP-b109),

1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-benzyloxyethyl acetate), N,N'-acetic acid (denoted herein DP-b440),

1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-dodecyloxyethyl acetate), N,N'-diacetic acid (denoted herein DP-b460),

1,2-bis(2-aminophenoxy)ethane, N,N'-di[2-(2-dodecyloxyethoxy)-ethyl acetate], N,N'-diacetic acid (denoted herein DP-b458), and

Currently most preferred compounds for inhibiting calpain activity are 1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-octoxyethyl acetate), N,N'-diacetic acid (DP-b99) and 1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-octodecyloxyethyl acetate), N,N'-diacetic acid (DP-109) and physiologically acceptable salts thereof.

In another aspect of the invention, there are provided methods for preventing, treating or managing diseases and pathological conditions associated with damaging MMP and/or calpain activities. The methods comprise administering to a mammal in need thereof, a pharmaceutical composition containing as an active ingredient a therapeutically effective amount of a compound of the above-mentioned general formula (I).

In yet another aspect of the invention, there is provided the use of a compound of the general formula (I) for the preparation of a medicament for inhibiting the activity of a protease selected from metalloproteinase, calpain and TACE.

The present invention further provides methods and the use of the compounds of the general formula (I) for the treatment of MMP- or calpain-related diseases, disorders or conditions, which may be selected from the group consisting of cancer (including metastasis cancer), angiogenesis-dependent diseases (e.g. cancerous tumors, arthritis, psoriasis, macular degeneration, chronic inflammation and diabetic retinopathy), ischemic or hypoxic tissue damage, oxidative injury, stroke, trauma, inflammatory conditions and diseases (e.g. arthritides, rheumatoid arthritis, osteoarthritis, restenosis, asthma, psoriasis, systemic lupus erythematosus, inflammatory bowel syndrome, Crohn's disease, gingivitis, periodontitis, meningitis, tropical spastic paraparesis, sepsis, bullous skin disorders, acne and inflammation due to infectious diseases), atherosclerosis, thrombotic disorders, arthritis, osteoporosis, diabetes, hemorrhage, autoimmune diseases, rheumatic diseases, ocular pathologies and retinopathies (e.g. diabetic retinopathy, glaucoma, macular degeneration, cataract, retinal detachment and retinal tears), burns, chronic wounds (e.g. ulcers), neurological and neurodegenerative diseases and disorders (e.g. multiple sclerosis (MS), Alzheimer's disease (AD), motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), Guillain-Barre, Parkinson's disease, Huntington disease, Pick's disease, dementia syndrome, vascular dementia, multiple infarct dementia, HIV-induced neural disorders, brain ischemia (both global and focal ischemia) and neuronal tissue trauma), migraine, cerebrovascular and cardiovascular disorders.

The methods of treatment in accordance with the invention may further comprise treating the patient with additional therapeutic treatment which may be carried out concurrently with, preceding or subsequent to the administration of the pharmaceutical composition comprising a compound of the general Formula (I).

It is important to note that not any chelator can inhibit the activity of the tested proteases. In contrast to the effect of DP-BAPTA compounds, the closely related known chelators, BAPTA and BAPTA-AM, at doses similar to DP-BAPTA, did not inhibit MMP-9 activity. In fact, BAPTA-AM even slightly enhanced the MMP-9 activity.

Another point to emphasize is that, under the experimental conditions employed, the tested DP-BAPTAs inhibited calpain and MMP-9 proteolytic activities, however no such effect could be demonstrated for the other gelatinase tested, MMP-2.

DETAILED DESCRIPTION OF THE INVENTION

The synthesis and some utilization of stable lipophilic diesters of BAPTA (DP-BAPTAs) have been disclosed in the International Patent Publication No. WO 99/16741 of the same applicant, the teaching and disclosure of which are expressly incorporated herein in their entirety by reference. In the WO 99/16741 publication, the neuroprotective effects of DP-BAPTAs were demonstrated in neuronal cell cultures in-vitro, and in ischemia model systems in-vivo. However, the effect of the DP-BAPTA molecules on activities of specific enzymes has not been taught or suggested in that or any other publication. Accordingly, it was neither taught, recognized or suspected that these compounds could be effectively use for the treatment of MMP- and calpain-related diseases and disorders as disclosed in the present application.

It is now disclosed, for the first time, that certain diesters of the chelating agent BAPTA are capable of inhibiting the activity of calpain and of certain proteases of the ADAM family, and in particular inhibiting the activity of matrix metalloproteinase-9 (MMP-9).

The useful compounds in accordance with the invention are of the general formula (I) as described above. It is to be understood that within the scope of the invention are included also pharmaceutically acceptable salts of the compounds of the general formula (I) including organic and inorganic cations, as well as various solvates, including hydrates, and other active forms of the compounds of the general formula (I).

Currently preferred compounds for inhibiting MMP or calpain activities are diesters of BAPTA with alkyl chains comprising from around 8 to 20 carbon atoms. The alkyl chains may be saturated or unsaturated alkyls including one or more double bonds and/or a triple bond. According to preferred embodiments of the invention, the alkyl chain is interrupted by from 1 to 3 oxygen atoms. According to most preferred embodiments, the R moiety of a compound of the general formula (I) includes a monoalkyl ether of ethylene glycols, preferably mono-, di- or tri-ethylene glycols.

The alkyl residue at position R of the compound of the general formula (I) may consist of or include cyclic elements that may be aromatic or non-aromatic ring structures. Preferably the cyclic elements have 5 or 6 carbon atoms.

Currently preferred cyclic R radicals comprise aromatic ring which is a phenyl residue. Other currently preferred cyclic elements included at position R are saturated or unsaturated cyclopentyl, cyclohexyl or cycloheptyl. The cyclic elements may be directly linked to the carboxy moiety of the compound of the general formula (I), or linked via a saturated or unsaturated alkyl chain that may include one or more oxygen and/or nitrogen atoms.

Preferably, the compound of the general formula (I) includes a monovalent cation at position M. Suitable pharmaceutically acceptable cations may include, but are not limited to, H.sup.+, Na.sup.+, Li.sup.+, K.sup.+, NH.sub.4.sup.+ and mono-alkylammonium. Also divalent cations may be included at position M. The choice of the preferred cation at position M of the general formula (I) depends on the intended therapeutic use of the compound, as well as on the specific formulation and route of administration employed. A person skilled in the art will be able to select the appropriate cation as required for the optimal pharmaceutical compositions and way of administration chosen in each particular treated case.

One of the most preferred DP-BAPTA compounds is 1,2-bis(2-aminophenoxy)ethane, N,N'-di(2-benzyloxyethyl acetate), N,N'-acetic acid (DP-b440), where the R moieties of the compound of the general formula (I) include an alkylaryl moiety. This compound was disclosed generally in the WO 99/16741 publication, but was not specifically claimed and not individually tested.

It has now been shown by the inventors of the present invention that DP-BAPTAs can attenuate or block both basal MMP-9 activity and TNF.alpha.- or PMA-induced activation of MMP-9. DP-BAPTAs can also inhibit calpain activity. Hence, DP-BAPTAs may be useful in reducing deleterious protease activities in pathological conditions due, for example, to ischemia and inflammatory responses. Accordingly, DP-BAPTA compounds may be useful in preventing, treating or managing diseases and pathological conditions associated with harmful activities of matrix metalloproteinases or calpains.

It is important to note that while MMP-9 activity was significantly inhibited by the DP-BAPTA compounds, such inhibitory activity could not be demonstrated with the related chelators tested, namely 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid (BAPTA) or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM).

The DP-BAPTA compounds in accordance with the invention may be useful in the treatment of a whole range of indications which involve degradation processes carried out or mediated by MMPs, TACE or calpain. These indications include, but are not limited to, diseases and conditions due to neuronal ischemia (e.g. global brain ischemia and focal brain ischemia), cardiac ischemia, trauma, stroke and inflammatory conditions including neuroinflammatory diseases and disorders, rheumatic and autoimmune diseases, neurological, cerebrovascular and cardiovascular diseases and disorders. The DP-BAPTA compounds may also be useful in compositions and methods for enhancing wound healing such as, for example, in burns and in chronic wounds (e.g. ulcers).

A large amount of data has been accumulated which show MMP- and/or calpain-involvement in progression of diseases and conditions where inflammatory processes are implicated. These pathological conditions include, but are not limited to, rheumatoid diseases (e.g. rheumatoid arthritis and osteoarthritis), asthma, psoriasis, systemic lupus erythematosus, inflammatory bowel syndrome, Crohn's disease, gingivitis, periodontitis, meningitis, tropical spastic paraparesis, sepsis, bullous skin disorders, acne and inflammation due to infectious diseases.

The infectious diseases may include, but are not limited to, infectious diseases caused by any type of microorganism such as bacteria, fungi (e.g. candidiatis, aspergilosis) and viruses (e.g. herpes viruses-related disorders, HIV-related diseases), by parasites (e.g. malaria, amebiasis) or by prions (e.g. Creutzfeld-Jacob Disease).

Inhibitors of MMPs or calpain can reduce proteolytic damage to tissues such as that caused during inflammatory processes. For example, may limit brain-blood-barrier (BBB) breakdown, inhibit neuroinflammation (e.g. as in meningitis), reduce damage associated with brain or cardiac ischemic injuries, and may diminish proteolytic effects caused by insults such as oxidative stress, burns, infections and central (CNS) and peripheral nervous system (PNS) injuries due to physical causes (e.g. trauma).

Elevated MMP or calpain activity has been linked to several neurodegenerative diseases and conditions including, but not limited to, multiple sclerosis (MS), motoneuron disease (MND), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Pick's disease, dementia syndrome, vascular dementia, multiple infarct dementia, HIV-induced neural disorders, brain ischemia (both global and focal ischemia) and neuronal tissue trauma.

MMPs have also been associated with pathological conditions such as ischemic or hypoxic tissue damage, oxidative damage, osteoporosis, hemorrhage, arterial restenosis, cardiovascular disorders (e.g. ischemic myocardiac infarction) as well as with various ocular pathologies and retinopathies including diabetic retinopathy, glaucoma, macular degeneration, cataract, retinal detachment and retinal tears.

Cancer is another major disease where it has been shown that proteolytic activities of metalloproteinases contribute to the progression of the disease. MMPs are involved in spread of cancer, and in particular facilitating the metastasis state of the disease. MMP-2 and MMP-9 are involved in the breakdown of Type IV collagen, which is a major component of basement membrane, and as such may be key factors in processes involving membrane degradation, for example, in angiogenesis and in tumor invasion and metastasis. Indeed, positive correlation has been found between tumor progression and expression of members of the MMP family. For example, increased expression of MMP-2 and MMP-9 genes has been associated with malignancies of gliomas.

A number of factors are important in the progression of malignancies. One of the crucial factors is angiogenesis, which is believed to be fundamental for primary tumor growth, tumor progression and metastasis. The first step in the mechanism of angiogenesis involves degradation of basement membrane so to facilitate the growth of a new capillary sprout. Thus, degradation and remodeling of the ECM are essential processes for the mechanism of angiogenesis, and methods of inhibiting these processes may be beneficial in blocking angiogenesis and hence diminishing malignancies.

Angiogenesis is also important in a number of other pathological processes, including arthritis, psoriasis, diabetic retinopathy, chronic inflammation, scleroderma, hemangioma, retrolental fibroplasia and abnormal capillary proliferation in hemophiliac joints, prolonged bleeding etc. MMP-inhibitors are expected to be useful for the treatment of these angiogenic-associated diseases.

The inability to control metastasis presents a major problem, as metastases are the leading cause of death in patients with cancer. To date, there is no satisfactory treatment for preventing or limiting metastasis growth. Thus, the use of the DP-BAPTA compounds in accordance with the present invention for inhibiting MMPs, and in particular for inhibiting the MMP-9 protease activity, may be beneficial in this respect.

The cancer subjected to treatment with DP-BAPTAs may include any type of tumors and neoplastic growths that may be benign or malignant growths including primary tumors as well as secondary tumors. The terms "cancer" and "neoplastic growth" are interchangeably used in the specification and claims and mean to cover all kinds of pathological uncontrolled cell growths including invasive and non-invasive neoplasms, solid and non-solid tumors, and including remote metastases.

The term "treatment" as used herein means to include therapeutic procedures aiming at preventing, ameliorating, palliating, inhibiting or delaying the onset and/or development and/or progression of a pathological condition or improving its manifestations.

It should be understood that the therapeutic activity of the compounds of the general formula (I), as disclosed and claimed herein, is irrespective of the exact mechanism of action of these compounds and is not meant to be limited to any particular mode of action by which these molecules exert their beneficial effect(s).

In accordance with the methods of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the general Formula (I) is administered to a patient in need thereof.

The administered pharmaceutical composition may include a compound(s) of the general Formula (I) as the sole active ingredient, or may include said compound(s) in combination with one or more additional agents known to be effective in the treatment of a particular disease or disorder. The compound(s) of the general Formula (I) and the additional therapeutically active agent(s) may be included in the same pharmaceutical composition or may be administered in separate compositions. Furthermore, the use of DP-BAPTA in combination with another therapeutically active agent (or another therapeutic means) may be concurrently or not. The methods of the invention include administration of the DP-BAPTA compound(s) either at the same time, preceding or following exposure to the additional therapeutic agent or procedure.

Additional agents that may be used in combination with the DP-BAPTA compounds may be therapeutic and prophylactic drugs, hormones, immuno-modifying agents etc. and may include other chelating agents, proteins, peptides, carbohydrates, lipidic molecules, DNA and RNA sequences etc.

These agents may be selected from, but are not limited to, anti-neoplastic, anti-proliferative, anti-inflammatory, antibiotic, anti-viral, anti-microbial, anti-mycotic, anti-allergic, cardiovascular agents, anti-convulsant, anti-depressant, anti-psychotic, analgesic, neurological agents, neuroprotective agents and bioactive peptides and proteins such as neurotransmitters, immuno-modulators, growth factors, hormones, antibodies etc.

For example, in the case of treating cancer, the DP-BAPTA compound(s) may be used alone or in combination, concurrently or not, with additional anti-cancer treatment. The additional anti-cancer treatment may include, but is not limited to, chemotherapy, irradiation therapy, immunotherapy, genetic therapy, surgery or any other anti-cancer treatment as known in the art. The additional treatment may be carried out concurrently with or consecutively to the administration of the compounds of the general formula (I), namely the additional treatment may be applied concurrently or successively, either preceding or subsequent to the administration of the compound of the general formula (I). The time interval between the two treatments and the overall regimen will be determined by a person skilled in the art taking into account the specific treated disease and the particular condition and response of the treated individual to the treatment.

Any anti-cancer drug that is suitable for use in chemotherapy procedures may be applied in combination with the compound of the general formula (I). Suitable anti-cancer drugs may include, but are not limited to, alkaloids (e.g. taxol, vinblastine, vindesine and vincristine), alkylating agents such as alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards (e.g. cyclophosphamide) and nitrosoureas, antibiotics and analogs (e.g. aclacinomycin, actinomycin, anthramycin, daunorubicin and doxorubicin), antimetabolites such as folic acid analogs (e.g. Tomudex.RTM.), purine and pyrimidine analogs and platinum complexes (e.g. carboplatin, cisplatin, miboplatin and oxaliplatin).

The combination treatment with additional therapeutic procedures may be beneficial also in treatment of other diseases and disorders. For example, in treatment of inflammatory, neuro- or cardiovascular conditions where the administration of the DP-BAPTA compounds may be in combination with (either concurrently, preceding or subsequent to) surgery and/or treatment with another medicament or therapeutic agent (e.g. antibiotics, antibodies etc.) to remove or kill infectious agents or other pathogenic elements.

It will be readily apparent to those of ordinary skill in the art that a large number of other beneficial drugs, reagents, means or procedures may be useful in the treatment of particular pathological conditions. Pharmaceutical compositions including these therapeutically effective agents and methods applying them or other medical procedures are also included within the scope of the invention as compositions and methods useful in combination with the compounds of the general formula (I). The exact protocol and the additional medicament or therapeutic procedure used, will be determined by a person skilled in the art taking into consideration the particulars of the specific medical condition treated, e.g. the stage of the disease or disorder, its severity and progression, as well as the condition of the patient.

The pharmaceutical compositions comprising the compound of the general formula (I) may be in a liquid, aerosol or solid dosage form, and may be formulated into any suitable formulation including, but not limited to, solutions, suspensions, micelles, emulsions, microemulsions, aerosols, ointments, gels, suppositories, capsules, tablets, and the like, as will be required for the appropriate route of administration.

Any suitable route of administration is encompassed by the invention including, but not being limited to, oral, intravenous, intraperitoneal, intramuscular, subcutaneous, inhalation, intranasal, topical, rectal or other known routes. In preferred embodiments, the useful pharmaceutical compositions are orally or intravenously administered. The dose ranges are those large enough to produce the desired proteinase inhibitory effect. The dosing range varies with the specific DP-BAPTA used, the treated pathological condition and the route of administration and is dependent on the additional treatment procedure, if such additional treatment is applied.

The dosage administered will also be dependent upon the age, sex, health, weight of the recipient, concurrent treatment, if any, frequency of treatment and the nature of the effect desired. The specific dosage, regimen and means of administration will be determined by the attending physician or other person skilled in the art.
 

Claim 1 of 8 Claims

1. A method for treating or managing a metalloproteinase (MMP) or calpain related disease or disorder in a mammal, the disease or disorder being glioma comprising administering to a mammal in need thereof, a pharmaceutical composition comrising a therapeutically effective amount of a compound of the general formula (I) -- see Original Patent.
 

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