PL191793B1 - Method of using cyclo-oxygenase-2 inhibitors as agents acting against overgrowth of vessels - Google Patents

Abstract

This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating angiogenic disorders.

Description

Description of the invention

The present invention relates to the use of cyclooxygenase-2 inhibitors in the manufacture of a medicament for the treatment of diseases related to angiogenesis.

Prostaglandins play a major role in the process of inflammation, and inhibition of prostaglandin production, especially PGG2, PGH2 and PGE2, has become a common target in the discovery of anti-inflammatory drugs. However, common non-steroidal anti-inflammatory drugs (NSAIDs), which actively reduce pain and swelling induced by prostaglandins associated with the inflammation process, also actively influence other non-inflammatory regulated processes by prostaglandins. Thus, the use of high doses of the most common NSAID's can produce severe side effects, including life-threatening ulcers, which limits their therapeutic potential. An alternative to NSAID's is the use of corticosteroids, which also have severe adverse effects, especially when it comes to long-term therapy.

NSAIDs have been found to prevent prostaglandin production by inhibiting enzymes in the human arachidonic acid / prostaglandin biochemical pathway, including the cyclooxygenase (COX) enzyme. The recent discovery of an inducible inflammation-related enzyme (termed cyclooxygenase-2 (COX-2) or prostaglandin G / H synthase II) offers a potential inhibitory target that is more effective in reducing inflammation and with fewer and less drastic side effects.

Vascular development is the development of new blood vessels in a tissue or organ. Under normal conditions, angiogenesis is observed with wound healing and embryonic development. Uncontrolled angiogenesis is associated with neoplastic disease, tumor metastasis, and other diseases related to angiogenesis.

Although glucocorticoids were originally developed for their anti-inflammatory properties, they are now believed to have a wide variety of therapeutic uses. For example, many steroids with anti-inflammatory activity inhibit angiogenesis (US Patent No. 5,646,136).

Compounds that selectively inhibit cyclooxygenase-2 are described in U.S. Patent Nos. 5,380,738, 5,344,991, 5,393,790, 5,434,178, 5,474,995, 5,475,018, 5,510,368, and WO96 / 06840, WO95 / 21817, WO96 / 03387, WO96 / 03388, WO96 / 03388. / 03392, WO96 / 25405, WO96 / 24584, WO96 / 03385, WO96 / 16934, WO95 / 15316, WO94 / 15932, WO94 / 27980, WO95 / 00501, WO94 / 13635, WO94 / 20480, and WO94 / 26731.

[Pyrazol-1-yl] benzenesulfonamides have been described as cyclooxygenase-2 inhibitors, and have shown promise in the treatment of inflammation, arthritis, and pain with minimal side effects in preclinical and clinical trials. Their use to prevent colon cancer is described in US Patent No. 5,466,823. However, their use for the treatment or prevention of diseases associated with angiogenesis has not been described so far.

There are several publications describing the benefits of inhibiting angiogenesis. WO Patent Publication No. 96/19469 describes that COX-2 inhibitors could be useful in the prevention and / or treatment of neoplastic angiogenesis and diabetic retinopathy. However, the structure of these COX-2 inhibitors differs from that of the compounds of the present invention. The compounds of the present invention not only differ from the structure of the compounds of WO 96/06840 and WO 96/19469, but are not obvious in their light. The publications cited, taken together or separately, do not describe or suggest a relationship between selective inhibitors and angiogenesis. They also do not describe or suggest the use of the compounds in the treatment of the conditions mentioned in this specification.

PL 191 793 B1

The invention relates to the use of an effective amount of a cyclooxygenase-2 inhibitor of formula (IIa) or (IIb)

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H- [pyrazol-1-yl] benzenesulfonamide (CELECOXIB)

4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of angiogenesis related diseases including metastasis, new ocular vascularization, new vascularization retinas, diabetic retinopathy, childhood hemangioma and disorders of the female reproductive system.

The above use would be useful for, but not limited to, treating a disorder associated with angiogenesis in a subject. According to the present invention, compounds of formula Ila or IIb are administered to a subject in need of angiogenesis inhibition. These compounds would be useful in the treatment of tumor formation including metastasis; ophthalmological conditions such as corneal transplant rejection, new eye vascularization, new retinal vascularization, including new vascularization after injury or infection, diabetic retinopathy, retrorepenticular fibrosis, and new vessel glaucoma; ulcerative diseases such as gastric ulcer; pathological but benign conditions such as hemangioma, including infantile hemangioma, nasopharyngeal angiofibroma, and avascular bone necrosis; and disorders of the female reproductive system such as endometriosis.

The term treatment includes the partial or complete inhibition of angiogenesis, including neoplastic growth, spread, or metastasis, as well as the partial or complete destruction of neoplastic cells.

The term prevention includes either preventing the onset of fully apparent clinical angiogenesis or preventing the onset of an apparent preclinical angiogenesis in a subject at risk. The term is also intended to include the prevention of malignant cell metastasis or the arrest or reversal of malignant cell growth. This includes prophylactic treatment for those at risk of developing angiogenesis.

PL 191 793 B1

The term therapeutically effective is intended to qualify the amount of each agent that will perform the task of improving disease severity and morbidity in treatment for each agent individually, avoiding the deleterious side effects typically associated with alternative therapies.

The term treated for treatment includes any human or animal being treated who has one of the known angiogenesis disorders. For methods of prevention, any human or animal treated is treated, and preferably any human or animal being treated is treated, and preferably a human at risk of a disorder related to angiogenesis, such as metastasis, is treated. The subject undergoing treatment may be exposed to carcinogens, being genetically predisposed to angiogenesis, etc. In addition to being useful for human treatment, these compounds are also useful for the veterinary treatment of mammals, including domestic and farm animals, such as, but not limited to, to this, horses, dogs, cats, cows, sheep and pigs. Preferably, the subject is human.

Arachidonic acid metabolism inhibitors of the cyclooxygenase pathway for the prevention and treatment of angiogenesis may inhibit enzyme activity through a variety of mechanisms. For example, the inhibitors used in the methods described herein can block the activity of the enzyme by directly acting as a substrate for the enzyme. The use of selective cyclooxygenase-2 inhibitors is highly advantageous in that it minimizes gastric side effects that can occur with non-selective NSAID's, especially when long-term prophylactic treatment is anticipated.

The term cyclooxygenase-2 inhibitor means a compound capable of inhibiting cyclooxygenase-2 without significantly inhibiting cyclooxygenase-1. Preferably, it includes compounds that have an IC50 of cyclooxygenase-2 of less than about 0.2 mM, and also have a proportion of cyclooxygenase-2 inhibition selectivity to inhibition of cyclooxygenase-1 of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC50 of greater than about 1 mM, and more preferably greater than 10 mM.

The compounds used according to the invention may be present as free bases or as pharmaceutically acceptable acid addition salts thereof. The term pharmaceutically acceptable salts includes alkali metal salts and refers to free acid or free base addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of formula I can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Suitable organic acids may be selected from the group consisting of the classes of organic aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, etc. ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, methanesulfonic, 4-hydroxybenzoic, phenylacetic, almond, embonic (pamoic), methanesulfonic, ethanesulfonic, benzetenesulfonate, sulfonic sulfonate, tetraethenesulfonic sulfonic acid , stearic, algene, hydroxybutyric, salicylic, galactar and galacturonic. Useful pharmaceutically acceptable base addition salts of compounds of Formula I include the metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts of N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared by conventional methods from an appropriate compound of formula I by reacting, for example, the appropriate acid or base with a compound of formula I.

Cyclooxygenase-2 inhibitor compounds of the invention can be synthesized according to Scheme I.

PL 191 793 B1

Synthetic Scheme I shows the preparation of cyclooxygenase-2 inhibitor compounds including compounds of formula Ia and IIb as described in US Patent No. 5,521,207 and WO95 / 15316, which is hereby incorporated by reference. In step 1, ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester or an ester equivalent to give diketone intermediate 2 (as enol) which is used without further purification. In step 2, the diketone 2 in an anhydrous protic solvent such as absolute ethanol or acetic acid is treated with a substituted hydrazine hydrochloride or free base at reflux to give a mixture of pyrazoles 3 and 4. Recrystallization or chromatography gives 3 usually as a solid. Similar pyrazoles can be prepared by the methods described in U.S. Patent Nos. 4,146,721, 5,051,518, 5,134,142, and 4,914,121, which are also incorporated by reference.

PL 191 793 B1

Scheme II shows the four-step procedure for the preparation of pyrazoles 8 are inhibitors of cyclooxygenase-2 as described in United States Patent No. 5,486,534 (where ^Ra is hydrogen or alkyl) from ketones 5. In step 1, ketone 5 is reacted with a base, such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide (LDA) to give the anion. In step 2, the anion is reacted with an acetylating reagent to give the diketone 6. In step 3, the reaction of diketone 6 with hydrazine or a substituted hydrazine gives pyrazole 7. In step 4, the pyrazole 7 is oxidized with an oxidizing reagent, such as oxone ^® (potassium peroxymonosulfate) , 3-chloroperbenzoic acid (MCPBA) or hydrogen peroxide to give a mixture of the desired 3- (alkylsulfonyl) phenyl-pyrazole 8 and the 5- (alkylsulfonyl) phenyl-pyrazole isomer. The desired pyrazole 8, usually a white or pale yellow solid, is obtained pure by chromatography or recrystallization.

Alternatively, the diketone 6 can be formed from the ketone 5 by treatment with a base such as sodium hydride in a solvent such as dimethylformamide followed by reaction with the nitrile to provide the amino aminoone. Acid treatment of the aminocetone forms the diketone 6. Similar pyrazoles can be prepared by the methods described in US Patent No. 3,984,431, which is hereby incorporated by reference.

Scheme III

Diaryl / heteroarylthiophenes as inhibitors of cyclooxygenase-2 (where T is S and R ^b is an alkyl group) can be prepared by the methods described in U.S. Patent Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT documents WO95 / 00501 and WO94 / 15932, which is hereby incorporated by reference. Similar pyrroles (where T is N); Furanones and furans (where T is O) can be prepared by the methods described in PCT documents WO 95/00501 and WO94 / 15932, and in EP799823.

PL 191 793 B1

Diaryl / heteroaryloxazoles as cyclooxygenase-2 inhibitors can be prepared by the methods described in US Pat. Nos. 3,743,656, 3,644,499 and 3,647,858, and PCT documents WO95 / 00501 and WO94 / 27980, which is incorporated by reference. Equivalent oxazole compounds can be prepared by WO96 / 19463 and WO6 / 19462.

PL 191 793 B1

Diaryl / heteroarylisoxazoles as cyclooxygenase-2 inhibitors can be prepared by the methods described in US Patent No. 5,633,272, PCT Documents WO / 05162, and WO92 / 19604, and European Patent No. 26928, which is incorporated by reference. Sulfonamides 24 can be formed from isoxazole 23 hydrate in a two step procedure. First, the hydrated isoxazole 23 is treated at about 0 ° C with two or three equivalents of chlorosulfonic acid to give the corresponding sulfonyl chloride. In the second step, the sulfonyl chloride thus formed is treated with concentrated ammonia to obtain the sulfonamide derivative 24.

Scheme VI shows the three step preparation of the cyclooxygenase-2 inhibitors of the imidazoles of the present invention. In step 1, the reaction of substituted nitriles (R ¹ CN) 25 with primary phenylamines 26 in the presence of organoaluminum reagents such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, diethylaluminum chloride in the presence of inert solvents such as toluene, benzene, and xylene gives the amidines 27. step 2, reacting amidine 27 with 2-haloketones (where X is Br or Cl) in the presence of bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, or hindered tertiary amines such as N, N'-diisopropylethylamine , gives 4,5-dihydroimidazoles 28 (where R ^b is an alkyl group). Some of the solvents useful for this reaction are isopropanol, acetone, and dimethylformamide. The reaction can be conducted at a temperature of about 20 ° C to about 90 ° C. In the step 3,4,5-dihydroimidazoles 28 can be dehydrated in the presence of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to give the 1,2-disubstituted imidazoles 29 of the invention. Useful solvents for this dehydration step are, for example, toluene, xylene and benzene. Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.

₃

In some cases (e.g., where R ³ = methyl or phenyl), intermediate 28 may not be easy to isolate. The reaction under the conditions described above goes directly to the formation of the target imidazoles.

Similarly, imidazoles can be prepared having sulfonylofenylową residue attached at position 2 and _one R ¹ attached at the nitrogen atom at position 1. Diaryl / heteroaryl imidazoles can be prepared by the methods described in United States Patent No. 4,822,805, U.S. Patent Application Nos 08 / 282.395 and PCT document WO 93/14082, which is hereby incorporated by reference.

PL 191 793 B1

The imidazole compounds 36, which are the object of the present invention as cyclooxygenase-2 inhibitors, can be synthesized according to the sequence outlined in Scheme VII. The aldehyde 30 can be converted to protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (ZnI2) or potassium cyanide (KCN). Reacting cyanohydrin 31 with a strong base followed by treatment with benzaldehyde 32 (where R ² is an alkyl group) and using both acid and base treatments in that order yields benzoin 33. Examples of strong bases useful for this reaction are lithium diisopropylamide (LDA ) and lithium hexamethyldisilazide. Benzoin 33 can be converted to dibenzoyl 34 by reaction with a suitable oxidant such as bismuth oxide or manganese dioxide, or by Swern oxidation using dimethylsulfoxide (DMSO) and trifluoroacetic anhydride. Dibenzoyl 34 can be obtained directly by reacting the cyanohydrin anion 31 with a substituted benzoic acid halide. Any of compounds 33 and 34 can be used as intermediates for conversion to imidazoles 35 (where ^R2 is alkyl) according to the procedures of chemical known to those skilled in the art and described by MR Grimmett, Advances in imidazoles Chemistry in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 34 to imidazoles is carried out by reaction with ammonium acetate and an appropriate aldehyde (R ³ CHO) in acetic acid. Benzoin 36 can be converted to imidazoles 38 by reaction with formamide. In addition, benzoin 36 can be converted to imidazoles by first acylating the appropriate acyl group (R ³ CO-) and then treating with ammonium hydroxide. Those skilled recognize that the oxidation of the sulfide (where R ² is methyl) to the sulfone can be carried out at any point en route starting from compounds 35, and including oxidation of imidazoles 38, using, eg. Reagents such as hydrogen peroxide in acetic acid, m- chloroperbenzoic acid (MCPBA) and potassium peroxymonosulfate (oXONE ^®).

PL 191 793 B1

Diaryl / heteroarylimidazoles can be prepared by the methods described in U.S. Patent Nos. 3,707,475, 4,686,231, 4,503,065, 4,472,422, 4,372,964, 4,576,958, 3,901,908, U.S. Patent Application No. 08 / 281,903, European Patent No. 372,445, and document No. 00501, which is hereby incorporated by reference.

Diaryl / heteroarylcyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in US Patent No. 5,344,991, and PCT document WO 95/00501, which is hereby incorporated by reference.

Scheme IX

PL 191 793 B1

Similarly, Synthetic Scheme IX shows a procedure for the preparation of 1,2-diarylbenzene cyclooxygenase-2 inhibitors 44 from 2-bromo-biphenyls intermediates 43 (prepared similarly to those described in synthetic scheme (VIII) and the appropriate substituted phenylboronic acids. Using a coupling procedure similar to that developed. by Suzuki et al [Synth. Commun., 11, 513 (1981)], intermediates 43 are reacted with boronic acids in toluene / ethanol at reflux in the presence of a Pd ⁰ catalyst, e.g., tetrakis (triphenylphosphine) palladium ( 0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene anti-inflammatory agents 44 of the present invention. Such terphenyl compounds can be prepared by the methods described in PCT patent WO96 / 16934, which is incorporated by reference.

Diaryl / heteroarylthiazoles as cyclooxygenase-2 inhibitors can be prepared by the methods described in US Patent Nos. 4,051,250,4,632,930, European Patent Application 592,664, and PCT Documents WO96 / 03392 and WO95 / 00501, which are incorporated by reference. Isothiazoles can be prepared as described in PCT WO95 / 00501.

Diaryl / heteroarylpyridines as cyclooxygenase-2 inhibitors can be prepared by the methods described in US Patent Nos. 5,169,857, 4,011,328, 4,533,666, and WO96 / 24584 and WO96 / 24585, which are hereby incorporated by reference.

Biological evaluation

Anti-vascular activity test

To determine the effect of COX-2 inhibitors on angiogenesis in vivo, we tested selective compounds in a micro-pocket test in the stratum corneum of mice and rats. A micro-pocket model of neovascularization of the stratum corneum of the mouse was made using materials, reagents and procedures essentially as described by Muthukkauppah et al., J. Natl. Cancer Inst., 69, 699708 (1982). In this test, a pellet containing basic fibroblast growth factor (FGF) was implanted into the stroma of the stratum corneum of the epidermis and newly formed vessels were measured using a slit lamp. In this model, COX-2 is expressed in the endothelial cells of the newly formed blood vessels. The COX-2 inhibitor, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide inhibited FGF-induced angiogenesis in mice (70-90%) at a dose of 6 mg / kg / day.

In the rat micro-pocket test, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, administered only once, inhibited FGF-induced angiogenesis (~ 90%).

We also determined the activity of the COX-2 inhibitor (4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide) on the stratum corneum of mice using a different angiogenesis stimulus, the vascular endothelial factor growth (VEGF). In this model, angiogenesis was inhibited (~ 50%) when the compound was administered at 6 mg / kg.

Metastasis model

The Lewis mouse lung cancer assay is performed as described by I. Anderson et al. [Can. Res., 56, 715 (1996)]. The COX-2 inhibitor is effective in inhibiting metastasis in this model.

A pharmaceutical composition for treating a vascular development disorder comprises a therapeutically effective amount of a compound of the invention in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to herein as carrier materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted to such a route, and in an effective dose for

The treatment intended. The active compounds and composition can, for example, be administered orally, intravascularly, intraperitoneally, intranasally, intrabronchially, subcutaneously, intramuscularly, or topically (including aerosol). If angiogenesis is localized, local administration with non-systemic administration is preferred. A formulation in a lipid carrier can be used to increase bioavailability.

Administration can be for the purpose of either prevention or treatment. The methods and compositions used herein can be used alone or in combination with additional therapies known to those of skill in the art of preventing or treating angiogenesis. Alternatively, the methods and compositions described herein can be used as adjunctive therapy. For example, a cyclooxygenase-2 inhibitor can be administered alone or in combination with other anti-cancer agents or other growth inhibitory agents or other drugs or nutrients.

There are a large number of antineoplastic agents available commercially, in clinical trials, and in preclinical development that can be selected for the treatment of angiogenesis by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic agents, alkylating agents, anti-metabolite agents, hormonal agents, immunological agents, interferon agents, and miscellaneous agents categories. Alternatively, other anti-cancer agents such as matrix metalloproteinase (MMP) inhibitors such as MMP-13 inhibitors including batiastat, marimastat, Agouron Pharmaceuticals AG-3340, and Roche RO-32-3555, or avb3 inhibitors can be used.

A first family of anti-neoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor include anti-neoplastic agents of the anti-metabolite type. Useful anti-metabolite anti-neoplastic agents may be selected from the group consisting of 5-FU-fibrinogen, acantipholic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine stearate phosphate, Dovrelan DDATF conjugates, Dovrelan DDATF, Lilly-LillydATF conjugates, Dovrelan DDATF. dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrolizine, Lilly LY188011, Lilly LY-264618, methobenzaprim, Wellcome, methotrexate MZPES, norspermidine, NCI NSC127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PLAC, Takeda TAC-788, thioguanine, Erbrexonturine TIF, Trimetrexonturine TIF , tyrosine kinase inhibitors, protein tyrosine kinase inhibitors, Taiho UFT, and uricytin.

A second family of anti-cancer agents that can be used in combination with a selective cyclooxygenase-2 inhibitor are alkylating-type anti-cancer agents. Useful alkylating-type antineoplastic agents may be selected from the group consisting of Shionogi 254S, aldo-phosphamide analogs, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chlorambucin-153, chlorambucin-153, , cisplatin, cyclophosphamid, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-210914R, IT , Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-264395, NCI 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK & F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teretreloxlatyne, and tetrelamolatyne.

A third family of anti-cancer agents that can be used in combination with a selective cyclooxygenase-2 inhibitor are antibiotic-type anti-cancer agents. Useful antibiotic type antineoplastic agents can be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplizinin derivatives, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anthracomycins, azino-anthracomycins mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol- Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate , bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, Kyowa Hakko DC92-B, Bitrisarubicin , Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa glidobact -A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hak PL 191 793 B1 ko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin , Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxalysin, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, sibitomomicin, sibitomomycin, sibitomomycin SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of anti-cancer agents that can be used in combination with a selective cyclooxygenase-2 inhibitor includes a family of various anti-cancer agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide , amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, Byphs-Ips-benrufflourracylin, 230IM , bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromophosphamide, Wellcome BW-502., Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfachinoxalone, Chemes CHK-2053, Chemex CHK-100, Warner Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnat ol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, NM Glaxo GR-63178, grifolanocholine Fecyl Cross-Hephosol Fecyl Cross HO -221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukorein , lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide , mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N (retinooyl) amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, naphazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC604782, NCI NSC-95580, ONreotide, Ono 112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, pyroxantrone, polyhaematoporphyrin, polyprenic acid , Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoksane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, RhonePoulenc RP-56976, SmithKline SK & F- 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strrypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506 -680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak JB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulphan, vincristine, vindesine, vinestramid, vinorelbine, vintriptol, vinolidzolidine, withanolidzolidine, with and Yamanouchi YM-534.

Examples of radioprotective agents that can be used in the combined chemotherapy of the present invention are AD-S, adchnon, amifostine analogs, detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanine, TGF-Genentech, tiprotimod, amifostine, WR -151327, FUT-187, Ketoprofen Transdermal, Nabumetone, Superoxide Dismutase (Chiron) and Enzon Superoxide Dismutase.

Methods for preparing the anti-cancer agents described above can be found in the literature. Methods for producing doxorubicin, for example, are described in US Patent Nos. 3,590,028 and 4,012,448.

Methods for producing matrix metalloprotease inhibitors are described in EP 780386, WO97 / 20824, WO96 / 15096. Methods of making SOD mimics are described in EP 524,101. Methods for producing avb3 inhibitors are described in WO97 / 08174.

In addition, a selective COX-2 inhibitor may be administered in conjunction with other anti-inflammatory agents for maximum safety and efficacy, including NSAID's, selective inhibitors,

PL 191 793 B1

COX-1 and inhibitors of the leukotriene pathway of biochemical transformations, including inhibitors of 5-lipoxygenase. Examples of NSAID's include indomethacin, naproxen, ibruprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, etodolacrofenbutazone, oxyfenbutazone, oxyfenbutazone, oxyfenbutazone.

The term adjunctive therapy (or combination therapy), in terms of the use of a cyclooxygenase-2 inhibitor and one or more pharmaceutical agents, is intended to include administering each agent sequentially in a regimen that will provide the beneficial effects of the combination of drugs, and is also intended to include co-administration of these agents in essentially simultaneous method, such as in a single preparation having a constant proportion of these active agents, or in multiple, separate preparations for each agent.

A pharmaceutical composition for oral administration may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules, or suspension, with customary additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection as a composition in which, for example, saline, glucose or water can be used as a suitable carrier.

For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, the compound can be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.

Such preparations can be prepared by dissolving the solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, etc., and having a buffered pH compatible with physiological conditions to form an aqueous solution, and sterilizing the solution. The formulations can be presented in unit-dose or multi-dose containers such as sealed ampoules or vials.

If the angiogenesis is localized in the gastrointestinal tract, the compound can be prepared with acid-resistant, alkali-labile coatings known in the art that begin to dissolve at a high pH of the small intestine. Preparations that enhance the local pharmacological action and reduce systemic absorption are preferred.

Formulations suitable for parenteral administration conveniently contain a sterile aqueous preparation of the active compound, which is preferably isotonic. Injectables can also be formulated by suspending or emulsifying the compounds in a non-aqueous solvent such as vegetable oil, synthetic fatty acid glycerides, higher aliphatic acid esters, or propylene glycol.

Topical formulations include known gels, creams, oils, etc. For aerosol delivery, the compounds may be formulated with known aerosol excipients such as saline and administered using commercially available nebulisers. A fatty acid formulation can be used to increase the biocompatibility. Aerosol delivery is the preferred method of prophylactic delivery in pulmonary vascular development.

For rectal administration, the active ingredient can be formulated as a suppository using base materials which are solid at room temperature and which will melt or dissolve at body temperature. Base materials typically used include cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene stearate.

The dosage form and amount can be readily determined by reference to known treatment or prophylactic regimens. The amount of therapeutically active compound to be administered and the dosage regimen for treating a disease state with the compounds and / or compositions of the present invention depends on a variety of factors including the age, weight, sex and medical condition to be treated, the severity of the disease, the route and frequency of administration, and the particular compound employed, the location of the angiogenesis as well as the pharmacokinetic properties of the subject being treated, and thus may vary widely. The dosage will generally be lower when the compounds are administered topically, not systemically, and prophylactically rather than therapeutically. Such treatment can be administered as often as necessary and for a period of time deemed necessary by the attending physician. One skilled in the art will recognize that the dosing regimen or therapeutically effective amount of inhibitor administered may need to be optimized for each individual. The pharmaceutical compositions may contain the active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 200 mg. A daily dose of about 0.01 to 100 mg / kg body weight, preferably between about 0.1 and about 50 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

Claims (1)

Patent claim Use of an effective amount of a cycloxygenase-2 inhibitor of formula (IIa) or (IIb) 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H- [pyrazol-1-yl] benzenesulfonamide (CELECOXIB) 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of angiogenesis related diseases including metastasis, new ocular vascularization, new vascularization retinas, diabetic retinopathy, childhood hemangioma and disorders of the female reproductive system.