UA112152C2 - POLYMORPH FORM OF 5-AMINO-1- (4- (4-CHLOROBENZOIL) -3,5-DICHLOROBENZYL) -1,2,3-TRIAZOLE-4-CARBOXAMAMIDE RELATED TO OXIDE ACID (TARISOTHYAN) ЇЇ APPLICATIONS IN DISEASE TREATMENT - Google Patents

Abstract

The invention discloses the polymorphic forms of 5-amino-1- (4- (4-chlorobenzoyl) -3,5-dichlorobenzyl) -1,2,3-triazole-4-carboxamide, bound with oroic acid, where the acetic acid is ion-bonded in a ratio of base: acid in the range from 1: 1 to 1: 4, and methods for their preparation. The compounds are suitable for use in the control and treatment of diseases, including, but not limited to, solid tumors, macular degeneration, retinopathy, chronic myeloid leukemia, AIDS, and diseases caused by aberrant signaling. Improved processes for the preparation of orotate preparations use a stable, effective and safer starting azide in the synthesis of carboxyamidotriazole polymorphs.

Description

This application is a continuation-in-part of US patent application Mo 12/584,448, filed September 4, 2009, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to new chemical compounds of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives (indicated in this document as carboxyamidotriazoles or SAI), technologies for the production of preparations of 5-amino- or substituted amino orotates -1,2,3-triazoles, as well as their substituted derivatives, (3 determined by base:acid, SRT ratios), production technologies of 5-amino orotates or substituted amino-1,2,3-triazoles, as well as their substituted derivatives and orotic acid (with defined ratios of base:acid, CAC) and safer manufacturing processes of the aforementioned, using stable, more effective and safer starting materials for the synthesis of intermediate azide compounds necessary in the synthesis of SAI and orotate drugs -

STO and SAS. In particular, the invention relates to new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives. The present invention even more specifically relates to novel 5-amino- or substituted amino-1,2,3-triazole oorotates (SRTs with optimal base:acid ratios in the range of 1:1 to 1:4), as well as 5-amino drugs - or substituted amino-1,2,3-triazoles, as well as their substituted derivatives and orotic acid (SAC) with an optimal base:acid ratio of 1:1 to 1:4, and the use of the aforementioned for the control and treatment of diseases, including but not limited to, solid cancers, macular degeneration, retinopathy, chronic myeloid leukemia, AIDS, and diseases caused by aberrant signal transmission and propagation.

PREREQUISITES FOR THE CREATION OF THE INVENTION

This invention relates to the field of creation of new polymorphs of 5-amino or substituted amino-1,2,3-triazoles (SAI), as well as their substituted derivatives, orotates of 5-amino- or substituted amino-1,2,3-triazoles, and as well as their substituted derivatives, and production technologies of 5-amino- or substituted amino-1,2,3-triazole preparations, as well as their substituted derivatives and orotic acid (in optimal base:acid ratios). The goal is to develop new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives, to improve chemical, biological, pharmacokinetic and toxicokinetic properties and improve therapeutic properties, including, but not limited to, anticancer activity, antimetastatic activity, calcium-mediated signal transduction, antiangiogenic, anti-

RIZ, anti-COX2, apoptosis, negative feedback of VSV-AVI protein in chronic myeloid leukemia, regulation of transcription AND AND HIV or anti-MESRI properties.

In 1986, it was shown that 5-amino- or substituted amino-1,2,3-triazole compounds, as well as their substituted derivatives, have anticoccidial activity. US Patent Mo 4,590,201, published in...

Vosniv et al., 1986, describes a method of obtaining 5-amino-1-(4-(4-chlorobenzoyl|-3,5-dichlorobenzyl)-Y, 2,3-triazole-4-carboxamide (1651582 or CA), which involves the use of sodium azide in the synthesis of one of the main intermediate compounds, 3,5-dichloro-4-(4-chlorobenzoyl)benzyl azide.

Later it was shown that 1651582 or SA! inhibit specific signaling pathways, including those involved in intracellular calcium entry, arachidonic acid release, and inositol phosphate formation. US Patent 5,359,078, published by ES Konp et al., 1994. "|651582" as used herein is 16515182, SAI, carboxyamidotriazole, M5C 609974 or 99519-84-3, described in the prior art.

In US Patent Mo. 5,912,346, published by EP. MUeyptapy, in 1999, in addition, inorganic and organic salts 651582 are described, and, in particular, the method of obtaining an orotate salt is described

Y651582. 1651582 was obtained by the method described in US Pat. No. 4,590,201.

II651582:orotate was in a ratio of 2:11 (base:acid) as characterized by proton NMR spectroscopy and has a melting point of 234-235 "С. As described above, the synthesis of the intermediate compound 3-(4-chlorobenzoyl)-4-chlorobenzylazide was carried out , using the intermediate 3-(4-chlorobenzoyl)-4-chlorobenzoyl bromide and sodium azide in ethanol, U.S. Patent No. 5,912,346 describes the improved antitumor activity of orotate

I 651582 (SAI orotate, base: acid, 2:1) compared with the equivalent dose of I 651582 in the model

Dunning (Yuppipd) on rats of androgen-independent H-3227-AT-1 prostate cancer.

Carboxyamidotriazole, 1651582, SAI, MOSS 609974 or 99519-84-3, an inhibitor of calcium-mediated signal transduction, is one of the first discovered anticancer drugs that is an inhibitor of cytostatic signaling. It was tested on patients suffering from solid cancers in phase I, phase II and phase II, the trial was conducted at the National Cancer Institute (Maiyopa! Sapseg Ipziytsiye). However, MS! discontinued development of I 651582 because the drug failed to demonstrate efficacy in human trials and/or was concerned about poor bioavailability, severe gastrointestinal toxicity, neurotoxicity, and tolerability issues that prevented optimal dosing for therapeutic effect. Capsules of the micronized drug were used in clinical studies

II 651582 in PEG-400 to improve the bioavailability of the drug. Kopp ES ei ai... Siipisai

Sapseg Vez 7:1600-1609 (2001); Vatseg KZ ey ai... Siipisa! Sapseg Kez 5: 2324-2329 (1999); Vepip ei ai., In Siip Ope 15: 781-789 (1997); Vepip .) hey a... Siiiipisa! Sapseg ge5 8: 86-94 (2002); Mavyi Nei a!., U Vioi Speth 45:28762-28770 (1997); AIezzapago R ei ai., In SeiII Rnuzio! 215:111-121 (2008).

Therefore, orotate 1651582 (base:acid 2:1), described in US patent Mo 5,912,346, which improved the efficacy of I 651582, based on pre-clinical studies, represented a potential path to the rescue of this promising drug. However, problems were encountered in the scale-up process of obtaining orotate 165I582 (base:acid ratio 2:1) in large quantities, according to the method described in US Pat. No. 5,912,346. and on TBDMS -SI /-/ imidazole a. OTBDMS stage one ----

DMAP, DMF type si si 8BBA1 3,5-dichlorobenzyl alcohol si o «-403-4 si a xporbenzoyl chloride DMAP, ZOS , heptane s

Stage two ----h"" x lumo thread stage three

Shensi V rportany refrigerator 8588

SI SI

SI SI

--- si i o Mother, NebiDHM m o, o Stage four

Si Si 858C 8580 mn nmer o s a » acetonitrile s si M osiam usho 8 orotic acid hydrate a g Stage six g u . methanol/water si fi si Ff vo u son 858E

Regarding the use of orotic acid to enhance the analgesic effect of drugs, US Patent No. 4,061,741, claimed by U/amteizsnek MU et al., 1977, describes the use of pravopropoxyphene-HCI, levopropoxyphene-HCI, or sodium silicylate in combination with choline orthoate, and concludes that the composition of the drug in combination with choline orthoate showed the best effect. Of course, the prior art presents conflicting teachings about the proportions and chemical nature of the binding of orotic acid to chemical compounds.

The synthesis scheme described in the prior art for orotate I 651582 is shown in the synthesis scheme I above. 858 is the identifying product, for example, 858A to 8580 are intermediate compounds. 858EE is a carboxyamidotriazole (CA!) 858E is a carboxyamidotriazole:orotic acid or carboxyamidotriazole:orotate, or STO as defined herein.

The proposed method of using choline orotate in combination with a drug is a preferred embodiment. Unfortunately, this did not solve the problems encountered in the presented invention when expanding production for clinical studies. It was unclear how the base:acid ratio in I 651582 orotate (271) was the optimal chemical structure for the drug. In addition, problems arose when the scale-up of production of I 651582 orotate (2:1) reached large industrial quantities.

Few plants had the equipment and facilities necessary to process large quantities of sodium azide, and such contractors had the facilities, resulting in high prices for services.

After the protection of the alcohol group in 3,5-dichlorobenzyl alcohol, as in the TBDMS ether stage (stage I), the ether reacts with 4-chlorobenzoyl chloride to form a substituted benzophenone (stage 2).

Benzophenone is treated with thionyl chloride (step 3) and then with sodium azide (step 4) to give 3,5-dichloro-4-(4-chlorobenzoyl)benzyl azide. Reaction of such azide with cyanoacetamide leads to 1/651582 (step 5). The reaction of 651582 with orotic acid gives

And 651582 orotate (21) (stage 6).

The use of sodium azide in the above process at stage 4 was a serious drawback for expanding the production of I 6515182 orotate in large quantities. Work with large quantities of sodium azide must be carried out in special pressure-sensitive reactors, because sodium azide is a dangerous substance with a high energy density. When working with sodium azide, special protective equipment was required, which usually increased the cost of production, since some manufacturers of the drug had the general production capacity to scale up the process to large quantities of the drug. This is because sodium azide is a fast-acting, potentially lethal chemical that exists as a white, odorless solid. When mixed with water or acid, sodium azide quickly turns into a toxic gas with a pungent odor. It also turns into a toxic gas when in contact with metals in the solid state. Survivors of severe sodium azide poisoning can have heart and brain problems, and the Centers for Disease Control and Prevention (CDC) advises victims to call a hotline immediately. (SOb-Rasiv Aroshi Bodiit A?gide, 2009). It is clear that it was necessary to develop a safe, new, affordable and efficient process for obtaining orotate I 651582 without the use of sodium azide. Competitive prices at an affordable cost were not possible because sodium azide (step 4) was necessary to obtain the intermediate compound: 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide,

Zo in the method of synthesis of orotate I 651582, as shown above. In this regard, it was necessary to develop an alternative, safe, more effective process for obtaining drug orotate with an optimal chemical configuration and base:acid ratio. The presented invention seeks to overcome these disadvantages.

Although orotate I651582 has been shown to have significantly higher antitumor activity in a rat model of prostate cancer (US Patent No. 5,912,346), there has been no idea or suggestion as to whether or not there are any chemical, pharmacological, or biological properties of orotate I651582 in the base:acid ratio. 2:11 a.m. Obviously, it is necessary to develop new polymorphs of SA! and orotate of the SAI compound, which exhibits optimal chemical, biological, pharmacological, therapeutic and toxicokinetic characteristics, confirmed by clinical studies.

Thus, the primary objective of the invention was to develop a preparation of SAI orotate (where the base:acid ratio is in the range of 17 to 1:4) that has improved efficacy, which is related to its bioavailability, which in turn depends on its solubility in fluids of the human body.

Another goal of the invention was to develop a safer, more cost-effective process for obtaining large quantities of SAI, STO (in the form of SAI orotate) and CAO (in the form of a drug

SAI mixed with orotic acid).

An important goal of the invention was to make SA safer! using safer and less toxic ingredients to produce intermediates instead of using sodium azide or potassium azide, which are highly toxic at very low concentrations. It was established that SAI, obtained by the method described in the prior art, causes serious neurotoxicity and gastrotoxicity in patients. Thus, it was important to use safer ingredients and an improved manufacturing process also resulted in new polymorphs of SAI and its orotate preparations.

The directly related object of the above references is specifically incorporated herein by reference in its entirety.

ABSTRACT OF THE INVENTION

The presented invention seeks to overcome the shortcomings known from the state of the art, providing compositions of new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives (indicated in this document as carboxyamidotriazole and or SAI);

technologies for obtaining orotate preparations of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives (with defined ratios of base: acid, SRT); and technologies for obtaining orotate preparations of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives and orotic acid (3 determined base:acid ratios, CAO).

The presented invention relates to safer processes for the production of the above-mentioned drugs, using stable, more effective and safer starting substances for the synthesis of intermediate azide compounds necessary in the methods of synthesis of SAI and orotate drugs - STO and CAO.

More specifically, the invention relates to new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles (SAI), as well as their substituted derivatives. SAI exists in several polymorphic forms, including, but not limited to, form 1 or form 2.

The present invention even more specifically relates to 5-amino- or substituted amino-1,2,3-triazole orotates (STOs with optimal base:acid ratios ranging from 1:1 to 14), as well as 5-amino- or substituted amino preparations -1,2,3-triazoles, as well as their substituted derivatives and orotic acid (SAC) in optimal base:acid, orotate (STO) ratios, as well as their substituted derivatives.

In another aspect, the invention relates to a method for the production of azide intermediates required for synthesis using stable, safer and affordable starting materials, including but not limited to diphenylphosphoryl azide or trimethylsilyl azide,

TM5M, instead of sodium azide or potassium azide.

More specifically, the present invention relates to new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives, their orotate derivatives (STO) (base:acid ratio in the range from 1:11 to 1: 4) and the use of the above in the treatment of diseases including, but not limited to, solid cancers, macular degeneration, retinopathy, chronic myeloid leukemia, AIDS and diseases that are caused by aberrant signal transmission and propagation, such as a potential independent calcium channel blocker, RIZ, SOH2, VSV-AVI,, apoptosis, NIM and TA transcription or MESRI.

In view of the above-mentioned state of the art, the present invention relates

From orotate derivatives of new 5-amino- or substituted amino-1,2,3-triazole or carboxyamidotriazole orotate (STO), containing a chemical organic residue that increases their bioavailability, delivery to the target, antitumor efficacy and reduced toxicity.

In particular, one of the orotate classes of carboxyamidotriazoles (STO) having ionic bonding in a ratio ranging from about 1:1 to 1:4 (triazole: orotic acid) forms new compounds of the invention.

In addition, preparations of 5-amino- or substituted amino-1,2,3-triazole (SAI), as well as their substituted derivatives, and orotic acid (with defined ratios of base: acid, from 171 to 1:4, CAO )

In another aspect, the invention relates to a process for the production of azide intermediates

of 3,5-dichloro-4-(4-chlorobenzoyl)benzyl without using sodium azide, but instead using diphenylphosphoryl azide (DFPA), or TMMIz, or safer azide equivalents.

DFFA is much safer than sodium azide and is used to directly convert alcohols into azides, and therefore eliminate the stage (stage C in the above scheme) in the method of synthesis of sto.

Another object of the invention is to increase the bioavailability of the SRT when administered orally or by other routes to humans and other mammals, and to improve the delivery of the SRT to the target, for example, by improving the absorption, delivery and transport through tissues, the blood-brain barrier and the choroid-retinal complex.

Another object of the invention is to reduce the toxicity of SRT and related compounds when administered in the form of orotate salts, by increasing the removal of the drug from the blood, tissues and organs.

In addition, the invention can be used to reduce drug interactions and side effects when STO or SAI is administered in combination with orotic acid (SAC) in the form of preparations. Another object of the invention is to provide SRT compositions for the treatment of neoplasms in humans, namely, primary or metastatic tumors, diseases involving neovascularization (formation of new vessels), such as macular degeneration, retinopathy, diabetic retinopathy, chronic myeloid leukemia, AIDS and diseases that are caused by aberrant signal transmission and propagation, such as potential-independent calcium channel blocker, RIZ, COX2, VSV-AVI, apoptosis, NIM and transcription or MES, and because the reduction of toxic side effects of the drug by reducing the levels of the drug in non-cancerous tissues , which are sensitive targets to the toxicity of the drug, from 10 95 to 100 95 compared to those provided by I 651582 or SAI.

A preferred embodiment of the invention includes SRT in a ratio of base:acid from 1:1, a more preferred embodiment - in a ratio of 1:2, and the most preferred embodiment of the invention includes compositions of SRT (in a ratio of about 0.7:1.3), obtained according to the new process of the invention, for the treatment of diseases including, but not limited to, solid cancers, macular degeneration, retinopathy, chronic myeloid leukemia and modulation of signaling pathways such as RIZ, COX2, VSV-AVI, 5TAT5, SIKI, apoptosis, NIM AND AND transcription,

ME or others.

BRIEF DESCRIPTION OF FIGURES

Fig. 1 illustrates the structure of STO according to NMR data, as SAGorotic acid or SAGorotate, of sample STO 902642, having form 1 or polymorphic sample 1 of SAI.

Fig. 2 illustrates the NMR structure of STO, as SAGorotic acid or SAGorotate, of sample STO 202643, having form 2 or polymorphic sample 2 of SAI.

Fig. C illustrates a high-resolution diffraction pattern of SRT sample 902642, which has form 1 or polymorphic sample 1 of SAI.

Fig. 4 illustrates a high-resolution diffraction pattern of STO sample 902643, which has a form 2 or polymorphic sample 2 SAI.

Fig. 5 illustrates the IR and Fourier transform of STO sample U02642, which has form 1 or polymorphic sample 1 of SAI.

Fig. b illustrates the IR and Fourier transform of STO sample U02643, which has form 2 or polymorphic sample 2 SAI.

DETAILED DESCRIPTION OF THE INVENTION

The presented invention relates to new polymorphs of 5-amino- or substituted amino-1,2,3-triazoles or their substituted amino-1,2,3-triazoles (CA), obtained by a new method and includes the class of compounds of formula I. New polymorphs of CA ! include, but are not limited to, Form 1 or Form 2 as characterized by techniques such as NMR, DSC (Differential Scanning Calorimetry), Fourier Transform IR and X-ray powder diffractometry.

The formula is the same, / in M le

Zo ; in which Ri has the formula II, where,

You are (Kv)a and --AOK (Ka)t derevidoOdo2; tevidO to 4; tap is from O to 5;

X is 0, 5, 50, 50", CO, CHOM, SNeo or C-MP5b, where He is hydrogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di(lower alkyl)amino- or cyano; and Ba and B5 are independently halogen (HE, CI, Bi), cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, trifluoromethoxy, acetamido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl , trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; Ve is amino, mono- or di(lower alkyl)amino, acetamido, acetimido, ureido, formamido, formimido or guanidino; and Bz is carbamoyl, cyano, carbazoyl, amidino or M-hydroxycarbamoyl; wherein lower alkyl, lower alkyl, lower alkyl, lower alkoxy and lower alkanoyl contain from 1 to 3 carbon atoms.

B5-Amino- or substituted amino-1,2,3-triazole compound interacts with orotic acid, forming orotate compounds of 5-amino- or substituted amino-1,2,3-triazole compound in a ratio ranging from 1:11 to 1 :4 (base:acid) according to the improved and safer process of the invention, forming SRT for use according to the methods of the present invention.

New polymorphs of SAI further react with orotic acid, forming orotate compounds of the class of compounds of formula I:

Formula I in 7

M

M. M

Kk in which orotic acid is ionically attached to 52,

Vi is (Kb) and er (Kadt derevidoOdo2; tevidoOdo4; tap is from 0 to 5;

X is 0, 5, 50, 50", CO, CHOM, SNeo or C-MP5b, where He is hydrogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di(lower alkyl)amino- or cyano; and Ba and B5 are independently halogen (HE, CI, Bi), cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, trifluoromethoxy, acetamido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl , trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; B»2 is amino, mono- or di(lower alkyl)amino, acetamido, acetimido, ureido, formamido, formimido or guanidino; and Bz is carbamoyl, cyano, carbazoyl, amidino or M-hydroxycarbamoyl; wherein lower alkyl, lower alkyl included in the group, lower alkoxy and lower alkanoyl contain from 1 to 3 carbon atoms.

Preferred embodiments of "STO" as defined herein have an empirical formula

Сг2НивСизМ?7Ове, molecular weight 580.76, two transitional melting points at 201 "С and 236 "С.

Three new polymorphs of SAI that ionically bind orotic acid. SA! has many polymorphs, including but not limited to Form 1 (Sample I) or Form 2 (Sample 2). Two incarnations

SRTs have different transition melting points, for example, SRT (form I, sample 1) has melting points at about 136 "C, 194 "C, and 235 "C; and SRT (form 2, sample 2) has melting points at about 137 " C and 234 "C. Two embodiments of STO have a "H NMR spectrum corresponding to the structure

SAGorotic acid (Fig. | and Fig. 2, respectively) and Fourier transform IR spectra of samples corresponding to form 1 and form 2 (Fig. C and Fig. 4, respectively). SRT is crystalline as shown in Fig

From X-ray powder diffraction patterns of samples for form 1 and form 2 (Fig. 5 and Fig. 6, respectively).

The chemical names of the preferred embodiment of SRT include:

B-amino-I-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide, compound with orotic acid; // 5-amino-I-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-II, -2,3-triazole-4-carboxamide, compound with orotic acid; and B-amino-I-CH3,5-dichloro-4-(4-chlorobenzoyl)phenyl|methyl)-IN-I, 2,3-triazole-4-carboxamide, compound with orotic acid.

More specifically, the chemical structure of STO polymorphs is:

i) d (e) MN sten nom . (in)

SI about NM 202-t M

SYA

SI

SI

SAGorotic acid

An additional embodiment includes the preparation of various CA polymorphs! and orotic acid (CAO).

New polymorphs of 5-amino- or substituted amino-1,2,3-triazole (CA!) or b5-amino- or substituted amino-1,2,3-triazoles are mixed with orotic acid in the range from 1:1 to 1: 4 (base: acid), which gives CAO preparations using the appropriate methods of the present invention.

New methods:

The new method of the invention, where the compounds of the invention can be obtained as shown below in reaction scheme I, in five (5) stages. More specifically, the new method uses diphenylphosphoryl azide to react with intermediate 858.8 in step C instead of sodium azide.

The new method eliminates step C in the prior art, which produces intermediate compound 858.0.

See scheme I above (six stages). The method is described in detail in the examples. 858.A through 858.E are intermediates and SRT as summarized below: 858.A is tert-butyldimethylsilyl-3,5-dichlorobenzyl ether. 858.B is 3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol. 858.C is 3,5-dichloro-4-(4-chlorobenzoyl)benzyl chloride. 858.0 is 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide. 858.E is 5-amino-1H-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. 858.E is 5-amino-I-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide, a compound with orotic acid, (SAGorotic acid) (SAGorotate) ) (STO)

SI SI

OH tBDMS -SI imidazolo/OTBDMS

Food 858.61 Stage one

DdMAP, DMF

SI SI

Z,5-dichlorobenzyl alcohol si 7 "Z

SI

SI (y 858.8 Stage two 4-chlorobenzoyl chloride no o en fo» 1) tgF, n-Vyyi, -740С si 2) aqueous district NSI

SI about

ІІ si

RpOU M,

Hz) 858.0 Stage three diphenylphosphorylazide chy

Yi nn Mu in!

DBU, toluene SI

MN. N.M y 2 o si 2 o c) N.M 2-cyanoacetamide Shchi F sni pn Fr» M 858E Stage four

We

K, CO, , acetonitrile si si M

What about N.M.? oh oh

N.Morotic acid - ny -eШЩШНН....--- F ,» Ii A | Stage tyat methanol/water mm o M sleep

SI si H 2 858E

Importantly, it was observed that different polymorphs of SAI, STO, and CAO, produced by the above-mentioned method, show lower stomach impressions and toxicity in rodents compared to SAI, synthesized by the methods described in the prior art. This may be due to the absence of toxic ingredients such as sodium azide or potassium azide.

The new method also results in obtaining new polymorphs of SAI, STO and

CAO. Thus, the compounds of the invention include molecules that crystallize in more than one distinct crystal structure and exhibit different chemical properties of different polymorphs

SAI as characterized by methods such as NMR, DSC, Fourier transform IR and X-ray powder diffractometry (Fig. 1-6).

Dosage and preparation

B-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives, were obtained in various polymorphic forms that have certain chemical and biological properties, which overcome the shortcomings of SAI, which was obtained according to the methods described in the state of the art .

In addition, 5-amino- or substituted amino-1,2,3-triazole, as well as substituted derivatives chemically react with orotic acid to form orotate (STO) in a ratio from 1:1 to 1:4 (base:acid, having unique bioavailability, pharmacokinetic properties, safety and efficacy.

An alternative embodiment includes polymorphs of 5-amino- or substituted amino-1,2,3-triazoles, as well as their substituted derivatives, mixed with orotic acid in a ratio of 1:1 to 1:4 (base:acid) to form SAI preparations and orotic acid (CAO).

The above pharmaceutical compositions and preparations can be formulated into pharmaceuticals for administration to mammals for the prevention and treatment of primary and metastatic neoplasms, chronic myeloid leukemia, macular degeneration, retinopathies and other cell proliferative diseases. Many of the triazolorotate compounds can be presented directly as salts of organic acids or with pharmaceutically compatible counterions, forms in which they are simply water soluble. Salts contribute to greater solubility in water or other protic solvents compared to the corresponding free base forms. Therapeutic compounds or pharmaceutical compositions can be administered intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally, orally, rectally, topically, or by aerosol.

Preparations suitable for oral administration include solid powder formulations, liquid solutions of the active compound dissolved in solvents such as saline, water or PEG 400; capsules or tablets, each of which contains a predetermined amount of the active agent as a solid, powder, granule or gelatinous substance; suspensions in an acceptable medium; and emulsions.

Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions that contain buffers, antioxidants and preservatives. Medicines can be in sealed containers with a single dose or multi-doses.

Patients receive oral doses of SRT ranging from 0.25-500 mg/day, generally 25-100 mg/day, and typically 50-400 mg/day. Expressed in units of the patient's body weight, the usual dosage is in the range of 0.005 to 10 mg/kg/day Expressed in units of the patient's body surface area, the usual dosage is in the range of 0.1 to 300 mg/mg/day, for a total of 20 up to 250 mg/m-/day, usually 25 to 50 mg/me/day. The number of doses and the interval between doses can be adjusted individually, ensuring the presence in the plasma of a certain level of the active component that is sufficient to maintain antiproliferative, antimetastatic, antiangiogenic or other therapeutic effects in diseases that are caused by aberrant signal transmission and propagation.

Doses can be adjusted depending on the route of administration, for example, for intravenous, for inhalation/aerosol, for direct intraperitoneal or subcutaneous, for local or for intrathecal administration.

Various delivery systems for pharmaceutical compounds can be used, including, but not limited to, liposomes, nanoparticles, suspensions, and emulsions. Pharmaceutical compositions may also contain carriers or excipients in an acceptable solid or gel phase. Examples

Such carriers or fillers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

In addition, the drug can be administered in a targeted drug delivery system, for example, in a liposome coated with a tumor-specific antibody, as nanoparticles and other forms. A tumor or other disease target can selectively absorb non-targeted liposomes or nanoparticles.

One of the most challenging properties for the construction of newly discovered lead molecules is the desired pharmacokinetic profile, particularly in the case of orally dosed compounds. "Most experienced medicinal chemists would prefer to start the design of a structural series with one that has essentially good pharmacokinetic properties, albeit with insufficient targeting potential, than to start designing with improved targeting potential, or work in the other direction," "Ogdapis Spetivmu ip Ogyd Oivsomegu, Ogyd Oivsomegu",

Zsiepse 303: 1810-1813(2004).

Improving the bioavailability of SRT when administered orally.

The present invention generally relates to a method of increasing the oral bioavailability, delivery and excretion of SRT, specific orotate I 651582 in a ratio of 11 to 1:4 (base:acid). The present invention provides processes for the production of orotate salts of water-insoluble drugs having an ionizable center to improve the bioavailability, toxicological profile, and effectiveness of drugs when administered orally. Predominantly SRT exists in a ratio of 1:1 and more preferably - in a ratio of 1:2 and most preferably - in a ratio of 0.7:1.3.

Absorption of drugs by the oral route of administration is the subject of intensive research in the pharmaceutical industry, as high bioavailability means that the drug is able to enter the systemic bloodstream from the oral cavity. Oral absorption is influenced by both drug properties and gastrointestinal physiology, including dissolution of the drug from the dosage form, the way the drug interacts with the aqueous medium and the membrane, membrane penetration, and the irreversibility of first-pass elimination, such as like intestines, liver and lungs. Some pharmaceutical agents exhibiting low solubility show low bioavailability or non-reproducible absorption, the degree of reproducibility being influenced by factors such as

such as the dosage level, the patient's nutritional status, and the physicochemical properties of the medicinal product.

The main absorption of the drug occurs in the small intestine, due to the large surface area, as the presence of villi and microvilli increases the absorbing area many times. The intestinal circulation is unique in that the intestine is the anterior or portal tissue that regulates substrate flow to the liver. The venous blood of the intestine is about 75-95% of the blood supply to the liver. Therefore, for drugs with high intestinal excretion, the contribution of the liver, kidneys and lungs to the metabolism of the drug will be reduced. In contrast, for drugs that are poorly extracted by the gut, the substrates are able to enter downstream organs, the liver and lungs, for elimination. Therefore, the concentration of drug entering the intestine and the rate of intestinal flow alter the rate of drug delivery and affect the rate of intestinal metabolism and elimination via first-pass hepatic metabolism. "Bioavailability of a medicinal product" is defined in this document as the systemically available amount of a medicinal product during a period of time. The presented invention increases the bioavailability of pharmaceutical agents by transforming them into orotate salts. This can be achieved by altering the hydrophilic and lipophilic properties of the drug so that the drug crosses the membrane wall and the rate of blood flow becomes the overall rate-limiting step for absorption, or by inhibiting biotransformation of the drug in the gut and/or by inhibiting active reverse transport systems in the gut, which will reduce the net transport of drugs across intestinal membranes into the bloodstream. IN

In another case, the composition responsible for increasing the bioavailability of the drug is an orotate salt of the pharmaceutical agent. For reasons not immediately apparent, it has been found that the transition from water-insoluble 651582 to STO (base:xacid, 05:11 to 12) provides a means of increasing the bioavailability of the pharmaceutical agent when administered orally to mammals in need of treatment.

Changes in total system concentrations over a period of time are shown by the area under the curve (AU) or Cmax, both parameters well known in the art.

The present invention relates to methods in which the composition provides enhancement

From the bioavailability of the orotate salt of the pharmaceutical agent, as determined by AOS, from at least 25 U to 100 Fo relative to the dosage of the pharmaceutical agent.

The invention relates to a composition that increases the bioavailability of an orotate salt of a pharmaceutical agent as determined by Stach from at least 50 95 to 100 Vol. "Side effects" or "toxicity" or "adverse drug reactions" of chemotherapeutic agents are observed in the acute phase of chemotherapy and in patients cured of cancer with subclinical tissue damage. There is greater variation in the tissue side effects associated with drugs, which can be quite severe, disabling and irreversible. The physician should be aware of possible tissue/organ complications from chemotherapeutic agents and perform a review of the appropriate tissue baseline prior to initiation of therapy. "Removal" of the medicinal product occurs through the bloodstream to the organs of excretion. "Excretion" refers to the quantitative ratio of the medicinal product present in the bloodstream to that present in the organ, which is irreversibly removed (excreted) or converted into another chemical form (metabolism).

The presented invention relates to a method that increases the excretion of orotate derivatives

SRT from non-cancerous or normal tissues, as determined by pharmacological studies, at least 25 95 to 100 95 relative to the dosage of the pharmaceutical agent. The "bioavailability" of a drug following oral dosing is a measure of the extent to which, or the rate at which, the active drug residue or metabolite enters the systemic circulation, thereby gaining access to the site of action. The physicochemical properties of the drug affect its absorption capacity and binding to serum proteins.

The effectiveness of the drug depends on its interaction with the target molecule. In addition, the properties of the dosage form partly depend on its chemical characteristics and on the processes of production of the medicinal product in large quantities. Differences in bioavailability, efficacy, transport, and excretion may have clinical significance among the chemicals of a given drug.

The rate of "absorption" is important because even when a drug is completely absorbed, it may be absorbed too slowly to achieve therapeutic blood levels quickly enough, or so quickly that it results in toxicity because of the high concentrations of drug given to achieve therapeutic level after each dose. Absorption occurs in one of three ways, either passive diffusion, active transport, or facilitated active transport. Passive diffusion is a simple passage of molecules through the mucous barrier until the concentration of molecules of osmotic balance is reached on both sides of the membrane. In active transport, the molecule is actively pumped through the mucous membrane. In facilitated transport, a carrier, usually a protein, is necessary to move the molecule across the membrane for absorption.

The presented invention relates to SRT compounds in chemical configurations that allow the drug to be successfully delivered to various tissues and organs and even through the blood-brain barrier to reach the brain.

Orotic acid, a free pyrimidine, is important in the synthesis of uridylate (PP) of the basic pyrimidine nucleotide. Pyrimidines play a central role in cellular regulation and metabolism. They are substrates for the biosynthesis of DNA/RNA, regulators of the biosynthesis of some amino acids, and cofactors in the biosynthesis of phospholipids, glycolipids, sugars, and polysaccharides.

The classical path of biosynthesis of new pyrimidines ends with the synthesis of OMR. Viospetivhigu, edj.

Gore Bpuye!, hey, M.N. Ргеетап а Со МУ, 4" ей, 739-762 (1995). The presented invention relates to a class of SRT that can be dissolved to release the drug as a charged molecule and free orotic acid, which can prevent the binding of the drug to proteins and facilitate transport to the target and quick withdrawal.

The invention provides an embodiment that demonstrates an increase in the effectiveness of SRT, as defined by an improvement in 1) the effectiveness of SRT compared to a drug with an equivalent dose of SRA - orotic acid, 2) the bioavailability and excretion of SRT, which is provided as an encapsulated solid

STO compared to STO in PEG-400, 3) transport of orally administered STO to the brain across the blood-brain barrier, 4) transport of orally administered STO to various tissues of the eye, including the choroid-retina complex and the vitreous body in dogs.

Importantly, the preclinical toxicity of SRT was determined in dogs by the oral route at a dosage of 175, 350, 1025 mg/kg/day and did not lead to death after 28 days.

EXAMPLES

Example 1. 4-Chlorobenzoyl chloride

3,5-Dichlorobenzyl alcohol (1 mol) is treated with tert-butyldimethylsilyl chloride (1.05 mol), imidazole, 99 95 (2.44 mol), 4-dimethylaminopyridine in M,M-dimethylformamide at low temperature to give tert-butyldimethylsilyl -3,5-dichlorobenzyl ether (858.A1) by the extraction procedure of product selection.

Example 2 3,5-Dichloro-4-(4-chlorobenzoyl)benzyl alcohol tert-butyldimethylsilyl-3,5-dichlorobenzyl ether (858.A1) (1 mol) interacts with n-butyllithium 1.6 M solution in hexane with the following by adding 4-chlorobenzoyl chloride (1.01 mol) in tetrahydrofuran, in the cold, and treating the intermediate compound with an aqueous solution of hydrochloric acid, obtaining 3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.8).

Example C 3,5-Dichloro-4-(4-chlorobenzoyl)benzylazide

3,5-Dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.8) (1 mol) reacts with diphenylphosphoryl azide (diphenylphosphonic azide) (DFFA) (1.2 mol, and 1,8-diazabicyclo/5.4.FO)undec -7-ene, (Synonym: DBU) (1.2 mol)) in toluene at low temperature, followed by isolation of the reaction product with water and alcohol titration, obtaining 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide (858.0 ). DFFA is an organic compound used in the synthesis of other organic compounds. A!yvi. U. Speth 26:1591-1593 (1973). The stability of DFFA with respect to heating is demonstrated by its distillation at 15720; and the fact that no vigorous release of nitrogen is observed upon reaching a temperature of 175260.

Example 4 5-Amino-1I-(4-(4-chlorobenzoyl-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide (SAI)

3,5-Dichloro-4-(4-chlorobenzoyl)benzylazide (858.0) (1 mol) reacts with cyanoacetamide (1.69 mol) in hot acetonitrile in the presence of potassium carbonate (6.2 mol) to give 5-amino- and 1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide (858.E).

Example 5 5-Amino-1I-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide compound with orotic acid. (Sahorotic acid)

B-Amino-1I-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide (858.E) (1 mol) reacts with orotic acid (1.03 mol) in a mixture of methanol/water, obtaining 5-amino-1I-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-I, 2,3-triazole-4-carboxamide, a solid compound with orotic acid, ( SAGorotic acid; 1: (STO) (858.E), molar mass 580.76, having transition melting points of about 15190, 2382b, and 33220, measured by differential scanning calorimetry. X-ray powder diffraction pattern demonstrates that STO consists of crystalline and of an amorphous (polymorphic) substance. Example 6 Comparison of the anticancer activity of STO (858.E) and SAI orotic acid (11)

Operation STO Mol. mass 580.8 and SA! Mol. mass 424.6 g - Orotic acid Mol. mass 156.1 was studied on male MSt-pi/pi mice without a thymus gland, which were subcutaneously implanted with NT2g9 foreign colon tumor. Mice aged 6 weeks were implanted with fragments of NTag9 and after 13 days were sorted into 3 groups of ten mice. During the next 14 days (13-26 days), group 1, control, (C) received the vehicle; group 2-343 mg/kg/dose; group 3-240 mg/kg/day CA!-103 mg/kg/day orotic acid. On day 41, the values of tumor volume (mm3U) determined are shown below:

Group 1 (control) - 1436 mm3

Corpse 2 (STO 343 mg/kg/day) - 864 mm3 (р-0.0050, St2 m5 C 1)

Group C (SAI 250 mg/kg/day and orotic acid 103 mg/kg/day) - 1268 mm (p-0.2706, Sg C m5

Sg 1). These results confirm that SRT is more effective in inhibiting tumor growth than an equivalent amount of SAI and orotic acid, which have not reacted chemically. However, the drug

However, orotic acid showed some tumor inhibition.

Example 7 Comparison of SRT given orally as a solid in a capsule or as a liquid in PEG-400

The bioavailability of SRT (base:acid, 0.7:1.3) was determined by administering a single dose of 685 mg/kg in a capsule (group 1) or orally using a probe in PEG-400 (group 2). Two dogs (1 female/1 male) were used in each group. Blood samples were taken after 0, 1, 2, 4, 8, 12, 24, 48, 72, and 92 hours. SAI was determined by HPLC/MS.

Capsule Group 1: Plasma concentrations at 1 hour were 155 and 174 ng/ml for male and female dogs. The level was 5800 ng/ml after 12 hours for the male and 7950 ng/ml after 24 hours for the female. Half-lives were 18 hours and 22.7 hours and AUC values were 326 and 277 μg/ml, for male and female, respectively.

Group 2 gavage in PEG-400: Plasma concentrations at 1 hour were 511 and 570 ng/ml for male and female dogs. The level was 6634 ng/ml after 24 hours for the male and 5350 ng/ml after 24 hours for the female. Bioavailability was 81.8 95 of that in group 1 (100 Ob).

These results show that SRT provided as a solid in a capsule had better absorption characteristics and bioavailability than SRT in PEG-400. based on these and

From additional results, SRT will be administered to patients in the form of a solid substance in capsules.

Example 8 SRT given orally to mice passes through the blood-brain barrier

SRT was given orally (in PEG-400) to six-week-old mice, divided into two groups of 6 mice each. Two dogs were administered - group 1-513 mg/kg; group 2-342 mg/kg. Eight hours after SRT administration, mice were euthanized to measure the concentration of SRT (as SAI) in brain tissue.

The obtained results were: group 1 - SA level! was 1516722372 ng/g of tissue; group 2 - the level of SAI was 10950x241704 ng/g of tissue, both within therapeutic limits (6000 ng/ml). These results showed that after oral administration, SRT passes through the blood-brain barrier and reaches the target organ, the brain.

The present invention is not limited to the embodiment disclosed in the example, which is intended to illustrate one aspect of the invention, and any methods that are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention other than those shown and described herein will become apparent to those skilled in the art from the above description. It is understood that such modifications fall within the scope of the proposed claims.

One of ordinary skill in the art will recognize or be able to ascertain, using no more than routine investigation, any equivalents to the specific embodiments of the invention described herein. It is understood that such equivalents are covered by the claims.

Claims (12)

FORMULA OF THE INVENTION 1. Polymorphic form 1 of 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide linked to orotic acid, where orotic acid is ionically bound in a base:acid ratio ranging from 1:1 to 1:4, having an X-ray powder diffraction pattern substantially as shown in FIG. 3. 2. Polymorphic form according to point 1, where the compound is polymorphic form 1 of 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, compound bound with orotic acid, having an X-ray powder diffraction pattern with peaks at 4.9, 20.2, 24.3, 26.5, and 60 28.7" at 29. C. The polymorphic form of claim 2 having an X-ray powder diffraction pattern further comprising peaks at 23.3, 28.0 and 27.07 at 28. 4. Polymorphic form 2 of 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide linked to orotic acid, where orotic acid is ionically bound in a base:acid ratio ranging from 1:1 to 1:4, having an X-ray powder diffraction pattern substantially as shown in FIG. 4. 5. Polymorphic form according to point 4, where the compound is polymorphic form 2 of 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, compound conjugated with orotic acid, having an X-ray powder diffraction pattern with peaks at 19.5, 23.2, 25.0, 28.7, and 29" at 29. b. The polymorphic form of claim 5 having an X-ray powder diffraction pattern further comprising peaks at 21.9, 20.1 and 19.17 at 26. 1. The method of obtaining B-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, in which the reaction of diphenylphosphoryl azide with 3,5-dichloro -4-(4'-chlorobenzoyl)benzyl alcohol to obtain 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide; and the reaction of 2-cyanoacetamide with 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide to obtain 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3- triazole-4-carboxamide. 8. The method of obtaining 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide bound to orotic acid, where orotic acid is ionic bound in the base:acid ratio in the range from 11 to 1:4, in which the reaction of diphenylphosphoryl azide with 3,5-dichloro-4-(4'i--chlorobenzoyl)benzyl alcohol is carried out to obtain 3,5-dichloro- 4-(4-chlorobenzoyl)benzylazide; and the reaction of 2-cyanoacetamide with 3,5-dichloro-4-(4-chlorobenzoyl)benzylazide to obtain 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3- triazole-4-carboxamide; and the reaction of orotic acid with 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. 9. Polymorphic form 1 according to any of items 1-2 or polymorphic form 2 according to any of items 4-6, where the base:acid ratio is in the range from 1:1 to 1:4. Zo 10. Polymorphic form 1 according to any of items 1-3 or polymorphic form 2 according to any of items 4-6, wherein the base:acid ratio is in the range of 0.7 to 1.3. 11. The polymorphic form according to any of items 1-6 for use in the treatment of diseases caused by aberrant signal transmission and signal propagation, including RZ, cOoX2, VSV-AVI, HIV or MEC. 12. The polymorphic form according to any one of items 1-6 for use in the treatment of solid tumors, age-related macular degeneration, retinopathy, chronic myeloid leukemia or AIDS. Zina FIG. as I in ! Vo. What did you eat! iv: ch she shi writes and y ne ny me shi zy disappeared zi z ne chi: Khiachnynh teuk cha