EA018259B1 - Substituted quinazolines - Google Patents

Abstract

This invention relates to the discovery of 3- and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.

Description

The present invention relates to 3- and 5-substituted analogues of a selective, platelet-lowering anagrelide drug with a reduced potential for the development of side effects from the cardiovascular system, which should improve patient compliance with the prescribed treatment regimen and safety in the treatment of myeloproliferative diseases. In particular, the present invention relates to certain imidazoquinazoline derivatives that are effective as human platelet lowering agents. The compounds of the present invention function by inhibiting megakaryocytopoiesis and hence platelet formation.

BACKGROUND OF THE INVENTION

Anagrelide hydrochloride (AdguNp®, Khadpy®) is a new, orally administered imidazoquinazoline that selectively reduces the number of platelets in humans and is used for these purposes in the treatment of myeloproliferative diseases such as essential thrombocythemia, in which an increased platelet count may put the patient at high risk for thrombosis. The chemical structure of anagrelide, 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride monohydrate is shown as the hydrochloride monohydrate of the following formula:

The preparation of anagrelide hydrochloride is described in US patent No. 3932407, No. 31617 and 4146718.

Anagrelide is a valuable, highly selective, platelet lowering drug. In studies of ίη νίίτο megakaryocytopoiesis in humans, it was suggested that ίη νίνο its thrombocytopenic activity was originally the result of an inhibitory effect on the maturation of megakaryocytes. Anagrelide inhibited thrombopoietin (TPO) induced megakaryocytopoiesis in a dose-dependent manner with a calculated 1C ₅₀ ~ 26 nM, which suggests that it is a highly active drug. Anagrelide does not affect erythroid or myelomonocytic differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factor, demonstrating the selectivity of this compound with respect to the megakaryocyte series.

It has been proven that a drug that exists both in the US and in Europe has significant clinical value in the treatment of myeloproliferative diseases, such as essential thrombocythemia. Anagrelide has proven to be a drug that is effective and selective for lowering and maintaining platelet counts close to or within the physiological range in patients with thrombocythemia against a background of myeloproliferative disorder. The time to complete response, determined by the number of platelets <600x10 ⁹ / l, ranged from 4 to 12 weeks. In most patients, platelet counts can be lowered and maintained at a dose of 1 to 3 mg / day.

In early volunteer trials, the most frequently reported adverse reactions to medication use, in addition to headache, were heart palpitations, postural dizziness, and nausea. During the examination of patients, the most frequent adverse reactions to the use of the drug were headache, palpitations, swelling / fluid retention, nausea / vomiting, diarrhea, dizziness, and abdominal pain. These effects are apparently due to the secondary pharmacology of cardiovascular diseases associated with anagrelide, resulting from its inhibitory effect on human phosphodiesterase III (ΡΌΕ III). Anagrelide is a potent inhibitor of the ΡΌΕ III enzyme with a GS50 value of ~ 29 nM (for comparison, milrinone, the classical ΡΌΕ III inhibitor, [C? ₅₀ = 170-350 nM). Inhibition of ΡΌΕ III myocardium leads to positive inotropic activity (an increase in the force of contraction of the heart muscles) and peripheral vasodilation. Such cardiovascular manifestations of this inhibition are usually observed in classical positive inotropic drugs, milrinone and enoximon, and therefore are used for short-term emergency treatment of coronary heart disease. However, in the treatment of so-called latent diseases (i.e. asymptomatic), such as essential thrombocythemia, adverse cardiovascular events in the form of heart palpitations and tachycardia associated with anagrelide, limit its effectiveness and a significant percentage of patients - according to reports, between 25 and 50% - can not tolerate the drug with prolonged treatment.

The properties of anagrelide to inhibit ΡΌΕ III activity are completely different from its platelet-lowering antimegakaryocytic effect. Indeed, the study showed the absence of a correlation between the activity of an ΡΌΕ III inhibitor and the antimegakaryocytic effect of anagrelide and its main pharmacologically active metabolite, 3-hydroxyanagrelide (3-OH anagrelide or 3-HA, in the past it was 8ΡΌ604 or VSN24426). It was unexpectedly discovered that, as an inhibitor of ΡΌΕ III, the latter is more than 40 times stronger than anagrelide. However, in relation to Inga

- 1 018259 of the cure of megakaryocytopoiesis (and, therefore, the potential for platelet reduction), it was not stronger than the original drug. The active metabolite of anagrelide, 3-HA, contains ίη νίνο in amounts 2-3 times higher than its amount in the initial drug with standard effects. Thus, it can be assumed that 3-OH anagrelide is apparently the main factor contributing to the pharmacological effect of the drug.

In addition to the unwanted side effects of the cardiovascular system associated with inhibition of III, the resulting increase in the concentration of cyclic adenosine monophosphate (cAMP) can lead to an antiaggregatory effect. Despite the fact that at first this property may be useful for patients with essential thrombocythemia who are prone to a high risk of thrombotic complications, such antiplatelet effects, if exceeded, can have hemorrhagic complications and may ultimately be undesirable. In fact, the hemorrhagic events that were sometimes observed in patients with essential thrombocythemia treated with anagrelide could result from a combination of antiaggregation effects significantly promoted by 3-OH anagrelide, and an abrupt decrease in platelet count, aggravated by a synergistic interaction with aspirin, which is often prescribed in parallel (it was proved that in some patients with essential thrombocythemia, the concentration of 3-OH anagrelide in the plasma may exceed ίη νίίτο values of 1С ₅₀ for inhibition of platelet aggregation by 3 times).

ΡΌΕ III-mediated side effects from the cardiovascular system associated with anagrelide therapy imply switching many patients to the only significant alternative therapy, namely hydroxyurea therapy. However, this drug is a simple chemical antimetabolite that inhibits ribonucleotide diphosphate reductase (ΒΝΡ). thereby inhibiting DNA synthesis. Ribonucleotide diphosphate reductase catalyzes the conversion of ribonucleosides to deoxyribonucleosides, which are the building blocks for DNA synthesis and reduction. Inhibition of ribonucleotide diphosphate reductase explains the cytostatic and - the most important mutagenic effects of this compound, as well as its platelet-lowering effect. Hydroxyurea is thus officially classified as a valid human carcinogen. In addition to possessing the potential to induce leukemic transformation, hydroxyurea is associated with the induction of difficult to treat foot ulcers.

When faced with the problem of choosing treatment options, there was a clear need for a new agent for the treatment of thrombocythemia, which is selective in its effect on megakaryocytopoiesis, but with reduced or minimal side effects. Despite the fact that anagrelide offers some selectivity in its mechanism of action, there are limitations in its use that are associated with cardiovascular effects as a result of its secondary pharmacology and which are greatly facilitated by the active metabolite of anagrelide, 3-hydroxyanagrelide.

Metabolism of anagrelide as a whole proceeds extremely rapidly, which leads to an not-so-ideal pharmacokinetic profile of the drug. Typically, the half-life of anagrelide is only 1.5 hours (2.5 hours for the metabolite), which inevitably entails repeated administration of the drug (up to 4 times a day). This, combined with a side effect profile, can lead to poor patient compliance with the prescribed treatment regimen. In addition, anagrelide undergoes a high first-uptake effect (> 50%), which leads to significant interindividual variability of the achieved effects and, therefore, the potential variability of the response to taking the drug. Also, the effects of a pharmacologically active metabolite vary greatly between patients, since its formation depends on SUR ^, an enzyme whose expression is highly dependent on the effects of inducing agents, such as cigarette smoke. In general, this may necessitate a more accurate dose titration for patients undergoing anagrelide treatment.

American patent I8 4256748 discloses a number of imidazo [2,1-b] quinazolin-2 (3H) -ones, which have a similar anagrelide structure and are considered effective in the treatment of thrombosis due to their anti-aggregation effect on platelets mediated by inhibition of III. However, this disclosure does not evaluate solely a specific antimegakaryocytic potential (decrease in platelet count), which may be related to some analogues.

Theoretically, there is a need for compounds that exhibit antimegecariocytic activity, at the same time, have a reduced level of inhibitory activity against в III and, consequently, side effects on the cardiovascular system.

The aim of the present invention is to eliminate various disadvantages or improve the properties known in this field of compounds. Thus, it is an object of the present invention to provide an anagrelide derivative that has improved activity and / or reduced cardiovascular toxicity compared to compounds known in the art in the treatment of diseases for which modulation of megakaryocytopoiesis provides an effective treatment. The compounds of the present invention are especially useful because they exhibit less inhibitory activity against phosphodiesterase III (ΡΌΕ III) and, in addition, surprisingly retain their

- 2 018259 antimegakaryocytic and therefore platelet lowering properties.

It is also desirable that the compounds of the present invention have an improved pharmacokinetic profile to facilitate patient compliance with the prescribed treatment regimen and to ensure a stable response to therapy. Thus, another goal is to provide compounds with a good duration of action, i.e. long half-life ίη νίνο. In addition, another goal is to provide compounds that will be available due to relatively convenient synthesis processes.

The compounds described in the present invention satisfy some or all of the above objectives.

SUMMARY OF THE INVENTION

We have found that anagrelide analogues, in which the main metabolic center is blocked by the corresponding group, probably should have not only improved pharmacokinetics, but also a better side effect profile. It should be expected that this will lead to better tolerance and better patient compliance with the prescribed treatment regimen, which will allow a wider range of patients to receive effective treatment.

The compounds of the present invention are useful for two reasons: they have significantly less inhibitory activity against ΡΌΕ III than 3-hydroxyanagrelide, although they still retain strong antimegakaryocytic activity. Of course, these compounds have therapeutic indicators, which, apparently, are more favorable than indicators for the anagrelide itself.

In one embodiment, the present invention encompasses anagrelide analogs comprising 3-, 5-, 3.3, or 5.5-substituted anagrelide compounds. So, for example, in 3-substituted derivatives, the presystemic metabolism of 3-hydroxyanagrelide is actually blocked. Surprisingly, these compounds still exhibit good antimegakaryocytic activity. Thus, one aspect of the present invention relates to anagrelide analogs comprising 3-substituted derivatives in which the presystemic metabolism of the corresponding 3-hydroxyanagrelide is virtually blocked. In the case of 5-substituted compounds, it can be expected that the larger group is more effective than the smaller group. It can be expected that groups such as ΐ-butyl and other large blocking groups are most useful when substituted at position 5. It is expected that a substituent including a large group at position 5 will spatially hinder access to position 3 due to the metabolizing active the center of cytochrome. This should inhibit the formation of a cardioactive metabolite, 3-hydroxyanagrelide.

According to one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof

in which K ¹ , B ² , B ^3, and B ⁴ independently represent hydrogen or a blocking group that functions to directly or indirectly prevent a metabolic reaction at position 3 of substitution; or in which B ¹ and B ² and / or B ³ and B ⁴ together with the carbon atom to which they are attached form a blocking group that functions to directly or indirectly prevent a metabolic reaction at each substitution position 3, with the remainder of the groups from B ¹ to B ⁴ is hydrogen;

⁵ is selected from the group consisting of fluoro, chloro, bromo and iodo;

B ⁶ is selected from the group consisting of fluoro, chloro, bromo and iodo;

B ⁷ and B ^{8 are} independently selected from the group consisting of H, halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; and

B ⁹ is H, C _1-6 alkyl or a group I of metal ions;

with the proviso that when B ¹ , B ² , B ³ and B ^{4 are} not all hydrogen or one of B ¹ and B ² is methyl and B ³ and B ⁴ are hydrogen, the other B ¹ and B ² are not hydrogen.

In one embodiment

B ¹ and B ^{2 are} independently selected from the group consisting of H, cyano, C _1-6 alkyl, 8C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups independently selected from the group consisting of halo, hydroxyl, cyano, nitro, C _1-4 alkylsulfonyl and COOH; C _1-6 hydroxyalkyl; C _1-6 carboxyalkyl and sulfide; or

B ¹ and B ² together with the carbon atom to which they are attached form a C _3-8 carbocyclic ring, which may optionally be substituted by 1 to 5 groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro , C _1-4 haloalkyl, C _1-4 alkylsulfonyl

- 3 018259 and COOH; or

K ¹ and K ² together represent a C _2-6 alkenyl or C _2-6 alkynyl group directly bonded by a double bond to the ring, and which may be optionally substituted with one to three groups independently selected from the group consisting of halogen, hydroxyl, cyano, C _1-4 haloalkyl and COOH.

In a preferred set of compounds, K ¹ is an optionally substituted C _1-4 alkyl or C _3-8 cycloalkyl group.

In a preferred set of compounds, K ² is an optionally substituted C _1-4 alkyl group or C _3-8 cycloalkyl.

In another preferred set of compounds, K ¹ and K ² together form an optionally substituted C _3-8 cycloalkyl group. Most preferred is a cyclopropyl group.

Other preferred compounds are those in which at least one of K ¹ and K ² is —C (H) _p (P) _t or —C (H) _p (P) _t —C (H) _p (P) _h , where m = 2 or 3, and n = (3-m), and p = 2 or 3, and c | = (3-p).

More preferably, at least one of K ¹ and K ^{2 is} CP3 or CHP2. Most preferably, at least one of K ¹ and K ^{2 is} CP3.

In one embodiment, it is preferred that K ^{1 is} methyl, cyclopropyl, CP3, or CHP2. More preferably, K ^{1 is} methyl or cyclopropyl. More preferably, K ^{1 is} methyl. In one embodiment, it is preferred that K ^{2 is} methyl, cyclopropyl, CP3, or CHP ₂ . More preferably, K ^{2 is} methyl or cyclopropyl. Most preferably, K ^{2 is} methyl.

In one embodiment

K ³ and K ⁴ independently from each other are selected from the group including: H; cyano; C _1-6 alkyl, 8C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, in which said alkyl, alkenyl, alkynyl or cycloalkyl groups may optionally be substituted with 1 to 5 groups independently selected from the group consisting of halo, hydroxyl, cyano, nitro, C _1-4 alkylsulfonyl and COOH; C _1-6 hydroxyalkyl; C _1-6 carboxyalkyl and sulfide; or

K ³ and K ^4, together with the carbon atom to which they are bonded, form a C _3-8 carbocyclic ring, which can be optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro C _1-4 haloalkyl, C _1-4 alkylsulfonyl and COOH; or

K ³ and K ⁴ together represent a C _2-6 alkenyl or C _2-6 alkynyl group directly bonded by a double bond to the ring, which may optionally be substituted with one to three groups independently selected from the group consisting of halogen, hydroxyl , cyano, C _1-4 haloalkyl and COOH.

In one embodiment, K ³ is H or C _1-6 alkyl. Preferably, K ^{3 is} N.

In one embodiment, K ⁴ is H or C _1-6 alkyl. Preferably, K ^{4 is} N.

In one embodiment, it is preferred that K ^{5 is} chlorine. In one embodiment, it is preferred that K ⁶ be chlorine. In one embodiment, K ⁷ is N. In one embodiment, K ⁸ is N.

In one embodiment, K ⁹ is H. In another embodiment, K ⁹ is C _1-6 alkyl, and in this case the inhibitory ΡΌΕ III activity is virtually eliminated. Me is a particularly preferred alkyl substituent. In another embodiment, K ⁹ is a group I of metal ions, in this case, the compounds exhibit significantly better solubility in water. A particularly preferred Group I metal is sodium.

In the following options:

K ¹ and K ² independently from each other are selected from the group including H; cyano; C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted with 1 to 5 groups independently selected from the group comprising halo, hydroxyl, cyano, nitro, C _1-4 alkylsulfonyl and COOH; C _1-6 hydroxyalkyl; C _1-6 carboxyalkyl and sulfide; or

K ¹ and K ² together with the carbon atom to which they are attached form a C _3-8 carbocyclic ring, can optionally be substituted by 1 to 5 groups, independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, C _1-4 haloalkyl, C _1-4 alkylsulfonyl and COOH; or

K ¹ and K ^2, together with the carbon atom to which they are bonded, represent a C _2-6 alkenyl or C2-6 alkynyl group directly bonded by a double bond to the ring, and are optionally substituted with one to three groups independently selected from a group comprising halo, hydroxyl, cyano, C _1-4 haloalkyl and COOH;

with the proviso that when K ¹ and K ² are both not hydrogen or one of K ¹ or K ² is methyl, the other is not hydrogen;

K ³ and K ⁴ are hydrogen;

K ⁵ is selected from the group consisting of fluoro, chloro, bromo and iodo;

K ⁶ is selected from the group consisting of fluoro, chloro, bromo, and iodo; and

- 4 018259

B ⁷ , B ⁸ and B ⁹ are hydrogen.

Another preferred group of compounds are those compounds in which neither B ¹ nor B ² are hydrogen. Among them, it is preferable that B ¹ and B ² , both, are independently selected from the group consisting of cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, in which the alkyl, alkenyl and alkynyl groups may optionally be substituted or in which B ¹ and B ² together with the carbon atom to which they are attached form an optionally substituted C3-8 carbocyclic ring or in which B ¹ and B ² together represent an optionally substituted C _2-6 alkenyl or C _2-6 alkynyl group.

Particularly preferred individual compounds of the invention include

methyleneanagrelide,

3.3, spiro cyclopropylanagrelide,

3,3-dimethylanagrelide, (B) -3 - (hydroxymethyl) anagrelide, (8) -3- (hydroxymethyl) anagrelide.

Particularly preferred compounds include 3,3-dimethylanagrelide and spiro [anagrelide-3,1'cyclopropane]. These compounds are generally prepared in the same way as HBg addition salts.

The individual enantiomers of 3-substituted derivatives have also been found to be effective. Therefore, the present invention also relates to both split mirror isomers of such compounds and mixtures of enantiomers. To compare the compounds of the present invention with anagrelide, it is correct to compare with the ΡΌΕ III inhibitory activity of the 3-hydroxyl metabolite of anagrelide, since it is the dominant component in plasma after anagrelide therapy.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable solvent or carrier, which may be adapted for oral, parenteral or topical administration;

a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate or pharmaceutical composition containing any of the above, for use as a medicine;

the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease selected from the following diseases: myeloproliferative diseases and / or generalized thrombotic diseases;

a method of treating a disease selected from the following diseases: myeloproliferative diseases and / or generalized thrombotic diseases of a person, which include treating said person with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate or pharmaceutical composition containing any of the above.

The present invention also encompasses a method of treating a patient having essential thrombocythemia or a high platelet count, a method which comprises administering to the patient a therapeutically effective amount of a compound of the present invention.

Another embodiment of the present invention includes a method for reducing platelet count in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.

The present invention includes the provision of compounds of the present invention for the methods listed above, along with other methods in which cardiotoxicity is reduced compared with the use of anagrelide.

Separately, we found that individually both (B) -3-methylanagrelide and (8) -3 methylanagrelide show good antimegakaryocytic activity and at the same time show significantly reduced inhibition of ΡΌΕ III compared to 3-OH anagrelide. Thus, it can be assumed that 3-methylanagrelide will be effective in the treatment of myeloproliferative diseases.

Accordingly, the invention also includes the use of 3-methylanagrelide or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of myeloproliferative diseases.

The invention thus also extends to a method for treating myeloproliferative diseases in humans, which comprises treating said person with an effective amount of 3-methylanagrelide or a pharmaceutically acceptable salt or solvate or pharmaceutical composition comprising any of the above.

The present invention also encompasses pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of a compound of the present invention and a pharmaceutically acceptable carrier.

- 5 018259

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to new 3- or 5-substituted analogues of the known platelet-lowering anagrelide preparation. It is expected that substitution at position 3 or adjacent position 5 of the anagrelide molecule will block or impede the main center of metabolism and potentially interfere with the formation of a highly effective inhibitor of ΡΏΕ III, 3-OH anagrelide, while it was found that the substitution at position 1 stops the inhibition of ΡΏΕ III. The compounds of the present invention retain the antimegakaryocytic properties (and therefore platelet lowering activity) of the parent drug molecule, but have reduced ΡΏΕ III inhibitory properties and, therefore, lower potential for undesirable side effects from the cardiovascular system and as a result of the anti-aggregation effect. They also have the potential for improved pharmacokinetic characteristics due to inhibition of metabolism.

These improved cardiovascular and pharmacokinetic properties have been demonstrated in studies in dogs. A comparison of the ΐπ νΐνο effect on the cardiovascular system of anagrelide, its active metabolite and a typical sample of an improved analogue is shown in the table below.

Comparative activity of anagrelide, its metabolite of 3-hydroxy anagrelide and a typical 3-alkyl substituted drug analogue

Compound 1p νϊίτο 1 Sed for RIE ΠΙ inhibitions Ιη νίνο for effects on the dog’s heart rate Ιη νίνο Εϋ20 for effects on the dog’s heart rate Ιη νίίΓο 1Szd for antimegakarionitarnogo exposure (human cell line) Anagrelide 29nM 986 mcg / kg 376 mcg / kg 26 nM 3-hydroxy anagrelide (active metabolite) 0.7nM 11.72 mcg / kg 7.1 mcg / kg 44nM 3.3 dimethyl anagrelide 164nM 3.557 mcg / kg 2.512 mcg / kg 166nM

The most important comparison of the data in the table above is the comparison between 3-hydroxy anagrelide - as an active metabolite of a drug - and a 3-alkyl substituted analogue, since the former is the dominant species present in the plasma of the patient being treated with the drug. Based on this, the therapeutic benefit of the potential for the coefficient of variation (CS), characterizing the ratio of side effects, is undoubtedly significantly improved for this 3-alkyl derivative.

A comparison of the pharmacokinetic profile in dogs for anagrelide and a typical 3-substituted analogue is shown below.

Comparison of the pharmacokinetics of anagrelide, its formed active metabolite and a typical 3-substituted analogue when administered intravenously at the rate of 1 mg / kg of an awake dog model

Compound The maximum plasma concentration of Smake (ng / ml) Area under the curve Ais "u (ng.h / ml) T _1st (h) Ground clearance * (ml / h / kg) Stable volume of distribution Uzz * (ml / kg) P (ACS0- 0) * Anagrelide 48.1 + 21 101 + 15 1.37 + 20 1156 + 4.56 1011 + 3.8 11.8 + 14.4 3-hydroxy anagrelide (resulting from anagrelide therapy) 60.1 + 14 179 + 14 1.57 + 24 Ν7Α Ν / Α 3.3 dimethyl anagrelide 167 + 33 1903 + 47 9.39 + 21 178 + 45.9 1967 + 24 39 + 25

The results represent geometric mean values and% CS.

* - after 1 mg / kg of intravenous administration.

The data in the above table clearly show a significantly longer half-life for the 3-alkyl substituted analog compared to the anagrelide itself (9.39 ν8 1.37 h), which will allow, in relation to humans, to administer the drug much less often and improve patient compliance with the prescribed treatment regimen compared with anagrelide. This comparatively longer period

- 6 018259 half-lives for 3,3-dimethylanagrelide observed in dogs was reflected in a ίη νίίΓΟ metabolic stability study, in which it was much more metabolically stable than anagrelide (see table below). Hepatic metabolism is known as an important mechanism for the purification of anagrelide in both animals and humans. In addition, most importantly, this significantly greater metabolic stability for the 3-substituted analogue was also observed in human hepatocytes, suggesting the possibility of improved human pharmacokinetics.

Comparative metabolic stability of anagrelide and a typical analogue in dog and human hepatocytes

Compound Ιη νίίΓΟ “half-life” in dog hepatocytes Ιη νίίΓΟ “half-life” in human hepatocytes Anagrelide 1.25h 6.62h 3.3 dimethyl anagrelide No pronounced decay during the study 22.8h

Pharmaceutically acceptable acid addition salts of certain compounds of formula (I) may also be prepared in a conventional manner. For example, a solution of a neutral base is treated with an appropriate acid in a pure or suitable solvent, and the resulting salt is isolated by filtration or by evaporation under reduced pressure of the reaction solvent. For an overview of suitable salts, see Nabboc OG Ryagtasei11ca1 8a115: Rregoreyek, 8e1esIop, apb Ike Bju 81aY apb / Uetsh111 (UNeu-Usn, Khutyeip. Segtapu, 2002).

Definition of terms.

Halogeno means a group selected from fluoro, chloro, bromo and iodo.

The term alkyl as used herein as a group or part of a group refers to a straight or branched hydrocarbon chain containing a certain number of carbon atoms. For example, C 1 _- 1 ₀ alkyl means a straight or branched alkyl containing at least 1 and at most 10 carbon atoms. Examples of alkyl used herein include, but are not limited to, methyl, ethyl, η-propyl, p-butyl, η-pentyl, isobutyl, isopropyl, ΐ-butyl, hexyl, heptyl, octyl, nonyl and decyl. The C _1-4 alkyl group is one option, for example, methyl, ethyl, p-propyl, isopropyl, p-butyl, isobutyl or 1-butyl.

As used herein, the term cycloalkyl refers to a non-aromatic monocyclic hydrocarbon ring containing from 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term spirocyclic as used herein refers to a ring system combined with a second ring system by one carbon atom.

As used herein, the term alkoxy refers to a straight or branched chain hydrocarbon chain containing oxygen and a certain number of carbon atoms. For example, C _1-6 alkoxy means straight or branched alkoxy containing at least 1 and at least 6 carbon atoms. Examples of alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-hydroxy, butoxy, but-2-hydroxy, 2-methylprop-1-hydroxy, 2-methylprop-2-hydroxy, pentoxy and hexyloxy . A C _1-4 alkoxy group is one embodiment, for example, methoxy, ethoxy, propoxy, prop-2-hydroxy, butoxy, but-2-hydroxy or 2-methylprop-2-hydroxy.

As used herein, the term hydroxyalkyl as a group refers to a straight or branched hydrocarbon chain containing a certain number of carbon atoms, which is substituted by 1 to 3 hydroxyl groups. For example, C _1-4 hydroxyalkyl means a straight or branched alkyl chain containing from 1 to 4 carbon atoms and at least one hydroxyl group; examples of such a group include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like.

The term alkenyl as used herein as a group or part of a group refers to a straight or branched hydrocarbon chain containing a certain number of carbon atoms and containing at least one double bond. For example, the term C _2-6 alkenyl means straight or branched alkenyl containing at least 2 and at least 6 carbon atoms and containing at least one double bond. Examples of alkenyl used here include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butenyl, 3methylbut-2-enyl, 3-hexenyl and 1,1-dimethylbut-2-enyl. It should be noted that in the groups of the form —O — C2-6 alkenyl, it is preferable that the double bond does not adhere to oxygen.

As used herein, the term alkynyl as a group or part of a group refers to a straight or branched hydrocarbon chain containing a certain number of carbon atoms and containing at least one triple bond. For example, the term C _2-6 alkynyl means straight or branched alkynyl containing at least 2 and at least 6 carbon atoms and containing at least one triple bond. Examples of the alkynyl used herein include, but are not limited to, ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3

7 018259 methylbut-2-ynyl, 3-hexynyl and 1,1-dimethylbut-2-ynyl. It should be noted that in the groups of the —O — C ₂ -b alkynyl form, it is preferable that the triple bond does not adhere to oxygen. The term halogen refers to halogens such as fluorine, chlorine, bromine and iodine atoms.

The term sulfide refers to the radical K _a -8-B _b , in which the sulfur atom is covalently linked to two hydrocarbon chains, K., and K _b , in which two hydrocarbon chains can be, for example, but not limited to, any of the above .

Compounds of the invention, i.e. the compounds of formula (I) exhibit antimegakaryocytic activity in humans. They can be especially useful in the treatment of myeloproliferative diseases. The compounds may also be useful in the treatment of generalized thrombotic diseases.

It should be noted that references to treatment include both prophylaxis and relief of established symptoms of the condition. The treatment or treatment of a condition, disorder or disease includes (1) preventing or delaying the manifestation of clinical symptoms of the condition, disorder or disease in a person who may be affected or predisposed to a condition, disorder or disease, but has not yet experienced or shown clinical or subclinical symptoms condition, disorder or disease, (2) inhibition of the condition, disorder or disease, namely, stopping, reducing or inhibiting the development of the disease or its relapse (in the case of supportive on treatment) or at least one of its clinical or subclinical symptoms, or (3) relieving the disease or mitigating, namely induction of remission state, disorder or disease or at least one of its clinical or subclinical symptom.

Myeloproliferative diseases that can be treated with the compounds of the present invention include essential thrombocythemia, true polycythemia, chronic idiopathic myelofibrosis, chronic myelogenous leukemia with residual thrombocytosis, reactive thrombocytosis immediately preceding surgical intervention, as an urgent or minimizing risk for surgery or after surgery.

Thrombotic cardiovascular disease (TSUE) (i.e., patients with an increased generalized thrombotic risk) who can also be treated with the compounds of the present invention include myocardial infarction (heart attack), thrombotic stroke, patients with coronary stenting.

The compounds of the present invention may be useful in reducing atherothrombotic events, such as the following: recent myocardial infarction, recent stroke or confirmed peripheral arterial disease, acute coronary syndrome (unstable angina pectoris / pop P \ taue,), cardiovascular death, myocardial infarction, stroke and refractory ischemia.

It will be understood that the compounds of formula (I) may contain one or more asymmetric carbon atoms, thus, the compounds of the invention can exist as two or more stereoisomers.

All stereoisomers, such as enantiomers and diastereoisomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including compounds representing more than one type of isomerism, and mixtures thereof can be included within the scope of the present invention.

A solubility study was carried out on a number of anagrelide derivatives according to the present invention in different control media. Control media included the following:

a) once distilled water (pH 5.0) - please note that no attempt has been made to remove dissolved CO ₂ ;

b) 50 mM formic acid ammonium (pH 7.9);

c) 0.1 M hydrochloric acid (pH 0.b).

The HPLC calibration curves for the peak area versus concentration were obtained in MeOH or MeOH / ΌΜδΘ in the range from 1000 to 1 μg / ml for each substance at a temperature of 20-22 ° С. In the HPLC method, C ₁₈ reverse phase columns and a mixture of water (0.b% formic acid) and acetonitrile were used as the mobile phase. To study solubility, saturated solutions were prepared by dissolving in the desired medium using an ultrasonic bath for 20 minutes and removing excess solid phase by centrifugation. The concentration of the substance in the supernatant was determined by the measured peak area.

Surprisingly, it was found that stable metal salts can be prepared after deprotonation at position 1 of the quinazoline ring system. The value of such salts lies in their relatively greater water solubility compared to the corresponding salts of NVg. This will obviously facilitate the rapid dissolution and quantitative absorption of these compounds, which are generally poorly soluble in water, and thus is an important clinical advantage. These salts are salts of Group I metals and are most often sodium or potassium salts. The following table shows the solubility measurements.

- 8 018259

The solubility of anagrelide and anagrelide derivatives (μg / ml at ~ 20 ° C)

Compound Ammonium formate (50 iM, pH 7.9) Vodya (pH 5.0) Hydrochloric acid (0.1 M, pH 0.6) Anagrelide hydrochloride 10 AND 169 3,3-dimethyl anagrelide sodium salt 6 409 212 3,3-dimethylanagrelide hydrobromide 4 twenty 215 3.3, spiro-cyclopropylanagrelide sodium salt 542 28

3,3-Spiro-cyclopropylanagrelide hydrobromide one 2 35 3-methyleneanagrelide 5 nine 43 3-methyleneanagrelide sodium salt 39 1830 189

Geometric isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography or fractional crystallization.

Stereoisomers can be separated by traditional technologies known to those skilled in the art, see, for example, 81geosos11S1Sh51gu οί Ogdashe Sotroipbk E. E11e1 (Aisu. Νο \ ν Wagk, 1994).

Compounds of formula I can be prepared using the techniques described in the literature and similarly to the methods described in formula I and formula II in American patent I8 4256748. The synthesis of 3-ethylanagrelide is described as an example in order to show how it can be prepared individual isomers of the invention. Similar techniques can be used to prepare other compounds of the invention using the appropriate alpha-halo esters.

The formation of 3-ethylanagrelide (compound (4a)) is shown in Scheme A below. 1-amino-2,3-dichloronitrobenzene (1a) is subjected to nucleophilic substitution with alpha-halo-ether B-ethyl-2-bromobutanoate to obtain compound (2a). The nitro group is then reduced to the amino group using tin chloride in ethanol to obtain the diamine compound (3a). Compound (3a) is then cyclized by cyanogen bromide in toluene to form 3-ethylanagrelide (4a).

Scheme A. Formation of 3-Ethylanagrelide

The formation of certain derivatives is carried out similarly to the synthesis shown in Scheme A above, or by rotating the positions of the ΝΗ ₂ groups and the Br groups in the starting materials, depending on the chemistry involved. In this case, alpha-amino ester and halogenbenzyl derivatives are used as starting materials. In general, the reaction can be represented as Scheme B below with respect to the 3-substituted compound.

Scheme B. The formation of 3-substituted anagrelides

where A is ΝΗ ₂ or Br and B is different from ΝΗ ₂ or Br.

The formation of (C.) - 3-ethylanagrelide can be carried out similarly to the synthesis shown in Scheme A. 5-ethyl-2-bromobutanoate. This technique is generally suitable.

In the case where single enantiomers are not required, the racemic alpha-haloether may

- 9 018259 used in the first stage of synthesis.

An expert in this field will know the options and alternatives to the methods described above and those methods specified in American patent I8 4256748, which allow you to get individual compounds defined by formula (I).

Also, an experienced specialist in this field should take into account that the compounds of the invention can be obtained using the methods described here and / or methods known in the art, for example, those mentioned here, or using standard textbooks such as Sotrgeei 81ue Ogdas Tgaikyogtayoik-A Sshbe 1o Eips! Jupa1 Ogoyr Tgapkyogtayoik, KS. Lagosk, UPeu-USN (1999 or later editions), Magsy'k Abuapseb Ogdashs SjetMgu - Keasyopz, Messyapshtk apb 81gis1ige. MV 8th, 1. Magsy, ^ beu, (5th ed. Or later) Abuapseb Ogdashs Syetschu, Paradise V, Keasbopk apb 8up1ye518, R.A. Sageu, Kk 8ipbbegd, K1i \\ e Asabet1c / P1epit RbNsabosch, (2001 or later editions), Ogdashs 8up1ye515-Thieu Eisopesbop Arrgoasy, 8. Huaggep (^ bеu), (1982 or later 8 more) Huaggep (\ Ubeu) (1983 or later editions), OshbeBook To Ogdashs 8up111e515 KK. Mask1e apb E.M. 8th (Bopdtap) (1982 or later), and others, and the references cited herein as a guide.

It will also be apparent to an experienced person that there may be a need to protect sensitive functional groups and deprotect during the synthesis of a compound of the invention. This can be achieved by traditional methods, for example, those described in Рgo! Esyue Ogoyrk ίπ Ogdashs 8up111e515 Lyu T. ^. Ogeep apb R.O.M. HUiK bo11p HUo1eu & 8opk 1ps. (1999), and the references cited herein.

It is contemplated that the compounds of the present invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained, for example, in the form of solid beads, powders or films by methods such as precipitation, crystallization, freeze-drying or spray drying or evaporative drying. For these purposes, induction or radio frequency drying can be used.

The compounds may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. In general, the compounds will be administered in dosage form in conjunction with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include one or more of the following excipients: antioxidants, colorants, flavors, preservatives, and flavoring agents.

Pharmaceutical compositions suitable for the manufacture of the compounds of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Röötschöpd Räägtaseijs1 8 ^ 1 ^ 57 19 ⁴¹¹ Ebüyup (Mask Rübköpd Sotrapu, 1995). A discussion of the composition of the tablets can be found in the Riagtaseis 1 Eokad Egtk: TaYeK Uo. 1, N. Lebetter and b. Easytap, Magse1 Eekkeg, Ν.Υ., Ν.Υ., 1980 (Ι8ΒΝ 0-82476918-X).

Methods of administration of the compounds include oral administration in the form of capsules, pills, tablets, powders, troches, chewable tablets, multi- and nanoparticles, gels, solid solutions, films, sprays or liquid formulations. Liquid forms include suspensions, solutions, and syrups. Such compositions can be used as fillers in soft and hard capsules and usually include a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by dissolving solid preforms, for example, from sachets.

The compounds may also be administered topically to the skin or mucous membrane, i.e., dermally or transdermally. Typical formulations for these purposes include solutions, sprays, powder formulations, gels, hydrogels, lotions, films and patches, and implants.

The compounds may also be administered parenterally or directly by injection into the blood, muscle or internal organ. Suitable agents for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, epigastric, intracranial, intramuscular and subcutaneous. Suitable instruments for parenteral administration include injectors with a needle (including a microneedle), injectors without a needle, and infusion methods.

The compositions may be with immediate and / or modified controlled release. Controlled release drug formulations include modified release kinetics formulations: delayed, delayed, and intermittent release.

Dosage

As a rule, the doctor determines the actual dose, which will be the most suitable for the individual patient. The specific dose level and frequency of dose for any particular person may vary and will depend on various factors, including the activity of the particular compound used, metabolic activity and duration of action of this compound, age, body weight, general health, gender, diet, regimen and time intake, excretion rate, drug combination, severity of a particular condition and ongoing treatment

- 10 018259 niy.

In general, however, a suitable dose will range from about 0.001 to 50 mg / kg body weight per day, in other embodiments, from about 0.001 to 5 mg / kg body weight per day; in still other embodiments, from about 0.001 to 0.5 mg / kg body weight per day; and in still other embodiments, from about 0.001 to 0.1 mg / kg body weight per day. In other embodiments, the range may be from about 0.1 to 750 mg / kg body weight per day. In yet other embodiments, the range may be from about 0.1 to 750 mg / kg body weight per day, in the range from 0.5 to 60 mg / kg / day and in the range from 1 to 20 mg / kg / day.

The required dose can usually be presented in the form of a single dose or a divided total dose, administered at certain intervals, for example, one, two, three, four or more doses per day. If the compounds are administered transdermally or in sustained release forms, the compounds may be taken once a day or less.

The compound is usually administered in unit dosage form; for example, containing from 0.1 to 50 mg, usually from 0.1 to 5 mg, most conveniently from 0.1 to 5 mg of the active component per unit dosage form. In still other embodiments, the compound may be administered in a unit dosage form; for example, containing from 10 to 1500 mg, from 20 to 1000 mg, from 50 to 700 mg of active ingredient per unit dosage form.

The compounds of the present invention and their activities are shown below.

Example 1. Comparative data of 1C ₅₀ anagrelide and some 3-alkyl substituted analogues as inhibitors of III and antimegacryocytic agents.

The table below shows the comparative activity of anagrelide and its analogues in relation to their effect on megakaryocytopoiesis (a process in which platelet enlargement occurs) and on ΡΌΕ III (inhibition of which leads to an adverse cardiovascular response).

Comparative ίη νίίτο assessment of possible therapeutic and adverse

E ( ) effects of anagrelide and its analogues Compound 1С50 FOR antimegakaryocytic activity (lowering of platelets) 1C _Yu for ΡϋΕ III inhibition (side effects for the cardiovascular system) The coefficient of the expected benefit (the ratio of therapy "effect to negative effects) Anagrelide 27nM 32nM * 0.024: 1

3- guide roxy anagrel id 44nM 0.7nM 0.016: 1 3.3 dimethylanagrelide 164nM 166 nm eleven 3spirocyclopropnl anagrelide 547nM 797nM 1.45: 1

* Pharmacokinetically determined values based on three times the systemic exposure of the active metabolite (3-hydroxyanagrelide) than the drug itself to humans.

Analysis of ίη νίίτο antimegakaryocytic activity and, consequently, the potential platelet lowering ability of 3-substituted anagrelide analogues was carried out using the well-known model of megakaryocytopoiesis (Soyep-§o1a1 e! A1., Tygot. Nastoy .. 1997, 78: 37-41 apb Сгатег е! А1., В1об, 1997, 89: 2336-46). It can be easily seen that with anagrelide, the coefficient of expected benefit (therapeutic effect to negative effects) was relatively low at 0.024: 1 (after taking into account the main effect of the cardiac metabolite ίη νί \ Ό). In contrast, 3-spirocyclopropyl and 3.3 dimethylanagrelide, both, showed a relatively better coefficient of expected benefit in these studies.

Claims (8)

CLAIM 1. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof - 11 018259 (I) in which I ¹ represents methyl, cyclopropyl, CP ₃ or CHP ₂ ; I ² represents methyl, cyclopropyl, CP ₃ or CHP ₂ or I ¹ and I ² together with the carbon atom to which they are attached form a cyclopropyl group; I ³ represents H; I ⁴ represents H; I ⁵ is selected from the group consisting of fluoro, chloro, bromo and iodo; I ⁶ is selected from the group consisting of fluoro, chloro, bromo and iodo; I ⁷ represents H; I ⁸ represents H and I ⁹ is H or Να. 2. The compound or its pharmaceutically acceptable salt or solvate according to claim 1, in which I ⁵ is chlorine. 3. The compound or its pharmaceutically acceptable salt or MES according to any one of the preceding paragraphs, in which I ⁶ is chlorine. 4. The compound or its pharmaceutically acceptable salt or solvate according to any one of the preceding paragraphs, in which I ¹ is methyl and I ² is methyl. 5. The compound or a pharmaceutically acceptable salt or solvate thereof according to claim 1, selected from 3.3, spiro-cyclopropylanagrelide and 3,3-dimethylanagrelide or their pharmaceutically acceptable salts. 6. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable solvent or carrier, which can be used for oral, parenteral or topical administration. 7. The use of a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of diseases selected from myeloproliferative diseases and generalized thrombotic diseases. 8. The use of the compounds of formula (I) according to any one of claims 1 to 5 to reduce platelet count. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2