KR20090094268A - 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

Substituted Quinazolin {SUBSTITUTED QUINAZOLINES}

The present invention relates to the discovery of 3-substituted and 5-substituted analogues of the selective platelet lowering agent anagrelide, which reduces the potential for cardiovascular side effects and improves the patient's acceptance and stability in treating myeloproliferative diseases. . More specifically, the present invention relates to certain imidazoquinazoline derivatives for use as platelet lowering agents in humans. The compounds of the present invention act by inhibiting the formation of platelets due to megakaryocytosis.

Anagrelide hydrochloride (Agrylin®, Xagrid®) is a myeloproliferative disease (MPD), such as idiopathic platelets, which can selectively reduce the number of human platelets and put the elevated platelet number at risk for thrombosis. It is a novel oral administration imidazoquinazoline that is used for that purpose in the treatment of increased ET. Anagrelide 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride monohydrate The chemical structure of hydrochloride is represented by Represented by monohydrate:

Preparation of anagrelide hydrochloride is described in US Pat. No. 3,932,407; Reference is made to RE31,617 and 4,146,718.

Anagrelide is a unique, highly selective platelet lowering agent. In vitro studies of human megakaryocytosis suggested that its thrombocytopenic activity in vivo is mainly derived from the inhibitory effect of megakaryocyte maturation. Anagrelide inhibits TPO-induced megakaryocytosis with an estimated IC ₅₀ value of ˜26 nM in a dose dependent manner, suggesting that this is a highly effective formulation. Anagrelide demonstrates the selectivity of these compounds for the megakaryocyte lineage by not affecting erythrocyte or osteoblast differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factors.

The drug, available in the United States and Europe, has proven to be of significant clinical value in the treatment of myeloproliferative diseases such as idiopathic thrombocytopenia. Anagrelide has been shown to be effective and selective in reducing and maintaining platelet numbers near or within the physiological range of patients with thrombocytopenia comparable to myeloproliferative diseases. The reaction completion time, defined as platelet count ≦ 600 × 10 ⁹ / L, ranges from 4 to 12 weeks. In most patients, platelet count can be reduced and maintained at a dose of 1-3 mg / day.

In early volunteer experiments, the most frequently reported adverse effects (AEs) in addition to headaches were palpitations, postural dizziness and nausea. During patient studies, the most frequently reported drug-related AEs were headache, palpitations, edema / fluid retention, nausea / vomiting, diarrhea, dizziness, and abdominal pain. All these effects result from secondary, cardiovascular pharmacology associated with anagrelide resulting from its inhibitory effect on human phosphodiesterase III (PDE III). Anagrelide is a potent PDE III inhibitor with an IC ₅₀ value of ˜29 nM (eg, the typical PDE III inhibitor milnon: IC ₅₀ = 170-350 nM). Inhibition of myocardial PDE III results in benign degeneration (increased heart contractility), increased variability (increased heart rate), and peripheral vasodilation. Such cardiovascular manifestations of such inhibition are commonly seen as typical benign metabolism agents, milnon and enoximon, and are utilized in short-term acute treatment of congestive heart failure. However, in the treatment of so-called silent diseases (ie, asymptomatic) such as ET, cardiovascular side effects of palpitations and tachycardia associated with anagrelide are associated with their usefulness and the proportion of significant patients who do not develop drug resistance during long-term treatment. (25 to 50% on recording) is limited.

Anagrelide's PDE III inhibitory properties are quite distinct from its anti-megakaryocytic effect, which lowers its platelets. In fact, research has shown PDE to anagrelide and its main pharmacologically active metabolite, 3-hydroxyanagrelide (previously known as SPD604 or BCH24426 or 3-HA). It has been shown that there is no correlation between efficacy as a III inhibitor and a megakaryocytopric effect. Surprisingly, the latter was found to be 40 times more potent than anagrelide as a PDE III inhibitor. However, with regard to inhibition of megakaryocytosis (and thus platelet lowering potential), it was not more potent than the parent drug. The active metabolite of anagrelide, 3-HA, is typically present in vivo in an amount that is significantly more than that of the parent drug with 2-3 times or more of exposure. Thus, implicitly 3-OH anagrelide is likely to be a major contributor to the pharmacological action of the drug.

In addition to the unwanted cardiovascular effects associated with PDE III inhibition, the resulting elevation of cAMP can lead to anticoagulant effects. Initially this property may seem advantageous for patients with idiopathic thrombocytopenia with greater thrombotic risk propensity, but such excess antiplatelet effect may result in hemorrhagic results and may eventually be undesirable. In fact, hemorrhagic events sometimes seen in ET patients treated with anagrelide are synergistic with aspirin, which is often concomitantly administered due to a combination of anticoagulant effects and excessive platelet reduction significantly caused by 3-OH anagrelide. It may be exacerbated by the interaction. (In some ET patients, the plasma concentration of 3-OH anagrelide was shown to exceed in vitro IC ₅₀ values for inhibition of platelet coagulation by three factors).

PDE III-mediated cardiovascular side effects with respect to anagrelide treatment mean that many patients must be converted to the only significant alternative therapy, hydroxyurea. However, these drugs are simple chemical anti-metabolites that inhibit ribonucleoside diphosphate reductase (RNR), which has a serious effect on DNA synthesis. Ribonucleoside diphosphate reductase catalyzes the conversion of ribonucleosides to deoxyribonucleosides, which are components of DNA synthesis and repair. Inhibition of ribonucleoside diphosphate reductase accounts for the cytopenic and (very important) mutagenic effects of the compound and its platelet lowering action. Thus hydroxyurea is officially classified as "presumed human carcinogen." As well as having the potential to induce leukemia transformation, hydroxyurea is associated with the induction of leg ulcers that are difficult to treat.

When faced with this dilemma in treatment choice, there is a clear need for new formulations whose effects are selective but with little or no side effects in the treatment of thrombocytopenia. While anagrelide provides some selectivity in its mechanism of action, the limitations on its use are related to the cardiovascular effects manifested by its secondary pharmacology and are mostly active metabolites of anagrelide, 3-hydroxyanagrely Contributed by DE.

Anagrelide metabolism generally proceeds extremely rapidly, producing less than the pharmacodynamic profile of an ideal drug. The typical half-life of anagrelide is only 1.5 hours (the metabolite is 2.5 hours) to require frequent drug administration (up to 4 times a day). This, together with the side effect profile, can lead to poor patient acceptance. In addition, anagrelide exerts a huge first pass effect (> 50%) which results in a significantly intersubjective change in the realized exposure resulting in a potentially variable drug response. In addition, exposure to pharmacologically active metabolites varies dramatically from patient to patient because its formation depends on enzymes whose formation varies considerably with exposure to CYP1A, i.e., an inducer such as tobacco smoke. Overall, this may require careful dosage in patients being treated with anagrelide.

US4256748 describes a number of imidazo [2,1-b] quinazolin-2s that have a structure similar to anagrelide and are said to be effective in the treatment of thrombosis that results in the anticoagulant effect of platelets mediated by PDE III inhibition. 3H) -on is initiated. However, the above does not reveal a completely isolated megakaryocyte-preventing potential (reduced platelet count) that may be associated with some analogs.

Ideally, there is a need for a compound that retains anti- megakaryocytic activity while at the same time having a reduced level of PDE III inhibitory activity and thus an unnecessary cardiovascular effect.

It is an object of the present invention to improve the properties of the compounds of the prior art or to overcome various disadvantages thereof. Accordingly, it is an object of the present invention to provide anagrelide derivatives having improved activity and / or reduced cardiovascular toxicity compared to compounds of the prior art in the treatment of diseases to provide effective treatment for the control of megakaryocytosis. It is. The compounds of the present invention are particularly advantageous because their inhibitory activity against phosphodiesterase III (PDE III) is shown to be weak but surprisingly still retains its anti-megakaryocytic properties and has platelet lowering properties.

It is also desirable for the compounds of the present invention to have an improved pharmacodynamic profile to help the patient's acceptance and to ensure the consistency of the treatment response. A further object is therefore to provide compounds with excellent action times, ie long half-lives in vivo. A further object is also to provide compounds that are available through relatively convenient synthetic processes.

The compounds described in connection with the present invention fulfill some or all of the above objects.

Summary of the Invention

We have found that analogs of anagrelide, where the main site of metabolism is protected by appropriate groups, can have improved pharmacokinetics and better side effect profiles. This is expected to result in good tolerability and improved patient acceptance to effectively treat a broad spectrum of patients.

The compounds of the present invention are surprisingly advantageous for two reasons: they have dramatically lower PDE III inhibitory activity compared to 3-hydroxyanagrelide, but still have potent megakaryocytic activity. In fact the compound has a therapeutic index that is even more desirable than anagrelide itself.

In one embodiment, the invention encompasses anagrelide analogs, including 3-substituted, 5-substituted, 3,3-substituted or 5,5-substituted anagrelide compounds. Thus, for example for 3-substituted derivatives, the first pass metabolism against 3-hydroxy anagrelide is effectively protected. Surprisingly, the compound still shows excellent anti-megakaryocytic activity. One aspect of the present invention therefore relates to an anagrelide analogue comprising a 3-substituted derivative in which the first pass metabolism against the corresponding 3-hydroxyanagrelide is effectively protected. For 5-substituted compounds, bulky groups are expected to be more effective than smaller groups. Thus groups such as t-butyl and other bulky protecting groups are expected to be most effective when substituted at the 5-position. Substituents comprising a macro group at the 5-position are expected to cause steric hindrance for the 3-positional access by the active site of metabolic cytochromes. It should inhibit the formation of the cardiofunctional metabolite, 3-hydroxyanagrelide.

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

Where

R ¹ , R ² , R ³ and R ⁴ independently represent hydrogen or a blocker which acts directly or indirectly to prevent metabolic reaction at the 3-position of the substituent; or

R ¹ and R ² , and / or R ³ and R ⁴ together with the carbon to which they are attached, form a blocking group which acts directly or indirectly to prevent metabolic reaction at the 3-position of the substituent, and in the groups R ¹ to R ⁴ The rest is hydrogen;

R ⁵ is selected from the group comprising fluoro, chloro, bromo and iodo;

R ⁶ is selected from the group comprising fluoro, chloro, bromo and iodo;

R ⁷ and R ⁸ are independently H; Halo; Cyano; C _{1 -6} alkyl, C _{1 -6} haloalkyl, C _{1 -6} alkoxy, C _{1 -6} and is selected from the group consisting of haloalkoxy;

R ⁹ is H, C _{1 -6} alkyl, or a Group 1 metal ion, and;

Provided that if R ¹ , R ² , R ³ and R ⁴ are not all hydrogen, or if R ³ and R ⁴ are hydrogen when one of R ¹ and R ² is methyl, then the other of R ¹ and R ² is It is not hydrogen.

In an embodiment,

R ¹ and R ² are independently H; Cyano; C _{1 -6} alkyl, SC _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{3 -8} is selected from the group consisting of cycloalkyl, the alkyl, alkenyl, alkynyl or cycloalkyl alkyl group is halo, hydroxyl, cyano, nitro, C _{1 -4} alkyl sulfonyl, and COOH; C _{1 -6} hydroxyalkyl; C _{1 -6-carboxy-alkyl;} And optionally 1-5 groups independently selected from the group comprising sulfides; or

R ¹ and R ² are taken together with the carbon to which they are attached, halo, hydroxyl, cyano, nitro, C _{1 -4} haloalkyl, C _{1 -4} alkyl sulfonyl, and of 1 to 5 independently selected from the group comprising COOH which may optionally be substituted with a C _{3 -8} form a carbocyclic ring, or; or

R ¹ and R ² together represent a C _{2 -6} alkenyl or C _2-6 alkynyl is attached through a double bond at the coupling ring, these groups are halo, hydroxyl, cyano, C _{1 -4} haloalkyl And may be optionally substituted with 1 to 3 groups independently selected from the group containing COOH.

In a preferred set of compounds, R ¹ is is an optionally substituted C _{1 -4} alkyl or C _{3 -8} cycloalkyl group.

In a preferred set of compounds, R ² is an optionally substituted C _{1 -4} alkyl group or a C _{3 -8} cycloalkyl.

In another preferred set of compounds, R ¹ and R ² together to form an optionally substituted C _{3 -8} cycloalkyl. Most preferably it is a cyclopropyl group.

Other preferred compounds include those wherein at least one of R ¹ and R ² is -C (H) _n (F) _m or -C (H) _n (F) _m -C (H) _p (F) _{q where} m = 2 or 3, and n = (3-m); and p = 2 or 3, and q = (3-p).

More preferably at least one R ¹ and R ² is CF ₃ or CHF ₂ . Most preferably, at least one R ¹ and R ² is CF ₃ .

In an embodiment, R ¹ is preferably methyl, cyclopropyl, CF ₃ or CHF ₂ . More preferably, R ¹ is methyl or cyclopropyl. Most preferably, R ¹ is methyl. In an embodiment, R ² is preferably methyl, cyclopropyl, CF ₃ or CHF ₂ . More preferably R ² is methyl or cyclopropyl. Most preferably R ² is methyl.

In an embodiment,

R ³ and R ⁴ are independently H; Cyano; C _{1 -6} alkyl, SCC _{1 -6} alkyl, CC _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{3 -8} selected from the group consisting of cycloalkyl and said alkyl, alkenyl, alkynyl or cycloalkyl group is halo, hydroxyl, cyano, nitro, C _{1 -4} alkyl sulfonyl, and COOH; C _{1 -6} hydroxyalkyl; C _{1 -6-carboxy-alkyl;} And optionally 1-5 groups independently selected from the group comprising sulfides; or

R ³ and R ⁴ are taken together with the carbon to which they are attached, halo, hydroxyl, cyano, nitro, C _1-4 haloalkyl, C _{1 -4} alkyl sulfonyl, and of 1 to 5 independently selected from the group comprising COOH which may optionally be substituted with a C _{3 -8} form a carbocyclic ring, or; or

R ³ and R ⁴ together represent a C _{2 -6} alkenyl or C _2-6 alkynyl is attached through a double bond at the coupling ring, these groups are halo, hydroxyl, cyano, C _{1 -4} haloalkyl And may be optionally substituted with 1 to 3 groups independently selected from the group containing COOH.

In embodiments, R ³ is H or C _{1 -6} alkyl. Preferably, R ³ is H.

In embodiments, R ⁴ is H or C _{1 -6} alkyl. Preferably, R ⁴ is H.

In an embodiment, R ⁵ is preferably chloro.

In an embodiment, R ⁶ is preferably chloro.

In an embodiment, R ⁷ is H.

In an embodiment, R ⁸ is H.

In an embodiment, R ⁹ is H. In an alternative embodiment, R ⁹ is a C _{1 -6} alkyl, in this case, PDE III inhibiting activity is effectively eliminated. Me represents a particularly preferred alkyl substituent. In another alternative embodiment, R ⁹ is a Group I metal ion, in which case the compound shows significantly improved water solubility. Sodium represents a particularly preferred Group I metal.

In further embodiments,

R ¹ and R ² are independently H; Cyano; C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{3 -8} is selected from the group including a cycloalkyl group wherein the alkyl, alkenyl, alkynyl or cycloalkyl, halo, hydroxyl, cyano, nitro, C _{1 -4} alkyl sulfonyl, and COOH; C _{1 -6} hydroxyalkyl; C _{1 -6-carboxy-alkyl;} And optionally 1-5 groups independently selected from the group comprising sulfides; or

R ¹ and R ² are taken together with the carbon to which they are attached, halo, hydroxyl, cyano, nitro, C _1-4 haloalkyl, C _{1 -4} alkyl sulfonyl, and of 1 to 5 independently selected from the group comprising COOH which may optionally be substituted with a C _{3 -8} form a carbocyclic ring, or; or

R ¹ and R ² are taken together with the carbon to which they are attached, is attached via a double bond at the coupling ring C _{2 -6} alkenyl or C _{2 -6} represents a alkynyl, halo, hydroxyl, cyano, C _{1 -4} Optionally substituted with 1 to 3 groups independently selected from the group comprising haloalkyl and COOH;

Provided that R ¹ and R ² are not both hydrogen, or when one of R ¹ and R ² is methyl, the other is not hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁵ is selected from the group comprising fluoro, chloro, bromo and iodo;

R ⁶ is selected from the group comprising fluoro, chloro, bromo and iodo;

R ⁷ , R ⁸ and R ⁹ are hydrogen.

Another preferred group of compounds is that R ¹ and R ² are not hydrogen. Among them, as R ¹ and R ² both independently cyano, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} is selected from the group consisting of alkynyl, wherein the alkyl, alkenyl, and alkynyl It is preferable that the group can be optionally substituted; or

R ¹ and R ² are taken together with the carbon to which they are attached, form an optionally substituted carbocyclic ring, or C _{3 -8;} or

R ¹ and R ² together represent an optionally substituted C _{2 -6} alkenyl or C _{2 -6-alkynyl.}

Particularly preferred individual compounds of the invention

3-methylene anagrelide

3,3, spiro-cyclopropyl-anagrelide

3,3-dimethylanagrelide

(R) -3- (hydroxymethyl) anagrelide

(S) -3- (hydroxymethyl) anagrelide

It includes.

Particularly preferred compounds include 3,3-dimethylanagrelide, and spiro [anagrelide-3,1′-cyclopropane]. Such compounds are usually prepared as HBr addition salts.

It was also found that each enantiomer of the 3-substituted derivatives showed efficacy. The present invention therefore also relates to mixtures of resolved optical and enantiomers of these compounds. To compare the compounds of the invention with anagrelide, the exact comparison consists of the PDE III inhibitory activity of the anagrelide 3-hydroxy metabolite, which is the main component in the plasma after anagrelide treatment. Because.

In connection with the use of the compounds of the invention in humans,

Pharmaceutical compositions which may be suitable for oral, parenteral or topical administration comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier;

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

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 myeloproliferative diseases and / or generalized thrombotic diseases,

A method of treating a disease selected from myeloproliferative diseases and / or systemic thrombotic diseases in humans, the method comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, or any of the above A method comprising treating said human with a composition

This is provided.

The invention also includes a method of treating a patient with idiopathic thrombocytopenia or high platelet count, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention.

Another embodiment of the invention includes a method of reducing the number of platelets in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention.

The present invention includes, among other things, providing the compounds of the present invention in the methods listed above, and myocardial toxicity is reduced when compared to the use of anagrelide.

Independently, we found that both (R) -3-methyl anagrelide and (S) -3-methyl anagrelide were better during PDE III inhibition significantly reduced compared to 3-OH anagrelide, respectively. It was found to exhibit megakaryocytoprotective activity. We therefore expect that 3-methyl anagrelide will have utility in treating myeloproliferative diseases.

Accordingly, the present invention also encompasses the use of 3-methyl anagrelide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating myeloproliferative diseases.

Accordingly, the present invention also provides a method for treating myeloproliferative diseases in humans, comprising: an effective amount of 3-methyl anagrelide, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the above It relates to a method comprising treating the human.

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

Detailed description of the invention

The present invention relates to novel 3- or 5-substituted analogues of the proven platelet lowering agent anagrelide. Substitution at the 3-position or adjacent 5-position of the anagrelide molecule is expected to protect or hinder major sites of metabolism, excluding the formation of 3-OH anagrelide, a potentially potent PDE III inhibitor. In contrast, substitutions at the 1-position have surprisingly been found to disrupt PDE III inhibition. The compounds of the present invention retain the anti-megakaryocytic properties (and thus platelet lowering activity) of the parent drug molecule but have reduced PDE III inhibitory properties, thus lowering the potential for unnecessary cardiovascular and anticoagulant side effects. They also have the potential for improved pharmacodynamic properties as a result of inhibition of metabolism.

These improved cardiovascular and pharmacodynamic properties have been demonstrated by studies in dogs. A comparison of the in vivo cardiovascular effects of examples of anagrelide, its active metabolites and representative enhanced analogs is presented in the table below.

Comparative activity of anagrelide, its metabolite 3-hydroxy anagrelide and representative 3-alkyl substituted analogs in the drug

compound PDE III  For suppression In vitro IC50 (Human enzyme) doggy At heart rate  Affecting student The body ED50 doggy At heart rate  Affecting student The body ED 20 Megakaryocytes prevention  For effect In vitro IC50 (Human cell line) Anagrelide 29 nM 986 μg / kg 376 μg / kg 26 nM 3-hydroxy anagrelide (active metabolite) 0.7 nM 11.72 μg / kg 7.1 μg / kg 44 nM 3,3 Dimethyl Anagrelide 164 nM 3,557 μg / kg 2,512 μg / kg 166 nM

The most significant comparison of the data cited in the table above is the 3-hydroxy anagrelide (as an active metabolite of the drug) and a 3-alkyl substituted analogue, because the former is present in the plasma of patients treated with the drug. Because it is a predominant species. Based on this, the therapeutic benefit to the potential of CV side effects rates is certainly much improved for the 3-alkyl derivatives.

A comparison of the pharmacodynamic profile in dogs of anagrelide and representative 3-substituted analogs is shown below.

Pharmacodynamic Comparison of Anagrelide Following 1 mg / kg iv, Active Metabolites Produced, and Representative 3-Substituted Analogs in a Conscious Dog Model

compound C _Value ( ng Of mL ) AUC _(0-t) ( ng .h / mL ) T _{One /2} (time) CL ^* ( mL / h / kg ) V _ss ^* ( mL Of kg ) F _{( AUC (0-t))} * Anagrelide 48.1 ± 21 101 ± 15 1.37 ± 20 1156 ± 4.56 1011 ± 3.8 11.8 ± 14.4 3-hydroxy anagrelide (caused by anagrelide treatment) 60.1 ± 14 179 ± 14 1.57 ± 24 Does not appear Does not appear 3,3 Dimethyl Anagrelide 167 ± 33 1903 ± 47 9.39 ± 21 178 ± 45.9 1967 ± 24 39 ± 25

Results show geometric mean and% CV

* After 1 mg / kg iv

The data in the table show a much longer half-life (9.39 hours versus 1.37 hours) for 3-alkyl substituted analogues when compared to anagrelide itself and when compared to those presented as anagrelide when reflected in humans. Much less frequent drug administration can be achieved and patient acceptance should be improved. This relatively long half-life for 3,3 dimethyl anagrelide observed in dogs was reflected in in vitro metabolic stability studies, which was certainly much more metabolically stable than anagrelide (see table below). Liver metabolism is known to be the major mechanism of anagrelide removal in animals and humans. In addition, and most importantly, much greater metabolic stability for these 3-substituted analogs has also been observed in human hepatocytes, suggesting improved pharmacodynamic potential in humans.

Comparative Metabolic Stability of Anagrelide and Representative Analogues in Dog and Human Hepatocytes

compound Dog liver cells In vitro  "Half-life" Human liver cells In vitro  "Half-life" Anagrelide 1.25 hours 6.62 hours 3,3-dimethyl analog No degradation over the course of the study 22.8 hours

Pharmaceutically acceptable acid addition salts of certain compounds of formula (I) can also be prepared in conventional manner. For example, the free base solution is treated with a suitable acid alone or in a suitable solvent and the resulting salt is isolated by filtration or evaporation of the reaction solvent under reduced pressure. For a review of suitable acids, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Term Definition

Halo means a group selected from fluoro, chloro, bromo or iodo.

As used herein as a group or part of a group, as used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon chain comprising a certain number of carbon atoms. For example, C _1-10 alkyl means straight or branched chain alkyl comprising one or more and ten or less. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl, nonyl and Contains decyl. C _1-4 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl are one embodiment.

As used herein, the term "cycloalkyl" refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms, by way of non-limiting example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.

As used herein, the term “spirocyclic” refers to a ring system connected at one carbon atom to a second ring system.

As used herein, the term "alkoxy" refers to a straight or branched chain hydrocarbon chain group comprising oxygen and a certain number of carbon atoms. For example, C _1-6 alkoxy means straight or branched alkoxy containing at least one and up to six carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1- Oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy. C _1-4 alkoxy groups such as methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy are one embodiment.

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

The term "alkenyl" as used herein as a group or as part of a group refers to a straight or branched chain hydrocarbon chain comprising a certain number of carbon atoms and one or more double bonds. For example, the term "C _2-6 alkenyl" refers to a straight or branched chain alkenyl comprising at least 2 and up to 6 carbon atoms and at least one double bond. Examples of “alkenyl” as used herein include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl- 2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and 1,1-dimethylbut-2-enyl. In groups of the -OC _2-6 alkenyl form, it will be appreciated that the double bond is preferably not adjacent to oxygen.

As used herein as a group or part of a group, the term “alkynyl” refers to a straight or branched hydrocarbon chain comprising a certain number of carbon atoms and one or more triple bonds. For example, the term "C _2-6 alkynyl" refers to straight or branched alkynyl containing two or more and six carbon atoms and one or more triple bonds. Examples of “alkynyl” as used herein include, but are not limited to, ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl- 2-butynyl, 3-methylbut-2-ynyl, 3-hexynyl and 1,1-dimethylbut-2-ynyl. In groups of the form -0-C _2-6 alkynyl, it will be appreciated that the triple bond is preferably not adjacent to oxygen. The term "halo" refers to a halogen such as a fluorine, chlorine, bromine or iodine atom.

The term “sulfide” means that a sulfur atom is covalently bonded to two hydrocarbon chains, R _a and R _b, and the two hydrocarbon chains are radicals of R _a -SR _b , which may be any of those discussed above, by way of non-limiting example. Refers to.

The compounds of the present invention, i.e. compounds of formula (I), possess antikaryocyte activity in humans. They may be particularly useful for the treatment of myeloproliferative diseases. The compounds may also find utility in the treatment of systemic thrombotic diseases.

Criteria for treatment include prevention and alleviation of the established symptoms of the condition. A “treating” or “treatment” of a condition, disease or condition is (1) suffering from, or having not yet experienced or indicated a clinical or subclinical symptom of the condition, disease or condition, but is likely to be affected. Preventing or delaying the appearance of clinical symptoms of a condition, disease or condition that develops in humans, and (2) inhibiting the condition, disease or condition, ie the development of the disease or its recurrence (in case of continuous treatment) Or arresting, reducing or delaying one or more clinical or subclinical symptoms thereof, or (3) alleviating or attenuating a disease, condition, disease or condition or degeneration of one or more clinical or subclinical symptoms thereof. Causing.

Myeloproliferative diseases that can be treated with the compounds of the present invention are idiopathic thrombocytopenia, true erythrocytosis, chronic idiopathic myeloid fibrosis, chronic myeloid leukemia with persistent thrombocytopenia, immediate or to minimize the risk of thrombus formation during or after surgery. As a prophylactic measure of subsequent surgery, the surgical procedure includes reactive thrombocytopenia immediately preceded.

Thrombotic cardiovascular disease (TCVD) (ie, patients with increased risk of systemic thrombosis) that may also be treated with the compounds of the present invention includes patients undergoing myocardial infarction (heart attack) thrombotic seizures, coronary stent placement. .

The compounds of the present invention are useful for the treatment of atherothrombotic events such as the following recent MI, recent seizures or established peripheral arterial disease, acute coronary syndrome (unstable angina / non-Qwave MI), cardiovascular death, MI, seizures, and refractory ischemia. Usefulness can be found for the reduction.

It is understood that compounds of formula (I) may include one or more asymmetric carbon atoms, so that compounds of the present invention may exist as two or more stereoisomers.

Included within the scope of the present invention are all stereoisomers of the compounds of formula (I), including enantiomers and diastereomers, all geometric isomers, including compounds exhibiting one or more types of isomerism, and one or more mixtures thereof. And tautomeric forms.

Solubility studies have been performed on a number of anagrelide derivatives in accordance with the present invention in various test media. Test medium

a) single distilled water (pH 5.0) [no attempt is made to remove dissolved CO ₂ ]

b) 50 mM ammonium formate (pH 7.9)

c) 0.1 M hydrochloric acid (pH 0.6).

Calibration plots of HPLC peak area versus concentration were obtained in MeOH or MeOH / DMSO over a range of 1000-1 μg / ml for each material at a temperature of 20-22 ° C. The HPLC method used a reverse phase C ₁₈ column with a gradient of water (0.6% formic acid) and acetonitrile. For solubility studies, saturated solutions were prepared by dissolving in the desired medium by ultrasonic bath for 20 minutes and excess solids were removed by centrifugation. Material concentration in the supernatant was determined at the measured peak area.

Unexpectedly, it has been found that stable metal salts can be prepared after deprotonation at the 1-position of the quinazoline ring structure. The value of such salts shows much higher aqueous solubility than the corresponding HBr salts. This is likely to present a major clinical benefit by facilitating rapid dissolution and quantitative absorption of these generally poor water soluble compounds. These salts are Group I metal salts and most are usually sodium or potassium salts. Table 1 below shows the results of solubility measurements.

Anagrelide  And Anagrelide  Solubility of derivatives (μg at about 20 ° C mL ^-One ) compound ammonium Formate (50 mM , pH  7.9) water ( pH  5.0) Hydrochloric acid (0.1 M, pH  0.6) Anagrelide Hydrochloride 10 11 169 3,3-dimethylanagrelide sodium salt 6 409 212 3,3-dimethylanagrelide hydrobromide 4 20 215 3,3, spiro-cyclopropyl-anagrelide sodium salt One 542 28 3,3-spiro-cyclopropyl-anagrelide hydrobromide One 2 35 3-methylene anagrelide 5 9 43 3-methylene anagrelide sodium salt 39 1830 189

Geometrical isomers may be separated by conventional techniques well known to those skilled in the art, for example by chromatography and fractional crystallization.

Stereoisomers may be separated by conventional techniques known to those skilled in the art-see, eg, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).

Compounds of formula (I) can be prepared using similar manners as described in the literature and in Scheme I and Scheme II of US Pat. No. 4,256,748. Synthesis of 3-ethyl anagrelide is described by way of example to show how each isomer of the present invention can be prepared. Similar procedures can be used to prepare other compounds of the invention by using suitable α-haloesters.

The formation of 3-ethyl anagrelide (Compound 4a ) is shown in Scheme A below. 1-amino-2, 3-dichloro nitrobenzene ( 1a ) is subjected to nucleophilic substitution with α-haloester R-ethyl-2-bromobutanoate to obtain compound ( 2a ). The nitro group is then reduced to an amine group using tin chloride in ethanol to give the diamine compound ( 3a ). Compound ( 3a ) is then cyclized to cyanogen bromide in toluene to give 3-ethyl anagrelide ( 4a ).

3- Of ethyl anagrelide  formation

The formation of certain derivatives is achieved by reversing the NH ₂ and Br group positions of the starting material, in a manner analogous to the synthesis set forth in Scheme A above, or where appropriate in the relevant chemistry. In this case, α-aminoester and halobenzyl derivatives are used as starting materials. The reaction is generally shown as shown in Scheme B below for the 3-substituted compound.

3-substituted Anagrelide  formation

(Wherein A is NH ₂ or Br and B is the other of NH ₂ or Br)

Formation of (R) -3-ethyl anagrelide is achieved in a similar manner to the synthesis presented in Scheme A above. In this case, the stereochemistry of the α-haloester, ie S-ethyl-2-bromobutanoate, is used which is the opposite of that used in Scheme A in the nucleophilic substitution step. This procedure is generally applicable.

Racemic α-haloesters can be used in the first stage of synthesis if no single enantiomer is required.

Those skilled in the art will know of the variations, and alternatives, to the processes mentioned in US Pat.

Those skilled in the art will also appreciate that compounds of the present invention may be modified by the methods described herein and / or by modifications in the industry, for example methods known in the art described herein, or by standard primers, such as "Comprehensive Organic Transformations-A Guide." to Functional Group Transformations ", RC Larock, Wiley-VCH (1999 or later)," March's Advanced Organic Chemistry-Reactions, Mechanisms and Structure ", MB Smith, J. March, Wiley, (5th or latest edition)" Advanced Organic Chemistry, Part B, Reactions and Synthesis ", FA Carey, RJ Sundberg, Kluwer Academic / Plenum Publications, (2001 or later)," Organic Synthesis-The Disconnection Approach ", S Warren (Wiley), (1982 or later) ), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later)), and the like. Would know that .

Those skilled in the art will also appreciate that it may be necessary for sensitive functional groups to be protected and deprotected during the synthesis of the compounds of the present invention. This can be realized, for example, by conventional methods as described in TW Greene and PGM Wuts' "Protective Groups in Organic Synthesis", John Wiley & Sons Inc (1999), and references therein.

Compounds of the invention contemplated for pharmaceutical use may be administered as crystalline or amorphous products. It can be obtained by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporation drying, for example as a solid plug, powder, or film. Microwave or radio frequency drying may be used for this purpose.

It 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. Generally, it will be administered with one or more pharmaceutically acceptable excipients as a preparation. Pharmaceutically acceptable excipients include one or more antioxidants, colorants, flavors, preservatives and taste-masking agents.

Pharmaceutical compositions suitable for the delivery of the compounds of the present invention and methods for their preparation will be readily appreciated by those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). The formulation of the tablets is described in [H. Lieberman and L. Lachman, "Pharmaceutical Dosage Forms: Tablets, Vol. 1", Marcel Dekker, N. Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Methods in which the compound may be administered include oral administration by capsules, pills, tablets, powders, lozenges, chew, multi and nanoparticulates, gels, solid solutions, films, sprays, or liquid formulations. Liquid forms include suspensions, solutions, and syrups. Such formulations can be used as fillers in soft or hard capsules and usually comprise a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations may also be formulated by, for example, reconstituting a solid formulation from an encapsulant.

The compounds may also be administered topically to the dermal or transdermal skin or mucosa. Common formulations for this purpose include pour-on solutions, sprays, powder formulations, gels, hydrogels, lotions, creams, ointments, films and patches, and implants. The compounds may also be administered parenterally or by direct injection into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, vesicle, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (microneedle) injection, extra needle injection, and infusion techniques.

The formulations may be immediate and / or modified controlled release. Modified controlled release formulations include delayed, sustained release, and pulsed release.

Dosage

Typically, the physician will determine the actual dosage that will be most appropriate for each subject. Specific dosage levels and dosage frequencies for any particular individual may vary and the activity of the particular compound employed, the stability of metabolism and the time of action, age, weight, general health, sex, diet, mode of administration, and It will vary depending on various factors including time of day, rate of excretion, drug combination, severity of the particular condition, and individual treatment regimen.

Generally, however, suitable doses are from about 0.001 to about 50 mg / kg of body weight per day, in further embodiments, from about 0.001 to about 5 mg / kg of body weight per day, and in further embodiments from about 0.001 to about 1 body weight per day. About 0.5 mg / kg, and in further embodiments will range from about 0.001 to about 0.1 mg / kg of body weight per day. In further embodiments, the range may be from about 0.1 to about 750 mg / kg of body weight per day, in the range of 0.5 to 60 mg / kg / day, and in the range of 1 to 20 mg / kg / day.

Preferred doses may conveniently be presented in a single dose or in divided doses administered at suitable intervals, such as once, twice, three times, four times or more per day. When the compound is administered transdermally or in an extended release form, the compound may be administered no more than once a day. The compound is conveniently administered in unit dose form, including, for example, 0.1-50 mg of active ingredient, conveniently 0.1-5 mg, most conveniently 0.1-5 mg per unit dose form. In further embodiments, the compound may be conveniently administered in unit dose form, eg, comprising 10-1500 mg, 20-1000 mg, or 50-700 mg of active ingredient per unit dose form.

Compounds of the invention and their activities are exemplified below.

Example 1

PDE III  As inhibitors and megakaryocytes Anagrelide  And some 3- Alkyl  On substituted analogs IC ₅₀ Data  compare

The table below shows the comparative activity of anagrelide and its analogs with regard to affecting megakaryocytosis (the process by which platelets develop) and PDE III (inhibition leading to cardiovascular adverse events).

In vitro comparative assessment of the potential therapeutic and adverse effects of anagrelide and its analogs

compound On megakaryocyte prevention  About IC ₅₀ (Platelet lowering activity) PDE III  For suppression IC ₅₀ (Cardiovascular effect) Gain ratio (Treatment effect vs. adverse effect) Anagrelide 3-hydroxy Anagrelide 27 nM44 nM 32 nM0.7 nM * 0.024: 10.016: 1 3,3 dimethyl Anagrelide 164 nM 166 nM 1: 1 3- Spirocyclo  Profile Anagrelide 547 nM 797 nM 1.45: 1

* Pharmacodynamically adjusted values based on three-fold or more systemic exposure of active metabolite (3-hydroxy anagrelide) in humans than in the drug itself

Evaluation of the in vitro megakaryocyte-protective activity (and potentially platelet lowering ability) of the 3-substituted analogs of anagrelide was performed using a well established model of megakaryocytosis. [Cohen-Solal et al. Thromb. Haemost. 1997, 78: 37-41 and Cramer et al., Blood, 1997, 89: 2336-46. It can be easily suggested that the benefit ratio (therapeutic effect counterpart) with anagrelide (after describing the prevailing exposure to cardiovascular metabolites in vivo) was relatively low at 0.024: 1. In contrast, both 3-spirocyclopropyl and 3,3 dimethyl anagrelide demonstrated relatively much better gain ratios in this study.

Claims (22)

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: [Formula I] In the above formula R ¹ and R ² independently represent a protecting group which acts to prevent metabolic reaction at the substitution position; R ³ and R ⁴ independently represent hydrogen or a protecting group which acts to prevent metabolic reaction at the substitution site; or R ¹ and R ² together with the carbon to which they are attached form a protecting group which acts to prevent metabolic reaction at the 3-position and R ³ and R ⁴ are hydrogen; or R ¹ and R ² , and R ³ and R ⁴ together with the carbon to which they are attached, form a protecting group which, directly or indirectly, acts to prevent metabolic reactions at the 3-position; R ⁵ is selected from the group comprising fluoro, chloro, bromo and iodo; R ⁶ is selected from the group comprising fluoro, chloro, bromo and iodo; R ⁷ and R ⁸ are independently H; Halo; Cyano; C _{1 -6} alkyl, C _{1 -6} haloalkyl, C _{1 -6} alkoxy, C _{1 -6} and is selected from the group consisting of haloalkoxy; R ⁹ is H, C _{1 -6} alkyl, or a Group I metal ion, However, R ¹ , R ² , R ³ and R ⁴ are not always all hydrogen. The method of claim 1, R ¹ and R ² are both independently cyano; C _{1 -6} alkyl, C _{2 -6} alkenyl is selected from, the group comprising C _{2 -6-alkynyl,} wherein the alkyl, alkenyl, alkynyl groups optionally can be substituted with either; or R ¹ and R ² are taken together with the carbon to which they are attached, form an optionally substituted carbocyclic ring, or C _{3 -8;} or R ¹ and R ² are taken together with the carbon to which they are attached, an optionally substituted C _{2 -6} alkenyl or C _{2 -6-alkynyl} represents a compound. The method according to claim 1 or 2, R ³ and R ⁴ are independently H; Cyano; C _{1 -6} alkyl, SC _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{3 -8} selected from the group consisting of cycloalkyl and said alkyl, alkenyl, alkynyl or cycloalkyl group is halo, hydroxyl, cyano, nitro, C _{1 -4} alkyl sulfonyl, and COOH; C _{1 -6} hydroxyalkyl; C _{1 -6-carboxy-alkyl;} And optionally 1-5 groups independently selected from the group comprising sulfides; or R ³ and R ⁴ are taken together with the carbon to which they are attached, halo, hydroxyl, cyano, nitro, C _1-4 haloalkyl, C _{1 -4} alkyl sulfonyl, and of 1 to 5 independently selected from the group comprising COOH which may optionally be substituted with a C _{3 -8} form a carbocyclic ring, or; or R ³ and R ⁴ together represent a C _{2 -6} alkenyl or C _2-6 alkynyl is attached through a double bond at the coupling ring, these groups are halo, hydroxyl, cyano, C _{1 -4} haloalkyl And optionally substituted with 1 to 3 groups independently selected from the group comprising COOH. Any one of claims 1 to A method according to any one of claims 3, wherein, R ³ is H or C _{1 -6} alkyl. Any one of claims 1 to A method according to any one of claims 4, R ⁴ is H or C _{1 -6} alkyl. 6. The compound of claim 1, wherein R ⁵ is chloro. The compound of any one of claims ^1-6 , wherein R ⁶ is chloro. 8. The compound of claim 1, wherein R ⁷ is H. ⁹ . The compound of any one of claims ^1-8 , wherein R ⁸ is H. ¹⁰ . The compound of any one of claims 1-9, wherein R ⁹ is H. ¹¹ . The compound of any one of claims 1-9, wherein R ⁹ is methyl. The compound of any one of claims 1-9, wherein R ⁹ is sodium. Any one of claims 1 to 12 in any of the preceding claims, wherein, R ¹ is an optionally substituted C _{1 -4} alkyl or C _{3 -8} cycloalkyl group compound. Any one of claims 1 to 13 in any of the preceding claims, wherein, R ² is an optionally substituted C _{1 -4} alkyl or C _{3 -8} cycloalkyl group compound. The compound of any one of claims 1-14 wherein R ¹ is methyl, cyclopropyl, CF ₃ or CHF ₂ . The compound of any one of claims 1-15, wherein R ² is methyl, cyclopropyl, CF ₃ or CHF ₂ . Any one of claims 1 to 12 in any of the preceding claims, wherein, R ¹ and R ² together, compounds which form an optionally substituted C _{3 -8} cycloalkyl. An oral or parenteral composition comprising a compound of formula (I) as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable diluent or carrier. Or pharmaceutical compositions that may be suitable for topical administration. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 17 for use as a medicament. A compound of formula (I) as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from myeloproliferative diseases and systemic thrombotic diseases, or Use of solvates. A method of treating a disease selected from myeloproliferative disease and systemic thrombotic disease in a human, comprising the compound of formula (I) as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvent thereof A method comprising treating said human with an effective amount of a cargo, or a pharmaceutical composition comprising any of the above. Use of a compound of formula (I) as defined in any one of claims 1 to 17 for reducing platelet count.