AU2007327048B2

AU2007327048B2 - Amino quinazolines derivatives with blood platelet reducing properties

Info

Publication number: AU2007327048B2
Application number: AU2007327048A
Authority: AU
Inventors: Richard Franklin; Bernard Golding
Original assignee: Shire LLC
Current assignee: Shire LLC
Priority date: 2006-11-28
Filing date: 2007-11-19
Publication date: 2012-01-12
Anticipated expiration: 2027-11-19
Also published as: AU2007327048A1; CA2670168A1; CN101558048B; EA200900742A1; JP2010511031A; MX2009005578A; BRPI0719568A2; EA017139B1; IL198808A0; TW200829252A; GB0623749D0; AR064003A1; MY149620A; KR20090089865A; EP2097390A1; WO2008065445A1; CN101558048A

Abstract

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

Description

PkOPER\MAL1009\30783 8 ipdoc-22/07/209 AMINO QUINAZOLNES DERIVATIVES WITH BLOOD PLATELET REDUCING PROPERTIES FIELD OF THE INVENTION This invention relates to the discovery of prodrugs of 3-or 5-substituted analogues of the 5 selective platelet lowering agent anagrelide which have reduced potential for cardiovascular side-effects and which should therefore lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to prodrugs of certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting the formation of 10 blood platelets. BACKGROUND OF THE INVENTION Anagrelide hydrochloride (Agrylin@, Xagrid@) is a novel orally administered 15 imidazoquinazoline which selectively reduces platelet count in humans and is used for such purposes in the treatment of myeloproliferative diseases (MPDs), such as essential thrombocythemia (ET), where an elevated platelet count may put the patient at increased thrombotic risk. The chemical structure of anagrelide, 6,7-dichloro-l.5-dihyclroimidazo[2,1-b] quinazolin-2(3H)-one (hydrochloride monohydrate), is shown in the following formula: N H N O.Hl.H 2 0 N cl C1 3 position 20 6,7-Dichloro-1,5-dihydroinidazo[2,1-b]-quinazolin-2(3H)-one hydrochloride monohydrate The principal side effects of anagrelide are cardiovascular in nature, tachycardia, palpitations etc 25 and limit the utility of the drug. These are largely attributed to its metabolism to 3 hydroxyanagrelide. This compound was surprisingly found to be some 40-fold more potent as an inhibitor of PDEIII, and therefore potential inotropic agent, than anagrelide itself. Furthermore plasma exposure to this metabolite after treatment with anagrelide is typically three times greater WO 2008/065445 PCT/GB2007/050698 than to the drug itself confirming its pivotal role. Consequently a series of 3-substituted anagrelide analogues has been investigated which has shown that it is possible to introduce metabolism blocking groups at that position and yet still retain the anti-megakaryocytic actions of the drug. Furthermore, these compounds have considerably less potential for cardiovascular 5 effects than 3-hydroxyanagrelide. Indirect steric hindrance to the formation of the 3-hydroxy metabolite may also be achieved by substitution at the 5-position. The 3-substituted compounds typified, by the dimethyl or spirocyclopropyl analogues, are notably less soluble at physiological pH (-7) than the parent compound which presents a significant challenge to their efficient absorption. 10 Anagrelide HCl itself is a poorly soluble drug substance. In the pH range of 4 - 8, the solubility is less than10 [tg/mL. The solubility increases at pH values above and below this range; for example in 0. 1M HCl the solubility is ~-170 .tg /mL and at pH 11.4 approaches 1mg/mL. The dissociation constants (pKal and pKa2) of 2.9 and 9.8 were estimated from the solubility/pH 15 profile of anagrelide HCl. Thus over much of the physiological pH range the drug has very poor aqueous solubility. Even material dissolving in the stomach at pH 1-2 may precipitate in the duodenum at pH 5-6. This presents potential problems for the quantitative absorption from the most likely site for absorption, namely the upper small intestine. As a consequence anagrelide is micronised prior to filling into capsules for clinical use to ensure maximal absorption. This and 20 anagrelide's inherent potency as an anti-megakaryocytic agent - in vitro IC 50 -27 nM and in vivo doses of just 1-2 mg - serve to limit the potential problem of incomplete absorption. Indeed, a radiolabelling study in humans showed that following the oral administration of 1 mg 1C labelled drug >75% of the administered radioactivity was recovered in the urine implying that at least after this dose absorption was >75%. However for those patients requiring larger doses 25 either as the result of relative insensitivity to the drug, higher first-pass pre-systemic metabolism or greater body weight, the possibility exists for incomplete absorption. This would be expected to lead to increased variability in attained plasma drug concentrations and consequential variability in patient response. 2 WO 2008/065445 PCT/GB2007/050698 Furthermore for less potent analogues of anagrelide, even though they may have better cardiovascular profiles, problems of incomplete absorption may be encountered. Improved water solubility though the use appropriate open ring pro-drugs of anagrelide may therefore offer significant advantage in minimizing this risk. 5 W02004/063172 relates to the use of 2-amino-2H-quinazoline derivatives for producing therapeutic agents for the treatment of myeloproliferative diseases, high blood pressure and bronchodilation. 10 SUMMARY OF THE INVENTION This invention provides for prodrugs of anagrelide derivatives substituted at either the 3- or 5 position. In these anagrelide derivatives, metabolism to an analogue of the cardioactive 3 hydroxyanagrelide is blocked either directly (3-substitution) or indirectly (5-substitution). The 15 prodrugs are notably more soluble in vitro (and under anticipated in vivo conditions) than their ring closed analogues offering the potential for better absorption from the GI tract. Such compounds would spontaneously and completely ring close at pH 7 or above thus offering a convenient means of delivering these ring closed anti-megakaryocytic (platelet lowering) agents to the systemic circulation. Since the preferred site of metabolism of anagrelide is the 3-position, 20 such compounds are likely to present improved pharmacokinetic profile and hence improve patient compliance and convenience enabling a broader spectrum of patients to be effectively treated. In the case of the 5-substituted compounds it is expected that a bulky group is more effective than a smaller group when cyclised to the 'closed ring' anagrelide analogue. Groups such as t-butyl and other bulky blocking groups are thus expected to be of most utility when 25 substituted at the 5-position. A substituent comprising a large group at the 5-position is expected to sterically hinder access to the 3-position by the metabolising cytochrome's active site. This should inhibit formation of the cardioactive metabolite, 3-hydroxyanagrelide. The ring closed compounds of the present invention are especially beneficial because 30 surprisingly they have dramatically lower PDE III inhibitory activity (and hence lower 3 WO 2008/065445 PCT/GB2007/050698 cardioactive potential) than the active metabolite of anagrelide, 3-hydroxyanagrelide and yet also surprisingly retain their anti-megakaryocytic activity. Indeed these compounds have therapeutic indices which are much more favourable than that for anagrelide itself. 5 In one embodiment, the present invention comprises a prodrug of an anagrelide analogue comprising a 3-, 5-, 3, 3- or 5,5-substituted anagrelide compound. Thus, for example, in the 3 substituted derivatives, first pass metabolism (of the rapidly ring closed analogue) to 3 hydroxyanagrelide is directly blocked. In particular, the invention relates to prodrugs of an anagrelide analogue wherein first pass metabolism to the corresponding analogue of 3 10 hydroxyanagrelide is effectively blocked. According to the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof

R

8 RN NHR 9

R

6 N 6 /N R 2 R R R 0 XR1 15 (1) wherein: R , R 2 , R 3 and R 4 independently represent hydrogen or a blocking group which functions to prevent metabolic reaction either directly or indirectly at the 3- position; 20 or R and R 2, and/or R3 and R 4 together with the carbon to which they are attached form a blocking group which functions to prevent metabolic reaction either directly or indirectly at the 3- or 5-position of substitution, the remainder of groups R to R 4 being hydrogen; 25 R 5 is selected from the group comprising: fluoro, chloro, bromo and iodo; 4 WO 2008/065445 PCT/GB2007/050698 R is selected from the group comprising: fluoro, chloro, bromo and iodo; and

R

7 and R 8 are independently selected from the group comprising: H; halo; cyano; C 1

_

6 alkyl, C 1

_

6 haloalkyl, C 1

_

6 alkoxy, and C 1

_

6 haloalkoxy; and 5

R

9 is H or C1_6 alkyl,

R

10 is selected from the group comprising: hydrogen; C 1

_

6 alkyl, C 2

_

6 alkenyl, C 2

_

6 alkynyl and

C

3

_

8 cycloalkyl wherein each of the foregoing groups may be optionally substituted by 1 to 5 10 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1

_

4 alkylsulphonyl and COOH; or R 10 is a pharmaceutically acceptable cation, and X is O or S, 15 provided always that R , R 2 , R 3 and R 4 are not all hydrogen. In an embodiment when one of R and R 2 is methyl and R 3 and R 4 are hydrogen then other of R 1 and R 2 is not hydrogen. 20 In one embodiment: R and R 2 , are independently selected from the group comprising: H; halo; 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 by 1 to 5 groups chosen independently from the group comprising: 25 halo, hydroxyl, cyano, nitro, C 1

_

4 alkylsulphonyl and COOH; C 1

_

6 hydroxyalkyl; C 1

_

6 carboxyalkyl; and sulphide; or R and R 2 together with the carbon to which they are attached form a C 3

_

8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: 30 halo, hydroxyl, cyano, nitro, C 1

_

4 haloalkyl, C 1

_

4 alkylsulphonyl and COOH; 5 WO 2008/065445 PCT/GB2007/050698 or R 1 and R 2 together with the carbon to which they are attached represent a C 2

_

6 alkenyl or C2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1

_

4 haloalkyl and COOH, provided always that one of R and R 2 is not 5 hydroxyl when the other is methyl. In a preferred set of compounds, R 1 is an optionally substituted C 1

_

4 alkyl or C 3

_

8 cycloalkyl group. 10 In a preferred set of compounds, R 2 is an optionally substituted C 1

_

4 alkyl or C 3

_

8 cycloalkyl group. Other preferred compounds are those in which at least one of R and R 2 is -C(H)(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). 15 More preferably at least one of R and R 2 is CF 3 or CHF 2 . Most preferably, at least one of R and

R

2 is CF 3 . In an embodiment, R 1 is preferably methyl, cyclopropyl, CF 3 or CHF 2 . Most preferably, R 1 is 20 methyl. In an embodiment, R 2 is preferably methyl, cyclopropyl, CF 3 or CHF 2 . Most preferably R 2 is methyl. 25 In another preferred set of compounds, R and R 2 together form an optionally substituted C 3

_

8 cycloalkyl group. Most preferably this is a cyclopropyl group. In an embodiment: 30 R 3 and R 4 are independently selected from the group comprising: H; halo; cyano; C 1

_

6 alkyl, C 2

-

6 alkenyl, C 2

_

6 alkynyl, C 3

_

8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl roups 6 WO 2008/065445 PCT/GB2007/050698 may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1

_

4 alkylsulphonyl and COOH; C 1

_

6 hydroxyalkyl; C 1

_

6 carboxyalkyl; and sulphide; 5 or R 3 and R 4 together with the carbon to which they are attached form a C 3

_

8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1

_

4 haloalkyl, C 1

_

4 alkylsulphonyl and COOH; or R 3 and R 4 together represent a C 2

_

6 alkenyl or C 2

_

6 alkynyl group bound through a double bond 10 to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1

_

4 haloalkyl and COOH. In an embodiment, R 3 is H or C 1

_

6 alkyl. Preferably, R 3 is H. 15 In an embodiment, R 4 is H or C 1

_

6 alkyl. Preferably, R 4 is H. In an embodiment, R 5 is chloro. 20 In an embodiment, R 6 is chloro. In an embodiment, R7 is H. In an embodiment, R8 is H. 25 In an embodiment, R 9 is H or Me. In one embodiment, R 9 is H and compounds in which R 9 is H enjoy good solubility. When R 9 is a C 1

_

6 alkyl group, such as Me, the PDE III inhibiting activity is effectively eliminated. Me represents a particularly preferred alkyl substituent. 30 In an embodiment, R 10 is H or optionally substituted C 1

_

6 alkyl. Most preferably, RIO is C 1

_

6 alkyl. In an alternative embodiment, RIO is Na or K, with Na being preferred. 7 WO 2008/065445 PCT/GB2007/050698 In an embodiment, X is 0. In a further embodiment, 5 R and R 2 are independently selected from the group comprising: 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 by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1

_

4 alkylsulphonyl and COOH; C 1

_

6 hydroxyalkyl; C 1

_

6 10 carboxyalkyl; and sulphide; or R and R 2 together with the carbon to which they are attached form a C 3 _8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1

_

4 haloalkyl, C 1

_

4 alkylsulphonyl and COOH; 15 or R and R 2 together represent a C 2

_

6 alkenyl or C 2

_

6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1

_

4 haloalkyl and COOH; 20

R

3 and R 4 are hydrogen;

R

5 is selected from the group comprising: fluoro, chloro, bromo and iodo; 25 R is selected from the group comprising: fluoro, chloro, bromo and iodo; and R , R , R 9 and R 10 are hydrogen. Another preferred group of compounds is those in which neither R nor R 2 is hydrogen. 30 Amongst these, it is preferred when R and R2 are both independently selected from the group 8 WO 2008/065445 PCT/GB2007/050698 comprising: cyano, C 1

_

6 alkyl, C 2

_

6 alkenyl, C 2

_

6 alkynyl, in which the alkyl, alkenyl, and alkynyl groups may be optionally substituted; or wherein R 1 and R 2 together with the carbon to which they are attached form an optionally 5 substituted C 3

_

8 carbocyclic ring or wherein R 1 and R 2 together represent an optionally substituted C 2

_

6 alkenyl or C 2

_

6 alkynyl group. 10 Particularly preferred individual compounds of the invention include: The 3-methylanagrelide derivative N NH 2 Me C11"N H CI CI o OMe 15 3,3-dimethylanagrelide derivative N

NH

2 Me N>Me o1 0 OMe and the corresponding spiro 3-cyclopropyl derivative N

NH

2 N CI CI o OMe 20 9 WO 2008/065445 PCT/GB2007/050698 Regarding the use of the compounds of the invention in humans, there is provided: a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable diluent or carrier, 5 which may be adapted for oral, parenteral or topical administration; a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the foregoing, for use as a medicament; 10 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: myeloprolific diseases and generalised thrombotic diseases. a method of treating a disease selected from: myeloprolific diseases and generalised thrombotic 15 diseases in a human, which comprises treating said human with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition containing any of the foregoing. The present invention also encompasses a method of treating a patient having essential 20 thrombocythemia or other myelproliferative disesase or thrombotic cardiovascular disease or high blood platelet count, which method 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 of reducing blood platelet count 25 within a patient, which method comprises administering to the patient a therapeutically effective amount of a compound of the present invention. The present invention encompasses providing the compounds of the present invention for the methods listed above, among others, wherein cardiotoxicity is reduced compared to using 30 anagrelide. 10 WO 2008/065445 PCT/GB2007/050698 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 Pharmaceutically acceptable salts of the compounds of Formula (I) include acid addition salts. Examples include hydrochloric and hydrobromide salts. DETAILED DESCRIPTION OF THE INVENTION 10 The present invention is directed to new prodrugs of 3-or 5-substituted analogues of the established platelet lowering agent anagrelide. These compounds spontaneously ring close at pH's 7 and above to yield 3-or 5-substituted anagrelides that retain the anti-megakaryocytic properties (hence platelet lowering activity) of anagrelide but have reduced PDEIII inhibitory 15 properties and hence lower potential for unwanted cardiovascular and anti-aggregatory side effects. Appropriate substitution at the 3-position of the anagrelide molecule effectively blocks the principal site of metabolism and thus precludes the formation of the highly potent PDEIII 20 inhibitor 3-OH anagrelide. The 5-substituted analogues have the potential to indirectly sterically hinder metabolism at the preferred 3-position. These 3-or 5-substituted analogues of anagrelide also have the potential for improved pharmacokinetic characteristics since the 3-position in the anagrelide molecule is known to be the major site of metabolism which is the principal mechanism of drug clearance. 25 Use of the corresponding "open ring" prodrugs of these 3- or 5-substituted analogues could offer the added value of improved rates of dissolution and water solubility, allowing easier formulation. For example the aqueous solubility of anagrelide at pH 7 is <10ug/ml. For ethyl 5,6-dichloro-3,4-dihydro-2- (1 H)-iminoquinazoline-3-acetate HBr - an unsubstituted but 30 representative example of these ring open prodrugs - the solubility is ~ 5.5mg/ml in distilled water. 11 WO 2008/065445 PCT/GB2007/050698 Such prodrugs are likely to be extremely rapidly and completely cyclised in plasma to the closed ring 3-alkylanagrelide analogues. For example the rapid and quantitative conversion of ethyl 5,6-dichloro-3,4-dihydro-2- (1 H)-iminoquinazoline-3-acetate HBr - an unsubstituted but representative example of these ring open prodrugs - to anagrelide was demonstrated in human 5 plasma using LC/MS-MS analytical techniques. Human plasma was spiked with anagrelide prodrug (final concentration 100 ng/mL). Immediately after mixing, and at 15, 30, 45 and 60 minutes afterward samples were analysed for anagrelide prodrug and anagrelide. Even at the first point of measurement no prodrug could be found demonstrating the rapid and complete conversion to anagrelide itself. Figure 1 shows the levels of anagrelide prodrug, ethyl-5,6 10 dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3 acetate and anagrelide observed in samples of human plasma, incubated at room temperature over one hour. The potential benefit of improved water solubility on the absorption of these open-ring analogues was shown in a comparative bioavailability study in the dog. Using the unsubstituted ethyl-5,6 15 dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate HBr as a model compound, a comparison was made of the systemic availability of anagrelide when given as this compound or as anagrelide itself in equimolar doses (7.7 & 6.1mg/kg respectively). Examination of pharmacokinetic parameters for the prodrug showed an approximately 17-fold higher Cmax, and a mean 16-fold higher AUC for anagrelide than when the drug itself was administered. 20 These results implied that the inherent absorption of anagrelide at this dose (6.1mg/kg, albeit 200 fold above the clinical dose) was comparatively poor (< 6.25 %) since there was little evidence for marked changes in metabolism, the likely alternative explanation. The metabolite-to-drug exposure ratio after anagrelide was 1.5 compared to 0.9 after the prodrug. 25 This study (see tables below) also showed that there was also considerably less variability in Cmax and AUC after the prodrug. For example Cmax for anagrelide after the prodrug ranged from 170 - 418 ngmL- 1 (relative standard deviation, RSD, 26%) compared to 9.5 to 44.3 ngmL- 1 after anagrelide itself (RSD 62.5%). Similarly the AUC for anagrelide after the prodrug ranged from 30 367 to 1470 ng.hmL- 1 (RSD 34%) compared to 21.6 to 188ng.hmL- (RSD 71%) after anagrelide 12 WO 2008/065445 PCT/GB2007/050698 itself. The lesser variability was consistent with more efficient absorption. This study illustrated the potential benefits of the open-ring prodrugs to improve absorption. Table 1 5 Pharmacokinetic parameters of anagrelide following a single oral (capsule) administration of anagrelide or an ester open ring prodrug of anagrelide to male dogs at equivalent molar doses Anagrelide (6.1 mg/kg) Dog ID Cmax Tmax AUCo, AUCinnfi k t number (ng/mL) (hours) (ng.h/mL) (ng.h/mL) (hours- 1 ) (hours) 1 15.7 16 141 - e 3 14.8 1.5 42.0 42.3c 0.4459c 1.6c 11 25.0 2 188 193c 0.3119c 2.2c 23 9.50 1.5 21.6 23

.

1 d 0

.

1953 d 3.5d 29 44.3 1 88.9 89.3 0.3031 2.3 Mean 21.9 1.5 96.3 - - SD 13.7 68.9 Ester prodrug of anagrelide (7.5 mg/kg) Dog ID CFmx Tmax AUCo 0 AUCinnfi k t number (ng/mL) (hours) (ng.h/mL) (ng.h/mL) (hours- 1 ) (hours) 1 213 3 678 679 0.1969 3.5 3a 170 1 367 369 0.3071 2.3 11 418 4 1440 1440d 0.

178 9 d 3.9d 23 334 3 951 952 0.4941 1.4 29 353 6 1470 1470 0.4857 1.4 Mean 330 3.5 1130 1030 0.3922 1.8f SD 86 390 400 0.1692 a Animal vomited ca 1 hour post-dose, excluded from calculation of mean b Median Estimate based on two data points only, therefore did not meet acceptance criteria, excluded from calculation of mean d Could not be estimated in accordance with all acceptance criteria, excluded from calculation of mean e Could not be estimated from the available data Calculated as In2/(mean rate constant) 10 13 WO 2008/065445 PCT/GB2007/050698 Table 2 Pharmacokinetic parameters of 3-hydroxy anagrelide, following a single oral (capsule) administration of anagrelide or an ester prodrug of anagrelide to male dogs at equivalent molar doses 5 Anagrelide (6.1 mg/kg) Dog ID Cmax Tmax AUCo, AUCinnfi k t number (ng/mL) (hours) (ng.h/mL) (ng.h/mL) (hours- 1 ) (hours) 1 14.1 16 131 - d 3 18.0 1.5 64.6 65.0 0.2854 2.4 11 29.9 16 274 - d 23 19.4 1.5 50.7 51.8 0.2314 3.0 29 43.0 1.5 122 123 0.2966 2.3 Mean 24.9 1.5 128 79.9 0.2711 2.6e SD 11.7 89 37.9 0.0349 Ester prodrug of anagrelide (7.5 mg/k 3) Dog ID Cmax Tmax AUCo, AUCinnfi k t number (ng/mL) (hours) (ng.h/mL) (ng.h/mL) (hours- 1 ) (hours) 1 185 3 564 566 0.1569 4.4 3a 106 1.5 303 303 0.2510 2.8 11 347 4 1280 1290c 0.1235c 5.6c 23 269 3 876 878 0.4425 1.6 29 241 6 1240 1240 0.3776 1.8 Mean 261 3.5 990 895 0.3257 2.1e SD 67 337 337 0.1497 a Animal vomited ca 1 hour post-dose, excluded from calculation of mean b Median Could not be estimated in accordance with all acceptance criteria (excluded from calculation of mean d Could not be estimated from the available data Calculated as In2/(mean rate constant) For those 3-or 5-substituted anagrelide analogues which have a lower therapeutic potency (but 10 not inherent activity) than anagrelide itself, a potentially higher absolute dose may be needed which could present problems for absorption. For example 3,3, dimethyl anagrelide (anti megakaryocytic IC 50 -60nM cf 27nM for anagrelide) may need to be given at 6 times the current clinical dose of anagrelide. In this situation absorption may be less than complete and a prodrug may be needed to ensure efficient absorption from the GI tract. 14 WO 2008/065445 PCT/GB2007/050698 The compounds of Formula I can be prepared in an analogous manner to those described in US 4256748 and US 6388073. The disclosures of the synthetic procedures used in each of these 5 documents is intended specifically to be incorporated into this disclosure and forms part of the disclosure of this invention. The contents are not presented here in full for the purposes of brevity but the skilled person is specifically directed to these documents. A person skilled in the art will be aware of variations of, and alternatives to, the processes 10 referred to in US 4256748 which allow the individual compounds defined by formula (I) to be obtained having been now revealed as desirable targets. The present invention thus further encompasses methods of manufacturing a compound of the present invention to the extent that such processes produce novel intermediates and / or employ novel process features. 15 It will also be appreciated by a person skilled in the art that the compounds of the invention could be made by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, 20 Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith 25 (Longman) (1982 or later editions), etc., and the references therein as a guide. It will also be apparent to a person skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic 30 Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. 15 WO 2008/065445 PCT/GB2007/050698 Definitions: Halo means a group selected from: fluoro, chloro, bromo or iodo. 5 The term "alkyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C 1 10 alkyl means a straight or branched alkyl containing at least 1 and at most 10 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n 10 pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl, nonyl and decyl. A C 1 4 alkyl group is one embodiment, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl. The term "cycloalkyl" as used herein refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms such as, for example, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 15 cyclohexyl or cycloheptyl. The term "spirocyclic" as used herein refers to a ring system joined to a second ring system at one carbon atom. 20 The term "alkoxy" as used herein refers to a straight or branched hydrocarbon chain group containing oxygen and the specified number of carbon atoms. For example, C 1 6 alkoxy means a straight or branched alkoxy containing at least 1 and at most 6 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. A C 1-4 25 alkoxy group is one embodiment, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy. The term "hydroxyalkyl" as used herein as a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms, which is substituted by 1-3 hydroxyl 30 groups. For example, C 1 4 hydroxyalkyl means a straight or branched alkyl chain containing from 16 WO 2008/065445 PCT/GB2007/050698 1 to 4 carbon atoms and at least one hydroxyl group; examples of such group include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like. The term "alkenyl" as used herein as a group or a part of a group refers to a straight or branched 5 hydrocarbon chain containing the specified number of carbon atoms and containing at least one double bond. For example, the term "C 2-6 alkenyl" means a straight or branched alkenyl containing at least 2 and at most 6 carbon atoms and containing 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 10 and 1,1-dimethylbut-2-enyl. It will be appreciated that in groups of the form -0-C2- 6 alkenyl, the double bond is preferably not adjacent to the oxygen. The term "alkynyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one 15 triple bond. For example, the term "C2- 6 alkynyl" means a straight or branched alkynyl containing at least 2 and at most 6 carbon atoms and containing at least one triple bond. 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. It will be appreciated that in groups of the form 20 -0-C2- 6 alkynyl, the triple bond is preferably not adjacent to the oxygen. The term "halo" refers to halogens such as fluorine, chlorine, bromine or iodine atoms. The term "sulfide" refers to a radical of Ra-S-Rb, wherein a sulfur atom is covalently attached to two hydrocarbon chains, Ra and Rb, wherein the two hydrocarbon chains may be, for example, 25 but not limited to, any discussed above. The compounds of the invention, i.e. those of formula (I), when cyclised may possess antimegakaryocytic activity in humans. Such activity may be assessed using a well established model. Assessment of the in vitro anti-megakaryocytic activity - and potentially therefore the 30 platelet lowering capability - of the anagrelide prodrugs can be determined using the model of megakaryocytopoiesis (Cohen-Solal et al., Thromb. Haemost. 1997, 78:37-41 and Cramer et al., 17 WO 2008/065445 PCT/GB2007/050698 Blood, 1997, 89:2336-46). This involves examining the differentiation of human CD34' stem cells into megakaryocytes which ultimately give rise to blood platelets. The compounds of the invention may be particularly useful in the treatment of 5 myeloproliferative diseases. The compounds may also find utility in the treatment of generalised thrombotic diseases. It is to be appreciated that references to treatment include prophylaxis as well as the alleviation and/or cure of established symptoms of a condition. "Treating" or "treatment" of a state, 10 disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of 15 maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. Myeloproliferative diseases which may be treatable with the compounds of the present invention 20 include: essential thrombocythemia, polycythema vera, chronic idiopathic myelofibrosis, chronic myeloid leukaemia with residual thrombocytosis, reactive thrombocytosis immediately preceding a surgical procedures, as an immediate or post operative preventative measures to minimise the risk of thrombus formation during or post surgery. 25 Thrombotic cardiovascular diseases (TCVD) (i.e. patients at increased generalised thrombotic risk) which may be treatable with the compounds of the present invention include: myocardial infarct (heart attack) thrombotic stroke, patients having undergone coronary stent placement. The compounds of the present invention may also find utility in indicated for the reduction of 30 atherothrombotic events as follows: recent MI, recent stroke or established peripheral arterial 18 WO 2008/065445 PCT/GB2007/050698 disease, acute coronary syndrome (unstable angina/non-Qwave MI), cardiovascular death, MI, stroke, and refractory ischemia. Example 1 5 The spirocyclopropylanagrelide derivative can be prepared using established chemistry as described previously according to the following reaction scheme. Other derivatives can be made in a likewise manner. The final product is obtained by cyclisation of the cyclopropyl precursor in the presence of cyanogen bromide and ethanol. 0

H

2 NJOMe + NH 2 kBrCN NH 0 Br CI OSO 2 Me CI N'KOMe DOCI N OMr 10 C' C' C' Example 2 The solubilities of various salts was investigated in three solvents [distilled water (pH 5.0), 50 15 mM ammonium formate (pH 7.9) and 0.1 M hydrochloric acid (pHO.6)]. An excess of the salt was suspended in the chosen medium and sonicated for 3 minutes. The mixture was centrifuged for 10 minutes, the supernatant liquid was collected and the solubility was measured. Table 3 shows the results of the measurements. 20 25 19 Solubilities of 2,2-Disubstituted 2-(2-Amino-5,6-dichloro-4H-quinazolin-3-yI)-propionates (pg mL 1 at ca. 20 "C) Compound Ammonium formate Water Hydrochloric acid (50 mM, pH 7.9) (pH 5.0) (0.1 M, pH 1 0.6) H Ma 4 20 215 C N CI Me M

NH

2 16- 7340 46 c N ONa Cl Me Me N , 1 2 35 H HC CI iiiN> ,E3,H~ unstable 7060 6430 H 1l,:;: O'I1 10 169 CI I 5 The figures show that the compounds of the invention have substantially improved solubilityover their corresponding closed ring counterparts. This means that the compounds can be formulated and administered to patients in higher dosages than is possible for the closed ring versions. This represents a major clinical advantage. 10 20 P \OPER\MAL2( 90083 IINs1Ipadoc-22/07/21X19 -20A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived 5 from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will 10 be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

1. A compound of Formula (1) or a pharmaceutically acceptable salt or solvate thereof R 8 R N NHR 9 N 2 R 6 N R R 5 R4 R 3 0 XR 10 5 wherein: R 1 and R 2 , are independently selected from the group comprising: H; halo; cyano; C1.6 alkyl, C2- alkenyl, C2.6 alkynyl, C3.8 cycloalkyl wherein said alkyl, alkenyl, 10 alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C1. alkylsulphonyl and COOH; C 1 . hydroxyalkyl; C1.6 carboxyalkyl; and sulphide; or wherein R 1 and R 2 together with the carbon to which they are attached form a C3.8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen 15 independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1 . 4 haloalkyl, C1.4 alkylsulphonyl and COOH; or wherein R 1 and R 2 together with the carbon to which they are attached represent a C2.6 alkenyl or C2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups 20 independently selected from the group comprising: halo, hydroxyl, cyano, C1. haloalkyl and COOH, provided always that one of R 1 and R 2 is not hydroxyl when the other is methyl; C :\NRPorbl\DCC\ XS4I025_.DOC.12/1/201I - 22 R 3 and R 4 are independently selected from the group comprising: H; halo; cyano; C1.e alkyl, C 2 - 6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C1.4 5 alkylsulphonyl and COOH; C1.6 hydroxyalkyl; C1.0 carboxyalkyl; and sulphide; or R 3 and R 4 together with the carbon to which they are attached form a C3-8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C14 10 haloalkyl, C14 alkylsulphonyl and COOH; or R 3 and R 4 together represent a C2-6 alkenyl or C2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, 15 hydroxyl, cyano, C14 haloalkyl and COOH; 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; 20 R 7 and R 8 are independently selected from the group comprising: H; halo; cyano; C1. alkyl, C1.6 haloalkyl, C1.6 alkoxy, and C1.6 haloalkoxy; R 9 is H or C1.6 alkyl; 25 R 10 is selected from the group comprising: hydrogen; C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl wherein each of the foregoing groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C1.4 alkylsulphonyl and COOH; or R* is a 30 pharmaceutically acceptable cation; X is O or S; and provided always that R 1 , R 2 , R 3 and R 4 are not all hydrogen. C:\NRPorbhDCC\RXSW02845_.DOC-12//2011 -23

2. A compound according to claim 1, wherein R 3 is H or C1.6 alkyl.

3. A compound according to claim 1 or 2, wherein R 4 is H or C1.6 alkyl. 5

4. A compound according to any one of claims 1 to 3, wherein R 5 is chloro.

5. A compound according to any one of claims 1 to 4, wherein R 6 is chloro. 10

6. A compound according to any one of claims 1 to 5, wherein R 7 is H.

7. A compound according to any one of claims 1 to 6, wherein R 8 is H.

8. A compound according to any one of claims 1 to 7, wherein R 9 is H or methyl. 15

9. A compound according to any one of claims 1 to 8, wherein R'O is C1.6 alkyl.

10. A compound according to any one of claims 1 to 9, wherein R 1 is an optionally substituted C1 alkyl or C3.5 cycloalkyl group. 20

11. A compound according to any one of claims 1 to 10, wherein R 2 is an optionally substituted C14 alkyl or C3.8 cycloalkyl group.

12. A compound according to any one of claims 1 to 11, wherein R 1 is methyl, 25 cyclopropyl, CF 3 or CHF 2 .

13. A compound according to any one of claims 1 to 12, wherein R 2 is methyl, cyclopropyl, CF 3 or CHF 2 . 30

14. A compound according to any one of claims 1 to 9, wherein R 1 and R 2 together form an optionally substituted C3.8 cycloalkyl group.

15. A compound according to claim 1 selected from: C:\NRPonbrDCC\RXS\402545_1.DOC.12/fl/20l -24 N NH 2 N NH 2 Me C1 N Me N Cl Cl O OMe or 0 OMe

16. A pharmaceutical composition comprising a compound of formula (1) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, 5 together with a pharmaceutically acceptable diluent or carrier, which may be adapted for oral, parenteral or topical administration.

17. Use of a compound of formula (1) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a 10 medicament for the treatment of a disease selected from: myeloprolific diseases and generalised thrombotic diseases.

18. A method of treating a disease selected from: myeloproliferative diseases and generalised thrombotic diseases in a human, which comprises treating said human 15 with an effective amount of a compound of formula (1) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition containing any of the foregoing.

19. Use of a compound of formula (1) as defined in any one of claims 1 to 15 in the 20 manufacture of a medicament for the reduction of platelet count.

20. A method of reducing the platelet count of a human including the step of administering to said human with an effective amount of a compound of formula (1) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt or 25 solvate thereof, or with a pharmaceutical composition containing any of the foregoing.