Abstract:
This invention relates to the discovery of 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 the general formula shown below wherein the substituents have the meanings defined in claim  1 : and 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:
FIELD OF THE INVENTION 
       [0001]    This invention relates to the discovery of 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. 
       BACKGROUND OF THE INVENTION 
       [0002]    Anagrelide hydrochloride (Agrylin®, Xagrid®) is a novel orally administered 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-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one is shown as the hydrochloride monohydrate in the following formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0003]    Preparation of anagrelide hydrochloride was referred to in U.S. Pat. Nos. 3,932,407; RE31,617 and 4,146,718. 
         [0004]    Anagrelide is a unique, highly selective platelet lowering agent. In vitro studies of human megakaryocytopoiesis suggested that, in vivo, its thrombocytopenic activity results primarily from an inhibitory effect on megakaryocyte maturation. Anagrelide inhibited TPO-induced megakaryocytopoiesis in a dose-dependent manner with an estimated IC 50  of ˜26 nM, showing it to be a highly potent agent. Anagrelide does not affect erythroid or myelomonocytic differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factor, demonstrating the selectivity of this compound against the megakaryocytic lineage. 
         [0005]    The drug, which is available in both the U.S. and Europe, has proven to be of considerable clinical value in the treatment of myeloproliferative diseases, such as essential thrombocythemia. Anagrelide was shown to be effective and selective in reducing and maintaining platelet count close to or within the physiological range in patients with thrombocythemia secondary to a myeloproliferative disorder. The time to complete response, defined as a platelet count ≦600×10 9 /L, ranged from 4 to 12 weeks. In the majority of patients, the platelet count can be reduced and maintained at a dose of 1 to 3 mg/day. 
         [0006]    In early volunteer trials, the most frequently reported adverse effects AEs other than headache were palpitations, postural dizziness and nausea. During patient studies, the most frequently reported drug-related AEs were headache, palpitations, oedema/fluid retention, nausea/vomiting, diarrhea, dizziness and abdominal pain. These effects are all likely to arise from the secondary, cardiovascular pharmacology associated with anagrelide resulting from its inhibitory effects on human phosphodiesterase III (PDE III). Anagrelide is a potent PDE III inhibitor with an IC 50  value of ˜29 nM (cf. milrinone, a classical PDE III inhibitor, IC 50 =170-350 nM). Inhibition of myocardial PDE III leads to positive inotropy (increasing of the force of contractions of the heart), increased chronotropy (increase in heart rate), and peripheral vasodilatation. Such cardiovascular manifestations of this inhibition are typically seen with the classical positive inotropes, milrinone and enoximone, and exploited in the short-term acute treatment of congestive heart failure. However, in the treatment of a so-called silent disease (i.e., asymptomatic) such as ET, the cardiovascular side-effects of palpitations and tachycardia associated with anagrelide limit its utility and a significant proportion of patients—reportedly between 25 and 50%—fail to tolerate the drug during long term treatment. 
         [0007]    The PDE III inhibitory properties of anagrelide are quite distinct from its platelet lowering anti-megakaryocytic effects. Indeed studies have shown no correlation between potency as a PDE III inhibitor and anti-megakaryocytic effects for anagrelide and its principal pharmacologically active metabolite, 3-hydroxyanagrelide (3-OH anagrelide or 3-HA, formerly known as SPD604 or BCH24426). Surprisingly the latter was found to be over 40-fold more potent than anagrelide as a PDE III inhibitor. With respect to inhibition of megakaryocytopoiesis (and therefore platelet lowering potential) it was however no more potent than the parent drug. Anagrelide&#39;s active metabolite, 3-HA, is present in vivo in amounts greatly exceeding those of the parent drug with typical exposures being 2-3 fold greater. Thus by implication 3-OH anagrelide is likely to be a major contributor to the pharmacological actions of the drug. 
         [0008]    In addition to the unwanted cardiovascular effects associated with PDE III inhibition, the consequent elevation of cAMP can result in an anti-aggregatory effect. While initially this property may appear to be beneficial in essential thrombocythemia patients predisposed to greater thrombotic risk, such anti-platelet effects, in excess, could have haemorrhagic consequences and on balance may not be desirable. Indeed the haemorrhagic events occasionally seen in ET patients treated with anagrelide might be due to a combination of the anti-aggregatory effects contributed largely by 3-OH anagrelide and an overshooting of platelet reduction, compounded by a synergistic interaction with aspirin that is frequently concomitantly administered. (In some ET patients, plasma concentrations of 3-OH anagrelide have been shown likely to exceed the in vitro IC 50  values for inhibition of platelet aggregation by a factor of 3). 
         [0009]    The PDE III mediated cardiovascular side-effects associated with anagrelide treatment mean that many patients have to be switched to the only significant alternative therapy, namely that with hydroxyurea. However, this drug is a simple chemical anti-metabolite which inhibits ribonucleoside diphosphate reductase (RNR) with resultant profound effects on DNA synthesis. Ribonucleoside diphosphate reductase catalyzes the conversion of ribonucleosides into deoxyribonucleosides, which are the building blocks of DNA synthesis and repair. Inhibition of ribonucleoside diphosphate reductase explains the cytoreductive and—most importantly—the mutagenic effects of this compound as well as its platelet lowering action. Hydroxyurea is thus officially classified as a “presumed human carcinogen.” As well as possessing the potential to induce leukemic transformation, hydroxyurea is associated with the induction of difficult-to-treat leg ulcers. 
         [0010]    Faced with this dilemma in treatment options, there is a clear need for a new agent in the treatment of thrombocythemia which is selective in its effects on megakaryocytopoiesis but with reduced or minimal side effects. While anagrelide offers some selectivity in its mechanism of action, the limitations to its use are those associated with cardiovascular effects resulting from its secondary pharmacology and contributed largely by the active metabolite of anagrelide, 3-hydroxyanagrelide. 
         [0011]    The metabolism of anagrelide generally proceeds extremely rapidly, resulting in a less than ideal pharmacokinetic profile of the drug. The typical half-life of anagrelide is just 1.5 hr (2.5 hr for the metabolite) necessitating frequent drug administration (up to 4 times per day). This, combined with the side-effects profile, can lead to poor patient compliance. Furthermore, anagrelide undergoes a large first pass effect (&gt;50%) leading to considerable intersubject variation in achieved exposures and, therefore, potentially variable drug response. Also, exposure to the pharmacologically active metabolite varies dramatically between patients since its formation is dependent on CYP1A, an enzyme whose expression is highly dependent on exposure to inducing agents such as cigarette smoke. Overall, this may result in the need for careful dose titration in patients being treated with anagrelide. 
         [0012]    U.S. Pat. No. 4,256,748 discloses a number of imidazo[2,1-b]quinazolin-2(3H)-ones which have an analogous structure to anagrelide and which are said to be effective in the treatment of thromboses resulting from their anti-aggregatory effects on blood platelets mediated by PDE III inhibition. However, this disclosure does not appreciate the entirely separate anti-megakaryocytic potential (reducing platelet numbers) which could be associated with some analogues. 
         [0013]    Ideally there is a need for compounds which possess anti-megakaryocytic activity whilst at the same time having a reduced level of PDE III inhibitory activity and therefore unwanted cardiovascular effects. 
         [0014]    It is an aim of the present invention to overcome various disadvantages of or to improve on the properties of prior art compounds. Thus it is an aim of the invention to provide an anagrelide derivative which has improved activity and/or reduced cardiovascular toxicity relative to prior art compounds in the treatment of diseases for which modulation of megakaryocytopoeisis provides an efficacious treatment. The compounds of the present invention are especially beneficial because they display less inhibitory activity towards phosphodiesterase III (PDE III) and yet surprisingly still retain their anti-megakarycocytic and hence platelet lowering properties. 
         [0015]    It is also desirable that the compounds of the present invention should have an improved pharmacokinetic profile to aid patient compliance and ensure consistency of therapeutic response. It is thus a further aim to provide compounds with a good duration of action i.e. long half-life in vivo. Additionally it is a further aim to provide compounds that are available via relatively convenient synthetic processes. 
         [0016]    The compounds described in relation to the present invention satisfy some or all of the above aims. 
       SUMMARY OF THE INVENTION 
       [0017]    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 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, 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 derivatives 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 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&#39;s active site. This should inhibit formation of the cardioactive metabolite, 3-hydroxyanagrelide. 
         [0018]    The ring closed compounds of the present invention are especially beneficial because surprisingly they have dramatically lower PDE III inhibitory activity (and hence lower 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. 
         [0019]    According to one aspect of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein: 
             one of R 1  and R 2  is R a , and the other is hydrogen or R a ; 
             or R 1  and R 2  together with the carbon atom to which they are attached form a blocking group which functions to prevent metabolic reaction at the 3-position; wherein said blocking group is a C 3-8  cycloalkyl group substituted with 1, 2, 3, 4 or 5 R b ; a C 2-6  alkenyl group substituted with 1, 2, 3, 4 or 5 R b ; or an optionally substituted heterocyclic group; 
             R 5 , R 6 , R 7  and R 8  are each independently selected from hydrogen, R f  and R g ; 
             R 9  is hydrogen, C 1-6  alkyl or a Group I or Group II metal ion; 
             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 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; 
             X is O or S; 
             R a  is selected from —C(O)R c , —C(O)OR c , —OC(O)R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , C 1-6  alkyl substituted with 1, 2, 3, 4 or 5 R b ; C 2-6  alkenyl substituted with 1, 2, 3, 4 or 5 R b ; carbocyclyl substituted with 1, 2, 3, 4 or 5 R b ; and optionally substituted heterocyclyl; 
             R b  is selected from —N(R c )R d , —C(O)N(R c )R d , carbocyclyl and heterocyclyl, wherein the carbocyclyl and heterocyclyl groups are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy; 
             R c  and R d  are each independently hydrogen or R e ; 
           
         
       
     
         [0030]    R e  is selected from C 1-6  alkyl and C 2-6  alkenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy;
       R f  is selected from C 1-6  alkyl and C 2-6  alkenyl, either of which is optionally substituted with 1, 2, 3, or 5 R g ;   R g  is selected from halo, trifluoromethyl, cyano, nitro, —OR c , —C(O)R c , —C(O)OR c , —OC(O)R c , —S(O) 1 R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , —S(O) 1 N(R c )R d  and —N(R c )S(O) 1 R d ;   l is 0, 1 or 2.       
 
         [0034]    In an embodiment the compound is of the following Formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or a pharmaceutically acceptable salt or solvate thereof. 
         [0035]    With regard to said Formula, R a  may be, for example, selected from —C(O)R c , —C(O)OR c , —OC(O)R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , C 1-6  alkyl substituted with 1, 2 or 3 R b ; C 2-6  alkenyl substituted with 1, 2 or 3 R b ; carbocyclyl substituted with 1, 2 or 3 R b ; and optionally substituted heterocyclyl; wherein R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy; and wherein R c  and R d  are each independently selected from hydrogen and C 1-4  alkyl. Where R a  is substituted carbocyclyl, the carbocyclyl group may be, for example, a substituted aryl group, e.g. a substituted phenyl group. Where R a  is an optionally substituted heterocyclic group, the heterocyclic group may be, for example, selected from pyridinyl, thiophenyl, furanyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R a  is selected from —C(O)OH, —C(O)NH 2  and NH 2 . 
         [0036]    In an embodiment the compound is of one of the following Formulae: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or, in each case, a pharmaceutically acceptable salt or solvate thereof. 
         [0037]    With regard to each of said Formulae, R a  may be, for example, selected from —C(O)R c , —C(O)OR c , —OC(O)R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , C 1-6  alkyl substituted with 1, 2 or 3 R b ; C 2-6  alkenyl substituted with 1, 2 or 3 R b ; carbocyclyl substituted with 1, 2 or 3 R b ; and optionally substituted heterocyclyl; wherein R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy; and wherein R c  and R d  are each independently selected from hydrogen and C 1-4  alkyl. Where R a  is substituted carbocyclyl, the carbocyclyl group may be, for example, a substituted aryl group, e.g. a substituted phenyl group. Where R a  is an optionally substituted heterocyclic group, the heterocyclic group may be, for example, selected from pyridinyl, thiophenyl, furanyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R a  is selected from —C(O)OH, —C(O)NH 2  and NH 2 . 
         [0038]    In an embodiment the compound is of the following Formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or a pharmaceutically acceptable salt or solvate thereof. 
         [0039]    With regard to each of said Formulae, each R a  may be, for example, independently selected from —C(O)R c , —C(O)OR c , —OC(O)R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , C 1-6  alkyl substituted with 1, 2 or 3 R b ; C 2-6  alkenyl substituted with 1, 2 or 3 R b ; carbocyclyl substituted with 1, 2 or 3 R b ; and optionally substituted heterocyclyl; wherein R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy; and wherein R c  and R d  are each independently selected from hydrogen and C 1-4  alkyl. Where R a  is substituted carbocyclyl, the carbocyclyl group may be, for example, a substituted aryl group, e.g. a substituted phenyl group. Where R a  is an optionally substituted heterocyclic group, the heterocyclic group may be, for example, selected from pyridinyl, thiophenyl, furanyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R a  is selected from —C(O)OH, —C(O)NH 2  and NH 2 . 
         [0040]    In an embodiment the compound is of one of the following Formulae: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or, in each case, a pharmaceutically acceptable salt or solvate thereof. 
         [0041]    With regard to each of said Formulae, each R a  may be, for example, independently selected from —C(O)R c , —C(O)OR c , —OC(O)R c , —N(R c )R d , —C(O)N(R c )R d , —N(R c )C(O)R d , C 1-6  alkyl substituted with 1, 2 or 3 R b ; C 2-6  alkenyl substituted with 1, 2 or 3 R b ; carbocyclyl substituted with 1, 2 or 3 R b ; and optionally substituted heterocyclyl; wherein R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy; and wherein R c  and R d  are each independently selected from hydrogen and C 1-4  alkyl. Where R a  is substituted carbocyclyl, the carbocyclyl group may be, for example, a substituted aryl group, e.g. a substituted phenyl group. Where R a  is an optionally substituted heterocyclic group, the heterocyclic group may be, for example, selected from pyridinyl, thiophenyl, furanyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R a  is selected from —C(O)OH, —C(O)NH 2  and NH 2 . 
         [0042]    In an embodiment the compound is of the following Formula: 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein R 1  and R 2  taken together with the carbon atom to which they are attached form a blocking group as defined in Formula (I);
 
or a pharmaceutically acceptable salt or solvate thereof.
 
           
         
       
     
         [0044]    With regard to said Formula, the blocking group may be a C 3-8  cycloalkyl group substituted with 1, 2, 3, 4 or 5 R b ; a C 2-6  alkenyl group substituted with 1, 2, 3, 4 or 5 R b ; or an optionally substituted heterocyclic group. The substituted C 3-8  cycloalkyl group may be, for example, substituted cyclopropyl. The substituted C 2-6  alkenyl group may be, for example, substituted ethenyl. Exemplary heterocyclic groups include piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. 
         [0045]    In an embodiment the compound is of one of the following Formulae: 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein R 1  and R 2  taken together with the carbon atom to which they are attached form a blocking group as defined in Formula (I);
 
or a pharmaceutically acceptable salt or solvate thereof.
 
           
         
       
     
         [0047]    With regard to each of said Formulae, the blocking group may be a C 3-8  cycloalkyl group substituted with 1, 2, 3, 4 or 5 R b ; a C 2-6  alkenyl group substituted with 1, 2, 3, 4 or 5 R b ; or an optionally substituted heterocyclic group. The substituted C 3-8  cycloalkyl group may be, for example, substituted cyclopropyl. The substituted C 2-6  alkenyl group may be, for example, substituted ethenyl. Exemplary heterocyclic groups include piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl and oxetanyl, any of which is optionally substituted, e.g. with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. In an embodiment, R b  is selected from —NH 2 , —C(O)NH 2  and aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro, C 1-6  alkyl and C 1-6  alkoxy. 
         [0048]    In an embodiment, R 5 , R 6 , R 7  and R 8  are each independently selected from H, R f  and R g ; wherein R f  is C 1-4  alkyl optionally substituted with 1, 2 or 3 R g ; and R f  is selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, nitro, —OR c , —C(O)R c , —C(O)OR c , —OC(O)R c , —S(O) 1 R c  and —N(R c )R d ; wherein R c  and R d  are each independently hydrogen or C 1-4  alkyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, amino, hydroxy, nitro and C 1-4  alkoxy. 
         [0049]    In an embodiment R 5 , R 6 , R 7  and R 8  are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, nitro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxylic acid, aminomethyl, fluoromethyl, chloromethyl, bromomethyl, dihalomethyl and methylsulphonyl. 
         [0050]    In an embodiment, R 5 , R 6 , R 7  and R 8  are each independently selected from H, halo, cyano, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy. 
         [0051]    In an embodiment: 
         [0000]    R 5  and R 6  are each independently selected from fluoro, chloro, bromo and iodo; and
 
R 7  and R 8  are independently selected from H, halo, cyano, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy.
 
         [0052]    In an embodiment, R 5  is preferably chloro. 
         [0053]    In an embodiment, R 6  is preferably chloro. 
         [0054]    In an embodiment R 7  is H. 
         [0055]    In an embodiment R 8  is H. 
         [0056]    In an embodiment, R 5 , R 6 , R 7  and R 8  are each H. 
         [0057]    In an embodiment, R 5 , R 7  and R 8  are each H; and R 6  is methoxy. 
         [0058]    In an embodiment, R 5 , R 7  and R 8  are each H; and R 6  is hydroxy. 
         [0059]    In an embodiment, R 5 , R 7  and R 8  are each H; and R 6  is chloro. 
         [0060]    In an embodiment R 9  is H. In another embodiment, R 9  is hydrogen, C 1-6  alkyl or a Group I metal ion. In an alternative embodiment, R 9  is C 1-6  alkyl and, in this case, the 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 and, in this case the compounds show significantly improved water solubility. Sodium represents a particularly preferred Group I metal. 
         [0061]    In an embodiment, R 10  is H or optionally substituted C 1-6  alkyl. Most preferably, R 10  is C 1-6  alkyl. In an alternative embodiment, R 10  is Na or K, with Na being preferred. 
         [0062]    The present invention also relates to both the resolved optical isomers of such compounds as well as mixtures of enantiomers. 
         [0063]    Regarding the use of the compounds of the invention in humans, there is provided: 
         [0000]    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, 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;
 
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/or generalised thrombotic diseases; and
 
a method of treating a disease selected from: myeloproliferative diseases and/or generalised thrombotic 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.
 
         [0064]    The present invention also encompasses a method of treating a patient having essential thrombocythemia or high blood platelet count, which method comprises administering to the patient a therapeutically effective amount of a compound of the present invention. 
         [0065]    Another embodiment of the present invention includes a method of reducing blood platelet count within a patient, which method comprises administering to the patient a therapeutically effective amount of a compound of the present invention. 
         [0066]    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 anagrelide. 
         [0067]    The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of myeloprolific diseases. 
         [0068]    The invention thus also extends to a method of treating myeloproliferative diseases in a human, which comprises treating said human with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition containing any of the foregoing. 
         [0069]    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. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0070]    The present invention is directed to new prodrugs of substituted analogues of the established platelet lowering agent anagrelide. These compounds spontaneously ring close at pH&#39;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 properties and hence lower potential for unwanted cardiovascular and anti-aggregatory side-effects. 
         [0071]    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 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. 
         [0072]    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 &lt;10 ug/ml. For ethyl-5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate HBr—an unsubstituted but representative example of these ring open prodrugs—the solubility is ˜5.5 mg/ml in distilled water. 
         [0073]    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-(1H)-iminoquinazoline-3-acetate HBr—an unsubstituted but representative example of these ring open prodrugs—to anagrelide was demonstrated in human 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.  FIG. 1  shows the levels of anagrelide prodrug, ethyl-5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3 acetate and anagrelide observed in samples of human plasma, incubated at room temperature over one hour. 
         [0074]    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-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 &amp; 6.1 mg/kg respectively). Examination of pharmacokinetic parameters for the prodrug showed an approximately 17-fold higher C max , and a mean 16-fold higher AUC for anagrelide than when the drug itself was administered. 
         [0075]    These results implied that the inherent absorption of anagrelide at this dose (6.1 mg/kg, albeit 200 fold above the clinical dose) was comparatively poor (&lt;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. 
         [0076]    This study (see tables below) also showed that there was also considerably less variability in C max  and AUC after the prodrug. For example C max  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 367 to 1470 ng·hmL −1  (RSD 34%) compared to 21.6 to 188 ng·hmL −1  (RSD 71%) after anagrelide itself. The lesser variability was consistent with more efficient absorption. This study illustrated the potential benefits of the open-ring prodrugs to improve absorption. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 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 
               
             
          
           
               
                   
                 C max   
                 T max   
                 AUC 0-t   
                 AUC infin   
                   
                 t½ 
               
               
                 Dog ID number 
                 (ng/mL) 
                 (hours) 
                 (ng · h/mL) 
                 (ng · h/mL) 
                 k (hours −1 ) 
                 (hours) 
               
               
                   
               
             
          
           
               
                 Anagrelide (6.1 mg/kg) 
               
             
          
           
               
                  1 
                 15.7 
                 16 
                 141 
                 — 
                 e 
                 — 
               
               
                  3 
                 14.8 
                 1.5 
                 42.0 
                       42.3 c   
                 0.4459 c   
                 1.6 c   
               
               
                 11 
                 25.0 
                 2 
                 188 
                      193 c   
                 0.3119 c   
                 2.2 c   
               
               
                 23 
                 9.50 
                 1.5 
                 21.6 
                      23.1 d   
                 0.1953 d   
                 3.5 d   
               
               
                 29 
                 44.3 
                 1 
                 88.9 
                   89.3 
                 0.3031 
                 2.3 
               
               
                 Mean 
                 21.9 
                 1.5 b   
                 96.3 
                 — 
                 — 
                 — 
               
               
                 SD 
                 13.7 
                   
                 68.9 
                 — 
                 — 
               
             
          
           
               
                 Ester prodrug of anagrelide (7.5 mg/kg) 
               
             
          
           
               
                  1 
                 213 
                 3 
                 678 
                 679 
                 0.1969 
                 3.5 
               
               
                      3 a   
                 170 
                 1 
                 367 
                 369 
                 0.3071 
                 2.3 
               
               
                 11 
                 418 
                 4 
                 1440 
                 1440 d    
                 0.1789 d   
                 3.9 d   
               
               
                 23 
                 334 
                 3 
                 951 
                 952 
                 0.4941 
                 1.4 
               
               
                 29 
                 353 
                 6 
                 1470 
                 1470  
                 0.4857 
                 1.4 
               
               
                 Mean 
                 330 
                 3.5 b   
                 1130 
                 1030  
                 0.3922 
                 1.8 f   
               
               
                 SD 
                 86 
                   
                 390 
                 400 
                 0.1692 
               
               
                   
               
               
                   a Animal vomited ca 1 hour post-dose, excluded from calculation of mean 
               
               
                   b Median 
               
               
                   c 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 
               
               
                   f Calculated as ln2/(mean rate constant) 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
             
           
               
                 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 
               
             
          
           
               
                   
                 C max   
                 T max   
                 AUG 0-t   
                 AUC infin   
                   
                 t½ 
               
               
                 Dog ID number 
                 (ng/mL) 
                 (hours) 
                 (ng · h/mL) 
                 (ng · h/mL) 
                 k (hours −1 ) 
                 (hours) 
               
               
                   
               
             
          
           
               
                 Anagrelide (6.1 mg/kg) 
               
             
          
           
               
                  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 b   
                 128 
                   79.9 
                 0.2711 
                 2.6 e   
               
               
                 SD 
                 11.7 
                   
                 89 
                   37.9 
                 0.0349 
               
             
          
           
               
                 Ester prodrug of anagrelide (7.5 mg/kg) 
               
             
          
           
               
                  1 
                 185 
                 3 
                 564 
                 566 
                 0.1569 
                 4.4 
               
               
                      3 a   
                 106 
                 1.5 
                 303 
                 303 
                 0.2510 
                 2.8 
               
               
                 11 
                 347 
                 4 
                 1280 
                 1290 c    
                 0.1235 c   
                 5.6 c   
               
               
                 23 
                 269 
                 3 
                 876 
                 878 
                 0.4425 
                 1.6 
               
               
                 29 
                 241 
                 6 
                 1240 
                 1240  
                 0.3776 
                 1.8 
               
               
                 Mean 
                 261 
                 3.5 b   
                 990 
                 895 
                 0.3257 
                 2.1 c   
               
               
                 SD 
                 67 
                   
                 337 
                 337 
                 0.1497 
               
               
                   
               
               
                   a Animal vomited ca 1 hour post-dose, excluded from calculation of mean 
               
               
                   b Median 
               
               
                   c Could not be estimated in accordance with all acceptance criteria (excluded from calculation of mean 
               
               
                 d Could not be estimated from the available data 
               
               
                   e Calculated as ln2/(mean rate constant) 
               
             
          
         
       
     
         [0077]    For those 3- or 5-substituted anagrelide analogues which have a lower therapeutic potency (but 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  ˜160 nM cf 27 nM 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. 
         [0078]    It is to be understood that compounds of formula (I) may contain one or more asymmetric carbon atoms, thus compounds of the invention can exist as two or more stereoisomers. 
         [0079]    Included within the scope of the present invention are all stereoisomers such as enantiomers and diastereomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. 
         [0080]    Geometric isomers may be separated by conventional techniques well known to those skilled in the art, for example, by chromatography and fractional crystallisation. 
         [0081]    Stereoisomers may be separated by conventional techniques known to those skilled in the art—see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994). 
         [0082]    The compounds of Formula I can be prepared in an analogous manner to those described in U.S. Pat. No. 4,256,748 and U.S. Pat. No. 6,388,073. The disclosures of the synthetic procedures used in each of these 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. 
         [0083]    A person skilled in the art will be aware of variations of, and alternatives to, the processes referred to in U.S. Pat. No. 4,256,748 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. 
         [0084]    By way of illustration, and without limitation, a compound of the invention may be obtained according to the following reaction scheme (in which R is, for example, ethyl or other alkyl), using commercially available compounds: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0085]    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”, R C Larock, Wiley-VCH (1999 or later editions), “March&#39;s Advanced Organic Chemistry—Reactions, Mechanisms and Structure”, M B Smith, J. March, Wiley, (5th edition or later) “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, F A Carey, R J 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” R K Mackie and D M Smith (Longman) (1982 or later editions), etc., and the references therein as a guide. 
         [0086]    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 Synthesis” by T W Greene and P G M Wuts, John Wiley &amp; Sons Inc (1999), and references therein. 
       DEFINITIONS 
       [0087]    Halo means a group selected from: fluoro, chloro, bromo or iodo. 
         [0088]    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-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. 
         [0089]    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, cyclohexyl or cycloheptyl. 
         [0090]    The term “spirocyclic” as used herein refers to a ring system joined to a second ring system at one carbon atom. 
         [0091]    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  alkoxy group is one embodiment, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy. 
         [0092]    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 groups. For example, C 1-4  hydroxyalkyl means a straight or branched alkyl chain containing from 1 to 4 carbon atoms and at least one hydroxyl group; examples of such group include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like. 
         [0093]    The term “alkenyl” 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 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 and 1,1-dimethylbut-2-enyl. It will be appreciated that in groups of the form —O—C 2-6  alkenyl, the double bond is preferably not adjacent to the oxygen. 
         [0094]    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 triple bond. For example, the term “C 2-6  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 —O—C 2-6  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. 
         [0095]    The term “sulfide” refers to a radical of R a —S—R b , wherein a sulfur atom is covalently attached to two hydrocarbon chains, R a  and R b , wherein the two hydrocarbon chains may be, for example, but not limited to, any discussed above. 
         [0096]    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 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., Blood, 1997, 89:2336-46). This involves examining the differentiation of human CD34 +  stem cells into megakaryocytes which ultimately give rise to blood platelets. 
         [0097]    The compounds of the invention may be particularly useful in the treatment of myeloproliferative diseases. The compounds may also find utility in the treatment of generalised thrombotic diseases. 
         [0098]    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, 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 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. 
         [0099]    Myeloproliferative diseases which may be treatable with the compounds of the present invention 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. 
         [0100]    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. 
         [0101]    The compounds of the present invention may also find utility in indicated for the reduction of atherothrombotic events as follows: recent MI, recent stroke or established peripheral arterial disease, acute coronary syndrome (unstable angina/non-Qwave MI), cardiovascular death, MI, stroke, and refractory ischemia. 
         [0102]    Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. 
         [0103]    They 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, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include one or more of: anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. 
         [0104]    Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington’ s Pharmaceutical Sciences&#39;, 19th Edition (Mack Publishing Company, 1995). The formulation of tablets is discussed in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X). 
         [0105]    The methods by which the compounds may be administered include oral administration by capsule, bolus, tablet, powders, lozenges, chews, multi and nanoparticulates, gels, solid solution, films, sprays, or liquid formulation. Liquid forms include suspensions, solutions, and syrups. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid preparation, for example, from a sachet. 
         [0106]    The compounds may also be administered topically to the skin or mucosa, that is dermally or transdermally. Typical formulations for this purpose include pour-on solutions, sprays, powder formulations, gels, hydrogels, lotions, creams, ointments, films and patches, and implants. 
         [0107]    The compounds can also be administered parenterally, or by injection directly into the blood stream, muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. 
         [0108]    Formulations may be immediate and/or modified controlled release. Controlled release formulations include Modified release formulations include: delayed-, sustained-, and pulsed-release. 
       Dosages 
       [0109]    Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. 
         [0110]    In general however a suitable dose will be in the range of from about 0.001 to about 50 mg/kg of body weight per day, in a further embodiment, of from about 0.001 to about 5 mg/kg of body weight per day; in a further embodiment of from about 0.001 to about 0.5 mg/kg of body weight per day and in yet a further embodiment of from about 0.001 to about 0.1 mg/kg of body weight per day. In further embodiments, the ranges can be of 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. 
         [0111]    The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as one, two, three, four or more doses per day. If the compounds are administered transdermally or in extended release form, the compounds could be dosed once a day or less. 
         [0112]    The compound is conveniently administered in unit dosage form; for example containing 0.1 to 50 mg, conveniently 0.1 to 5 mg, most conveniently 0.1 to 5 mg of active ingredient per unit dosage form. In yet a further embodiment, the compound can conveniently administered in unit dosage form; for example containing 10 to 1500 mg, 20 to 1000 mg, or 50 to 700 mg of active ingredient per unit dosage form.