WO2008057599A2

WO2008057599A2 - Methods for the treatment of abeta related disorders and compositions therefor

Info

Publication number: WO2008057599A2
Application number: PCT/US2007/023663
Authority: WO
Inventors: Lawrence P. Wennogle
Original assignee: Intra-Cellular Therapies, Inc.
Priority date: 2006-11-10
Filing date: 2007-11-09
Publication date: 2008-05-15
Also published as: WO2008057599A3

Abstract

The invention provides methods for treating Aβ peptide related disorders such as Alzheimer's disease comprising administering to a patient in need thereof a substituted 2-(pyrimidinylamino)-thiazole-5-carboxamides in free or pharmaceutically acceptable salt form, preferably dasatinib, in an amount effective to inhibit or reduce accumulation of Aβ peptide.

Description

METHODS FOR THE TREATMENT OF Aβ RELATED DISORDERS AND COMPOSITIONS THEREFOR

This application claims priority from U.S. Provisional Application No. 60/858,330, filed November 10, 2006, the contents of which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

[0001] The present invention relates to a new use of compounds of Formula I and salts thereof:

Formula I

preferably, compounds of Formula II and salts thereof:

Formula II

in the treatment of diseases involving the over production of Amyloid-β (Abeta or Aβ) peptide, such as Alzheimer's disease (AD). More preferably, the new use is of substituted 2-(pyrimidinylamino)-thiazole-5-carboxamides. Most preferably, the new use is ofN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-piperazin-l-yl]-2- methylpyrimidin-4-yl]-amino]-thiazole-5-carboxamide ("dasatinib").

BACKGROUND OF THE INVENTION

[0002] It is widely accepted that Aβ peptide is a causative agent in the development of Alzheimer's disease. Aβ peptides are metabolites of Amyloid -β precursor protein (Alzheimer's disease-associated precursor protein or APP), and consist mainly of 40 to 42 amino acids, Aβl-40 ("Aβ40") and Aβl-42 ("Aβ42"), respectively. Aβ40 and Aβ42 are generated by two enzymatic cleavages occurring close to the C-terminus of APP. The enzymes responsible for the cleavage, the aspartyl protease beta- secretase ("BACE") and the presenilin-dependent protease γ- secretase ("γ-secretase"), generate the N- and C-termini of Aβ, respectively. The amino terminus of Aβ is formed by β-secretase cleavage between methionine residue 596 and aspartate residue 597 of APP (numbering based on APP 695 isoform). γ- secretase cleaves at varying positions (38-, 40- or 43-residues C-terminal of this β- secretase cleavage product) to release the Aβ peptides. A third enzyme, α-secretase, cleaves the precursor protein between the β- and γ-cleavage sites, thus precluding Aβ production and releasing an approximately 3 kDa peptide known as P3, which is non- pathological. Both β- and α-secretase cleavage also result in soluble, secreted- terminal fragments of APP, known as sAPPβ and sAPPα, respectively. The sAPPα fragment has been suggested to be neuroprotective. These secretases may also be involved in the processing of other important proteins. For example, γ-secretase also cleaves Notch- 1 protein.

[0003] In normal individuals, the Aβ peptide is found in two predominant forms, the majority Aβ-40 (also known as Aβl-40) form and the minority Aβ42 (also known as Aβl-42) form, each having a distinct COOH-terminus. The major histological lesions of AD are neuritic plaques and neurofibrillary tangles occurring in affected brain regions. Neuritic plaques consist of Aβ peptides, primarily Aβ40 and Aβ42. Although healthy neurons produce at least ten times more Aβ40 compared to Aβ42, plaques contain a larger proportion of the less soluble Aβ42. Patients with the most common form of familial Alzheimer's disease show an increase in the amount of the Aβ42 form. The Aβ40 form is not associated with early deposits of amyloid plaques. In contrast, the Aβ42 form accumulates early and predominantly in the parenchymal plaques and there is strong evidence that Aβ42 plays a major role in amyloid plaque deposits in familial Alzheimer's disease patients. Neurofibrillary tangles consist of aggregated tau protein and their role in AD pathology is less clear. AD symptoms are most closely correlated with total brain Aβ rather than plaques. About 10% of AD cases result from autosomal dominant inheritance of mutations in either the APP or the presenilin 1 and presenilin 2 genes. In both cases, increased production of total Aβ or Aβ42 versus Aβ40 results.

[0004] [0004] WO 00/62778, US 6,596,746 and Lombardo, et al. J. Med. Chem. 2004, 47:6658-6661, the contents of all of which are incorporated herein by reference, disclose certain substituted 2-(pyrimidinylamino)-thiazole-5-carboxamide compounds for the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders. However, these references do not teach or suggest that these compounds are useful for the treatment of AB related disorder such as Alzheimer's disease. WO 2005/123048 does disclose "BMS-354825" (dasatinib) as a small molecule inhibitor of AbI kinase for the treatment of a tauopathy, including Alzheimer's disease, however, this reference does not disclose use of this compound in amounts effective to reduce AB levels. Rather, the emphasis of this reference is on the use of the compound to prevent the hyperphosphorylation of tau by inhibiting the activity of certain protein tyrosine kinases.

[0005] We have now surprisingly discovered that N-(2-chloro-6-methylphenyl)- 2-[[6-[4-(2-hydroxyethyl)-piperazin-l-yl]-2-methylpyrimidin-4-yl]-amino]-thiazole- 5-carboxamide ("dasatinib") can reduce the formation of β-amyloid peptide produced in mouse cells expressing human APP. Significantly, dasatinib can inhibit Aβ production in the same range as Gleevec®, which has previously been shown to inhibit Aβ production (see, e.g., WO/03/057165). Thus, it is contemplated herein that compounds of Formula I as disclosed in US 6,596,746, preferably compounds of Formula II, more preferably substituted 2-(pyrimidinylamino)thiazole-5- carboxamides, and most preferably N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)-piperazin-l-yl]-2-rnethylpyrimidin-4-yl]-amino]-thiazole-5- carboxamide, for example the compound disclosed as Example 455 in WO 00/62778 or US 6,596,746 (i.e. "dasatinib") may serve as novel therapeutic agents for the treatment of conditions characterized by overproduction of Aβ peptide, referred to collectively herein as "Aβ related disorders" and which include, but are not limited to, Alzheimer's disease.

SUMMARY OF THE INVENTION

[0006] The invention relates to a method (Method 1) to treat, control or manage Aβ related disorders, including Alzheimer's disease, comprising administering a compound of Formula I, preferably Formula II, e.g., as disclosed in US 6,596,746, in free or pharmaceutically acceptable salt form to a subject in need thereof in an amount effective to inhibit or reduce accumulation of Aβ peptide, e.g., in accordance with any of the following methods:

1.1 Method 1 wherein the Aβ related disorder is any disease characterized by accumulation of abnormal protein aggregates, especially in the brain, e.g., amyloid plaques and neurofibrillary tangles, for example precipitates of tau or amyloid proteins, e.g., Aβ;

1.2 Method 1 or 1.1 wherein the disease is selected from Alzheimer's disease, progressive supranuclear palsy, Down's Syndrome, memory and cognitive disorders, dementia, amyloid neuropathies, brain inflammation, nerve and brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease, Huntington's disease, prion disease and/or vascular, neurological, and/or neurodegenerative disorders related to the abnormal expression or accumulation of tau or amyloid proteins, e.g., Aβ;

1.3 Any of the preceding methods wherein the disease is Alzheimer's Disease;

1.4 Any of the preceding methods wherein the Compound of Formula I is a Compound of Formula II;

1.5 Any of the preceding methods 1-1.4 wherein the Compound of Formula I or II is a substituted 2-(pyrimidinylamino)thiazole-5- carboxamide in free or pharmaceutically acceptable salt form;

1.6 Any of the preceding methods 1-1.5 wherein the Compound of Formula I or II is dasatinib in free or pharmaceutically acceptable salt form; 1.7 Any of the foregoing methods additionally comprising administering an effective amount of an acetylcholinesterase inhibitor;

1.8 Method 1.7 wherein the acetylcholinesterase inhibitor is selected from donepezil (Aricept®), rivastigmine (Exelon®), tacrine (Cognex®) and galantamine (Reminyl®) in free or pharmaceutically acceptable salt form;

1.9 Any of the foregoing methods comprising administering a composition in accordance with any of Compositions 1 - 1.8 below.

[0007] In another aspect, the invention relates to a method to treat Aβ related disorders, including Alzheimer's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a Compound of Formula I, preferably Compound of Formula II as disclosed in US 6,596,746, in free or pharmaceutically acceptable salt form as described in any of methods 1-1.9 above. In various embodiments, said pharmaceutical composition preferably comprises any of the substituted 2-(pyrimidinylamino)thiazole-5- carboxamides disclosed therein, preferably dasatinib, Example 455 of US 6,596,746, in free or pharmaceutically acceptable salt form.

[0008] In another aspect, the invention relates to a pharmaceutical composition (Composition 1) comprising a Compound of Formula I, preferably Compound of Formula II as disclosed in US 6,596,746 in free or pharmaceutically acceptable salt form, in an amount effective to treat Aβ related disorders, including Alzheimer's disease, by inhibiting or reducing the accumulation of Aβ peptide in a subject in need thereof, in combination or association with a pharmaceutically acceptable diluent or carrier; e.g., in accordance with any of the following compositions:

1.1 Composition 1 wherein the Aβ related disorder is any disease characterized by accumulation of abnormal protein aggregates, especially in the brain, e.g., amyloid plaques and neurofibrillary tangles, for example precipitates of tau or amyloid proteins, e.g., Aβ;

1.2 Composition 1 or 1.1 wherein the disease is selected from Alzheimer's disease, progressive supranuclear palsy, Down's Syndrome, memory and cognitive disorders, dementia, amyloid neuropathies, brain inflammation, nerve and brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease, Huntington's disease, prion disease and/or vascular, neurological, and/or neurodegenerative disorders related to the abnormal expression or accumulation of tau or amyloid proteins, e.g., Aβ;

1.3 Any of the preceding compositions wherein the disease is Alzheimer's Disease;

1.4 Any of the preceding compositions wherein the Compound of Formula I is Compound of Formula II;

1.5 Any of the preceding compositions wherein the Compound of Formula I or II is a substituted 2-(pyrimidinylamino)thiazole-5-carboxamide in free or pharmaceutically acceptable salt form;

1.6 Any of the preceding compositions 1-1.5 wherein the Compound of Formula I or II is dasatinib in free or pharmaceutically acceptable salt form;

1.7 Any of the foregoing compositions further comprising an effective amount of an acetylcholinesterase inhibitor;

1.8 Composition 1.7 wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, galantamine and tacrine in free or pharmaceutically acceptable salt form.

[0009] The present invention also pertains to the use of a Compound of Formula I, preferably Compound of Formula II as disclosed in US 6,596,746 in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment or amelioration of an Aβ related disorder, including Alzheimer's disease, e.g. for use in any of Methods 1 - 1.9; for example wherein the Compound of Formula I is Compound of Formula II , e.g., substituted 2-

(pyrimidinylamino)thiazole-5-carboxamide, e.g. dasatinib, in free or pharmaceutically acceptable salt form, or wherein the medicament is a composition in accordance with any of Compositions 1 - 1.8.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The term "Aβ", "Aβ peptide", "amyloid β" and the like are synonymous, and refer to one or more peptide components of about 38-43 amino acids derived from beta amyloid precursor protein (β-APP), as described hereinabove.

[0011] US 6,596,746 discloses cyclic tyrosine kinase inhibitors referred to therein as "Formula I", and salts thereof, the structure of which is provided hereinbelow:

Formula I

where Q is:

(1) a 5-membered heteroaryl ring;

(2) a 6-membered heteroaryl ring; or

(3) an aryl ring; optionally substituted with one or more groups Ri;

Z is:

(1) a single bond;

(2) --Ri₅C=CH--; or

(3) ~(CH₂)_m --, where m is 1 to 2;

Xi and X₂ are each hydrogen, or together form =0 or =S;

Ri is:

(1) hydrogen Or R₆, where R₆ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Zi, Z₂ and one or more (preferably, one or two) groups Z₃ ;

(2) -OH or -OR₆ ; (3) --SH or -SR₆ ;

(4) -C(O)₂ H, -C(O)_q R₆, or ~O~C(O)_q R₆, where q is 1 or 2;

(5) -SO₃ H or -S(O)_q R₆ ;

(6) halo;

(7) cyano;

(8) nitro;

(9) -Z₄ -NR₇ R₈ ;

(10) -Z₄ -N(R₉)-Z₅ -NR₁₀ R₁ , ; (H) -Z₄ -N(Rn)-Z₅ -R₆ ; (12) -P(O)(OR₆), ;

R₂ and R₃ are each independently:

(1) hydrogen or R₆ ;

(2) -Z₄ -R₆ ; or

(3) -Z₁₃ -NR₇ R₈ ;

R₄ and R₅ :

(1) are each independently hydrogen or R₆ ;

(2) --Z₄ ^»N(R₉)^»Z₅ --NR₁₀ Ri , ;

(3) -N(R₉)Z₄ R₆ ; or

(4) together with the nitrogen atom to which they are attached complete a 3- to 8- membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Zi, Z₂ and Z₃, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Zi, Z₂ and Z₃ ;

R₇, R₈, R₉, Rio, Rn, and R₁₂ :

(1) are each independently hydrogen or R₆ ;

(2) R₇ and R₈ may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z₁, Z₂ and Z₃; or

(3) any two of R₉, R₁₀, and Rn may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Zi, Z₂ and Z₃; Ri₃ is:

(1) cyano;

(2) nitro; (3) --NH₂ ;

(4) -NHOalkyl; (5) --OH;

(6) -NHOaryl;

(7) -NHCOOalkyl;

(8) -NHCOOaryl;

(9) -NHSO₂ alkyl; (10) --NHSO₂ aryl; (H) aryl;

(12) heteroaryl; (13) -Oalkyl; or (14) --Oaryl;

R_H is:

(1) -NO₂ ;

(2) "COOalkyl; or

(3) -COOaryl;

R₁₅ is:

(1) hydrogen;

(2) alkyl;

(3) aryl;

(4) arylalkyl; or

(5) cycloalkyl;

Zi, Z₂ and Z₃are each independently:

(1) hydrogen or Z₆, where Z₆ is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Zi, Z₂ and Z₃; (2) -OH or -OZ₆ ;

(3) -SH or -SZ₆ ;

(4) -C(0)_q H, --C(0)_q Z₆, or ~O-C(O)_q Z₆ ;

(5) -SO₃ H, -S(0)_q Z₆ ; or S(0)_q N(Z₉)Z₆ ;

(6) halo;

(7) cyano;

(8) nitro;

(9) -Z₄ -NZ₇ Z₈ ;

(10) -Z₄ "N(Zo)-Z₅ -NZ₇ Z₈ ; (H)-Z₄-N(Z_1O)-Z₅-Z₆;

(13)oxo;

(14) -0-C(O)-Z₆ ;

(15) any two of Zi, Z₂ and Z₃inay together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or

(16) any two of Zi, Z₂ and Z₃may together be — O— (CH₂)_r — O— , where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

Z₄ and Z₅ are each independently: (1) a single bond;

(2) -Z₁₁ -S(O), -Z₁₂-; (3) -Z₁₁ --C(O)-Z₁₂-; (4) -Z₁ ,-C(S)- Z₁₂ -; (5) -Z₁₁ -O- Z₁₂-; (6) -Z₁₁ -S-Z₁₂-; (T)-Z₁₁-O-C(O)-Z₁₂-SOr (8) -Z₁ ,-C(O)-O-Z₁₂-;

Z₇, Z₈, Z₉ and Z₁₀ :

(1) are each independently hydrogen or Z₆ ;

(2) Z₇ and Z₈, or Z₆ and Z₁₀, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Zi, Z₂ and Z₃ ; or (3) Z₇ or Z₈, together with Z₉, may be alkylene or alkenylene completing a 3- to 8- membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Zi, Z₂ and Z₃;

Zn and Z)₂ are each independently:

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene; and

(1) a single bond;

(2) -Zi, --S(OV-Z₁₂--;

(3) -Z₁, -C(O)-Z₁₂-;

(4) -Z₁, -C(S)- Z,₂ -;

(5) - Z,, -O- Z₁₂-;

— ; (T)-Z₁₁-O-C(O)-Z₁₂-; (S)-Z₁₁-C(O)-O-Z₁₂-; (9) -C(NR₁₃)-;

(H)-C(C(RH)₂)-

in free or pharmaceutically acceptable salt form.

[0012] Compounds within Formula I disclosed in US 6,596,746, include compounds of Formula II, and salts thereof, the structure of which is provided hereinbelow:

Formula II

where n is 1 or 2

A is selected from carbon and nitrogen;

B is selected from nitrogen, oxygen and sulfur;

X₃ is oxygen or sulfur; and

Ri, R₂, R₃, R₄ and R₅ are as described above

in free or pharmaceutically acceptable salt form.

[0013] Compounds of Formula I or Formula II may exist in free or salt form, e.g., as acid addition salts. In this specification, unless otherwise indicated, language such as "Compounds of Formula I" or "Compounds of Formula II" is to be understood as embracing the compounds in any form, for example free or acid addition salt form, and/or in amorphous or crystalline form, e.g., as a solvate or hydrate. For example, dasatinib is preferably provided in the form of the free base monohydrate crystal. The Compounds of Formula I or II are used as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Pharmaceutically acceptable salts are salts that are not toxic or harmful at the dosages to be used.

[0014] As used herein, the terms "alk" or "alkyl" refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to alkyl groups of 1 to 4 carbon atoms.

[0015] The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.

[0016] The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.

[0017] The term "alkylene" refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., --(CH₂)_X -- wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

[0018] The term "alkenylene" refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are - CH=CH-CH=CH-, -CH₂ -CH=CH-, -CH₂ -CH=CH-CH₂ --, -C(CH₃)₂ CH=CH-- and -CH(C₂ H₅)- CH=CH-.

[0019] The term "alkynylene" refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are -C≡C-, ~CH₂-C≡C-, -CH(CH₃)-C≡C- and -C≡C-CH(C₂ H₅)CH₂ -.

[0020] The terms "ar" or "aryl" refer to aromatic cyclic groups which contain 6 to 14 carbon atoms. Aromatic cyclic groups may include mono or polycyclic systems (for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems). Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene. Polycyclic system may also include systems that have at least one aromatic ring connected or fused to non-aromatic rings (e.g. cycloalkyl).

[0021] The terms "cycloalkyl" and "cycloalkenyl" refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.

[0022] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

[0023] The term "unsaturated ring" includes partially unsaturated and aromatic rings.

[0024] The terms "heterocycle", "heterocyclic" or "heterocyclo" refer to fully saturated or unsaturated, including aromatic (i.e. "heteroaryl") cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. Heterocyclic group may also include systems that have at least one heteroaromatic ring connected or fused to non-aromatic rings (e.g. cycloalkyl).

[0025] Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-dioxothienyl, triazolyl, triazinyl, and the like.

[0026] Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra- hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2- b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

[0027] Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like. [0028] The term "heteroaryl" refers to aromatic heterocyclic groups.

[0029] Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.

Where q is 1 or 2, "~C(O)_q H" denotes -C(O)-H or -C(O)-OH; "--C(O)_q R₆ " or "-- C(O)_q Z₆ " denote, respectively, -C(O)-R₆ or -C(O)-OR₆, or -C(O)-Z₆ or -C(O)- OZ₆ ; "~0-C(0)_q R₆ " or "~0~C(0)_q Z₆ " denote, respectively, -0-C(O)-R₆ or ~ 0-C(O)-OR₆, or -0-C(O)-Z₆ or -0-C(O)-OZ₆ ; and "~S(0)_q R₆ " or ^M-S(0)_q Z₆ " denote, respectively, -SO-R₆ or -SO₂ -R₆, or -SO-Z₆ or -SO₂ -Z₆.

[0030] The term "Compound of Formula I" or "Compound of Formula II" includes, but is not limited to, substituted 2-(pyrimidinylamino)thiazole-5- carboxamide compounds disclosed in US 6,596,746 and free or pharmaceutically acceptable salts thereof. Particularly preferred is N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-piperazin-l-yl]-2-methylpyrirnidin-4-yl]-amino]-thiazole-5- carboxamide, disclosed as Example 455 in US 6,596,746 and WO 00/62778 (alternatively named therein as "'N-(2-Chloro-6-methyl-phenyl)-2-[[6-[4-(2- hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide"). The compound is also disclosed as "Compound 13" or "BMS-254625" in Lombardo, et al. J. Med. Chem. 2004, 47:6658-6661. Also known as "dasatinib", the compound is commercially available from Bristol-Myers Squibb as "SPRYCEL", having recently been approved by the FDA for adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia which exhibits resistance or intolerance to prior therapy.

[0031] The words "treatment" and "treating" are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.

[0032] "Pathological effects of Aβ related disorders", "symptoms of Aβ related disorders" and like terms refer to, but are not limited to, memory dysfunction (which can range from mild forgetfulness to severe and debilitating memory loss), neurodegeneration, the formation and/or presence of senile plaques and/or neurofibrillary tangles and neuronal cell loss.

[0033] The term "sample" as used herein, is used in its broadest sense. A biological sample from a subject may comprise blood, urine or other biological material with which a desired activity may be assayed. A biological sample may include neuronal material such as brain biopsies and especially cortical or neocortical biopsies (e.g. middle frontal gyrus (Brodmann area 8); inferior frontal gyrus (Brodmann area 44); anterior cingulate gyrus (Brodmann area 32); superior, middle, and inferior temporal gyri (Brodmann areas 22, 21, and 20, respectively); the entorhinal cortex (Brodmann area 36/28); the inferior parietal lobule (Brodmann area 7); and the primary visual cortex (Brodmann area 17)) or non-neuronal sample such as blood cells, cerebrospinal fluid, or skin biopsies (as described, for example, for Aβ peptide in Joachim CL et al., Nature, 1989 Sep 21 ;341(6239):226-30).

[0034] An "Aβ related disorder" as defined herein includes, but is not limited to, any physical or mental disorder characterized by an abnormal level of Aβ peptides (of any size) compared to levels in healthy controls. Such disorders include but are not limited to, any and all forms of Alzheimer's disease, including Early-onset Alzheimer's, Late-onset dementia, and Familial Alzheimer's disease (FAD), mild cognitive impairment as well as any other condition mediated or affected by abnormal production of Aβ such as hereditary cerebral hemorrhage (cerebral amyloid angiopathy), Down's Syndrome, or Parkinson's disease.

[0035] "Subject" refers to any human or any nonhuman mammal.

[0036] The invention is based on the surprising discovery that dasatinib causes a decrease in Aβ peptide production in mouse cells. Thus, it is contemplated herein that the Compounds of Formula II as disclosed in US 6,596,746, preferably substituted 2- (pyrimidinylamino)-thiazole-5-carboxamides, preferably N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-piperazin-l-yl]-2-methylpyrimidin-4-yl]- amino]-thiazole-5-carboxamide ("dasatinib"), in free or pharmaceutically acceptable salt form, are useful therapeutics for the treatment of an Aβ related disorders, including Alzheimer's disease.

[0037] In another aspect, the invention relates to a method to treat an Aβ related disorder, including Alzheimer's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising a Compound of Formula I, preferably Compound of Formula II, more preferably, a substituted 2- (pyrimidinylamino)-thiazole-5-carboxamide, most preferably dasatinib, in free or pharmaceutically acceptable salt form, in an amount effective to inhibit accumulation ofAβ.

[0038] A "therapeutically effective amount" and like terms is the amount of drug (e.g., dasatinib) sufficient to treat an Aβ related disorder. For example, a therapeutically effective amount may be an amount shown to lessen or prevent the pathological accumulation of Aβ peptide that is seen in Alzheimer's disease and/or that can lessen or prevent the pathological effects of such accumulation. Improvements in the physical and/or mental state of an individual suffering from Alzheimer's disease may be measured by techniques and combinations of techniques familiar to one of skill in the art, including but not limited to, Clinical Dementia Rating (CDR) assessment, the mini-mental state exam (MMSE), the mini-cog exam, as well as positron emission tomography (PET), magnetic resonance imaging (MRI) and computed tomography (CT). Further diagnostic tests may include tests of biological fluids and tissues for various biochemical markers and activities. Factors for consideration for optimizing a therapy for a patient include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the site of delivery of the active compound, the particular type of the active compound, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The therapeutically effective amount of an active compound to be administered will be governed by such considerations, and is the minimum amount necessary for the treatment of an Aβ related disorder, preferably Alzheimer's disease.

[0039] The compounds used in the methods disclosed herein may be used as a sole therapeutic agent, but it is contemplated herein that they may also be used in combination with, or for co-administration with, other active agents. For example, any one. or more of these compounds may be simultaneously, sequentially, or contemporaneously administered with conventional medications proven useful for the treatment of Alzheimer's disease. These medications include cholinesterase inhibitors such as Razadyne® (formerly known as Reminyl®) (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine) as well as Namenda® (memantine), an N-methyl D-aspartate (NMDA) antagonist. Additionally, drugs that have not yet been approved by the FDA for the treatment of Alzheimer's disease but which have recently been show to affect Aβ levels, may be used in combination with or for co-administration with the compounds disclosed herein. These drugs include such drugs as Gleevec® (unidentified target(s)), GSK3β modulators/inhibitors (e.g. LiCl, Kenpaullone),and CDK5 modulators/inhibitors (e.g. roscovitine).

[0040] The present invention also provides

(i) a Compound of Formula I, preferably Compound of Formula II, preferably a substituted 2-(pyrimidinylamino)-thiazole-5-carboxamide, preferably dasatinib, in free or pharmaceutically acceptable salt form, for use in the treatment of any disease or condition as hereinbefore set forth, or in a method of treatment as hereinbefore set forth;

(ii) the use of a Compound of Formula I or II, preferably a substituted 2-(pyrimidinylamino)-thiazole-5-carboxamide, preferably dasatinib, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating a disease or condition as hereinbefore set forth, or manufacture of a medicament for use in a method of treatment as hereinbefore set forth; and

(iii) a pharmaceutical composition comprising a Compound of Formula I or II, preferably a substituted 2-(pyrimidinylamino)-thiazole-5-carboxamides, preferably dasatinib, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment of a disease or condition as hereinbefore set forth, or for use in a method of treatment as hereinbefore set forth.

[0041] The compounds used in the methods disclosed herein may be prepared by methods disclosed in WO 00/62778, US 6,596,746 and Lombardo, et al. J. Med. Chem. 2004, 47:6658-6661. [0042] The compounds of the present invention can be administered as pharmaceutical compositions. Such pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.

[0043] Thus, the compounds disclosed herein and their pharmaceutically acceptable salts and solvates may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or topical, oral, buccal, parenteral or rectal administration.

[0044] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

[0045] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0046] For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner. [0047] For administration by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0048] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0049] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0050] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0051] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0052] Pharmaceutical compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0053] For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of suitable cells, or in animal models. The animal model may also be used to determine the appropriate concentration range and route of administration. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms). Such information can then be used to determine useful doses and routes for administration in humans. In addition, with regard to a therapeutically effective dose of a compound disclosed herein, therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0054] The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors that may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0055] Dosages employed in practicing the present invention will, of course, vary depending, e.g., on the particular disease or condition to be treated, the particular compound to be used, the mode of administration, and the therapy desired. The compounds for use in the instant invention may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g., for the treatment of diseases as hereinbefore set forth, are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 10.0 mg/kg (all weights are given as the equivalent of compound in free form, although the compound may be provided in free or pharmaceutically acceptable salt form). In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 750 mg, e.g., 50-500 mg, conveniently administered once, or in divided doses 2 to 4 times daily, or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 250 mg, e.g., from about 0.2 or 2.0 to 50, 75, 100 or 200 mg of compound, together with a pharmaceutically acceptable diluent or carrier therefor.

[0056] The following examples further illustrate the present invention and are not intended to limit the invention.

EXAMPLES

Example 1

Dasatinib Inhibits AB production in vitro Experimental Procedures

[0057] In order to determine the effects of dasatinib on the production of Aβ, APP processing and Aβ production are assayed using a cell based assay as reported in Thinakaran, et al. J Biol Chem. 1996 Apr 19;271 (16):9390-7. a. Cell Based Assay for measuring AB levels: Dosing

[0058] N2A mouse neuroblastoma cells stably expressing APP (N2A-APP695 cells) (Thinakaran, et al., J Biol Chem. 1996 Apr 19;271 (16):9390-7) are plated at 60,000 cells/well in 96-well multiwell plates (Corning Costar, Corning, NY, catalog #3595) in N2A medium (50% DMEM-high glucose, 50% Opti-MEM, (Invitrogen, Carlsbad, CA), 5% fetal bovine serum (Hyclone, Logan, UT), plus Penicillin/Streptomycin (100 units/100 ug per liter (Invitrogen) and 2 mM L- glutamine (Invitrogen)) plus 5 mM butyrate and grown overnight at 37°C. The medium is changed the following morning to N2A medium plus test compound, at 6 doses from 50 uM - 0.21 uM (serial dilutions in steps of 3) and cells are incubated plus test compound for 2 hours at 37⁰C. Medium is changed at this point to 100 μL N2A medium plus test compound for a final 2 hour incubation. Any detached cells are spun out in a benchtop centrifuge, 5 min at 2500 rpm, and aliquots of media are transferred to a fresh 96-well plate and frozen at -2O⁰C for Western blot analysis for AB.

b. Cell Based Assay for measuring AB levels: Analysis

[0059] Aliquots of media from the cell based assay described above are subjected to Western analysis. Briefly, fifteen μL aliquots are separated on a polyacrylamide gel and proteins are transferred to polyvinylidene fluoride (PVDF; Biorad Laboratories, Hercules, CA) according to conventional methods. AB peptide in the samples is detected by immunodecoration with 6E10 mouse monoclonal anti AB antibody (Chemicon, Temecula, CA) and fluorescent anti-mouse IgG secondary antibody (Invitrogen, Carlsbad, CA) according to conventional methods. Relative amounts of AB in the medium are then quantitated using a Odyssey infrared fluorescence detector (LiCor, Lincoln, NE) according to manufacturer's instructions.

Results

[0060] Results indicate that dasatinib inhibits AB production in this cell-based assay for APP processing with a potency similar to the reference compound, Gleevec®. Specifically, data indicate that dasatinib reduces AB production in the same range (IC₅₀ = 7.89 uM) as Gleevec® (IC₅₀ = 9.03).

Claims

What is claimed is:

1. A method of treating an Aβ related disorder comprising administering to a subject in need thereof an amount of a Compound of Formula I (as hereinbefore described) in free or pharmaceutically acceptable salt form effective to inhibit or reduce accumulation of Aβ peptide.

2. The method of claim 1 wherein said Compound of Formula I is Compound of Formula II (as hereinbefore described) in free or pharmaceutically acceptable salt form effective to inhibit or reduce accumulation of Aβ peptide.

3. The method of claim 1 or 2 wherein said Aβ related disorder is Alzheimer's disease.

4. The method of claim 1, 2 or 3 wherein said Compound of Formula I or Compound of Formula II is a substituted 2-(pyrimidinylamino)-thiazole-5-carboxamide in free or pharmaceutically acceptable salt form.

5. The method of claim 1, 2, 3 or 4 wherein said Compound of Formula I or Compound of Formula II is dasatinib in free or pharmaceutically acceptable salt form.

6. A method to treat an Aβ related disorder comprising administering to a subject in need thereof a pharmaceutical composition comprising an amount of a Compound of Formula I in free or pharmaceutically acceptable salt form effective to inhibit or reduce accumulation of Aβ peptide.

7. The method of claim 5 wherein said Compound of Formula I is Compound of Formula II in free or pharmaceutically acceptable salt form.

8. The method of claim 5 or 6 wherein said Aβ related disorder is Alzheimer's disease.

. The method of claim 5 , 6 or 7 wherein said Compound of Formula I or II is a substituted 2-(pyrimidinylarnino)thiazole-5-carboxamide in free or pharmaceutically acceptable salt form.

10. The method of claim 5, 6 , 7 or 8 wherein said Compound of Formula I or II is dasatinib in free or pharmaceutically acceptable salt form.

11. A pharmaceutical composition comprising a Compound of Formula I in free or pharmaceutically acceptable salt form for use in reducing or inhibiting the accumulation of Aβ peptide in treating an Aβ related disorder in a subject in need thereof.

12. The pharmaceutical composition according to claim 1 1 wherein said Compound of Formula I is Compound of Formula II in free or pharmaceutically acceptable salt form.

13. The pharmaceutical composition according to claim 1 1 or 12 wherein said Compound of Formula I or II is a substituted 2-(pyrimidinylamino)-thiazole-5- carboxamide in free or pharmaceutically acceptable salt form.

14. The pharmaceutical composition according to claim 11, 12 or 13 wherein said Compound of Formula I or II is dasatinib in free or pharmaceutically acceptable salt form

15. The pharmaceutical composition according to claim 11, 12, 13 or 14 wherein said Aβ related disorder is Alzheimer's disease.

16. Use of a Compound of Formula I (as hereinbefore described) in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment or amelioration of an Aβ related disorder.

17. Use according to claim 16, wherein Compound of Formula I is Compound of Formula II, in free or pharmaceutically acceptable salt form.

18. Use according to claim 16 or 17, wherein Compound of Formula I or II is a substituted 2-(pyrimidinylamino)-thiazole-5-carboxarnide in free or pharmaceutically acceptable salt form.

19. Use according to claim 16, 17 or 18, wherein Compound of Formula I or II is dasatinib in free or pharmaceutically acceptable salt form.