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Definitions

• TPO thrombopoietin
• Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising ⁇ 0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold.
• TPO thrombopoietin
• TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
• TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects (see Harker et al. Blood 91: 4427-4433 (1998)). Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients (see Basser et al. Blood 89: 3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336: 404-409 (1997)).
• Thrombopoietin is a glycoprotein with at least two forms, with apparent molecular masses of 25 kDa and 31 kDa, with a common N-terminal amino acid; sequence. See, Baatout, Haemostasis 27: 1-8 (1997); Kaushansky, New Engl. J. Med.
• Thrombopoietin appears to have two distinct regions separated by a potential Arg-Arg cleavage site.
• the amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-a and interferon-b.
• the carboxy- terminal region shows wide species divergence.
• TPO- R human TPO receptor
• c-mpl human TPO receptor
• TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region.
• TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34+ cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation.
• TPO mimetic It would be desirable to provide compounds which allow for the treatment of thrombocytopenia by acting as a TPO mimetic. As disclosed herein it has unexpectedly been discovered that certain hydroxy- 1-azo- benzene derivatives are effective as agonists of the TPO receptor, they are potent TPO mimetics.
• R, R.1, R2 and R ⁇ are each independently selected from hydrogen, C ⁇ _galkyl,
• p is 0-6, n is 0-2, V, W, X and Z are each independently selected from O, S and NR ⁇ , where Rl6 is selected from: hydrogen, alkyl, cycloalkyl, C ⁇ -Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-C ⁇ aryl,
• R4 is selected from: hydrogen, alkyl, cycloalkyl, Ci-Ci ⁇ aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-C ⁇ aryl, and R ⁇ and R° are each independently selected from hydrogen, alkyl, substituted alkyl, C3_gcycloalkyl, and aryl, or R5 and R" taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; m is 0-6; and
• AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(0)OR 4 , -C ⁇ NR ⁇ R 11 , - S(O) 2 NR 10 R 1 !, -S(0) n R 4 and protected -OH, where n is 0-2, R 4 is hydrogen, alkyl, cycloalkyl, Ci -C ⁇
• RIO and R ⁇ are independently hydrogen, cycloalkyl, C ⁇ -Ci2 r yl > substituted cycloalkyl, substituted Cj-C ⁇ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(0)OR 4 , -S(0) n R 4 , -C(0)NR 4 R 4 , - S(0)2NR 4 R 4 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH, or RIO and R!
• R, Rl, R ⁇ and R ⁇ is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III).
• This invention relates to a method of treating thrombocytopenia, which comprises administering to a subject in need thereof an effective amount of a TPO mimetic compound of Formula (I).
• the present invention also relates to the discovery that the compounds of Formula (I) are active as agonists of the TPO receptor.
• compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
• Also included in the present invention are methods of co-administering the presently invented TPO mimetic compounds with further active ingredients.
• R, Rl, R2 and R ⁇ are each independently selected from hydrogen, C j .galkyl, C ⁇ _galkoxy, -(CH2)pOR , -C(0)OR 4 , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(0) n R 4 , cycloalkyl, -NR ⁇ R ⁇ , protected - OH, -CONR5R6 ; phosphonic acid, sulfonic acid, phosphinic acid and -
• R 4 is selected from: hydrogen, alkyl, cycloalkyl, C]-Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted C ⁇ -C ⁇ 2aryl, and R and R° are each independently selected from hydrogen, alkyl, substituted alkyl, C3_gcycloalkyl, and aryl, or R ⁇ and R° taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
• n 0-6;
• AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(0)0R 4 , -C(0)NR1°RH, - S(O) 2 NR 10 R 1 1 , -S(0) n R 4 and protected -OH, where n is 0-2, R 4 is hydrogen, alkyl, cycloalkyl, C ⁇ -C
• RIO and R ⁇ are independently hydrogen, cycloalkyl, Ci -C ⁇ aryl, substituted cycloalkyl, substituted C ⁇ -Ci 2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(0)OR 4 -S(0) n R 4 -C(0)NR 4 R 4 , - S(0)2NR 4 R 4 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH, or RIO and R* 1 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where R 4 is as described above and n is 0-2; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof;
• R, Rl, R 2 and R ⁇ are each independently selected from hydrogen, Ci.galkyl, -(CH2)pOR 4 , -C(0)OR 4 , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(0) n R 4 , cycloalkyl, -NR 5 R 6 , protected -OH, -CONR 5 R 6 , phosphonic acid, sulfonic acid, phosphinic acid, -S ⁇ 2NR ⁇ R", and a heterocyclic methylene substituent as represented by Formula (III),
• V, W, X and Z are each independently selected from O, S, and N 16, where R!6 is selected from: hydrogen, alkyl, cycloalkyl, C j -C ⁇ ryl, substituted alkyl, substituted cycloalkyl and substituted Ci -C ⁇ aryl,
• R 4 is hydrogen, alkyl, cycloalkyl, Ci -C ⁇ aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-C ⁇ aryl, and
• R and R" are each independently selected from hydrogen, alkyl, substituted alkyl, C3_6cycloalkyl, and aryl, or R5 and R ⁇ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
• Rl5 is selected from the group consisting of alkyl, Ci-C ⁇ aryl, hydroxy, alkoxy, substituted alkyl, substituted C ⁇ -Ci 2aryl and halogen;
• n 0-6;
• Y is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing from one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, C1-C12 ryl, substituted cycloalkyl, substituted C1-C12 ryl, hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected -OH;
• R, Rl, R 2 and R ⁇ is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III).
• R, Rl, R 2 and R ⁇ are each independently selected from hydrogen, Ci.galkyl, C2_galkoxy, -(CH2) p OR 4 , -C(0)OR 4 formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(0) n R 4 , cycloalkyl, -NR 5 R 6 , protected - OH, -CONR R°, phosphonic acid, sulfonic acid, phosphinic acid and - S0 2 NR 5 R 6 , where p is 0-6, n is 0-2,
• R 4 is hydrogen, alkyl, cycloalkyl, Ci-C ⁇ aryl, substituted alkyl, substituted cycloalkyl and substituted Ci -C ⁇ aryl, and
• R and R" are each independently selected from hydrogen, alkyl, substituted alkyl, C3_6cycloalkyl, and aryl, or R5 and R° taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
• R!5 is selected from the group consisting of alkyl, Ci -C ⁇ aryl, hydroxy, alkoxy, substituted alkyl, substituted C ⁇ -Ci2 ryl and halogen;
• n 0-6;
• Y is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing from one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12 ryl, hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected -OH;
• R, Rl, R 2 and R ⁇ is a substituted aryl group.
• R is a substituted aryl; and R is hydrogen; or:
• R is hydrogen; and R! is a substituted aryl; and in either case:
• R 2 and R ⁇ are each independently selected from hydrogen, C ⁇ .galkyl, C j .galkoxy, nitro, cyano,- halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid;
• R 5 is selected from the group consisting of alkyl, substituted alkyl, Ci-C ⁇ aryl, alkoxy and halogen;
• m is 0-4; and
• Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected, from the group consisting of: alkyl, substituted alkyl, C ⁇ -Ci2aryl, substituted C j -C ⁇ aryl, alkoxy and halogen; and pharmaceutically acceptable salts, hydrates, solvates and est
• R is a substituted C1-C12aryl
• R! is hydrogen
• R 2 and R- are each independently selected from hydrogen, Ci.galkyl, C j _galkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl;
• R! is selected from the group consisting of alkyl, substituted alkyl, alkoxy and halogen;
• m is 0-2; and
• Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, Ci-C ⁇ aryl, substituted C j -C ⁇ aryl, alkoxy and halogen; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
• R is a substituted phenyl or pyridinyl ring; and R! is hydrogen; R 2 and R ⁇ are each independently selected from hydrogen, Cj.galkyl, substituted alkyl and halogen;
• Rl5 i s selected from the group consisting of C ⁇ _4alkyl, Ci ⁇ alkoxy, C j -C ⁇ aryl and halogen; m is 0; and
• Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl is optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C j -C ⁇ aryl, substituted C j -C ⁇ aryl, alkoxy and halogen; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
• Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention.
• protected hydroxy or “protected -OH” as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art such as described in “Protective Groups In Organic Synthesis” by Theodora W.
• aryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 1 to 14 carbon atoms and optionally containing from one to five heteroatoms, provided that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom.
• C -C 2aryl as used herein, unless otherwise defined, is meant phenyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole and tetrazole.
• substituted when referring to compounds of Formula (I) and (II), the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: -CO2R , aryl, -
• R° > is hydrogen or alkyl
• R ⁇ is selected form hydrogen, C -C4alkyl, aryl and trifluoromethyl
• R 2 * and R 22 are independently selected form hydrogen, C ⁇ -C4alkyl, aryl and trifluoromethyl
• V, W, X and Z are each independently selected from O, S, and NR1 , where R " is selected from: hydrogen, alkyl, cycloalkyl, C -C ⁇ 2 ryl, substituted alkyl, substituted cycloalkyl and substituted C ⁇ -C 2aryl
• n is 0-2.
• substituted when referring to compounds of Formula (V) and (VI), the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: -CO2R 2 , aryl, - C(0)NHS(0) 2 R 20 , -NHS(0) 2 R 20 , hydroxyalkyl, alkoxy, -C(0)NR 21 R 22 , acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH2) g C(0)OR°, -S(0) n R ⁇ , nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl and protected -OH, where g is 0-6, R° > is hydrogen or alkyl, R ⁇ is selected form hydrogen, C ⁇ -C4alkyl, aryl and trifluoromethyl, and R 2 ⁇ and R 22 are independently selected form hydrogen, C ⁇ -C4alkyl
• cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12.
• cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl and cyclopentyl.
• acyloxy as used herein is meant -OC(0)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein include: -OC(0)CH3, - OC(0)CH(CH 3 ) 2 and -OC(0)(CH 2 )3CH 3 .
• N-acylamino as used herein is meant -N(H)C(0)alkyl, where alkyl is as described herein.
• Examples of N-acylamino substituents as used herein include: - N(H)C(0)CH 3 , -N(H)C(0)CH(CH 3 ) 2 and -N(H)C(0)(CH 2 )3CH 3 .
• aryloxy as used herein is meant -Oaryl where aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, -(CH2) g C(0)OR° ⁇ -S(0) n R ⁇ , nitro, cyano, halogen and protected -OH, where g is 0-6, R° is hydrogen or alkyl, and n is 0-2.
• substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
• heteroatom oxygen, nitrogen or sulfur.
• halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride. :
• alkyl and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms.
• treating and derivatives thereof as used herein, is meant prophylatic and therapeutic therapy.
• esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations.
• novel compounds of Formulas I and II are prepared as shown in Schemes I to IV below, or by analogous methods, wherein the ⁇ .' substituents, AR, Y and m are as defined in Formulas I and II respectively and provided that the ⁇ .' and m substituents, AR and Y do not include any such substituents that render inoperative the processes of Schemes I to IV. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.
• nitric acid nitric acid
• sulfuric acid nitric acid
• 4-carboxyphenylboronic acid Pd(PPh 3 ) 4 , Na2C03, dioxane, water
• H 2 , Pd-C iv) NaN0 2 , AR, NaHC0 3 , water, EtOH
• Scheme I outlines the formation of Formula I compounds.
• a 3-bromophenol (a) is nitrated with nitric acid or sodium nitrate and sulfuric acid to give nitro phenol (b).
• a substituted arylboronic acid such as 3- carboxyphenylboronic acid or 4-carboxyphenylboronic acid in the presence of a catalyst, preferably tetrakistriphenylphosphino palladium and a base such as sodium carbonate ot triethylamine in a suitable solvent such as aqueous 1,4-dioxane or dimethylformamide afforded substituted aryl compound (c).
• Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid or water gives the aniline (d).
• Compound (d) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably an ethanol- water mixture to produce a diazonium species which is directly converted to compoud (e) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium hydrogen carbonate, or an acid, preferably hydrochloric acid.
• a base preferably sodium hydrogen carbonate
• an acid preferably hydrochloric acid.
• an alkylating agent such as benzyl bromide or preferably methyl iodide
• a base such as sodium hydride or potassium carbonate
• a suitable solvent such as dimethylformamide, tetrahydrofuran or acetone
• Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid; or water gives the aniline (k).
• Compound (k) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol-water mixture to produce a diazonium species which is directly converted to compoud (1) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium hydrogen carbonate, or an acid, preferably hydrochloric acid.
• an appropriate acid such as nitric acid, sulfuric acid or, preferably, hydrochloric acid
• Scheme III outline a further procedure for the synthesis of Formula I compounds.
• a protected hydroxyphenylboronic acid; (m) (Prot alkyl or substituted alkyl, e.g. methyl, benzyl) such as 5-chloro-2-methoxyphenylboronic acid, 5-fluoro-2-methoxyphenyl, boronic acid or 2-methoxy-5-formy lpheny Iboronic acid, is coupled with a substituted halogenoaryl species, such as 5-(3-bromophenyl)tetrazole or 5-bromonicotinic acid, in the presence of a catalyst, preferably tetrakistriphenylphosphino palladium, and a base, such as sodium carbonate or triethylamine in a suitable solvent such as aqueous 1,4-dioxane or dimethylformamide afforded substituted aryl compound (n).
• a catalyst preferably tetrakistriphenylphos
• Removal of the protecting group Prot is accomplished using an protic or Lewis acid, such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (o).
• an protic or Lewis acid such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (o).
• Nitration of (o) with nitric acid, or sodium nitrate in the presence of an acid, such as acetic or hydrochloric acid affords the nitro compound (p).
• Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid or water gives the aniline (q).
• Compound (q) is diazotized by reaction with sodium nitrite and an appropriate acid, such as nitric acid, sulfuric acid or, preferably, hydrochloric acid, in an appropriate aqueous solvent, such as water or, preferably, an ethanol- water mixture to produce a diazonium species which is directly converted to compoud (r) in a coupling reaction with an appropriate aryl species in the presence of a base, preferably sodium hydrogen carbonate, or an acid, preferably hydrochloric acid.
• an appropriate acid such as nitric acid, sulfuric acid or, preferably, hydrochloric acid
• Scheme IV outlines the formation of pyrazoles for use in scheme I-III.
• An amine such as 4-methylaniline, compound (s)
• an appropriate acid such as hydrochloric acid, nitric acid or sulfuric acid
• an appropriate aqueous solvent system such as water or ethanol-water mixtures
• hydrazine is then condensed with a electrophilic carbonyl species such as ethyl acetoacetate (u), ethyl cyanoacetate or diethyl malonate, in an appropriate solvent such as acetic acid or ethanol at an appropriate temperature typically 0-100° to give the corresponding pyrazole, compound (v) as described herein.
• a electrophilic carbonyl species such as ethyl acetoacetate (u), ethyl cyanoacetate or diethyl malonate
• thrombocytopenia is accomplished by increasing the production of platelets.
• co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a TPO mimetic compound, as described herein, and a further active ingredient or ingredients, known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production.
• further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered with TPO or a TPO mimetic.
• the compounds are administered in a close time proximity to each other.
• TPO mimetic compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
• chemoprotective or myeloprotective agents such as G-CSF, BB 10010 (Clemons et al., Breast Cancer Res. Treatment, 1999, 57, 127), amifostine (Ethyol) (Fetscher et al., Current Opinion in Hemat..
• Tpo has been demonstrated to act as a mobilizer of stem cells into the peripheral blood (Neumann T. A. et al., Cytokines. Cell. & Mol. Ther., 2000, 6, 47-56). This activity can synergize with stem cell mobilizers such as G-CSF (Somolo et al., Blood, 1999, 93, 2798-2806).
• the TPO mimetic compounds of the present invention are thus useful in increasing the numbers of stem cells in circulation in donors prior to leukapheresis for hematopoietic stem-cell transplantation in patients receiving myelo-ablative chemotherapy.
• TPO stimulates growth of myeloid cells, particularly those of granulocyte/macrophage lineage (Holly et al., US-5989537).
• Granulocyte/macrophage progenitors are cells of the myeloid lineage that mature as neutrophils, monocytes, basophils and eosinophils.
• the compounds described in the present invention have thus therapeutic utility in stimulating the poliferation of neutrophils in patients with neutropenic conditions.
• TPO mimetic compounds include but are not limited to: stem cell, megakaryocyte, neutrophil mobilizers such as chemotherapeutic agents (i.e., cytoxan, etoposide, cisplatin, Ballestrero A. et al., Oncology, 2000, 59, 7-13), chemokines, IL-8, Gro-beta (King, A. G. et al. J.
• chemotherapeutic agents i.e., cytoxan, etoposide, cisplatin, Ballestrero A. et al., Oncology, 2000, 59, 7-13
• chemokines i.e., cytoxan, etoposide, cisplatin, Ballestrero A. et al., Oncology, 2000, 59, 7-13
• chemokines i.e., cytoxan, etoposide, cisplatin, Ballestrero A.
• thrombocytopenia and derivatives thereof as used herein is to be broadly interpreted as any decrease in the number of blood platelets below what is considered normal or desired for a healthy individual. Thrombocytopenia is known to have many causative factors, including but not limited to, radiation therapy, chemotherapy, immune therapy, immune thrombocytopenic purpura (ITP, Bussel J.
• MDS myelodysplastic syndrom
• AML aplastic anemia
• CML viral infections (including, but not limited to; HIV, hepatitis C, parvovirus) liver disease, myeloablation, bone marrow transplant, stem cell transplant, peripheral blood stem cell transplant, progenitor cell defect, polymorphisms in stem cells and progenitor cells, defects in Tpo, neutropenia (Sawai, N. J. Leukocyte Biol., 2000, 68, 137-43), dendritic cell mobilization (Kuter D. J.
• the pharmaceutically active compounds of this invention are useful in treating thrombocytopenia regardless of the factor or factors causing the condition.
• the pharmaceutically active compounds of this invention are also useful in treating thrombocytopenia when the causative factor or factors of the condition are unknown or have yet to be identified.
• Prophylactic use of the compounds of this invention is contemplated whenever a decrease in blood or blood platelets is anticipated. Prophylactic use of the compounds of this invention results in a build up of platelets or a commencement of platelet production prior to an anticipated loss of blood or blood platelets. Prophylactic uses of the compounds of this invention includes but is not limited to transplant surgery, surgery, anesthesia prior to child birth and gut protection. Human dendritic cells have been shown to express the TPO receptor (Kumamoto et al., Br. J. Haem. 1999, 105, 1025-1033) and TPO is a potent mobilizer of dendritic cells.
• the TPO mimetic compounds of the current invention are also useful as a vaccine adjuvant in that they increase the activity and mobility of dendritic cells.
• the pharmaceutically active compounds of this invention are useful as an immunological adjuvant, given in combination with an orally, transdermally or subcutaneously delivered vaccine and/or immunomodulator, by increasing the activity and mobility of dendritic cells.
• Tpo is known to have various effects including anti-apototic/survival effects on megakaryocytes, platelets and stem cells, and proliferative effects on stem cells and megakaryocytic cells (Kuter D. J. Seminars in Hematology, 2000, 37, 41-9). These Tpo activities effectively increase the number of stem and progenitor cells so that there is synergistic effects when Tpo is used in conjunction with other cytokines that induce differentiation.
• the TPO mimetic compounds of the current invention are also useful in acting on cells for survival or proliferation in conjunction with other agents known to act on cells for survival or proliferation.
• agents include but are not limited to: G-CSF, GM- CSF, TPO, M-CSF, EPO, Gro-beta, IL-11, SCF, FLT3 ligand, LIF, IL-3, IL-6, IL-1, Progenipoietin, NESP, SD-01, or IL-5 or a biologically active derivative of any of the aforementioned agents, KT6352 (Shiotsu Y. et al., Exp. Hemat. 1998, 26, 1195-1201), uteroferrin (Laurenz JC, et al.
• UT7TPO cells are a human megakaryoblastic cell line that express Tpo-R, whose survival and growth is dependent on the presence of TPO ( Komatsu et al. Blood 1996, 87,4552).
• some of the most preferred compounds of this invention were also positive in stimulating the maturation of megakaryocytes from human bone marrow cells.
• purified human CD34+ progenitor cells were incubated in liquid culture with test compounds for 10 days and the number of cells expressing the transmembrane glycoprotein CD41 (gpllb), a megakaryocytic marker, was then measured by flow cytometry (see Cwirla, S. E. et al Science, 1997, 276, 1696).
• the pharmaceutically active compounds within the scope of this invention are useful as TPO mimetics in mammals, particularly humans, in need thereof.
• the preferred compounds within the scope of the invention showed activation from about 4% to 100% control at a concentration of 0.001-10 uM in the luciferase assay.
• the preferred compounds of the invention also promoted the proliferation of UT7TPO and 32D-mpl cells at a concentration of 0.003 to 30 uM.
• the preferred compounds of the invention also showed activity in the CD41 megakaryocytic assay at a concentration of 0.003 to 30 uM.
• the present invention therefore provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof in a quantity effective to enhance platelet production.
• the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics.
• the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
• Solid or liquid pharmaceutical carriers are employed.
• Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid;.
• Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
• the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
• the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
• the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
• the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
• Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg kg of active compound, preferably 0.001 - 50 mg kg.
• the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
• Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
• Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
• Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular TPO mimetic in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
• the method of this invention of inducing TPO mimetic activity in mammals, including humans comprises administering to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention.
• the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as a TPO mimetic.
• the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.
• the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in enhancing platelet production.
• the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating thrombocytopenia.
• the invention also provides for a pharmaceutical composition for use as a TPO mimetic which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
• the invention also provides for a pharmaceutical composition for use in the treatment of thrombocytopenia which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
• a pharmaceutical composition for use in enhancing platelet production which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
• the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic.
• Contemplated Equivalents It will be appreciated by the person of ordinary skill in the art that the compounds of Formulas I and II may also exist in tautomeric forms. For example, in Formula I, the double bond that is drawn between the two nitrogen atoms exists between the lower nitrogen atom and the AR substituent.
• Tautomeric forms of the compounds of Formulas I and II are exemplified by the following Formula (IV): where the ⁇ .' groups are as defined above. All such compounds are included in the scope of the invention and inherently included in the definition of the compounds of Formulas I and II. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
• 3-Bromophenol (32.9 g, 0.19 mol) was added slowly to a cold (10°C) solution of sodium nitrate (29.0 g, 0.34 mol) in cone, sulfuric acid; (40.0 g) and water (70.0 mL) and the resulting mixture was allowed to stir at room temperature for 2h. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgS04), filtered and concentrated.
• Example le Following the procedure of Example le), except substituting 4-amino-3 - hydroxybiphenyl-3-carboxylic acid;, hydrochloride salt for 4-amino-3'-hydroxybiphenyl-4- carboxylic acid;, hydrochloride salt, the title compound was prepared 1.04 g; 62%) as an orange solid, mp 282°C (dec).
• Example 3e Following the procedure of Example le), except substituting the compound from Example 3e) for 4-amino-3'-hydroxybiphenyl-4-carboxylic acid;, hydrochloride salt, the title compound was prepared (0.055 g; 32%) as an orange solid, mp 228°C (dec).
• Example 6 2-Aza-3 - ⁇ N -ri-(4-tert-butylphenyl)-3-methyl-5-oxo-l,5-dihvdropyrazol-4- ylidenelhydrazino ⁇ -2'-hydroxybiphenyl-3-carboxylic acid; a) 6-(5-chloro-2-methoxyphenyl)-pyridine-2-carboxylic acid;: Following the procedure of Example lb), except substituting 2-methoxy-5- chlorophenylboronic acid; for 4-carboxyphenylboronic acid; , and substituting 6- bromopyridine-2-carboxylic acid; for the compound of la), the title compound was prepared (6.7 g; 100%) as a white powder. MS(ES) m/z 264 [M+H]. b) 6-(5-chloro-2-hydroxyphenyl)-pyridine-2-carboxylic acid;:
• Example 7 3-Aza-3 -IN - [ l-(4-?g? -butylphenyl)-3-methyl-5-oxo- 1 ,5-dihydropyrazol-4- ylidenelhy drazino ) -2'-hvdroxybiphenyl-5-carboxylic acid; : a) 5-(5-chloro-2-methoxyphenyl)-nicotinic acid;:
• Example 6c The compound from Example 6c) (1 g, 3.39 mmol) in ethanol was treated with tin chloride (3.2 g, 17 mmol) and refluxed for 3 hours. After quenched with 3N hydrochloride, the precipitate was collected and washed with ether, l.lg crude product was isolated. Following the procedure of Example le), except substituting the above crude product for the compound from Example lc), the title compound was prepared as powder (75%).
• Example 9 2-Aza-3 -IN- r l-(4-te -buty lpheny l)-3-methyl-5-oxo- 1 ,5-dihydropyrazol-4- ylidene1hydrazino)-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid;: a) 6-(2-hydroxy-5-methy lpheny l)-pyridine-2-carboxy lie acid;:
• Example 11 3 - ⁇ N - r 1 -(4-ter?-Butylphenyl)-3-methy 1-5-oxo- 1 ,5-dihvdropyrazol-4-ylidene1hy drazino ⁇ - 2 -hydroxy-5 -methylbiphenyl-3-carboxylic acid; : a) 2-Hydroxy-5'-methylbiphenyl-3-carboxylic acid;:
• Example lb Following the procedure of Example lb), except substituting 2-methoxy-5- methylphenylboronic acid; for 4-carboxyphenylboronic acid; and 3-bromophenylcarboxylic acid; for the compound from example la), the crude compound was isolated and treated with 1:1 of hydrobromide and acetic acid;. The reaction mixture was refluxed for 4 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The exact was dried (MgS ⁇ 4), filtered and concentrated to the title product (50%, two steps).
• Example 14 7-( ⁇ N'-[l-(3.4-dimethylphenyl)-3-methyl-5-oxo- 5-dihvdropyrazol-4-ylidenelhydrazino
• Example 15 7-( (N - [ 1 -(4-tert-butyl-phenyl)-3-methy 1-5-oxo- 1 ,5-dihy dropyrazol-4-ylidenelhy drazino ⁇ - 2-hydroxyphenyl)quinolin-4r lHl-one-3-carboxylic acid; : Following the procedure of Example 14, except substituting the compounds of 4a) for the compound of Id), the title compound was prepared (0.24 g, 40%) as solid.
• Example 17 3- Aza-3 -(N -r 1- ⁇ 3-methyH4-( l-methylethyl)phenyl]-5-oxo- 1 ,5-dihydropyrazol-4- ylidene ) hydrazino)-2 -hydroxybiphenyl-5-carboxylic acid: : a) 1 -(4-isopropy lpheny l)-3-methyl-3-pyrazolin-5-one Following the procedure of example Id), except substituting 4- isopropylphenylhydrazine hydrochloride for 3, 4-dimethy lpheny lhydrazine hydrochloride, the title compound was prepared (3.2 g; 89%).
• 0.23M aq. sodium nitrite (1 mL, 0.23 mmol) was added dropwise to a stirred suspension of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid;, hydrochloride salt (0.050 g, 0.188 mmol) in IM aq. hydrochloric acid; (2.5 mL) at 5°C.
• the mixture was stirred 10 min. and a solution of ethyl 3-methyl-3-pyrazolin-5-one-l -acetate (0.035 g, 0.188 mmol) in ethanol (3 mL) added.
• 2'-hvdroxybiphenyl-3,5-dicarboxylic acid : a) 5'-Chloro-2 -hydroxy-3'-nitrobiphenyl-3,5-dicarboxylic acid;:
• Example lb Following the procedure of Example lb), except substituting 2-methoxy-5- chlorophenylboronic acid; for 4-carboxyphenylboronic acid; , and substituting 5-bromo- isophthalic acid; for the compound of la), the crude product was isolated and treated with glacial acetic acid; (25.0 mL) and 48% aqueous hydrobromic acid; (25.0 mL) was stirred and heated under reflux for 5h. The mixture was cooled and filtered to afford the crude compound as a powder. Then, following the procedure of Example la), except substituting the above crude compound for 3-bromophenol, the title compound was prepared as solid (0.58 g; 33%, three steps) as a solid.
• Example 27 3-Aza-3 - ⁇ N -[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-1.5-dihvdropyrazol-4- ylidenelhvdrazino ⁇ -2 -hydroxy-5 -methylbiphenyl-5-carboxylic acid;: a) 5-methyl-2-methoxyphenylboronic acid;:
• Example 28 3 - ⁇ N - T l-(3 ,4-Dimethy lpheny l)-3-methyl-5-oxo- 1 ,5-dihy dropyrazol-4-ylidenelhydrazino 1 - 2'-hydroxybiphenyl-4-carboxylic acid; : a) 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-4-carboxylic acid;:
• Example le Following the procedure of Example le), except substituting the compound from Example 3e) for the compound from Example lc) and the compound from Example 30a) for the compound from Example Id) and washing the crude product with chloroform, the title compound was prepared (0.146 g; 49%) as an orange solid.
• Example 31 3-lN'-ri-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1.5-dihvdropyrazol-4-ylidenelhydrazinol- 2-hydroxy-3'-trifluoromethanesulfonamidobiphenyl a) N-(2'-methoxy-3'-nitrobiphenyl-3-yl)-acetamide: Following the procedure of example lb), except substituting 3- acetamidobenzeneboronic acid; for the compound of 4-carboxyphenylboronic acid; and 1- bromo-2-methoxyl-3-nitrobenzene for the compound of example la), the title compound was prepared as solid. (1.16 g, 98%).
• Example le Following the procedure of Example le), except substituting the compound from Example 3e) for the compound from Example lc) and the compound from Example 37a) for the compound from Example Id) and washing the crude product with chloroform, the title compound was prepared (0.253 g; 78%) as an orange solid.
• Example 34 Following the procedure of Example le), except substituting the compound from Example 3e) for the compound from Example lc) and the compound from Example 38a) for the compound from Example Id) and washing the crude product with chloroform, the title compound was prepared (0.241 g; 66%) as an orange solid. MS(ES) m/z 483 (M+H) + .
• Example 34
• Example le Following the procedure of Example le), except substituting the compound from Example 3e) for the compound from Example lc) and the compound from Example 36a) for the compound from Example Id) and washing the crude product with chloroform, the title compound was prepared (0.21 g; 58%) as an orange solid.
• the compound of example 37a) was dissolved in iodotrimethylsilane (lOmL), The reaction mixture was stirred at room temperature for 18 hrs, and then heated at 60°C for 18hrs. After cooling down to room temperature, ice water was poured in, causing precipitation. The solid was collected and further purified through Si02 chromatography (3%MeOH/CH 2 Cl 2 ). The title compound was prepared as yellow gum(0.12 g, 30%).
• Example 39 3 - ⁇ N , -[3-methyl-l-(4-methylphenyl)-5-oxo-l,5-dihydropyrazol-4-ylidene1hvdrazino ⁇ -2 - hydroxybiphenyl-3-carboxylic acid ;
• Example 40 3 - 1 N - r 1 -(4-chlorophenyl)-3-methy 1-5-oxo- 1 ,5-dihydropyrazol-4-ylidenelhy drazino 1 -2 - hydroxybiphenyl-3-carboxylic acid;
• Example 41 3 - 1 N'-r 1 -(4-fluorophenyl)-3-methyl-5-oxo- 1 ,5-dihy dropyrazol-4-ylidene]hvdrazino 1-2 - hydroxybiphenyl-3-carboxylic acid: : a) 2-(4-Fluorophenyl)-5-methyl-2,4-dihydropyrazol-3-one:
• Example 43 3 '- 1 N- 1 " 1 -(3 ,4-dimethy lphenylV 3-ethoxy-5-oxo- 1 ,5-dihydropy razol-4-y lidenelhvdrazino 1 - 2'-hydroxybiphenyl-3-carboxylic acid; a) Acetic acid; N'-(3,4-dimethylphenyl)hydrazide:
• Example 44 3 '- ⁇ N -f l-(3 ,4-dimethyl ⁇ henv l)-3-( 1 -methylethoxyV 5-oxo- 1.5-dihydropyrazol-4- ylidenelhydrazino 1-2 -hvdroxybiphenyl-3-carboxylic acid; a) 2-(3,4-dimethylphenyl)-5-isopropoxy-2,4-dihydropyrazole-3-one: Following the procedure of example 43c), except substituting isopropanol for ethanol, the title compound was prepared as a solid (0.28 g, 28%).
• Example 46 3'-
• Example 48 3'- ⁇ N-[l-(3.4-dimethylphenyl)-3-phenyl-5-oxo-l,5-dihydropyrazol-4-ylidenelhvdrazinol- 2 -hydroxybiphenyl-3-carboxylic acid;
• Example 51 3- ⁇ N'-f 1 -(3,4-dimethylphenyl)-3-ethoxy-5-oxo- 1 ,5-dihvdropyrazol-4-ylidenelhy drazino 1 -
• Example 56 3 ( N- [ 1 -(3.4-dimethylphenyl)-3-(pyridin-4-y 1-5-oxo- 1 ,5-dihvdro ⁇ yrazol-4- ylidenelhydrazino l-2'-hydroxybiphenyl-3-carbo ⁇ ylic acid:: a) 2-(3,4-Dimethylphenyl)-5-pyridin-4-yl-2,4-dihydropyrazol-3-one:
• Example 58 3- IN- T l-(3,4-dimethylphenyl)-3-pyridin-2-yl-5-oxo- 1 ,5-dihydropyrazol-4- ylidenelhvdrazino ⁇ -2-hvdroxy-3'-tetrazol-5-ylbiphenyl a) 2-(3,4-dimethylphenyl)-5-pyridin-2-yl-2,4-dihydropyrazol-3-one: Following the procedure of example Id), except substituting ethyl picolinylacetate for ethyl acetoacetate, the title compound was prepared as solid(1.5 g, 44%).
• 3-Fluoro-4-methylaniline (5.0 g, 40 mmol) was combined with a mixture of acetic acid; (125 mL), water (50 mL), and concentrated (50 mL)hydrochloric acid;. The resulting solution was cooled in an ice bath and treated portion-wise with NaNO 2 (3.1 g, 45 mmol) in water (50 mL). After the reaction mixture had stirred at low temperature for 15 minutes, it was added to a solution of tin chloride (45 g, 200 mmol) in 100 ml concentrated hydrochloric acid; that was also cooled in an ice bath. The reaction mixture was then allowed to warm to room temperature and stirred for 30 minutes.
• the resulting slurry was extracted with ethyl acetate (400 mL), and the organic layer was washed with brine and dried over magnesium sulfate. The solution was then filtered and the solvent removed under reduced pressure. The yellow solid thus obtained was partitioned between 1 M sodium hydroxide (200 mL) and ethyl acetate (600mL)and the two-phase mixture filtered and separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was taken up in diethyl ether and treated with hydrogen chloride gas.
• Example 62 3 - ⁇ N- [3-methy 1-5-oxo- 1 -(4-trifluoromethylpyrimidin-2-yl)- 1 ,5-dihydropyrazol-4- ylidenelhydrazino 1-2 -hvdroxybiphenyl-3-carboxylic acid; a) 3-methyl- l-(4-trifluoromethyl-2-pyrimidyl)-3-pyrazolin-5-one
• Example 64 3 -amino-3- ⁇ N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-1.5-dihydropyrazol-4- ylidenelhydrazino I -2-hvdro ⁇ ybiphenyl
• the compound from example 63b) (0.03 , 0.06 mmol) was treated with 0.45ml trifluoroacetic acid; in methylene chloride (5 mL). After stirring at room temperature for 2 hrs, the reaction mixture was concentrated and washed with diethyl ether to give the title compound as a red powder(0.02 g, 65%).
• Example 65
• Example 73 3 '- 1 N'- [ 1 -(3 ,4-dimethylphenyl)-5-oxo-3-trifluoromethyl- 1 ,5-dih ydropyrazol-4- ylidenelhydrazino )-2 -hvdroxybiphenyl-3-carboxylic acid; a) 3,4-dimethylphenyltrifluoromethyl-2,4-dihydropyrazol-3-one: Following the procedure of example Id), except substituting 4,4,4-trifluoro-3-oxo- butyric acid; for 3, 4-dimethy lpheny lhydrazine hydrochloride, the title compound was prepared as solid (4.0 g, 52%).
• Example 80 3-
• Example 86 3'-
• Example 88 3 -(N-fl-(3,4-dimethylphenyl)-5-oxo-3-thien-2-yl-1.5-dihvdropyrazol-4- ylidene1hvdrazino)-2'-hvdroxybiphenyl-3-carboxylic acid: a) 3-oxo-3-thiophen-2-yl-propionic acid; ethyl ester:
• Example 90 3 - ⁇ N , -[l-(3,4-dimethylphenyl)-5-oxo-3-thiazol-2-yl-l,5-dihydropyrazol-4- ylidene1hvdrazino ⁇ -2'-hydroxybiphenyl-3-carboxylic acid; a) 3-oxo-3-thiazol-2-yl-propionic acid; ethyl ester:
• Example 95 3'-jN'-r5-oxo-l-(4-trifluoromethylphenyl)-l,5-dihydropyrazol-4-ylidene1hvdrazino)-2 - hvdroxybiphenyl-3-carboxylic acid; a) l-(4-trifluoromethy lpheny l)-5-oxo-4,5-dihydro-lH-pyrazole-4-carboxylic acid; ethyl ester: Following the procedure of example ld) > except substituting diethyl(ethoxymethylene) malonate for ethyl acetoacetate and trifluoromethylhydrazine for 3, 4-dimethy lpheny lhydrazine, the title compound was prepared as a solid.
• Example 99 3 - ⁇ N-r-l-(3,4-dimethylphenyl)-5-oxo-3-thiophen-3-yl-l,5-dihydropyrazol-4- ylidenelhydrazino ⁇ -2 -hvdroxybiphenyl-3-carboxylic acid; a) 3-oxo-3-thiophen-3-yl-propionic acid; ethyl ester:
• Example 77a follows the procedure of example 77a), except substituting 3-acetylthiophene for 3- acetyl-1-methyl-pyrazole, the title compound was prepared as solid (9.8 g, 74%).
• Example 100 3'-IN-[5-oxo-l-(4-trifluoromethylphenyl)-3-thiophen-3-yl-1.5-dihydropyrazol-4- ylidenelhydrazino ⁇ -2 -hvdroxybiphenyl-3-carboxylic acid; a) 5-thiophen-3-yl-2-(4-trifluoromethy lpheny l)-2,4-dihydropyrazol-3-one :
• Example 101 3 - ⁇ N - [5-oxo- l-(4-trifluoromethylphenyl)-3-methylsulfanylmethyl- 1 ,5-dihy dropyrazol-4- ylidenelhydrazino ⁇ -2 -hy droxybiphenyI-3-carboxy lie acid; a) 5-methylsulfanyl-2-(4-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one:
• Example 102 N-(3 '- 1 N - r 1 -(3 ,4-dimethylphenyl)-3-methy 1-5-oxo- 1 ,5-dihydro-pyrazol-4- ylidenelhydrazino ) -2'-hydroxybiphenyl-3-yl)methanesulf onamide a) N-(3'-nitro-2'-hydroxybiphenyl-3-yl)-methanesulfonamide: 3 -amino-3-nitrobiphenyl-2-ol (0.37 g, 1.62 mmol) in chloroform (10 mL) was treated with methylsulfonic chloride (2.4 mmol).
• Example 103 3 -f N'-( 1 -benzo[ 1 ,31dioxol-5-yl-3-methyl-5-oxo- 1 ,5-dihvdropyrazol-4-ylidene)hydrazinol- 2'-hvdroxybiphenyl-3-carboxylic acid; a) 2-benzo[l,3]dioxol-5-yl-5-methyl ⁇ 2,4-dihydropyrazole-3-one:
• Aqueous sodium nitrite (0.69 g, 10 mmol) was added slowly to a stirred solution of [l,3]dioxol-5-phenylaniline (1.27 g, lOmmol) in aqueous HCl (0.5 mL) at -10°C to -20°C over 20 min. Then a solution of tin chloride in aqueous HCl was added rapidly. After 30 min. at -20°C, the solid was collected and washed with diethyl ether to afford a crude product.
• Example 104 3'-(N'-ri-(3,5-dimethylphenyl)-3-methyl-5-oxo-l,5-dihvdropyrazol-4-ylidenelhvdrazino
• Example 105 3 -(N'-ri-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydropyrazol-4-ylidenelhvdrazino ⁇ - 4'-hydroxybiphenyl-4-carboxylic acid; a) 3'-nitro-4'-hydroxybiphenyl-4-carboxylic acid;: follow the procedure of example 7c), except substituting 4'-hydroxybiphenyl-4- carboxylic acid; for 6-(5-chloro-2-hydroxyphenyl)-pyridine-2-carboxylic acid;, the title compound was prepared as a solid (1 g, 84 %). MS(ES) m/z 260 (M+H) + . b) 3 -amino-4'-hydroxybiphenyl-4-carboxylic acid;:
• Example 106 3 -fN'-ri-(3-chloro-4-methylphenyl)-3-methyl-5-oxo-1.5-dihvdropyrazol-4- ylidenelhydrazino ⁇ -2 -hydroxybiphenyl-3-carboxylic acid; a) 2-(3-chloro-4-methylphenyl)-5-methyl-2,4-dihydropyrazol-3-one:
• Example 107 3 '- ( N - T 1 -(3,4-dimethy lpheny l)-3-methy 1-5-OXO- 1 ,5-dihydropyrazol-4-ylidenelhydrazino ⁇ - 4 -hydroxybiphenyl-3-carboxylic acid; a) 3'-amino-4'-hydroxybiphenyl-3-carboxylic acid;:
• Example 109 3 - ⁇ N'-ri-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihvdropyrazol-4-ylidenelhvdrazino ⁇ - 2 -hvdroxybiphenyl-3,4-dicarboxylic acid; a) 5 -Chloro-2'-methoxy-biphenyl-3,4-dicarboxylic acid;:
• Example 110 2 ,6-dihydroxy-3 '- ⁇ N '- ⁇ 1 -(3 ,4-dimethy lphenyl)-3-methyl-5-oxo- 1 ,5-dihy dropyrazol-4- ylidenelhydrazino ⁇ biphenyl-3-carboxylic acid; a) 5'-Chloro-4-hydroxy-2 -methoxy-biphenyl-3-carboxylic acid;:
• Example 111 4-aza-3 - ⁇ N '- [ l-(3,4-dimethylphenyl)-3-methyl-5-oxo- 1 ,5-dihy dropyrazol-4- ylidene]hy drazino ⁇ -2-hy droxybiphenyl-5-carboxy lie acid; a) 2-(5-chloro-2-methoxyphenyl)isonicotinic acid;:
• Example 112 3 - ⁇ N'-[l-(3,4-dimethylphenyl)-5-oxo-l,5-dihydropyrazol-4-ylidene]hydrazino ⁇ -2- hydroxybipheny 1-3-carboxylic acid ; a) l-(3,4-dimethylphenyl)-l,2-dihydropyrazol-3-one A suspension of 3,4-dimethylphenylhydrazine hydrochloride (2.0 g; 0.012 mol.) and potassium carbonate (3.2 g; 0.023 mol.) in anhydrous ethanol (40.0 mL) was treated dropwise with diethyl(ethoxymethyleen)malonate (2.5 g; 0.012 mol.) and the mixture stirred and heated under reflux for 3 h.
• Example 113 3 '- ⁇ N'-f l-(3,4-dimethylphenyl)-3-methyl-5-oxo- 1 ,5-dihydropyrazol-4-ylidene]hy drazino 1 - 2'-hydroxybiphenyl-3-sulfonic acid; a) 5 -chloro-2'-methoxybiphenyl-3-sulfonic acid;:
• Example 1 lOd for the compound from example lc), the title compound was obtained as a red solid (0.01 g). MS(ES) m/z 479 (M+H).
• Example 1(e) Following the procedure of Example 1(e) except substituting the compound from Example 114(d) for the compound from Example 1(c), the title compound was prepared (52 mg; 100%) as a brown solid. MS(ES+) m/e 526 [M+Hf.
• Example 115- Capsule Composition An oral dosage form for administering a presently invented agonist of the TPO receptor is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below. Table I
• Example 116 - Injectable Parenteral Composition An injectable form for administering a presently invented agonist of the TPO receptor is produced by stirring 1.5% by weight of 4'- ⁇ N'-[l-(3,4-dimethylphenyl)-3- methyl-5-oxo-l,5-dihydropyrazol-4-ylidene]hydrazino ⁇ -3'-hydroxybiphenyl-3-carboxylic acid; (Compound of Example 2) in 10% by volume propylene glycol in water.
• Example 117 - Tablet Composition The sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor, as shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
• Preferred among the compounds of the present invention are the following; 3 '- ⁇ N- [3-cyclopropy 1- 1 -(3, 4-dimethy lpheny l)-5-oxo- 1 ,5-dihy dropyrazol-4- ylidene]hydrazino ⁇ -2'-hydroxybiphenyl-3-carboxylic acid;

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