US20070293525A1 - 2-anilino-4-aminoalkyleneaminopyrimidines - Google Patents

2-anilino-4-aminoalkyleneaminopyrimidines Download PDF

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US20070293525A1
US20070293525A1 US11/762,406 US76240607A US2007293525A1 US 20070293525 A1 US20070293525 A1 US 20070293525A1 US 76240607 A US76240607 A US 76240607A US 2007293525 A1 US2007293525 A1 US 2007293525A1
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diamine
pyrimidine
dimethylamino
propyl
ethyl
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Jane Djung
Adam Golebiowski
Jack Hunter
Gary Shrum
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority to US12/411,760 priority patent/US8158641B2/en
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    • A61K31/4164—1,3-Diazoles
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • PKC ⁇ , ⁇ I, ⁇ II, and ⁇ are calcium- and lipid-activated, while the novel isozymes ( ⁇ , ⁇ , ⁇ , and ⁇ ) and atypical isozymes ( ⁇ , ⁇ , ⁇ , and ⁇ ) are calcium independent but activated by distinct lipids.
  • Alterations in PKC activity has been suggested to contribute to human diseases, inter alia, diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases and heart failure and inhibition of PKC in these settings could be used to treat or prevent human disease. Lending support to the modulation of PKC in cardiac disease, PKC activation has been associated with cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and mitogen stimulation.
  • the risk of death due to heart failure is 5-10% annually in patients with mild symptoms of heart failure, and increases to 30-40% annually in patients with advanced heart failure, with a 50% overall mortality rate at 5 years.
  • the current mainstays of heart failure therapy are drugs that act on the renin-angiotensin-aldosterone system (ACEI, ARB, aldosterone inhibitor), diuretics, digoxin and ⁇ -adrenergic receptor blockers.
  • ACEI renin-angiotensin-aldosterone system
  • diuretics diuretics
  • digoxin and ⁇ -adrenergic receptor blockers Despite the fact that multiple drug classes are used to treat heart failure patients, new cases of heart failure are growing at over 10% per year.
  • ADHF acute decompensated heart failure
  • the primary function of the heart is to generate and sustain an arterial blood pressure necessary to provide adequate perfusion of organs. It has, therefore, become an area of intense investigation to decipher the mechanism(s) which initiate and contribute to the development of heart failure rather than relying on a means for treating the symptoms of heart failure alone.
  • cardiomyocyte cardiac contractile cells
  • impaired calcium cycling is a hallmark of heart failure as is the basis of contractile abnormalities.
  • Calcium plays a key role in regulating kinases, phosphatases and transcription factors believed to influence the remodeling process indicating that both acute and sustained alterations in intracellular calcium levels may have profound effect on cardiac function and remodeling (i.e., changes in wall thickness or chamber volume). This theory would support the proposition that the development of new therapies addressing the slowing and preventing of the disease progression, would be perhaps more effective against heart failure than palliation of heart failure.
  • the present invention meets the aforementioned needs in that it has been found that certain 2-arylamino-4-(aminoalkylene)aminopyrimidines are effective for inhibiting Protein Kinase C-alpha (PKC- ⁇ ) thereby improving myocardial contraction and relaxation performance and slowing the progression of heart failure.
  • PKC- ⁇ Protein Kinase C-alpha
  • the present invention encompasses three major aspects each of which have their own separate categories, aspects, iterations, and specific iterative examples.
  • the major aspects of the present invention include:
  • the first aspect of the present invention as a whole, relates to compounds, which include all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof; said compounds having the formula:
  • R is a unit having the formula:
  • R 2 and R 3 are each independently chosen from:
  • L is a linking unit having the formula: —[C(R 4a R 4b )] n —
  • each R 4 is independently chosen from
  • the index n is from 1 to 4.
  • R 1 is substituted or unsubstituted aryl.
  • compositions comprising:
  • the third major aspect of the present invention relates to methods of use.
  • the PKC- ⁇ inhibitors of the present invention are important for improving myocardial contraction and relaxation performance and thereby slowing the progression of heart failure and their administration to humans is, therefore, an effective treatment for humans suffering from acute heart failure.
  • the present invention addresses several unmet medical needs, inter alia:
  • PKC- ⁇ inhibitors of the present invention which are capable of blocking Protein Kinase C-alpha from impairing sarcoplasmic reticulum Ca 2+ uptake.
  • hydrocarbyl stands for any carbon atom-based unit (organic molecule), said units optionally containing one or more organic functional group, including inorganic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts.
  • organic hydrocarbyl Within the broad meaning of the term “hydrocarbyl” are the classes “acyclic hydrocarbyl” and “cyclic hydrocarbyl” which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.
  • cyclic hydrocarbyl units may comprise only carbon atoms in the ring (hydrocarbyl and aryl rings) or may comprise one or more heteroatoms in the ring (heterocyclic and heteroaryl).
  • hydrocarbyl rings the lowest number of carbon atoms in a ring are 3 carbon atoms; cyclopropyl.
  • aryl the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl.
  • heterocyclic the lowest number of carbon atoms in a ring is 1 carbon atom; diazirinyl, epoxy.
  • heteroaryl rings the lowest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl.
  • acyclic hydrocarbyl and “cyclic hydrocarbyl” as used herein.
  • fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1,2,3,4-tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit.
  • 6,7-Dihydro-5H-cyclopentapyrimidine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • the aryl ring will predominate and determine the type of category to which the ring is assigned.
  • 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • Three hydrogen replacement includes cyano, and the like.
  • substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced.
  • 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”
  • (N,N-dimethyl-5-amino)octanyl is a “substituted C 8 alkyl unit
  • 3-guanidinopropyl is a “substituted C 3 alkyl unit”
  • 2-carboxypyridinyl is a “substituted heteroaryl unit.”
  • R 5 units according to the present invention include the following:
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N—(C 1 -C 4 alkyl) 4 + salts.
  • R 1 is substituted or unsubstituted aryl having the formula: wherein R 5 represents one or more (from 1 to 5) optionally present, and independently selected, substitutes for hydrogen as outlined herein above and described in the categories, aspects, iterations, examples, and tables herein below.
  • R 1 units which are biphenyl wherein R 5 is phenyl, for example, a compound having the formula:
  • R 1 units which are substituted biphenyl non-limiting examples of which include 2′-fluoro-biphenyl-2-yl, 2′-fluoro-biphenyl-3-yl, 2′-fluoro-biphenyl-4-yl, 3′-fluoro-biphenyl-2-yl, 3′-fluoro-biphenyl-3-yl, 3′-fluoro-biphenyl-4-yl, 4′-fluoro-biphenyl-2-yl, 4′-fluoro-biphenyl-3-yl, 4′-fluoro-biphenyl-4-yl, 2′-chloro-biphenyl-2-yl, 2′-chloro-biphenyl-3-yl, 2′-chloro-biphenyl-4-yl, 3′-chloro-biphenyl-2-yl, 3′-chloro-biphenyl, 3′
  • the third category of R 1 units relates to phenyl units which are substituted by one or more R 5 units which are substituted or unsubstituted C 3 , C 4 or C 5 heteroaryl units.
  • Non-limiting examples of this aspect of the third category of R 1 include imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, and the like.
  • the first category of L units relates to unsubstituted alkylene units chosen from:
  • the first aspect of the first category of L units encompasses linking groups which are —CH 2 CH 2 CH 2 —, propylene; as exemplified in the generic formula:
  • the second aspect of the first category of L units encompasses linking groups which are —CH 2 CH 2 —, ethylene.
  • the second category of L units relates to alkyl substituted alkylene units chosen from:
  • the first aspect of the second category of L units encompasses linking groups which are —CH(CH 3 )CH 2 CH 2 —, 1-methylpropylene; as exemplified in the generic formula: wherein the above formula encompasses both the R and the S enantiomers of the linking unit.
  • 2-(Substituted or unsubstituted phenylamino)-4-chloro-pyrimidine To a 2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one (5.02 g, 22.6 mmol) and N,N-dimethyl-aniline (450 mL) is added of phosphorus oxychloride (450 mL). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue is neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3 ⁇ 250 mL). The combined organic layers are dried (MgSO 4 ) and concentrated in vacuo. The residue can be conveniently purified over silica (5% EtOAc in hexanes) to afford the desired compound.
  • 2-(Substituted or unsubstituted phenylamino)-4-chloro-pyrimidine To a 2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one (3.00 g, 13.5 mmol) in toluene (30 mL) is added N,N-dimethyl-aniline (3.57 mL, 28.4 mmol) and phosphorus oxychloride (1.24 mL, 13.5 mmol). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3 ⁇ 250 mL). The combined organic layers are dried (MgSO 4 ) and concentrated in vacuo. The residue can be conveniently purified over silica (5% EtOAc in hexanes) to afford the desired compound.
  • analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein.
  • the arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
  • R, R 1 , and R 2 are defined herein below in Table I. TABLE I No R R 1 R 2 1 3-chlorophenyl —H —H 2 3-chlorophenyl —CH 3 —H 3 3-chlorophenyl —CH 3 —CH 3 4 3-chlorophenyl —CH 2 CH 3 —H 5 3-chlorophenyl —CH 2 CH 3 —CH 3 6 3-chlorophenyl —CH 2 CH 3 —CH 2 CH 3 7 4-chlorophenyl —H —H 8 4-chlorophenyl —CH 3 —H 9 4-chlorophenyl —CH 3 —CH 3 10 4-chlorophenyl —CH 2 CH 3 —H 11 4-chlorophenyl —CH 2 CH 3 —CH 3 12 4-chlorophenyl —CH 2 CH 3 —CH 2 CH 3 13 3,4-dichlorophenyl —H —H 14 3,4-dichlorophen
  • N 2 -(3-chlorophenyl)-N 4 -(3-(methylamino)propyl)pyrimidine-2,4-diamine 1 H NMR (CD 3 OD, 300 MHz): ⁇ 2.02-2.11 (m, 2H), 2.72 (s, 3H), 3.06-3.11 (m, 2H), 3.60-3.65 (m, 2H), 6.32-6.34 (m, 1H), 7.29-7.51 (m, 3H), 7.72-7.79 (m, 2H).
  • the compounds which comprise Category II of the present invention are 2-(substituted phenylamino)-4-(amino- or substituted amino-ethylene, or substituted amino-butylene)-aminopyrimidines having the formula:
  • R 2 , R 3 , R 5 , and L are defined herein below in Table II. TABLE II No. L R 2 R 3 R 5 61 —CH 2 — —H —H 3-chloro 62 —CH 2 — —CH 3 —H 3-chloro 63 —CH 2 — —CH 3 —CH 3 3-chloro 64 —CH 2 — —CH 2 CH 3 —H 3-chloro 65 —CH 2 — —CH 2 CH 3 —CH 3 3-chloro 66 —CH 2 — —CH 2 CH 3 —CH 2 CH 3 3-chloro 67 —CH 2 CH 2 — —H —H 3-chloro 68 —CH 2 CH 2 — —CH 3 —H 3-chloro 69 —CH 2 CH 2 — —CH 3 —CH 3 3-chloro 70 —CH 2 CH 2 — —CH 2 CH 3 —H 3-chloro 71 —CH 2 CH 2 — —
  • the reaction is cooled to room temperature and partitioned between EtOAc and water.
  • the organic layer is dried (MgSO 4 ), concentrated in vacuo, and purified over silica (5% MeOH ramped to 6% MeOH in CH 2 Cl 2 with 0.7% added triethylamine) to give an oil.
  • the oil is dissolved in MeOH (0.5 mL) and Et 2 O (20 mL) and cooled to 0° C. To this solution is added a solution of 4M HCl in dioxane (0.25 mL) in one portion.
  • the reaction is cooled to room temperature and concentrated in vacuo to afford a residue which is purified over silica (95:3:2 CH 2 Cl 2 MeOH/7N NH 3 in MeOH) to afford 61 mg (48% yield) of the desired compound.
  • the hydrochloride salt can be formed by treatment of the neutral compound with HCl in dioxane (4M).
  • the reaction is cooled to room temperature and partitioned between EtOAc and water.
  • the organic layer is dried (MgSO 4 ), concentrated in vacuo, and purified over silica (5% MeOH ramped to 6% MeOH in CH 2 Cl 2 with 0.7% added triethylamine) to give an oil.
  • the oil is dissolved in MeOH (0.5 mL) and Et 2 O (20 mL) and cooled to 0° C. To this solution is added a solution of 4M HCl in dioxane (0.25 mL) in one portion.
  • the compounds of the present invention are inhibitors of Protein Kinase C-alpha (PKC- ⁇ ), therefore, they are PKC- ⁇ inhibitors which are capable of improving myocardial contraction and relaxation performance and slow the progression of heart failure.
  • PKC- ⁇ Protein Kinase C-alpha
  • the compounds potentially inhibit additional isoforms of conventional PKC, such as PKC- ⁇ or PKc- ⁇ . This is not undesired and can lead to increased pharmacological effects.
  • compositions or formulations which comprise the PKC- ⁇ inhibitors according to the present invention comprise:
  • compositions according to the present invention include:
  • an effective amount means “an amount of one or more PKC- ⁇ inhibitors, effective at dosages and for periods of time necessary to achieve the desired result.”
  • An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.
  • dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the compositions of the present invention can be administered as frequently as necessary to achieve a therapeutic amount.
  • the present invention also relates to a method for improving cardiac contraction/relaxation parameters in heart failure patients and/or attenuating adverse cardiac remodeling and prevent or slow the progression of worsening heart failure.
  • the present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the PKC- ⁇ inhibitors according to the present invention.
  • a present invention also relates to a method of treating or preventing chronic or acute heart failure, said method comprised of the step of administering to a patient in need thereof a pharmaceutically acceptable amount of a compound according to claim 1 or a therapeutically acceptable salt thereof in combination with a drug selected that acts on the renin-angiotensin-aldosterone system, a diuretic, digoxin or a ⁇ -adrenergic receptor blockers, natriuretic peptides and inotropic agents.
  • BSA bovine serum albumin
  • EDTA ethylenediaminetetraacetic acid
  • the reaction is initiated by addition of adenosine triphosphate (ATP; final concentration 45 ⁇ M) and a peptide substrate consisting of amino acids 28-43 (Ala-Ala-Lys-Ile-Gln-Ala-Ser-Phe-Arg-Gly-His-Met-Ala-Arg-Lys-Lys) of neurogranin (Promega; final concentration 22 ⁇ M). After a 30 minute incubation at 24° C.
  • ATP adenosine triphosphate
  • a peptide substrate consisting of amino acids 28-43 (Ala-Ala-Lys-Ile-Gln-Ala-Ser-Phe-Arg-Gly-His-Met-Ala-Arg-Lys-Lys) of neurogranin (Promega; final concentration 22 ⁇ M).
  • spectra are collected on an Applied Biosystems 4700 Proteomics Analyzer MALDI-TOF MS equipped with a Nd:YAG laser (355 nm, 3 ns pulse width, 200 Hz repetition rate) in negative ion reflector mode.
  • the system is operated with 4700 Explorer software, version 3.0.
  • Automated acquisition parameters are adjusted to capture and average only those individual spectra within defined success criteria. Specifically, signal intensities for the substrate peptide are set to a minimum threshold of 3000 counts and a maximum intensity of 65,000 counts. This ensured that neither null spectra nor saturated spectra are averaged into the final readout. Between 1000 and 1500 laser shots are averaged for each sample. Data are collected in triplicate from 3 successive days to capture the maximum variability related to preparation of enzyme reaction, transfer of samples to MALDI target plates, data collection, and data extraction.
  • the isotope cluster areas for each peptide substrate and product peaks are extracted into a Microsoft Excel worksheet from the 10 ⁇ 10 array of spectral data simultaneously using the automated analysis function provided within the 4700 Explore software.
  • the isotope cluster area is defined by the software algorithm based on the molecular weight and the general elemental composition of the peptides.
  • the medium is removed and replaced with serum free Claycomb medium supplemented with 200 mM glutamine containing different concentrations of compound at a final volume of 50 ⁇ l.
  • Compounds are dissolved in 100% dimethylsulfoxide (DMSO) and final DMSO concentrations are maintained at 0.5%. Plates are then incubated for 30 minutes at 37° C. in a 5% CO 2 incubator. The medium is then removed and the plates are rinsed 1 ⁇ with ice-cold 100 ⁇ l PBS.
  • DMSO dimethylsulfoxide
  • the PBS is removed and replaced with 10 ⁇ l of ice-cold lysis buffer consisting of B-PERII detergent (Pierce) diluted 1:1 in distilled water and including a final concentration of 0.3% ( ⁇ -mercaptoethanol, 50 ⁇ g/ml phenylmethylsulfonylfluoride (PMSF) 10 mM benzamidine, 10 nM okadaic acid, 20 ⁇ g/ml leupeptin and 20 ⁇ g/ml soybean trypsin inhibitor.
  • the plates are gently mixed for 10-20 minutes at 4° C.
  • 90N1 of coactivation buffer consisting of 0.1 mg/ml BSA, 250 ⁇ M EDTA, 400 ⁇ M CaCl 2 , is added to each well.
  • a thoracotomy is performed at the fourth intercostal space to visualize the heart, the pericardium is opened and a suture is placed around the left anterior descending (LAD) coronary artery approximately 3-4 mm from its origin.
  • LAD left anterior descending
  • the LAD is permanently ligated to induce a myocardial infarction.
  • Severe arrhythmia are treated with the administration of lidocaine.
  • cardiac function stabilized approximately 40-60 min after ligation and baseline hemodynamic values are measured.
  • the effects of treatment are normalized to pre-treatment baseline values and expressed as a percentage.
  • Statistical significance (p ⁇ 0.05) is evaluated using one-way ANOVA and Dunnett's multiple comparison test.
  • Selected PKC ⁇ inhibitors are evaluated in rats with myocardial infarction (MI) for effects on cardiac contractility and hemodynamics.
  • MI myocardial infarction
  • the effects of inhibitors on cardiac contractility and hemodynamics are evaluated in MI rats as follows.
  • the animals are anesthetized with isoflurane.
  • a femoral artery is isolated and cannulated for the measurement of systemic blood pressure.
  • a jugular vein is isolated and cannulated for the intravenous infusion of inhibitor.
  • the right carotid artery is isolated and a Millar conductance catheter is inserted to the left ventricle (LV) of the heart.
  • the LV systolic pressure, end-diastolic pressure, +dP/dt max , ⁇ dP/dt min , and heart rate are derived from the LV pressure waveform.
  • Mean arterial blood pressure is derived from the systemic blood pressure waveform. Data are recorded continuously and derived using computerized data acquisition software (Notocord or Powerlab).
  • PKC- ⁇ inhibitors are infused at the following infusion doses in MI rats: 10, 30, 100, 300 and 1000 nmol/kg/min. The infusion of each dose is allowed to run for at least five minutes. At the end of the test infusions, 5.0 ⁇ g/kg/min of dobutamine is infused. The effects of treatment are normalized to pretreatment baseline values and expressed as a percentage. Statistical significance (p ⁇ 0.05) is evaluated using a one-way ANOVA and Dunnett's multiple comparison test.
  • Table IV provides non-limiting examples of PKC- ⁇ IC 50 values for representative compounds of the present invention. TABLE IV PKC- ⁇ No. Compound IC 50 (nM) 1 N 2 -(3-chlorophenyl)-N 4 -(3-aminopropyl)pyrimidine-2,4-diamine 312 2 N 2 -(3-chlorophenyl)-N 4 -[3-(methylamino)propyl]pyrimidine-2,4- 4 diamine 3 N 2 -(3-chlorophenyl)-N 4 -[3-(dimethylamino)propyl]pyrimidine-2,4- 0.8 diamine 6 N 2 -(3-chlorophenyl)-N 4 -[3-(diethylamino)propyl]pyrimidine-2,4- 1 diamine 15 N 2 -(3,4-dichlorophenyl)-N 4 -[3-(dimethylamino)propyl

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KR101876514B1 (ko) * 2016-11-08 2018-07-10 한국화학연구원 신규한 피리미딘화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암 및 염증질환의 예방 또는 치료용 약학적 조성물
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US10752699B2 (en) 2015-06-29 2020-08-25 Regents Of The University Of Minnesota Anti-APOBEC3 antibodies and methods of making and using

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