US20070293494A1 - 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines - Google Patents

2-Anilino-4-(Heterocyclic) Amino-Pyrimidines Download PDF

Info

Publication number
US20070293494A1
US20070293494A1 US11/762,394 US76239407A US2007293494A1 US 20070293494 A1 US20070293494 A1 US 20070293494A1 US 76239407 A US76239407 A US 76239407A US 2007293494 A1 US2007293494 A1 US 2007293494A1
Authority
US
United States
Prior art keywords
pyrimidine
diamine
propyl
phenyl
biphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/762,394
Other languages
English (en)
Inventor
Jane Djung
Adam Golebiowski
Jack Hunter
Gary Shrum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38608732&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070293494(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US11/762,394 priority Critical patent/US20070293494A1/en
Publication of US20070293494A1 publication Critical patent/US20070293494A1/en
Priority to US12/465,704 priority patent/US8354407B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 2-arylamino-4-(heterocyclic)aminopyrimidines which are inhibitors of Protein Kinase C-alpha (PKC- ⁇ ).
  • PKC- ⁇ inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure.
  • the present invention further relates to compositions comprising said 2-arylamino-4-(heterocyclic)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • DAG diacylglycerol
  • PKC protein kinase C family of calcium and/or lipid-activated serine-threonine kinases function downstream of nearly all membrane-associated signal transduction pathways.
  • 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.
  • GPCR G ⁇ q-coupled G-protein coupled receptors
  • PLC phospholipase C
  • IP 3 and DAG can activate the different isoforms of PKC by mobilizing calcium (calcium sensitive enzymes) or by directly activating PKC, respectively.
  • RACKs Receptor for Activated C Kinases
  • 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.
  • Heart disease is the leading cause of death in industrialized countries. Historically heart failure (HF) has been a product of hypertension, coronary heart disease, genetic disorders, valvular deformities, diabetes or cardiomyopathy. While the root cause of heart failure is multifaceted, it uniformly is marked by impaired diastolic and/or systolic function and can be accompanied by chamber enlargement which ultimately manifest in symptomatic heart failure (fatigue, pulmonary edema, circulatory congestion, etc.)
  • 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-(heterocyclic)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 four 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:
  • 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 fourth major aspect of the present invention relates to a process for preparing the PKC- ⁇ inhibitors of the present invention.
  • 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 atoms 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 the lowest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl.
  • 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.
  • substituted is used throughout the specification.
  • substituted is defined herein as “a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.”
  • the units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • 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 replacements 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 a cyclic or acyclic hydrocarbyl unit, described herein below as R 5 units, wherein in the non-limiting examples provided herein below, R 12 is hydrogen, C 1 -C 10 linear or branched alkyl, C 2 -C 10 linear or branched alkenyl, C 2 -C 10 linear or branched alkynyl, and C 6 or C 10 aryl.
  • R 5 units according to the present invention may include the following substitutions either comprising R 5 itself or when R 5 comprises an R 6 unit which is bonded to the core phenyl unit by a linking unit:
  • the compounds of the present invention are 2-arylamino-4-(heterocyclicalkylene)-aminopyrimidines having the core scaffold: which includes a core pyrimidine ring and a core phenyl ring 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.
  • the unit R 1 which contains the core phenyl ring may be depicted throughout the specification and claims equally well by the following general formulae: wherein R, R 1 , R 5 , R 6 , L, L 1 and y are further described herein below.
  • R units are substituted or unsubstituted heterocyclic units containing from 3 to 7 atoms.
  • the first category of R units relates to heterocyclic units wherein the linking group L is bonded to a nitrogen atom, said units having the formula: wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents.
  • the first aspect of category one of R units relates to C 3 , C 4 and C 5 unsubstituted heterocycles.
  • Non-limiting examples of this aspect includes units chosen from pyrrolidin-1-yl, pyrrolin-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, pyrazolin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
  • the second aspect of category one of R units relates to C 3 , C 4 and C 5 substituted heterocycles.
  • Non-limiting examples of this aspect includes units chosen from 5,5-di-methyl-imidazolin-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, and 4-methane-sulfonyl-piperazin-1-yl.
  • the second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, the first aspect of said units having the formula: wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
  • One iteration of the first aspect of category two of R units relates to C 3 , C 4 and C 5 substituted or unsubstituted heterocycles non-limiting examples of which include units chosen from pyrrolidin-2-yl, N-methyl-pyrrolidin-2-yl, N-methyl-pyrrolidin-2-one-5-yl, pyrrolin-2-yl, imidazolidin-2-yl, imidazolin-2-yl, pyrazolidin-2-yl, pyrazolin-2-yl, piperidin-2-yl, N-methylpiperidin-2-yl, morpholin-3-yl, and N-methylmorpholin-3-yl.
  • a further iteration of the first aspect of category two of R units relates to C 3 , C 4 and C 5 substituted or unsubstituted heterocycles having a chiral center in the R units and wherein a particular enantiomer is selected, for example, one of the two enantiomeric R units having the formula:
  • the second aspect of the second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, said units having the formula: wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
  • R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
  • Non-limiting examples of this aspect includes pyrrolidin-3-yl, N-methyl-pyrrolidin-3-yl, piperidin-3-yl, N-methylpiperidin-3-yl, morpholin-2-yl, and N-methylmorpholin-2-yl.
  • the third aspect of the second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, said units having the formula: wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
  • R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
  • Non-limiting examples of this aspect include piperidin-4-yl, N-methylpiperidin-4-yl, and 2,2,6,6-tetramethyl-piperidin-4-yl.
  • R 1 is substituted or unsubstituted phenyl having the formula:
  • R 5 is hydrogen or one or more independently chosen substitutes for hydrogen, R 5 has the formula: -(L 1 ) y -R 6 the index y has the value 0 when L 1 is absent, and the value 1 when L 1 is present;
  • R 6 is a unit chosen from:
  • the first category of R 1 relates to substituted phenyl units wherein L 1 is absent (the index y is equal to 0) and R 5 comprises one or more substitutes for hydrogen each of which is independently chosen from:
  • the first aspect of Category one of R 1 relates to units which are substituted by one or more units from groups (ii)-(vii).
  • Non-limiting examples of this aspect include 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chloro-phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-ethylphenyl, and 3-isopropylphenyl.
  • the second aspect of Category one of R 1 relates to units which are substituted by one or more halogen atom, for example, —F, —Cl, —Br, and —I.
  • Non-limiting examples of this aspect include 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichloro-phenyl, 2,3,4-trichlorophenyl
  • the third aspect of Category one of R 1 relates to units which are substituted by one or more C 1 -C 4 linear or branched alkyl, for example, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), and tert-butyl (C 4 ).
  • C 1 -C 4 linear or branched alkyl for example, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), and tert-butyl (C 4 ).
  • Non-limiting examples of this aspect include 2-methylphenyl, 4-methylphenyl, 2,3-dimethyl-phenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethyl-phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethyl-phenyl, 2,3,6-trimethylphenyl, 2,4,5-tri-methylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethyl-phenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, and 2,4,6-tri
  • the fourth aspect of Category one of R 1 relates to units which are substituted by one or more C 1 -C 4 linear or branched alkoxy, for example, methoxy (C 1 ), ethoxy (C 2 ), n-propoxy (C 3 ), iso-propoxy (C 3 ), n-butoxy (C 4 ), sec-butoxy (C 4 ), iso-butoxy (C 4 ), and tert-butoxy (C 4 ).
  • Non-limiting examples of this aspect include 2-methoxyphenyl, 4-methoxy-phenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-di-methoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, and 2,4,6-trimethoxyphenyl.
  • the fifth aspect of Category one of R 1 relates to units which are substituted by one or more hydroxy units, non-limiting examples of this aspect include 2-hydroxy-phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxy-phenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, and 2,4,6-trihydroxyphenyl.
  • R 1 Other aspects of Category one of R 1 include combinations of R 1 substituents which comprise substitute classes (ii)-(vii) not specifically exemplified herein.
  • the second category of R 1 relates to substituted core phenyl units wherein the index y is equal to 0 or 1 and R 5 comprises one or more substitutes for hydrogen each of which is independently chosen from units which comprise:
  • Substituted or unsubstituted phenyl units are present in the second category of R 1 when linked to the core phenyl units by way of a linking unit L 1 .
  • the core C 3 -C 9 heteroaryl rings of the second category of R 1 encompass the following non-limiting examples of substituted and unsubstituted rings: triazinyl (C 3 ), thiazoyl (C 3 ), 1H-imidazoyl (C 3 ), furanyl (C 4 ), thiophenyl (C 4 ), pyrimidinyl (C 4 ), 2-phenylpyrimidinyl (C 4 ), pyridinyl (C 5 ), 3-methylpyridinyl (C 5 ), 4-dimethylamino-pyridinyl (C 5 ), 7H-purinyl (C 5 ), 9H-purinyl (C 5 ), 6-amino-9H-purinyl (C 5 ), 5H-pyrrolo[3,2-d]pyrimidinyl (C 6 ), 7H-pyrrolo[2,3-d]pyrimidinyl (C 6 ), pyrido[2,3-d]pyrimidiny
  • the first aspect of the second category of R 1 relates to units wherein the linking unit L 1 is absent (the index y is equal to 0), non-limiting examples of which include units chosen from: 2-(pyrimidin-2-yl)phenyl, 2-(pyrimidin-3-yl)phenyl, 2-(pyrimidin-4-yl)phenyl, 3-(pyrimidin-2-yl)phenyl, 3-(pyrimidin-3-yl)phenyl, 3-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-3-yl)phenyl, 4-(pyrimidin-4-yl)phenyl, 2-(pyridin-2-yl)phenyl, 2-(pyridin-3-yl)phenyl, 2-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl
  • the second aspect of the second category of R 1 relates to units wherein L 1 is a unit having the formula: —[CH 2 ] j — wherein the index j is equal to 1 or 2, non-limiting examples of which include units chosen from: 2-[(pyrimidin-2-yl)phenyl]methyl, 2-[(pyrimidin-3-yl)phenyl]methyl, 2-[(pyrimidin-4-yl)phenyl]methyl, 3-[(pyrimidin-2-yl)phenyl]methyl, 3-[(pyrimidin-3-yl)phenyl]methyl, 3-[(pyrimidin-4-yl)phenyl]methyl, 4-[(pyrimidin-2-yl)phenyl]methyl, 4-[(pyrimidin-3-yl)phenyl]methyl, 4-[(pyrimidin-4-yl)phenyl]methyl, 2-[(pyridin-2-yl)phenyl]methyl, 2-[(pyridin-3-yl)phenyl]methyl, 2-[(pyridin-4
  • the third aspect of the second category of R 1 relates to units wherein L 1 is a unit having the formula: —O[CH 2 ] k — wherein the index k is equal to 1 or 2, non-limiting examples of which include R 5 units chosen from: 2-(pyrimidin-2-yl)phenyl, 2-(pyrimidin-3-yl)phenyl, 2-(pyrimidin-4-yl)phenyl, 3-(pyrimidin-2-yl)phenyl, 3-(pyrimidin-3-yl)phenyl, 3-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-3-yl)phenyl, 4-(pyrimidin-4-yl)phenyl, 2-(pyridin-2-yl)phenyl, 2-(pyridin-3-yl)phenyl, 2-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl
  • the fourth aspect of the second category of R 1 relates to units wherein L 1 is a unit having the formula: —SO 2 NH— and R 5 is a unit chosen from:
  • R 5 units which are chosen from:
  • R 1 units encompassed within this iteration include: benzene-sulfonamide, N-methyl-benzenesulfonamide, N-ethyl-benzenesulfon-amide, N-(n-propyl)-benzenesulfonamide, N-(iso-propyl)-benzenesulfonamide, N-(n-butyl)-benzenesulfonamide, N-(sec-butyl)-benzenesulfonamide, N-(iso-butyl)-benzene-sulfonamide, and N-(tert-butyl)-benzenesulfonamide.
  • R 5 units which are chosen from:
  • R 1 units encompassed within this iteration include: N-phenyl-benzene-sulfonamide, N-(pyrimidin-2-yl)-benzenesulfonamide, N-(pyrimidin-4-yl)-benzenesulfonamide, N-(pyrimidin-5-yl)-benzenesulfonamide, N-(pyridin-2-yl)-benzenesulfonamide, N-(pyridin-3-yl)-benzenesulfonamide, and N-(pyridin-4-yl)-benzenesulfonamide.
  • the fifth aspect of the second category of R 1 relates to units wherein L 1 is a unit having the formula: —[C(R 7a R 7b )] j NR 9 C(O)[C(R 8a R 8b )] k —; or —[C(R 7a R 7b )] j C(O)NR 9 [C(R 8a R 8b )] k — wherein R 7a , R 7b , R 8a , R 8b , and R 9 are each independently hydrogen, methyl, or ethyl; the indices j and k are each independently from 0 to 3.
  • the first iteration of the fifth aspect of the second category of R 1 units relates to R 1 units wherein R 6 units are linked to the phenyl ring by way of a L 1 unit chosen from units having the formula.
  • Non-limiting examples of the first iteration of the fifth aspect of the second category of R 1 units includes substituted or unsubstituted phenyl units linked with amide bond linking units having the formula —C(O)NH— or —NH(CO)—.
  • R 1 relates to substituted phenyl units wherein L 1 is absent (the index y is equal to 0) and R 5 comprises one or more substitutes for hydrogen each of which is independently chosen from units which comprise:
  • the core C 2 -C 5 heterocyclic rings of the third category of R 1 encompass the following unsubstituted rings: aziridinyl (C 2 ), [1,2,3]triazolyl (C 2 ), [1,2,4]triazolyl (C 2 ), urazolyl (C 2 ), oxazolyl (C 3 ), azetidinyl (C 3 ), pyrazolidinyl (C 3 ), imidazolidinyl (C 3 ), oxazolidinyl (C 3 ), isoxazolinyl (C 3 ), oxazolyl (C 3 ) isoxazolyl (C 3 ), thiazolidinyl (C 3 ), thiazolyl (C 3 ), imidazolidinonyl (C 3 ), isothiazolyl (C 3 ), isothiazolinyl (C 3 ), oxathiazolidinonyl (C 3 ), oxazolid
  • L is a linking unit having the formula: —[C(R 4a R 4b )] n — wherein each R 4a and R 4b unit is independently chosen from:
  • 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 )Cl 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.
  • L 1 is a linking unit which when present provides R 5 units with the formula: -(L 1 ) y -R 6 wherein y is equal to 1 when L 1 is present.
  • L 1 is a linking unit chosen from:
  • L 1 The various categories, aspects, iterations, and examples of L 1 can be found in the definitions of R 1 and in the examples and tables described and listed herein below.
  • the compounds of the present invention can be prepared by the following general procedure, the formulator adjusting the reaction conditions as is necessary and which one skilled in the art will be able to accomplish without undo experimentation.
  • Step 1 Preparation of intermediate 2-(methylthio)pyrimidine-4(3H)-one. This compound can be used in the preparation of each analog encompassed by the present invention. The general procedure follows.
  • Step 2 Formation of 2-anilino intermediate.
  • 2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one To a 2-(methyl-thio)pyrimidine-4(3H)-one (14.2 g, 100 mmol) in diglyme (60 mL) is added the substituted or unsubstituted aniline of choice (200 mmol). The resulting mixture is heated to reflux and stirred for approximately 18 hours. The product which typically forms as a solid upon cooling the mixture to room temperature, is washed with solvent (pentane, hexane, or isopentane). However, solvent can be added to the reaction mixture to induce crystallization if necessary.
  • solvent penentane, hexane, or isopentane
  • 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 retlux 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.
  • Step 4 Formation of final compounds (analogs) of the present invention.
  • 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.
  • the compounds which comprise Category I of the present invention are 2,4-di-aminopyrimidines having the formula: wherein linking group L is a propylene (—CH 2 CH 2 CH 2 —) unit and R units are heterocyclic units attached to the core scaffold by way of a ring nitrogen atom.
  • the first aspect of Category I encompasses R 1 units which are phenyl units substituted by one or more R 5 units chosen from:
  • the compounds which comprise the second aspect of Category I of the present invention are 2,4-di-aminopyrimidines having the formula: wherein R 1 units are substituted by one or more R 5 units chosen from:
  • the product was diluted with 5 mL of aqueous saturated sodium bicarbonate solution and extracted with EtOAc (3 ⁇ 10 ml). The combined organics are washed with 20 ml water and saturated aqueous NaCl (2 ⁇ 10 ml), then dried over magnesium sulfate and concentrated in vacuo. The residue is purified over silica (5-8% MeOH in CH 2 Cl 2 ) to afford 61 mg (38% yield) of the desired compound.
  • N 2 -biphenyl-3-yl-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (10) To 4-chloro-N-(3-biphenyl)pyrimidin-2-amine (301.0 mg, 1.07 mmol) in 5 mL THF is added potassium carbonate (396 mg, 2.15 mmol) followed by 3-morpholinopropyl-amine (0.3 mL, 2.05 mmol). The resulting mixture is heated at reflux for 96 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is diluted with 15 mL of water and extracted with EtOAc (3 ⁇ 20 mL).
  • the compounds which comprise Category II of the present invention are 2,4-di-aminopyrimidines having the formula: wherein R is a heterocyclic unit attached to the core scaffold by way of a nitrogen atom and R 1 is a phenyl unit substituted by different category of R 5 units having the formula: -L 1 -R 6
  • the intermediate, 3-amino-N-phenylbenzenesulfonamide (12), can be conveniently prepared by the following steps from aniline and 3-nitrobenzene-1-sulfonyl chloride.
  • Other sulfonamide intermediates can be prepared in a like manner, the formulator making adjustments to the reaction conditions which are well known to those skilled in the art.
  • the compounds which comprise Category III of the present invention are 2,4-di-aminopyrimidines having the formula: wherein R is a heterocyclic unit chosen from: wherein R 2 , R 3 , and R 10 are each defined herein above.
  • the first aspect of Category III relates to R 1 units which are phenyl units substituted by one or more R 5 units chosen from:
  • the second aspect of Category III relates to R units which comprise a chiral carbon atom.
  • Scheme VI herein below and the following examples illustrate this second aspect of Category III of the present invention.
  • the (2R) enantiomer can be prepared in the same manner as described herein above,
  • 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. Certain exemplified compounds may also potentially inhibit additional isoforms of conventional PKC, such as PKC- ⁇ or PKC- ⁇ . This is not undesirable and can lead to increased pharmacological effects.
  • PKC- ⁇ Protein Kinase C-alpha
  • the level of disease for example, the relative degree of heart failure due to PKC- ⁇ activity will vary from patient to patient and be predicated by other exacerbating circumstances, inter alia, presence of other disease conditions (diabetes, high blood pressure, and the like) or patients may suffer from other conditions such as obesity. Therefore, the formulator may be required to employ differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the known testing procedures known to the artisan.
  • the present invention also relates to compositions or formulations which comprise the PKC- ⁇ inhibitors according to the present invention.
  • the compositions of the present invention comprise.
  • excipient and “carrier” are used interchangeably throughout the description of the present invention.
  • excipient and carrier relate to their definition in terms of a medicament, said terms are defined in that respect as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • 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.
  • the present method comprised a method for treating or preventing a disease or medical condition selected from 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, cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and suboptimal mitogen stimulation said method comprised of the steps of administering to a patient in need thereof a therapeutic amount of a PKC- ⁇ inhibitor as disclosed herein.
  • a disease or medical condition selected from diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease
  • the present invention also relates to the use of the 2-arylamino-4-(heterocyclic)-amino-pyrimidines or salts thereof, according to the present invention in the manufacture of a medicament for the treatment of heart disease wherein inhibition of PKC- ⁇ provides a benefit.
  • 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).
  • the reaction is terminated by adding; 5 ⁇ L of the reaction mixture into 50 ⁇ L of MALDI matrix solution (5 mg/ml ⁇ -cyano-4-hydroxy-cinnamic acid in 50% Acetonitrile/H 2 O, 0.1% TFA, 5 mM ammonium phosphate). Two microliters of the stopped reaction mixture is transferred onto a MALDI-TOF mass spectrometer target plate.
  • MALDI matrix solution 5 mg/ml ⁇ -cyano-4-hydroxy-cinnamic acid in 50% Acetonitrile/H 2 O, 0.1% TFA, 5 mM ammonium phosphate.
  • 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.
  • % MA % Maximal Activity
  • PKC(X activity in cells is determined using murine HL-1 atrial cardiac muscle cells.
  • HL-1 cells are plated at 18,000 cells/well in a 96-well tissue culture plate
  • Cells are cultured in 0.1 ml Claycomb growth medium (without norepinephrine) supplemented with 10% fetal bovine serum, 200 mM glutamine and 1% antibiotic/antimycotic.
  • PBS phosphate buffered saline
  • 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.
  • PMSF phenylmethylsulfonylfluoride
  • coactivation buffer consisting of 0.1 mg/ml BSA, 250 ⁇ M EDTA, 400 ⁇ M CaCl 2 .
  • the reaction is terminated by adding 5 ⁇ L of the reaction mixture into 50 ⁇ L of MALDI matrix solution (5 mg/ml ⁇ -cyano-4-hydroxycinnamic acid in 50% Acetonitrile/H 2 O, 0.1% TFA, 5 mM ammonium phosphate). Two microliters of the stopped reaction mixture is transferred onto a MALDI-TOF mass spectrometer target plate. Dose-dependent inhibition is measured by mass spectrometry as % maximal activity as described above for the isolated PKC ⁇ inhibition assays.
  • Selected PKC ⁇ inhibitors are evaluated in rats with acute heart failure (HF) after myocardial infarction (MI) for effects on cardiac contractility and hemodynamics.
  • HF acute heart failure
  • MI myocardial infarction
  • Male, Sprague-Dawley rats are anesthetized with isoflurane, intubated, placed on ventilators and maintained at a surgical plane of anesthesia during the course of the experiment.
  • the animals are instrumented, for the measurement of left ventricular function (+dP/dt, LVDP), arterial blood pressure, and the ECG is monitored for the incidence of arrhythmias.
  • 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 VI provides non-limiting examples of PKC- ⁇ IC 50 values for representative compounds of the present invention.
  • PKC- ⁇ Compound IC 50 (nM) N 2 -(3-Chlorophenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 2 N 2 -(3-Chlorophenyl)-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine- 5 2,4-diamine 1- ⁇ 3-[2-(3-Chlorophenylamino)-pyrimidin-4-ylamino]-propyl ⁇ -pyrrolidin-2- 710 one N 2 -[3-Trifluoromethyl-phenyl]-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine- 0.5 2,4-diamine N 4 -(3-Pyrrolidin-1-yl-propyl)-N

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US11/762,394 2006-06-15 2007-06-13 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines Abandoned US20070293494A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/762,394 US20070293494A1 (en) 2006-06-15 2007-06-13 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines
US12/465,704 US8354407B2 (en) 2006-06-15 2009-05-14 2-anilino-4-(heterocyclic)amino-pyrimidines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81395606P 2006-06-15 2006-06-15
US11/762,394 US20070293494A1 (en) 2006-06-15 2007-06-13 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/465,704 Continuation US8354407B2 (en) 2006-06-15 2009-05-14 2-anilino-4-(heterocyclic)amino-pyrimidines

Publications (1)

Publication Number Publication Date
US20070293494A1 true US20070293494A1 (en) 2007-12-20

Family

ID=38608732

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/762,394 Abandoned US20070293494A1 (en) 2006-06-15 2007-06-13 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines
US12/465,704 Active 2028-12-01 US8354407B2 (en) 2006-06-15 2009-05-14 2-anilino-4-(heterocyclic)amino-pyrimidines

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/465,704 Active 2028-12-01 US8354407B2 (en) 2006-06-15 2009-05-14 2-anilino-4-(heterocyclic)amino-pyrimidines

Country Status (16)

Country Link
US (2) US20070293494A1 (enExample)
EP (1) EP2054392A2 (enExample)
JP (1) JP2009540013A (enExample)
KR (1) KR20090019011A (enExample)
CN (1) CN101506175A (enExample)
AR (1) AR061380A1 (enExample)
AU (1) AU2007257650A1 (enExample)
BR (1) BRPI0713696A2 (enExample)
CA (1) CA2653777A1 (enExample)
CL (1) CL2007001749A1 (enExample)
IL (1) IL195864A0 (enExample)
MX (1) MX2008016004A (enExample)
RU (1) RU2008152195A (enExample)
TW (1) TW200815424A (enExample)
WO (1) WO2007146981A2 (enExample)
ZA (1) ZA200809941B (enExample)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293525A1 (en) * 2006-06-15 2007-12-20 Djung Jane F 2-anilino-4-aminoalkyleneaminopyrimidines
US20100113445A1 (en) * 2007-03-20 2010-05-06 Smithkline Beecham Corporation Chemical Compounds
US20100130486A1 (en) * 2007-07-17 2010-05-27 Rigel Pharmaceuticals, Inc. Cyclic amine substituted pyrimidinediamines as pkc inhibitors
US20100179164A1 (en) * 2009-01-14 2010-07-15 Hui Li 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders
US20100179165A1 (en) * 2009-01-14 2010-07-15 Tarikere Gururaja Methods for treating inflammatory disorders using 2,4-pyrimidinediamine compounds
WO2011041584A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
WO2016060963A1 (en) * 2014-10-14 2016-04-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
US9732070B2 (en) 2009-12-01 2017-08-15 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
WO2021014365A1 (en) 2019-07-22 2021-01-28 Lupin Limited Macrocyclic compounds as sting agonists and methods and uses thereof

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2387572B1 (en) * 2009-01-15 2015-09-16 Rigel Pharmaceuticals, Inc. Protein kinase c inhibitors and uses thereof
AR076024A1 (es) * 2009-04-03 2011-05-11 Schering Corp Derivados de heterociclos biciclicos puenteados y metodos de uso de los mismos
AU2011205485B2 (en) * 2010-01-13 2014-09-25 Glaxosmithkline Llc Compounds and methods
CN104169272A (zh) * 2011-12-23 2014-11-26 赛尔佐姆有限公司 作为激酶抑制剂的嘧啶-2,4-二胺衍生物
CN102746255A (zh) * 2012-07-24 2012-10-24 安徽中医学院 具有抗肿瘤活性的化合物、制备方法及应用
US10202356B2 (en) 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
EA201691498A1 (ru) 2014-01-29 2017-02-28 Юниверсите Де Стразбур Новая мишень для лечения и профилактики диабета
MX376760B (es) * 2016-02-22 2025-03-07 Hoffmann La Roche Proceso para la fabricación de derivados de 3-piperazin-1-il-propilamina.
EP3421485A1 (en) 2017-06-30 2019-01-02 Université de Strasbourg Peptides for treatment and prevention of hyperglycaemia
BR112020020246A8 (pt) 2018-04-05 2022-10-18 Sumitomo Dainippon Pharma Oncology Inc Inibidores de cinase axl e uso dos mesmos
EP3826684A4 (en) 2018-07-26 2022-04-06 Sumitomo Dainippon Pharma Oncology, Inc. METHODS OF TREATMENT OF DISEASES ASSOCIATED WITH ABNORMAL ACVR1 EXPRESSION AND ACVR1 INHIBITORS FOR USE IN THE SAME
HUE065486T2 (hu) 2019-05-10 2024-05-28 Deciphera Pharmaceuticals Llc Fenilaminopirimidinamid autophágia inhibitorok és azok felhasználási eljárásai
PE20220592A1 (es) 2019-05-10 2022-04-22 Deciphera Pharmaceuticals Llc Inhibidores de la autofagia de heteroarilaminopirimidina amida y metodos de uso de estos
CA3143489A1 (en) 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Aminopyrimidine amide autophagy inhibitors and methods of use thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2437683A (en) * 1948-03-16 Pyrimedine compounds and method of
US2443305A (en) * 1948-06-15 Pyrimidine derivatives
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6518286B1 (en) * 1999-03-26 2003-02-11 Astrazeneca Ab Compounds
US20040186118A1 (en) * 2002-11-28 2004-09-23 Judi Bryant Chk-, Pdk- and Akt-inhibitory pyrimidines, their production and use as pharmaceutical agents
US20050090493A1 (en) * 1998-08-29 2005-04-28 Astrazeneca Ab 2,4-Diamino pyrimidine compounds having anti-cell proliferative activity
US6943172B2 (en) * 2002-01-23 2005-09-13 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
US20050209231A1 (en) * 2004-01-16 2005-09-22 Xu Wu Compositions and methods for inducing cardiomyogenesis
US7122542B2 (en) * 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US20070293525A1 (en) * 2006-06-15 2007-12-20 Djung Jane F 2-anilino-4-aminoalkyleneaminopyrimidines

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB592928A (en) 1943-06-11 1947-10-03 Francis Henry Swinden Curd New pyrimidine compounds
DE833651C (de) 1943-11-02 1952-03-10 Ici Ltd Verfahren zur Herstellung von neuen Pyrimidinabkoemmlingen
GB587550A (en) 1944-09-25 1947-04-29 Francis Henry Swinden Curd New pyrimidine compounds
US3445467A (en) 1964-05-25 1969-05-20 Ciba Geigy Corp Biphenyl diphenylalkane and diphenylether compounds,amino - substituted on the phenyl rings
FR2244520B1 (enExample) 1973-07-06 1977-02-04 Ugine Kuhlmann
EP0945442A1 (en) 1998-03-27 1999-09-29 Janssen Pharmaceutica N.V. Trisubstituted pyrimidine derivatives
EP1245567B1 (en) 1998-03-27 2011-03-02 Janssen Pharmaceutica NV HIV inhibiting pyrimidine derivatives
GB9924092D0 (en) * 1999-10-13 1999-12-15 Zeneca Ltd Pyrimidine derivatives
CA2400447C (en) * 2000-02-17 2008-04-22 Amgen Inc. Kinase inhibitors
GB0016877D0 (en) * 2000-07-11 2000-08-30 Astrazeneca Ab Chemical compounds
PL367130A1 (en) * 2001-05-29 2005-02-21 Schering Aktiengesellschaft Cdk inhibiting pyrimidines, production thereof and their use as medicaments
US7115617B2 (en) * 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
US6939874B2 (en) * 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
WO2003026666A1 (en) * 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 2-phenylamino-4- (5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, as src kinase inhibitors
WO2003040141A1 (en) 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders
EP1453516A2 (de) 2001-10-17 2004-09-08 Boehringer Ingelheim Pharma GmbH & Co.KG 5-substituierte 4-amino-2-phenylamino-pyrimdinderivate und ihre verwendung als beta-amyloid modulatoren
EP1438053B1 (de) * 2001-10-17 2008-09-10 Boehringer Ingelheim Pharma GmbH & Co.KG Pyrimidinderivate, arzneimittel enthaltend diese verbindungen, deren verwendung und verfahren zu ihrer herstellung
MXPA04004178A (es) * 2001-11-01 2004-09-06 Janssen Pharmaceutica Nv Heteroarilaminas como inhibidores de glucogeno cintasa cinasa 3beta.
GB0206215D0 (en) * 2002-03-15 2002-05-01 Novartis Ag Organic compounds
AR039540A1 (es) 2002-05-13 2005-02-23 Tibotec Pharm Ltd Compuestos microbicidas con contenido de pirimidina o triazina
WO2004052862A1 (ja) 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. 含窒素複素環化合物およびその医薬用途
US20050014753A1 (en) * 2003-04-04 2005-01-20 Irm Llc Novel compounds and compositions as protein kinase inhibitors
WO2005003103A2 (en) 2003-06-30 2005-01-13 Astrazeneca Ab 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases
ES2365223T3 (es) 2003-08-07 2011-09-26 Rigel Pharmaceuticals, Inc. Compuestos 2,4-pirimidindiamínicos y usos como agentes antiproliferativos.
CA2564355C (en) * 2004-05-07 2012-07-03 Amgen Inc. Protein kinase modulators and method of use
JP5208516B2 (ja) * 2004-12-30 2013-06-12 エグゼリクシス， インコーポレイテッド キナーゼモジュレーターとしてのピリミジン誘導体および使用方法
DE102005016634A1 (de) * 2005-04-12 2006-10-19 Merck Patent Gmbh Neuartige Aza-Hetercyclen als Kinase-Inhibitoren
WO2006124874A2 (en) * 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibitors of b-raf kinase
MX286273B (es) 2005-06-08 2011-05-04 Rigel Pharmaceuticals Inc Composiciones y metodos para inhibicion de la via jak.
EP1746096A1 (en) 2005-07-15 2007-01-24 4Sc Ag 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
US8604042B2 (en) * 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
TW200812645A (en) 2006-06-15 2008-03-16 Serenex Inc Tetracycline package formulations
TW200808705A (en) 2006-06-15 2008-02-16 Sanofi Aventis Aryl- and heteroaryl-ethyl-acylguanidine derivatives, their preparation and their application in therapeutics
US20080039433A1 (en) 2006-06-15 2008-02-14 Smith Alexander D Stabilized Tetracycline Compositions
CL2009000600A1 (es) * 2008-03-20 2010-05-07 Bayer Cropscience Ag Uso de compuestos de diaminopirimidina como agentes fitosanitarios; compuestos de diaminopirimidina; su procedimiento de preparacion; agente que los contiene; procedimiento para la preparacion de dicho agente; y procedimiento para combatir plagas de animales y/u hongos dañinos patogenos de plantas.
US20110144107A1 (en) * 2008-06-11 2011-06-16 Irm Llc Compounds and compositions useful for the treatment of malaria
WO2010045306A2 (en) * 2008-10-16 2010-04-22 Schering Corporation Azine derivatives and methods of use thereof
US20110071158A1 (en) 2009-03-18 2011-03-24 Boehringer Ingelheim International Gmbh New compounds
US8410126B2 (en) 2009-05-29 2013-04-02 Boehringer Ingelheim International Gmbh Pyrimidine inhibitors of PKTK2

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2437683A (en) * 1948-03-16 Pyrimedine compounds and method of
US2443305A (en) * 1948-06-15 Pyrimidine derivatives
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US20050090493A1 (en) * 1998-08-29 2005-04-28 Astrazeneca Ab 2,4-Diamino pyrimidine compounds having anti-cell proliferative activity
US6518286B1 (en) * 1999-03-26 2003-02-11 Astrazeneca Ab Compounds
US6943172B2 (en) * 2002-01-23 2005-09-13 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
US20040186118A1 (en) * 2002-11-28 2004-09-23 Judi Bryant Chk-, Pdk- and Akt-inhibitory pyrimidines, their production and use as pharmaceutical agents
US7122542B2 (en) * 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US20050209231A1 (en) * 2004-01-16 2005-09-22 Xu Wu Compositions and methods for inducing cardiomyogenesis
US20070293525A1 (en) * 2006-06-15 2007-12-20 Djung Jane F 2-anilino-4-aminoalkyleneaminopyrimidines

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8158641B2 (en) 2006-06-15 2012-04-17 Boehringer Ingelheim International Gmbh 2-anilino-4-aminoalkyleneaminopyrimidines
US20070293525A1 (en) * 2006-06-15 2007-12-20 Djung Jane F 2-anilino-4-aminoalkyleneaminopyrimidines
US20100113445A1 (en) * 2007-03-20 2010-05-06 Smithkline Beecham Corporation Chemical Compounds
US20100130486A1 (en) * 2007-07-17 2010-05-27 Rigel Pharmaceuticals, Inc. Cyclic amine substituted pyrimidinediamines as pkc inhibitors
US8993585B2 (en) 2007-07-17 2015-03-31 Rigel Pharmaceuticals, Inc. Cyclic amine substituted pyrimidinediamines as PKC inhibitors
US8334297B2 (en) * 2009-01-14 2012-12-18 Rigel Pharmaceuticals Inc. 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders
CN102317265A (zh) * 2009-01-14 2012-01-11 里格尔药品股份有限公司 用于治疗炎性疾病的2,4-嘧啶二胺化合物
WO2010083241A3 (en) * 2009-01-14 2010-12-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders
US20100179165A1 (en) * 2009-01-14 2010-07-15 Tarikere Gururaja Methods for treating inflammatory disorders using 2,4-pyrimidinediamine compounds
US8575165B2 (en) 2009-01-14 2013-11-05 Rigel Pharmaceuticals, Inc. Methods for treating inflammatory disorders using 2,4-pyrimidinediamine compounds
CN102317265B (zh) * 2009-01-14 2015-03-25 里格尔药品股份有限公司 用于治疗炎性疾病的2,4-嘧啶二胺化合物
US20100179164A1 (en) * 2009-01-14 2010-07-15 Hui Li 2,4-pyrimidinediamine compounds for treatment of inflammatory disorders
WO2011041582A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products
WO2011041584A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products
US9732070B2 (en) 2009-12-01 2017-08-15 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
WO2016060963A1 (en) * 2014-10-14 2016-04-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
WO2021014365A1 (en) 2019-07-22 2021-01-28 Lupin Limited Macrocyclic compounds as sting agonists and methods and uses thereof
US12479858B2 (en) 2019-07-22 2025-11-25 Lupin Limited Macrocyclic compounds as sting agonists and methods and uses thereof

Also Published As

Publication number Publication date
WO2007146981A3 (en) 2008-02-21
AU2007257650A1 (en) 2007-12-21
BRPI0713696A2 (pt) 2012-11-06
CL2007001749A1 (es) 2008-01-25
CA2653777A1 (en) 2007-12-21
CN101506175A (zh) 2009-08-12
US20090227586A1 (en) 2009-09-10
RU2008152195A (ru) 2010-07-20
JP2009540013A (ja) 2009-11-19
EP2054392A2 (en) 2009-05-06
TW200815424A (en) 2008-04-01
AR061380A1 (es) 2008-08-20
WO2007146981A2 (en) 2007-12-21
IL195864A0 (en) 2009-09-01
US8354407B2 (en) 2013-01-15
KR20090019011A (ko) 2009-02-24
ZA200809941B (en) 2009-07-29
MX2008016004A (es) 2009-01-16

Similar Documents

Publication Publication Date Title
US8354407B2 (en) 2-anilino-4-(heterocyclic)amino-pyrimidines
US8158641B2 (en) 2-anilino-4-aminoalkyleneaminopyrimidines
US10865206B2 (en) Inhibitors of cyclin-dependent kinase 7 (CDK7)
US9150519B2 (en) 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (S1P) receptor for the treatment of multiple sclerosis
US7122544B2 (en) Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
CN101925584B (zh) 用于治疗哮喘、copd、过敏性鼻炎、过敏性结膜炎、特应性皮炎、癌症、乙型肝炎、丙型肝炎、hiv、hpv、细菌感染和皮肤病的嘧啶衍生物
JP6048406B2 (ja) 新規化合物、医薬組成物及びこれらの使用
US20090131436A1 (en) Pyrimidine Derivatives
US20100105674A1 (en) Chemical Compounds
US10676464B2 (en) 5-hydroxytryptamine receptor 7 activity modulators and their method of use
US9221807B2 (en) Substituted pyridones and pyrazinones and their use as inhibitors of neutrophil elastase activity

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION