WO2005107760A1 - Composes et compositions en tant qu'inducteurs de la differenciation de keratinocytes - Google Patents

Composes et compositions en tant qu'inducteurs de la differenciation de keratinocytes Download PDF

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Publication number
WO2005107760A1
WO2005107760A1 PCT/US2005/015118 US2005015118W WO2005107760A1 WO 2005107760 A1 WO2005107760 A1 WO 2005107760A1 US 2005015118 W US2005015118 W US 2005015118W WO 2005107760 A1 WO2005107760 A1 WO 2005107760A1
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Prior art keywords
formamidyl
methyl
ethyl
chosen
alkyl
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PCT/US2005/015118
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English (en)
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Jiyong Hong
Nathanael S. Gray
Peter Schultz
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Irm Llc
The Scripps Research Institute
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Publication of WO2005107760A1 publication Critical patent/WO2005107760A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to induce undifferentiated keratinocytes to differentiate into terminally differentiated keratinocytes.
  • the invention further provides compounds for the treatment of diseases or disorders associated with casein kinase II, TANK- binding kinase 1 and NIMA-related kinase 9.
  • the protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function.
  • a partial, non-limiting, list of these kinases include casein kinase II (CKII or CK-2), TANK-binding kinase 1 (TBK1) and NIMA-related kinase 9 (NEK9).
  • CKII or CK-2 casein kinase II
  • TTK1 TANK-binding kinase 1
  • NIMA-related kinase 9 NIMA-related kinase 9
  • Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems.
  • the compounds of this invention modulate the activity of protein kinases and are, therefore, expected to be useful in the treatment of diseases associated with protein kinase activity. Further, the identification of small molecules that permit precise regulation of keratinocytes differentiation could inhibit or restore skin damage and facilitate therapeutic treatments of psoriasis and melanoma.
  • the present invention provides a method for inducing undifferentiated keratinocytes to differentiate into terminally differentiated keratinocytes, said method comprising contacting said undifferentiated keratinocytes with a compound of Formula I:
  • W is chosen from -NR 4 -, -S-, -0-, -S(O)- and -S(0) 2 -; wherein J ⁇ is chosen from hydrogen and
  • Ri is chosen from C 3 - ⁇ 2 cycloalkyl-
  • R 5 is chosen from hydrogen, C ⁇ - 6 alkyl and Cs.ncycloalkyl-Co ⁇ alkyl; and Re is chosen from C 3 . 8 heterocycloalkyl- Co ⁇ alkyl and C 5 - ⁇ oheteroaryl-C 0 - alkyl optionally substituted by 1 to 3 radicals chosen from Ci. ⁇ alkyl and -C(0)OH; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent of Ri is further optionally substituted by 1 to 5 radicals independently chosen from C ⁇ - 6 alkyl and Ci- ⁇ alkoxy;
  • R 2 is chosen from C 3 - ⁇ 2 cycloalkyl-
  • any arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl of R 2 is optionally substituted by 1 to 3 radicals independently chosen from halo, nitro, cyano, C ⁇ - 6 alkyl, C ⁇ - 6 alkenyl, C
  • R 3 is chosen from halo, hydroxy, -XSR 5 , -XS(0)R 5 , -XS(0) 2 R 5 , -XC(0)R 5 and
  • X is a bond or Ci ⁇ alkylene
  • R 5 is chosen from hydrogen, C ⁇ - 6 alkyl and and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which inhibition of kinase activity, particularly casein kinase II (CK2), TANK- binding kinase 1 (TBK1) and/or NIMA-related kinase 9 (NEK9) activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • CK2 casein kinase II
  • TK1 TANK- binding kinase 1
  • NIMA-related kinase 9 NIMA-related kinase 9
  • the present invention provides the use of a compound of
  • Formula I in the manufacture of a medicament for treating a disease in an animal in which kinase activity, particularly casein kinase II (CK2), TANK-binding kinase 1 (TBK1) and/or NIMA- related kinase 9 (NEK9) activity, contributes to the pathology and/or symptomology of the disease.
  • kinase activity particularly casein kinase II (CK2), TANK-binding kinase 1 (TBK1) and/or NIMA- related kinase 9 (NEK9) activity
  • the present invention provides methods for screening for compounds that induce the differentiation of undifferentiated keratinocytes into differentiated keratinocytes.
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched. includes, methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl may be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom.
  • heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3 - ⁇ ocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3 - 8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, l,l-dioxo-116-thiomorpholin-4-yl, etc.
  • Halogen (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.
  • "Involucrin” is a protein present in keratinocytes of epidermis and other stratified squamous epithelia. Involucrin first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the compounds of this invention can induce the differentiation of undifferentiated keratinocytes into differentiated keratinocytes.
  • Compounds of the invention are also useful in the inhibition of kinases and are illustrated by a compound of Formula I as detailed in the Summary of the Invention.
  • W is chosen from -N-Ri- and -O-; wherein R 4 is chosen from hydrogen and C ⁇ - 6 alkyl.
  • R 4 is chosen from hydrogen and C ⁇ - 6 alkyl.
  • any arylalkyl and heteroarylalkyl of Ri is optionally substituted by 1 to 3 radicals independently chosen from halo, nitro, C 5 - ⁇ 0 heteroaryl, C ⁇ - 6 alkoxy, halo-substituted-C ⁇ - 6 alkyl, -XNR 5 R 5 , -XOR 5 , -XSR 5 , -XNR 5 XNR 5 R 5 , -XNR 5 XOR 5 , - XC(0)NR 5 R 5 , -XOXRe and -XC(0)R 6 j wherein X is a bond or C].
  • R 5 is chosen from hydrogen, - ⁇ alkyl and C 3 -i 2 cycloalkyl-Co-- ⁇ alkyl; and Re is chosen from C 3 . 8 heterocycloalkyl- optionally substituted by 1 to 3 radicals chosen from Ci- 6 alkyl and -C(0)OH; wherein any heteroaryl substituent of R ⁇ is further optionally substituted by 1 to 5 C h alky! radicals.
  • R 2 is chosen from and C 5 . ioheteroaryl-Co--ialkyl; wherein any arylalkyl or heteroarylalkyl of R 2 is optionally substituted by 1 to 3 radicals independently chosen from halo, nitro, cyano, C ⁇ - 6 alkyl, C ⁇ - 6 alkenyl, Ci- ⁇ alkoxy, halo-substituted-C,.
  • R 5 is chosen from hydrogen, C ⁇ - 6 alkyl and R 6 is chosen from C 3 - 8 heterocycloalkyl-Co- 4 alkyl and C 5 .ioheteroaryl-C 0 - 4 alkyl optionally substituted by 1 to 3 radicals chosen from C ⁇ .6alkyl and -C(0)OH; and R 7 is cyano.
  • R 3 is chosen from halo, hydroxy, -XC(0)R 5 and -
  • XC(0)OR 5 wherein X is a bond or Ci- ⁇ alkylene; and R5 is chosen from hydrogen, C ⁇ - 6 alkyl and C 3 - 12 cycl oalky 1 -C 0 - al ky 1.
  • W is chosen from -NH- and -O-; and Ri is chosen from phenyl, benzyl, 5,6,7,8-tetrahydro-naphthalenyl, benzo[l,3]dioxolyl, lH-indazol-7-yl, indan-4-yl and lH-indolyl; wherein any arylalkyl and heteroarylalkyl of R] is optionally substituted by 1 to 3 radicals independently chosen from methoxy, methyl, amino, halo, hydroxy methyl, hydroxy, quinoxalinyl, ethyl, pyridinyl, methoxy-phenyl, piperazinyl-carbonyl, ethyl-(2-hydroxy-ethyl)-amino 2-(4-methyl-piperazin-l-yl)-ethoxy, formamyl, isopropyl, methyl-sulfanyl, tri-
  • R 2 is chosen from pyridinyl, phenyl, thiazolyl, pyridinyl-methyl, pyridinyl-ethyl, thiophenyl, benzyl, quinolinyl, 7-oxo-5,6,7,8-tetrahydro- naphthalenyl, naphthyl and pyrimidinyl; wherein any arylalkyl or heteroarylalkyl of R 2 is optionally substituted by 1 to 3 radicals independently chosen from halo, nitro, cyano, methyl, propyl-sulfamoyl, methyl-sulfamoyl, methoxy, methyl-carboxy, 2-dimethylamino-ethyl- formamyl, carboxy, amino, cyano-ethyl, cyano-methyl, ethenyl, tri-fluoro-methyl, hydroxy- methyl, ethyl
  • the present invention provides a method for inducing undifferentiated keratinocytes to differentiate into terminally differentiated keratinocytes, said method comprising contacting said undifferentiated keratinocytes with a compound chosen from 4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridine-2-carboxylic acid (2-hydroxy-ethyl)- amide, 3-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-benzonitrile, 3-[2-(3-chloro-phenylamino)- pyrimidin-4-yl]-N-(2-hydroxy-ethyl)-benzamide and 3-amino-6-hydroxy-2-phenyl-chromen-4- one.
  • the present invention provides methods for screening for compounds that induce the differentiation of undifferentiated keratinocytes into terminally differentiated keratinocytes.
  • the method involves: (a) contacting a kinase chosen from CK2, TBK1 and NEK9 with test compounds to identify one or more compounds that modulate a biological activity of the kinase; and (b) testing the modulating compound for its ability to induce the differentiation of undifferentiated keratinocytes into terminally differentiated keratinocytes.
  • the modulating compounds reduce the cellular level of the kinase.
  • the modulating compounds inhibit the kinase activity.
  • Methods for assaying cellular level of a kinase or kinase activity are well known in the art, e.g., as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y., Second (1989) and Third (2000) Editions; and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York (1987-1999).
  • modulatory compounds can be tested for inducing expression of a specific keratinocytes terminal differentiation marker, for example, Involucrin, filaggrin or transglutaminase.
  • a specific keratinocytes terminal differentiation marker for example, Involucrin, filaggrin or transglutaminase.
  • Compounds of the invention modulate the activity of protein kinases and, as such, are useful for treating diseases or disorders in which protein kinases, particularly CK2,
  • TBK1 and/or NEK9 contribute to the pathology and/or symptomology of the disease.
  • TBK1, CK2 and NEK9 are serine/threonine protein kinases that have been shown to play a role in cell cycle progression, liver regeneration, viral replication, apoptosis, transduction of growth signals, prostrate cancer, breast cancer, insulin signaling and Alzheimer's disease.
  • CK2 may result in the regulation of HIV-1 transcription by phosphorylating cellular proteins involved in HIV-1 trans-activation that contain multiple CK2 phosphorylation consensus sequences.
  • TBK1 mediates TANK'S ability to activate NF- ⁇ B.
  • NF- ⁇ B is a ubiquitously expressed transcription factor that regulates the induction of genes involved in immune and inflammatory cell function, anti-apoptotic response, and antiviral response through regulation of interferon gene expression. Inappropriate regulation of NF- B contributes to a wide range of human disorders, including cancers, neurodegenerative diseases, ataxia-telangiectasia, arthritis, asthma, inflammatory bowel disease, and numerous other inflammatory conditions.
  • Compounds of the invention, in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example, as indicated by the assays described in Example 5 and are therefore indicated for therapy.
  • Mammalian epidermis is renewed throughout adult life by proliferation of stem cells and differentiation of their progeny.
  • Epidermal stem cells are pluripotent, giving rise to interfollicular epidermis, sebaceous glands and all the lineages of the hair follicle.
  • the human epidermis is a stratifying squamous epithelium comprised of a single, basally located, layer of proliferating keratinocytes and multiple suprabasal layers of differentiating keratinocytes.
  • keratinocytes undergo a choreographed series of mo ⁇ hological and biochemical changes that result in the assembly of a protective cornified envelope.
  • Compounds of the invention can efficiently induce proliferating normal human epidermal keratinocytes (NHEKs) to terminally differentiate.
  • Compounds of the invention induce the differentiation of up to 100% of undifferentiated keratinocytes into terminally differentiated keratinocytes.
  • treatment of undifferentiated keratinocytes with 330nM of compound 85 (table 1) causes a 4.2 fold (approximately 70%) increase of terminally differentiated keratinocytes after 48 hours.
  • Compounds of the invention can serve as useful chemical probes for study signaling pathways in epidermal stem cell differentiation and for the identification of genes and signaling pathways that play roles in the differentiation/dedifferentiation of epidermal stem cells.
  • Compounds of the invention can also be used in novel therapeutic approaches, such as cell therapy, for the treatment of many diseases including psoriasis and cancers, for example, melanoma.
  • Psoriasis is one of the most common human skin disorders characterized by complex alterations of various cell types. These include epidermal keratinocyte hyper- proliferation and altered differentiation, as well as intra-epidermal accumulation of leukocytes and lymphocytic infiltration around the capillary vessels in the dermis. Psoriasis can be classified into four types: plaque-type psoriasis, guttate psoriasis, localized pustular psoriasis and generalized pustular psoriasis. The less common forms of psoriasis include pustular (localized and generalized) and erythrodermic variants. The most common form is plaque-type psoriasis.
  • Guttate psoriasis is characterized by numerous small, oval (teardrop shaped) lesions that develop after an acute upper respiratory tract infection. These lesions are often not as scaly or as red as the classic lesions of plaque-type psoriasis.
  • guttate psoriasis must be differentiated from pityriasis roseas, another indication characterized by the sudden outbreak of red scaly lesions.
  • psoriatic lesions are thicker and scalier, and the lesions are not usually distributed along skin oreases.
  • the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutical ly effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a therapeutical ly effective amount See, "Administration and Pharmaceutical Compositions ", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • compounds of the invention will be administered in therapeutical ly effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutical ly valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutical ly effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • therapeutic agents for example, synergistic effects can occur with other immunomodulatory, anti-inflammatory or any substances used in the treatment of the diseases mentioned above, for example when used in combination with cyclosporin, rapamycin, or ascomycin, or immunosuppressant analogues thereof, for example cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparable compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, 15-deoxyspergualin, immunosuppressant antibodies, especially monoclonal antibodies for leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their lig
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of Formula I and a co-agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W.
  • a compound of Formula la can be prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a suitable base (e.g., potassium tertiary butoxide and diisopropylethyl amine, and the like), a suitable solvent (e.g., 1,4-dioxane and butanol, and the like). The reaction is carried out at 50 to 130°C and can take up to 4 hours to complete. Similarly, using appropriate starting materials, reaction with a compound of formula 3 results in compounds of Formula lb, Ic, Id and Ie.
  • a suitable base e.g., potassium tertiary butoxide and diisopropylethyl amine, and the like
  • a suitable solvent e.g., 1,4-dioxane and butanol, and the like
  • a compound of Formula la can be prepared by reacting a compound of formula 4 with a compound of formula 5 in the presence of a suitable solvent (e.g., DMSO, and the like) and a suitable base (e.g., potassium tertiary butoxide, and the like). The reaction is carried out at 50 to 130 °C and can take up to 4 hours to complete.
  • a suitable solvent e.g., DMSO, and the like
  • a suitable base e.g., potassium tertiary butoxide, and the like.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al.,
  • prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of Formula I can be made by a process, which involves:
  • the present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds of Formula I (Examples) and intermediates (References) according to the invention.
  • reaction mixture is cooled to room temperature, diluted with ethyl acetate, and washed with water and brine.
  • the organic extract was dried over MgS0 4 , filtered, and concentrated under reduced pressure. Purification by column chromatography (Si0 2 , Hexane : Ethyl acetate / 5:1) provided 4 (0.69g, 87%) as a white solid.
  • Method 1 To a solution of 2-chloro-7-pyridin-2-yl-7H-pyrrolo[2,3- d]pyrimidine in 1,4-dioxane is added 3,4,5-trimethoxy aniline (3 equivalents) followed by adding potassium tert-butoxide solution (1.0 M in tetrahydrofuran, 3 equivalents) dropwise. After addition, the reaction mixture is heated at 80°C for 2 hours. The solvent is removed after cooling to room temperature. Purification by reverse phase HPLC gives (7-pyridin-2-yl-7H- pyrrolo[2,3-d]pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine as a white solid. [0061] Method 2.
  • Example 5 Assays [0067] The ability of the compounds of the invention to induce the differentiation of undifferentiated keratinocytes into terminally differentiated keratinocytes was measured by monitoring the expression of the keratinocyte differentiation marker, involucrin. [0068] Normal human epidermal keratinocyte (NHEK) cultures are purchased from
  • the transfected cells are plated into 96-well assay plates and incubated for 24 hours.
  • the cells are treated with an appropriate amount of a compound of the invention and incubated for a further 2 days.
  • the reported gene activity in the cells is measured using the Bright-GloTM luciferase assay system (Promega) and an Analyst ® AD system (Molecular Devices).
  • the induction of luciferase activity of transfected NHEKs in 1.4mM CaC was used as a positive control and no treatment of NHEKs is used as a baseline measurement.
  • NHEKs transfected with the reporter plasmid exhibits a 5-fold induction of the luciferase activity when incubated with medium containing 1.4 mM CaCh for 48 hours, compared to cells that are maintained in medium with 0.03 mM CaCl 2 .

Abstract

L'invention concerne des composés, des compositions pharmaceutiques contenant de tels composés et des méthodes d'utilisation de ces composés dans l'induction de kératinocytes non différenciés de manière à les différencier en kératinocytes différenciés au niveau du terminal. Cette invention a aussi pour objet des composés destinés au traitement de maladies ou de troubles liés à la caséine kinase II (CK2), à la kinase 1 de liaison TANK (TBK1) et à la kinase 9 associée à NIMA.
PCT/US2005/015118 2004-04-30 2005-04-29 Composes et compositions en tant qu'inducteurs de la differenciation de keratinocytes WO2005107760A1 (fr)

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