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WO2006089874A1 - BENZO[2,3]AZÉPINO[4,5-b]INDOL-6-ONES - Google Patents

BENZO[2,3]AZÉPINO[4,5-b]INDOL-6-ONES Download PDF

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Publication number
WO2006089874A1
WO2006089874A1 PCT/EP2006/060100 EP2006060100W WO2006089874A1 WO 2006089874 A1 WO2006089874 A1 WO 2006089874A1 EP 2006060100 W EP2006060100 W EP 2006060100W WO 2006089874 A1 WO2006089874 A1 WO 2006089874A1
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disorder
diseases
disorders
disease
infection
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Inventor
Bert Klebl
Lars Neumann
Doris Hafenbradl
Zoltán Greff
György Kéri
László ÖRFI
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Agennix AG
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GPC Biotech AG
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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
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to benzo[2,3]azepino[4,5-b]indol-6-ones and/or pharmaceutically acceptable salts thereof, the use of these compounds as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke. Furthermore, the present invention is directed towards pharmaceutical composition containing at least one of the benzo[2,3]azepino[4,5-b]indol-6-ones and/or pharmaceutically acceptable salts thereof.
  • infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke.
  • R 1 - R 8 , R 81 , R 82 represent independently of each other -R 11 , -R 12 -R 13 , -R 14 ,
  • R 9 represents -CHR 68 -CHR 67 -CO-NR 81 R 82 , -CHR ⁇ 6 b 7 / -C0-NR 3 8°1'R D 8°2 -CO-NR 81 R 82 , -CHR 68 -CHR 67 -CO-R 81 , -CHR 67 -CO-R 81 , -CO-R 81 , -CHR 68 -CHR 67 -CO-OR 81 , -CHR 67 -CO-OR 81 ;
  • R 11 - R 80 represent independently of each other -H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-CyCIo-C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH(CH 3 ) 2 , -SC(CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7
  • R 67 and R 68 represent independently of each other -R 69 , -R 70 , -CH 2 -R 69 , -CHR 70 R 71 , -CR 72 R 73 R 74 , -(CH 2 ) n -R 75 , -(CH 2 ) P -CHR 76 R 77 , -(CH 2 ) m -CR 78 R 79 R 80 , -C 6 H 4 -R 72 , -CH 2 -C 6 H 4 -R 73 ,
  • NR 81 R 82 may also represent
  • n, p, q, r, s, t are independently of each other integer from 0 - 10; and stereoisomeric forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts thereof.
  • R ) 1 - DR9 and R have the meanings as defined in claim 1.
  • the compound according to general formula (I) is selected from the group of compounds depicted in Table 1 :
  • Target PDGFRbeta GST Target CDK2/CycA ® Target PKA
  • Target CRIK citron kinase
  • Table Il shows inhibition rates greater than 30% of various kinases.
  • the results exhibited in table Il prove that the compounds of the present invention are potent pharmaceutically active agents against various diseases that can be treated and/or prohibited by inhibition of the targets ® - (D, O - ⁇ .
  • the present invention also comprises pharmaceutically acceptable salts of the compounds according to the general formula (I), all stereoisomeric forms of the compounds according to the general formula (I) as well as solvates, especially hydrates or prodrugs thereof.
  • a prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body.
  • the compounds of the present invention are basic and may form salts with organic or inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenes
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the compounds bear acidic substituents, the formation of salts with inorganic or organic bases may be possible. Examples for such bases are NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, lysine or arginine and the like.
  • Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
  • Some of the compounds of the present invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • compounds of the general formula (I) may exist in the form of optical isomers, e.g. enantiomers, diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof.
  • an isomeric form of a compound of the invention When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomer(s).
  • the afore-mentioned compounds are useful as pharmaceutically active agents, i.d. as drugs or medicine.
  • novel compounds according to the general formula (I) are used as pharmaceutically active agent.
  • inventive benzo[2,3]azepino[4,5-b]indol-6-ones are identified as inhibitors of kinases and phosphatases, especially of human tyrosin kinases, human serin kinases or human threonin kinases.
  • Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke.
  • infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke.
  • diseases related to trypanosomes and protozoa such as Chagas disease, South American trypanosomiasis, African trypanosomiasis, Sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL), espundia, mucocutaneous leishmaniasis (MCL), trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, Malaria tropica, Malaria tertiana, Malaria quartana, Pneumocystis carinii, pneumonia, pneumocystosis, and Balantidium dysentery.
  • CL cutaneous leishmaniasis
  • MCL mucocutaneous
  • the compounds according to the general formula (I) are for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases and opportunistic infections.
  • infectious diseases comprises infections caused by viruses, bacteria, prions and/or fungi.
  • virally induced infectious diseases including opportunistic diseases
  • the virally induced infectious diseases are caused by retroviruses, human endogenous retroviruses (HERVs), hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses.
  • HERVs human endogenous retroviruses
  • hepadnaviruses hepadnaviruses
  • herpesviruses herpesviruses
  • flaviviridae flaviviridae
  • adenoviruses adenoviruses
  • the retroviruses are selected from Antiviruses or oncoretroviruses, wherein the lentivirus is preferably selected from the group comprising: HIV-1 , HIV-2, feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), sivian immunodeficiency viruses (SIVs), chimeras of HIV and SIV (SHIV), caprine arthritis encephalitis virus (CAEV), visna/maedi virus (VMV) or equine infectious anemia virus (EIAV), preferably HIV-1 and HIV-2, and the oncoretrovirus is preferably selected from HTLV-I, HTLV-II or bovine leukemia virus (BLV), preferably HTLV-I and HTLV-II.
  • FMV feline immunodeficiency virus
  • BIV bovine immunodeficiency virus
  • SIVs sivian immunodeficiency viruses
  • SHIV chimeras of HIV and SIV
  • CAEV caprine arthritis encephalitis
  • the hepadnavirus is preferably selected from HBV, ground squirrel hepatitis virus (GSHV) or woodchuck hepatitis virus (WHV), preferably HBV
  • the herpesvirus is selected from the group comprising: Herpes simplex virus I (HSV I), herpes simplex virus Il (HSV II), Epstein-Barr virus (EBV), varicella zoster virus (VZV), human cytomegalovirus (HCMV) or human herpesvirus 8 (HHV-8), preferably HCMV
  • the flaviviridae is selected from HCV, West nile or Yellow Fever. It is to be understood, that all the viruses mentioned above, also comprise drug resistant virus strains.
  • infective diseases are AIDS, Alveolar Hydatid Disease (AHD, Echinococcosis), Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Baylisascaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominis Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chickenpox (Varicella-Zoster virus), Cholera, Chronic Fatigue Syndrome, CJD (Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans,
  • Coccidioidomycosis Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease), Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora Infection), Cytomegalovirus Infection, Dengue / Dengue Fever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease), Encephalitis, Enterobiasis (Pinworm Infection), Enterovirus Infection (Non-Polio), Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Foot and mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal Disease, Group
  • the compounds according to the general formula (I) are also useful for the preparation of a pharmaceutical composition for prophylaxis and / or treatment of bacterially induced infectious diseases, including opportunistic diseases and opportunistic infections, wherein the bacterially induced infectious diseases, including opportunistic diseases, are selected from tuberculosis, leprosy or mycobacteria-induced meningitis.
  • bacterially induced infectious diseases including opportunistic diseases
  • opportunistic diseases are selected from tuberculosis, leprosy or mycobacteria-induced meningitis.
  • One advantage of the inventive compounds disclosed herein is there use against drug resistant bacteria strains.
  • Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of prion diseases.
  • Prions are infectious agents, which do not have a nucleic acid genome. It seems that a protein alone is the infectious agent. A prion has been defined as "small proteinaceous infectious particle, which resists inactivation, by procedures that modify nucleic acids". The discovery that proteins alone can transmit an infectious disease has come as a considerable surprise to the scientific community. Prion diseases are often called “transmissible spongiform encephalopathies", because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum. Probably most mammalian species develop these diseases. Prion diseases are a group of neurodegenerative disorders of humans and animals and the prion diseases can manifest as sporadic, genetic or infectious disorders.
  • Examples for prion diseases acquired by exogenous infection are the Bovine spongiform encephalitis (BSE) of cattle and the new variant of Creutzfeld-Jakob disease (vCJD) caused by BSE as well as scrapie of animals.
  • BSE Bovine spongiform encephalitis
  • vCJD Creutzfeld-Jakob disease
  • human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Straussler-Scheinker (GSS) disease, fatal familial insomnia (FFI), and especially the new variant CJD (nvCJD or vCJD).
  • prion is used to describe the causative agents, which underlie the transmissible spongiform encephalopathies.
  • a prion is proposed to be a novel infectious particle that differs from viruses and viroids. It is composed solely of one unique protein that resists most inactivation procedures such as heat, radiation, and proteases. The latter characteristic has led to the term protease- resistant isoform of the prion protein. The protease-resistant isoform has been proposed to slowly catalyze the conversion of the normal prion protein into the abnormal form.
  • isoform in the context of prions means two proteins with exactly the same ammo acid sequence, that are folded into molecules with dramatically different tertiary structures.
  • the normal cellular isoform of the prion protein (PrP c ) has a high a-helix content, a low b-sheet content, and is sensitive to protease digestion.
  • the abnormal, disease-causing isoform (PrP Sc ) has a lower a-helix content, a much higher b-sheet content, and is much more resistant to protease digestion.
  • prion diseases refers to transmissible spongiform encephalopathies.
  • Examples for prion diseases comprise Scrapie (sheep, goat), TME (transmissible mink encephalopathy; mink), CWD (chronic wasting disease; muledeer, deer, elk), BSE (bovine spongiform encephalopathy; cows, catties), CJD (Creutzfeld-Jacob Disease), vCJD, GSS (Gerstmann-Straussler-Scheinker syndrome), FFI (Fatal familial Insomnia), Kuru, and Alpers Syndrome.
  • BSE vCJD
  • CJD transmissible spongiform encephalopathies.
  • CJD chronic wasting disease
  • muledeer deer
  • elk chronic wasting disease
  • BSE bovine spongiform encephalopathy
  • cows, catties CJD (Creutzfeld-Ja
  • Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of immunological diseases, neuroimmunological diseases, and autoimmune diseases.
  • Immunological diseases are, for instance, asthma and diabetes, rheumatic and autoimmune diseases, AIDS, rejection of transplanted organs and tissues (cf. below), rhinitis, chronic obstructive pulmonary diseases, osteoporisis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, and other manifestations of allergic disease, as well as uncommon problems such as primary immunodeficiencies, including antibody deficiency states, cell mediated immunodeficiencies (e.g., severe combined immunodeficiency, DiGeorge syndrome, Hyper-lgE syndrome, Wiskott- Aldrich syndrome, ataxia- telangiectasia), immune mediated cancers, and white cell defects I O
  • autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes mellitus, immune mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's disease, psoriasis, autoimmune thyroid diseases, and Hashimoto's disease, dermatomyositis, goodpastture syndrome, myasthenia gravis pseudoparalytica, ophtalmia sympatica, phakogene uveitis, chronical agressivce hepatitis, primary billiary cirrhosis, autoimunehemolytic anemy, Werlof disease, specific cells uncontrollably attack the body's own tissues and organs (autoimmunity), producing inflammatory reactions and other serious symptoms and
  • Hashimoto's thyroiditis is one of the most common autoimmune diseases. "Autoimmune disease” refers to a category of more than 80 chronic illnesses, each very different in nature, that can affect everything from the endocrine glands (like the thyroid) to organs like the kidneys, as well as to the digestive system.
  • autoimmune diseases There are many different autoimmune diseases, and they can each affect the body in different ways.
  • the autoimmune reaction is directed against the brain in multiple sclerosis and the gut in Crohn's disease.
  • autoimmune diseases such as systemic lupus erythematosus (lupus)
  • affected tissues and organs may vary among individuals with the same disease.
  • One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs.
  • damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus.
  • Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of bipolar and clinical disorders.
  • bipolar and clinical disorders shall refer to adjustment disorders, anxiety disorders, delirium, dementia, amnestic and other cognitive disorders, disorders usually first diagnosed in infancy, childhood, or adolescence, dissociative disorders, eating disorders, factitious disorders, impulse-control disorders, mental disorders due to a general medical condition, mood disorders, other conditions that may be a focus of clinical attention, personality disorders, schizophrenia and other psychotic disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorder, panic disorder, phobia, agoraphobia, obsessive-compulsive disorder, stress, acute stress disorder, anxiety neurosis, nervousness, phobia, posttraumatic stress disorder, posttraumatic stress disorder (PTSD), abuse, ADHD, obsessive-compulsive disorder (OCD), manic depressive psychosis, specific phobias, social phobia, adjustment disorder with anxious features.
  • anxiety disorders are: acute stress disorder, agoraphobia without history of panic disorder, anxiety disorder due to general medical condition, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, specific phobia, social phobia, substance-induced anxiety disorder.
  • Examples for delirium, dementia, amnestic and other cognitive disorders are: delirium due to a general medical condition, substance intoxication delirium, substance withdrawal delirium, delirium due to multiple etiologies, Alzheimer's, Creutzfeldt-Jakob disease, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, substance-induced persisting, vascular, dementia due to other general medical conditions, dementia due to multiple etiologies, amnestic disorder due to a general medical condition, substance-induced persisting amnestic disorder.
  • disorders usually first diagnosed in infancy, childhood, or adolescence are mental retardation, learning disorders, mathematics disorder, reading disorder, disorder of written expression, learning disorder, motor skills disorders, developmental coordination disorder, communication disorders, expressive language disorder, phonological disorder, mixed receptive-expressive language disorder, stuttering, pervasive developmental disorders, Asperger's disorder, autistic disorder, childhood disintegrative disorder, Rett's disorder, pervasive developmental disorder, attention-deficit/hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, feeding disorder of infancy or early childhood, pica, rumination disorder, tic disorders, chronic motor or vocal tic disorder, Tourette's disorder, elimination disorders, encopresis, enuresis, selective mutism, separation anxiety disorder, reactive attachment disorder of infancy or early childhood, stereotypic movement disorder.
  • dissociative disorders are: dissociative amnesia, depersonalization disorder, dissociative fugue and dissociative identity disorder.
  • Examples for eating disorders are anorexia nervosa and bulimia nervosa.
  • mood disorders are: mood episodes, major depressive episode, hypomanic episode, manic episode, mixed episode, depressive disorders, dysthymic disorder, major depressive disorder, single episode, recurrent, bipolar disorders, bipolar I disorder, bipolar Il disorder, cyclothymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder.
  • Examples for schizophrenia and other psychotic disorders are: schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, delusions, hallucinations, substance-induced psychotic disorder.
  • sexual and gender identity disorders are: female sexual arousal disorder, orgasmic disorders, premature ejaculation, sexual pain disorders, dyspareunia, vaginismus, sexual dysfunction due to a general medical condition, female dyspareunia, female hypoactive sexual desire disorder, male erectile disorder, male hypoactive sexual desire disorder, male dyspareunia, other female sexual dysfunction, other male sexual dysfunction, substance-induced sexual dysfunction, sexual dysfunction, paraphilias, exhibitionism, fetishism, frotteurism, pedophilia, masochism, sadism, transvestic fetishism, voyeurism, paraphilia, gender identity disorder.
  • sleep disorders are: dyssomnias, breathing-related sleep disorder, circadian rhythm sleep disorder, hypersomnia, hypersomnia related to another mental disorder, insomnia, insomnia related to another mental disorder, narcolepsy, dyssomnia, parasomnias, nightmare disorder, sleep terror disorder, sleepwalking disorder, parasomnia.
  • somatoform disorders are: body dysmorphic disorder, conversion disorder, hypochondriasis, pain disorder, somatization disorder, undifferentiated somatoform disorder.
  • substance-related disorders examples include alcohol related disorders, amphetamine related disorders, caffeine related disorders, cannabis related disorders, cocaine related disorders, hallucinogen related disorders, inhalant related disorders, nicotine related disorders, opioid related disorders, psychotic disorder, psychotic disorder, phencyclidine-related disorder, abuse, persisting amnestic disorder, anxiety disorder, persisting dementia, dependence, intoxication, intoxication delirium, mood disorder, psychotic disorder, withdrawal, withdrawal delirium, sexual dysfunction, sleep disorder.
  • inventive compounds are also useful for prophylaxis and/or treatment of cardiovascular diseases such as adult congenital heart disease, aneurysm, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, aritiythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cardiovascular disease prevention, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart diseases, congestive heart failure, heart valve diseases, heart attack, epidural
  • the cell proliferative disease is cancer, which is preferably selected from the group comprising:
  • the proliferation disorders and cancers are preferably selected from the group comprising adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia
  • said diabetes is selected from Type I diabetes or Type Il diabetes.
  • said inflammation is mediated preferably by the cytokines TNF- ⁇ , IL-1 Ii, GM-CSF, IL-6 and/or IL-8.
  • the compounds according to general formula (I) are pharmaceutically active agents for prophylaxis and/or treatment of inflammatory diseases.
  • these compounds are used for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of inflammations and inflammatory diseases in mammals, including humans.
  • Inflammatory diseases can emanate from infectious and non-infectious inflammatory conditions which may result from infection by an invading organism or from irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic causes as shown in the following list.
  • the compounds disclosed herein can be used for prophylaxis and/or treatment of inflammations caused by invading organisms such as viruses, bacteria, prions, and parasites as well as for prophylaxis and/or treatment of inflammations caused by irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic reasons.
  • the disclosed compounds are useful for prophylaxis and/or treatment of inflammatory diseases which are initiated or caused by viruses, parasites, and bacteria which are connected to or involved in inflammations.
  • mycoplasma pulmonis causes e.g. chronic lung diseases (CLD), murine chronic respiratory disease), Helicobacter pylori (human coronary heart disease, stomach ulcers).
  • CLD chronic lung diseases
  • Hcobacter pylori human coronary heart disease, stomach ulcers.
  • viruses are known to cause inflammatory diseases: herpesviruses especially cytomegalovirus (causes human coronary heart disease).
  • the compounds disclosed herein are useful for prophylaxis and/or treatment of inflammatory diseases caused and/or induced and/or initiated and/or enhanced by the afore-mentioned bacteria or viruses.
  • the compounds of formula (I) are useful for prophylaxis and/or treatment of inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory disease uveitis, inflammatory diseases of the larynx.
  • CNS central nervous system
  • inflammatory rheumatic diseases inflammatory diseases of blood vessels
  • inflammatory diseases of the middle ear inflammatory diseases of the middle ear
  • inflammatory bowel diseases inflammatory diseases of the skin
  • inflammatory disease uveitis inflammatory diseases of the larynx.
  • inflammatory diseases of the central nervous system are algal disorders, protothecosis, bacterial disorders, abscessation, idiopathic inflammatory disorders, feline polioencephalomyelitis, granulomatous meningoencephalomyelitis, necrotizing encephalitis, pug dog encephalitis, pyogranulomatous meningoencephalomyelitis, shaker dog disease, mycotic diseases of the CNS, parasitic encephalomyelitis, prion protein induced diseases, feline spongiform encephalopathy, protO2Oal encephalitis-encephalomyelitis, neosporosis, sarcocystosis, encephalitozoonosis, acanthamebiasis, babesiosis, rickettsial disorders, rocky mountain spotted fever, canine ehrlichiosis, salmon poisoning, viral disorders, aujeszky's disease, borna disease
  • CNS central
  • inflammatory rheumatic diseases are rheumatoid arthritis, scleroderma, lupus, polymyositis, dermatomyositis, psoriatic arthritis, ankylosing spondylitis, Reiters's syndrome, juvenile rheumatoid arthritis, bursitis, tendinitis (tendonitis), and fibromyositis.
  • vasculitis examples for inflammatory diseases of blood vessels are vasculitis, autoantibodies in vasculitis, microscopic polyangiitis, giant cell arteritis, Takayasu's arteritis, vasculitis of the central nervous system, thromboangiitis obliterans (Buerger's Disease), vasculitis secondary to bacterial, fungal, and parasitic infection, vasculitis and rheumatoid arthritis, vasculitis in systemic lupus erythematosus, vasculitis in the idiopathic inflammatory myopathies, relapsing polychondritis, systemic vasculitis in sarcoidosis, vasculitis and malignancy, and drug-induced vasculitis.
  • vasculitis examples for inflammatory diseases of blood vessels are vasculitis, autoantibodies in vasculitis, microscopic polyangiitis, giant cell arteritis, Takayasu's arteritis
  • inflammatory diseases of the middle ear are acute suppurative otitis media, bullous myringitis, granular myringitis, and chronic suppurative otitis media, which can manifest as mucosal disease, cholesteatoma, or both.
  • Examples for inflammatory bowel diseases are ulcerative colitis, Crohn's disease.
  • inflammatory diseases of the skin are acute inflammatory dermatoses, urticaria (hives), spongiotic dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, erythemal multiforme (EM minor), Stevens-Johnson syndrome (SJS, EM major), toxic epidermal necrolysis (TEN), chronic inflammatory dermatoses, psoriasis, lichen planus, discoid lupus erythematosus, and acne vulgaris
  • Uveitis are inflammations located in and/or on the eye and may be associated with inflammation elsewhere in the body In most circumstances, patients who have uveitis as part of a disease elsewhere in the body are aware of that illness. The majority of patients with uveitis do not have an apparent associated systemic illness Causes of uveitis can be infectious causes, masquerade syndromes, suspected immune-mediated diseases, and/or syndromes confined primarily to the eye
  • viruses are associated with inflammations: human immunodeficiency virus-l, herpes simplex virus, herpes zoster virus, and cytomegalovirus.
  • Bacterial or spirochetal caused, induced, initiated and/or enhanced inflammations are tuberculosis, leprosy, proprionobacterium, syphilis, Whipple's disease, leptospirosis, brucellosis, and lyme disease.
  • inflammatory diseases caused, induced, initiated and/or enhanced by fungi are histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, sporotrichosis, blastomycosis, and cryptococcosis.
  • Masquerade syndromes are, for instance, leukemia, lymphoma, retinitis pigmentosa, and retinoblastoma.
  • Suspected immune-mediated diseases can be selected from the group comprising ankylosing spondylitis, Behcet's disease, Crohn's disease, drug or hypersensitivity reaction, interstitial nephritis, juvenile rheumatoid arthritis,
  • Kawasaki's disease multiple sclerosis, psoriatic arthritis, Reiter * s syndrome, relapsing polychondritis, sarcoidosis, Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis, vasculitis, vitiligo, Vogt Koyanagi Harada syndrome
  • Syndromes confined primarily to the eye are, for instance, acute multifocal placoid pigmentary epitheliopathy, acute retinal necrosis, birdshot choroidopathy, Fuch's heterochromic cyclitis, glaucomatocyclitic crisis, lens-induced uveitis, multifocal choroiditis, pars planitis, serpiginous choroiditis, sympathetic ophthalmia, and trauma
  • inflammatory diseases of the larynx are gastroesophageal (laryngopharyngeal) reflux disease, pediatric laryngitis, acute laryngeal infections of adults, chronic (granulomatous) diseases, allergic, immune, and idiopathic disorders and miscellaneous inflammatory conditions.
  • Pediatric laryngitis is known as acute (viral or bacterial) infection such as laryngotracheitis (croup), supraglottitis (epiglottitis), diphtheria, and noninfectious causes are for example spasmodic croup and traumatic laryngitis.
  • Acute laryngeal infections of adults are, for instance, viral laryngitis, common upper respiratory infection, laryngotracheitis, herpes simplex, bacterial laryngitis, supraglottitis, laryngeal abscess, and gonorrhea.
  • Chronic (granulomatous) diseases can be selected from the group comprising bacterial diseases, tuberculosis, leprosy, scleroma, actinomycosis, tularemia, glanders, spirochetal (syphilis) diseases, mycotic (fungal) diseases, candidiasis, blastomycosis, histoplasmosis, coccidiomycosis, aspergillosis, idiopathic diseases, sarcoidosis, and Wegener's granulomatosis.
  • bacterial diseases tuberculosis, leprosy, scleroma, actinomycosis, tularemia, glanders, spirochetal (syphilis) diseases, mycotic (fungal) diseases, candidiasis, blastomycosis, histoplasmosis, coccidiomycosis, aspergillosis, idiopathic diseases, sarcoidosis, and Wegener's
  • Allergic, immune, and idiopathic disorders are, for example, hypersensitivity reactions, angioedema, Stevens-Johnson syndrome, immune and idiopathic disorders, infections of the immunocompromised host, rheuatoid arthritis, systeic lupus erythematosus, cicatricial pemphigoid, relapsing polychondritis, Sjogren's syndrome, and amyloidosis.
  • Miscellaneous inflammatory conditions are, for instance, parasitic infections, trichinosis, schistosomiasis, syngamus laryngeus, inhalation laryngitis, acute (thermal) injury, pollution and inhalant allergy, carcinogens, radiation injury, radiation laryngitis, radionecrosis, vocal abuse, vocal-cord hemorrhage, muscle tension dysphonias, and contact ulcer and granuloma.
  • Transplant rejection is when a transplant recipient's immune system attacks a transplanted organ or tissue. No two people (except identical twins) have identical tissue antigens. Therefore, in the absence of immunosuppressive drugs, organ and tissue transplantation would almost always cause an immune response against the foreign tissue (rejection), which would result in destruction of the transplant. Though tissue typing ensures that the organ or tissue is as similar as possible to the tissues of the recipient, unless the donor is an identical twin, no match is perfect and the possibility of organ/tissue rejection remains.
  • inventive compounds of general formula (I) are used as immunosuppressive drugs and/or anti-rejection drugs in order to prevent transplant rejection.
  • transplant rejection is the graft-versus-host-disease (GVHD) that can occur following bone marrow transplant.
  • GVHD graft-versus-host-disease
  • the donor's immune cells in the transplanted marrow make antibodies against the host's (transplant patient's) tissues and attack the patient's vital organs.
  • Transplant rejections also known as graft rejection or tissue/organ rejection
  • Said organs comprise especially inner organs such as heart, heart-lungs, lungs, liver, kidney, pancreas, spleen, skin, tissue, bone marrow, spinal marrow, hormone producing glands, gonads and gonadal glands.
  • Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of neurodegeneration and neurodegenerative disorders.
  • Neurodegenerative disorders of the central nervous system can be grouped into diseases of the cerebral cortex (Alzheimer disease), the basal ganglia (Parkinson disease), the brain-stem and cerebellum, or the spinal cord (amyotrophic lateral sclerosis).
  • neurodegeneration and neurodegenerative disorders are Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, AIDS-related dementia, retinitis pigmentosa, spinal muscular atrophy and cerebrellar degeneration, fragile X-associated tremor/ataxia syndrome (FXTAS), progressive supranuclear palsy (PSP), and striatonigral degeneration (SND), which is included with olivopontocerebellar degeneration (OPCD), and Shy Drager syndrome (SDS) in a syndrome known as multiple system atrophy (MSA).
  • FXTAS fragile X-associated tremor/ataxia syndrome
  • PSP progressive supranuclear palsy
  • SND striatonigral degeneration
  • OPCD olivopontocerebellar degeneration
  • SDS Shy Drager syndrome
  • the compounds according to the general formula (I) as well as pharmaceutically acceptable salts thereof are used as an inhibitor for a protein kinase, preferably as an inhibitor for a cellular protein kinase.
  • a kinase “inhibitor” refers to any compound capable of downregulating, decreasing, suppressing or otherwise regulating the amount and/or activity of a kinase. Inhibition of these kinases can be achieved by any of a variety of mechanisms known in the art, including, but not limited to binding directly to the kinase polypeptide, denaturing or otherwise inactivating the kinase, or inhibiting the expression of the gene (e.g., transcription to mRNA, translation to a nascent polypeptide, and/or final polypeptide modifications to a mature protein), which encodes the kinase.
  • the gene e.g., transcription to mRNA, translation to a nascent polypeptide, and/or final polypeptide modifications to a mature protein
  • kinase inhibitors may be proteins, polypeptides, nucleic acids, small molecules, or other chemical moieties.
  • inhibiting refers to the ability of an compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein and/or the virus replication.
  • a method for preventing and/or treating infectious diseases, including opportunistic diseases, in a mammal, especially in a human comprises administering to the mammal an amount of at least one compound according to the general formula (I), effective to prevent and/or treat said infectious diseases, including opportunistic diseases.
  • the infectious diseases, including opportunistic diseases are virally induced infectious diseases.
  • the virally induced infectious diseases, including opportunistic diseases are caused by retroviruses, hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses.
  • the retroviruses are selected from lentiviruses or oncoretroviruses, wherein the lentivirus is selected from the group comprising: HIV- 1 , HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-1 or HIV-2 and wherein the oncoretrovirus is selected from the group consisting of: HTLV-I, HTLV-II or BLV.
  • the hepadnavirus is selected from HBV, GSHV or WHV, preferably HBV
  • the herpesvirus is selected from the group comprising: HSV I 1 HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV
  • the flaviviridae is selected from HCV, West nile or Yellow Fever.
  • methods for preventing and/or treating infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases, and stroke in a mammal, especially in a human comprise administering to the mammal an amount of at least one compound according to the general formula (I) and/or pharmaceutically acceptable salts thereof, effective to prevent and/or treat said infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases, and stroke.
  • the specific diseases addressed as infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases, and stroke are selected from the groups disclosed above.
  • inventive compounds may be administered in combination with anti-retroviral drugs, selected from the following five classes:
  • NRTIs Nucleoside reverse transcriptase inhibitors
  • NRTIs Non-nucleoside reverse transcriptase inhibitors
  • Another aspect of the present invention relates to drug combinations comprising at least one inventive compound according to general formula (I) and/or pharmaceutically acceptable salts thereof together with at least one anti-retroviral drug, especially at least one of the drugs mentioned above.
  • compositions according to the present invention comprise at least one compound according to the present invention as an active ingredient together with at least one pharmaceutically acceptable (i.e. non-toxic) carrier, excipient and/or diluent.
  • pharmaceutically acceptable (i.e. non-toxic) carrier, excipient and/or diluent i.e. non-toxic carrier, excipient and/or diluent.
  • the pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way
  • the preferred preparations are adapted for oral application.
  • These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
  • compositions according to the present invention containing at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule.
  • Powders and tablets may contain about 5 to about 95-weight % of the 4,6-disubstituted pyrimdine derivative according to the general formula (I) or analogues compound thereof or the respective pharmaceutically active salt as active ingredient.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Suitable disintegrants include starch, methylcellulose, guar gum, and the like.
  • Sweetening and flavoring agents as well as preservatives may also be included, where appropriate.
  • the disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glyce ⁇ des like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • the compounds according to the present invention may also be delivered transdermally.
  • the transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
  • capsule refers to a specific container or enclosure made e.g. of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s).
  • Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives.
  • a compressed or moulded solid dosage form which comprises the active ingredients with suitable diluents.
  • the tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art
  • Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi-solid matrix.
  • Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.
  • Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.
  • disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, "cold water soluble” o
  • modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to about 10 weight %.
  • Binders are substances which bind or "glue” together powder particles and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.
  • Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules.
  • the amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.
  • Ghdents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable ghdents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.
  • Nucleotide-binding proteins play an important role in the metabolism of an organism.
  • enzymes of the protein kinase family are essential switches of the cellular signal transduction machinery in all eucaryotic cells. They have been implicated with the control of numerous physiological and pathophysiological processes in eucaryotic organisms and therefore represent an important class of drug targets for a variety of indications such as cancer, inflammation and infectious diseases.
  • Efficient and selective enrichment is a prerequisite for subsequent identification of protein kinase targets by a proteomics approach. Efficient pre-fractionation techniques are described in WO 04/013633.
  • the compounds of the present invention can be synthesized according to following general scheme:
  • R', R", R 1 , R 4 - R 6 , R 8 , R 10 are hydrogen.
  • the reaction mixture was extracted with 20 cm 3 ethyl acetate and the pH of the water phase was changed to 3 using 3 N hydrochloride solution.
  • the water solution of the product was extracted three times with 20 cm 3 ethyl-acetate, the combined organic phases was washed with 10 cm 3 brine, was dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the crude product was re-crystallized from diethyl ether to give pure product.
  • Reaction Temperature room temperature
  • Assay Plate 96 well U bottom plate (Greiner, 650161 )
  • MultiScreen-PH Plate 96 well MAPH Filter Plates (Millipore, MAPHNOB50)
  • kinase Use kinase cone, yielding 10% ATP turn over.
  • MBP Myelin Basic Protein

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Abstract

La présente invention concerne des benzo[2,3]azépino[4,5-b]indol-6-ones de formule générale (I) : et des sels acceptables du point de vue pharmaceutique de celles-ci, l'utilisation de ces composés comme agents actifs du point de vue pharmaceutique, en particulier pour la prophylaxie et/ou le traitement de maladies infectieuses, dont des maladies opportunistes, des maladies liées au prion, des maladies immunologiques, des maladies auto-immunes, des troubles maniacodépressifs et cliniques, des maladies cardiovasculaires, des maladies de prolifération de cellules, le diabète, une inflammation, des rejets de greffe, un trouble de l'érection, des maladies neurodégénératives et un accident cérébrovasculaire. En outre, la présente invention concerne une composition pharmaceutique contenant au moins l'un des benzo[2,3]azépino[4,5-b]indol-6-ones et/ou des sels acceptables du point de vue pharmaceutique de celles-ci.
PCT/EP2006/060100 2005-02-22 2006-02-20 BENZO[2,3]AZÉPINO[4,5-b]INDOL-6-ONES Ceased WO2006089874A1 (fr)

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US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
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Cited By (9)

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Publication number Priority date Publication date Assignee Title
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof

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