NEUMANN LARS (DE)
HAFENBRADL DORIS (DE)
GREFF ZOLTAN (HU)
KERI GYOERGY (HU)
OERFI LASZLO (HU)
KLEBL BERT (DE)
NEUMANN LARS (DE)
HAFENBRADL DORIS (DE)
GREFF ZOLTAN (HU)
KERI GYOERGY (HU)
OERFI LASZLO (HU)
| WO2003027275A1 | 2003-04-03 | |||
| WO1999065910A1 | 1999-12-23 |
| 1. | Compounds having the general formula (I): wherein R1 R8, R81, R82 represent independently of each other R11, R12, R13, _R14, _Ri5f _R16_ _Ri7j _R18 .CH^RIS1 _CH2R2°, CH2R21, CH2R22, CHR23R24, CHR25R26, CHR27R28, CHR29R30, CR31R32R33, CR34R35R36, CH2CH2R37, CH2CH2R38, CH2CHR39R40, CH2CHR41R42, CR43R44CR45R46R47, CR48R49CR50R51R52, _CR53R54CR55R56CR57R58R59, CR60R61CR62R63CR64R65R66, H, (CH2)qCR60R61(CH2)rR64, (CH2)SR65, (CH2)tR66; R9 represents CHR∞CHR^CONR^R82, CHR67CONR81R82, CONR81R82, CHR68CHR67COR81, CHR67COR81, COR81, CHR68CHR67COOR81, CHR67COOR81, COOF?81; R1, R" and R10 represent independently of each other H, CPh3, CH3, C2H5, C3H7, CyCIoC3H5, CH(CH3)2, C4H9, CH2CH(CH3)2, CH(CH3)C2H5i C(CH3)3, C5H11, C$Hi3, C7H15, CeHi7, C9H19, Ci0H21 , Ph, CH2Ph, CH=CH2, CH2CH=CH2, C(CH3)=CH2, CH=CHCH3, C2H4CH=CH2, CH=C(CH3)2, C≡CH, C≡CCH3, CH2C=CH; R1 1 R8 0 represent independently of each other H, OH, OCH3, OC2H5, OC3H7, 0CyCIoC3H5, OCH(CH3)2, OC(CH3)3, OC4H9, OPh1 OCH2Ph, OCPh3, SH, SCH3, SC2H5, SC3H7, SCyClOC3H5, SCH(CH3)2, SC(CH3)3, NO2, F, Cl, Br, I1 N3, CN, OCN, NCO1 SCN, NCS, CHO, COCH3, COC2H5, COC3H7, COCyClOC3H5, COCH(CH3)2, COC(CH3)3, COOH, COCN, COOCH3, COOC2H5, COOC3H7, COOcycloC3H5, COOCH(CH3)2, COOC(CH3)3, 00CCH3, 0OCC2H5, 0OCC3H7, 0OCCyCIoC3H5, OOCCH(CH3)2) OOCC(CH3)3, CONH2, CONHCH3, CONHC2H5, CONHC3H7, CONHCyClOC3H5, C0NH[CH(CH3)d, CONH[C(CH3)3], CON(CH3)2, CON(C2Hs)2, CON(C3HT)2, CON(cycloC3H5)2, CON[CH(CH3)2]2, CON[C(CH3)3]2, NH2, NHCH3, NHC2H5, NHC3H7, NHCyClOC3H5, NHCH(CH3)2, NHC(CHs)3, N(CH3)2, N(C2Hs)2, N(C3H7)2, N(cycloC3H5)2, N[CH(CH3)2]2, N[C(CH3)3]2, SOCH3, SOC2H5, SOC3H7, SOCyClOC3H5, SOCH(CH3),2, SOC(CH3)3, SO2CH3, SO2C2H5, SO2C3H7, SO2CyCIoC3H5, SO2CH(CH3)2, SO2C(CHa)3, SO3H, SO3CH3, SO3C2H5, SO3C3H7, SO3CyCbC3H5, SO3CH(CH3)2, SO3C(CHa)3, OCF3, OC2F5, 0COOCH3, 0COOC2H5, 0COOC3H7, 0COOCyCIoC3H5, OCOOCH(CH3)2, OCOOC(CH3)3, NHCONH2, NHCONHCH3, NHCONHC2H5, NHCONHC3H7, NHCONHCyCIoC3H5, NHCONH[CH(CH3)2], NHCONH[C(CH3)3], NHCON(CH3)2, NHCON(C2H5)2, NHCON(C3H7)2, NHCON(cycloC3H5)2> NHCON[CH(CH3)2]2) N HCON [C(CH3)3]2, NHCSNH2, NHCSNHCyClOC3H5, NHCSNHC3H7, NHCSNH[CH(CHs)2], NHCSNH[C(CHs)3], NHCSN(CH3)2, NHCSN(C2Hs)2, NHCSN(C3H7J2, NHCSN(cycloC3H5)2, MHC(=NH>NH2, NHCSNHC2H5, NHCSNHCH3, 0CONH2, 0CONHCH3, 0CONHC2H5, 0CONHC3H7, 0CONHCyCIoC3H5, OCONH[CH(CH3)2], 0CONH[C(CHa)3], OCON(CH3)2, 0CON(C2Hs)2, OCON(C3H7)2l OCON(cycloC3H5)2, OCON[CH(CH3)2]2, OCON[C(CH3)3]2, 0COOCH3, 0COOC2H5, 0COOC3H7, 0COOCyClOC3H5, OCOOCH(CH3)2, OCOOC(CH3)3, CH2F CHF2, CF3, CH2CI, CHCI2, CCI3, CH2Br, CHBr2, CBr3, CPh3, CH2CH2F CH2CHF2, CH2CF3, CH2CH2CI, CH2CHCI2, CH2CCI3, CH2CH2Br CH2CHBr2, CH2CBr3, CH3, C2H5, C3H7, cycloC3H5, CH(CH3)2, C(CHs)3, C4H9, CH2CH(CH3)2, CH(CH3)C2H5ι C(CH3)3, C5HIi, CΘHI3, C7HI5, CβHiz, C9H19, C10H2I, Ph, CH2Ph, CH=CH2, CH2CH=CH2, C(CH3)=CH2, CH=CHCH3, C2H4CH=CH2, CH=C(CH3)2, C≡CH, C≡CCH3, CH2C≡CH, CH2CH2SCH3, CH2OH, CH(OH)CH3, CH2NH2, CH2CONH2, CH2CH2CONH2, CH2SH, (CH2)3NHC(=NH)NH2, (CHz)4NH2, NHC(=NH)NH2, CH2COOH, CH2CH2COOH; R67 and R68 represent independently of each other R69, R70, CH2R69, CHR70R71, CR72R73R74, (CH2)nR75, (CH2)PCHR76R77, (CH2)mCR78R79R80, C6H4R72, CH2C6H4R73, R69 R80 also represent independently of each other NR81R82 may also represent m, n, p, q, r, s, t are independently of each other integer from 0 10; and stereoisomer^ forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts thereof, . |
| 2. | Compound according to claim 1 having the general formula II, wherein R1 R8 and R11 have the meanings as defined in claim 1 . |
| 3. | Compound according to claim 1 , 2 or 3, wherein the compound is selected from the group comprising (9Bromo6oxo6,7dihydro5Hbenzo[2,3]azepino[4,5b]indol12yl)acetic acid, (6Oxo9trιfluoromethyl6,7dihydro5Hbenzo[2,3]azepιno|4,5b]ιndol12 yl)acetιc acid, (9Bromo2,3dιmethoxy6oxo6,7dιhydro5Hbenzo[2,3]azepιno[4,5 b]ιndol12yl)acetιc acid, (9Methoxy6oxo6,7dιhydro5Hbenzo[2,3]azepιno[4,5b]ιndol12yl) acetic acid, (2,3Dιmethoxy6oxo9trifluoromethyl6,7dιhydro5H benzo[2,3]azepιno[4,5b]indol12yl)acetιc acιd, 2(9Bromo6oxo6,7dιhydro5//benzo[2,3]azepιno[4,5b]ιndol l 2yl)Λ/ (2methylamιnoethyl)acetamιde, 2(9Bromo2,3dιmethoxy6oxo6,7dιhydro5Hbenzo[2,3]azepιno[4,5 b]ιndol12yl)A/(3dιmethylamιnopropyl)acetamιde, 2(9Bromo6oxo6,7dihydro5Hbenzo[2,3]azepιno[4,5b]ιndol 12yl)N (3dιmethylamιnopropyl)acetamιde, Λ/(3Dιmethylamιnopropyl)2(6oxo9trιfluoromethyl6,7dιhydro5H benzo[2,3]azepιno[4,5b]ιndol12yl)acetamιde, 2(9Bromo6oxo6,7dιhydro5Hbenzo[2,3]azepιno[4,5b]ιndol12yl)Λ/ (2dιmethylamιnoethyl)acetamιde, 2(9Bromo6oxo6,7dιhydro5Hbenzo[2,3]azepιno[4,5b]ιndol12yl)A/ (2dιethylamιnoethyl)acetamιde, N(6Amιnohexyl)2(2,3dimethoxy6oxo9trιfluoromethyl6,7dιhydro5H benzo[2,3]azepino[4,5b]indol12yl)acetamide, 2(9Bromo2,3dimethoxy6oxo6,7dihydro5Hbenzo[2,3]|azepino[4,5 b]ιndol12yl)/V(2piperidin1 ylethyl)acetamide, 2(9Bromo6oxo6,7dihydro5//benzo[2,3]azepino[4,5b]ιndol12yl)Λ/ (2piperazin1ylethyl)acetamide, 2(9Bromo6oxo6,7dihydro5//benzo[2,3]azepino[4,5b]indol12yl)Λ/ [3(2methylpiperidin1yl)propyl]acetamide, N(6Aminohexyl)2(9Bromo2,3dimethoxy6oxo6,7dihydro5H benzo[2,3]azepino[4,5b]indol12yl)acetamide, 2(6Oxo9trifluoromethyl6Jdihydro5Hbenzo[2,3]azepino[4,5b]indol 12yl)Λ/(2piperidin1 ylethyl)acetamide, N(6Aminohexyl)2(9bromo6oxo6,7dihydro5// benzo[2,3]azepino[4,5b]indol12yl)acetamide, N(6Aminohexyl)2(6oxo9trifluoromethyl6,7dihydro5H benzo[2,3]azepino[4,5b]indol12yl)acetamide, 2(9Bromo6oxo6,7dihydro5Hbenzo[2,3]azepino[4,5b]indol12yl)Λ/ (2piperidin1ylethyl)acetamide, 2(9Bromo2,3dimethoxy6oxo6,7dihydro5//benzo[2,3]azepino[4,5 b]indol12yl)Λ/(2morpholin4ylethyl)acetamide, 2(9Bromo6oxo6,7dihydro5Hbenzo[2,3]azepino[4,5b]iπdol12yl)N (2morpholin4ylethyl)acetamide, 2(9Bromo6oxo6,7dihydro5Hbenzo[2,3]azepiπo[4,5b]indol12yl)N (3imidazol1 ylpropyl)acetamide, 2(2,3Dimethoxy6oxo9trifluoromethyl6,7dihydro5H benzo[2,3]azepino[4,5b]indol12yl)N(2morpholin4ylethyl)acetamide, N(6Aminohexyl)2(9methoxy6oxo6,7dihydro5H benzo[2,3]azepino[4,5b]indol12yl)acetamide hydrochloride, (9Bromo2,3dimethoxy6oxo6,7dihydro5Hbenzo[2,3]azepiπo[4,5 b]indol12yl)acetic acid ethyl ester. Compound according to any previous claim for use as a pharmaceutically active agent. Use of a compound according to any one of climas 1 4 as kinase inhibitor or phosphatase inhibitor. |
| 4. | Use of a compound according to claim. |
| 5. | or. |
| 6. | or prophylaxis and/or treatment of diseases associated with the kinases or phosphatases. |
| 7. | 7 Use of a compound according to any one of claims 1 3 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. |
| 8. | 8 Use according to claim 7, wherein the infectious diseases, including opportunistic diseases, are virally induced infectious diseases, including opportunistic diseases. |
| 9. | 9 Use according to claim 8, wherein the virally induced infectious diseases, including opportunistic diseases, are caused by retroviruses, human endogenous retroviruses, lentiviruses, oncoretroviruses, hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses. |
| 10. | 10 Use according to claim 9, wherein the lentivirus, oncoretrovirus, hepadnavirus or herpesvirus is selected from the group comprising: HIV1 , HIV2, FIV, BIV, SIVs, SHIVs, CAEV, VMV or EIAV, preferably HIV1 and HIV2; HTLVI, HTLVII or BLV, preferably HTLVI or HTLVII; HBV, GSHV or WHV, preferably HBV; HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV. |
| 11. | 1 Use according to claim 7 or 8, wherein the infective disease including opportunistic infection is selected from the group comprising 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 (VaricellaZoster virus), Cholera, Chronic Fatigue Syndrome, CJD (CreutzfeldtJakob Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans, Hookworm Infection), 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 (NonPolio), EpsteinBarr Virus Infection, Escherichia coli Infection, Foodbome Infection, Foot and mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal Disease, Group B streptococcal Disease, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis), Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis (HCV, HBV), Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, lsosporiasis (Isospora Infection), Lassa Fever, Leprosy, Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Marburg Hemorrhagic Fever, Measles, Mosquitoborne Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, Rotavirus Infection, Roundworms Infection, Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles, Smallpox, Streptococcal Infection, Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow Fever, tuberculosis, leprosy, mycobacteriainduced meningitis. Use according to claim 7, wherein the prion diseases is selected from the group comprising Scrapie, TME, CWD, BSE, CJD, vCJD, GSS, FFI, Kuru, and Alpers Syndrome. Use according to claim 7, wherein the immunological disease and/or autoimmune disease is selected from the group comprising: asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, 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, manifestations of allergic diseases, primary immunodeficiencies, antibody deficiency states, cell mediated immunodeficiencies, severe combined immunodeficiency, DiGeorge syndrome, HyperlgE syndrome, Wiskott Aldrich syndrome, ataxiatelangiectasia, immune mediated cancers, white cell defects, autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), immunemediated 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, Hashimoto's disease, dermatomyositis, goodpastture syndrome, myasthenia gravis pseudoparalytica, ophtalmia sympatica, phakogene uveitis, chronical agressivce hepatitis, primary billiary cirrhosis, autoimunehemolytic anemy, Werlof disease. 14 Use according to claim 7, wherein the bipolar and/or clinical disorder is selected from the group comprising: 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, impulsecontrol 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, substancerelated disorders, generalized anxiety disorder, panic disorder, phobia, agoraphobia, obsessivecompulsive disorder, stress, acute stress disorder, anxiety neurosis, nervousness, phobia, posttraumatic stress disorder, posttraumatic stress disorder (PTSD), abuse, ADHD, obsessivecompulsive disorder (OCD), manic depressive psychosis, specific phobias, social phobia, adjustment disorder with anxious features. |
| 12. | 15 Use according to claim 14, wherein the anxiety disorders, delirium, dementia, amnestic and other cognitive disorders, disorders usually first diagnosed in infancy, childhood, or adolescence, dissociative disorders, eating disorders, mood disorders, schizophrenia and other psychotic disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance related disorders are selected from the group comprising: 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, substanceinduced anxiety disorder, delirium due to a general medical condition, substance intoxication delirium, substance withdrawal delirium, delirium due to multiple etiologies, Alzheimer's, CreutzfeldtJakob disease, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, substanceinduced persisting, vascular, dementia due to other general medical conditions, dementia due to multiple etiologies, amnestic disorder due to a general medical condition, substanceinduced persisting amnestic disorder, 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 receptiveexpressive 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 amnesia, depersonalization disorder, dissociative fugue, dissociative identity disorder, anorexia nervosa, bulimia nervosa, 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, substanceinduced mood disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, delusions, hallucinations, substanceinduced psychotic disorder, 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, substanceinduced sexual dysfunction, sexual dysfunction, paraphilias, exhibitionism, fetishism, frotteurism, pedophilia, masochism, sadism, transvestic fetishism, voyeurism, paraphilia, gender identity disorder, dyssomnias, breathingrelated 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, body dysmorphic disorder, conversion disorder, hypochondriasis, pain disorder, somatization disorder, undifferentiated somatoform disorder, 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, phencyclidinerelated disorder, abuse, persisting amnestic disorder, anxiety disorder, persisting dementia, dependence, intoxication, intoxication delirium, mood disorder, psychotic disorder, withdrawal, withdrawal delirium, sexual dysfunction, sleep disorder. 16 Use according to claim 7, wherein the cardiovascular diseases are selected from the group consisting of: adult congenital heart disease, aneurysm, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic 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, ChurgStrauss 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 hematoma, hematoma, subdural, HippelLindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel TrenaunayWeber syndrome, lateral medullary syndrome, long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm, ventricular fibrillatipn, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff ParkinsonWhite syndrome. 17 Use according to claim 7, wherein the proliferative disease is 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, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/NonHodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, nonHodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, Tcell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer. 5 18 Use according to claim 7, wherein said diabetes is selected from Type I diabetes or Type Il diabetes. |
| 13. | 19 Use according to claim 7, wherein said inflammation is mediated by the cytokines TNFα, IL1 β, GMCSF, IL6 and/or IL8. i o 20 Use according to claim 7 or 19 wherein the inflammatory disease is caused, induced, initiated and/or enhanced by bacteria, viruses, prions, parasites, fungi, and/or caused by irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic reasons. |
| 14. | 1 5 21 Use according to claim 20 wherein the viruses and bacteria are selected from the group comprising human immunodeficiency virusl, herpes viruses, herpes simplex virus, herpes zoster virus, cytomegalovirus, mycoplasma pulmonis, ureaplasma urealyticum, Helicobacter pylori, and propriono 20 bacterium. 22 Use according to any one of the claims 7, 19 21 , wherein the inflammatory disease is selected from the group comprising inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic 25 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. |
| 15. | 23 Use according to claim 22 wherein the inflammatory diseases of the central 30 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 are selected from the group comprising: 35 abscessation, acanthamebiasis, acne vulgaris, actinomycosis, acute inflammatory dermatoses, acute laryngeal infections of adults, acute multifocal placoid pigmentary epitheliopathy, acute (thermal) injury, acute retinal necrosis, acute suppurative otitis media, algal disorders, allergic contact dermatitis, amyloidosis angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, Aujeszky's disease, autoantibodies in vasculitis, babesiosis, bacterial disorders, bacterial laryngitis, Behcet's disease, birdshot choroidopathy, blastomycosis, borna disease, brucellosis, bullous myringitis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in immature animals, canine ehrlichiosis, canine herpes virus encephalomyelitis, cholesteatoma, chronic (granulomatous) diseases, chronic inflammatory dermatoses, chronic relapsing encephalomyelitis, chronic suppurative otitis media, cicatricial pemphigoid, coccidiomycosis, coccidioidomycosis, common upper respiratory infection, contact ulcer and granuloma, Crohn's disease, cryptococcosis, dermatomyositis, diphtheria, discoid lupus erythematosus, druginduced vasculitis, drug or hypersensitivity reaction, encephalitozoonosis, erythemal multiforme (EM minor), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalomyelitis, feline spongiform encephalopathy, fibromyositis, Fuch's heterochromic cyclitis, gastroesophageal (laryngopharyngeal) reflux disease, giant cell arteritis, glanders, glaucomatocyclitic crisis, gonorrhea granular myringitis, granulomatous meningoencephalomyelitis, herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune and idiopathic disorders, infections of the immunocompromised host, infectious canine hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki's disease, La Crosse virus encephalitis, laryngeal abscess, laryngotracheitis (croup), lensinduced uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lyme disease, microscopic polyangiitis, multifocal choroiditis, multifocal distemper encephalomyelitis in mature animals, multiple sclerosis, muscle tension dysphonias, mycotic (fungal) diseases, mycotic diseases of the CNS, necrotizing encephalitis, neosporosis, old dog encephalitis, parasitic encephalomyelitis, parasitic infections, pars planitis, parvovirus encephalitis, pediatric laryngitis, pollution and inhalant allergy, polymyositis, postvaccinal canine distemper encephalitis, postvaccinal rabies, prion protein induced diseases, protothecosis, protozoal encephalitisencephalomyelitis, psoriasis, psoriatic arthritis, pug dog encephalitis, pyogranulomatous meningoencephalomyelitis, rabies, radiation injury, radiation laryngitis, radionecrosis, relapsing polychondritis, Reiters's syndrome, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, rickettsial disorders, rocky mountain spotted fever, salmon poisoning, sarcocystosis, sarcoidosis, schistosomiasis, scleroderma, scleroma, serpiginous choroiditis, shaker dog disease, Sjogren's syndrome, spasmodic croup, spirochetal (syphilis) diseases, spongiotic dermatitis, sporotrichosis, StevensJohnson syndrome (SJS, EM major), supraglottis (epiglottitis), sympathetic ophthalmia, syngamus laryngeus, syphilis, systemic lupus erythematosus, systemic vasculitis in sarcoidosis, Takayasu's arteritis, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's Disease), tick borne encephalitis in dogs, toxic epidermal necrolysis (TEN), trauma, traumatic laryngitis, trichinosis, tuberculosis, tularemia, ulcerative colitis, urticaria (hives), vasculitis, vasculitis and malignancy, vasculitis and rheumatoid arthritis, vasculitis in systemic lupus erythematosus, vasculitis in the idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal, and parasitic infection, viral disorders, viral laryngitis, vitiligo, vocal abuse, vocalcord hemorrhage, Vogt Koyanagi Harada syndrome, Wegener's granulomatosis, and Whipple's disease. |
| 16. | 24 Use according to claim 7, wherein the transplant rejection is selected from the group comprising heart transplant rejection, heartlung transplant rejection, lung transplant rejection, liver transplant rejection, kidney transplant rejection, pancreas transplant rejection, spleen transplant rejection, skin transplant rejection, tissue transplant rejection, bone marrow transplant rejection, spinal marrow transplant rejection, hormone producing glands transplant rejection, gonads and gonadal gland transplant rejection, graftversushostdiseases and hostversusgraftdiseases. |
| 17. | 25 Use according to claim 7, wherein the neurodegenerative diseases are selected from the group comprising: Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, AIDSrelated dementia, retinitis pigmentosa, spinal muscular atrophy and cerebrellar degeneration, fragile Xassociated tremor/ataxia syndrome (FXTAS), progressive supranuclear palsy (PSP), and striatonigral degeneration (SND), which is included with olivopontocerebellear degeneration (OPCD), and Shy Drager syndrome (SDS) in a syndrome known as multiple system atrophy (MSA). 26 Use of a compound according to any one of claims 1 3 in combination with an antiHIV drug, antiproliferative drug, cytotoxic or cytostatic drug, ganciclovir, foscamet, cidofovir, valganciclovir, fomivirsen, penciclovir or valaciclovir. 27 Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. |
Specification
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.
Background of the invention
Compounds similar to the benzo[2,3]azepino[4,5-b]indol-6-ones are known from WO 2004091663, WO 2003084926, WO 2003027275 and WO 9965910.
It is object of the present invention to provide compounds, stereoisomer^ forms and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially 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.
The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.
The novel benzo[2,3]azepino[4,5-b]indol-6-ones according to the present invention are represented by the following general formula (I)
wherein
R 1 - R 8 , R 81 , R 82 represent independently of each other -R 11 , -R 12 -R 13 , -R 14 ,
-R 15 , -R 16 , -R 17 , -R 18 , -CH 2 -R 19 , -CH 2 -R 20 -CH 2 -R 21 , -CH 2 -R 22 , -CHR 23 R 24 ,
-CHR 25 R 26 , -CHR 27 R 28 , -CHR 29 R 30 , -CR 31 R 32 R 33 , -CR 34 R 35 R 36 , -CH 2 -CH 2 -R 37 ,
-CH 2 -CH 2 -R 38 , -CH 2 -CHR 39 R 40 , -CH 2 -CHR 41 R 42 , -CR 43 R^-CR 45 R 46 R 47 ,
-CR 48 R^-CR 50 R 51 R 52 , -(CH 2 ) s -R 65 , -(CH 2 ) t -R 66 , -CR^R^-CR^R^-CR^R^R 59 ,
-CR 60 R 61 -CR 62 R 63 -CR 64 R 65 R 66 , -(CH 2 ) q -CR∞R^CH^R 64 , -H;
R 9 represents -CHR 68 -CHR 67 -CO-NR 81 R 82 , -CHR ϊ 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 , -CO-OR 81 ;
R', R" and R 10 represent independently of each other -H, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CyCIo-C 3 H 5 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CHs) 2 , -CH(CHs)-C 2 H 5 , -C(CH 3 ) 3 , -C 5 H 11 , -C 6 H 13 , -C 7 HI 5 , -CβH-i 7 , -C 9 H- 19 , -CioH 2 i, -Ph, -CH 2 -Ph, -CH=CH 2 , -CH 2 -CH=CH 2 , -C(CH 3 J=CH 2 , -CH=CH-CH 3 , -C 2 H 4 -CH=CH 2 , -CH=C(CHa) 2 , -C≡CH, -C=C-CH 3 , -CH 2 -C=CH;
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 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5) -COOCH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -OOC-CH 3 , -0OC-C 2 H 5 , -OOC-C 3 H 7 , -OOC-cyclo-C 3 H 5 , -OOC-CH(CHs) 2 ,
-OOC-C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-cyclo-C 3 H 5 , -CONH[CH(CH 3 ) 2 ], -CONH[C(CH 3 ) 3 ], -CON(CH 3 ) 2 , -CON(C 2 H 5 ) 2 , -CON(C 3 H 7 ) 2 , -CON(cyclo-C 3 H 5 ) 2 , -CON[CH(CH 3 ) 2 ] 2 ,
-CON[C(CH 3 ) 3 ] 2 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 ,
-NH-cyclo-C 3 H 5 , -NHCH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -N(CHs) 2 , -N(C 2 H 5 ) 2 , -N(C 3 H 7 ) 2 , -N(cyclo-C 3 H 5 )2, -N[CH(CH 3 ) 2 ] 2 , -N[C(CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-CyCIo-C 3 H 5 , -SOCH(CH 3 ) 2 , -SOC(CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -CyCIo-C 3 H 5 , -SO 2 CH(CH 3 ) 2 , -SO 2 C(CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 ,
-SO 3 -CyCIo-C 3 H 5 , -SO 3 CH(CH 3 ) 2 , -SO 3 C(CH 3 ) 3 , -OCF 3 , -OC 2 F 5 , -0-COOCH 3 , -0-COOC 2 H 5 , -0-COOC 3 H 7 , -0-COO-CyCIo-C 3 H 5 , -O-COOCH(CH 3 ) 2 , -O-COOC(CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO-NH-CyCIo-C 3 H 5 ,
-NH-CO-NH[CH(CH 3 ) 2 ], -NH-CO-NH[C(CH 3 ) 3 ], -NH-CO-N(CH 3 ) 2 ,
-NH-CO-N(C 2 Hs) 2 , -NH-CO-N(C 3 H 7 ) 2 , -NH-CO-N(cyclo-C 3 H 5 ) 2 ,
-NH-CO-N[CH(CH 3 ) 2 ] 2 , -NH-CO-N[C(CH 3 ) 3 ] 2 , -NH-CS-NH 2 ,
-NH-CS-NH-CyCIo-C 3 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH[CH(CHa) 2 ], -NH-CS-NH[C(CH 3 ) 3 ], -NH-CS-N(CH 3 ) 2 , -NH-CS-N(C 2 Hs) 2 ,
-NH-CS-N(C 3 H 7 ) 2 , -NH-CS-N(cyclo-C 3 H 5 ) 2 , -NH-C^NH)-NH 2 ,
-NH-CS-NHC 2 H 5 , -NH-CS-NHCH 3 , -0-CO-NH 2 , -0-CO-NHCH 3 ,
-0-CO-NHC 2 H 5 , -0-CO-NHC 3 H 7 , -0-CO-NH-CyCIo-C 3 H 5 ,
_O-CO-NH[CH(CH 3 ) 2 ], -0-CO-NH[C(CHa) 3 ], -O-CO-N(CH 3 ) 2 , -0-CO-N(C 2 Hs) 2 , -O-CO-N(C 3 H 7 ) 2 , -O-CO-N(cyclo-C 3 H 5 ) 2 ,
-O-CO-N[CH(CH 3 ) 2 ] 2 , -O-CO-N[C(CH 3 ) 3 ] 2 , -0-CO-OCH 3 ,
-0-CO-OC 2 H 5 , -0-CO-OC 3 H 7 , -0-CO-O-CyCIo-C 3 H 5 ,
-O-CO-OCH(CH 3 ) 2 , -O-CO-OC(CH 3 ) 3 , -CH 2 F -CHF 2 , -CF 3 , -CH 2 CI, -CHCI 2 , -CCI 3 , -CH 2 Br -CHBr 2 , -CBr 3 , -CPh 3 , -CH 2 -CH 2 F -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 CI, -CH 2 -CHCI 2 , -CH 2 -CCI 3 , -CH 2 -CH 2 Br
-CH 2 -CHBr 2 , -CH 2 -CBr 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CyCIo-C 3 H 5 , -CH(CH 3 ) 2 ,
C(CHa) 3 , -C 4 H 9 , -CH 2 -CH(CHa) 2 , -CH(CH 3 )-C 2 H 5 , -C(CH 3 ) 3 , -C 5 H 11 ,
-C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 9 H 19 , -C 10 H 21 , -Ph, -CH 2 -Ph, -CH=CH 2 ,
-CH 2 -CH=CH 2 , -C(CH 3 )=CH 2l -CH=CH-CH 3 , -C 2 H 4 -CH=CH 2 , -CH=C(CH 3 ) 2 , -C≡CH, -C=C-CH 3 , -CH 2 -C=CH, -CH 2 -CH 2 -SCH 3 , CH 2 OH, -CH(OH)-CH 3 , -CH 2 NH 2 , -CH 2 -CONH 2 , -CH 2 -CH 2 -CONH 2 , CH 2 SH, _(CH 2 ) 3 -NH-C(=NH)-NH 2 , -(CH 2 ) 4 -NH 2 , -NH-C(=NH)-NH 2 , CH 2 COOH, -CH 2 -CH 2 -COOH;
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
m, 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.
The following subformula (II) - (VII) of formula (I) are especially preferred:
wherein
R ) 1 - DR9 and R have the meanings as defined in claim 1.
In yet another preferred embodiment of the present invention the compound according to general formula (I) is selected from the group of compounds depicted in Table 1 :
Table 1 : Claimed compounds according to the present invention
Comp. No. IUPAC name
(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3] azepino[4,5-b]indol-12-yl)-acetic acid
(6-Oxo-9-trifluoromethyl-6,7-dihydro-5H-benzo [2,3]azepino[4,5-b]indol-12- yl)-acetic acid
(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]aze pino[4,5- b]indol-12-yl)-acetic acid
(9-Methoxy-6-oxo-6,7-dihydro-5H-benzo[2,3] azepino[4,5-b]indol- 12-yl)- acetic acid
(2,3-Dimethoxy-6-oxo-9-trifluoromethyl-6,7-dihydro-5H- benzo[2,3]azepino[4,5-b]ιndol-12-yl)-acetic acid
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-bli ndol-12-yl)-/V- (2-dιmethylamino-ethyl)-acetamide
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-bli ndol-12-yl)-N- (3-dιmethylamιno-propyl)-acetamιde
Λ/-(3-DιmeThylamιno-propyl)-2-(6-oxo-9-trifluoromethyl -6,7-dιhydro-5/-/- benzo[2,3] azepino[4,5-b]indol-12-yl)-acetamide
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-bli ndol-12-yl)-Λ/- (2-dιethylamino-ethyl)-acetamide
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b)i ndol-12-yl)-Λ/- (2-methylamino-ethyl)-acetamide
2-(9-Bromo-2,3-dιmethoxy-6-oxo-6,7-dιhydro-5H-benzo[2,3 ]azepιno[4,5- b]ιndol-12-yl)-Λ/-(3-dιmethylamino-propyl)-acetamide 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12-yl)-N-
(2-morpholin-4-yl-ethyl)-acetamide
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b|i ndol-12-yl)-N-
(3-ιmιdazol-1-yl-propyl)-acetamide
2-(2 > 3-Dιmethoxy-6-oxo-9-trifluoromethyl-6,7-dihydro-5H- benzo[2,3]azepino[4,5-b]indol-12-yl)-N-(2-morpholin-4-yl-elh yl)-acetamιde
{6-[2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5 -b]indol-12-yl)- acetylamino]-hexyl}-carbamic acid terf-butyl ester
{e-p-CΘ-Bromo^.S-dimethoxy-e-oxo-ej-dihydro-δH-benzop.S Jazepinoμ.S- bjindol-^-ylJ-acetylaminol-hexylJ-carbamic acid teAt-butyl ester |{6-[2-(9-Methoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5 -b]indol-12- yl)-acetylamιno]-hexyl}-carbamιc acid tert-butyl ester
{6-[2-(2,3-Dimethoxy-6-oxo-9-trifluoromethyl-6,7-dihydro- 5H-benzo[2,3] azepino^.S-bjindol-^-ylJ-acetylaminoj-hexylJ-carbamic acid tert-buiy\ ester
N-(6-Amino-hexyl)-2-(9-methoxy-6-oxo-6,7-dihydro-5H- benzo[2,3]azepιno[4,5-b]indol-12-yl)-acetamιde hydrochloride
N-(6-Amino-hexyl)-2-(2,3-dimethoxy-6-oxo-9-trifluoromethy l-6,7-dihydro- 5/-/-benzo[2.31 azenιnof4 5-h1ιndol-12-vh-ar.fitamide
5/-/-benzo[2,3] azepino[4,5-b]indol-12-yl)-acetamide
(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]aze pino[4,5- b]indol-12-yl)-acetic acid ethyl ester
2-(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5/-/-benzo[2,3 ]azepino[4,5- b]indol-12-yl)-/V-(2-pιperidin-1-yl-ethyl)-acetamide
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]i ndol-12-yl)-Λ/- ^-piperazin-i-yl-ethyO-acetamide
2-(^-Brorno^oxo-6,7-dihydro-5/-/-benzo[2,3]azepino[4,5-b] indol-12-yl)-Λ/- [3-(2-methyl-piperidιn-1-yl)-propyl]-acetamide
N-(6-Amino-hexyl)-2-(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihy dro-5H- benzo[2,3]azepino[4,5-b]indol-12-yl)-acetamide
2-(6-Oxo-9-trifluoromethyl-6,7-dihydro-5H-benzo[2,3]azepi no[4,5-b]indol- 12-yl)-Λ/-(2-piperidin-1 -yl-ethyl)-acetamide
N-(6-Amino-hexyl)-2-(9-bromo-6-oxo-6,7-dihydro-5/-/- benzo[2,3]azepino[4,5-b]indol-12-yl)-acetamide
N-(6-Amino-hexyl)-2-(6-oxo-9-trifluoromethyl-6,7-dihydro- 5W- benzo[2,3]azepino[4,5-b]indol-12-yl)-acetamιde
2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]i ndol-12-yl)-/V- (2-pιperidin-1-yl-ethyl)-acetamide
Σ-CΘ-Bromo^.S-dimethoxy-θ-oxo-βJ-dihydro-SH-benzop.Sl azepinoμ.δ- b]ιndol-12-yl)-Λ/-(2-morpholin-4-yl-ethyl)-acetamide
Table Il Inhibitory effect of the compounds of the present invention on different targets (+ = >30% inhibition at concentration 10 μM)
Compound Number © Target PDGFRbeta GST
© Target CDK2/CycA ® Target PKA
3 Target CRIK (citron kinase) ® Target RICK -STREP 1
© Target DDR1 O Target c-Raf
G ) Target EGFR GST-HIS θ Target c-Src HIS © Target GSK-3beta HIS © Target p56Lck
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. Examples of 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-toluenesulfonic acid, naphthylsulforiic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. 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. In case, 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.
In the case of chiral substituents, 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. Where 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. 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.
In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent. Furthermore, the 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.
Excluded from the scope of the present invention are 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.
Infectious diseases including opportunistic infections
In yet another aspect of the present invention, 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. The term infectious diseases comprises infections caused by viruses, bacteria, prions and/or fungi.
Especially, virally induced infectious diseases, including opportunistic diseases are addressed. In a preferred embodiment of this aspect, the virally induced infectious diseases, including opportunistic diseases, are caused by retroviruses, human endogenous retroviruses (HERVs), hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses. Preferably, 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.
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, and 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.
Examples of 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, Hookworm Infection),
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 B streptococcal Disease, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis), Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis (HCV, HBV), Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, lsosporiasis (Isospora Infection), Lassa Fever, Leprosy, Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Marburg Hemorrhagic Fever, Measles, Mosquito-borne Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, Rotavirus Infection, Roundworms Infection, Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles, Smallpox, Streptococcal Infection, Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow Fever.
Bacterial infections
As described above, 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. One advantage of the inventive compounds disclosed herein is there use against drug resistant bacteria strains.
Prion diseases
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. Examples of 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).
The name "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.
The term "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.
As used herein the term "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. Preferred are BSE, vCJD, and CJD.
Immunological diseases
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
In 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 diseases.
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.
There are many different autoimmune diseases, and they can each affect the body in different ways. For example, the autoimmune reaction is directed against the brain in multiple sclerosis and the gut in Crohn's disease. In other 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. Ultimately, 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.
Bipolar and clinical disorders
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.
The term "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.
Examples for 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.
Examples for 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.
Examples for dissociative disorders are: dissociative amnesia, depersonalization disorder, dissociative fugue and dissociative identity disorder.
Examples for eating disorders are anorexia nervosa and bulimia nervosa.
Examples for 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.
Examples for 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.
Examples for 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.
Examples for somatoform disorders are: body dysmorphic disorder, conversion disorder, hypochondriasis, pain disorder, somatization disorder, undifferentiated somatoform disorder.
Examples for substance-related disorders are: 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.
Cardiovascular diseases
The 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 hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
Preferred are adult congenital heart disease, aneurysms, angina,, angina pectoris, arrhythmias, cardiovascular disease prevention, cardiomyopathies, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis and arteriosclerosis.
Proliferative disease
In yet another preferred embodiment, 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, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Wilrn's tumor, cervical carcinoma and tongue cancer.
Preferred are the following cancer types: bladder, breast, central nervous system, colon, gastric, lung, kidney, melanoma, head and neck, ovarian, cervix,
glioblastoma, pancreas, prostate, stomach, skin testis, leukemia, Hodgkin ' s lymphoma, liver and renal cancer.
Diabetes In yet another preferred embodiment, said diabetes is selected from Type I diabetes or Type Il diabetes.
Inflammation
In yet another preferred embodiment, said inflammation is mediated preferably by the cytokines TNF-α, IL-1 Ii, GM-CSF, IL-6 and/or IL-8.
As described above, the compounds according to general formula (I) are pharmaceutically active agents for prophylaxis and/or treatment of inflammatory diseases. Thus, 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.
I Acute infections
A Viral B. Bacterial
II Noninfectious causes
III. Chronic (granulomatous) diseases
A. Bacterial B. Spirochetal C. Mycotic (Fungal) D. Idiopathic
IV. Allergic, immune, and idiopathic disorders
A. Hypersensitivity reactions
B. Immune and idiopathic disorders
V Miscellaneous inflammatory conditions A. Parasitic infections B Inhalation causes: - Acute (thermal) injury
- Pollution and inhalant allergy
- Carcinogens C Radiation injury: - Radionecrosis
Thus, 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.
Consequently, 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.
The following bacteria are known to cause inflammatory diseases: mycoplasma pulmonis (causes e.g. chronic lung diseases (CLD), murine chronic respiratory disease), Helicobacter pylori (human coronary heart disease, stomach ulcers).
The following 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.
Furthermore, 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.
Examples for inflammatory diseases of the central nervous system (CNS) 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, canine herpes virus encephalomyelitis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in immature animals, multifocal distemper encephalomyelitis in mature animals, old dog encephalitis, chronic relapsing encephalomyelitis, postvaccinal canine distemper encephalitis, fel ne immunodeficiency virus, feline infectious peritonitis, feline leukemia virus, infectious canine hepatitis, La Crosse virus encephalitis, parvovirus encephalitis, rabies, post-vaccinal rabies, tick- borne encephalitis in dogs.
Examples for 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.
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.
Examples for 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.
Examples for 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
The following 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.
Examples of 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
Examples for 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.
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
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.
The inventive compounds of general formula (I) are used as immunosuppressive drugs and/or anti-rejection drugs in order to prevent transplant rejection.
One example of transplant rejection is the graft-versus-host-disease (GVHD) that can occur following bone marrow transplant. 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) may commonly occur when tissue or organs, which need blood supply, are transplanted. 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.
Neurodegenerative diseases
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.
Among the hundreds of different neurodegenerative disorders, the attention has been given only to a handful, including Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis.
It is worth to mention that the same neurodegenerative process cεm affect different areas of the brain, making a given disease appear very different from a symptomatic standpoint.
Neurodegenerative disorders of the central nervous system (CNS) 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).
Examples for 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).
In another aspect of the present invention, 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.
As used herein, 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. Generally, kinase inhibitors may be proteins, polypeptides, nucleic acids, small molecules, or other chemical moieties. As used herein the term "inhibiting" or "inhibition" 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.
In a further aspect of the present invention, a method for preventing and/or treating infectious diseases, including opportunistic diseases, in a mammal, especially in a human, is provided, which method 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. In a preferred embodiment of this method, 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. In a further preferred embodiment of this method, 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. In a further preferred embodiment of this method, 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 and the flaviviridae is selected from HCV, West nile or Yellow Fever.
In a further aspect of the present invention, 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, are provided, which methods 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.
In further preferred embodiments, 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.
The compounds shown explicitly in Table 2 are preferred to be used within the methods or indications disclosed herein. Another aspect of the present invention is that at least one compound according to the general formula (I) used as a pharmaceutically active agent may be administered in combination with further therapeutic compounds.
For the indication HIV, the inventive compounds may be administered in combination with anti-retroviral drugs, selected from the following five classes:
1 ) Nucleoside reverse transcriptase inhibitors (NRTIs),
2) Non-nucleoside reverse transcriptase inhibitors (NNRTIs),
3) Protease inhibitors (PIs), 4) Fusion inhibitors or
5) Immune stimuli.
Thus, 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.
The pharmaceutical 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. 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.
Furthermore, 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.
The pharmaceutical 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. For example, for oral administration in the form of tablets or capsules, 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. Moreover, 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. Among 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.
Moreover, the pharmaceutical 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.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceπdes 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.
Also included are 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.
The term capsule as recited herein 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.
Under tablet a compressed or moulded solid dosage form is understood 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 %.
The term 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. E.g., 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.
EXPERIMENTAL PART:
Synthesis of compounds:
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.
General method 1 :
Preparation of (9-substituted-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b] indol- 12-yl)-acetic acides (example 1-5)
0.33 g (1 .00 mmol) 9-substituted-5,12-dihydro-7H-benzo[2,3]azepino[4,5-b]indol- 6- one in 20 cm 3 anhydrous tetrahydrofuran was treated with 0.10 g (1.50 mmol) sodium ethoxide. After stirring one hour at room temperature 0.25 g, 0.17 cm 3 (1.50 mmol) ethyl-bromoacetate was added in one portion to the reaction mixture, and it was stirred another 24 hours at this temperature. Then 20 cm 3 water and 2 cm 3 1 N sodium-hydroxide solution was added, and the stirring was continued for four hours. 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.
Example 1 : (9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indol- 12-yl)- acetic acid
Yield: 0.20 g (48 %) Mp.: 285-290 0 C LCMS: rt=3.23 M =383.9
1 H-NMR (DMSO-d 6 ) 3.10 (broad s, 1 H), 4.00 (broad s, 1 H), 4.32 (s, 2H), 7.28 (d, J=8 61 Hz, 1 H), 7.42 (m, 4H), 7.73 (d, J=7.95 Hz, 1 H), 7.93 (s, 1 H), 11.91 (s, 1 H), 12 72 (broad s, 1 H) ppm.
Example 2: (6-Oxo-9-trifluoromethyl-6,7-dihydro-5H-benzo[2,3]azepino[4, 5- b]indol-12-yl)-acetic acid
Yield: 0.20 g (50 %) Mp.: 270-272 0 C LCMS: rt=3.29 M =373.1
1 H-NMR (DMSOd 6 ) 3.30 (broad s, 1 H), 4.10 (broad s, 1 H), 4.33 (s, 2H), 7.48 (m, 4H), 7 63 (d, J=8.52 Hz, 1 H), 7.76 (d, J=7.32 Hz, 1 H), 8.16 (s, 1 H), 12.21 (s, 1 H) ppm
Example 3: (9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepin o [4,5-b]indol-12-yl)-acetic acid
Yield. 0.17 g (36 %) Mp.: 240-242 °C LCMS: rt=3.25 M " =444.0
1 H-NMR (DMSOd 6 ) 3.00 (broad s, 1 H), 3.82 (s, 3H), 3.88 (s, 3H), 3.95 (broad s, 1 H), 4 33 (s, 2H), 7.08 (s, 1 H), 7.24 (s, 1 H), 7.27 (d, J=1.89 Hz, 1 H), 7.41 (d, J=8.58 Hz, 1 H), 7.88 (d, J=1.77 Hz, 1 H), 11.1 1 (s, 1 H) ppm.
Example 4: (9-Methoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-acetic acid
Yield 0.20 g (60 %) Mp.: 125-130 0 C LCMS: rt=3.05 M " =335.1 1 H-NMR (DMSO-d 6 ) 3.00 (broad s, 1 H), 3.80 (s. 3H), 3.95 (broad s, 1 H), 4.15 ( broad s, 2H), 6.82 ( dd, J 1 =8.79 Hz, J 2 =2.40 Hz, 1 H), 7.20 (d, J=2.31 Hz, 1 H), 7.50 (m, 4H), 7.70 (dd, J 1 =7.35 Hz, J 2 =1.14 Hz, 1 H), 11.53 (s, 1 H), 12.60 (broad s, 1 H) ppm
Example 5: (2,3-Dimethoxy-6-oxo-9-trifluoromethyl-6,7-dihydro-5H-benzo[ 2,3] azepιno[4,5-b]indol-12-yl)-acetic acid
Yield. 0.24 g (54 %) Mp.: 280-290 0 C LCMS: rt=3.25, 3.42 M ' =433.0
H-NMR (DMSO-ds) 3.10 (broad s, 1 H), 3.83 (s, 3H), 3.89 (s, 3H), 4.10 (broad s,
1 H), 4.35 (s, 2H), 7.10 (s, 1 H), 7.28 (s, 1 H), 7.44 (dd, J 1 =8.65 Hz, J 2 =1.29 Hz, 1 H), 7 62 (d, J=8.52 Hz, 1 H), 8.11 (s, 1 H), 12.07 (s, 1 H), 12.80 (broad s, 1 H) ppm
General method 2:
Preparation of 2-(9-substituted-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5- b]ιndol-12-yl)-N-substituted-acetamides (example 6-18)
0 50 mmol (9-substituted-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5b] indol-12- yl)-acetιc acid derivative (example 1-3) and 0.10 g (0.60 mmol) N 1 N ' - carbonyldiimidazole was refluxed in 10 cm 3 anhydrous terahydrofuran for six hours Then the reaction mixture was cooled to room temperature, and it was treated with 0 60 mmol corresponding amine derivative. After stirring four hours at room temperature, and half an hour at 0 0 C the precipitated product was filtered off, and was washed with 5 cm 3 diethyl ether to give pure product.
Example 6: 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-N-(2-dimethylamino-ethyl)-acetamide Yield: 0.15 g (66 %) LCMS: rt=2.66, 2.79 M =454.0
1 H-NMR (DMSO-d 6 ) 2.13 (s, 6H), 2.27 (t, J=6.69 Hz, 2H), 3.16 (m, 2H), 3.34 (s, 2H), 3.95 (broad s, 1 H), 4.30 (broad s, 1 H), 7.28 (dd, J 1 =8.61 Hz, J 2 =1.86 Hz, 1 H), 7.43 (m, 3H), 7.46 (m, 1 H), 7.71 (d, J=7.65 Hz, 1 H), 7.93 (m, 2H), 11.93 (s, 1 H) ppm.
Example 7: 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-N-(3-dimethylamino-propyl)-acetamide
Yield: 0.17 g (74 %) LCMS: rt=2.66, 2.79 M " =468
1 H-NMR (DMSO-de) 1.53 (m, 2H), 2.10 (s, 6H), 2.19 (t, J=7.14 Hz, 2H) 1 3.09 (m,
2H), 3.34 (s, 2H), 3.90 (broad s, 1 H), 4.20 (broad s, 1 H), 7.44 (m, 5H), 7.71 (m,
1 H), 7.94 (d, J=1.71 Hz, 1 H), 7.98 (m, 1 H) 1 11.93 (s, 1 H) ppm.
Example 8: N-(3-Dimethylamino-propyl)-2-(6-oxo-9-trifluoromethyl-6,7-di hydro-
5H-benzo[2,3]azepino[4,5-b]indol-12-yl)-acetamide
Yield: 0.10 g (45 %) LCMS: rt=2.67, 2.79 M " =457.1
1 H-NMR (DMSO-de) 1.51 (m, 2H), 2.11 (s, 6H), 2.19 (t, J=7.02 Hz, 2H), 3.09 (m, 2H), 3.33 (s, 2H), 4.10 (broad s, 2H), 7.48 (m, 4H), 7.64 (d, J=8.58 Hz, 1 H), 7.75
(dd, J 1 =7.59 Hz, J 2 =1.29 Hz, 1 H), 7.96 (m, 1 H), 8.15 (s, 1 H), 1 1.93 (s, 1 H) ppm.
Example 9: 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-N-(2-diethylamino-ethyl)-acetamide Yield: 0.12 g (50 %) LCMS: rt=2.69, 2.79 M =482.0
1 H-NMR (DMSO-de) 0.94 (t, J=7.08 Hz, 6H), 2.44 (m, 6H), 3.13 (m, 2H), 3.32 (s,
2H), 4.00 (broad s, 1 H), 4.30 (broad s, 1 H), 7.14 (m, 1 H), 7.43 (m, 3H), 7.56 (d,
J=7.95 Hz, 1 H), 7.71 (d, J=6.96 Hz, 1 H), 7.87 (m, 1 H), 7.94 (s, 1 H), 1 1.92 (s, 1 H) ppm.
ExamplelO: 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-N-(2-methylamino-ethyl)-acetamide
Yield: 0.07 g (32 %) LCMS: rt=2.64, 2.79 M " =440.0
1 H-NMR (DMSO-de) 2.27 (s, 3H), 2.54 (m, 2H), 3.16 (m, 2H), 3.32 (s, 2H), 4.00 (broad s, 1 H), 4.30 (broad s, 1 H), 7.29 (d, J=8.49 Hz, 1 H), 7.43 (m, 3H) 1 7.56 (d,
J=8.07 Hz, 1 H), 7.71 (d, J=7.11 Hz, 1 H), 7.94 (s, 1 H), 7.96 (s, 1 H), 1 1.92 (s, 1 H) ppm.
Example 1 1 2-(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dιhydro-5H-benzo[2,3]aze pino [4,5-b]ιndol-12-yl)-N-(3-dιmethylamino-propyl)-acetamιde Yield 0 15 g (57 %) LCMS: rt=2.66, 2.68 M =528.0
1 H-NMR (DMSO-de) 1.50 (m, 2H), 2.09 (s, 6H), 2.18 (t, J=7.08 Hz 1 2H), 3.07 (m, 2H), 3 36 (S, 2H), 3 76 (s, 3H) 1 3 87 (s, 3H) 1 4 10 broad s, 1 H), 4.30 (broad s, 1 H), 7 19 (s, 1 H), 7.25 (m, 2H), 7.41 (d, J=8.61 Hz, 1 H) 1 7.88 (d, J=1.74 Hz 1 1 H) 1 7.95 (m, 1 H), 1 1 83 (s, 1 H) ppm
Example 12 2-(9-Bromo-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12- yl)-N-(2-morpholιn-4-yl-ethyl)-acetamιde
Yield 0 16 g (64 %) LCMS: rt=2.65, 2.79 M =496.0
1 H-NMR (DMSO-d 6 ) 2 34 (m, 6H), 3.22 (m, 2H), 3.35 (s, 2H), 3.56 (m, 4H), 3.90 (broad s, 1 H), 4.30 (broad s, 1 H) 1 7.28 (dd, J 1 =8.64 Hz 1 J 2 =1.86 Hz 1 1 H) 1 7.46 (m, 3H), 7 56 (d, J=7 35 Hz, 1 H), 7 71 (dd, J 1 =7 59 Hz, J 2 =1.47 Hz, 1 H), 7 94 (m, 2H), 1 1 93 (s, 1 H) ppm
Example 13" 2-(9-Bromo-6-oxo-6,7-dιhydro-5H-benzo[2,3]azepιno[4,5-b]iÏ €dol-12- yl)-N-(3-ιmιdazol-1-yl-propyl)-acetamide Yield 0 15 g (61 %) LCMS: rt=2.58, 2.65, 2.78 M " =491.0 1 H-NMR (DMSO-de) 1.75 (m, 2H), 3.05 (m, 2H), 3.35 (s, 2H), 3.60 (m, 2H), 4.30 (broad s, 1 H), 6.88 (s, 1 H), 7.28 (dd, J 1 =8.61 Hz, J 2 =1.71 Hz, 1 H) 1 7.46 (m, 4H), 7 59 (m, 2H), 7 72 (d, J=6.75 Hz 1 1 H), 7.93 (d, J=1.26 Hz, 1 H), 8 10 (m, 1 H), 11.93 (s, 1 H) ppm
Example 14. 2-(2 1 3-Dιmethoxy-6-oxo-9-tπfluoromethyl-6,7-dihydro-5H-be nzo[2,3] azepιno[4,5-b]ιndol-12-yl)-N-(2-morpholin-4-yl-ethyl)-acet amide Yield 0 19 g (70 %)
1 H-NMR (DMSO-de) 2 32 (m, 6H), 3 15 (m, 2H), 3.37 (s, 2H) 1 3 53 (m, 4H) 1 3 81 (S, 3H), 3.89 (s, 3H), 4.20 broad s, 1 H), 4 40 (broad s, 1 H), 7.20 (s, 1 H), 7.27 (s, 1 H), 7 46 (d, J=8.64 Hz, 1 H), 7.63 (d, J=8.49 Hz, 1 H) 1 7.87 (t, J=5.01 Hz, 1 H), 8.11 (s, 1 H), 12 08 (s, 1 H) ppm
Example 15 {6-[2-(9-Bromo-6-oxo-6,7-dιhydro-5H-benzo[2,3]azepιno[4,5- b]ιndol- 12-yl)-acetylamιno]-hexyl}-carbamic acid ferf-butyl ester Yield 0 15 g 51 (%) LCMS: rt=3 40 M " =583 0
1 H-NMR (DMSO-de) 1 22 (m, 4H), 1.36 (m, 13H), 2 90 (m, 2H) 1 3.05 (m, 2H) 1 3.35 (s, 2H), 4 05 (broad s, 1 H), 430 (broad s, 1 H) 1 6.77 (t, J=5.49 Hz 1 1 H) 1 7.28 (dd, J 1 =8 61 Hz, J 2 =1.80 Hz, 1 H), 7.46 (m, 3H) 1 7.54 (d, J=8.04 Hz, 1H), 7 71 (dd,
J 1 =7 59 Hz, J 2 =1 26 Hz, 1 H), 7.9 (m, 2H) 1 1 1.93 (s, 1 H) ppm.
Example 16: {6-[2-(9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3] azepιno[4,5-b]indol-12-yl)-acetylamino]-hexyl}-carbamic acid te/t-butyl ester Yield: 0.20 g (60 %) LCMS: rt=3.14 M + =439.0
1 H-NMR (DMSO-de) 1.20 (m, 4H), 1.37 (m, 13H), 2.90 (m, 2H), 3.04 (m, 2H), 3.39 (s, 2H), 3.79 (s, 3H), 3.87 (s, 3H), 4.10 (broad s, 1 H), 4.30 (broad s, 1 H), 6.73 (m, 1 H), 7 19 (s, 1 H), 7.26 (m, 2H), 7.41 (d, J=8.58 Hz, 1 H), 7.87 (m, 2H), 11.95 (s, 1 H) ppm
Example 17: {6-[2-(9-Methoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5- b]indol-12-yl)-acetylamino]-hexyl}-carbamic acid terf-butyl ester Yield: 0.17 g (62 %) LCMS: rt=3.23 M-=533.2
1 H-NMR (DMSO-d 6 ) 1.23 (m, 4H), 1.37 (m, 13H), 2.87 (m, 2H), 3.07 (m, 2H), 3.33 (s, 2H), 3.80 (s, 3H), 4.00 (broad s, 1 H), 4.30 (broad s, 1 H), 6.77 (m, 1 H), 6.82 (dd, J 1 =8.79 Hz, J 2 =2.31 Hz, 1 H), 7.19 (d, J=2.10 Hz, 1 H), 7.40 (m, 3H), 7.53 (d, J=7.71 Hz, 1 H), 7.68 (dd, J 1 =7.71 Hz, J 2 =7.56 Hz, J 2 =1.35 Hz 1 1 H), 7.93 (t, J=5.22 Hz, 1 H), 1 1 51 (s, 1 H) ppm.
Example 18: {6-[2-(2,3-Dimethoxy-6-oxo-9-trifluoromethyl-6,7-dihydro-5H- benzo P^azepino^.S-blindol-^-yO-acetylaminol-hexylJ-carbamic acid terf-butyl ester Yield: 0.2O g (63 %) LCMS: rt=3.36 M " =632.0
1 H-NMR (DMSO-d 6 ) 1.21 (m, 4H), 1.37 (m, 13H), 2.89 (m, 2H), 3.05 (m, 2H), 3.34 (s, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 4.10 (broad s, 1 H), 4.30 (broad s, 1 H), 6.74 (m, 1 H), 7.21 (s, 1 H), 7.26 (s, 1 H), 7.44 (dd, J 1 =8.64 Hz, J 2 =1.38 Hz, 1 H), 7.63 (d, J=6.52 Hz, 1 H), 7.91 (t, J=5.46 Hz, 1 H), 8.10 (s, 1 H), 12.07 (s, 1 H) ppm.
General method 3:
Preparation of 2-(9-substituted-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5- b]ιndol-12-yl)-N-(6-amino-1 -hexyl)-acetamide hydrochlorides (example 19-20)
0 5 mmol 2-(9-substituted-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5- b]indol-12- yl)-N-(6-te/?-butoxycarboxamido-1-hexyl)-acetamide (example 17-18) was dissolved in the mixture of 20 cm 3 methanol and 3 cm 3 3 M hydrochloride solution. The reaction mixture was stirred for 24 hours at room temperature, then the half of the solvent was evaporated. After stirring at O 0 C the precipitated product hydrochloride salt was filtered off, was washed with 5 cm 3 1 to 2 mixture of 2- propanol and diisopropyl ether, and finally 5 cm 3 diisopropyl ether.
Example 19: N-(6-Amino-hexyl)-2-(9-methoxy-6-oxo-6,7-dihydro-5H-benzo[2, 3] azepino[4,5-b]indol-12-yl)-acetamide hydrochloride
Yield 0 21 g (90 %) LCMS: rt=2.59, 2.71 M ' =433.3
1 H-NMR (DMSO-O 6 ) 1 .29 (m, 4H), 1.39 (m, 2H), 1.53 (m, 2H), 2.76 (t, J=7.50 Hz, 2H), 3.08 (m, 2H), 3.33 (s. 2H), 3.80 (s, 3H), 4.00 (broad s, 1 H), 4.30 (broad s, 1 H), 6.81 (dd, J 1 =8.70 Hz, J 2 =2.40 Hz, 1 H), 7.19 (d, J=2.10 Hz, 1 H), 7.43 (m, 3H), 5 7 53 (d, J=7.80 Hz, 1 H), 7.70 (d, J=7.50 Hz, 1 H), 7.97 (broad s, 3H), 7.99 (t, J=5.40 Hz, 1 H), 1 1.58 (s, 1 H) ppm.
Example 20: N-(6-Amino-hexyl)-2-(2,3-dimethoxy-6-oxo-9-trifluoromethyl-6 ,7- dιhydro-5H-benzo[2,3]azepino[4,5-b]indol-12-yl)-acetamide hydrochloride O Yield: 0.27 (95 %)
1 H-NMR (DMSO-de) 1.26 (m, 4H), 1.36 (m, 2H), 1.51 (m, 2H), 2.75 (t, J=7.20 Hz, 2H), 3.06 (m, 2H), 3.34 (s, 2H), 3.80 (s, 3H), 3.89 (s, 3H), 4.10 (broad s, 1 H), 4.40 (broad s, 1 H), 7.22 (s, 1 H), 7.30 (s, 1 H), 7.44 (d, J=8.43 Hz, 1 H), 7.80 (broad s,
3H), 7.97 (m, 1 H), 8.10 (s, 1 H), 12.19 (s, 1 H) ppm. 5
Example 21 : (9-Bromo-2,3-dimethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepin o [4,5-b]indol-12-yl)-acetic acid ethyl ester
This compound was prepared as a by-product of the synthesis of (9-bromo-2,3- 0 dιmethoxy-6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indo l-12-yl)-acetic acid
(example 3). The first ethyl acetate extract was washed with 10 cm 3 brine, was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure The residue was crystallized from ethanol to give pure product.
Yield: 0.09 g (2.0 %) LCMS: rt=3.30 M " =472.0 5 1 H-NMR (DMSO-de) 1 -09 (t, J=7.1 1 Hz, 3H), 3.00 (broad s, 1 H), 3.83 (s, 3H), 3.88
(s, 3H), 3.99 (m, 3H), 4.30 (s, 2H), 7.07 (s, 1 H), 7.25 (m, 2H), 7.41 (d, J=8.58 Hz,
1 H), 7.88 (d, J=1.71 Hz, 1 H), 11.82 (s, 1 H) ppm.
Materials and methods: 0
General Kinase Assays:
Reaction Volume: 40 μl
Reaction Time: 60 min
Reaction Temperature: room temperature b Assay Plate. 96 well U bottom plate (Greiner, 650161 )
MultiScreen-PH Plate: 96 well MAPH Filter Plates (Millipore, MAPHNOB50)
Filter Washing Solution: 0.75% H3PO4
Szmtilation Liquid: Supermix Liquid Szintillator (PerkinElmer, 1200-439)
Controls:
Negative Control (C-): 100 mM EDTA, no Inhibitor
Positive Control (C+): no Inhibitor
Reaction Buffer:
20 mM Tris-HCI, pH 7.5 1 O mM MgCI2 1 mM DTT
Final Assay Concentrations:
Kinase: Use kinase cone, yielding 10% ATP turn over.
ATP: 1 μM
Adenosine 5"-[g- 33 P]triphosphate:12.5 μCi/ml (Amersham Biosciences, BF1000)
Myelin Basic Protein (MBP): 10 μM (Invitrogen, 13228-010)
Pipetting Sequence:
1 ) Add 8 μl 50 μM MBP in Reaction Buffer to each well of Assay Plate
2) Add 10 μl 500 mM EDTA in H2O to C- wells
3) Add 8 μl 62.5 μCi/ml Adenosine 5'-[g- 33 P]triphosphate + 5 μM ATP in Reaction Buffer to each well
4) Add 8 μl 5 fold concentrated inhibitor in 5% DMSO in Reaction Buffer to each well except to C- and C+ wells
5) Add 8 μl 5% DMSO in Reaction Buffer to C- and C+ wells
6) Add 8 μl 5 fold concentrated kinase in Reaction Buffer to each well 7) Incubate 1 hr at room temperature
8) Add 10 μl 50 mM EDTA in H2O to each well except to C- wells
9) Prepare MAPH plates by adding 200 μl 0.75% H3PO4 to each well
10) Exhaust 0.75% H3PO4 using Millipore vacuum station
1 1 ) Add 60 μl 0.75% H3PO4 to each well of MAPH Filter Plate 12) Transfer 30 μl sample per well from Assay Plate to corresponding well of
MAPH Filter Plate
13) Incubate 30 min at room temperature
14) Wash each well of MAPH Filter Plates 3x with 200 μl 0.75% H3PO4 using Millipore vacuum station 15) Add 20 μl Szintilation Liquid to each well of MAPH Filter Plate
16) Seal MAPH Filter Plate
17) Store MAPH Filter Plate 30 min in darkness
18) Quantify radioactivity