HRP20140836T1 - Sinteza polimernih konjugata spojeva indolokarbazola - Google Patents
Sinteza polimernih konjugata spojeva indolokarbazola Download PDFInfo
- Publication number
- HRP20140836T1 HRP20140836T1 HRP20140836AT HRP20140836T HRP20140836T1 HR P20140836 T1 HRP20140836 T1 HR P20140836T1 HR P20140836A T HRP20140836A T HR P20140836AT HR P20140836 T HRP20140836 T HR P20140836T HR P20140836 T1 HRP20140836 T1 HR P20140836T1
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- Croatia
- Prior art keywords
- substituted
- unsubstituted
- diseases
- hydrogen
- unsubstituted lower
- Prior art date
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- 229920000642 polymer Polymers 0.000 title claims 20
- 230000015572 biosynthetic process Effects 0.000 title 1
- VVVPGLRKXQSQSZ-UHFFFAOYSA-N indolo[3,2-c]carbazole Chemical class C1=CC=CC2=NC3=C4C5=CC=CC=C5N=C4C=CC3=C21 VVVPGLRKXQSQSZ-UHFFFAOYSA-N 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims 16
- 239000001257 hydrogen Substances 0.000 claims 15
- 229910052739 hydrogen Inorganic materials 0.000 claims 15
- 125000000217 alkyl group Chemical group 0.000 claims 14
- 150000002431 hydrogen Chemical class 0.000 claims 10
- 125000003342 alkenyl group Chemical group 0.000 claims 9
- 125000000304 alkynyl group Chemical group 0.000 claims 9
- 150000001875 compounds Chemical class 0.000 claims 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
- 125000003118 aryl group Chemical group 0.000 claims 6
- 125000001072 heteroaryl group Chemical group 0.000 claims 6
- 229920001223 polyethylene glycol Polymers 0.000 claims 6
- 230000002265 prevention Effects 0.000 claims 6
- 125000003545 alkoxy group Chemical group 0.000 claims 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 5
- 229910052736 halogen Inorganic materials 0.000 claims 5
- 150000002367 halogens Chemical class 0.000 claims 5
- 230000007170 pathology Effects 0.000 claims 5
- 125000002252 acyl group Chemical group 0.000 claims 4
- 201000010099 disease Diseases 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 230000000116 mitigating effect Effects 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 239000002585 base Substances 0.000 claims 3
- PJVZQNVOUCOJGE-CALCHBBNSA-N chembl289853 Chemical compound N1([C@H]2CC[C@H](O2)N2[C]3C=CC=CC3=C3C2=C11)C2=CC=C[CH]C2=C1C1=C3C(=O)N(C)C1=O PJVZQNVOUCOJGE-CALCHBBNSA-N 0.000 claims 3
- 230000002500 effect on skin Effects 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 239000003960 organic solvent Substances 0.000 claims 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- 208000035473 Communicable disease Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000012902 Nervous system disease Diseases 0.000 claims 2
- 208000025966 Neurological disease Diseases 0.000 claims 2
- 201000004681 Psoriasis Diseases 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 210000003169 central nervous system Anatomy 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 229920001427 mPEG Polymers 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims 2
- 230000000699 topical effect Effects 0.000 claims 2
- 208000002874 Acne Vulgaris Diseases 0.000 claims 1
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- 208000012657 Atopic disease Diseases 0.000 claims 1
- 208000027496 Behcet disease Diseases 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 206010006895 Cachexia Diseases 0.000 claims 1
- 208000032544 Cicatrix Diseases 0.000 claims 1
- 208000027205 Congenital disease Diseases 0.000 claims 1
- 201000004624 Dermatitis Diseases 0.000 claims 1
- 206010012438 Dermatitis atopic Diseases 0.000 claims 1
- 102000055207 HMGB1 Human genes 0.000 claims 1
- 108700010013 HMGB1 Proteins 0.000 claims 1
- 101150021904 HMGB1 gene Proteins 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000004454 Hyperalgesia Diseases 0.000 claims 1
- 208000035154 Hyperesthesia Diseases 0.000 claims 1
- 208000002260 Keloid Diseases 0.000 claims 1
- 208000004852 Lung Injury Diseases 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- 206010029098 Neoplasm skin Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 206010063837 Reperfusion injury Diseases 0.000 claims 1
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 206010038923 Retinopathy Diseases 0.000 claims 1
- 206010040047 Sepsis Diseases 0.000 claims 1
- 208000021386 Sjogren Syndrome Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 206010069363 Traumatic lung injury Diseases 0.000 claims 1
- 206010046851 Uveitis Diseases 0.000 claims 1
- 206010047115 Vasculitis Diseases 0.000 claims 1
- 206010000496 acne Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 1
- 125000005103 alkyl silyl group Chemical group 0.000 claims 1
- 208000026935 allergic disease Diseases 0.000 claims 1
- 230000000172 allergic effect Effects 0.000 claims 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 239000012300 argon atmosphere Substances 0.000 claims 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims 1
- 239000012298 atmosphere Substances 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 201000008937 atopic dermatitis Diseases 0.000 claims 1
- 239000007853 buffer solution Substances 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 238000011097 chromatography purification Methods 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002526 effect on cardiovascular system Effects 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 230000001969 hypertrophic effect Effects 0.000 claims 1
- 230000000642 iatrogenic effect Effects 0.000 claims 1
- 208000036260 idiopathic disease Diseases 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 238000001802 infusion Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 230000035987 intoxication Effects 0.000 claims 1
- 231100000566 intoxication Toxicity 0.000 claims 1
- 210000001117 keloid Anatomy 0.000 claims 1
- 210000002510 keratinocyte Anatomy 0.000 claims 1
- 208000017169 kidney disease Diseases 0.000 claims 1
- 239000002502 liposome Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 231100000515 lung injury Toxicity 0.000 claims 1
- 206010025135 lupus erythematosus Diseases 0.000 claims 1
- 208000030159 metabolic disease Diseases 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 claims 1
- 230000007823 neuropathy Effects 0.000 claims 1
- 201000001119 neuropathy Diseases 0.000 claims 1
- -1 nitro, carbamoyl Chemical group 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 210000000056 organ Anatomy 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 206010035116 pityriasis rubra pilaris Diseases 0.000 claims 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 208000037803 restenosis Diseases 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 231100000241 scar Toxicity 0.000 claims 1
- 230000037387 scars Effects 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 238000007910 systemic administration Methods 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 238000002054 transplantation Methods 0.000 claims 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
-
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
- C07D243/36—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings containing an indole or hydrogenated indole ring system
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Obesity (AREA)
- Reproductive Health (AREA)
- Ophthalmology & Optometry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (19)
1. Postupak za pripremu polimernog konjugata spoja indolokarbazola formule (I)
[image]
gdje
R1 i R2 su isti ili različiti ostatak i svaki od njih je nezavisno izabran iz grupe koju čine:
(a) vodik, halogen, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, hidroksi, niži alkoksi, karboksi, niži alkoksikarbonil, acil, nitro, karbamoil, niži alkilaminokarbonil, -NR5R6, gdje su i R5 i R6 nezavisno izabrani iz grupe koju čine vodik, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril, supstituiran ili nesupstituiran aralkil, supstituiran ili nesupstituiran niži alkilaminokarbonil, supstituiran ili nesupstituiran niži arilaminokarbonil, alkoksikarbonil, karbamoil, acil ili R5 i R6 su kombinirani sa atomom dušika tako da formiraju heterocikličnu grupu,
(b) -CO(CH2)jR4, gdje je 1 do 6, i R4 je izabran iz grupe koju čine
(i) vodik, halogen, -N3,
(ii) -NR5R6, gdje su R5 i R6 kao što su definirani u prethodnom tekstu,
(iii) -SR7, gdje R7 je izabran iz grupe koju čine vodik, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril, supstituiran ili nesupstituiran aralkil, -(CH2)äCO2R10 (gdje a je 1 ili 2, i gdje R10 je izabran iz grupe koju čine vodik i supstituiran ili nesupstituiran niži alkil) i -(CH2)aCO2NR5R6,
(iv) -OR8, -OCOR8, gdje R8 je izabran iz grupe koju čine vodik, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril
(c) -CH(OH)(CH2)j R4, gdje su j i R4 kao što su definirani u prethodnom tekstu;
(d) -(CH2)dCHR11CO2R12 ili -(CH2)dCHR11CONR5R6, gdje d je 0 do 5, R11 je vodik, -CONR5R6, ili -CO2R13, gdje R13 je vodik ili gdje supstituiran ili nesupstituiran niži alkil, i R12 je vodik ili supstituiran ili nesupstituiran niži alkil;
(e) -(CH2)kR14, gdje k je 2 do 6 i R14 je halogen, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril, -COOR15, -OR15, (gdje R15 je vodik, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril ili acil), -SR7 (gdje R7 je kao što je definiran u prethodnom tekstu), -CONR5R6, -NR5R6 (gdje su R5 i R6 kao što su definirani u prethodnom tekstu) ili -N3;
(f) -CH=CH(CH2)mR16, gdje m je 0 do 4, i R16 je vodik, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran niži alkenil, supstituiran ili nesupstituiran niži alkinil, supstituiran ili nesupstituiran aril, supstituiran ili nesupstituiran heteroaril, -COOR15, -OR15 (gdje R15 je kao što je definiran u prethodnom tekstu) -CONR5R6 ili -NR5R6 (gdje su R5 i R6 kao što su definirani u prethodnom tekstu);
(g) -CH=C(CO2R12)2, gdje R12 je kao što je definiran u prethodnom tekstu;
(h) -C≡C(CH2)nR16, gdje n je 0 do 4 i R16 je kao što je definiran u prethodnom tekstu;
(i) -CH2OR22, gdje R22 je tri-niži alkil silil u kojem su tri niže alkil grupe iste ili različite ili gdje R22 ima isto značenje kao R8.
(j) -CH(SR23)2 i -CH2-SR7, gdje R23 je niži alkil, niži alkenil ili niži alkinil i gdje R7 je kao što je definiran u prethodnom tekstu; i
R3 je vodik, halogen, acil, karbamoil, supstituiran ili nesupstituiran niži alkil, supstituiran ili nesupstituiran alkenil, supstituiran ili nesupstituiran niži alkinil ili amino;
pri čemu se termin se "niži alkil", kada je korišten pojedinačno ili u kombinaciji sa drugim grupama, odnosi na ravnolančanu ili razgranatu nižu alkil grupu koja sadrži od 1-6 atoma ugljika;
termin "niži alkenil" označava C2-C6 alkenil grupe koje mogu biti ravnolančane ili razgranate i mogu biti u Z ili E obliku;
termin "niže alkinil" grupe označava C2-C6-alkinil grupe koje mogu biti ravnolančane ili razgranate; i
termin "niži alkoksi" označava alkoksi grupu koja sadrži od 1 do 6 atoma ugljika; i
W1 i W2 su nezavisno vodik, hidroksi ili W1 i W2 zajedno predstavljaju kisik;
i gdje X je polimerna grupa,
pri čemu postupak sadrži reakciju polimernog spoja ω-1H-imidazol-karboksamida opće formule (II)
[image]
gdje X je definiran kao u prethodnom tekstu,
sa spojem indolokarbazola opće formule (III)
[image]
gdje su R1, R2, R3, W1 i W2 definirani kao u prethodnom tekstu i koji su izborno zaštićeni zaštitnim grupama i gdje Y predstavlja odlazeću grupu, i gdje postupak dalje izborno sadrži deprotekciju grupa R1, R2, R3, W1 i W2 da se dobije spoj formule (I).
2. Postupak prema patentnom zahtjevu 1, naznačen time što se postupak izvodi u prisustvu baze u organskom otapalu, pri čemu baza može biti izabrana iz grupe hidrida alkalnih metala, posebno natrijeva hidrida, i pri čemu molarni odnos baze prema spoju formule (III) može biti između oko 1:1 i oko 4:1, poželjno oko 1:1 do oko 1.5:1 i poželjnije oko 1:1.
3. Postupak prema bilo kojem od patentnih zahtjeva 1 do 2, naznačen time što se postupak izvodi u organskom otapalu, poželjno u anhidriranom organskom otapalu, izabranom iz grupe koju čine diklorometan, kloroform i N,N-dimetilformamid ili što se postupak izvodi pod inertnom atmosferom plina, poželjno pod atmosferom dušika ili argona.
4. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što se postupak izvodi na temperaturi od -10 do 60°C, poželjno od 0°C do 25°C i najpoželjnije na sobnoj temperaturi poslije početnog koraka na 0°C.
5. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što je spoj konjugat polimera formule (I) direktno dobijen kromatografskim pročišćavanjem, pri čemu se pročišćavanje spoja konjugata polimera formule (I) poželjno izvodi u otapalu, poželjno izabranom od diklorometana, vode, metanola, acetonitrila, puferske otopine amonijeva formiata u različitim proporcijama smjese.
6. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što ima za rezultat prinos spoja formule (I) od oko 40% do oko 95% prema težini, poželjno od oko 50% do oko 95% prema težini na osnovu težine spoja formule (III).
7. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što je odlazeća grupa Y izabrana od triflata, tozilata, mezilata, sulfata, halogena, hidroksi ili niže alkoksi grupe, i time što je odlazeća grupa Y poželjno niža alkoksi grupa, poželjnije metoksi grupa.
8. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što je polimer X izabran od poli(alkilen oksida), posebno od (polietilen) oksida, pri čemu polimer X poželjno ima molekularnu težinu od oko 100 do oko 100.000 Da, poželjnije od oko 200 do oko 50.000 Da, i pri čemu polimer X je poželjno (polietilen) glikol (PEG), poželjnije izabran od terminalno alkoksi-supstituiranih polietilen glikola kao što je metoksi-polietilen glikol (m-PEG).
9. Postupak prema patentnom zahtjevu 8, naznačen time što polimer X je (polietilen) glikol, npr. mPEG sa prosječnom molekularnom masom od oko 500 do oko 10000 Da, npr. od oko 550 Da, oko 1100 Da, oko 2000 Da ili oko 5000 Da.
10. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što R1, R2, R3, W1 i W2 su vodik.
11. Polimerni konjugat spoja indolokarbazola formule (I)
[image]
u kojem
R1, R2, R3, W1, W2 i X su kao što su definirani u patentnom zahtjevu 1 ili patentnim zahtjevima 8 do 10;
ili njegova farmaceutski prihvatljiva sol, gdje R1, R2, R3, W1 i W2 su poželjno vodik, i
gdje polimer X je poželjno (polietilen) glikol, npr. mPEG sa prosječnom molekularnom masom od oko 500 do oko 10000 Da, npr. od oko 550 Da, oko 1100 Da, oko 2000 Da ili oko 5000 Da.
12. Polimerni konjugat prema patentnom zahtjevu 11 za uporabu kao lijek, npr. za topikalne primjene, ili za sustavne primjene, npr. injekcijom, infuzijom ili inhalacijom.
13. Farmaceutska kompozicija koja sadrži najmanje jedan polimerni konjugat prema patentnom zahtjevu 11, izborno zajedno sa farmaceutski prihvatljivim nosačima, adjuvantima, razblaživačima i/ili aditivima, posebno za dijagnostičke i/ili terapeutske primjene.
14. Polimerni konjugat prema bilo kojem od patentnih zahtjeva 11 ili 12 za uporabu kao lijek za prevenciju, ublažavanje i/ili liječenje patologija povezanih sa HMGB1, posebno izabranih od stenoze, restenoze, ateroskleroze, reumatoidnog artritisa, autoimunih bolesti, tumora, infektivnih bolesti, sepse, akutne inflamatorne povrede pluća, lupus eritematodesa, neurodegenerativnih bolesti, bolesti središnjeg i perifernog živčanog sustava i multiple skleroze.
15. Polimerni konjugat za uporabu prema patentnom zahtjevu 14, naznačen time što je polimerni konjugat reverzibilno imobiliziran na površini medicinskog uređaja.
16. Polimerni konjugat prema patentnom zahtjevu 11 za uporabu
(i) u prevenciji, ublažavanju i/ili liječenju neuroloških poremećaja, neuropatija i neurodegenerativnih poremećaja središnjeg i perifernog živčanog sustava,
(ii) u prevenciji, ublažavanju i/ili liječenju dermalnih patologija, posebno naznačenih hiperproliferacijom keratinocita,
(iii) u prevenciji, ublažavanju i/ili liječenju bolova povezanih sa NGF i hiperalgezije,
(iv) u prevenciji, ublažavanju i/ili liječenju inflamatornih bolesti, autoimunih bolesti, sustavnog sindroma inflamatornog odgovora, reperfuzione povrede poslije transplantacije organa, kardiovaskularnih afekcija, akušerskih i ginekoloških bolesti, infektivnih bolesti, alergijskih i atopijskih bolesti, patologija solidnog i tekućeg tumora, bolesti odbacivanja transplanta, kongenitalnih bolesti, dermatoloških bolesti, neuroloških bolesti, kaheksije, renalnih bolesti, stanja jatrogene intoksikacije, metaboličkih i idiopatskih bolesti i oftalmoloških bolesti, ili
(v) u prevenciji, ublažavanju i/ili liječenju Behçet-ove bolesti, Sjogren-ovog sindroma, vaskulitisa, uveitisa, retinopatija.
17. Polimerni konjugat za uporabu prema patentnom zahtjevu 16, naznačen time što dermalne patologije su psorijaza, atopijski dermatitis, kronični ekcem, akne, pitiriazis rubra pilaris, keloidi, hipertrofični ožiljci i tumori kože, i pri čemu dermalna patologija je posebno psorijaza.
18. Polimerni konjugat za uporabu prema patentnom zahtjevu 17 za topikalnu primjenu, posebno u obliku lipozoma.
19. Polimerni konjugat za uporabu prema patentnom zahtjevu 16 za sustavnu primjenu, ili u kombinaciji sa najmanje jednim anti-inflamatornim lijekom.
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| US13981608P | 2008-12-22 | 2008-12-22 | |
| US15205509P | 2009-02-12 | 2009-02-12 | |
| PCT/EP2009/067817 WO2010072795A1 (en) | 2008-12-22 | 2009-12-22 | Synthesis of polymer conjugates of indolocarbazole compounds |
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| WO2014177510A2 (en) * | 2013-05-03 | 2014-11-06 | Creabilis Sa | Polymer conjugates of indolocarbazole compounds in the treatment of pruritus |
| JP6445802B2 (ja) * | 2014-07-16 | 2018-12-26 | 学校法人慶應義塾 | インフラマソーム活性化制御物質のスクリーニング方法 |
| WO2018175302A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Polymer conjugates targeting c-src with reduced exposure |
| WO2018175340A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Reduced exposure conjugates modulating therapeutic targets |
| WO2018175315A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Polymer conjugates of staurosporine derivatives having reduced exposure |
| WO2018175301A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Polymer conjugate of montesanib with reduced exposure |
| WO2018208369A1 (en) | 2017-05-10 | 2018-11-15 | Sienna Biopharmaceuticals, Inc. | Uses of polymer conjugates of indolocarbazole compounds with reduced exposure |
| US20190209472A1 (en) * | 2017-12-04 | 2019-07-11 | Sienna Biopharmaceuticals, Inc. | Formulations for dermal delivery of polymer conjugates of indolocarbazole compounds with reduced exposure |
| WO2020023387A1 (en) * | 2018-07-23 | 2020-01-30 | Sienna Biopharmaceuticals, Inc. | Uses of polymer conjugates of indolocarbazole compounds with reduced exposure |
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| US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| AU4406793A (en) | 1992-06-04 | 1993-12-30 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
| US6326353B1 (en) * | 1993-03-23 | 2001-12-04 | Sequus Pharmaceuticals, Inc. | Enhanced circulation effector composition and method |
| US5468872A (en) | 1993-09-16 | 1995-11-21 | Cephalon, Inc. | K-252a functional derivatives potentiate neurotrophin-3 for the treatment of neurological disorders |
| UA67725C2 (en) * | 1996-06-03 | 2004-07-15 | Cephalon Inc | K-252a derivatives and a method for improvement of functioning and cell survival enhancement |
| WO2005014003A1 (en) | 2003-07-23 | 2005-02-17 | Creabilis Therapeutics S.R.L. | Topical use of tyrosine kinase inhibitors of microbial origin to prevent and treat skin disorders characterised by excessive cell proliferation |
| ATE399014T1 (de) | 2004-07-02 | 2008-07-15 | Creabilis Therapeutics Spa | Nukleinsäuren zur behandlung von erkrankungen im zusammenhang mit hmgb1 |
| SI1919979T2 (sl) * | 2005-08-25 | 2017-07-31 | Creabilis Therapeutics S.P.A. | Polimerni konjugati K-252A in njihovi derivati |
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