HRP20020592A2 - Substituted benzoylguanidines, method for their production, their use as a medicament or diagnostic agent and a medicament containing the same - Google Patents
Substituted benzoylguanidines, method for their production, their use as a medicament or diagnostic agent and a medicament containing the same Download PDFInfo
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- HRP20020592A2 HRP20020592A2 HR20020592A HRP20020592A HRP20020592A2 HR P20020592 A2 HRP20020592 A2 HR P20020592A2 HR 20020592 A HR20020592 A HR 20020592A HR P20020592 A HRP20020592 A HR P20020592A HR P20020592 A2 HRP20020592 A2 HR P20020592A2
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- Prior art keywords
- alkyl
- production
- methyl
- compound according
- treatment
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- 238000000034 method Methods 0.000 title claims description 8
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- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- XUAPMUNNKKKKJF-UHFFFAOYSA-N methyl 4-(2-imidazol-1-ylphenoxy)-2-methyl-5-(trifluoromethyl)benzoate Chemical compound C1=C(C)C(C(=O)OC)=CC(C(F)(F)F)=C1OC1=CC=CC=C1N1C=NC=C1 XUAPMUNNKKKKJF-UHFFFAOYSA-N 0.000 description 1
- GEISXGJCBRQRRD-UHFFFAOYSA-N methyl 4-fluoro-2-methyl-3-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(F)C(C(F)(F)F)=C1C GEISXGJCBRQRRD-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- GRXSDEMBBAEEOH-UHFFFAOYSA-N n-(diaminomethylidene)-2-methyl-4-[2-(triazol-1-yl)phenoxy]-5-(trifluoromethyl)benzamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=C(C(=O)N=C(N)N)C(C)=CC(OC=2C(=CC=CC=2)N2N=NC=C2)=C1C(F)(F)F GRXSDEMBBAEEOH-UHFFFAOYSA-N 0.000 description 1
- PVAMIAXVACOCSV-UHFFFAOYSA-N n-carbamimidoyl-2-methyl-n-[4-(triazol-1-yl)phenoxy]-3-(trifluoromethyl)benzamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=CC=C(C(F)(F)F)C(C)=C1C(=O)N(C(N)=N)OC1=CC=C(N2N=NC=C2)C=C1 PVAMIAXVACOCSV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000000054 salidiuretic effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Description
Izum se odnosi na benzoilgvanidine formule (I)
[image]
u kojoj
R1 predstavlja vodik, F, Cl, Br, J, NO2, CN, -Xo-(CH2)p-(CF2)q-CF3, R5-SOm-, R6-CO-, R6R7N-CO- ili R6R7N-SO2-;
X je kisik, -S- ili NR14;
m je nula, 1 ili 2;
o je nula ili 1;
p je nula, 1 ili 2;
q je nula, 1, 2, 3, 4, 5 ili 6;
R5 i R6 međusobno neovisno predstavljaju (C1-C8)-alkil, (C3-C6)-alkenil, -CnH2n-R8 i CF3;
n je nula, 1, 2, 3 ili 4;
R8 je (C3-C7)-cikloalkil ili fenil, koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 su H i (C1-C4) -alkil; ili
R6 je vodik;
R7 je vodik ili (C1-C4)-alkil; ili
R6 i R7 mogu zajedno biti 4 ili 5 metilenskih skupina, od kojih jedna metilenska skupina može biti zamijenjena s kisikom, S, NH, N-CH3, ili N-benzilom;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9)-heteroaril, koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, hidroksi, amino, metilamino, dimetilamino i benzil;
Y je kisik, -S- ili NR12;
R12 je H ili (C1-C4)-alkil;
R3 je definiran kao R1; ili
R3 je (C1-C6)-alkil ili -X-R13;
X je kisik, -S- ili NR14;
R14 je H ili (C1-C3) -alkil;
R13 je H, (C1-C6)-alkil, (C3-C8) -cikloalkil ili -CbH2b-R15;
b je nula, 1, 2, 3 ili 4;
R15 je fenil koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 predstavljaju H ili (C1-C4)-alkil; ili
R13 i R14 zajedno tvore 4 ili 5 metilenskih skupina, od kojih jedna metilenska skupina može biti zamijenjena s kisikom, S, NH, N-CH3 ili s N-benzilom;
R4 je F, Cl, Br, J ili C1-C4-alkil;
kao i njihove farmaceutski podnošljive soli.
Prednost se daje spojevima formule (I) u kojoj:
R1 predstavlja vodik, F, Cl, CN, CF3, R5-SOm-, R6-CO-, R6R7N-CO- ili R6R7N-SO2-;
m je nula, 1, ili 2;
R5 i R6 međusobno neovisno predstavljaju (C1-C8)-alkil, (C3-C4)-alkenil, -CnH2n-R8 i CF3;
n je nula ili 1;
R8 je (C3-C6)-cikloalkil ili fenil, koji nije supstituiran, ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 predstavljaju H ili metil; ili
R6 je vodik;
R7 je vodik ili metil;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)–R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9) -heteroaril koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, hidroksi, amino, metilamino, dimetilamino i benzil;
Y je kisik, -S- ili NR12;
R12 je H ili (C1-C4) -alkil;
R3 je vodik, metil, CN, CF3, F ili Cl;
R4 je F, Cl ili (C1-C4)-alkil; te njihovim farmaceutski podnošljivim solima.
Posebnu prednost se daje spojevima formule (I) u kojoj:
R1 predstavlja vodik, F, Cl, CN, CF3 ili R5-SOm-;
m je nula, 1 ili 2;
R5 je metil ili CF3;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9)-heteroaril koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino, i benzil;
Y je kisik;
R3 je vodik, metil, CN, CF3, F ili Cl;
R4 je (C1-C4)-alkil; te njihovim farmaceutski podnošljivim solima.
Naročitu prednost se daje spojevima formule (I) u kojoj:
R1 predstavlja vodik, F, Cl, CN, CF3 ili R5-SO2-;
R5 je metil ili CF33;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C5)-heteroaril koji je povezan preko C ili N i koji nije supstituiran, ili je supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino i benzil;
Y je kisik;
R3 je vodik;
R4 je (C1-C4)-alkil;
kao i njihovim farmaceutski podnošljivim solima.
Posve posebnu prednost se daje spojevima formule (I) u kojoj:
R1 je CF3;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je imidazolil ili triazolil, nesupstituiran, ili supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino i benzil;
Y je kisik;
R3 je vodik;
R4 je metil;
te njihovim farmaceutski podnošljivim solima.
Svi navedeni alkilni ostaci mogu imati ravan ili razgranati lanac.
Pod (C1-C9)-heteroarilom podrazumijevaju se radikali koji su derivirani od fenila ili naftila, u kojima je jedna ili je više CH skupina zamijenjeno s N, i/ili u kojima su najmanje dvije susjedne CH skupine zamijenjene sa S, NH, ili O (s nastankom peteročlanog aromatskog prstena). K tome, jedan ili obadva atoma na mjestu kondenzacije bicikličkog radikala mogu također biti (kao u indolizinilu) N atomi.
Kao heteroaril podrazumijevaju se naročito furanil, tienil, pirolil, imidazolil, pirazolil, triazolil, tetrazolil, oksazolil, izoksazolil, tiazolil, izotiazolil, piridil, pirazinil, pirimidinil, piridazinil, indolil, indazolil, kinolil, izokinolil, ftalazinil, kinoksalinil, kinazolinil ili cinolinil; posebno furanil, tienil, pirolil, imidazolil, pirazolil, triazolil, tiazolil, piridil, indolil, kinolil, i izokinolil.
Izum se nadalje odnosi na postupak za pripravu spoja I, koji je naznačen time, da spoj formule (II)
[image]
u kojoj R1 i R4 imaju gore navedena značenja, i L je izlazna skupina koja se može lako nukleofilno supstituirati, reagira s gvanidinom.
Aktivirani kiselinski derivati formule (II), u kojoj L predstavlja alkoksi skupinu, ponajprije metoksi skupinu, fenoksi skupinu, feniltio, metiltio ili 2-piridiltio skupinu, ili heterocikl s dušikom, ponajprije 1-imidazolil, dobiju se ponajprije na način koji je poznat u struci, iz osnovnih klorida karboksilnih kiselina (formula II, L = Cl), koji se sa svoje strane mogu proizvesti na poznat način iz osnovnih karboksilnih kiselina (formula II, L = OH), na primjer upotrebom tionil klorida.
Osim klorida karboksilnih kiselina formule II (L = Cl), na poznat način se također mogu proizvesti i drugi aktivirani kiselinski derivati formule II izravno iz derivata osnovne benzojeve kiseline (formula II, 1 = OH). Takovi aktivirani kiselinski derivati uključuju metil estere formule (II) u kojoj L = OCH3, koji se dobiju obradom s plinovitim HCl u metanolu; imidazolide formule II, koji se dobiju obradom s karboniidiimidazolom (L = 1-imidazolil, Staab, Angew. Chem. Int. Ed. Engl. l, 351-367 (1962)); miješane anhidride II, koji se dobiju sa Cl-COOC2H5 ili s tosil kloridom u presutnosti trietilamina u inertnom otapalu; kao i aktivacijom benzojeve kiseline s diciklo-heksilkarbodiimidom (DCC) ili s O-[(cijano-(etoksi-karbonil)metilen)amino]-1,1,3,3-tetrametiluronijevim tetra-fluorboratom (TOTU) (Proceedings of 21. European Peptide Symposium, Peptides 1990, izd. E. Giralt i D. Andreu, Escom, Leiden, 1991). Niz prikladnih metoda za pripravu aktiviranih derivata karboksilnih kiselina formule II dato je s navodom izvorne literature u J. March, Advanced Organic Chemistry, 3. izdanje, (John Wiley & Sons, 1985), str. 350.
Reakcija aktiviranog derivata karboksilne kiseline formule II s gvanidinom odvija se na poznat način u protonskom ili aprotonskom organskom otapalu, koje je polarno ali inertno. U tom pogledu, za upotrebu u reakciji metil estera benzojeve kiseline (formula II, L = OMe) s gvanidinom prikladnim su se pokazali metanol, izopropanol ili THF pri temperaturi od 20°C pa sve do temperature vrelišta tih otapala. Za većinu reakcija spojeva formule II s gvanidinom koji ne sadrži sol, povoljnom se je pokazala upotreba aprotonskih, inertnih otapala, kao što je THF, dimetoksietan i dioksan. Međutim, pri upotrebi baze kao što je na primjer NaOH, kao otapalo u reakcijama spojeva formule II s gvanidinom također se može upotrijebiti u vodu.
Ako L predstavlja Cl, korisno je raditi s dodatkom sredstva za vezanje kiseline, npr. u obliku suviška gvanidina za vezanje halogenovodične kiseline.
Neki derivati osnovne benzojeve kiseline formule II su poznati i opisani su u literaturi. Nepoznati spojevi formule II mogu se proizvesti metodama koje su poznate iz literature. Dobivene benzojeve kiseline pretvaraju se u spojeve formule I prema izumu u skladu s nekom od gore opisanih inačica postupka.
Uvođenje nekih supstituenata u položaju 2, 3, 4 i 5 vrši se metodama koje su poznate iz literature a koje uključuju unakrsno povezivanje aril halogenida ili aril triflata s, na primjer, organskim spojevima kositra, organskim bornim kiselinama, organskim boranima, organskim spojevima bakra, ili s organskim spojevima cinka. Ovo povezivanje vrši se posredstvom paladija.
Benzoilgvanidini formule I su općenito slabe baze i mogu se vezati na kiseline uz tvorbu soli. Kao kiselinske adicijske soli u obzir dolaze soli svih farmakološki podnošljivih kiselina, na primjer, halogenidi, posebno hidrokloridi, laktati, sulfati, citrati, tartarati, acetati, fosfati, metilsulfonati i p-toluensulfonati.
Spojevi formule I su supstituirani acilgvanidini. Spojevi slični spojevima formule I su opisani u europskoj objavljenoj publikaciji 640 593 (HOE 93/F 220). Međutim, oni uvijek imaju drugačije supstituente u položaju R4 (orto položaj); spojevi prema izumu tamo nisu spomenuti niti se oni mogu tamo naslutiti.
U usporedbi s poznatim spojevima, spojevi prema izumu se odlikuju izvanredno visokom učinkovitošću u inhibiciji izmjene Na+/H+, kao i poboljšanom topivošću u vodi.
Slično nekim poznatim spojevima, ovi spojevi nemaju nikakva neželjena i/ili štetna salidiuretička svojstva, već kao i poznati spojevi oni imaju vrlo dobra antiaritmijska svojstva. Takova svojstva važna su, na primjer, za liječenje bolesti koje se pojavljuju u slučaju nedostatka kisika. Zbog njihovih farmakoloških svojstava, spojevi izuma su izvanredno prikladni kao antiaritmijski lijekovi s kardioprotektivnom komponentom za profilaksu i liječenje infarkta i za liječenje angine pektoris, pri čemu oni također preventivno inhibiraju ili jako smanjuju patofiziološke procese kod nastanka ozljeda uzrokovanih ishemijom, posebno u kod nastanka srčanih aritmija uzrokovanih ishemijom.
Zbog njihovog zaštitnog djelovanja protiv patoloških hipoksičkih i ishemijskih stanja, spojevi formule I prema izumu, zbog inhibicije staničnog mehanizma izmjene Na+/H+, mogu se upotrijebiti kao lijekovi za liječenje svih akutnih ili kroničnih ozljeda uzrokovanih ishemijom ili bolesti koje su time uzrokovano primarno ili sekundarno. To se također odnosi i na njihovu upotrebu kao lijekova pri kirurškim intervencijama, npr. kod transplantacija organa, pri čemu se ovi spojevi mogu upotrijebiti kako za zaštitu organa u davaocu prije i tijekom vađenja, za zaštitu izvađenih organa, na primjer tijekom obrade ili njihovog pohranjivanja u kupelj s fiziološkim tekućinama, tako također i tijekom prenošenja u tijelo primaoca. Ovi spojevi su također dragocjeni lijekovi koji imaju zaštitno djelovanje pri provedbi angioplastičnih kirurških intervencija, na primjer na srcu i na perifernim krvnim žilama. U skladu s njihovim zaštitnim djelovanjem protiv ozljeda uzrokovanih ishemijom, ovi spojevi su također prikladni kao lijekovi za liječenje ishemije nervnog sistema, posebno CNS-a, pri čemu su oni prikladni, na primjer, za liječenje udara kapi ili cerebralnog edema. Osim toga, spojevi formule I prema izumu su također prikladni za liječenje nekih oblika šoka, kao što je alergijski, kardiogeni, hipovolemijski i bakterijski šok. Spojevi formule I prema izumu se osim toga odlikuju jakim inhibicijskim djelovanjem na proliferaciju stanica, na primjer, staničnu proliferaciju fibroblasta i proliferaciju glatkih vaskularnih mišićnih stanica. Spojevi formule I su zbog toga prikladni kao dragocjeni terapeutici za bolesti u kojima je proliferacija stanica primarni ili sekundarni uzrok, i oni se zbog toga upotrebljavaju kao antiaterosklerotici, sredstva protiv kasnih komplikacija dijabetesa, bolesti raka, fibroznih poremećaja kao što je plućna fibroza, fibroza jetre ili bubrega, hipertrofija i hiperplazija organa, posebno hiperplazija i hipertrofija prostate.
Spojevi prema izumu su učinkoviti inhibitori staničnih natrij-proton antiportera (Na+/H+-izmjenjivači) koji su uključeni u brojne poremećaje (esencijalna hipertenzija, ateroskleroza, dijabetes, itd.) i koji su također povišeni u onim stanicama koje su lako dostupne za mjerenja, kao na primjer u eritrocitima, trombocitima ili leukocitima. Spojevi prema izumu su stoga prikladni kao istaknuto i jednostavno znanstveno sredstvo, na primjer u njihovoj upotrebi kao dijagnostika za određivanje i razlikovanje određenih oblika hipertenzije, ali također i ateroskleroze, dijabetesa, proliferativnih oboljenja, itd. Osim toga, spojevi formule I su prikladni za terapiju u sprečavanju geneze visokog krvnog tlaka, na primjer, u prevenciji esencijalne hipertenzije.
Pronađeno je, osim toga, da spojevi formule I djeluju povoljno na serumske lipoproteine. Priznato je općenito da je previsoke vrijednosti masnoće u krvi, takozvana hiper-lipoproteinemija, predstavljaju bitan faktor rizika za nastanak arteriosklerotičnih vaskularnih promjena, posebno koronarnih srčanih bolesti. Za profilaksu i regresiju aterosklerotičnih promjena je stoga posebno važno sniženje povišenih lipoproteina u serumu. Osim smanjenja ukupnog kolesterola u serumu, sniženje udjela specifičnih aterogenih lipidnih frakcija tog ukupnog kolesterola, posebno lipoproteina niske gustoće (LDL) i lipoproteina vrlo niske gustoće (VLDL), je posebno važno, jer su te lipidne frakcije aterogeni faktor rizika. Suprotno tome, lipoproteinima visoke gustoće se pripisuje zaštitno djelovanje protiv koronarne srčane bolesti. S tim u skladu, hipolipidemici moraju biti u stanju sniziti u serumu ne samo ukupni kolesterol, već posebno frakcije VLDL i LDL kolesterola.
Sada je pronađeno da spojevi formule I pokazuju dragocjena terapeutski korisna svojstva što se tiče utjecaja na količine lipida u serumu. Tako spojevi izuma značajno snizuju povišenu koncentraciju LDL i VLDL u serumu, koja se opaža, na primjer, kod povećanog dijetetskog uzimanja hrane obogaćene s kolesterolom i lipidima ili kod patoloških promjena metabolizna, na primjer, kod genetski uvjetovane hiperlipidemije. Oni se zbog toga mogu upotrijebiti i za regresiju atero-sklerotičnih promjena s odstranjivanjem uzročnog faktora rizika. Tu spadaju ne samo primarne hiperlipidemije, već također i određene sekundarne hiperlipidemije, kao one koje se pojavljuju, na primjer, kod dijabetesa.
Osim toga, spojevi formule I dovode do zamjetnog smanjenja infarkta induciranog s metaboličkim anomalijama i posebno do značajnog smanjenja veličine infarkta i stupnja njegove ozbiljnosti. Spojevi formule I osim toga pružaju učinkovitu zaštitu protiv ozljeda endotela uzrokovanu metaboličkim anomalijama. S tom zaštitom krvnih žila protiv sindroma endotelne disfunkcije, spojevi formule I su dragocjeni lijekovi na prevenciju i za liječenje koronarnih vazospazmi, aterogeneze i ateroskleroze, lijeve ventrikularne hipertrofije, dilatacijske kardiomiopatije i tromboznih oboljenja.
Spojevi izuma se zbog toga mogu upotrijebiti za proizvodnju lijeka za liječenje hiperkolesteremije; za prevenciju aterogeneze, za proizvodnju lijeka za prevenciju i liječenje ateroskleroze, za proizvodnju lijeka za prevenciju i liječenje bolesti koje su uzrokovane s povišenom količinom kolesterola, za proizvodnju lijeka za prevenciju i liječenje bolesti koje su uzrokovane s endotelnom disfunkcijom, za proizvodnju lijeka za prevenciju i liječenje s aterosklerozom uzrokovane hipertenzije, za proizvodnju lijeka za prevenciju i liječenje tromboze uzrokovane aterosklerozom, za proizvodnju lijeka za prevenciju i liječenje hiperkolesteremije i endotelne disfunkcije uzrokovane ishemijskom ozljedom i postishemijskom reperfuzijskom ozljedom, za proizvodnju lijeka za prevenciju i liječenje hiperkolesteremijom i endotelnom disfunkcijom inducirane kardijalne hipertrofije i kardiomiopatije, i za proizvodnju lijeka za prevenciju i liječenje hiperkolesteremijom i endotelnom disfunkcijom induciranih koronarnih vazospazmi i miokardijalnog infarkta.
K tome, spojevi izuma mogu se upotrijebiti za proizvodnju lijeka za liječenje bolesti koje su ranije spomenute u kombinaciji s hipotenzivnim tvarima, ponajprije s inhibitorima enzima koji pretvara angiotenzin (e. angiotensin converting enzyme, (ACE)) i angiotenzin receptor antagonistima; kombinacija od najmanje jednog spoja formule I koji je NHE inhibitor s aktivnim spojem koji snizuje količinu masti u krvi, ponajprije s inhibitirom HMG-CoA reduktaze (npr., lovastatin ili pravastatin), pri čemu potonja tvar ima hipolipidemijski učinak i time povisuje hipolipidemijska svojstva NHE inhibitora formule (I), pokazala se je kao najpovoljnija kombinacija s pojačanim djelovanjem i smanjenom količinom upotrijebljenog aktivnog spoja.
Predmet zahtjeva je davanje inhibitora izmjene natrij -protona formule I kao novih lijekova za sniženje povišene količine masti u krvi, kao i kombinacije inhibitora izmjene natrij-protona s hipotenzivnim lijekovima i/ili lijekovima koji imaju hipolipidemijsko djelovanje.
U tom smislu, lijekovi koji sadrže najmanje jedan spoj formule I mogu se dati oralno, parenteralno, intravenski, ili rektalno, ili inhalacijom, pri čemu prednosni način davanja ovisi o dotičnoj pojavnoj slici bolesti. U tom smislu, spojevi izuma mogu se upotrijebiti sami, ili zajedno s farmaceutskim pomoćnim sredstvima u veterini i u humanoj medicini.
Zahvaljujući svom stručnom znanju, stručnjak će znati koje je pomoćno sredstvo prikladno za željenu farmaceutsku formulaciju. Osim otapala, sredstava za tvorbu gela, osnove za čepiće, pomoćnih sredstava za tablete i drugih nosača aktivnog spoja, mogu se upotrijebiti, na primjer, anti-oksidanti, disperzanti, emulgatori, sredstva protiv stvaranja pjene, sredstva za korekciju okusa, konzervansi, sredstva za pospješivanje otapanja ili bojila.
Za pripravu formulacije za oralnu upotrebu, aktivni spojevi se pomiješaju s dodacima koji su prikladni za tu svrhu, kao što su nosači, stabilizatori ili inertna sredstva za razredivanje, i uobičajenim postupcima prerađuju se u oblike koji su prikladni za aplikaciju, kao što su tablete, prevučene tablete, tvrde želatinske kapsule ili vodene, alkoholne ili uljne otopine. Kao inertni nosači mogu se upotrijebiti guma arabika, magnezijev oksid, magnezijev karbonat, kalijev fosfat, laktoza, glukoza ili škrob, na primjer kukuruzni škrob. Pri tome, mogu se proizvesti pripravci u obliku suhog ili mokrog granata. Biljna ulja ili životinjska ulja, kao što je na primjer suncokretovo ulje ili jetreno riblje ulje su prikladna za upotrebu kao uljni nosači ili kao otapala.
Za supkutano ili intravensko davanje aktivni spojevi, po želji zajedno s tvarima koje su uobičajene za tu svrhu, kao što su sredstva za pospješivanje otapanja, emulgatori ili dodatna pomoćna sredstva, dovode se u otopinu, suspenziju, ili emulziju. Kao otapala u obzir dolaze na primjeri voda, fiziološka otopina soli, ili alkohol, na primjer etanol, propanol ili glicerol, te također i otopine šećera kao što su otopine glukoze ili manitola, ili također mješavina tih različitih otapala.
Kao farmaceutske formulacije koje se daju u obliku aerosola ili spreja prikladne su npr. otopine, suspenzije ili emulzije aktivnog spoja formule I u farmaceutski nedvojbenom otapalu, kao što su posebno etanol ili voda, ili mješavina takovih otapala.
Prema potrebi, formulacija može sadržavati dodatna farmaceutska pomoćna sredstva, kao što su tenzidi, emulgatori i stabilizatori, kao i potisni plin. Takav pripravak sadrži obično aktivan spoj koncentracijom od pribl. 0,1 to 10%, na primjer, pribl. 0,3 do 3 mas. %.
Doziranje aktivnog spoja formule I pri aplikaciji, i učestalost davanja ovise o jačini i trajanju djelovanja upotrijebljenog spoja. Primijenjeno doziranje također ovisi o naravi i ozbiljnosti bolesti koju se liječi, kao i o spolu, starosti, težini i pojedinačnoj reakciji sisavca kojeg se liječi.
Prosječna dnevna doza spoja formule I za pacijenta teškog pribl. 75 kg je najmanje 0,001 mg/kg, ali može biti i najmanje 0,01 mg/kg, naročito najmanje 0,1 mg/kg do najviše 10 mg/kg, ponajprije najviše 1 mg/kg. Kod akutnog izbijanja bolesti, na primjer neposredno nakon pretrpljenog kardijalnog infarkta, može također biti potrebno dati viša i/ili češća doziranja, npr. sve do 4 pojedinačne doze dnevno. Posebno kod intravenske aplikacije, na primjer u slučaju pacijenta s infarktom na intenzivnoj njezi može biti potrebno sve do 200 mg dnevno.
Popis kratica
CDI karboniIdiimidazol,
MeOH metanol,
DMF N,N-dimetilformamid,
RT sobna temperatura,
EA etil acetat (EtOAc),
eq ekivalent,
ES ionizacija elektrosprejom.
EKSPERIMENTALNI DIO
PRIMJER 1
4-[(imidazol-1-il)fenoksi]-2-metil-5-trifluormetilbenzoil gvanidin dihidroklorid,
bezbojna kruta tvar, M+H (ES)=404.
Put sinteze
a) Metil ester 4-[(imidazol-1-il)fenoksi]-2-metil-5-trifluormetil-benzojeve kiseline
se dobije reakcijom metil 4-fluor-2-metil-3-trifluor-metilbenzoata s 1 ekvivalentom 4-(imidazol-1-il)fenola u prisustnosti 4 ekvivalenta kalijevog karbonata u DMF pri 120°C tijekom 16 h. Ostatak nakon isparavanja otapala podvrgne se vodenoj obradi i ekstrahira mućkanjem s EA. Otapalo se ispari nakon sušenja, čime se dobije bezbojno ulje, M+ (ES) = 376.
b) 4-[(imidazol-1-il)fenoksi]-2-metil-5-trifluormetil-benzojeva kiselina
se dobije lužnatom hidrolizom upotrebom suviška 2N aq. NaOH u MeOH pri sobnoj temperaturi tijekom 2 h. Zakiseli se 2N HCl i ekstrahira s EA. Otapalo se osuši i zatim ispari, čime se dobije bezbojno ulje, M+ (ES) = 362.
4-[(imidazol-1-il)fenoksi]-2-metil-5-tri-fluormetil-benzoil-gvanidin dihidroklorid dobije se aktivacijom s 2 ekvivalenta CDI u DMF-u i zatim reakcijom sa 6 ekvivalenata gvanidinijevog hidroklorida u prisutnosti 7 ekvivalenata diizopropiletilamina pri sobnoj temperaturi tijekom 3 h.
Nakon odstranjivanja otapala slijedi preparativna HPLC (CH3CN/H2O) i zatim tvorba sol s eterskom solnom kiselinom.
PRIMJER 2
4-(triazol-1-il)fenoksi-2-metil-3-trifluormetilbenzoil-gvanidin bistrifluoracetat,
bezbojna kruta tvar, M+H+ (ES)=405.
Put sinteze
a) Metil ester 4-[(triazol-1-il)fenoksi]-2-metil-5-trifluormetil-benzojeve kiseline
je dobiven analogno primjeru 1 a) reakcijom s 1 ekvivalentom 4-(triazol-1-il)fenola, kao bezbojno ulje, M+ (ES) = 377.
b) 4-[(triazol-1-il)fenoksi]-2-metil-5-trifluormetil-benzojeva kiselina
je dobivena analogno primjeru 1 b) kao bezbojno ulje, M+ (ES) (ES) = 363.
c) 4-[(triazol-1-il)fenoksi]-2-metil-5-trifluormetil-benzoilgvanidin bis-trifluoracetat
je dobiven analogno primjeru 1 c), pri čemu je tvorba soli izvršena s trifluoroctenom kiselinom.
Claims (19)
1. Benzoilgvanidini formule (I)
[image]
naznačeni time, da
R1 predstavlja vodik, F, Cl, Br, J, NO2, CN, -Xo-(CH2)p-(CF2)q-CF3, R5-SOm-, R6-CO-, R6R7N-CO- ili R6R7N-SO2-;
X je kisik, -S- ili NR14;
m je nula, 1 ili 2;
o je nula ili 1;
p je nula, 1 ili 2;
q je nula, 1, 2, 3, 4, 5 ili 6;
R5 i R6 međusobno neovisno predstavljaju (C1-C8)-alkil, (C3-C6)-alkenil, -CnH2n-R8 i CF3;
n je nula, 1, 2, 3 ili 4;
R8 je (C3-C7)-cikloalkil ili fenil, koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 su H i (C1-C4)-alkil; ili
R6 je vodik;
R7 je vodik ili (C1-C4)-alkil; ili
R6 i R7 mogu zajedno biti 4 ili 5 metilenskih skupina, od kojih jedna metilenska skupina može biti zamijenjena s kisikom, S, NH, N-CH3, ili N-benzilom;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9)-heteroaril, koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, hidroksi, amino, metilamino, dimetilamino i benzil;
Y je kisik, -S- ili NR12;
R12 je H ili (C1-C4)-alkil;
R3 je definiran kao R1; ili
R3 je (C1-C6)-alkil ili -X-R13;
X je kisik, -S- ili NR14;
R14 je H ili (C1-C3) -alkil;
R13 je H, (C1-C6)-alkil, (C3-C8) -cikloalkil ili -CbH2b-R15;
b je nula, 1, 2, 3 ili 4;
R15 je fenil koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 predstavljaju H ili (C1-C4)-alkil; ili
R13 i R14 zajedno tvore 4 ili 5 metilenskih skupina, od kojih jedna metilenska skupina može biti zamijenjena s kisikom, S, NH, N-CH3 ili s N-benzilom;
R4 je F, Cl, Br, J ili C1-C4-alkil;
kao i njihove farmaceutski podnošljive soli.
2. Spojevi prema zahtjevu 1, naznačeni time, da
R1 predstavlja vodik, F, Cl, CN, CF3, R5-SOm-, R6-CO-, R6R7N-CO- ili R6R7N-SO2-;
m je nula, 1, ili 2;
R5 i R6 međusobno neovisno predstavljaju (C1-C8)-alkil, (C3-C4) -alkenil, -CnH2n-R8 i CF3;
n je nula ili 1;
R8 je (C3-C6)-cikloalkil ili fenil, koji nije supstituiran, ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, metil, metoksi i NR9R10;
R9 i R10 predstavljaju H ili metil; ili
R6 je vodik;
R7 je vodik ili metil;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9)-heteroaril koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 3 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, hidroksi, amino, metilamino, dimetilamino i benzil;
Y je kisik, -S- ili NR12;
R12 je H ili (C1-C4)-alkil;
R3 je vodik, metil, CN, CF3, F ili Cl;
R4 je F, Cl ili (C1-C4)-alkil;
te njihove farmaceutski podnošljive soli.
3. Spojevi prema zahtjevu 1, naznačeni time, da
R1 predstavlja vodik, F, Cl, CN, CF3 ili R5-SOm-;
m je nula, 1 ili 2;
R5 je metil ili CF3;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C9)-heteroaril koji je povezan preko C ili N i koji nije supstituiran ili je supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino, i benzil;
Y je kisik;
R3 je vodik, metil, CN, CF3, F ili Cl;
R4 je (C1-C4)-alkil;
te njihove farmaceutski podnošljive soli.
4. Spojevi prema zahtjevu l, naznačeni time, da
R1 predstavlja vodik, F, Cl, CN, CF3 ili R5-SO2-;
R5 je metil ili CF33;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je (C1-C5)-heteroaril koji je povezan preko C ili N i koji nije supstituiran, ili je supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino i benzil;
Y je kisik;
R3 je vodik;
R4 je (C1-C4)-alkil;
kao i njihove farmaceutski podnošljive soli.
5. Spojevi prema zahtjevu l, naznačeni time, da
R1 je CF3;
R2 je -Y-p-(C6H4)-R11, -Y-m-(C6H4)-R11 ili -Y-o-(C6H4)-R11;
R11 je imidazolil ili triazolil, nesupstituiran, ili supstituiran s 1 do 2 supstituenta odabrana iz skupine koju čine F, Cl, CF3, CH3, metoksi, dimetilamino i benzil;
Y je kisik;
R3 je vodik;
R4 je metil;
kao i njihove farmaceutski podnošljive soli.
6. Postupak za pripravu spoja formule (I), naznačen time, da uključuje reakciju spoja formule (II)
[image]
u kojoj su R1 do R4 definirani kao u zahtjevu 1, i L je izlazna skupina koja se može lako nukleofilno supstituirati, s gvanidinom.
7. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu bolesti uzrokovanih ishemijskim stanjima.
8. Postupak za liječenje ili profilaksu bolesti uzrokovanih ishemijskim stanjima, naznačen time, da se učinkovitu količinu spoja prema zahtjevu 1 pomiješa s uobičajenim dodacima i dovede u oblik prikladan za aplikaciju.
9. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu srčanog infarkta i aritmija.
10. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu angine pektoris.
11. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja srca.
12. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernog i središnjeg nervnog sistema i udara kapi.
13. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemjskih stanja perifernih organa i udova.
14. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje stanja šoka.
15. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka koji se rabi pri kirurškim operacijama i presađivanju organa.
16. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za konzerviranje ili odlaganje organa za presađivanje.
17. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje bolesti kod kojih proliferacija stanica predstavlja primarni ili sekundarni uzrok.
18. Upotreba spoja prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu poremećaja metabolizma masnih tvari.
19. Lijek, naznačen time, da sadrži učinkovitu količinu spoja prema jednom ili više zahtjeva 1 do 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10001879A DE10001879A1 (de) | 2000-01-19 | 2000-01-19 | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| PCT/EP2001/000137 WO2001053256A1 (de) | 2000-01-19 | 2001-01-08 | Substituierte benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament oder diagnostikum sowie sie enthaltendes medikament |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20020592A2 true HRP20020592A2 (en) | 2004-08-31 |
Family
ID=7627855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20020592A HRP20020592A2 (en) | 2000-01-19 | 2002-07-16 | Substituted benzoylguanidines, method for their production, their use as a medicament or diagnostic agent and a medicament containing the same |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US6703411B2 (hr) |
| EP (1) | EP1259481B1 (hr) |
| JP (1) | JP4880849B2 (hr) |
| KR (1) | KR100726701B1 (hr) |
| CN (1) | CN1184196C (hr) |
| AR (1) | AR027237A1 (hr) |
| AT (1) | ATE530518T1 (hr) |
| AU (1) | AU780466B2 (hr) |
| BR (1) | BR0107660A (hr) |
| CA (1) | CA2397531A1 (hr) |
| CZ (1) | CZ20022465A3 (hr) |
| DE (1) | DE10001879A1 (hr) |
| EE (1) | EE200200381A (hr) |
| HK (1) | HK1051853A1 (hr) |
| HR (1) | HRP20020592A2 (hr) |
| HU (1) | HUP0204095A3 (hr) |
| IL (1) | IL150740A0 (hr) |
| MX (1) | MXPA02006431A (hr) |
| NO (1) | NO20023383L (hr) |
| NZ (1) | NZ520213A (hr) |
| PL (1) | PL356589A1 (hr) |
| RU (1) | RU2267486C2 (hr) |
| SK (1) | SK10382002A3 (hr) |
| TW (1) | TWI240718B (hr) |
| WO (1) | WO2001053256A1 (hr) |
| YU (1) | YU52202A (hr) |
| ZA (1) | ZA200205696B (hr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10204989A1 (de) * | 2002-02-07 | 2003-08-21 | Aventis Pharma Gmbh | Dihydro-thia-phenanthren-carbonyl-guanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| US20050124666A1 (en) | 2003-11-13 | 2005-06-09 | Aventis Pharma Deutschland Gmbh | Pentafluorosulfanylbenzoylguanidines, process for their preparation, use as a medicament or diagnostic aid, and medicament comprising same |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE59307360D1 (de) * | 1992-02-15 | 1997-10-23 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| JP2689058B2 (ja) * | 1992-11-02 | 1997-12-10 | 新日本製鐵株式会社 | 塗装体の乾燥・焼付装置 |
| DE4325822A1 (de) * | 1993-07-31 | 1995-02-02 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4328869A1 (de) | 1993-08-27 | 1995-03-02 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4430916A1 (de) | 1994-08-31 | 1996-03-07 | Merck Patent Gmbh | Alkyl-benzoylguanidin-Derivate |
| DE4430861A1 (de) * | 1994-08-31 | 1996-03-07 | Merck Patent Gmbh | Heterocyclyl-benzoylguanidine |
| DE19529612A1 (de) * | 1995-08-11 | 1997-02-13 | Merck Patent Gmbh | Sulfonyl- oder Sulfinyl-benzoylguanidin-Derivate |
| DE19608161A1 (de) * | 1996-03-04 | 1997-09-11 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19621319A1 (de) * | 1996-05-28 | 1997-12-04 | Hoechst Ag | Bis-ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19624178A1 (de) * | 1996-06-18 | 1998-01-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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2000
- 2000-01-19 DE DE10001879A patent/DE10001879A1/de not_active Withdrawn
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- 2001-01-08 KR KR1020027009256A patent/KR100726701B1/ko not_active IP Right Cessation
- 2001-01-08 BR BR0107660-4A patent/BR0107660A/pt not_active IP Right Cessation
- 2001-01-08 YU YU52202A patent/YU52202A/sh unknown
- 2001-01-08 WO PCT/EP2001/000137 patent/WO2001053256A1/de active IP Right Grant
- 2001-01-08 SK SK1038-2002A patent/SK10382002A3/sk not_active Application Discontinuation
- 2001-01-08 IL IL15074001A patent/IL150740A0/xx unknown
- 2001-01-08 RU RU2002122089/04A patent/RU2267486C2/ru not_active IP Right Cessation
- 2001-01-08 CA CA002397531A patent/CA2397531A1/en not_active Abandoned
- 2001-01-08 EE EEP200200381A patent/EE200200381A/xx unknown
- 2001-01-08 EP EP01900139A patent/EP1259481B1/de not_active Expired - Lifetime
- 2001-01-08 CZ CZ20022465A patent/CZ20022465A3/cs unknown
- 2001-01-08 JP JP2001553261A patent/JP4880849B2/ja not_active Expired - Fee Related
- 2001-01-08 PL PL01356589A patent/PL356589A1/xx not_active Application Discontinuation
- 2001-01-08 CN CNB018038247A patent/CN1184196C/zh not_active Expired - Fee Related
- 2001-01-08 MX MXPA02006431A patent/MXPA02006431A/es active IP Right Grant
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- 2001-01-08 AT AT01900139T patent/ATE530518T1/de active
- 2001-01-08 AU AU23732/01A patent/AU780466B2/en not_active Ceased
- 2001-01-08 HU HU0204095A patent/HUP0204095A3/hu unknown
- 2001-01-17 TW TW090100987A patent/TWI240718B/zh not_active IP Right Cessation
- 2001-01-17 US US09/760,670 patent/US6703411B2/en not_active Expired - Fee Related
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- 2002-07-12 NO NO20023383A patent/NO20023383L/no not_active Application Discontinuation
- 2002-07-16 HR HR20020592A patent/HRP20020592A2/hr not_active Application Discontinuation
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