CN1170716A - 双-邻位取代的苯甲酰胍、其制备方法、用途及含有它们的药物 - Google Patents
双-邻位取代的苯甲酰胍、其制备方法、用途及含有它们的药物Info
- Publication number
- CN1170716A CN1170716A CN97113032A CN97113032A CN1170716A CN 1170716 A CN1170716 A CN 1170716A CN 97113032 A CN97113032 A CN 97113032A CN 97113032 A CN97113032 A CN 97113032A CN 1170716 A CN1170716 A CN 1170716A
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- 210000003677 hemocyte Anatomy 0.000 description 1
- 229940000351 hemocyte Drugs 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000006210 lotion Substances 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
- 229960004844 lovastatin Drugs 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
- 235000004213 low-fat Nutrition 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 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
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical compound CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- AQIAIZBHFAKICS-UHFFFAOYSA-N methylaminomethyl Chemical compound [CH2]NC AQIAIZBHFAKICS-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
式Ⅰ的双-邻位取代的苯甲酰胍,其中R(1)至R(5)具有权利要求所示含义,它们适于作为心脏保护性抗心率不齐药物,用于梗死的预防和治疗,并用于治疗心绞痛。它们还预防性地抑制局部缺血诱发损伤形成的病生理学进程,尤其是局部缺血诱发的心率不齐的出现。
Description
各自独立是R(10)-SOa-或R(14)R(15)N-SO2-;
a是0,1或2,
R(10),R(14)和R(15)
各自独立是含1,2,3,4,5,6,7或8个碳原子的烷基,含1,2,
3,4,5,6,7或8个碳原子的全氟烷基,含3,4,5或6个碳原子
的链烯基或者-CabH2ab-R(16);
ab是0,1,2,3或4;
R(16)是含3,4,5,6或7个碳原子的环烷基,或者苯基,它们
是未取代的或者被1-3个取代基取代,所述取代基选自F,Cl,
CF3,甲基,甲氧基和NR(17)R(18);
R(17)和R(18)
各自独立是氢,CF3或含1,2,3或4个碳原子的烷基;或者R(14)和R(15)
一起是4或5亚甲基,其中一个CH2-基可被氧、硫、NH、N-CH3或
N-苄基置换;
或者
R(14)和R(15)
是氢;或者R(1),R(2)和R(3)
各自独立地是SR(21),-OR(22),-NR(23)R(24)或
-CR(25)R(26)R(27);
R(21),R(22),R(23)和R(25)
各自独立地是-CbH2b-(C1-C9)杂芳基,
该杂芳基是未取代的或被1-3取代基取代,所述取代基选自F,Cl,
CF3,CH3,甲氧基,羟基,氨基,甲氨基和二甲基;
b是0,1或2;
R(24),R(26)和R(27)
各自独立地是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,Br,I,CN,-(Xa)dg-CdaH2da+1,-(Xb)dh-
(CH2)db-CdeF2de+1,含3,4,5,6,7或8个碳原子的链烯基或者-
CdfH2dfR(30);
(Xa)是氧,硫或NR(33);
R(33)是氢,含1,2,3或4个碳原子的烷基或含1,2,3或4个碳
原子的全氟烷基,
dg 是0或1;
(Xb)是氧,硫或NR(34);
R(34)是氢,含1,2,3或4个碳原子的烷基或含1,2,3或4
个碳原子的全氟烷基;
dh 是0或1;
da 是0,1,2,3,4,5,6,7或8;
db 是0,1,2,3或4;
de 是0,1,2,3,4,5,6或7;
df 是0,1,2,3或4;
R(30)是含3,4,5,6,7或8个碳原子的环烷基,苯基,联苯甚或萘基;
所述芳香系苯基,联苯基或萘基是未取代的或者被1-3
个取代基取代,所述取代基选自F,Cl,CF3,甲基,甲氧基
和NR(31)R(32);
R(31)和R(32)
是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟基;或者R(1),R(2)和R(3)
各自独立地是NR(40)R(41)或-(Xe)-(CH2)ebR(45);
R(40)和R(41)
各自独立地是氢,含1,2,3,4,5,6,7或8个碳原子的烷基,含
1,2,3,4,5,6,7或8个碳原子的全氟烷基或者(CH2)e-R(42);
e 是0,1,2,3或4;
R(42)是含3,4,5,6或7个碳原子的环烷基或者苯基,它们是
未取代的或者被1-3个取代基取代,所述取代基选自F,Cl,CF3,
甲基,甲氧基和NR(43)R(44);
R(43)和R(44)
各自独立地是氢,CF3或含1,2,3或4个碳原子的
烷基;
或者
R(40)和R(41)
一起是4或5亚甲基,其中一个CH2-基可被氧、硫、
NH、N-CH3或N-苄基置换;(Xe)是氧,硫或NR(47);
R(47)是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟烷基;
eb 是0,1,2,3或4;
R(45)是含3,4,5,6或7个碳原子的环烷基或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基
选自F,Cl,CF3,甲基,甲氧基和NR(50)R(51)和-(Xfa)-
(CH2)ed-(Xfb)R(46);
Xfa是CH2,氧,硫或NR(48);
Xfb是氧,硫或NR(49);
R(48),R(49),R(50)和R(51)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;
ed 是1,2,3或4;
R(46)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)
各自独立地是-CHR(52)R(53);
R(52)是-(CH2)g-(CHOH)h-(CH)i-(CHOH)k-R(54)或-(CH2)g-O-(CH2-CH2O)h-R(54);
R(54)是氢或甲基;
g,h,i
彼此相同或不同,是0,1,2,3或4;
k是1,2,3或4;
R(53)是氢或含1,2,3或4个碳原子的烷基;或者R(1),R(2)和R(3)
各自独立地是-C(OH)R(55)R(56);
R(55)和R(56)
相同或不同,是氢或含1,2,3或4个碳原子的烷基;
或者
R(55)和R(56)
一起是含3,4,5或6个碳原子的环烷基;
或者
R(55)是-CH2OH;并且R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子的烷氧基,OH,F,Cl,Br,I,CN,-On-(CH2)o-(CF2)p-CF3;
n是0或1;
o是0,1或2;
p是0,1或2。
优选的式I化合物及其可药用盐中:R(1),R(2)和R(3)
各自独立是R(10)-SOa-;
R(10)是含1,2,3,4,5,6,7或8个碳原子的烷基,含1,2,3,
4,5,6,7或8个碳原子的全氟基,含3,4,5或6个碳原
子的链烯基或者-CabH2ab-R(16);
ab是0,1,2,3或4;
R(16)是含3,4,5,6或7个碳原子的环烷基,或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基选
自F,Cl,CF3,甲基,甲氧基和NR(17)R(18);
R(17)和R(18)
各自独立是氢,CF3或含1,2,3或4个碳原子的烷基;或者R(1),R(2)和R(3)
各自独立地是-OR(22)或-CR(25)R(26)R(27);
R(22)和R(25)
各自独立地是-CbH2b-(C1-C9)杂芳基,
该杂芳基是未取代的或被1-3个取代基取代,所述取代基选
自F,Cl,CF3,CH3,甲氧基,羟基,氨基,甲氨基和二甲氨基,
b是0,1或2;
R(26)和R(27)
各自独立地是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,Br,I,CN,-Odg-CdaH2da+1,-Odh-(CH2)db-
CdeF2de+1,含3,4,5或6个碳原子的链烯基或者-CdfH2dfR(30);
dg 是0或1;
dh 是0或1;
da 是0,1,2,3或4;
db 是0,1,2,4或4;
de 是0,1,2,3,4,5,6或7;
df 是0,1,2,3或4;
R(30)是含3,4,5,6,7或8个碳原子的环烷基,苯基,联苯基或
萘基;
所述芳香系苯基,联苯基或萘基是未取代的或者被1-3个取代基
取代,所述取代基选自F,Cl,CF3,甲基和甲氧基;或者R(1),R(2)和R(3)
各自独立地是-O-(CH2)eb-R(45);
eb 是0,1或2;
R(45)是含3,4,5,6或7个碳原子的环烷基或者基,它们是未
取代的或者被1-3个取代基取代,所述取代基选自F,Cl,CF3,甲基,
甲氧基和-(Xfa)-(CH2)ed-(Xfb)R(46);
Xfa 是CH2,氧,硫或NR(48);
Xfb 是氧,硫或NR(49);
ed是1或2;
R(46)是氢,含1,2,3或4个碳原子的烷基或者含1,2,3或4
个碳原子的全氟烷基;
R(48)和R(49)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)
各自独立地是-CHR(52)R(53);
R(52)是-(CH2)g-(CHOH)h-(CH2)i-(CHOH)k-R(54)或-(CH2)g-O-(CH2-CH2O)h-R(54);
R(53)和R(54)
是氢或甲基;
g,h,i
彼此相同或不同,是0,1或2;
k是1或2;或者R(1),R(2)和R(3)各自独立地是-C(OH)R(55)R(56);R(55)和R(56)
相同或不同,是氢或含1,2,3或4个碳原子的烷基;
或者
R(55)和R(56)
一起是含3,4,5或6个碳原子的环烷基;
或者
R(55)是-CH2OH;R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子的烷氧基,OH,F,Cl,CN,-On-(CF2)p-CF3;
n是0或1;
p是0,1或2。
特别优选的式I化合物及其可药用盐中:
R(1),R(2)和R(3)
各自独立是R(10)-SO2-;
R(10)是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子
的全氟烷基,含3,4,5或6个碳原子的链烯基或者-CabH2ab-R(16);
R(16)是含3,4,5,6或7个碳原子的环基,或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基选
自F,Cl,CF3,甲基和甲基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,OH,CN,CF3,含1,2,3或4个碳原子的烷
基,含5或6个碳原子的环烷基或者含1,2,3或4个碳原子的烷氧基;或者R(1),R(2)和R(3)
各自独立地是-O-(CH2)eb-R(45);
eb 是0,1或2;
R(45)是含1,2,3或4个碳原子的环烷基或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基
选自F,Cl,CF3,甲基和甲氧基;或者R(1),R(2)和R(3)
各自独立地是-CH(CH3)-CH2OH,-C(OH)(CH3)2或-C(OH)(CH3)-CH2OH;以及R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子的烷氧基,OH,F,Cl,CN或-CF3。
(C1-C9)杂芳基的含义基团应理解为是由苯基或萘基衍生的基团,其中的一个或多个CH基被N置换和/或其中的至少两个相邻CH基被氧、硫或NH置换(形成五元芳环)。此外,双环基团的稠合位置的一或两个原子可以是氮原子。
杂芳基可列举呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、喹啉基、异喹啉基、2,3-二氮杂萘基、喹喔啉基、喹唑啉基、1,2-二氮杂萘基。
如果取代基R(1)至R(5)之一包含一个或多个不对称中心,其可以是S或R构型的。这些化合物可以旋光异构体、非对映体、外消旋体或它们的混合物形式存在。
所述烷基和全氟烷基可以是直连或支链的。
本发明还涉及式I化合物的制备方法,该方法包括,将式II化合物与胍反应,式II中,R(1)至R(5)含义如上所述,且L是易被亲核取代的离去基团。
其中L是烷氧基的式II的活泼酸衍生物可方便地采用先前已知的方法,由相应的酰氯(式II,L=Cl)获得,该酰氯的部分又可以先前已知的方法使用硫酰氯由相应的羧酸(式II,L=OH)制备,所述L烷氧基优选甲氧基、苯氧基、苯硫基、甲硫基或2-吡啶硫基,或者氮杂环,优选1-咪唑基。除式II的酰氯外,其它式II的活泼酸衍生物也可采用已知方法,直接用甲醇中的HCl气处理相应的苯甲酸衍生物(式II,L=OH),例如其中L=OCH3的式II的甲酯;用羰基二咪唑处理式II的咪唑[L=1-咪唑基,Staab,Angew.Chem.Int.Ed.Engl.1,351-367(1962)];在惰性溶剂中、存在三乙胺的条件下,将混合酸酐II与Cl-COOC2H5或甲苯磺酰氯反应制备;苯甲酸的活化也可使用二环己基碳化二亚胺(DCC)或使用四氟硼酸O-[(氰基(乙氧羰基)-亚甲基)氨基]-1,1,3,3-四甲基(TOTU)[Wesis和Krommer,化学家时报98,817(1974)]。多种制备式II的活泼羧酸衍生物的方法详述于文献J.March,高等有机化学,第三版(John wiley & Sons,1985),第350页。
式II的活泼羧酸衍生物与胍的反应以先前已知的方式、在质子或非质子传递的极性并且惰性的有机溶剂中进行。据证明,20℃至沸点温度的甲醇、异丙醇或THF是苯甲酸甲酯(L=OCH3)与胍反应的适宜溶剂。式II化合物与非盐的胍的绝大多数反应在非质子传递的惰性溶剂如THF、二甲氧基乙烷或二噁烷中进行是有益的。但在式II与胍的反应中使用碱如NaOH时,则可使用水为溶剂。
如果L=Cl,该反应中加入酸清除剂是有益的,例如以过量胍用于结合氢卤酸。
式II的某些相应的苯甲酸衍生物是已知的并有文献记载。式II的未知化合物可采用文献已知方法制备。所得的苯甲酸可参照上述各种之一反应得到本发明的式I化合物。
采用文献记载的方法,使用酰卤化物或酰基triflate,例如有机锡烷、有机硼酸或有机硼烷,或者有机铜或-锌化合物,通过钯介导的交联,将某些取代基引入苯环。
一般来说,苯甲酰胍I是弱碱性的,可与酸结合形成盐。酸加成盐可以是所有可药用盐,例如氢卤化物,尤其是盐酸盐,乳酸盐,硫酸盐,柠檬酸盐,酒石酸盐,乙酸盐,磷酸盐,甲磺酸盐和对甲苯磺酸盐。
式I化合物是取代的酰基胍类。
EP-A 628 543(HOE 93/F 154-新西兰专利260 681)公开了在两个邻位上都有取代基的化合物,但其3-位总是酰基或酰氨基取代基,该取代基在本发明的化合物中是不存在的。
EP-A 690 048(HOE 94/F 182-新西兰专利272449)也公开了在两个邻位带有取代基的化合物,但其中之一总是邻位氨基。
EP-A 704 431(南非95 07 161)描述带有一个邻位取代基的化合物,但并不是两个邻位上都带有取代基。
与已知化合物相比,本发明的化合物对Na+/H+交换具有特别高的抑制活性。
与已知化合物一样,它们不具有令人不如意的和不利的利尿盐特性,但具有很好的抗心率不齐特性,对于例如治疗氧缺乏综合症中发生的疾病具有重要意义。考虑到它们的药理学特性,本发明的化合物特别适于作为抗心率不齐药物成分,用于梗死的预防和治疗,并用于治疗心绞痛,它们还可以预防的方式抑制或微微减轻局部缺血诱发损伤形成的疾病生理学进程,特别是局部缺血诱发的心率不齐的出现。由于它们对病理性低氧或局部缺血症状的预防作用,使用本发明的式I化合物可抑制细胞Na+/H+交换机制,作为治疗因局部缺血或疾病诱发的原发性或继发性急性或慢性损伤的药物。这与它们作为外科手术用药物的用途有关,例如在器官移植中,本发明化合物可保护移取前和移取期间的供体器官,以保护移植的器官,例如使用其治疗期间或将其贮存于生理浴液中,或者在移植到受体期间保护器官。当施行例如心脏或外周血管血管成形外科手术时,本发明化合物也作为保护性药物。相应于它们对局部缺血诱发的损伤的预防作用,本发明化合物适于作为治疗神经系统,尤其是CNS的局部缺血,它们适于治疗中风或大脑水肿。此外,本发明化合物还适于治疗各种休克,例如过敏性休克、心原性休克、血容量减少性休克和细菌性休克。
另外,本发明式I化合物对细胞增殖,例如成纤维细胞增殖和血管平滑肌细胞增殖有很强抑制作用。因此,式I化合物适于作为其中细胞增殖是原发性或继发型病因的疾病治疗剂,可作为抗动脉粥样硬化药,治疗糖尿病后期综合症,癌症,纤维化疾病,如肺纤维化、肝纤维化或肾纤维化,器官肥大或增生,尤其是前列腺增生或前列腺肥大的药物。
本发明的化合物是细胞钠-质子反向转运子(Na+/H+交换子)的有效抑制剂,该转运子在多种疾病(原发性高血压、动脉粥样硬化、糖尿病等)中,甚至在那些易于检测的细胞,如红细胞、血小板或白细胞中也是升高的。因此本发明的化合物适于作为出色的简便科学工具,例如它们作为诊断剂用于确定和鉴别某些类型的高血压、动脉粥样硬化、糖尿病和增殖性疾病等。并且,式I化合物适于预防高血压,如原发性高血压发生的预防性治疗。
另外还发现式I化合物对血浆脂蛋白具有有益效果。一般认为动脉粥样性血管变化的形成,尤其是冠心病的形成,特别是高血脂值的出现,即所谓高脂血症的形成是十分危险的因素。为预防和消退动脉粥样硬化性变化,降低升高的血浆脂蛋白水平显得尤为重要。除降低总血浆胆固醇外,降低该总胆固醇中的特种致动脉粥样硬化的脂质的比率,尤其是低密度脂蛋白(LDL)和极低密度脂蛋白(VLDL)具有特别重要的意义,因为这些是致动脉粥样硬化的危险因素。相反,据述高密度脂蛋白对冠心病有预防作用。因此,低脂血症不仅能降低总胆固醇,更可降低VLDL和LDL的血浆胆固醇比率。现已发现,式I化合物由于其对血脂的影响而具有有益的治疗价值。它们可明显降低升高的LDL和VLDL血浆浓度,据观察,这是由于升高的LDL和VLDL血浆浓度是由于富胆固醇和富脂质膳食增加或是由于病理性代谢变化,例如与遗传有关的高脂血症的结果。因此,它们可用于预防和消退动脉粥样性硬化的变化,由此消除危险因素。这不仅包括原发性各自脂血症,还包括某些继发型,如发生于糖尿病的脂血症。此外,式I化合物可明显降低由代谢异常诱发的梗死,尤其是可明显减少诱发性梗死的规模并降低其严重程度。再有,式I化合物可有效地预防由代谢异常诱发的内皮损伤。由于对内皮异常综合症的血管的保护作用,式I化合物是一种有价值的药物,用于预防和治疗动脉粥样硬化形成和动脉粥样硬化、左心室肥大和扩张性心肌病的冠状动脉痉挛。
因此,所述化合物可有益地用于生产治疗高脂血症的药物;用于生产预防动脉粥样硬化形成的药物;用于生产预防和治疗动脉粥样硬化的药物;用于生产预防和治疗因升高的胆固醇水平诱发的疾病的药物;用于生产预防和治疗内皮细胞异常诱发的疾病的药物;用于生产预防和治疗高血压诱发的动脉粥样硬化的药物;用于生产预防和治疗动脉粥样硬化诱发的血栓的药物;用于生产预防和治疗高脂血症和内皮异常诱发的局部缺血性损伤和局部缺血后回灌所致损伤的药物;用于生产预防和治疗高脂血症和内皮异常诱发的心脏肥大和心肌病的药物;用于生产预防和治疗高脂血症和内皮异常诱发的冠状动脉痉挛和心肌梗死的药物;用于生产与高血压药物合用的治疗所述病症的药物,所述高血压药物优选血管紧张素转化酶(ACE)抑制剂和血管紧张素受体拮抗剂,据证明式I的NHE抑制剂与降低血脂水平的活性化合物合用可有益地增强和减弱活性化合物的作用,后者具有低脂血作用并因此增强式I的NHE抑制剂的低脂血作用,所述活性化合物优选HMG-CoA还原酶抑制剂(如洛伐他汀或普伐它汀)。
本发明请求保护式I钠-质子交换抑制剂,它作为新的降低升高的血脂水平的药物给药,以及钠-质子交换抑制剂与高血压和/或低脂血症药物的组合物。
含式I化合物的药物可口服、经非胃肠道、静脉、直肠或吸入给药,优选的给药方式可取决于病症的特殊临床性质。在兽医和人类医学中,可单独使用式I化合物本身或将其与药物辅剂一起使用。
本领域普通技术人员根据其专业知识可获知适于目的药物配方的辅剂。除溶剂外,可使用胶凝剂,栓剂基质,片剂辅剂和其它活性化合物赋形剂,例如抗氧剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、增溶剂或着色剂。
对于口服给药形式,有效化合物可与适合该目的的添加剂,如与赋形剂、增溶剂或惰性溶剂混合,采用常规方法制成适宜的给药形式,如片剂、包衣片剂、硬明胶胶囊、水溶液、醇溶液或油溶液。可使用的惰性赋形剂是例如阿拉伯胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉,尤其是玉米淀粉。可采用干粉或湿颗粒形式制备。适宜的油性赋形剂或溶剂是例如植物或动物油,如葵花子油或鱼肝油。
对于皮下或静脉给药,如果需要,可将活性化合物与常用于此目的的物质制成溶液、混悬液或乳液,所述物质例如增溶剂、乳化剂或其它辅剂。可使用的溶剂是例如:水,生理盐水溶液或醇类,如乙醇、丙醇、甘油,此外还有其它糖溶液,如葡萄糖会甘露醇溶液,或者可使用上述各种溶剂的混合物。
适于以气雾剂或喷雾剂形式给药的药物制剂是例如式I活性成分的可药用溶剂,具体如乙醇或水或者此类溶剂的混合物的溶液、混悬液或乳液。
如果需要,制剂也可含有其它药物助剂,如表面活性剂、乳化剂和增溶剂,以及抛射剂。这种制剂通常含有的活性化合物浓度为0.1-10,尤其是0.3-3%(重量)。
式I化合物的给药剂量和给药频率取决于所用化合物的作用强度和时间;还有所治疗疾病的性质和严重程度及所医治哺乳动物的性别、年龄和个体反应。
对体重为约75公斤的患者而言,式I化合物的平均每日剂量是至少0.001mg/kg,优选0.01mg/kg,至最多10mg/kg,优选1mg/kg体重。在急性病情时,如患心肌梗死的即刻,也可能需更高剂量和特别是更快频率的剂量,如多至每日4次剂量。尤其是例如对监护病房的梗死患者,静脉给药所需的每日剂量可高达200mg。缩略语:MeOH 甲醇DMF N,N-二甲基甲酰胺室温 室温EA 乙酸乙酯(EtOAc)M.P. 熔点THF 四氢呋喃当量. 当量实施例部分制备苯甲酰胍的一般步骤(I)方法A:由苯甲酸(II,L=OH)制备
将1.0当量式II的苯甲酸衍生物溶于或悬浮于无水THF(5ml/mmol),然后用1.1当量羰基二咪唑处理。在室温下搅拌2小时,将5.0当量胍加到反应溶液中。搅拌过夜后,减压(旋转蒸发器)蒸出THF,用水处理残余物并用2N HCl调至pH 6-7,滤出相应的苯甲酰胍(式I)。再用盐酸或其它可药用酸的水、醇或醚溶液将所得苯甲酰胍处理,转化为相应的盐。方法B:由苯甲酸烷基酯(II,L=O-烷基)制备
将1.0当量式II的苯甲酸烷基酯和5.0当量胍(游离碱)溶于异丙醇或悬浮于THF中,加热至沸腾(典型反应时间为2-5小时)直至转化完全(薄层检测)。减压(旋转蒸发器)蒸除溶剂,将残余物加到EA中,用NaHCO3溶液洗3次。有机相经Na2SO4干燥,真空蒸除溶剂,残余物用适宜的洗脱剂,如EA/MeOH 5∶1进行硅胶色谱。(比较方法A的盐形成)实施例1:2,6-二氯苯甲酸胍盐酸盐无色结晶,m.p.>300℃,参照方法A由2,6-二氯苯甲酸制备。实施例2:3-氯-2,6-二甲氧基苯甲酸胍盐酸盐无色结晶,m.p.148℃,参照方法A由3-氯-2,6-二甲氧基苯甲酸制备。实施例3:4-羟基-2,3,5,6-四氟苯甲酰胍盐酸盐无色固体,m.p.184℃,参照方法A由4-羟基-2,3,5,6-四氟苯甲酸制备。实施例4:2,6-二氟苯甲酰胍盐酸盐无色结晶,m.p.208-10℃,参照方法A由2,6-二氟苯甲酸制备。实施例5:2-氟-6-三氟甲基苯甲酰胍盐酸盐无色固体,m.p.178-80℃,参照方法A由2-氟-6-三氟甲基苯甲酸制备。实施例6:3-三氟甲基-2,6-二甲氧基苯甲酰胍盐酸盐无色结晶,m.p.189℃,在碘化铜(I)的存在下,在二甲基甲酰胺中将3-溴-2,6-二甲氧基苯甲酸与三氟醋酸钾反应,随后参照方法A制备。药理数据:对兔红细胞Na+/H+交换子的抑制
使白色新西兰兔(Ivanovas)接受6周含2%胆固醇的饲料,以激活Na+/H+交换,如此可采用火焰光度法测定经Na+/H+交换迁入红细胞的Na+。由耳静脉采血并用25 IU肝素钠防凝。使用每份血样的一部分,通过离心重复测定血细胞容量。每次使用等份的100微升测定红细胞的Na+交换量。
为测定胺氯吡脒敏感的钠迁入,将100微升血样每份在37℃、pH7.4的5ml高摩尔糖-盐培养基(mmol/l:140NaCl,3KCl,150蔗糖,0.1乌本苷,20三羟基甲氨基甲烷)中培养。然后用冰冷的MgCl2-乌本苷溶液(mmol/l:112 MgCl2,0.1乌本苷)洗三次,并在2.0ml蒸馏水中溶血。采用火焰光度法测定细胞内的钠含量。
由钠起始值和培养后红细胞的钠含量之差计算Na+的净迁入。由加或不加3×10-4mol/l胺氯吡脒培养后红细胞的钠含量之差得到胺氯吡脒抑制的钠迁入。对本发明的化合物也采用相同方法。结果:Na+/H+交换的抑制:实施例 IC50(μmol/l)1 102 8.53 0.34 >105 106 >10
Claims (16)
1.式I的双-邻位取代的苯甲酰胍及其可药用盐其中:R(1),R(2)和R(3)
各自独立是R(10)-SOa-或R(14)R(15)N-SO2-;
a是0,1或2,
R(10),R(14)和R(15)
各自独立是含1,2,3,4,5,6,7或8个碳原子的烷基,含1,2,
3,4,5,6,7或8个碳原子的全氟烷基,含3,4,5或6个碳原子
的链烯基或者-CabH2ab-R(16);
ab是0,1,2,3或4;
R(16)是含3,4,5,6或7个碳原子的环烷基,或者苯基,它们
是未取代的或者被1-3个取代基取代,所述取代基选自F,Cl,
CF3,甲基,甲氧基和NR(17)R(18);
R(17)和R(18)
各自独立是氢,CF3或含1,2,3或4个碳原子的烷基;或者R(14)和R(15)
一起是4或5个亚甲基,其中一个CH2-基可被氧、硫、NH、N-CH3或N-苄基置换;
或者
R(14)和R(15)
是氢;或者R(1),R(2)和R(3)
各自独立地是SR(21),-OR(22),-NR(23)R(24)或
-CR(25)R(26)R(27);
R(21),R(22),R(23)和R(25)
各自独立地是-CbH2b-(C1-C9)杂芳基,
该杂芳基是未取代的或被1-3取代基取代,所述取代基选F,Cl,
CF3,CH3,甲氧基,羟基,氨基,甲氨基和二甲氨基;
b是0,1或2;
R(24),R(26)和R(27)
各自独立地是氢,含1,2,3或4个碳原子的烷基或者含1,2,3或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,Br,I,CN,-(Xa)dg-CdaH2da+1,-(Xb)dh-
(CH2)db-CdeF2de+1,含3,4,5,6,7或8个碳原子的链烯基或者-
CdfH2dfR(30);
(Xa)是氧,硫或NR(33);
R(33)是氢,含1,2,3或4个碳原子的烷基或含1,2,3或4个碳
原子的全氟烷基;
dg是0或1;
(Xb)是氧,硫成NR(34);
R(34)是氢,含1,2,3或4个碳原子的烷基或含1,2,3或4
个碳原子的全氟烷基;
dh是0或1;
da 是0,1,2,3,4,5,6,7或8;
db 是0,1,2,3或4;
de 是0,1,2,3,4,5,6或7;
df 是0,1,2,3或4;
R(30)是含3,4,5,6,7或8个碳原子的环烷基,苯基,联苯基或
萘基;
所述芳香系苯基,联苯基或萘基是未取代的或者被1-3个取代
基取代,所述取代基选自F,Cl,CF3,甲基,甲氧基和NR(31)
R(32);
R(31)和R(32)
是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)各自独立地是NR(40)R(41)或-(Xe)-(CH2)ebR(45);R(40)和R(41)
各自独立地是氢,含1,2,3,4,5,6,7或8个碳原子的烷基,含
1,2,3,4,5,6,7或8个碳原子的全氟烷基或者(CH2)e-R(42);
e 是0,1,2,3或4;
R(42)是含3,4,5,6或7个碳原子的环烷基或者苯基,它们是
未取代的或者被1-3个取代基取代,所述取代基选自F,
Cl,CF3,甲基,甲氧基和NR(43)R(44);
R(43)和R(44)
各自独立地是氢,CF3或含1,2,3或4个碳原子的
烷基;或者R(40)和R(41)
一起是4或5个亚甲基,其中一个CH2-基可被氧、硫、NH、N-CH3
或N-苄基置换;(Xe)是氧,硫成NR(47);
R(47)是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟烷基;eb 是0,1,2,3或4;R(45)是含3,4,5,6或7个碳原子的环烷基或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基
选自F,Cl,CF3,甲基,甲氧基和NR(50)R(51)和-(Xfa)-
(CH2)ed-(Xfb)R(46);
Xfa 是CH2,氧,硫或NR(48);
Xfb 是氧,硫或NR(49);
R(48),R(49),R(50)和R(51)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;
ed 是1,2,3或4;
R(46)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;
或者
R(1),R(2)和R(3)
各自独立地是-CHR(52)R(53);
R(52)是-(CH2)g-(CHOH)h-(CH)i-(CHOH)k-R(54)或-(CH2)g-O-(CH2-
CH2O)h-R(54);
R(54)是氢或甲基;
g,h,i
彼此相同或不同,是0,1,2,3或4;
k是1,2,3或4;
R(53)是氢或含1,2,3或4个碳原子的烷基;
或者
R(1),R(2)和R(3)
各自独立地是-C(OH)R(55)R(56);
R(55)和R(56)
相同或不同,是氢或含1,2,3或4个碳原子的烷基;
或者
R(55)和R(56)
一起是含3,4,5或6个碳原子的环烷基;
或者
R(55)是-CH2OH;并且R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子的烷氧基,OH,F,Cl,Br,I,CN,-On-(CH2)o-(CF2)p-CF3;
n是0或1;
o是0,1或2;
p是0,1或2。
2.权利要求1的式I化合物及其可药用盐,其中:R(1),R(2)和R(3)
各自独立是R(10)-SOa-;
R(10)是含1,2,3,4,5,6,7或8个碳原子的烷基,含1,2,3,
4,5,6,7或8个碳原子的全氟烷基,含3,4,5或6个碳原
子的链烯基或者-CabH2ab-R(16);
ab是0,1,2,3或4;
R(16)是含3,4,5,6或7个碳原子的环烷基,或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基选
自F,Cl,CF3,甲基,甲氧基和NR(17)R(18);
R(17)和R(18)
各自独立是氢,CF3或含1,2,3或4个碳原子的烷基;或者R(1),R(2)和R(3)
各自独立地是-OR(22)或-CR(25)R(26)R(27);
R(22)和R(25)
各自独立地是-CbH2b-(C1-C9)杂芳基,
该杂芳基是未取代的或被1-3个取代基取代,所述取代基选
自F,Cl,CF3,CH3,甲氧基,羟基,氨基,甲氨基和二甲氨
基;
b是0,1或2;
R(26)和R(27)
各自独立地是氢,含1,2,3或4个碳原子的烷基或者含1,2,3
或4个碳原子的全氟基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,Br,I,CN,-Odg-CdaH2da+1,-Odh-(CH2)db-
CdeF2de+1,含3,4,5或6个碳原子的链烯基或者-CdfH2dfR(30);
dg 是0或1;
dh 是0或1;
da 是0,1,2,3或4;
db 是0,1,2,4或4;
de 是0,1,2,3,4,5,6或7;
df 是0,1,2,3或4;
R(30)是含3,4,5,6,7或8个碳原子的环烷基,苯基,联苯基或
萘基;
所述芳香系苯基,联苯基或萘基是未取代的或者被1-3
个取代基取代,所述取代基选自F,Cl,CF3,甲基和甲
氧基;或者R(1),R(2)和R(3)
各自独立地是-O-(CH2)eb-R(45);
eb 是0,1或2;
R(45)是含3,4,5,6或7个碳原子的环烷基或者苯基,它们是未
取代的或者被1-3个取代基取代,所述取代基选自F,Cl,
CF3,甲基,甲氧基和-(Xfa)-(CH2)ed-(Xfb)R(46);
Xfa是CH2,氧,硫或NR(48);
Xfb是氧,硫或NR(49);
ed是1或2;
R(46)是氢,含1,2,3或4个碳原子的烷基或者含1,2,3或4个碳原子的全氟烷基;
R(48)和R(49)
各自独立地是氢,含1,2,3或4个碳原子的烷基
或者含1,2,3或4个碳原子的全氟烷基;或者R(1),R(2)和R(3)
各自独立地是-CHR(52)R(53);
R(52)是-(CH2)g-(CHOH)h-(CH2)i-(CHOH)k-R(54)或
-(CH2)g-O-(CH2-CH2O)h-R(54);
R(53)和R(54)
各自独立地是氢或甲基;
g,h,i
彼此相同或不同,是0,1或2;
k是1或2;或者R(1),R(2)和R(3)
各自独立地是-C(OH)R(55)R(56);
R(55)和R(56)
相同或不同,是氢或含1,2,3或4个碳原子的烷基;
或者
R(55)和R(56)
一起是含3,4,5或6个碳原子的环烷基;
或者
R(55)是-CH2OH;R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,合1,2,3或4个碳原子的烷氧基,OH,F,Cl,CN,-On-(CF2)p-CF3;
n是0或1;
p是0,1或2。
3.权利要求1或2的式I化合物及其可药用盐,其中:R(1),R(2)和R(3)
各自独立是R(10)-SO2-;
R(10)是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子
的全氟烷基,含3,4,5或6个碳原子的链烯基或者-CabH2ab-R(16);
R(16)是含3,4,5,6或7个碳原子的环烷基,或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基选自F,Cl,CF3,甲基和甲基;或者R(1),R(2)和R(3)
各自独立地是氢,F,Cl,OH,CN,CF3,含1,2,3或4个碳原子的烷
基,含5或6个碳原子的环烷基或者含1,2,3或4个碳原子的烷氧基;或者R(1),R(2)和R(3)
各自独立地是-O-(CH2)eb-R(45);
eb 是0,1或2;
R(45)是含1,2,3或4个碳原子的环烷基或者苯基,
它们是未取代的或者被1-3个取代基取代,所述取代基
选自F,Cl,CF3,甲基和甲基;或者R(1),R(2)和R(3)
各自独立地是-CH(CH3)-CH2OH,-C(OH)(CH3)2或-C(OH)(CH3)-CH2OH;且R(4)和R(5)
各自独立地是含1,2,3或4个碳原子的烷基,含1,2,3或4个碳原子的烷氧基,OH,F,Cl,CN或-CF3。
5.如权利要求1的式I化合物的用途,用于生产治疗或预防由局部缺血症状造成的疾病的药物。
6.如权利要求1的式I化合物的用途,用于生产治疗或预防心肌梗死的药物。
7.如权利要求1的式I化合物的用途,用于生产治疗或预防心绞痛的药物。
8.如权利要求1的式I化合物的用途,用于生产治疗或预防心脏局部缺血症状的药物。
9.如权利要求1的式I化合物的用途,用于生产治疗或预防外周和中枢神经系统及中风的局部缺血症状的药物。
10.如权利要求1的式I化合物的用途,用于生产治疗或预防外周器官或膜的局部缺血症状的药物。
11.如权利要求1的式I化合物的用途,用于生产治疗休克的药物。
12.如权利要求1的式I化合物的用途,用于生产用于外科手术和器官移植的药物。
13.如权利要求1的式I化合物的用途,用于生产手术移植物的防腐和贮存药物。
14.如权利要求1的式I化合物的用途,用于生产治疗其中细胞增殖是原发性或继发型病因的药物,它们可用于生产抗动脉粥样硬化药,治疗糖尿病后期综合症,癌症,纤维化疾病,如肺纤维化、肝纤维化或肾纤维化,及前列腺肥大的药物。
15.如权利要求1的式I化合物的用途,用于生产治疗或预防脂质代谢疾病的药物。
16.一种药物组合物,它含有有效量的如权利要求1-4的式I化合物。
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DE4422685A1 (de) * | 1994-06-29 | 1996-01-04 | Hoechst Ag | Ortho-amino-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE4432101A1 (de) * | 1994-09-09 | 1996-03-14 | Hoechst Ag | Aminosäure-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE4432106A1 (de) * | 1994-09-09 | 1996-03-14 | Hoechst Ag | Mit Heterocyclen-N-Oxid-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum, sie enthaltendes Medikament sowie Zwischenprodukte zu ihrer Herstellung |
-
1996
- 1996-05-28 DE DE19621319A patent/DE19621319A1/de not_active Withdrawn
-
1997
- 1997-02-28 PL PL97318722A patent/PL318722A1/xx unknown
- 1997-05-15 EP EP97107903A patent/EP0810207A1/de not_active Withdrawn
- 1997-05-26 IL IL12090897A patent/IL120908A0/xx unknown
- 1997-05-26 CN CN97113032A patent/CN1170716A/zh active Pending
- 1997-05-26 NZ NZ314900A patent/NZ314900A/en unknown
- 1997-05-26 CZ CZ971616A patent/CZ161697A3/cs unknown
- 1997-05-26 SK SK664-97A patent/SK66497A3/sk unknown
- 1997-05-26 TR TR97/00423A patent/TR199700423A2/xx unknown
- 1997-05-26 AU AU23598/97A patent/AU2359897A/en not_active Abandoned
- 1997-05-26 AR ARP970102237A patent/AR007497A1/es unknown
- 1997-05-27 NO NO972406A patent/NO972406L/no unknown
- 1997-05-27 JP JP9136223A patent/JPH1081662A/ja active Pending
- 1997-05-27 HU HU9700953A patent/HUP9700953A3/hu unknown
- 1997-05-27 ZA ZA9704607A patent/ZA974607B/xx unknown
- 1997-05-27 HR HR19621319.3A patent/HRP970293A2/xx not_active Application Discontinuation
- 1997-05-27 CA CA002206198A patent/CA2206198A1/en not_active Abandoned
- 1997-05-28 KR KR1019970021105A patent/KR970074756A/ko not_active Application Discontinuation
- 1997-05-28 ID IDP971812A patent/ID16988A/id unknown
- 1997-05-28 BR BR9703326A patent/BR9703326A/pt not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CZ161697A3 (cs) | 1998-06-17 |
ID16988A (id) | 1997-11-27 |
SK66497A3 (en) | 1997-12-10 |
ZA974607B (en) | 1997-11-28 |
PL318722A1 (en) | 1997-12-08 |
KR970074756A (ko) | 1997-12-10 |
NO972406L (no) | 1997-12-01 |
AR007497A1 (es) | 1999-11-10 |
CA2206198A1 (en) | 1997-11-28 |
MX9703871A (es) | 1997-11-29 |
IL120908A0 (en) | 1997-09-30 |
DE19621319A1 (de) | 1997-12-04 |
BR9703326A (pt) | 1998-09-22 |
EP0810207A1 (de) | 1997-12-03 |
HRP970293A2 (en) | 1998-04-30 |
NZ314900A (en) | 1998-02-26 |
NO972406D0 (no) | 1997-05-27 |
HUP9700953A2 (hu) | 1998-03-02 |
JPH1081662A (ja) | 1998-03-31 |
TR199700423A2 (xx) | 1997-12-21 |
HU9700953D0 (en) | 1997-07-28 |
HUP9700953A3 (en) | 1998-04-28 |
AU2359897A (en) | 1997-12-04 |
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