LV10945B - Renin inhibiting n-(2-amino-2-oxoethyl)butanediamide derivatives - Google Patents
Renin inhibiting n-(2-amino-2-oxoethyl)butanediamide derivatives Download PDFInfo
- Publication number
- LV10945B LV10945B LVP-95-107A LV950107A LV10945B LV 10945 B LV10945 B LV 10945B LV 950107 A LV950107 A LV 950107A LV 10945 B LV10945 B LV 10945B
- Authority
- LV
- Latvia
- Prior art keywords
- methyl
- cyclohexylmethyl
- amino
- oxoethyl
- dihydroxy
- Prior art date
Links
- 108090000783 Renin Proteins 0.000 title abstract description 27
- 102100028255 Renin Human genes 0.000 title abstract description 27
- 230000002401 inhibitory effect Effects 0.000 title description 4
- -1 2-(2-pyridinyl)ethyl Chemical group 0.000 claims abstract description 545
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 190
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 141
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 107
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000007704 transition Effects 0.000 claims abstract description 7
- 125000005505 thiomorpholino group Chemical group 0.000 claims abstract description 4
- 125000003287 1H-imidazol-4-ylmethyl group Chemical group [H]N1C([H])=NC(C([H])([H])[*])=C1[H] 0.000 claims abstract 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 218
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical class NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 146
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 112
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 54
- 239000002253 acid Substances 0.000 claims description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 13
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000006622 cycloheptylmethyl group Chemical group 0.000 claims description 11
- 239000002461 renin inhibitor Substances 0.000 claims description 11
- 229940086526 renin-inhibitors Drugs 0.000 claims description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- VHHROMDSBXTZLS-UHFFFAOYSA-N n'-(2-amino-2-oxoethyl)butanediamide Chemical class NC(=O)CCC(=O)NCC(N)=O VHHROMDSBXTZLS-UHFFFAOYSA-N 0.000 claims description 8
- XRRDFIPYLFCYLU-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical group [CH2]C1=CC(C)=CC(C)=C1 XRRDFIPYLFCYLU-UHFFFAOYSA-N 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- QEJTYZRPRCPARS-RXMQYKEDSA-N (2R)-2-propylbutanediamide Chemical compound C(CC)[C@@H](C(=O)N)CC(=O)N QEJTYZRPRCPARS-RXMQYKEDSA-N 0.000 claims 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 2
- 125000004193 piperazinyl group Chemical group 0.000 claims 2
- KGXQHPSVLZVNKT-UHFFFAOYSA-N 2-(cyclopropylmethyl)butanediamide Chemical compound NC(=O)CC(C(N)=O)CC1CC1 KGXQHPSVLZVNKT-UHFFFAOYSA-N 0.000 claims 1
- UVSRABJNEKWEOZ-UHFFFAOYSA-N 2-(pyridin-2-ylmethyl)butanediamide Chemical compound N1=C(C=CC=C1)CC(C(=O)N)CC(=O)N UVSRABJNEKWEOZ-UHFFFAOYSA-N 0.000 claims 1
- QVYARBLCAHCSFJ-UHFFFAOYSA-N butane-1,1-diamine Chemical class CCCC(N)N QVYARBLCAHCSFJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000539 dimer Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims 1
- 125000006308 propyl amino group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 206010020772 Hypertension Diseases 0.000 abstract description 8
- 102000004881 Angiotensinogen Human genes 0.000 abstract description 7
- 108090001067 Angiotensinogen Proteins 0.000 abstract description 7
- 238000011282 treatment Methods 0.000 abstract description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 4
- 206010019280 Heart failures Diseases 0.000 abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 88
- 239000000203 mixture Substances 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 239000007864 aqueous solution Substances 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 230000002829 reductive effect Effects 0.000 description 33
- 101150041968 CDC13 gene Proteins 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000012267 brine Substances 0.000 description 31
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000003480 eluent Substances 0.000 description 25
- 230000008878 coupling Effects 0.000 description 24
- 238000010168 coupling process Methods 0.000 description 24
- 238000005859 coupling reaction Methods 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 238000010265 fast atom bombardment Methods 0.000 description 21
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 17
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 12
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
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- 101800000734 Angiotensin-1 Proteins 0.000 description 8
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- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Peptides Or Proteins (AREA)
- Pyrrole Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Claims (5)
- LV 10945 Patentformulas punkti (1) 1. N-(2-amino-2-oksoetil)butāndiamīda atvasinājumi ar kopējo formulu A-N(R’ )C(0)CH2CH(R2)C(0)-B (1) kur A ir R3R4NC(0)CH2, kurā (a) R3 ir ūdeņraža atoms vai zemākā alkilgrupa; R4 ir ūdeņraža atoms, zemākā alkilgrupa, ar zemāko cikloalkilgrupu aizvietota zemākā alkilgrupa, fenilgrupa, neaizvietots, vienaizvietots vai div-aizvietots piecu vai sešu locekļu heterocikls, kurš satur vienu vai divus heteroatomus, kas ņemti no grupas, kurā ietilpst N, O un S, un kurā katrs aizvietotājs neatkarīgi ņemts no grupas, kurā ietilpst zemākā alkilgrupa, zemākā alkoksigrupa, halogēna atoms, zemākā alkilaminogrupa; vai (b) R3 ir zemākā alkilgrupa un R4 ir R5R6N-Alk, kur R5 un R6 neatkarīgi viens no otra ir ūdeņraža atoms vai zemākā alkilgrupa, un Alk ir divvērtīga alkilgrupa, kas iegūta atņemot divus ūdeņraža atomus, pie tam katru no sava oglekļa atoma, no ogļūdeņraža ar taisnu vai sazarotu vienu līdz sešu oglekļa atomu ķēdi; vai (c) R3 ir zemākā alkilgrupa un 1 R4 ir grupa R5AR6ANCH2CH2/ kurR5A ir zemākā alkilgrupa un R6A ir piperidinokarbonilgrupa, morfolinokarbonilgrupa, tiomorfolinokarbonilgrupa, piperazinokarbonilgrupa vai 4-(zemākā alkilgrupa)-1-piperazinilkarbonilgrupa; (d) R3 ir zemākā alkilgrupa un R4 ir QC(0)(CH2)m , kur Q ir piperidinogrupa, morfolinogrupa, tiomorfolinogrupa, piperazinogrupa vai 4-(zemākā alkilgrupajpiperazinilgrupa, un m ir 1 vai 2; (e) R3 ir zemākā alkilgrupa un R4 ir zemākā alkoksigrupa; vai (f) R3 un R4 kopā ar slāpekļa atomu, pie kura tie abi piesaistīti, veido pirolidinogrupu, piperidinogrupu, 4-hidroksipiperidinilgrupu, 4-[(zemākā alkoksigrupa)-(zemākā alkoksigrupa)-1 -piperidinilgrupu, morfolinogrupu, tiomorfolinogrupu vai 4-(zemākā alkilgrupa)piperazinilgrupu; R1 ir Cļ.g-alkilgrupa; ar zemāko cikloalkiIgrupu aizvietota zemākā alkilgrupa; stāvoklī 1 ar zemāko alkilgrupu aizvietota zemākā cikloalkilgrupa; bicik-lo[2.2.1 ]hept-2-ilgrupa; fenilgrupa; stāvoklī 2 ar zemāko alkilgrupu aizvietota fenilgrupa; stāvoklī 2 ar zemāko alkoksigrupu aizvietota fenilgrupa; 2-halogēn-fenilgrupa; stāvoklī 4 ar zemāko alkilgrupu aizvietota fenilgrua; stāvoklī 4 ar zemāko alkoksigrupu aizvietota fenilgrupa; 4-halogēnfenilgrupa; stāvokļos 3 un 5 ar zemākām alkilgrupām aizvietota fenilgrupa; (3,4-metilēndioksi)fenilgrupa; 1-naftilgrupa; 2-naftilgrupa vai heterocikls ar jau minētām nozīmēm; R2 ir zemākā alkilgrupa, ar zemāko cikloalkilgrupu aizvietota metilgrupa, ben-zilgrupa, grupa Het-CH2, kur Het ir šajā punktā jau minētais heterocikls ar minētām nozīmēm; B ir pārejas stāvokļa analogs grupai NHCH(R7)CH(OH)-Z, kurā R7 ir zemākā alkilgrupa, ar zemāko cikloalkilgrupu aizvietota metilgrupa, benzilgrupa, [4-(zemākā al ki lgrupa)feni I] meti Igrupa, [4-(zemākā alk- oksigrupa)fenil]metilgrupa, (4-halogēnfenil)metilgrupa;
- 2 LV 10945 Z ir zemākā alkilgrupa, zemākā cikloalkilgrupa, ar zemāko cikloalkil- 8 i 8 grupu aizvietota metilgrupa, C(0)0R , kur R ir zemākā alkilgrupa, palieka ar formulu 0kurā R9 ir zemākā alkilgrupa, R10 un R11 neatkarīgi viens no otra ir ūdeņraža atoms vai zemākā alkilgrupa, [(1-metil-1 H-tetrazol-5-il)tio]metilgrupa vai grupa CH(OH)R12, kur R12 ir zemākā alkilgrupa vai zemākā cikloalkilgrupa, ar tādu noteikumu, ka (1) asimetriskais oglekļa atoms, pie kura atrodas R7, ir (S) konfigurācijā; (2) kad Z ir zemākā alkilgrupa, zemākā cikloalkilgrupa, ar zemāko cikloalkil-grupu aizvietota metilgrupa, vai augšminētā palieka, tad tas asimetriskais oglekļa atoms paliekā NHCH(R7)CH(OH), pie kura atrodas hidroksilgrupa, ir (S) konfigurācijā; (3) kad Z ir C(=0)0R8, kur R8 ir zemākā alkilgrupa, vai kad Z ir [(1-metil-1 H-tetrazol-5-il)tio]metilgrupa, tad tas asimetriskais oglekļa atoms paliekā NHCH(R7)CH(OH), pie kura atrodas hidroksilgrupa, ir (R) konfigurācijā; (4) kad Z ir CH(OH)R12, kur R12 ir zemākā alkilgrupa vai zemākā cikloalkilgrupa, tad tie asimetriskie oglekļa atomi paliekā NHCH(R7)CH(OH) un paliekā Z, pie kuriem atrodas hidroksilgrupa, ir attiecīgi (R) un (S) konfigurācijā; (5) tas oglekļa atoms, pie kura atrodas R2, ir (R) konfigurācijā, izņemot to gadījumu, kad R2 ir -CH2-Het, kur Het pievienots ar slāpekļa atomu un/vai tajā ir sēra atoms blakus Het pievienošanas vietai (atomiem C vai N) pie metilēn-grupas (CH2); minētajā izņēmuma gadījumā tas oglekļa atoms, pie kura atrodas R2, ir (S) konfigurācijā; kā arī šo savienojumu sālis ar skābēm.
- 3 2. N-(2-amino-2-oksoetil)butāndiamīda atvasinājumi ar kopējo formulu (1) pēc punkta 1, kurā A ir R3R4NC(0)CH2/ kur: (a) R3 ir zemākā alkilgrupa un R4 ir zemākā alkilgrupa vai ar fenilgrupu aizvietota zemākā alkilgrupa, vai heterocikls, kura nozīmes atbilst punktā 1 minētajām; (b) R3 ir zemākā alkilgrupa un R4 ir R3R6N-Alk, kur R3 un R6 neatkarīgi viens no otra ir zemākā alkilgrupa, un Alk nozīmes atbilst punktā 1 minētajām; (c) R3 ir zemākā alkilgrupa un R4 ir grupa R5AR6ANCH2CH2, kurR5A ir zemākā alkilgrupa un R6A ir piperidinokarbonilgrupa, morfolinokarbonilgrupa, vai 4-(zemākā alkilgrupa)-1-piperazinilkarbonilgrupa; (d) R3 ir zemākā alkilgrupa un R4 ir 2-morfolino-2-oksoetilgrupa, 3- morfolino-3-oksopropilgrupa vai 3-(4-metil-1 -piperazinil)-3-oksopropilgrupa; (e) R3 ir zemākā alkilgrupa un R4 ir zemākā alkoksigrupa; (f) R3 un R4 kopā ar slāpekļa atomu, kam tie piesaistīti, veido pirolidino-grupu, piperidinogrupu, 4-(metoksimetoksi)-1-piperidinilgrupu, morfolinogrupu, tiomorfolinogrupu vai 4-metil-1 -piperazinilgrupu; R1 ir Cļ.s-alkilgrupa; ar zemāko cikloalkilgrupu aizvietota zemākā alkilgrupa; ar zemāko alkilgrupu stāvoklī 1 aizvietota zemākā cikloalkilgrupa; biciklo[2.2.1 ] heptilgrupa; fenilgrupa; 2-metilfenilgrupa; 2-fluorfenilgrupa; 4- metilfenilgrupa; 4-metoksifenilgrupa; 4-hlorfenilgrupa; 4-fluorfenilgrupa; 3,5-dimetilfenilgrupa; (3,4-metilēndioksi)fenilgrupa; 1-naftilgrupa; 2-naftilgrupa vai heterocikls, kura nozīmes ir jau minētās; R2 ir zemākā alkilgrupa, ar zemāko cikloalkilgrupu aizvietota metilgrupa, benzilgrupa, 1 H-imidazol-2-ilmetilgrupa, 1 H-imidazol-4-ilmetilgrupa, (1-metil-1 H-imidazol-4-il)metilgrupa, 2-tienilmetilgrupa, 2-oksazolilmetilgrupa, 4-oksazolilmetilgrupa, 2-tiazolilmetilgrupa, 4-tiazolilmetilgrupa, (2-metil-4-tiazolil)metilgrupa, (2-amino-4-tiazolil)metilgrupa, [2-(metilamino)-4-tiazolil]metilgrupa, 2-piridinilmetilgrupa, 3-piridinilmetilgrupa; B ir punktā 1 jau minētās nozīmes; vai minēto savienojumu sālis ar skābēm.
- 4 LV 10945 3. N-(2-amiiiCh2--.QksQetil)butāndiannīda atvasinājumi ar kopējo formulu (1) pēc punkta 2, kurā A ir R3R4NC(0)CH2, kur: R3 ir metilgrupa, etilgrupa vai propilgrupa un R4 ir metilgrupa, etilgrupa, propilgrupa, 1,1-dimetiletilgrupa, 2-(dimetilamino)etilgrupa, 2-(dietilamino)-etilgrupa; vai Het-(CH2)n-, kur Het ir 2-pirolilgrupa, 2-furanilgrupa, 2-tienil-grupa, 1 H-imidazol-2-ilgrupa, 1 H-imidazol-4-ilgrupa, 2-izoksazolilgrupa, 2-tiazolilgrupa, 4-tiazolilgrupa, 2-amino-4-tiazolilgrupa, morfolinogrupa, 4-metil-1-piperazinilgrupa, 2-piridinilgrupa, 3-piridinilgrupa, 4-piridinilgrupa, 2-pirimidilgrupa; n ir 1,2 vai 3; vai arī R3 ir metilgrupa un R4 ir 2-[metil(morfolinokarbonil)amino]etilgrupa vai 2-{metil[(4-metil-1 -piperazinil)karbonil]amino}etilgrupa; vai arī R3 ir metilgrupa un R4 ir 3-morfolino-3-oksopropilgrupa vai 3-(4-metil- 1-piperazinil)-3-oksopropilgrupa; vai R3 ir metilgrupa un R4 ir metoksigrupa; vai R3 un R4 abi kopā ar to slāpekļa atomu, kuram tie piesaistīti, veido pirolidi-nogrupu, piperidinogrupu, 4-hidroksipiperidinilgrupu, 4-metoksimetoksipipe-ridinilgrupu, morfolinogrupu vai 4-metil-1-piperazinilgrupu; R ir 2-metilpropilgrupa, 2-etilbutilgrupa, 1-propilbutilgrupa, 2-propilpentil-grupa, ciklopentilmetilgrupa, 2-ci klopenti letilgrupa, cikloheksilmetilgrupa, (S)-1 -cikloheksiletilgrupa, 2-cikloheksiletilgrupa, cikloheptilmetilgrupa, (l-metilcikloheksil)metilgrupa, (l-metilcikloheptil)metilgrupa, (biciklo[2.2.1 ]-hept-2-il)metilgrupa, benzilgrupa, (S)-1-feniletilgrupa, 2-feniletilgrupa, (R vai S)-2-fenilpropilgrupa, 2-metil-2-fenilpropilgrupa, 3-fenilpropilgrupa, (2-fluor-feniDmetilgrupa, (2-metilfenil)metilgrupa, (4-metoksifenil)metilgrupa, (4-hlor-fenibmetilgrupa, (4-fluorfenil)metilgrupa, (3,5-dimetilfenil)metilgrupa, 1- naftilmetilgrupa, (S)-1 -(1 -naftiDetilgrupa, 2-naftilmetilgrupa, 2-pirolil-metilgrupa, 1 H-imidazol-2-ilmetilgrupa, 1 H-imidazol-4-ilmetilgrupa, 2- piridinilmetilgrupa, 3-piridinilmetilgrupa, 2-furanilmetilgrupa, 3-furanil-metilgrupa, 2-tienilmetilgrupa, (3-metil-2-tienil)metiļgrupa, 2-oksazolil-metilgrupa, 4-oksazolilmetilgrupa, 2-tiazolilmetilgrupa, 4-tiazolilmetilgrupa, (2-amino-4-tiazolil)metilgrupa; 5 R2 ir propilgrupa, 2-metilpropilgrupa, ciklopropilmetilgrupa, ciklopentil-metilgrupa, cikloheksilmetilgrupa, benzilgrupa, 1 H-imidazol-2-ilmetilgrupa, 1 H-imidazol-4-ilmetilgrupa, (1 -metil-1 H-imidazol-4-il)metilgrupa, 2-tienilmetilgrupa, 2-oksazolilmetilgrupa, 4-oksazolilmetilgrupa, 2-tiazolil-metilgrupa, 4-tiazolilmetilgrupa, (2-amino-4-tiazolil)metilgrupa; (2-metil-4-tiazolil)metilgrupa; [(2-metilamino)-4-tiazolil)metilgrupa; 2- piridinilmetilgrupa, 3-piridinilmetilgrupa; B ir [1(S)-(2-metilpropil)-2(S)-hidroksi-5-metilheksil]aminogrupa, [1 (S)-(ciklo-heksilmetil)-2(S)-hidroksi-5-metilheksil]aminogrupa, {1(S)-[(4-metoksifeniD-metil]-2(S)-hidroksi-5-metilheksil]aminogrupa, [1 (S)-(cikloheksilmetil)- 2(S)-hidroksi-4-metilpentil]aminogrupa, [1(S)-(cikloheksilmetil)-2(S)-hidroksi- (3-ciklopropilpropil)]aminogrupa, [1(S)-(2-metilpropil)-2(R),3(S)-dihidroksi-5-metilheksil]aminogrupa, [1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metil-heksillaminogrupa, {1 (S)-[(4-metoksifenil)metil]-2(R),3(S)-dihidroksi-5-metil-heksil}aminogrupa, [1 (S)-(2-metilpropil)-2(R),3(S)-dihidroksi-(3-ciklopropil- propiljaminogrupa, [1 (S)-(cikloheksilmetiD-2(R),3(S)-dihidroksi-(3-ciklopropil-propil)]aminogrupa, [1 (S)-(fenilmeti l)-2(R),3(S)-dihidroksi-(3-ci klopropilpro- pil)]aminogrupa, {1 (S)-[(4-metoksifenil)metil-2(R),3(S)-dihidroksi-(3-ciklopro-pilpropil)}aminogrupa, [1 (S)-(cikloheksi lmetil)-2(R)-hidroksi-3-(1 -metiletoksi)- 3- oksopropil]aminogrupa, [1 (S)-(cikloheksilmetil)-2(S)-hidroksi-2-(1,5,5-trimetil- 2- oksopirolidin-3(S)-il)etil]aminogrupa, {1 (S)-(cikloheksilmetil)-2(R)-hidroksi- 3- [(1 -metil-1 H-tetrazol-5-il)tio]propil}aminogrupa; vai arī minēto savienojumu sālis ar skābēm. 4. N-(2;aminoT2-oksoetil)butāndiamīda atvasinājumi ar kopējo formulu (1) pēc punkta 1, kas ņemti no grupas, kurā ietilpst: N4-benzil-N4-(2-morfolino-2-oksoetil)-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, 6 LV 10945 N^benzil-NMU-idimetilamino^-oksoetiD-N1-^ (S)-(cikloheksilmetib- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-(2-feniletil)-N1-[1 (S)-(cikloheksilmetib-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-(3-fenilpropil)-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-{2-[metil(1,1 -dimetiletil)amino]-2-oksoetil}- NMl(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-[2-(metilamino)-2-oksoetil]-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-(2-amino-2-oksoetil)-N4-benzil-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-{2-[(metoksi)metilamino]-2-oksoetil}-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-(1-naftilmetil)-N1-[1(S)-(cikloheksilmetil)- 2(R)/3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[(4-metoksifenil)metil]-N1 -[1 (S)-(cikloheksi lmetil)-2(R),3(S)-dihidroksi-5-meti Iheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-[(2-(dietilamino-2-oksoetil)-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, 7 N4-benzil-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-nMi (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-(2-piridinilmetil)-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-(3-piridinilmetil)-N1-[1(S)-(cikloheksilmetil)- 2(R)/3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamids, N4-/2-\metil{2-metil(morfolinokarbonil)amino]etilļamino\-2-oksoetil/- N4-[1(S)-feniletil]-N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1 (R)-feniletil]-N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1(S)-feniletil]-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1 (S)-(1 -naftibetil]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dibidroksi-5-metilheksil]- 2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[2(R)-fenilpropil]-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[2(S)-fenilpropil]-N'-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamids, N4-[(2-(dimetilamino-2-oksoetil)-N4-(2-metil-2-fenilpropil)- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(ciklopropilmetil)butāndiamids, 8 LV 10945 N4-[1 (S)-feni leti l]-N4-/2-{metil [2-(2-piridinil)eti l]amino}-2-oksoetil/-N1 -[1 (S)-(cikloheksi Imeti l)-2(R)/3(S)-dih idroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-/2-{[2-(dimetilamino)etil]metilamino}-2-oksoetil/-N4-[1(S)-feniletil]-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-/2-{[2-(dietilamino)etil]metilamino}-2-oksoetil/-N4-[1 (S)-feniletil]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(ciklopropilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1 (S)-feniletilj-N1 -[1 (S)-(cikloheksilmeti I)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-propilbutāndiamīds, N4-benzil-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/- NMl(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-rnetilheksil]- 2(R)-propilbutāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1(S)-feniletil)-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(1H-imidazol-4-ilmetil)butāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1 (Sļ-feniletill-N1 -[1 (S)-(cikloheksilmetil)-2(R)/3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-benzil-N4-/2-{metil[2-(4-piridinil)etil]amino}-2-oksoetil/- NMl(S)-(cikloheksilmetil)-2(R)3(S)<lihidroksi-5HTietilheksil]- 2(R)-(ciklopropilmetil)butāndiamīds/ N4-[(2-(dimetilamino-2-oksoetil)-N4-[1(S)-feniletM]-N1-[1 (S)-(cikloheksi Imetil)-2(R)/3(S)-dihidroksi-5-metilheksil]-2(R)-(4-tiazolilmetil)butāndiamīds, 9 N4-(ci kloheksi lmetil)-N4-[(2-(dimeti lamino-2-oksoetil)-N'-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ci klopropi Imeti Dbutāndiamīds, N4-[(2-(dimetilamino-2-oksoetil)-N4-[1 (SI-feniletilJ-NMl (S)-(cikloheksilmetib-2(R),3(S)-dihidroksi-5-metilheksil]-2(S)-(2-tienilmetil)butāndiamīds, N4-[1 (S)-feniletil]-N4'(2-morfolino-2-oksoetil)-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-NMl (S)-(cikloheksi lmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(S)-(2-tieni Imeti Dbutāndiamīds, N4-(cikloheksilmetil)-N4-(2-morfolino-2-oksoetil)-N1-[1 (S)-(cikloheksilmetiD-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetiDbutāndiamīds, N4-(cikloheksilmetil)-N4-[(2-(dimetilamino-2-oksoetil]-NMl (S)-(cikloheksilmeti l)-2(R),3(S)-dihidroksi-5-meti Iheksil]-2(R)-(4-tiazolilmetil)butāndiamīds, N4-(c i kloheksi I meti l)-N4- [2-(dimeti lam ino)-2-oksoeti I]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(S)-(2-tiazolilmetil)butāndiamīds, N4-[1 (S)-(cikloheksiletil]-N4-[2-(dimetilamino)-2-oksoetilj-N1 -[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-meti Iheksilļ-2(R)-(ciklopropilmetil)butāndiamīds, N4-(cikloheksilmetil)-N4-(2-morfolino-2-oksoetil)-N1-[1(S)-(cikloheksilmetiD-2(R),3(S)-dihidroksi-5-metilheksil]-2(S)-(2-tiazolilmeti Dbutāndiamīds, 10 LV 10945 N4-[2-(dimetilamino-2-oksoetil]-N4-[2(S)-fenilpropil]- N1 -[1 (S)-(cikloheksilmetil)-2(R)y,3(S)-dihidroksi-5-metilheksil]- 2(S)-(2-tiazolilmetil)butāndiamīds, N4-benzil-N4-/2-{metil [2-(2-piridinil)etil]amino}-2-oksoetil/-N1 -[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(S)-(2-tiazolilmetil)butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[1 (S)-feniletil]-N’-[1 (S)-(cikloheksilmetil)-2(S)-hidroksi-2-(1,5,5-trimetil-2-oksopirolidin-3(S)-il)etil]-2(R)-(dklopropilme-tiDbutāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[1(S)-feniletil]-N1-[1(S)-(cikloheksilmetil)- 2(R),3(S)-dihidroksi-(3-ciklopropilpropil)]-2(R)-[(2-amino-4-tiazolil)metil]- butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[1(S)-feniletil]-N1-[1(S)-(cikloheksilmetil)-2(S)-hidroksi-2-(1,5,5-trimetil-2-oksopirolidin-3(S)-il)etil]-2(R)-[( 2-amino-4-tiazolil)metil]butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[1 (S)-feniletil]-N1-[l(S)-(cikloheksilmetil)- 2(S)-hidroksi-3-(1-metiletoksi)-3-oksopropil]-2(R)-[(2-amino-4-tiazolil)metil]- butāndiamīds, N4-(cikloheksilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N1-[1 (S)-(cikloheksilmetil)-2(R)/3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-(cikloheksilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- NMl(S)-(dkloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-metil-4-tiazolil)metil]butāndiamīds, 11 N4-(cikloheksilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- N1 - [1 (S)-(cikloheksilmeti l)-2(R)/3iS)-dihidroksi-5-meti Iheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheksilmetil)-N4-(2-morfolino-2-oksoetil)-N1-[l (S)-(cikloheksilmetil)-2(R),3(S)-di hidroksi-5-meti I heksi I]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheksilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino)-2-oksoetil/-N1 - [1 (S)-(ci kloheksi lmetil)-2(R),3(S)-dihidroksi-5-meti I heksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds; N4-[2-(dimetilamino)-2-oksoetil]-N4-[2-(2-piridinil)etil]-N’-fl (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(ciklopropilmetil)butāndiamīds, N4-benzil-N4-[2-(dimetilamino)-2-oksoetil]- NMl (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-benzil-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-n’-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(4-tiazolilmetil)butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[1(S)-feniletil]- N1-[1(S)-(cikloheksilmetil)-2(R)/3(S)-dihidroksi-5-metilheksil]- 2(S)-(2-tiazolilmetil)butāndiamīds, N4-(cikloheksilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(fenilmetil)butāndiamīds, 12 LV 10945 N4-{1 (S),2(R),4(S)- un 1 (R),2(S),4(R)-(biciklo[2.2.1 ]hept-2-il)metil}-N4-[2-(dimetilamino)-2-oksoetil]-N1-[1 (S)-(cikloheksilmeti l)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(4-tiazolilmetil)butāndiamīds, N4-benzil-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-NMl(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)- [(2-am i no-4-tiazol i Dmeti I] butānd iamīds, N4-(cikloheksilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(3-piridinilmetil)butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-(2-feniletil)- N4-[l (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-[2(S)-fenilpropil]- N1 -[1 (S)-(ci kloheksilmeti l)-2(R),3(S)-dihidroksi-5-meti Iheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-{2-[4-(metoksimetoksi)piperidinil]-2-oksoetil}-N4-(cikloheksilmetil-N1-[1 (S)-(cikloheksilmeti l)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazoli Dmeti l]butāndiamīds, N4-[l(S)-cikloheksi leti l]-N4-/2-{metil[2-(2-piridini Dēti l]amino}-2-oksoeti I/-N’-fl (S)-(cikloheksilmeti l)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-[2-(dimetilamino)-2-oksoetil]-N4-(2-piridinilmetil)- NI-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, 13 N4-(cikloheksilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/- N1 -{1 (S)-(cikloheksilmetil)-2(R)-hidroksi-3-[(1 -metil-1 H-tetrazol-5-il)tio]propil}- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(ci kloheksilmeti l)-N4-/2-{metil [2-(2-piridinil)eti l]amino}-2-oksoeti I/-NMl (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(3-piridinilmetil)butāndiamīds, N4-(cikloheksilmetil)-N4-(2-morfolino-2-oksoetil)-N1-[l(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(2-piridinilmeti Dbutāndiamīds, N4-(ci kloheksilmeti l)-N4-[2-(dimeti lamino)-2-oksoeti I]-N1-[1 (S)-(ci kloheksilmeti l)-2(R)/3(S)-dihidroksi-5-meti Iheksil]-2(R)-(2-piridin i Imeti Dbutāndiamīds, N4-(ciklopentilmetil)-N4-[2-(dimetilamino)-2-oksoetil]-N1 - [ 1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-(3-piridinilmeti Dbutāndiamīds, N4-(cikloheptilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-(3-piridinilmetiDbutāndiamīds, N4-(ciklopentilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-Nl-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)meti Dbutāndiamīds, N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N4-(2-tienilmetil)-N1 -[1 (S)-(cikloheksi lmetil)-2(R),3(S)-dihidroksi-5-meti Iheksi I]-2(R)-[(2-amino-4-tiazolil)meti Dbutāndiamīds, 14 N4-[2-(dimetilamino)-2-oksoetil]-N4-[(3,5-dimetilfenil)metil]-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamids, N4-(cikloheksilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-n’-[1 (S)-(cikloheksilmetil)-2(R)-hidroksi-3-(1-metiletoksi)-3-oksopropil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-/2-(metil [2-(2-piridinil)etil]amino}-2-oksoetil/-N4-[1 (S)-feniletilļ- Nl-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheksilmetil)-N4-/2-{metil[2-(3-piridinil)etil]amino}-2-oksoetil/-N1 -[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīdsi N4-(cikloheksilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N1-[l (S)-(cikloheksilmetil)-2(S)-hidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheptilmetil)-N4-[2-(dimetilamino)-2-oksoetil]- N’-fKSMcikloheksilmetiD^iRi^iSi-dihidroksi-S-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(2-furanilmetil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/- N1-[1(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(ciklopentilmetil)-N4-(2-morfolino-2-oksoetil)- NMl(SMcikloheksilmetil)-2(R),3(S)-dihidrc>ksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheptilmetil)-N4-/2-{metil [2-(2-piridinil)etil]amino}-2-oksoetil/-N1 - [ 1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-[(2-fluorfenil)metil]-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/- NMl(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds/ N4-(cikloheksilmetil)-N4-/2-\metil{2-metil(morfolinokarbonil)amino]etil}amino\-2-oksoeti I/-N1 -[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(2-eti Ibuti l)-N4-/2-{metil [2-(2-piridini l)eti l]amino}-2-oksoetil/~ NMl(S)-(cikloheksilmetil)-2(R)3(S)<lihidroksi-5-metilheksil]-2(R)-[(2-amino- 4-tiazolil)metil]butāndiamīds/ N4-(ciklopentilmetil)-N4-[2-(dimetilamino)-2-oksoetil]-N1-[l (S)-(cikloheksi lmetil)-2(R),3(S)-di hidroksi-5-meti Iheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N4-(2-tiazolilmetil)-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(2-ciklopentiletil)-N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N4-[(3-metil-2-tienil)metil]-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metiiheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, 16 LV 10945 N4-(3-furanilmetil)-N4-/2-{metil-[2-(2-piridinil)etil]amino}-2-oksoetil/- NMl(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]- 2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-(cikloheksilmetil)-N4-{2-[metil-(2-morfolinoetil)amino]-2-oksoetil}-N’-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazol i Dmeti I] butānd iamīds, N4-/2-{meti I [2-(2-piridini Detil] amino}-2-oksoetil/-N4-(1 -propilbutil)-N’-[1 (S)-(ci kloheksi lmetil)-2(R)/3(S)-dihidroksi-5-meti Iheksil]-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-/2-{metil[2-(2-piridinil)etil]amino}-2-oksoetil/-N4-(2-propilpentil)-N1-[1 (S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksilj-2(R)-[(2-amino-4-tiazolil)metil]butāndiamīds, N4-{2-[metil-(2-morfolinoetil)amino]-2-oksoetil}-N4-[1 (S)-feniletil]-N1-[l(S)-(cikloheksilmetil)-2(R),3(S)-dihidroksi-5-metilheksil]-2(R)-[(2-amino-4-tiazol i Dmeti I] butāndiamīds.
- 5. Farmaceitiskā kompozīcija ar renīna inhibitora īpašībām, kas satur vismaz vienu farmaceitiski pieņemamu nesēju un aminoskābes atvasinājumu kā aktīvo vielu efektīvā daudzumā, a t š ķ i r a s ar to, ka par aminoskābes atvasinājumu minētā kompozīcija satur savienojumu ar kopējo formulu (1) pēc punkta 1, vai tā terapeitiski pieņemamu sāli. 17
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|---|---|---|---|---|
| NZ255300A (en) * | 1992-09-25 | 1997-05-26 | Bio Mega Boehringer Ingelheim | N-(hydroxyethyl)butane diamide derivatives, preparation and pharmaceutical compositions thereof |
| CA2165996C (en) * | 1995-12-22 | 2002-01-29 | Murray Douglas Bailey | Stereoselective preparation of 2-substituted succinic derivatives |
| US6096759A (en) * | 1997-09-19 | 2000-08-01 | Georgetown University | Method for treating essential hypertension |
| US20050209141A1 (en) * | 2003-10-17 | 2005-09-22 | Silver Randi B | Mast cell-derived renin |
| US10517839B2 (en) * | 2008-06-09 | 2019-12-31 | Cornell University | Mast cell inhibition in diseases of the retina and vitreous |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5142056A (en) | 1989-05-23 | 1992-08-25 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| US5006511A (en) * | 1981-10-14 | 1991-04-09 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in achpa |
| EP0278158A3 (en) | 1986-11-12 | 1990-05-23 | Merck & Co. Inc. | Renin inhibitors containing phenylalanyl-histidine replacements |
| US4839357A (en) | 1987-10-02 | 1989-06-13 | Merck & Co., Inc. | Renin inhibitors containing phenylalanyl-histidine replacements |
| US5001113A (en) | 1987-10-14 | 1991-03-19 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in ACHPA |
| EP0312283A3 (en) * | 1987-10-14 | 1990-05-09 | Merck & Co. Inc. | Di-or tripeptide renin inhibitors containing lactam conformational restrictions in achpa |
| CA1329680C (en) * | 1987-11-23 | 1994-05-17 | Harold Norris Weller, Iii | N-heterocyclic alcohol derivatives |
| US5055466A (en) * | 1987-11-23 | 1991-10-08 | E. R. Squibb & Sons, Inc. | N-morpholino derivatives and their use as anti-hypertensive agents |
| FI893212A (fi) * | 1988-07-01 | 1990-01-02 | Searle & Co | Antihypertensiva aminoalkylaminokarbo- nylaminodiolaminsyraderivat. |
| IE902446A1 (en) * | 1989-07-26 | 1991-02-13 | Abbott Lab | Peptidyl aminodiol renin inhibitors |
| US5063208A (en) * | 1989-07-26 | 1991-11-05 | Abbott Laboratories | Peptidyl aminodiol renin inhibitors |
| ATE135368T1 (de) * | 1989-09-12 | 1996-03-15 | Hoechst Ag | Aminosäurederivate mit reninhemmenden eigenschaften, verfahren zu deren herstellung, diese enthaltende mittel und deren verwendung |
| JPH0532602A (ja) * | 1991-07-26 | 1993-02-09 | Terumo Corp | ナフチルメチルアミン誘導体及びこれを含有するレニン阻害剤 |
-
1993
- 1993-09-15 AU AU49403/93A patent/AU680829B2/en not_active Ceased
- 1993-09-15 CA CA002143300A patent/CA2143300C/en not_active Expired - Fee Related
- 1993-09-15 BR BR9307110A patent/BR9307110A/pt not_active Application Discontinuation
- 1993-09-15 NZ NZ255301A patent/NZ255301A/en unknown
- 1993-09-15 CZ CZ95748A patent/CZ74895A3/cs unknown
- 1993-09-15 WO PCT/CA1993/000380 patent/WO1994007846A1/en not_active Application Discontinuation
- 1993-09-15 KR KR1019950701149A patent/KR950703520A/ko not_active Application Discontinuation
- 1993-09-15 JP JP50854294A patent/JP3490442B2/ja not_active Expired - Fee Related
- 1993-09-15 HU HU9500871A patent/HUT70432A/hu unknown
- 1993-09-15 RU RU95113586/04A patent/RU95113586A/ru unknown
- 1993-09-15 PL PL93308180A patent/PL174454B1/pl unknown
- 1993-09-15 SK SK376-95A patent/SK37695A3/sk unknown
- 1993-09-17 US US08/122,280 patent/US5541163A/en not_active Expired - Lifetime
- 1993-09-23 DE DE69307446T patent/DE69307446T2/de not_active Expired - Lifetime
- 1993-09-23 LT LTIP1092A patent/LT3072B/lt not_active IP Right Cessation
- 1993-09-23 AT AT93115326T patent/ATE147720T1/de not_active IP Right Cessation
- 1993-09-23 IL IL107092A patent/IL107092A/xx not_active IP Right Cessation
- 1993-09-23 EP EP93115326A patent/EP0589445B1/en not_active Expired - Lifetime
- 1993-09-23 PH PH46946A patent/PH30881A/en unknown
- 1993-09-24 ZA ZA937079A patent/ZA937079B/xx unknown
- 1993-09-24 TW TW082107871A patent/TW239117B/zh active
- 1993-09-24 CO CO93410100A patent/CO4560549A1/es unknown
- 1993-09-24 MX MX9305918A patent/MX9305918A/es not_active IP Right Cessation
- 1993-09-25 CN CN93117983A patent/CN1090278A/zh active Pending
-
1994
- 1994-11-23 EE EE9400334A patent/EE03083B1/xx unknown
-
1995
- 1995-03-24 NO NO951133A patent/NO951133L/no unknown
- 1995-03-24 FI FI951398A patent/FI951398A/fi not_active Application Discontinuation
- 1995-04-03 BG BG99542A patent/BG99542A/bg unknown
- 1995-04-25 LV LVP-95-107A patent/LV10945B/en unknown
- 1995-06-23 HU HU95P/P00428P patent/HU211315A9/hu unknown
-
1996
- 1996-02-01 US US08/595,327 patent/US5693619A/en not_active Expired - Lifetime
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