IE60496B1 - Pharmaceutical composition for use against hypertension and congestive heart failure - Google Patents
Pharmaceutical composition for use against hypertension and congestive heart failureInfo
- Publication number
- IE60496B1 IE60496B1 IE295187A IE295187A IE60496B1 IE 60496 B1 IE60496 B1 IE 60496B1 IE 295187 A IE295187 A IE 295187A IE 295187 A IE295187 A IE 295187A IE 60496 B1 IE60496 B1 IE 60496B1
- Authority
- IE
- Ireland
- Prior art keywords
- carbon atoms
- alkyl
- composition according
- hydroxy
- independently
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 206010007559 Cardiac failure congestive Diseases 0.000 title claims description 14
- 206010019280 Heart failures Diseases 0.000 title claims description 14
- 206010020772 Hypertension Diseases 0.000 title claims description 14
- 229940127291 Calcium channel antagonist Drugs 0.000 claims abstract description 26
- 239000000480 calcium channel blocker Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 15
- -1 nitro, hydroxy Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000006193 alkinyl group Chemical group 0.000 claims description 12
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 2
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 2
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 34
- 239000002775 capsule Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 241000700159 Rattus Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000003276 anti-hypertensive effect Effects 0.000 description 5
- 239000002934 diuretic Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940030606 diuretics Drugs 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000001452 natriuretic effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II 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-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 229920003102 Methocel™ E4M Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101150029512 SCG2 gene Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 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 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 1
- 230000003684 cardiac depression Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 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
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- LUDDKAMNGZPYBT-GTDRIFFSSA-M sodium dodecyl sulfate (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O LUDDKAMNGZPYBT-GTDRIFFSSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 1
- 229960002909 spirapril Drugs 0.000 description 1
- 108700035424 spirapril Proteins 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Pharmaceutical compositions contg. (a) a calcium antagonist and (b) 7-(N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-(S)-alanyl)-1,4-dithia-7 -azaspiro-(4,4)nonane-8(S)-carboxyl acid (I) and its pharmaceutically acceptable salts are new.
Description
This invention relates to novel pharmaceutical compositions effective against hypertension and congestive heart failure and to their production and use.
The present invention provide® a pharmaceutical composition containing as active agents. a) a Calcium-Antagonist and b ) 7- < H~ |i 1 < S } -B thoxycar bony 1-3-Pheny Ipropy 1 ]—( S ) -Alanyl )-1,4Dithia~7-Azaspiro~|[4,4]Non8ne-8-(S)-Carboxyllc Acid and its pharmaceutically acceptable salts. - 2 Case 100-6972 The calcium antagonists comprise a class of physiologically active substances characterised by their calcium antagonistic or calcium channel blocking activity. A wide range of such compounds are now known and have found wide therapeutic application, in particular in the treatment of cardiovascular disturbances or disease, for example in the treatment of coronary insufficiency, disturbance in cerebral circulation, hypertension and in the treatment of other disturbances in peripheral circulation. Typically,the calcium antagonists are employed as vasodilators» e.g. in the treatment of hypertension.
Component b) is an angiotensin-converting enzyme (ACE-) inhibitor. Little has been published on its pharmacological and biopharmaceutical properties. ACE inhibitors are known compounds that influence the transformation of angiotensin I in angiotensin II and that are useful in the lowering of elevated blood pressure when this is du® to the action of angiotension II. ACB-blocking compounds when administered alone have to be used in relatively high amounts that may lead to unwanted side effects.
The pharmaceutical composition of the invention and also co-administration of component a) and component b) possess surprisingly and unexpectedly advantageous pharmaceutical properties with an especially favourable or improved pharmacological/therapeutic profile. In particular it has been found that co-administration of a component a) and a component b) as aforesaid in conjunction results in unexpected enhancement of antihypertensive activity and an surprisingly potent activity against congestive heart failure.
Th® component a) induce# increase in central venous pressure and consequently the increase in cardiac output is blunted in component b) pretreated animals. The increase of central venous - 3 Case 100-6972 pressure in the absence of cardiac depression (cardiac contractility vas accurately assessed with a strain gauge sewn onto the myocardium) indicates an increased venous return caused by arteriolar dilatation. Th® blunted effect of component a) hence indicates an increased venous compliance after ACE inhibition.
Preferred calcium antagonists for use in the compositions of the invention are those of the dihydropyridine class, e.g. of the formula 1 A vherein A is a residue of formula (a), (b) or (c) - A Cass 100-6972 (a) (b) (c) R^ is hydrogen, (C, g)alkyl, hydroxy(C^ -)alkyl, (Cgg)alkoxyalkyl, (Cg_g)alkenyl, (Cg_g)alkinyl, (C3Pcycloalkyl or (C4 g)cycloalkylalkyl, or (C- 0)phenylalkyl or (Co .^phenylalkenyl, wherein ths phenyl ring is unsubstituted or mono-, di- or tri-substituted by halogen, hydroxy, (C^ 4)alkyl or (C^ 4)alkoxy, and Rg are each independently hydrogen» (Cj -)alkyl» pheaylalkyl, (Cg_pcycloalkyl or (C4_8)cycloalkylalkyl, whereby, when A is a residue b, one ot R? and Rg may also be (C^ 4)hydroxyalkyl or cyano, Rg and R^ ar® independently -CM, -COOR-, -CORg, -S(0)nRo or -COO-B-M Χθ R1V n is 0.1 or 2, Rg is hydrogen, halogen, (C1-A)alkyl, (·,_*)alkoxy, (C1->A)alkyl thio, (C., ^alkylsulfonyl, trifluoromethyl» nitro, hydroxy, azido, amino, (Cl4)alkylamino. dii(C1Aalkyljamino, (C15) - 5 Case 100-6972 alkanoylamino, (C^pcarbalkoxy, arainocarbonyl, trifluoromethoxy,cyano, sulfamoyl. (C.. alkylsulfamoyl or diJ(C1 galkyl] sulfamoyl, X is oxygen or sulphur, m is 0, 1 or 2, R,, Ηθ and Re ara each independently (C^ -)alkyl, (Cg -)alkenyl, (Cgg)alkinyl, (Cgj)cycioalkyl- (CA g)cycloalkylalkylt hydroxy-(C^ galkyl, (Cg-)alkoxyslkyl, hydrosey (C^_g)alkoxyalkyl, araino-CC^ -)alkyl, (C^ )alkylamino(Cg -)alkyl, di[(C, alkylJarainoalkyl, phenyl, (Cj ., θ) pheny lalkyl, a 5- or 6-iaembered heterocyclic ring, containing a nitrogen or oxygen or sulphur ato· and vhich may also contain 1, 2 or 3 additional ring nitrogen atoms, or (Cj_^)alkyl optionally substituted by a 5- or ό-membersd heterocyclic ring containing a nitrogen or oxygen or sulphur atom as heteroatom and which may additionally contain 1. 2 or 3 further ring ntrogen atoms, whereby, when A is a residue b, IU may also be trifluoroethyl, B is (Cj .,palkylene, Rj,q and R,, are each independently (C^ -)alkyl, (Cg ,)alkenyl, (Cg_-)alkinyl, (Cgj)eycloalkyl, (C4_g)cycloalkylalkyl, hydroxy(Cg_-)alkyl. (Cg_ -)alkoxyalky1, hydroxy(C^ g)alkoxyalky1, amino(Cg_-)alkyl, (C^ 4)alkylamino(Cg_-)alkyl.. di(C1A)alkyl]asaino->(C1A)alkyl, phenyl, or - 6 Case 100-6972 containing a further heteroatosa selected from oxygen or sulphur or a group -N-R12 wherein R12 -s (Εχ ^)alkyl, benzyl or bis- phenylmethyl, optionally mono- or independently dlsubstituted in the phenyl ring(s) by halogen of atomic number from 9 to 35 or alkoxy of 1 to 4 carbon atoms.
In formula I, (C1 ,)alfcyl groups preferably contain 1 to 4 carbon atoms- more preferably 1 or 2 carbon atoms, methyl groups being most preferred. (C^^J-alkyl, -alkoxy, -alkylthio and -alkylsulfonyl groups preferably contain 1 or 2 carbon atoms. Hydroxy, alkoxy, hydroxyalkoxy, amino and alkylamino moieties of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl groups R- in residues -COOR? are preferably not attached at the e-carbon atom. Suitably they are in the terminal position. Preferred alkylene moi ties of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aainoalkyl and alkylaminoalkyl ar® ethylene and propylene. The alkylene moiety ox cycloalkylalkyl groups is suitably methylene. Cycloalkyl moieties of cycloalkylalkyl groups are suitably cyclopropyl, cyclopentyl or cyclohexyi. By halogen is meant fluorine, chlorine or bromine, in particular chlorine.
The multiple bond in alkenyl, alkinyl and phenylalkenyl groups R^ or -COOR- is preferably net in the e,0-position. Alkenyl and alkinyl groups preferably have 3 to 5 carbon atoms. Alkenyl is suitably allyl or 2-methylallyl is suitably propionyl. Phanylalkenyl groups preferably have the trans-configuration and include» e.g. cinnamyl. When Rj is phenyl this is preferably unsubstituted. Whan Rj is di- or tri-substitutsd phenyl, the substituents are preferably the same and are halogen© or alkyl. Hetrocyclic rings as Ry, Rg and Ro are, e.g. furyl, thienyl, pyrrolyl, thiasolyl, isofhiasolyl, thiadiazolyl, oxazolyl, isoxasolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrasinyl, pyridazinyl, piperidinyl, morpho- 7 Case 100-6972 linyl and triazinyl. Hetrocyclie rings comprised by and R^, together with the nitrogen atom to which they are attached are preferably saturated and include pyrrolidine, piperidine, piperazine, N-alkylpiperazine and morpholine rings. Host preferred is however, di-phenyl-nethyl-piperazine that can be substituted in the phenylring(s) as described above. R? and R^ are preferably identical. R. is suitably halogen, alkyl, alkoxy, nitro or trifluoromethyl and is preferably in the o- or m-position with respect to the position of attachement of the dihydropyridine residue. When A is a residue a), Rg is preferably hydrogen.
In -COOBNR^q R-n 3 stands for an alkylene chain of 1 to 14 carbon atoms preferably of 5 to 14 carbon atoms especially of 10 carbon atoms.
Particularly suitable compounds of formula I, wherein A is a residue (a), for use in accordance with the present invention are those shown in the following table (the figure indicated under "y reoresents the position of attachment of (a) to the di hydropyridine nucleus Compound No.R2R3 «4Ilg R, o X y 1 HCHj CH COO-i-Bu A H 0 4 2 H CH^ COOC-Hp 2 5 SO'^CH A 11 0 4 3 11 ch3 CH C00CoKr ί 9 ch3 ll 0 4 4 H ch3 CN COOC-11P .1 3 CHj H s 4 5 11 CHj CN CG0CH2CH{CI!3i2 A 11 s 4 6 H CH-j cooch3 COCrlk A H 0 4 7 H CH- CH- / COO(CH-) ΛΙ CCOC-HP ' C1I3 H 0 ’ 4 J - - \ , CHgC ’A CH- / J 8 H CH., J COO (CH2)2N COOC,Hr 2 5 CM - J H 4 - CH2C;A 9 HCH3 COO (CH?) 2N? COO(CH2)2N{CH3)2 cn3 H o 4 Case 100-6972 Compound No.
IU X H CH3 H CH . H ' CH ' C00iCH2)2NiCH3i2 ch2)2k(ch3)2 COO{CH2i2H(Cii3) h ch3 c$©cch2>?h, CH.,, ‘2* 2Wv H CH.
COO(CH2) 16 Η Δ CQQC,H .I 1? H A COOCH3 13H Δ COOCH3 ch3 CH,C CH, x J ft CH,C„ ft H, M, '5 HS COO{CH2)2H{CH3)2 ch3 COOCjHg CQOG,H, COOC-Hp 2 3 COOC^Hp GOOCH.
COOC-HP COOCH, COOCH.
CH CH ii es-u h s CH, H 0 CH, CH, H 0 j· CH, H © fi Case 100-6972 Compound No, RjR3 »4Rs Rg X y 19 H Δ C00C,Hr 2 f> COOC?H5 ' Δ H 0 4 20 H CH-' 3 C00iCH2)2"CgHs COOCH3 CH3 H 0 4 21 H ch3 COOCHy COOCiUCUk 2 6 -3 CH, H 0 4 22 K CH- 3 CQQC»H- «· ΰ COOC2Hg CHj H 0 4 23 H CHj COOCJfr ί ύ C00C9iig OH j H s 4 24 H ch3 COOCCCHj) j COOC(CHj)J CH, 3 H s 4 25 11 CHj COOCff- J GOOCH3 CHj 7 Cl 0 4 26 H • CH3 GOOCH j COOCHj ch3 H s 4 27 H CHj COOC-Hf 2 3 COOC,Hr 2 3 CHj 5-OCH, 3 s 4 28 a CH, 3 COOC-Hr 2 b COOC,HS 2 S CH, 3 7-C1 s 4 29 fiCK3 COOC2H5 COOC-H- 2 5 ch3 H s 5 30 K CHj COOCjHg COOC-H2 5C!13 4-Cl s 5 Case 100-6972 Compound Ho. ^χ 3.1 32 33 fi H H ck3 CHj CH» 3 COG (Οψ 3 COCH ~ coa-k. «? 34 H CH. COC.Hp 3 35 H ch3 COCjH5 36 · H CHj COC?.H^ 37 K CI 1« COC.Hp J 2 5 36 If CH» 3 C0CH3 3# H Clg coch3 40 H CH^ COCH-j 4L H ch3 COOCI12CH(CH3) , 4 2 H CH, CGOCH.
Rg Rg X COC(CT3> 3 coch3 CHg, CH^ H 7-Cl s 0 4 4 COCK, 3 ck3 H s 4 coc,hp CH3 5-OCHj 3 4 COC-Hr ί 5 Ci'Lj 7-Cl S 4 COCUip ί b CH, J H s 5 CO€,H- CH, 3 4=CX s 5 COCK» J CHj H 0 4 CGOC,HP 2 » CH, 3 Ji 0 4 COOC»fk cn, H C c? 4 2 S> 3 COOCH, 3 • CH3 H 0 4 COOCH, . CH- if 0 4 -cLS^ 100—69/2 Compound R, No. 1R2 R3 R4 B3 Rg X y 43 H ch3 COOC,HP CQOC,Hr 2 5 ch3 H 0 5 44 H ch3 COOCH2Cii (CH3) 2 COOC-H- 2 5 ch3 H s 4 45 H CH, 3 COOCH2CH(CH3)2 COOCyH^ ch3 H 0 4 4 6 H CIi3 COOCiCH^) 3 COOC{CH3) 3 CHj if 0 4' 4? H CH3 COOCH2CH(CH)2 COOCH?CH {CIi3) 2 CH- 3 H O' 4 48 if ch3 COO(Cil2) 2Οδ2Η5 COOC-Hr & 3l· CH3 ii 0 4 49 H ch3 COOCCHj) 20^1¼ COGCyHj. oh3 H s 4 50 HCH3 coo (cup2oc2hs COQC,Hf CH-j ii s 5 51 · ii ch3 COOCH (CH^i 2 COOCH 3 CH, 3 H O 4 52 ·* H ch3 COO'CCfij) 2OCH3 COOCH, 3 ch3 ii 0 4 . S3 H Cfl3 COOiCHyJ jOCHiCHp2 COOCH3 CK3 H 0 4 54 iiC«3 COOCCHjI 2OC2H5 COOCH, 3 ch3 Π 0 4 COOCH H CH3 coo\ CH3 HO 4 h ch coo(ch2)2cch3 COOCH (CH,) , CH3 η 0 4 Case 100-6972 Compound No.R2R3nsRs X y 57 Li ch3 COOCHg CO0C2H5 CH3 u 0 4 58 cb3 ch3 CO0C2H5 COOCjHg CHj H 0 4 59 n- 'C3H7 ch3 COOCjHg CO0C2H§ ch3 « 0 4 60 K ch3 coo(ch2),o- θΖ j COOCH3 ch3 H 0 4 Suitable ccmpounds of formula I, wherein A is a residue (b), for use in accordance with the present invention are those shown in the following table:R1R2 *3 %R5R6 X y 61 HCH3 C00CB2CF3 COOCHgCH3 Q-Cl = = 62 H CHg cooch3 COOC?H . CH3 2 ! s3-di-Cl - - 63 H ch3 cooc?h5 CCOC2H5 CH2OH m-HOg - ,= 64 H ch3 COOCH(CH3}2 cooch3 -CH m-H02 =, » CH 65 H ch3 COO(CH ) H 3 COOCH3 "3 m-H02 - - CH2-CrH5 66 H CK3 COOCH3 COOCH3 ch3 o-N02 - 67 H CM, 3 COO(CH2)2OC3H7 COO(CH2)2OC3H?C«3 m-N02 - - m co ί Case 100-6972 Compound f5 68 H CH3 COG(CH2i2OCHg CQQCH(CH-)„ 3 C Ln. 3 m-HO. Z — «ΞΙ K 69 H ch3 CQOCH, 3 C00CH?CH(CHg)2 CK. 3 O"H0p - - ΐ 70 H ch3 COOCJL £ 3 COOCHg CH. *5 m-NQg - - 1 71 H CH, J COOC^Hg COOCJL 2 5 CH, 3 o-Cf3 - 1 • I A suitable compound of formula I, wherein A is a residue (c); invention is compound No. 72 wherein: for use in accordance with the present Rj = K, R2 = CHg, Rg = C00C2H5, » COOC2H5‘ % CHg, and Rg = o-SCHq .
Case 100-5972 - 15 Case 100-6972 Especially prafered calcium-antagonists according to a) have the formula V A wherein is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycioalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms., the phenyl ring being unsubstituted or mono-, di- or trisubstitutsd independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms.
Rj' and R^, independently, are hydrogen or alkyl of 1 to 6 carbon atoms. and , independently, are alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycioalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms? alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of k to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylalkoxy of 4 to 8 carbon atoms, or Ry has the significance O-IV-R?’, vherin IV is an alkylene chain of 9 to 14 carbon - 16 Case 100-6972 atoms and IU' *s piperidine or piperazine both substituted in the 4 position by methyl, benzyl or bis-phenyImethyl optionally mono- or independently disubstituted in the phenyl ring(s by halogen of atomic number from 9 to 53 or alkoxy of 1 to 4 carbon atoms and R'^ has the significance cited above.
R/ is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl. each of 1 to 4 carbon atoms, trifluoromethyl. nitro or hydroxy, and X has the above significance.
The calcium antagonists used according to the invention are generally described together with their calcium antagonistic and i.a. antihypertensive activity in earlier published patents. In these Patents may also be mentioned that salt forms of the calcium-antagonists of formula I may be used instead of the free bases. Further it may be contemplated that when the substituents in the 2 and 6 positions and/or 3 and 5 positions of th© 1.4- dihydropyridinyl moiety are different fhe calcium antagonists may exist in racemic form or in idividual enentioaer forms.
Particularly interesting calcium-antagonists of formula I or of formula la are 4-(2,l,3-bensoxadiasol-4-yl)-l,4-dihydro-2,6dimethyl-pyrldine-3,5-dicarboxylic aeid diethyl ester, hereinafter referred to as compound Ko 1;4-(23?3-benzoxadiazol-4-yl)1.4- dihydro~2,6-dimethyl-3-methoxycarbonyl-pyridine-5carboxylic acid isopropyl ester, hereinafter referred to as compound Ko 2.4-(2,1,3-benzoxathiadiazol-4-yl)-2.6-dimathyl1.4- dihydropyridine-3,5-dicarboxylic acid dimethyl ester, hereinafter referred to as compound Ko 3 and (+)-(8)-4(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl2,6-diraethyl-3-pyridine carboxylic acid-(10-|4-(diphenyImethyl)- 17 Case 100-6972 piperazin-l-yl]decylJester referred to as compound No 4; especially interesting are compounds No 2 and No 4. 7-(N-[1(S)-E thoxycarbony1-3-Phenylpropy1]-(S)Alanyl)-1,4Di thia-7-Azaspiro[4.4]Nonane-8-(S)-Carbo3tylie Acid has the alternative chemical name [8S-[7[R«)]s8R^]]-7-[2-[[l(Ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]-l?4-dithia-7-a zaspiro(4.4]nonane-8-carboxylic acid. It is also identified by SCHERING as SCO-33844 and has th® generic name SPIRAPRIL. This compound is described in Example 3 of th® US-Patent No 4.470,972. In this US-Patent it is also stated that the compound has antihypertensive activity. Pharmaceutical acceptable salt forms may be used. The hydrate may be used. In this US-Patent different salt forms are described that can be used instead of the free base e.g. the hydrochloride as described in Example 4 of this patent or the hemimaleate as described in Example 5 of this patent. The preferred form is the monohydrochloride monohydrate.
The co-administration of a calcium antagonist and component b) exhibits potent anti-hypertensive activity and activity against congestive heart failure as indicated in pharmacological experiments.
Post example vhen a calcium antagonist especially a compound of formula I and a component b) are co-administered to animals, the natriuretic and diuretic activity of the calcium antagonists especially of the compounds of formula I may be surprisingly retained. Co-administering a calcium antagonist especially a compound of formula I with th® above ACE-inhibitor thus reduces the need for further diuretics and/or beta-blockers. This is shown in the hydrated rat test (method of Fluckiger et al·, Schweiz.
Med. tfochenschrift 93, No 35 (1963J 1232-7) described in the followings - 18 Case 100-6972 Groups of 12 rats are used. Component a) at a diuresis inducing doses e.g. at 0.3 mg/kg p.o. to 3 mg/kg p.o. is investigated alone or in combination with component b) at a dosage of 3 mg/kg s.c.
The compounds are administered at the same time. Urine is collected for 3 hours and its volume and sodium excretion measured, This effect is confirmed in sodium-depleted rats. Rats are given furosemide (50 mg/kg/day) with drinking water for two days. Groups of 6 animals are used. The calcium antagonist is administered at diuresis dosages e.g. of 0.3 to 3 mg/kg p.o and component b) at dosages of 3 mg/kg s.c. The compounds are administered at the same time. Urine is collected for 3 hours and its volume and sodium excretion measured. Similar values as in the hydrated rat test are obtained.
Xt has thus been unexpectedly found that the diuretic and natriuretic activity is generally maintained .
This is surprising and makes the combinations of the invention particularly well-suited in the treatment of hypertension and congestive heart failure and reduces the need for diuretics.
The importance of this effect is highlighted by the increasing concerns in informed circles about the metabolic consequences of diuretics administration over extended periods. The antihypertensive effect of the co-administering a calcium antagonist and component b), is further supplemented by the renal effect.
Both components a) and b) may be - as discussed above - in the free base or where appropriate In salt. e.g. in acid addition salt form. - 19 Case 100-6972 The new composition may be prepared by a process comprising formulating a calcium antagonist and component b) in a state of purity sufficient for pharmaceutical acceptability. Conventional pharmaceutical excipient including carrier and diluents, may also be formulated therewith.
The compositions of the invention are therefore indicated for use in the treatment of hypertension and congestive heart failure.
The calcium antagonist may be administered at e.g. one third to 100 percent of the normal dose for treating e.g. hypertension or congestive heart failure. An indicated oral daily dosage of compounds of formula X is from about 0.2 mg to about 350 mg, particularly from about 1 to 70 rag, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.05 mg to about 175 mg e.g. to 20 mg of the compounds, or in sustained release form. The prefered compound is compound Ko. 2. An indicated dose is from about 2.0 to about 10 mg twice or once a day p.o.
An indicated preferred weight ratio of a calcium antagonist to the component b) calculated on the free base moiety thereof, may be from about 50:1 to about 1:10, particularly from about 10:1 to about 1:5, preferably from about 5:1 to about 1:3. Component b) may be administered at e.g. one third to 100 percent of the normal dose for treating hypertension or congestive heart failure. Contemplated dosage forms include 3 rag, 6 mg, 12 mg and 24 mg.
Thus for compound Ko 2 and the component b) preferred ratio is from about 50:1 to about 1:5, especially about e.g. 5:1 to 1.1 such as 1:1, 4:1, 3:1 or 2:1. - 20 Conveniently, components a) and b) are administered in the form of a pharmaceutical composition in association with a pharmaceutical carrier or diluent. Sueh compositions nay be formulated in conventional sanner so as to be. for example, a solution such as an injectable solution or suspension, or preferably a, solid form sueh as a tablet or capsule. If desired one or both of the components may be in sustained release form, e.g. in the case ox compound No. and 2 as described in GB 218 1 053 A or 216 0 100 A.
If desired the active agents nay be arranged in a pack to facilitate administration of a particular dosage regimen, e.g. ia a particular order in a blister pack» A suitable fore of administration nay consist of a pack or dispenser device containing the composition of the invention together with instructions for use in hypertension or congestive heart failure.
A suitable composition may also consist of a pack containing separately a component a) and component b) required for concomitant administration, conveniently together with instructions for the concomitant administration of a predetermined amount of a component a) and of a predetermined amount of the component b).
The following Examples are illustrative of compositions for use is the invention- 21 Case 100-5972 BX&MgLB Is Hard gelatine capsules for oral administration Hard gelatine capsules containing the ingredients indicated below may be prepared by conventional techniques, and be administered once a day for the treatment of hypertension and congestive heart failure. iBigr'sdieat . ©eight Compound Mo 2 10.0 mg Component b) 2.0 rag Lactose 157.0 mg Sodium lauryl sulfate 5.5 mg Corn starch 128.0 mg Aerosil 200 1.5 mg Polyethylenglycol 5000 8.0 mg 322.0 mg BZfiHgLB 2,- Tablets for oral administration Sufficient amounts of the components are mixed in conventional manner and filled into gelatine capsules or compressed fo tablets, which are administered once a day for the treatment of hypertension and congestive heart failure. - 22 Case 100-6972 Ingredient Weight Compound No 2 10.0 rag Component b) 2.0 mg Lactose Sodium lauryl sulfate 2.0 mg Polyvinylpyrrolidone 8.0 mg Corn starch 13.0 mg Magnesium stearate 2.6 mg 262.0 mg EXAMPLE 3s Separate Co-administration Capsules of compound No. 2 may be made up with the following composition Compound No 2 10 mg Microcrystalline Cellulose (Avacel) 47 mg Cetyl Palmitate 10 mg Hydroxypropyl methylcellulose (Methocel E4M) 90 mg Silica colloidal 1 rag Magnesium stearate 2 mg 160 mg and Capsules of component b) may be made up with the following composition - 23 Casa 100-6972 Component b) 12 mg Lactose 349 mg Silica (colloidal) 8 mg Maleic acid (ground) 5 mg Stearic acid 16 rag 400 mg These may ba arranged in calendar packs. If desired combined capsules containing both active agents may be produced.
Claims (14)
1. A pharmaceutical composition comprising a) A calcium antagonist and b ) 7-(N-(1(S) · Ethoxycarbony1-3-PhenyIpropylJ-(S)-Alanyl)l,4-Dithia-7-Azaspiro-[4,4]Monane-8-(S)-Carboxylic Acid and the pharmaceutically acceptable salts thereof.
2. ) A pharmaceutical composition according to claim 1 characterized in that the calcium-antagonists are those of formula I A wherein A is a residue of formula (a), (b) or (e) (ε) (c) - 25 Case 100-6972 is hydrogen. ( 1& )alkyl, hydroxy(C2-6)alkyl, (C^,)alkoxyalkyl. (Cg-)alkenyl. (Cg-)alkinyl, (C^y)cycloalkyl or (Ο^,θ) cycloalky lalkyl, or (Cy_ 6 )phenylalkyl or (C?_ 19 )phenylalkenyl, wherein the phenyl ring is unsubstituted or mono-, di- or tri-substituted by halogen, hydroxy, (C^ J alkoxy, Rg and Mg are each independently hydrogen, (C^-)alkyl, (C^^q)— phenylalkyl, (Cg y)cycloalkyl or (C, „)cycloalkylalkyl, whereby, when A is a residue b, one of Mg and Rg may also be (C| phydroxyalkyl or cyano, Rg and R £ are independently -CN, -COOMy, -COMg, -S(0)^R Q or -COO-B-K Μχθ R 1 ,, n is 0, 1 or 2, M, is hydrogen, halogen, (Cl-4)alkyl, (Cj_^alko3«y, (C 1 palkylthio, iC i y .)®lkylsulfoayl, trifluoromethyl, nitro, hydroxy, aside, amino, (C^ ^)alkylamino, diKC2_^)alkylJamino, (C, g)alkanoylamino, (C 9 g)carbalkoxy, arainoearbonyl, trifluoromethoxy, cyano, sulfamoyl, (Cj_^)alkylsulfamoyl or di [(C 3 _ A )alkyli! sulfamoyl, I is oxygen or sulphur, m is 0, 1 or 2, My, Μ § and R Q are each Independently (C 1 _,)alkyl, (Cg-)alkenyl, (Cgg)alkinyl, (Cg -)cycloalkyl, (C^ θ) cycloalky lalkyl, hydroxy- ί Cg -) ality 1 ' ' C '3-5 alkoxyalky 1, hydroxy (C^ θ) alkoxyalkyl, amino-(Cg)alkyl,(C^_^)alkylamino(Cg_-)- 26 Case 100-6972 alkyl, di iC^JalkylJaminoalkyl, phenyl, (C 7 _ 1Q )phenylalky1. a 5- or 6-mambered heterocyclic ring, containing a nitrogen or oxygen or sulphur atom and which may also contain 1, 2 or 3 additional ring nitrogen atoms, or (C^ z )alkyl optionally substituted by a 5- or δ-membered heterocyclic ring containing a nitrogen or oxygen or sulphur atom as heteroatom and which may additonally contain 1, 2 or 3 further ring nitrogen atoms, whereby, when A is a residue b, Ry may also be trifluorosthyl, B is (C l-14 )alkylene, and ar® each independently (C^,)alkyl, (C^-Jalkenyl, (C^ ,)alkinyl, (C^ -)cycloalkyl, (C^ θ)cycloalkylalkyl, hydroxy(C 9 _g)alkyl, (C 3 _g)alkoxyalkyl, hydroxy(ϋ ζ _θ)alkoxyalkyl, aminotCj -)alkyl. (C^ palkylarainoiCg g)alkyl, di-[(C^ z )alkyljamino-(C 1 z )alkyl, phenyl, or (C^^Jphenylalkyl, or and R,.. form together with the nitrogenatom to which they are attached a 5-, 6- or 7-membered heterocyclic ring optinally containing a further heteroatom selected from oxygen or sulphur or a group wherein R 1? is (CX“4)alkyl, benzyl or bis- phenylmethyl optionally monoor independently disubstituted in the phenyl ring(s) by halogen of atomic number from 9 to 35 or (C 1 _ A )alkoxy.
3. A pharmaceutical composition according to claims 1 and 2 characterized in that the calcium-antagonists are those of Formula la I Case 100-6972 wherein R 1 ' is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycioalkyl of 3 to 7 carbon atoms, eycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms. Rg* and Rg', independently, are hydrogen or alkyl of 1 to 6 carbon atoms, Rg' and R^', independently, are alkyl of 1 to 6 carbon atoms. alkenyl or alkinyl of 3 to 6 carbon atoms, cycioalkyl of 3 to 7 carbon atoms, eycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 ίο δ carbon atoms, cycloalkoyoxy of 3 to 7 carbon atoms or cyeloalkylalkoxy of 4 to 8 carbon atoms, or Rg' has the significance O-B'-Rj', wherein 3' is an alkylene chain of 9 to 14 carbon atoms and R- is piperidine or piperazine both substituted in - 28 Case 100-6972 the 4 position by methyl, bansyl or bis-phenylmsthyl optionally mono- or independently disubstituted in the phenyl ring(s) by halogen of atomic number from 9 to 53 or alkoxy of 1 to 4 carbon atoms and R^' has the significance cited above. Rg' is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl. nitro or hydroxy, and X has the significance stated in claim 2.
4. A composition according to any of the claims 1 to 3, wherein component a) is selected from 4-(2,1,3-benzoxadiazol-4-yl)1»4-dihydro-2,6-dim®thyl-pyridine-3,5-dicarboxylie acid diethyl ester? 4-(2,l,3)-benzoxadiazol-4-yl-1.4-dihydro-2,6dimethyl-3~methoxycarbonyl-pyridine-5-carboxylie acid isopropyl ester; 4-(2,1,3-benaoxathiadiazol-4_yl)-2,6-dimethyl-l,4=dihydropyridin-3,5-dicarboxylic acid dimethyl ester and ( + )-(S)-4-(2,,1,3-benzoxad ίazol-4-y1)-1,4-dihydro-5-me thoxycarbonyl-2,6-dimethyl-3~pyridine carboxylic acid-(10(4-(diphenylmethyl)-piperazin-l-yljdecylJester.
5. A composition according to any of the claims 1 to 4 for use in the treatment of hypertension and congestive heart failure.
6. A composition according to claim 5 wherein the calcium antagonist is the 4-(2,l,3-Benzoxadiazol)-4-yl-l,4-dihydro2,6-dimethyl-3-miethoxycarbonyl-pyridine-5-carboxylic acid isopropylester.
7. A composition according to claim 5 wherein the calcium antagonist antagonist is the 4-(2,l,3-Benzoxadiazol-4-yl)-l,4- 29 dihydro-2,6-diraethyl-pyridine-3,5~dicarboxylic aeid diethy1ostar.
8.- A composition according to claim 5 wherein the calcium antagonist is the 4-(2,1,3-Benzoxathiadiazol-4-yl)-2,6-diraethyl-X s 4-dihydropyridine-3,5-dicarbo3Eylic acid, dimethylester.
9. A composition according to claim 5 wherein the calcium antagonist is the (i-)-(S)-4-(2 y l r 3-benzoxadiazol>*4-yl)-l > 4-dl-> hydro-5*mechoxy~carbonyl~2,6*-dimethyl<-3-*pyridine carboxylic acid-(10'-(diphenylmethyl)-piperazin-l-yl]|decyl Jester,
10. A composition according to claim 5 wherein component b) is the 7-(N-(1(S)-ethoxycarbony1-3-phenyIpropy1] - ( S)-alanyl)-1,4~dithia-7-azaspiro-¢4,4jnonane-8-(S)-carboxylic acid monohydrochloride monohydrate.
11. A composition according to any of the claims 1 to 10 characterized ia that the weight ratio of component a) co component b) is from 5s1 to Is3.
12. A composition according to claim 11 wherein the weight ratio is from 5s1 to 1:1.
13. A pack or dispenser device containing a pharmaceutical composition according to any one of the claims 1 to 12 together with instructions for us® in hypertension or congestive heart failure. - 30
14. use of a combination of component a) and component b) as defined in any of the claims 1 co 12 in th© manufacture of a pharmaceutical composition for the treatment of hypertension a congestive heart failure.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868626217A GB8626217D0 (en) | 1986-11-03 | 1986-11-03 | Pharmaceutical compositions |
| GB878713349A GB8713349D0 (en) | 1987-06-08 | 1987-06-08 | Pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE872951L IE872951L (en) | 1988-05-03 |
| IE60496B1 true IE60496B1 (en) | 1994-07-27 |
Family
ID=26291485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE295187A IE60496B1 (en) | 1986-11-03 | 1987-11-02 | Pharmaceutical composition for use against hypertension and congestive heart failure |
Country Status (25)
| Country | Link |
|---|---|
| KR (1) | KR960005145B1 (en) |
| AT (1) | AT397343B (en) |
| AU (1) | AU615883B2 (en) |
| BE (1) | BE1002063A4 (en) |
| CA (1) | CA1314222C (en) |
| CH (1) | CH677189A5 (en) |
| DE (1) | DE3736505A1 (en) |
| DK (1) | DK574087A (en) |
| ES (1) | ES2010524A6 (en) |
| FI (1) | FI874823A (en) |
| FR (1) | FR2605885B1 (en) |
| GR (1) | GR871680B (en) |
| HK (1) | HK138893A (en) |
| HU (1) | HU199681B (en) |
| IE (1) | IE60496B1 (en) |
| IL (1) | IL84343A (en) |
| IT (1) | IT1212037B (en) |
| LU (1) | LU87034A1 (en) |
| MY (1) | MY102124A (en) |
| NL (1) | NL8702502A (en) |
| NO (1) | NO874539L (en) |
| NZ (1) | NZ222401A (en) |
| PH (1) | PH23249A (en) |
| PT (1) | PT86062B (en) |
| SE (1) | SE8704272L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3818245A1 (en) * | 1988-05-28 | 1989-12-07 | Hoechst Ag | COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH COLD CHANNEL MODULATORS AND THEIR USE IN MEDICINAL PRODUCTS |
| FR2733911B1 (en) * | 1995-05-09 | 1998-05-29 | Takeda Chemical Industries Ltd | PHARMACEUTICAL COMPOSITION FOR RENAL OR CARDIOVASCULAR DISEASES |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4470972A (en) * | 1981-04-28 | 1984-09-11 | Schering Corporation | 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids |
| US4520021A (en) * | 1982-07-02 | 1985-05-28 | Merck & Co., Inc. | Substituted caprolactam derivatives as antihypertensives |
| DE3437917A1 (en) * | 1984-10-17 | 1986-04-17 | Bayer Ag, 5090 Leverkusen | COMBINATION OF DIHYDROPYRIDINE WITH ACE INHIBITORS AND THEIR USE IN MEDICINAL PRODUCTS |
| DE3633496A1 (en) * | 1986-10-02 | 1988-04-14 | Hoechst Ag | COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH CALCIUMANTAGONISTS AND THEIR USE IN MEDICINAL PRODUCTS |
| GB2198641B (en) * | 1986-11-03 | 1990-09-19 | Sandoz Ltd | Pharmaceutical composition for use against hypertension and congestive heart failure |
| IL88502A (en) * | 1987-12-14 | 1993-04-04 | Squibb & Sons Inc | Pharmaceutical compositions containing an angiotensin converting enzyme inhibitor |
-
1987
- 1987-10-20 HU HU874712A patent/HU199681B/en not_active IP Right Cessation
- 1987-10-20 NL NL8702502A patent/NL8702502A/en not_active Application Discontinuation
- 1987-10-28 CH CH4224/87A patent/CH677189A5/de not_active IP Right Cessation
- 1987-10-28 DE DE19873736505 patent/DE3736505A1/en not_active Ceased
- 1987-10-30 BE BE8701236A patent/BE1002063A4/en not_active IP Right Cessation
- 1987-10-30 LU LU87034A patent/LU87034A1/en unknown
- 1987-10-30 FR FR8715186A patent/FR2605885B1/en not_active Expired - Fee Related
- 1987-10-30 CA CA000551575A patent/CA1314222C/en not_active Expired - Fee Related
- 1987-10-30 IT IT8748553A patent/IT1212037B/en active
- 1987-11-02 FI FI874823A patent/FI874823A/en not_active Application Discontinuation
- 1987-11-02 IE IE295187A patent/IE60496B1/en not_active IP Right Cessation
- 1987-11-02 MY MYPI87003005A patent/MY102124A/en unknown
- 1987-11-02 AT AT0286987A patent/AT397343B/en not_active IP Right Cessation
- 1987-11-02 AU AU80576/87A patent/AU615883B2/en not_active Ceased
- 1987-11-02 NO NO874539A patent/NO874539L/en unknown
- 1987-11-02 GR GR871680A patent/GR871680B/en unknown
- 1987-11-02 PT PT86062A patent/PT86062B/en not_active IP Right Cessation
- 1987-11-02 SE SE8704272A patent/SE8704272L/en unknown
- 1987-11-02 DK DK574087A patent/DK574087A/en not_active Application Discontinuation
- 1987-11-02 IL IL84343A patent/IL84343A/en unknown
- 1987-11-02 KR KR1019870012319A patent/KR960005145B1/en active IP Right Grant
- 1987-11-02 NZ NZ222401A patent/NZ222401A/en unknown
- 1987-11-03 ES ES8703141A patent/ES2010524A6/en not_active Expired
- 1987-11-03 PH PH36019A patent/PH23249A/en unknown
-
1993
- 1993-12-16 HK HK1388/93A patent/HK138893A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |