IE49497B1 - 1,4-dihydropyridines,their preparation and pharmaceutical compositions containing them - Google Patents
1,4-dihydropyridines,their preparation and pharmaceutical compositions containing themInfo
- Publication number
- IE49497B1 IE49497B1 IE1165/83A IE116583A IE49497B1 IE 49497 B1 IE49497 B1 IE 49497B1 IE 1165/83 A IE1165/83 A IE 1165/83A IE 116583 A IE116583 A IE 116583A IE 49497 B1 IE49497 B1 IE 49497B1
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- compound
- formula
- stated
- compounds
- dihydropyridines
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Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
- 229940126657 Compound 17 Drugs 0.000 claims 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 claims 1
- 229940125773 compound 10 Drugs 0.000 claims 1
- 229940125797 compound 12 Drugs 0.000 claims 1
- 229940126543 compound 14 Drugs 0.000 claims 1
- 229940125758 compound 15 Drugs 0.000 claims 1
- 229940126142 compound 16 Drugs 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 206010022562 Intermittent claudication Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 208000021156 intermittent vascular claudication Diseases 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YBBRQAXNTWMMFZ-UHFFFAOYSA-N 2,1,3-benzoxadiazole-4-carbaldehyde Chemical compound O=CC1=CC=CC2=NON=C12 YBBRQAXNTWMMFZ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010058842 Cerebrovascular insufficiency Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 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
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N isobutyl acetate Chemical compound CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
The compounds of formula I fall under the scope of European Patent Application Ho .78100165.6, but are not specifically disclosed therein. It has now been found that the compounds of formula I have particularly valuable pharmacological properties, e.g. their coronary activity is particularly long lasting and potent. Their calcium antagonistic activity is particularly potent.
They also possess a good tolerability.
A process for the , production of a compound of formula I as defined above,may comprise replacing the moiety -HC=Y in a compound of formula II, / II HC=Y wherein X is as defined above,and -HC = Y is i) formyl , ii) a radical of formula -HC=C-C(=Z)CH3 COOR} or COOR.
I HC-C(=Z)CH, / ** iii) a radical of formula -HC ^HC-C^Z* )CH3 coor2 wherein Z and 1' are independently oxygen or NR^, and and R3 are as defined above, by a moiety of COOR, wherein and R3 are as defined above.
III -4The process may be effected in conventional manner for analogous dihydropyridine syntheses, e.g. according to Hantzsch. When the moiety -HC=Y is formyl and when it is desired to produce a compound of formula I, wherein R^ is identical to R2> it is convenient to react a compound of formula II with a compound of formula IV, ch3-co-ch2-coor2 IV wherein R2 is as defined above, in the presence of a compound of formula V, h2nr3 V wherein R3 is as defined above.
Preferably at 1nast 2 moles of a compound of formula IV per mole of a compound of formula II are present. Alternatively a compound of formula II may be reacted with a compound of formula VI, ch3-c(hhr3)=ch-coor2 VI wherein R2 and R3 are as defined above.
Preferably at least 2 moles of a compound of formula VI per mole of a compound of formula II are present.
When the moiety -HC=Y is formyl and preferably when it is desired to produce a compound of formula I wherein R^ is different to R2, it is also possible to react such a compound of formula II with a compound of formula IV and a compound of formula VII, . 43487 -5ch3-c(hhr3)=ch-coor1 VII wherein R^ and R3 are as defined above.
It will be appreciated that a compound of formula VI may be formed as an intermediate during the reaction of a compound of formula IV and a compound of formula V. A compound of formula II, wherein -HC=Y is a radical ii) or iii), may be formed as an intermediate in the above reactions. They may however be produced by different processes Alternatively or particularly for the production of a com10 pound of formula I, wherein R^ is different to P2, convenient to react a compound of formula II, wherein the moiety -HOY is a radical ii) with a compound of formula IV or VI, and where appropriate, with a compound of formula V. A compound of formula II, wherein the moiety -HOY is a radical iii) may be an intermediate.
In the above reactions it is possible in certain instances when R-j and R., ere not identical that more than one isomer of formula I may be formed. If so these may be separated in conventional manner, e.g. by column or thin layer chromatography.
When the starting material is a compound of formula II, wherein -HOY is a radical iii), the reaction is a ring cyclisation. When Z and Z’ are both oxygen, then an amine of formula V should be present.
However, all the above reactions may be effected under the same conditions.
The reaction may be effected conveniently in solution. A suitable solvent is water, ethanol, dioxane, dimethyl formamide, dimethyl sulphoxide, pyridine or.glacial acetic acid. Suitable reaction temperatures may be from 20 to 49407 -6160°C, preferably from 60 to 120°C.
Insofar as the production of starting materials is not particularly described these compounds are known or may be produced in analogous manner to known compounds.
In the following Examples the temperatures given are in degrees Centigrade and are uncorrected. 43*97 -7EXAHPLE 1 : 4^(2,1.3;Benzoxadiazol-4-yl)-2,6;dimethyl; ±4;di hydro 4ΪΠ?ξ -carboxylic acid^isobutyl ester g of 2,1,3-benzoxadiazole-4-aldehyde, 3.2.g of aceto5 acetic acid isobutyl ester, 2.3 g' β-aminocrotonic acid methyl ester and 10 ml of ethanol are stirred under reflux for 3 hours. The mixture is subsequently evaporated and the residue is chromatorgraphed on silica gel with chioroform/acetic acid ethyl ester (8:1) to yield the title compound. The product is recrystaliised from diisopropyl ether and methylcyclohexane, m.pt. 148-158°.
By using the process described in Example 1, and corresponding starting compounds, e.g. a compound of formula II, wherein -HC=Y is a radical i) and compounds of formula IV and V, and for Examples 4,5 and 8 -16 a compound of formula II, wherein -HC=Y is a radical ii), wherein Z is oxygen and a compound of formula VI, the following compounds of formula I may be obtained, wherein y indicates the position of the dihydropyridine moiety:- Comp .R1R2R3 y X m.p. 2 CH3 ch3 K 4 0 215-221 3 C,HrC2H5 H 5 0 173-174 4 CH2CH(CH3)2C2H5 H 4 s 85-95 5 CH2CH(CH3)2C2H5 H 4 0 145-146.5 25 6 C(CH3)3 C(CH3)3 H 4 0 207-210 7 CH2CH(CH3)z Ch'2CH(CH3: l2 H 4 0 135.5-137 8 (ch2)2oc2h5C2H5 H 4 0 126-128 S (ch2)2oc2h5C2H5 H 4 s Oil 10 (ch2)2oc2h5C2H5 H 5 s 72-78 30 11 (ch2)2och3 ch3 H 4 0 151-153 12 (ch2)2och(ch3: >2 CH3 H 4 0 114-120 13 (CH2)20C2Hs ch3 H 4 0 140-147 •48497 Comp. R.R2 • R3 y X m.p.,4 aCH3 H 4 0 156-163 15 (CH2)20CH3 ch(ch3: l2 H 4 0 119 16 CH3C2H5 H 4 0 15917 C2H5C2H5 ch3 4 0 10618 C2H5C2H5 n-C3H7 4 0 99 The compounds of formula I exhibit pharmacological activity. In particular, they lead to a dilation of the coronary vessels as demonstrated by the results of tests measuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere method (Rudolph A.M. and Heymann N.S.: Circulation Research 2, 153, 1967) upon administration of from 30 to 50 jug/kg i.v. or of from 50 to '150 JJg/kg i.d. of the active substance.
The compounds of formula I also possess a favourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the active substance.
The compounds of formula I are therefore indicated for use in the treatment of coronary insufficiency.
The compounds of formula I increase the blood flow to limbs, e.g. leg musculature, as can be shown by means of the microsphere method on the anaesthetised cat upon administration of from 30 to 50 jug/kg i.v. or from 50 tc 150 ^-ig/kg i.d. of the compounds.
The compounds of formula I are therefore indicated for use in the treatment of intermittent claudication and other peripheral disturbances of blood flow to limb muscles. -9Tlit? compounds of formula I increase cerebral blood flow, as can be shown by means of the microsphere method on the anaesthetised cat upon administration of from 30 to 50 yjg/kg i.v. or from 50 to 150 yjg/k’g i.d. of the compounds.
The compounds of formula I are therefore indicated for use in the treatment of cerebrovascular insults.
The compounds of formula I possess calcium-antagonistic activity as indicated in standard tests, for example by an inhibition of a calcium induced contraction of isolated dog coronary arteries suspended in a depolarizing solution at concentration of 10 to 10 M of the compounds according to the principles of Godfraind and Kaba, Brit. J.Pharm. 35, 549-550, 1959.
The compounds of formula 1 are therefore indicated for use as spasmolytic agents for the treatment of spasms of muscles. For the above indication an indicated daily dose is from '5 to 100 mg, conVeliiiin'tTy admi'rfi'stered in divided doses 2 to 4 times a day in unit dsoage form containing from 1.25 mg to 50 rag, or in sustained release form.
Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollraan rate test [see A.Grollman,Proc.Soc.Expt. Biol.and Had. 57,104 (1944)] on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compounds.
The compounds of formula I are therefore further indicated for use as antihypertensive agents. For this use an indicated daily dose is from 5 to 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing 1.25 mg to 500 mg, or.in sustained release form. 49467 -10The compounds of formula I may be administered in the form of a pharmaceuti cal composition. The present invention accordingly provides a pharmaceutical composition compri-’ sing a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be formulated by conventional techniques to be in conventional forms, for example capsules or tablets.
Compounds 1, 5, 11, 12, 13, 14, 15, 16, 17 and 18 are particularly interesting. Compound 1 is especially interesting. The coronary insufficiency, the intermittent claudication, the cerebrovascular insufficiency and the spasmolytic activities are the preferred utilities for compounds of formula I.
Claims (21)
1. WHAT WE CLAIM IS: 1A compound of formula I wherein and X are as y indicates the ring position moi c ty : defined as follows, and of the dihydropyridine Compound 1 2 3 R 1 ch 3 CH, cX 2 o R 2 CH 2 CH(CH 3 ) 2 CH- C 2 H 5 R 3 H H H y 4 4 5 X 0 0 0 10 4 CH 2 CH(CH,) 2 c 2 h 5 H 4 s 5 ch 2 ch(ch‘ 3 ) 2 C 2 H 5 H 4 0 6 c.(ch 3 ) 3 ' C(Ch' 3 ) 3 H 4 0 7 CH 2 CH(CH 3 ) 2 ch 2 ch(ch 3 ) 2 H 4 0 8 (CH 2 ) C 2 H 5 H 4 0 15 9 (CH 2 ) 2 0C 2 H 5 C 2 H 5 H 4 s 10 (ch 2 ) 2 oc 2 k 5 C 2 H 5 H 5 s 11 (CH 2 ) 2 OCH, CH, H 4 0 12 (ch ? ) 2 och(ch 3 ; ) 2 CH 3 H 4 0 1 3 (CII ? ) 2 0C 2 H s ch 3 H 4 0 20 14 Q ch 3 H 4 0 15 (CH 2 ) 2 OCH 3 CH(CH 3 ) 2 H 4 0 16 ch 3 C 2 H 5 H 4 0 17 C 2 H 5 C 2 H 5 ch 3 4 0 18 C 2 H 5 C 2 H 5 n-C 3 H y 4 0
2. Compound 1, stated in claim 1. 5
3. Compound 2, stated i n cl aim 1.
4. Compound 3, stated i n claim 1.
5. Compound 4 , stated in claim 1.
6. Compound 5, stated i n claim 1.
7. Compound 6, stated i n claim 1. 10
8. Compound 7, stated i n claim 1.
9. Compound 8, stated in claim 1.
10.Compound 9, stated in claim 1.
11. Compound 10,sta ted in cl aim 1.
12.Compound 11,s ta ted i n claim 1. 15
13.Compound 12,stated in claim 1.
14.Compound 13,stated in claim 1.
15.Compound 14.stated in claim 1.
16.Compound 15.stated i n claim 1.
17.Compound 16, stated in claim 1. 20
18.Compound 17,stated i n claim 1.
19.Compound 18,stated in claim 1 .
20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19 in association with a pharmaceutical carrier or diluent.
21. A process for the production of a compound of formula I substantially as described herein by way of Example.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1283578A CH639659A5 (en) | 1978-12-18 | 1978-12-18 | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| IE2445/79A IE49496B1 (en) | 1978-12-18 | 1979-12-17 | A 1,4-dihydropyridine derivative,its preparation and pharmaceutical compositions containing it |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE831165L IE831165L (en) | 1980-06-18 |
| IE49497B1 true IE49497B1 (en) | 1985-10-16 |
Family
ID=25711093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1165/83A IE49497B1 (en) | 1978-12-18 | 1979-12-17 | 1,4-dihydropyridines,their preparation and pharmaceutical compositions containing them |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE49497B1 (en) |
-
1979
- 1979-12-17 IE IE1165/83A patent/IE49497B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE831165L (en) | 1980-06-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |