# US 4,400,381 A · Piperazine derivatives of theophylline > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,400,381 A - Document ID: US4400381A - Status: Granted - Kind: A - Application number: 06/288,836 - Filed: 1981-07-31 - Granted: 1983-08-23 - Earliest claimed: 1981-07-31 - Assignees: Laroche Navarron S.A. - Inventors: Colette Favier; Henri Pinhas; Serge Beranger; Jean-Claude Pascal - Web page: https://patentgrep.com/patent/US4400381A ## CPC - C07C 321/00: Thiols, sulfides, hydropolysulfides or polysulfides - C07D 473/06: with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 - C07D 473/08: with methyl radicals in positions 1 and 3, e.g. theophylline - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract New compounds of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein M is selected from the group consisting of hydrogen, morpholino, benzylamino, di-n-lower alkylamine, n-lower alkylamine, and aryl piperazino; Z.sub.1 and Z.sub.2 are each independently selected from the group consisting of CH.sub.2, CHOB and C.dbd.O, wherein B is selected from the group consisting of hydrogen and alkanoyl; Y is oxygen or sulfur; n is an integer from 0-4 but cannot be zero when Z.sub.1 is CHOB; m is an integer from 0-4 but cannot be zero when Z.sub.2 is CHOB, or when m is hydrogen; R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, halogen, hydroxy, trifluoromethyl, alkyl or alkoxy; and R.sub.4 and R.sub.5 are each independently lower alkyl, with the proviso that both R.sub.4 and R.sub.5 cannot be methyl when M is hydrogen; are antihistamines and are therefore useful in the treatment of respiratory diseases including asthma, hay fever, allergies and the common cold. They are also vasodilators. ## Claims ### Claim 1 A compound of the formula ##STR10## and the pharmaceutically acceptable acid addition salts thereof, wherein M is selected from the group consisting of hydrogen, morpholino, benzylamino, di-n-lower alkylamino, n-lower alkylamino, and ##STR11## wherein Ar is optionally substituted phenyl; Z.sub.1 and Z.sub.2 are each independently selected from the group consisting of CH.sub.2, CHOB and C.dbd.O, wherein B is selected from the group consisting of hydrogen and alkanoyl; Y is oxygen or sulfur; n is an integer from 0-4 but cannot be zero when Z.sub.1 is CHOB; m is an integer from 0-4 but cannot be zero when Z.sub.2 is CHOB, or when M is hydrogen; R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, halogen, hydroxy, trifluoromethyl, alkyl or alkoxy; and R.sub.4 and R.sub.5 are each independently lower alkyl, with the proviso that both R.sub.4 and R.sub.5 cannot be methyl when M is hydrogen. ### Claim 2 (depends on 1) The compound of claim 1 and the pharmaceutically acceptable acid addition salts thereof wherein Z.sub.1 and Z.sub.2 are each independently CH.sub.2 or CHOH; m and n are both 1; and at least one of R.sub.1, R.sub.2 and R.sub.3 is hydrogen. ### Claim 3 (depends on 2) The compound of claim 2 and the pharmaceutically acceptable acid addition salts thereof wherein either at least one of R.sub.4 and R.sub.5 is methyl, or both R.sub.4 and R.sub.5 are identical; and either at least two of R.sub.1, R.sub.2 and R.sub.3 are hydrogen or two of these are otherwise identical. ### Claim 4 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypro pyl]-4-(3-phenylthiopropyl)-piperazine. ### Claim 5 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-(3-(8-morpholino-3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl) -2-hydroxypropyl]-4-(3-phenylthiopropyl)piperazine. ### Claim 6 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypro pyl]-4-(3-phenoxypropyl)piperazine. ### Claim 7 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypro pyl]-4-(3-phenylthio-2-hydroxypropyl)piperazine. ### Claim 8 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypro pyl]-4-[3-(4-methylphenylthio)-propyl]piperazine. ### Claim 9 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-n-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypro pyl]-4-(3-phenylthiopropyl)-piperazine. ### Claim 10 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)propyl]-4-(3- phenoxypropyl)piperazine. ### Claim 11 (depends on 3) The compounds of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(8-morpholino-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hyd roxypropyl]-4-(3-phenylthiopropyl)piperazine. ### Claim 12 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(8-morpholino-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hyd roxypropyl]-4-[3-(4-methylphenylthiopropyl]piperazine; ### Claim 13 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(8-n-butylamino-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-h ydroxypropyl]-4-[3-(2,6-dimethylphenoxy)-propyl]piperazine. ### Claim 14 (depends on 3) The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof which is 1-[3-(8-morpholino-3-n-butyl-1-methyl-3,7-dihydro-1H-purine-2,6-dion-7-yl) -2-hydroxypropyl]-4-(3-phenylthiopropyl)piperazine. ### Claim 15 (depends on 1) A pharmaceutical composition for treating respiratory diseases or effecting vasodilation in mammals, which comprises a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable, non-toxic excipient. ### Claim 16 (depends on 1) A method for treating respiratory diseases in mammals, which method comprises administering to a subject in need of such treatment, an effective amount of, or a pharmaceutical composition containing an effective amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof. ### Claim 17 (depends on 1) A method for effecting vasodilation in human beings which method comprises administering to a subject in need of such treatment a therapeutically effective amount of, or a pharmaceutical composition containing a therapeutically effective amount of, the compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof.