# US 8,785,431 B2 · Prodrugs of (1S,9S)-9-[[(1S)-1-carboxy-3-phenylpropyl]amino]octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid and their use in transdermal therapeutic systems > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,431 B2 - Document ID: US8785431B2 - Status: Granted - Kind: B2 - Application number: 14/127,622 - Filed: 2012-06-20 - Published: 2014-05-29 - Granted: 2014-07-22 - Earliest claimed: 2011-06-22 - Assignees: Hexal AG - Applicants: Günther Bernhardt; Miriam Ertel; Armin Buschauer; Jörg Nink - Inventors: Günther Bernhardt; Miriam Ertel; Armin Buschauer; Jörg Nink - Web page: https://patentgrep.com/patent/US8785431B2 ## CPC - A61K 9/703: {characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches} - A61K 9/7053: {obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene} - A61K 9/7061: {Polyacrylates} - A61K 47/54: the modifying agent being an organic compound - A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)} - A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/12: Antihypertensives - C07D 487/04: Ortho-condensed systems - C07K 5/06017: {and aliphatic} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract The present invention relates to diester prodrugs of cilazaprilate which undergo enzymatic cleavage to release the active metabolite cilazaprilate that is used for the treatment of hypertension and congestive heart failure. Furthermore the diester prodrugs of cilazaprilate possess all the properties necessary to be topically administered, preferably via transdermal therapeutic systems. ## Claims ### Claim 1 A compound selected from the group consisting of: (1S,9S)-1-(ethoxycarbonyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; (1S,9S)-1-(cyclohexyloxycarbonyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; (1S,9S)-2-morpholinoethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; (1S,9S)-1-(isopropyloxycarbonyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; (1S,9S)-1-(acetoxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; (1S,9S)-1-(2,2-dimethylpropanoyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate; and (1S,9S)-1-(2-morpholinoacetoxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate. ### Claim 2 (depends on 1) A transdermal therapeutic system comprising at least one compound according to claim 1. ### Claim 3 (depends on 2) The transdermal therapeutic system according to claim 2, further comprising: a) at least one pressure sensitive adhesive, b) a backing layer, and c) a release liner. ### Claim 4 (depends on 3) The transdermal therapeutic system according to claim 3, wherein the compound is dissolved or suspended in the pressure sensitive adhesive(s). ### Claim 5 (depends on 3) The transdermal therapeutic system according to claim 3, wherein the pressure sensitive adhesive is present in at least one adhesive layer. ### Claim 6 (depends on 4) The transdermal therapeutic system according to claim 4, wherein the pressure sensitive adhesive is present in at least one adhesive layer. ### Claim 7 (depends on 1, 3) The transdermal therapeutic system according to claim 3, further comprising an adhesive layer which does not comprise the compound of claim 1. ### Claim 8 (depends on 1, 4) The transdermal therapeutic system according to claim 4, further comprising an adhesive layer which does not comprise the compound of claim 1. ### Claim 9 (depends on 1, 5) The transdermal therapeutic system according to claim 5, further comprising an adhesive layer which does not comprise the compound of claim 1. ### Claim 10 (depends on 5) The transdermal therapeutic system according to claim 5, wherein the at least one of the adhesive layer further comprises at least one penetration and/or permeation enhancer. ### Claim 11 (depends on 5) The transdermal therapeutic system according to claim 5, wherein the at least one of the adhesive layer further comprises at least one tackifier. ### Claim 12 (depends on 5) The transdermal therapeutic system according to claim 5, wherein the at least one of the adhesive layer further comprises at least one crystallization inhibitor. ### Claim 13 (depends on 3) The transdermal therapeutic system according to claim 3, wherein the pressure sensitive adhesive is silicon, polyacrylate and/or polyisobutylene based. ### Claim 14 (depends on 3) The transdermal therapeutic system according to claim 3, further comprising a coverpatch. ### Claim 15 (depends on 1) A method of treating hypertension and/or congestive heart failure comprising treating a patient with hypertension and/or congestive heart failure by applying a transdermal therapeutic system to the skin of the patient, wherein the transdermal therapeutic system comprises at least one compound according to claim 1. ### Claim 16 (depends on 15) The method according to claim 15, wherein the transdermal therapeutic system comprises: a) at least one pressure sensitive adhesive, b) a backing layer, and c) a release liner. ### Claim 17 (depends on 16) The method according to claim 16, wherein the compound is dissolved or suspended in the pressure sensitive adhesive(s). ### Claim 18 (depends on 17) The method according to claim 17, wherein the pressure sensitive adhesive is present in at least one adhesive layer. ### Claim 19 (depends on 1) A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound according to claim 1. ### Claim 20 (depends on 1) A method of treating hypertension and/or congestive heart failure comprising treating a patient with hypertension and/or congestive heart failure by delivering at least one compound according to claim 1 to the patient.