AT512084A1 - DIAZABICYCLO AND DIAZASPIRO ALKAN DERIVATIVES AS PHOSPHODIESTERASE-5 INHIBITORS - Google Patents
DIAZABICYCLO AND DIAZASPIRO ALKAN DERIVATIVES AS PHOSPHODIESTERASE-5 INHIBITORS Download PDFInfo
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- AT512084A1 AT512084A1 ATA1536/2011A AT15362011A AT512084A1 AT 512084 A1 AT512084 A1 AT 512084A1 AT 15362011 A AT15362011 A AT 15362011A AT 512084 A1 AT512084 A1 AT 512084A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Die vorliegende Erfindung beschreibt neue PDE5-Hemmer welche einen Diazabicyclo- bzw. Diazaspiro-alkanrest enthalten. Diese Diazabicyclo- bzw. Diazaspiro-alkanreste können als komformativ fixierte Piperazin-Analoga aufgefaßt werden, wobei einige dieser neuen Verbindungen beispielsweise im Vergleich zu Vardenafil und Sildenafil verbesserte Eigenschaften aufweisenThe present invention describes novel PDE5 inhibitors which contain a diazabicyclo or diazaspiroalkane radical. These diazabicyclo or diazaspiro-alkane radicals can be regarded as comformatively fixed piperazine analogs, some of these new compounds having improved properties, for example compared to vardenafil and sildenafil
Description
TU001AT «· t· ·· ···· ·*·TU001AT «· t · ·· ···· · * ·
Diazabicyclo- und Diazaspiro-Alkanderivate als Phosphodiesterase-5Diazabicyclo and diazaspiro-alkane derivatives as phosphodiesterase-5
Inhibitoreninhibitors
Zyklisches Guanosin 3',5-monophosphat (cGMP) bzw. zyklisches Adenosin 3\5'-monophosphat (cAMP) sind sekundäre Botenstoffe, die eine Vielzahl von essenziellen biologischen Prozessen regulieren, zu denen unter anderem kardiovaskuläre Muskelaktivität, Genexpression, Neurotransmission und hormonale Sekretionen zählen. Die Familie der zyklischen Nukleotid Phosphodiesterasen (PDEs) katalysieren die Hydrolyse dieser zyklischen Nukleotide zu den entsprechenden 5' Monophosphaten und deaktivieren dabei die Signaltransmission.Cyclic guanosine 3 ', 5-monophosphate (cGMP) and cyclic adenosine 3'5'-monophosphate (cAMP) are secondary messengers that regulate a variety of essential biological processes, including cardiovascular muscle activity, gene expression, neurotransmission, and hormonal secretions counting. The family of cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of these cyclic nucleotides to the corresponding 5 'monophosphates, thereby deactivating signal transduction.
Innerhalb der zahlreichen bekannten PDE Subtypen, stellt der cGMP spezifische Subtyp 5 (PDE5) ein prominentes pharmazeutisches Target dar. PDE5 ist in vaskulären glatten Muskelzellen stark expremiert und zeigt eine regiospezifische Verteilung und hat somit eine wesentliche Bedeutung in der Beeinflussung des Tonus der glatten Muskulatur und des Blutflusses. Pharmazeutika, die als selektive PDE5-Hemmer wirken, inkludieren Sildenafil (US5250534) und Vardenafil (W099/24433) und stellen wichtige Wirkstoffe zur Behandlung der erektilen Dysfunktion und gewisser Formen der pulmonalen Hypertonie dar.Within the many known PDE subtypes, the cGMP specific subtype 5 (PDE5) represents a prominent pharmaceutical target. PDE5 is highly expressed in vascular smooth muscle cells and exhibits a regiospecific distribution and thus has a significant impact on the smooth muscle tone and tone of blood flow. Pharmaceuticals that act as selective PDE5 inhibitors include sildenafil (US5250534) and vardenafil (WO99 / 24433) and are important drugs for the treatment of erectile dysfunction and some forms of pulmonary hypertension.
Vardenafil (Levitra) Sildenafil (Viagra)Vardenafil (Levitra) Sildenafil (Viagra)
Eine große Anzahl von Beschwerden steht unter dem Einfluss der Signalübertragung von cGMP, und eine Behandlung mit PDE5 Inhibitoren wurde für viele dieser Beschwerden beansprucht.A large number of complaints are under the influence of cGMP signaling and treatment with PDE5 inhibitors has been claimed for many of these conditions.
Die internationalen Patentanmeldungen WO94/28902 und W099/24433 offenbaren PDE5 Inhibitoren zur Behandlung der männlichen erektilen DysfunktionInternational patent applications WO94 / 28902 and WO99 / 24433 disclose PDE5 inhibitors for the treatment of male erectile dysfunction
TU001AT • · ·♦···· · · « « « « » · f · · · *·** ·· ···· ·«· und weiblicher Sexuaistörungen. WO99/02161 offenbart PDE5 Inhibitoren zur Behandlung von Prostatakrankheiten. W002/40027 beansprucht PDE5 Inhibitoren für die Behandlung vorzeitiger Ejakulation in Patienten mit normaler erektiler Funktion.TU001AT • · · · · ··································································································. WO99 / 02161 discloses PDE5 inhibitors for the treatment of prostate diseases. W002 / 40027 claims PDE5 inhibitors for the treatment of premature ejaculation in patients with normal erectile function.
Das EP1097911 offenbart die Verwendung von PDE5 Inhibitoren zur Behandlung von pulmonaler Hypertonie. Prasad et al. {New Engl J Med2000; 343: 1342) postulieren die Anwendbarkeit von Sildenafil in primärer (idiopathischer) pulmonaler Hypertonie. Des Weiteren beschreiben Ghofrani et al. {Lancet 2002; 360: 895) Effekte einer Sildenafiltherapie bei Patienten mit pulmonaler Hypertonie bei Lungenfibrose. W003/101276 offenbart die Anwendbarkeit von PDE5 Inhibitoren zur Verhinderung oder Limitierung von Verletzungen bei myokardischer Ischemia und Reperfusion bei Herzoperationen. WO02/13798 zeigt eine Methode zur Behandlung des insulinresistenz-syndroms mit PDE5 Hemmern auf. W002/60422 beansprucht Vardenafil für die Behandlung von Diabetes mellitus. W02007/010337 offenbart PDE5 Inhibitoren zur Prävention oder Behandlung von Adipositas. W001/51042 beansprucht PDE5 Inhibitoren für diabetischen Ulzera. Desweiteren beschreibt WO02/15893 die Behandlung von chronischen venösen Ulzera, Dekubitus und akuten Wunden. WO03/063875 beansprucht PDE5 Hemmer zur Behandlung oder Prävention von Narbenbildung oder Fibrose. W003/066061 beansprucht die Verwendung von Pyrazolopyrimidinon PDE5 Inhibitoren für die Behandlung von polyzystischem Ovarialsyndrom. W02006/091542 zeigt, dass die selektive Steigerung der Durchlässigkeit der Blut-Hirn-Schranke durch Verabreichung von PDE5 Hemmern eine gezielte Zufuhr von Therapeutika zu anormalem Hirngewebe wie etwa Hirntumor ermöglicht.EP1097911 discloses the use of PDE5 inhibitors for the treatment of pulmonary hypertension. Prasad et al. {New Engl J Med2000; 343: 1342) postulate the applicability of sildenafil in primary (idiopathic) pulmonary hypertension. Furthermore, Ghofrani et al. {Lancet 2002; 360: 895) Effects of sildenafil therapy in patients with pulmonary hypertension in pulmonary fibrosis. W003 / 101276 discloses the applicability of PDE5 inhibitors to prevent or limit injury in myocardial ischemia and reperfusion in cardiac surgery. WO02 / 13798 discloses a method of treating insulin resistance syndrome with PDE5 inhibitors. W002 / 60422 claims vardenafil for the treatment of diabetes mellitus. W02007 / 010337 discloses PDE5 inhibitors for the prevention or treatment of obesity. W001 / 51042 claims PDE5 inhibitors for diabetic ulcers. Furthermore, WO02 / 15893 describes the treatment of chronic venous ulcers, pressure ulcers and acute wounds. WO03 / 063875 claims PDE5 inhibitors for the treatment or prevention of scarring or fibrosis. W003 / 066061 claims the use of pyrazolopyrimidinone PDE5 inhibitors for the treatment of polycystic ovarian syndrome. W02006 / 091542 shows that the selective enhancement of blood-brain barrier permeability by administration of PDE5 inhibitors allows targeted delivery of therapeutics to abnormal brain tissue such as brain tumor.
TU001AT *.·"-3-ϊ· Μ »· ···· ΜΙ W02006/112973 zeigt eine effektive Behandlung von Schizophrenie und verwandten psychischen Störungen mit PDE5 Inhibitoren, die in das zentrale Nervensystem eindringen. W02006/180088 beansprucht PDE5 Hemmer zur Prävention und Behandlung von Hypopigmentierungsstörungen wie Vitiligo (erworbene Depigmentierung der Epidermis). W02009/067273 zeigt den Nutzen von PDE5 zur Behandlung von Arthrose-bedingten Schmerzen. WO 2005/089766 zeigt die Anwendung von PDE5-Hemmern bei Krankheiten welche im Zusammenhang mit zerebrale vaskuläre Reaktivität stehen. Des Weiteren wird die Anwendung von PDE5-Hemmern bei multipler Sklerose sowie die neuroprotektive Wirkung im Zusammenhang von Gehirnschlag und Alzheimer beschrieben (Pifarre, Paula; et al., Acta Neuropathologica (2011), 121(4), 499-508.)TU001AT *. * W02006 / 112973 shows effective treatment of schizophrenia and related mental disorders with PDE5 inhibitors that invade the central nervous system. W02006 / 180088 claims PDE5 inhibitors for the prevention and treatment of hypopigmentive disorders such as vitiligo (acquired depigmentation of the epidermis). W02009 / 067273 shows the benefit of PDE5 for the treatment of arthritis-related pain. WO 2005/089766 shows the use of PDE5 inhibitors in diseases associated with cerebral vascular reactivity. Furthermore, the use of PDE5 inhibitors in multiple sclerosis and the neuroprotective effect associated with stroke and Alzheimer's are described (Pifarre, Paula, et al., Acta Neuropathologica (2011), 121 (4), 499-508.)
Dieser große Bereich an Forschung und Entwicklung indiziert das profunde therapeutische Interesse an PDE5 Inhibitoren. Jedoch der Schwerpunkt dieser Aktivitäten lag mehr auf neuen Anwendungen und neuen Darreichungsformen als an neuen Verbindungen. Somit bleibt ein ausgesprochener Bedarf an neuen PDE5 Hemmern, welche die Eigenschaften von bekannten PDE5 Hemmern wie Sildenafil und Vardenafil verbessern.This large area of research and development indicates the profound therapeutic interest in PDE5 inhibitors. However, the focus of these activities has been more on new applications and new forms of administration than on new compounds. Thus, there remains a pronounced need for new PDE5 inhibitors which enhance the properties of known PDE5 inhibitors such as sildenafil and vardenafil.
Einige Analoga von Sildenafil und Vardenafil sind bereits bekannt. Dazu gehören Prodrugs wie Sildenafil N-oxid (W02009/000798) oder Metaboliten wie Norsildenafil (WOOO/44363). Weiters wurden Sildenafil Analoga beschrieben, in den statt eines Phenylringes ein Benzopyran oder 1,3-Benzodioxol vorkommt (Kim et al., Bioorg Med Chem 2001; 9:1609-1616) sowie Sildenafil Analoga mit kurzen Alkyl Substituenten am Phenylrest (Paramashivappa et al., J Arie Food Chem 2002; 50: 7709-13). Struktur-Aktivitätsbeziehungen wurden auf Basis dieser und anderer chemischer Modifikationen vorgeschlagen (interalia, Yoo et al., Bioorg Med Chem LeU. 2007; 17(15): 4271-4; Flores Toque et al., J Med Chem. 2008; 51(9): 2807-15; Erös et al., Curr Med Chem 2008; 15: 1570-85). Jedoch enthalten keine derSome analogues of sildenafil and vardenafil are already known. These include prodrugs such as Sildenafil N-oxide (W02009 / 000798) or metabolites such as Norsildenafil (WOOO / 44363). Furthermore, sildenafil analogues have been described in which instead of a phenyl ring a benzopyran or 1,3-benzodioxole occurs (Kim et al., Bioorg Med Chem 2001, 9: 1609-1616) and sildenafil analogues with short alkyl substituents on the phenyl radical (Paramashivappa et al , J Arie Food Chem 2002; 50: 7709-13). Structure-activity relationships have been proposed based on these and other chemical modifications (Interalia, Yoo et al., Bioorg Med Chem LeU., 2007; 17 (15): 4271-4; Flores Toque et al., J. Med. Chem. 2008; 51 (51). 9): 2807-15, Erös et al., Curr Med Chem 2008; 15: 1570-85). However, none of them contain
TU001ATTU001AT
• · i«t • *• i * t • *
beschriebenen Analoga solche Modifikationen, in denen die Piperazin-Substruktur, welche für Sildenafil und Vardenafil charakteristisch ist, überbrückt ist.analogs described those modifications in which the piperazine substructure, which is characteristic of sildenafil and vardenafil bridged.
Kurze Beschreibung der Erfindung 5 Die vorliegende Erfindung beschreibt neue PDE5-Hemmer welche einenBrief Description of the Invention The present invention describes novel PDE5 inhibitors which have a
Diazabicyclo- bzw. Diazaspiro-alkanrest enthalten. Diese Diazabicyclo- bzw. Diazaspiro-alkanreste können als komformativ fixierte Piperazin-Analoga aufgefaßt werden, wobei überaschenderweise gefunden wurde, dass einige dieser neuen Verbindungen z.B. im Vergleich zu Vardenafil und Sildenafil verbesserte 10 Eigenschaften besitzen.Diazabicyclo- or diazaspiro-alkane contain. These diazabicyclo- or diazaspiro-alkane radicals can be regarded as comformatively fixed piperazine analogs, it being surprisingly found that some of these new compounds are e.g. compared to vardenafil and sildenafil have improved 10 properties.
Ausführliche Beschreibung der ErfindungDetailed description of the invention
Die vorliegende Erfindung betrifft Verbindungen der allgemeinen Formel (I)The present invention relates to compounds of the general formula (I)
XX
(l) 15 worin A ein bicyclischer Heterozyklus, und X O oder S, und R2 und R3 jeweils unabhängig voneinander von H, Ci^Alkyl, C7-ioAralkyl oder Ce-ioHeteroaralkyl, und 20 R1 ein Rest der Formel (II),(l) where A is a bicyclic heterocycle, and X is O or S, and R 2 and R 3 are each independently of H, C 1-4 alkyl, C 7-10 aralkyl or ceto-heteroaralkyl, and R 20 is a radical of formula (II)
Y C oder N, und R4 Ci.sAlkyl oder Ci-4Alkoxyalkyl, undY is C or N, and R4 is Ci.sAlkyl or Ci-4Alkoxyalkyl, and
TU001ATTU001AT
B bicyclisches oder spiro-Heterocycloalkyl und R5 Ci_sAlkyl oder C7-ioAralkyl bedeuten, gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze.B bicyclic or spiro-heterocycloalkyl and R5 Ci_sAlkyl or C7-ioAralkyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
Ein Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei A ausgewählt ist aus der Gruppe bestehend aus:One aspect of the invention are compounds of the general formula (I) wherein A is selected from the group consisting of:
R3 und R1, R2, R3 und X wie vorstehend definiert sind.R3 and R1, R2, R3 and X are as defined above.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei R2 Methyl und R3 Propyl bedeuten.Another aspect of the invention are compounds of general formula (I) wherein R 2 is methyl and R 3 is propyl.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei X O bedeutet.Another aspect of the invention are compounds of general formula (I) wherein X is O.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei B einen Diazabicyclo- oder Diazaspiroring darstellt.Another aspect of the invention are compounds of the general formula (I) wherein B represents a diazabicyclo or diazaspiroring.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei R4 Ethyl oder Methoxypropyl bedeutet.Another aspect of the invention are compounds of the general formula (I) wherein R4 is ethyl or methoxypropyl.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), wobei Y C bedeutet.Another aspect of the invention are compounds of the general formula (I) wherein Y is C.
TU001ATTU001AT
»« *·»« *
Ein weiterer Aspekt der Erfindung sind Verbindungen ausgewählt aus der Gruppe bestehend ausAnother aspect of the invention are compounds selected from the group consisting of
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel 5 (I), oder deren pharmazeutisch wirksamen Salze, zur Verwendung als Arzneimittel.Another aspect of the invention are compounds of general formula 5 (I), or their pharmaceutically active salts, for use as pharmaceuticals.
TU001ATTU001AT
• · ♦ ··• · ♦ ··
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I), oder deren pharmazeutisch wirksamen Salze, zur Verwendung als Arzneimittel mit PDE5 inhibierender Wirkung.A further aspect of the invention are compounds of the general formula (I), or their pharmaceutically active salts, for use as medicaments with PDE5-inhibiting activity.
Ein weiterer Aspekt der Erfindung sind pharmazeutische Zubereitungen, enthaltend eine oder mehrere Verbindungen der allgemeinen Formel (I) oder deren pharmazeutisch wirksamen Salze gegebenenfalls in Kombination mit üblichen Hilfs-und/oder T rägerstoffen.A further aspect of the invention are pharmaceutical preparations comprising one or more compounds of the general formula (I) or their pharmaceutically active salts, optionally in combination with customary auxiliaries and / or carriers.
Ein weiterer Aspekt der Erfindung sind Verbindungen der allgemeinen Formel (I) zur Verwendung in der Behandlung und/oder Prävention von männlichen Erektionsstörungen oder vorzeitiger Ejakulation, weiblicher sexueller Dysfunktion, Frühgeburten, Dysmenorrhö , gutartige Hyperplasie der Prostata, Blasenentleerungsstörung, Inkontinenz, instabiler und Variant-(Prinzmetal-)Angina, Bluthochdruck, pulmonale Hypertonie, kongestivem Herzversagen, Atherosklerose, ischämischen Schlaganfall, peripher arteriosklerotische Gefäßerkrankung, Zuständen einer verringerten Durchgängigkeit der Blutgefäße, chronischem Asthma, Bronchitis, allergischem Asthma, allergischer Rhinitis,, Glaukom, retinale mikrovaskuläre Erkrankung, Schmerzen, die von degenerativen Gelenkerkrankungen, Krankheiten, die durch Störungen der Darmmotilität gekennzeichnet, Depigmentierungsstörungen der Haut, Schizophrenie, Zuständen, die die vorübergehende Öffnung der Blut-Hirn-Schranke erfordern, gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmazeutisch wirksamen Salze.A further aspect of the invention are compounds of general formula (I) for use in the treatment and / or prevention of male erectile dysfunction or premature ejaculation, female sexual dysfunction, prematurity, dysmenorrhea, benign prostate hyperplasia, bladder dysfunction, incontinence, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, ischemic stroke, peripheral arteriosclerotic vascular disease, conditions of decreased patency of the blood vessels, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, retinal microvascular disease, pain, those characterized by degenerative joint diseases, diseases characterized by disorders of intestinal motility, depigmentation disorders of the skin, schizophrenia, conditions requiring the temporary opening of the blood-brain barrier, possibly in For m their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmaceutically active salts.
Ein weiterer Aspekt der Erfindung ist eine pharmazeutische Präparation umfassend eine Verbindung der allgemeinen Formel (I) und mindestens eine weitere, von Formel (t) verschiedene Wirksubstanz, gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmazeutisch wirksamen Salze.A further aspect of the invention is a pharmaceutical preparation comprising a compound of the general formula (I) and at least one other active substance other than formula (t), optionally in the form of its tautomers, its racemates, its enantiomers, its diastereomers and their mixtures, and optionally their pharmaceutically active salts.
Ein weiterer Aspekt der Erfindung umfasst ein Verfahren zur Herstellung einer Verbindung der allgemeinen Formel (I), dadurch gekennzeichnet, dass eineAnother aspect of the invention comprises a process for the preparation of a compound of general formula (I), characterized in that a
TU001AT « ft • ft *»· *· * ft ft* ·TU001AT «ft • ft *» · * · * ft ft * ·
Verbindung der allgemeinen Fornriel (VI) mit einer Verbindung der allgmeinen Formel III zu einer Verbindung der allgmeinen Formel II umgesetzt wird, wobei die A, B, R4 und R5 die die in den Ansprüchen 1 bis 7 angegebenen Bedeutung aufweisen.Compound of general Fornriel (VI) is reacted with a compound of the general formula III to a compound of the general formula II, wherein the A, B, R4 and R5 have the meaning given in claims 1 to 7.
Definitionendefinitions
Ci-6-Alkyl bezeichnet einen unverzweigten oder verzweigten Kohlenstoffrest mit 1 bis 6 Kohlenstoffen. Beispiele für Alkyl umfassen, sind jedoch nicht beschränkt auf Methyl, Ethyl, Propyl (einschließlich n-Propyl und Isopropyl), Butyl (einschließlich n-Butyl, Isobutyl, sek.-Butyl und t-Butyl), Pentyl (einschließlich n-Pentyl und Isoamyl), Hexyl, und dergleichen.Ci-6-alkyl denotes a straight or branched carbon radical having 1 to 6 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and t-butyl), pentyl (including n-pentyl and Isoamyl), hexyl, and the like.
Ci-4-Alkoxy bezeichnet einen Alkylrest, wie er vorstehend definiert ist, der direkt an ein Sauerstoffatom gebunden ist (d. h. -OCi^-Alkyl). Beispiele umfassen Methoxy, Ethoxy, n-Propoxy, Isopropoxy, n-Butoxy, t-Butoxy, Isobutoxy, sec-Butoxy und dergleichen.Ci-4-Alkoxy refers to an alkyl radical as defined above which is bonded directly to an oxygen atom (i.e., -OCi ^ -alkyl). Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, sec-butoxy, and the like.
Aralkyl umfasst eine nicht-zyklische Alkylgruppe, in der ein an einem Kohlenstoffatom gebundenes Wasserstoffatom durch eine Arylgruppe ersetzt ist, wie beispielsweise Benzyl, Diphenylmethyl, Triphenylmethyl, Phenethyl, Diphenethyl und dergleichen.Aralkyl includes a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom is replaced by an aryl group, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, diphenethyl and the like.
Heteroaralkyl umfasst eine nicht-zyklische Alkylgruppe, in der ein an einem Kohlenstoffatom gebundenes Wasserstoffatom durch eine Arylgruppe ersetzt ist, wobei die Arylgruppe ein oder mehrere Heteroatome enthält.Heteroaralkyl includes a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom is replaced by an aryl group, wherein the aryl group contains one or more heteroatoms.
Heterocycloalkyl bezieht sich auf 7-11 Kohlenstoffatome umfassende gesättigte bizyklische, überbrückte oder spiro-Ringsysteme, welche anstelle von zwei Kohlenstoffatomen zwei Stickstoffatome enthalten. Bevorzugt liegen zwischen den beiden Stickstoffatomen jeweils mindestens zwei Kohlenstoffatome. Beispiele für solche bicyclischen, überbrückten oder spiro-Heterocycloalkylreste sind:Heterocycloalkyl refers to saturated bicyclic, bridged or spiro ring systems containing 7-11 carbon atoms which contain two nitrogen atoms instead of two carbon atoms. Preferably, in each case at least two carbon atoms are located between the two nitrogen atoms. Examples of such bicyclic, bridged or spiro-heterocycloalkyl radicals are:
TU001AT * * · · t ·TU001AT * * · · t ·
Diazabicydo- uid DiazasprofieplBneH JL H N-Diazabicydo- uid DiazasprofieplBneH JL H N-
NHNH
''Ν'' H'' Ν '' H
lQ hnOOlQ hnOO
DiazabicyclD- uid Diazaspüo-octaneDiazabicyclD-uid Diazaspüo-octane
-ec- -οό 6^ d^t» öo-ec- -οό 6 ^ d ^ t »öo
Diazabicyclo-indDlazaspininonaneDiazabicyclo-indDlazaspininonane
Weitere Diazabicydo- iml DjazasproalraneOther diazabicydo-iml Djazasproalrane
TU001AT ·· · «· ·« 99 ♦ • « ·· · · * · 9 *9 • ψ 99· 999 9 9 9 9 9 · 9 9 • a « ·* · * · 99 -PW* ·· ·« ♦·♦· ·♦·TU001AT ··· «« «99 ♦ •« ·································································································································································································································· ♦ · ♦ · · ♦ ·
In einer Ausführungsform umfasst die Erfindung PDE5-Hemmer, welche einen Diazabicyclo- bzw. Diazaspiro-alkanrest enthalten sowie deren pharmazeutisch akzeptablen Salze und polymorphen Formen. 5 Pharmazeutisch akzeptable Salze der von der Erfindung beanspruchten Ver bindungen umfassen z.B. nicht-toxische Salze mit anorganischen Säuren wie z. B. Chlorwasserstoff-, Bromwasserstoff-, Jodwasserstoff-, Schwefel-, Salpeter- und Phosphorsäure, sowie mit Carbonsäuren oder anorganischen oder organischen Sulfonsäuren. Nicht einschränkende Beispiele für die letzterwähnten Klassen von 10 Salzen umfassen Acetat-, Benzoat-, Succinat-, Saccharat-, Fumarat-, Maleat-, Lactat-, Citrat-, Tartrat-, Gluconat-, Kampfersulfonat-, Methansulfonat-, Ethansulfonat-, Benzolsulfonat-, Tosylat-, Phenylsulfonat-, Napthalinsulfonat-, Sulfamat- und Pamoat-Salze. Weitere nicht-limitierende Beispiele umfassen Ascorbat-, Carbonat-, 2-Hydroxy-1,2,3-propantricarboxylat sowie Salze von W,W-Bis(carboxymethyl)-glycin. Weitere 15 pharmazeutisch akzeptable Salze stellen z. B. Ammoniumsalze dar, oder Salze, welche von den erfindungsgemäßen Verbindungen mit quartären Ammoniumsalzen wie z. B. 2-Hydroxy-W,W, W-trimethylethanaminiurn oder analogen Verbindungen des Ethylamins, Di-oder Triethylamins, Di- oderTriethanolamins , Dicyclohexylamin, Dimethylaminoethanol, Arginin, Lysin, Ethylenediamin oder 2-Phenylethylamin gebildet 20 werden. Nicht-toxische Alkali- oder Erdalkali-Metallsalze der erfindungsgemäßen Verbindungen, wie z. B, Natrium, Kalium, Aluminium, Calcium, Magnesium oder Zink werden ebenfalls durch diese Erfindung umfasst.In one embodiment, the invention encompasses PDE5 inhibitors containing a diazabicyclo or diazaspiroalkane moiety, as well as their pharmaceutically acceptable salts and polymorphic forms. Pharmaceutically acceptable salts of the compounds claimed by the invention include e.g. non-toxic salts with inorganic acids such. As hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, and with carboxylic acids or inorganic or organic sulfonic acids. Non-limiting examples of the last-mentioned classes of salts include acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camphorsulfonate, methanesulfonate, ethanesulfonate, Benzenesulfonate, tosylate, phenylsulfonate, naphthalenesulfonate, sulfamate and pamoate salts. Other non-limiting examples include ascorbate, carbonate, 2-hydroxy-1,2,3-propane tricarboxylate and salts of W, W-bis (carboxymethyl) glycine. Another 15 pharmaceutically acceptable salts provide z. For example, ammonium salts, or salts, which of the compounds of the invention with quaternary ammonium salts such. B. 2-hydroxy-W, W, W-trimethylethanaminiurn or analogous compounds of ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine are formed. Non-toxic alkali or alkaline earth metal salts of the compounds of the invention, such as. B, sodium, potassium, aluminum, calcium, magnesium or zinc are also encompassed by this invention.
Polymorphe Formen von Salzen der erfindungsgemäßen Verbindungen 25 inkludieren amorphe und kristalline Formen (unterschieden durch unterschiedliche Anordnung und/oder Konformationen der Moleküle im Kristallgitter) sowie Hydrat- und Solvatformen. Solvate sind Kristallformen, die entweder stöchiometrische oder nichtstöchiometrische Mengen eines Lösungsmittels enthalten. Handelt es sich bei dem eingelagerten Lösungsmittel um Wasser, so spricht man von Hydraten. 30 Für den Fachmann ist es klar, dass die Gesamtzahl der Wasserstoffatome in einer beliebigen erfindungsgemäßen Verbindung eine natürlich vorkommende Verteilung von Wasserstoffisotopen enthält. Die überwiegende Mehrzahl (>99.98%) der Wasserstoffisotope besteht aus 1H, ca. 0.015% bestehen aus dem stabilen IsotopPolymorphic forms of salts of the compounds of the invention include amorphous and crystalline forms (distinguished by different arrangement and / or conformations of the molecules in the crystal lattice) as well as hydrate and solvate forms. Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the stored solvent is water, it is called hydrates. It will be clear to those skilled in the art that the total number of hydrogen atoms in any compound of the invention will contain a naturally occurring distribution of hydrogen isotopes. The vast majority (> 99.98%) of the hydrogen isotopes consists of 1H, about 0.015% consist of the stable isotope
TU001AT #« · #· * * Μ * « * «t · · · · »«* I f ··*·** t · « · » * · « * • « j * · ·· i · · «· «pf·* ·· ** ···* ·** 2H (Deuterium) und ein extrem kleine Rest besteht aus radioaktivem 3H (Tritium). Dem Fachmann ist klar, dass dieses natürliche Isotopenverhältnis künstlich verändert werden kann und die so hergestellten isotopisch-analogen Verbindungen subtil veränderte pharmakokinetische Eigenschaften besitzen bzw. radioaktive Verbindungen 5 darstellen, deren pharmazeutische Eigenschaften jenen der Mutterverbindungen stark ähneln. Solche deuterierten oder tritiierten Varianten der erfindungsgemäßen Verbindungen und deren pharmazeutisch akzeptable Derivate, Salze oder Kombinationen davon sind auch von der Erfindung mitumfasst. 10 In einer weiteren Ausführungsform umfasst die Erfindung überbrückte diazaheterozyclische Analoga von Sildenafil und Vardenafil entsprechend der allgemeinen Formel (I) sowie deren pharmazeutisch akzeptablen Salze und polymorphen Formen welche optional ein oder mehrere zusätzliche Therapeutika enthalten, mit optional einer oder mehreren zusätzlichen Verbindungen, welche im 15 Allgemeinen als sichere und pharmazeutisch akzeptable Trägerstoffe gelten.TU001AT # «* # * * * Μ *« * «t · · · · ·« * * f * * * * t * «*» «* *« j * · · · i · · «· «Pf · * ·· ** ··· * · ** 2H (deuterium) and an extremely small remainder consists of radioactive 3H (tritium). It is clear to the person skilled in the art that this natural isotope ratio can be artificially changed and the isotopically analogous compounds thus produced have subtly altered pharmacokinetic properties or represent radioactive compounds 5 whose pharmaceutical properties closely resemble those of the parent compounds. Such deuterated or tritiated variants of the compounds of the invention and their pharmaceutically acceptable derivatives, salts or combinations thereof are also encompassed by the invention. In a further embodiment, the invention encompasses bridged diazaheterocyclic analogs of sildenafil and vardenafil according to general formula (I) and their pharmaceutically acceptable salts and polymorphic forms which optionally contain one or more additional therapeutics, optionally with one or more additional compounds which are described in the 15th Generally considered to be safe and pharmaceutically acceptable excipients.
Der Begriff „pharmazeutisch akzeptabler TrägerstofT bezieht sich auf ein Material, Zusammensetzung oder Trägersubstanz wie z. B. Flüssigkeit, festem Füllstoff, Verdünnungsmittel, Arzneistoffträger, Lösungsmittel oder Einkapselungs-20 material, welches mit den anderen Inhaltsstoffen einer pharmazeutischen Formulierung verträglich ist. Es darf auch im Kontakt mit menschlichem oder Säugetiergewebe keine exzessiven (einer vernünftigen Nutzen/Risiko Abwägung angemessen), Toxizitäten, Irritationen, allergische Reaktionen, Immunogenität oder andere medizinische Probleme oder Komplikationen hervorrufen. Der Begriff “allgemein als 25 ausreichend sicher” (“generally regarded as safe”, GRAS) bezieht sich auf Additive, welche sich aus langer Erfahrung für den menschlichen Verzehr eignen und welche in von der U.S. Food and Drug Administration aktuell gehaltenen Listen angeführt sind (siehe http://www.fda.aov/Food/FoodlnaredientsPackaaina/Generallv RecoanizedasSafeGRAS/GRASSubstancesSCQGSDatabase/ucm084104.htm).The term "pharmaceutically acceptable carrier" refers to a material, composition or carrier such as, for example, Liquid, solid filler, diluent, excipient, solvent or encapsulating material which is compatible with the other ingredients of a pharmaceutical formulation. It must not cause excessive (appropriate for reasonable benefit / risk consideration), toxicities, irritations, allergic reactions, immunogenicity or other medical problems or complications, even when in contact with human or mammalian tissue. The term "generally regarded as safe" (GRAS) refers to additives which are of long experience for human consumption and which are described in U.S. Pat. Food and Drug Administration lists are currently listed (see http://www.fda.aov/Food/FoodlnaredientsPackaaina/Generallv RecoanizedasSafeGRAS / GRASSubstancesSCQGSDatabase / ucm084104.htm).
Pharmazeutisch akzeptable Trägersubstanzen im Zusammenhang mit dieser Erfindung umfassen auch dauerhafte oder entfembare implantierbare Medizinprodukte, welche mit den erfindungsgemäßen Verbindungen beschickt werden oder 30Pharmaceutically acceptable carriers in the context of this invention also include durable or removable implantable medical devices that are loaded with the compounds of the present invention
TU001AT « · · ·· »« M t • f #t · · Φ · ··«TU001AT «· · ··» «M t • f #t · · Φ · ··«
I I ·*···· « V • t > · · · t • · Ar· · ·· ♦ ♦ · M - ·· *· ···« auf welche diese über eine Oberflächenfixierung zur langsamen oder verzögerten Freisetzung aufgetragen werden.I I · * ···· «V • t > These are applied via a surface fixation for slow or delayed release.
Solche Medizinprodukte können fest (z. B. vaskuläre oder urethrale Stents, Katheder und Transplantate), halbfest oder gelatinös, optional resorbierbare biokompatible polymere Matrixeinlagen sein, welche entweder für die Einbringung in den Körper vorgeformt oder per Injektion subdermal, submucosal, subretinal, intravitreal, intramuskulär, oder intracerebroventriculär verabreicht werden.Such medical devices may be solid (eg, vascular or urethral stents, catheters, and grafts), semi-solid or gelatinous, optionally resorbable biocompatible polymeric matrix inserts, preformed either for injection into the body or injected subdermally, submucosal, subretinal, intravitreal, by injection. be administered intramuscularly, or intracerebroventricularly.
Erfindungsgemäße pharmazeutische Darreichungsformen können auch die Form von flüssigen (Lösungen, Suspensionen, Emulsionen), halbfesten (Cremen, Salben, Gelen) oder festen Präparaten (Tabletten, Pillen, Kapseln, Lutschtabletten, Suppositorien) haben oder in Form von dispergierbaren Feststoffen (Puder) vorliegen. Diese Darreichungsformen können mittels Methoden, welche auf dem Gebiet der Pharmazie gut etabliert und dokumentiert sind, wie z. B. beschrieben in Remington: The Science and Practice of Pharmacy (ed. A. R.Gennard., 20th Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000), hergestellt werden.Pharmaceutical dosage forms according to the invention may also be in the form of liquid (solutions, suspensions, emulsions), semi-solid (creams, ointments, gels) or solid preparations (tablets, pills, capsules, lozenges, suppositories) or in the form of dispersible solids (powders) , These dosage forms can be prepared by methods that are well established and documented in the field of pharmacy, such. As described in Remington: The Science and Practice of Pharmacy (Ed., A.R.Gennard., 20th Edition, Baltimore, MD: Lippincott Williams & Wilkins, 2000).
In einerweiteren Ausführungsform beinhaltet die Erfindung Methoden zur Behandlung von solchen Zuständen, von denen bekannt ist, dass sie durch die Inhibierung der Phosphodiestrase 5 verbessert werden können, indem eine therapeutische Menge eines überbrückten diazaheterozyclischen Analogons von Sildenafil und Vardenafil entsprechend der allgemeinen Formel (I) oder pharmazeutisch akzeptablen Salzen, Hydraten oder Solvaten dargereicht wird. Die erfindungsgemäßen Behandlungsmethoden umfassen die Herstellung des Kontaks des Säugetieres (inklusive des Menschen) mit einer definierten Menge von einer oder mehreren erfindungsgemäßen Verbindungen.In another embodiment, the invention includes methods of treating such conditions which are known to be improved by the inhibition of phosphodiesterase 5 by providing a therapeutic amount of a bridged diazaheterocyclic analog of sildenafil and vardenafil corresponding to general formula (I) or pharmaceutically acceptable salts, hydrates or solvates. The treatment methods according to the invention comprise the preparation of the contact of the mammal (including the human) with a defined amount of one or more compounds according to the invention.
Die Begriffe “verbessern” und “behandeln” können in diesem Zusammenhang austauschbar verwendet werden und umfassen sowohl therapeutische als auch prophylaktische Aktionen, welche dazu dienen, das Entstehen der Krankheit oder der Störung bzw. deren Symptome (d.h., ein Zustand, welcher die normale Funktion einer Zelle, eines Gewebes, eines Organes oder eines Organsystems beeinflusst) zu unterdrücken, zu vermindern oder abzumildem, bzw. die nachteilige Zunahme oderThe terms "improve" and "treat" may be used interchangeably in this context and encompass both therapeutic and prophylactic actions that serve to promote the onset of the disease or disorder or its symptoms (ie, a condition that interferes with normal function a cell, a tissue, an organ or an organ system influenced) to suppress, reduce or abate, or the adverse increase or
TU001AT m* · »# ·· «· · ···#·## k 9 ·9 I « »19 »·· 9 « 9 I * · · · t «•4*4·+·# · i« - flj« ♦* ♦· ···· «··TU001AT m * · »# ··« · · ··· # · ## k 9 · 9 I «» 19 »· 9« 9 I * · · · t «• 4 * 4 · + · # · i« - flj «♦ * ♦ · ····« ··
Verschlimmerung der Symptome aufzuhalten oder zu stabilisieren. Krankheiten oder Störungen, welche durch die erfindungsgemäßen Verbindungen behandelt werden können, umfassen sexuelle Dysfunktion, (insb. männliche erektile Dysfunktion), Prostataerkrankung, kardiovaskuläre Störungen (Herzmuskelerkrankung, systemische Hypertonie, pulmonale Hypertonie), Insulinresistenz, diabetische Komplikationen (diabetische Nephropatie, retinale Mikrozirkulationsstörung einschließlich diabetischer Retinapathie und diabetischem Makulaödem), Hautgeschwüre und Fibrosen, Depigmentierungsstörungen der Haut, peripheren Schmerz (einschließlich Arthroseschmerzen), polyzystisches Ovarialsyndrom, psychiatrische Krankheiten (insbesondere schizophrenoforme Störungen) und Leiden, die durch eine temporäre Öffnung der Blut-Hirn-Schranke gebessert werden können.To stop or stabilize the aggravation of the symptoms. Diseases or disorders that may be treated by the compounds of the present invention include sexual dysfunction, (especially male erectile dysfunction), prostate disease, cardiovascular disorders (heart muscle disease, systemic hypertension, pulmonary hypertension), insulin resistance, diabetic complications (diabetic nephropathy, retinal microcirculation disorder, including diabetic retinopathy and diabetic macular edema), skin ulcers and fibrosis, depigmentation disorders of the skin, peripheral pain (including arthritic pain), polycystic ovary syndrome, psychiatric disorders (especially schizophreniform disorders) and conditions that can be ameliorated by temporary opening of the blood-brain barrier.
Die Auswahl der pharmazeutischen Darreichungsform, welche die erfindungsgemäßen Verbindungen enthält und deren Verabreichungsweg zum menschlichen oder anderen Säugetierkörper hängt von der Behandlungsart ab. Unter „Darreichungsform“ wird die Art der Einbringung der pharmazeutischen Zubereitung in oder auf den zu behandelnden Organismus verstanden, welche eine oder mehrere erfindungsgemäße Verbindungen enthält. Nicht einschränkende Beispiele solcher Anwendungsformen umfassen perorale Darreichung in den Verdauungstrakt; Infusionen in Blutgefäße, in zerebrale Vesikel oder in die Harnblase; Injektion in ein Gewebe oder in ein abgeschlossenes Körperkompartiment (im speziellen in das posteriore Augensegment); äußerliche Verabreichung auf die Haut oder Schleimhaut, inklusive transdermale, buccale, intranasale, vaginale, rektale oder okuläre Anwendung; oder pulmonale Verabreichung durch Inhalation.The choice of the pharmaceutical dosage form containing the compounds of the invention and their route of administration to the human or other mammalian body depends on the mode of treatment. By "dosage form" is meant the nature of the introduction of the pharmaceutical preparation into or onto the organism to be treated, which contains one or more compounds according to the invention. Non-limiting examples of such uses include peroral administration to the digestive tract; Infusions into blood vessels, into cerebral vesicles or into the urinary bladder; Injection into a tissue or into a closed body compartment (especially in the posterior segment of the eye); topical administration to the skin or mucous membrane, including transdermal, buccal, intranasal, vaginal, rectal or ocular application; or pulmonary administration by inhalation.
Infundierbare pharmazeutische Darreichungsformen der erfindungsgemäßen Verbindungen können durch kontrollierte Freisetzung mittels mechanischer Hilfsmittel wie intravaskuläre oder intrazerebroventrikuläre Infusionspumpen verabreicht werden. In einem Aspekt können diese Infusionspumpen programmiert werden, sodass vorgegebene Mengen der erfindungsgemäßen Verbindungen in vorgegebenen Intervallen freigesetzt werden. In einem anderen Aspekt können die Infusionspumpen mit einem dynamischen elektronischen Feedback-System verbunden sein, welche einen Sensor enthalten, welcher die Freisetzung der erfindungsgemäßen Verbindungen in Abhängigkeit von deren Konzentration in jenem Körperteil, in den dieInfusible pharmaceutical dosage forms of the compounds of the invention may be administered by controlled release by mechanical means such as intravascular or intracerebroventricular infusion pumps. In one aspect, these infusion pumps may be programmed so that predetermined amounts of the compounds of the invention are released at predetermined intervals. In another aspect, the infusion pumps may be connected to a dynamic electronic feedback system which includes a sensor which detects the release of the compounds of the invention as a function of their concentration in that body part into which the
TU001AT * · ·* « · · · ·»· * · · Φ · ·«« ψ 9 • * Λ^Α · · · · · ψ • * “Wn“ · · · ·»«· · · φTU001AT * · * «· · • • • • • • • • • • • • • • • • • • • • • • • • • • • • • * * * *
Verbindungen freigesetzt werden sollen, oder in Abhängigkeit eines anderen chemischen oder physikalischen Parameters von physiologischer Relevanz bewirkt.Compounds are to be released, or effected in dependence of another chemical or physical parameter of physiological relevance.
Einige erfindungsgemäße Verbindungen könnten eine geringe Löslichkeit und Auflösungsrate in physiologischen Körperflüssigkeiten und somit eine verringerte Bioverfügbarkeit aufweisen. Derartige erfindungsgemäße Verbindungen können auch in fein verteilter Form (mit einer durchschnittlichen Teilchengröße von etwa 10 pm bzw. bis zu 5 pm) oder als Nanopartikel-Zubereitungen (mit einer durchschnittlichen Teilchengröße kleiner als ca. 2 pm) verabreicht werden, wobei allenfalls ein Oberflächen-Stabilisator zur Anwendung kommt, der an die Oberfläche dieser Partikel adsorbiert oder assoziiert ist. Solche fein verteilten Partikel oder Nanopartikel können amorph, als (semi)kristalline Phase oder als Mischungen von diesen vorliegen.Some compounds of the invention may have low solubility and dissolution rate in physiological body fluids and thus reduced bioavailability. Such compounds according to the invention can also be administered in finely divided form (with an average particle size of about 10 μm or up to 5 μm) or as nanoparticle preparations (with an average particle size of less than about 2 μm), with at most one surface Stabilizer is used, which is adsorbed or associated to the surface of these particles. Such finely divided particles or nanoparticles may be amorphous, (semi) crystalline, or mixtures of these.
Die Teilchengröße der erfindungsgemäßen Verbindungen und jene des festen Carriers oder Oberflächenstabilisators können auf das angestrebte Niveau durch konventionelle Methoden, wie z. B. durch Vermahlung in einer Luftstrahlmühle, Kugelmühle oder Vibratormühle, durch Mikro-Fällung, Sprühtrocknung, Lyophilisieren oder Rekristallisation aus superkritischen Medien gebracht werden.The particle size of the compounds of the invention and those of the solid carrier or surface stabilizer can be raised to the desired level by conventional methods such. B. by grinding in an air jet mill, ball mill or vibrator mill, are brought by micro-precipitation, spray drying, lyophilization or recrystallization from supercritical media.
Fein- oder nanoverteilte erfindungsgemäße Darreichungsformen, können weiters in Zerstäubern in Form inhalierbarer Aerosole oder Dispersionen in wässrigen, organischen oder organisch-wässrigen Medien angewendet werden. Desweiteren können fein- oder nanoverteilte erfindungsgemäße Verbindungen in Form von Gelatine- oder Plastik-Kapseln oder Blistern oder als Trockenpulverfür Inhalationsapparate oder in einem Reservoir für einen Mehrfachdosierungs-Inhalationsapparat zur Anwendung kommen.Fine or nanoparticulate dosage forms according to the invention can furthermore be used in atomizers in the form of inhalable aerosols or dispersions in aqueous, organic or organic-aqueous media. Furthermore, fine or nanoparticulate compounds of the invention may be used in the form of gelatin or plastic capsules or blisters or as dry powder for inhalers or in a reservoir for a multi-dose inhaler.
In einer Ausführung umfasst die Erfindung Methoden zur Herstellung von PDE5-Hemmer welche einen Diazabicyclo- bzw. Diazaspiro-alkanrest enthalten entsprechend der allgemeinen Formel (I) sowie deren pharmazeutisch akzeptablen Salze und polymorphen Formen und Lösungen.In one embodiment, the invention encompasses methods for the preparation of PDE5 inhibitors which contain a diazabicyclo or diazaspiroalkane radical according to the general formula (I) and their pharmaceutically acceptable salts and polymorphic forms and solutions.
Zahlreiche Methoden zur Herstellung von Sildenafil bzw. von Zwischenprodukten zur Herstellung von Sildenafil sind bekannt, u.a. jene, welche inNumerous methods for producing sildenafil or intermediates for the preparation of sildenafil are known, i.a. those who are in
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W02007/141805, W02008/074194, W02008/074512 und WO2008/152177 beschreiben sind. Weiters sind zahlreiche Methoden zur Herstellung von Vardenafil und dessen Zwischenprodukten bekannt, u.a. jene welche in W02006/127368, W02009/030095 und W02009/082845 beschrieben sind.W02007 / 141805, W02008 / 074194, W02008 / 074512 and WO2008 / 152177 are described. Furthermore, numerous methods for the production of vardenafil and its intermediates are known, i.a. those which are described in W02006 / 127368, W02009 / 030095 and W02009 / 082845.
Ohne Beschränkung auf den hier angegebenen Syntheseweg, werden die erfindungsgemäßen Verbindungen durch nukleophile Substitution von Sulfonsäurechloriden (III) mit Basen der allgemeinen Formel (IV) gemäß folgender Reaktion hergestellt, wobei die Symbole die oben angegebene Bedeutung haben:Without being limited to the synthetic route given here, the compounds according to the invention are prepared by nucleophilic substitution of sulfonyl chlorides (III) with bases of the general formula (IV) according to the following reaction, where the symbols have the abovementioned meaning:
(IV) (III) (II)(IV) (III) (II)
Details der verschiedenen Auführungsformen der Erfindung werden in den nachstehenden Beispielen offengelegt. Besondere Eigenschaften und Vorteile der Erfindung werden durch die Beschreibungen und die Patentansprüche geoffenbart.Details of the various embodiments of the invention are disclosed in the following examples. Particular features and advantages of the invention are disclosed by the descriptions and the claims.
BeispieleExamples
Synthese der erfindungsgemäßen VerbindungenSynthesis of the compounds of the invention
Die unterschiedlichen Diazabicycloalkane, welche in den folgenden Synthesen verwendet warden, sind entweder kommerziell erhältlich oder literaturbekannt.The different diazabicycloalkanes used in the following syntheses are either commercially available or known from the literature.
Allgemeine ArbeitsvorschrifM: 0.250 mmol des Diazabicycloalkans wurde zu einer Lösung von 0.245 mmol des entsprechenden Benzolsulfonylchlorids (A oder B, siehe oben) und 0.245 mmol Triethylamin in 20mL trockenem Dichlormethan unter Argon bei RT (Raumtemperatur) zugefügt und die Lösung 4-16 h lang gerüht. Nach Zufügen von 50 mL Dichlormethan wurde zweimal mit je 50 mL gesättigter Natriumbicarbonatlösung sowie 50 mL gesättigter Natriumchloridlösung gewaschen. Die organische Phase wurde über Natriumsulfat getrocknet und eingedampft. Falls das so erhaltene Produkt unrein war TU001AT wurde es durch Radialchromatographie mit Ethylacetat: Methanol: 28% Ammoniak im Verhältnis von 9:1:0.4 gereinigt.General procedure: 0.250 mmol of the diazabicycloalkane was added to a solution of 0.245 mmol of the corresponding benzenesulfonyl chloride (A or B, see above) and 0.245 mmol of triethylamine in 20 mL of dry dichloromethane under argon at RT (room temperature) and the solution was stirred for 4-16 h , After adding 50 mL of dichloromethane, it was washed twice with 50 mL each of saturated sodium bicarbonate solution and 50 mL of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. If the product so obtained was impure TU001AT, it was purified by radial chromatography with ethyl acetate: methanol: 28% ammonia in the ratio of 9: 1: 0.4.
Beispiel 1 5-[2-Ethoxy-5-[([1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptanyl)sulfonyl] phenyl]-1,6-dihydro-1-methyi-3-propyl- 7H-pyrazolo[4,3-d]pyrimidin-7-onExample 1 5- [2-Ethoxy-5 - [([1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl 3-propyl-7H-pyrazolo [4,3-d] pyrimidin-7-one
Zu einer Lösung von 0.100g (0.243 mmol) 3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-c/]pyrimidin-5-yl)-4 ethoxybenzensulfonylchlorid in 10 mL trockenem Dichlormethan wurden unter Argon 0.0821g (0.300 mmol, 1.23 eq) (1S,4S) 2-Methyl-2,5-diazabicyclo[2.2.1]heptan Dihydrobromid sowie eine Lösung von 0.0501g (0.495 mmol, 2.03 eq) trockenem Triethylamine in 5mL trockenem Dichloromethan zugefügt und die Lösung bei RT unter Argon 16 h gerührt wobei gemäß Dünnschichtchromatographie der Umsatz praktisch vollständig war. Aufarbeitung gemäß allgemeiner Arbeitsvorschrift 1 ergab 0.115g des Produktes (97 %). 1HNMR (δ ppm, CDCI3, 400MHz) 10.94 (s breit, 1H), 8.77 (s, 1H), 7.85 (dd, J=2.3Hz, J=8.8Hz, 1H), 7.11 (d, J=8.8Hz, 1HJ4.33 (q, J=7.0Hz, 2H), 4.31-4.27 (m, 1H), 4.22 (s, 3H), 3.57 (d, J=9.7Hz, 1H), 3.37 (s breit, 1H), 3.04 (dd, J=1.7Hz, J=9.7Hz, 1H), 2.88 (q, J=7.4Hz, 2H), 2.85 (s breit, 1H), 2.68 (d, J=9.9Hz, 1H), 2.35 (s, 3H), 1.82 (sextet, J=7.4Hz, 2H), 1.74 (d, J=9.9Hz, 1H), 1.59 (t, J=6.9Hz, 3H), 1.24 (d, J=9.9Hz, 1H), 0.99 (t, J=7.4Hz, 3H). 13CNMR (δ ppm, CDCI3, 100MHz) 159.3, 153.7, 146.8, 146.6, 138.3, 136.7,To a solution of 0.100 g (0.243 mmol) of 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-c /] pyrimidin-5-yl) -4 ethoxybenzenesulfonyl chloride in 10 mL of dry dichloromethane under argon were added 0.0821 g (0.300 mmol, 1.23 eq) of (1S, 4S) 2-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrobromide and a solution of 0.0501 g (0.495 mmol, 2.03 eq) dry triethylamine in 5mL dry dichloromethane was added and the solution was stirred at RT under argon for 16 h whereby, according to thin layer chromatography, the conversion was virtually complete. Workup according to general procedure 1 gave 0.115 g of the product (97%). 1HNMR (δ ppm, CDCI3, 400MHz) 10.94 (s wide, 1H), 8.77 (s, 1H), 7.85 (dd, J = 2.3Hz, J = 8.8Hz, 1H), 7.11 (d, J = 8.8Hz, 1HJ4.33 (q, J = 7.0Hz, 2H), 4.31-4.27 (m, 1H), 4.22 (s, 3H), 3.57 (d, J = 9.7Hz, 1H), 3.37 (s wide, 1H), 3.04 (dd, J = 1.7Hz, J = 9.7Hz, 1H), 2.88 (q, J = 7.4Hz, 2H), 2.85 (s wide, 1H), 2.68 (d, J = 9.9Hz, 1H), 2.35 (s, 3H), 1.82 (sextet, J = 7.4Hz, 2H), 1.74 (d, J = 9.9Hz, 1H), 1.59 (t, J = 6.9Hz, 3H), 1.24 (d, J = 9.9Hz , 1H), 0.99 (t, J = 7.4Hz, 3H), 13CNMR (δ ppm, CDCl 3, 100MHz) 159.3, 153.7, 146.8, 146.6, 138.3, 136.7,
27.7, 22.2, 14.5, 14.0.27.7, 22.2, 14.5, 14.0.
Beispiel 2 5-[2-Ethoxy-5-[([rac.]-9-methyl-3,9-diazabicyclo[4.2.1]nonanyl)sulfonyl]phenyl]-1,6-dihydro-1 -methyl-3-propyl- 7H-pyrazo!o[4,3-d]pyrimidin-7-onExample 2 5- [2-Ethoxy-5 - [([rac.] - 9-methyl-3,9-diazabicyclo [4.2.1] nonanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl-3 -propyl-7H-pyrazolo! o [4,3-d] pyrimidin-7-one
XIXI
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Herstellung gemäß allgemeiner Arbeitsvorschrift 1 mit 0.0778g (0.365 mmol) rac. 9-Methyl-3,9-diazabicyclo[4.2.1]nonan Dihydrochlorid ergab 0.121g (0.235 mol, 97%) des Produktes. 5 1HNMR (δ ppm, CDCI3, 400MHz) 10.93 (s breit, 1H), 8.69 (s, 1H), 7.76 (dd, J=2.5Hz, J=8.7Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 4.31 (q, J=7.0Hz, 2H), 4.21 (s, 3H), 3.68-3.59 (m, 1H), 3.58-3.51 (m, 1H), 3.29 (t breit, J=7.8Hz, 1H), 3.23 (d breit, J=7.6Hz, 1H), 2.99-2.90 (m, 1H), 2.91-2.81 (m, 3H), 2.42 (s, 2H), 2.34-2.22 (m, 1H), 2.17-2.04 (m, 1H), 2.02-1.91 (m, 1H), 1.91-1.84 (m, 1H), 1.82(sextet, J=7.5Hz, 2H), 10 1.78-1.70 (m, 4H), 1.70-1.59 (m, 1H), 1.57 (t, J=7.0Hz, 3H), 0.99 (t, J=7.3Hz, 3H). 13CNMR (δ ppm, CDCI3, 100MHz) 159.0, 153.7, 146.8, 146.6, 138.3, 132.4, 130.8, 130.0, 124.4, 121.1, 113.1,65.9, 63.2, 55.2,46.8, 43.5, 38.2, 35.2, 31.9, 27.7, 26.0, 22.2, 14.5, 14.1. 15 Beispiel 3 5-[2-Ethoxy-5-[([rac.j-10-methyl-3,10-diazabicyclo[4.3.1 ]decanyl)sulfonyl] phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-onPreparation according to general procedure 1 with 0.0778 g (0.365 mmol) of rac. 9-Methyl-3,9-diazabicyclo [4.2.1] nonane dihydrochloride gave 0.121 g (0.235 mol, 97%) of the product. 5 1HNMR (δ ppm, CDCI3, 400MHz) 10.93 (s wide, 1H), 8.69 (s, 1H), 7.76 (dd, J = 2.5Hz, J = 8.7Hz, 1H), 7.08 (d, J = 8.8Hz , 1H), 4.31 (q, J = 7.0Hz, 2H), 4.21 (s, 3H), 3.68-3.59 (m, 1H), 3.58-3.51 (m, 1H), 3.29 (t wide, J = 7.8Hz , 1H), 3.23 (d wide, J = 7.6Hz, 1H), 2.99-2.90 (m, 1H), 2.91-2.81 (m, 3H), 2.42 (s, 2H), 2.34-2.22 (m, 1H) , 2.17-2.04 (m, 1H), 2.02-1.91 (m, 1H), 1.91-1.84 (m, 1H), 1.82 (sextet, J = 7.5Hz, 2H), 10 1.78-1.70 (m, 4H), 1.70-1.59 (m, 1H), 1.57 (t, J = 7.0Hz, 3H), 0.99 (t, J = 7.3Hz, 3H). 13CNMR (δ ppm, CDCl 3, 100 MHz) 159.0, 153.7, 146.8, 146.6, 138.3, 132.4, 130.8, 130.0, 124.4, 121.1, 113.1, 63.9, 63.2, 55.2, 46.8, 43.5, 38.2, 35.2, 31.9, 27.7, 26.0 , 22.2, 14.5, 14.1. Example 3 5- [2-Ethoxy-5 - [([rac.j-10-methyl-3,10-diazabicyclo [4.3.1] decanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl- 3-propyl-7H-pyrazolo [4,3-d] pyrimidin-7-one
Herstellung gemäß allgemeiner Arbeitsvorschrift 1 mit 0.104g (0.674 mmol, 2.8 20 eq) 10-Methyl-3,10-diazabicylco[4.3.1]decan ergab 0.116g (0.219 mmol, 90%) des Produktes. 1HNMR (δ ppm, CDCI3,400MHz) 10.99-10.83 (s breit, 1H), 8.77 (d, J=2.4Hz, 1H), 7.83 (dd, J=2.5Hz, J=8.8Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 4.34 (q, J=7.0Hz, 2H),Preparation according to general procedure 1 with 0.104 g (0.674 mmol, 2.8 20 eq) of 10-methyl-3,10-diazabicyclo [4.3.1] decane gave 0.116 g (0.219 mmol, 90%) of the product. 1HNMR (δ ppm, CDCI3,400MHz) 10.99-10.83 (s wide, 1H), 8.77 (d, J = 2.4Hz, 1H), 7.83 (dd, J = 2.5Hz, J = 8.8Hz, 1H), 7.11 ( d, J = 8.8Hz, 1H), 4.34 (q, J = 7.0Hz, 2H),
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• · Q · · · v ρφ— » ·• · Q · · · v ρφ- · ·
4.24 (s, 3H), 3.69-3.57 (m, 2H), 3.23 (dd, J=4.2Hz, J=13.5Hz, 1H), 3.13-2.99 (m, 2H), 2.91 (t, J=7.4Hz, 2H), 2.89-2.83 (m, 1H), 2.47 (s, 3H), 2.21-2.00 (m, 2H), 1.49-1.78 (m, 5H), 1.60 (t, J=7.0Hz, 3H), 1.60-1.46 (m, 2H), 1.31-1.21 (d breit, J=12.7Hz, 1H), 1.00 (t, J=7.4Hz, 3H). 13CNMR (δ ppm, CDCI3j 100MHz) 159.1, 153.7, 146.9, 146.7, 138.4, 132.6, 131.0, 130.1, 124.5, 121.0, 113.3, 66.1, 56.0, 54.4, 52.0, 47.3, 43.1, 38.2, 32.8, 27.7, 26.9, 25.0, 22.4, 15.8, 14.5, 14.1.4.24 (s, 3H), 3.69-3.57 (m, 2H), 3.23 (dd, J = 4.2Hz, J = 13.5Hz, 1H), 3.13-2.99 (m, 2H), 2.91 (t, J = 7.4Hz , 2H), 2.89-2.83 (m, 1H), 2.47 (s, 3H), 2.21-2.00 (m, 2H), 1.49-1.78 (m, 5H), 1.60 (t, J = 7.0Hz, 3H), 1.60-1.46 (m, 2H), 1.31-1.21 (d wide, J = 12.7Hz, 1H), 1.00 (t, J = 7.4Hz, 3H). 13CNMR (δ ppm, CDCl 3j 100 MHz) 159.1, 153.7, 146.9, 146.7, 138.4, 132.6, 131.0, 130.1, 124.5, 121.0, 113.3, 66.1, 56.0, 54.4, 52.0, 47.3, 43.1, 38.2, 32.8, 27.7, 26.9, 25.0, 22.4, 15.8, 14.5, 14.1.
Folgende Beispiele wurden ebenfalls gemäß der allgemeinen Arbeitsvorschrift 1 hergestellt.The following examples were also prepared according to general procedure 1.
Beispiel 4 5-[2-Ethoxy-5-[(10-methyl-9,10-diazatricyclo[4.2.1.1 2,5]decanyl)sulfonyl]phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-onExample 4 5- [2-Ethoxy-5 - [(10-methyl-9,10-diazatricyclo [4.2.1.1 2,5] decanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl-3-propyl -7H-pyrazolo [4,3-d] pyrimidin-7-one
Ausbeute: 93 % MP: 172-174°C. 1HNMR (δ ppm, CDCI3, 400MHz) 10.85 (s breit, 1H), 8.77 (s, 1H), 7.80 (dd, J=2.2Hz, J=8.7Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 4.27 (q, J=7.0Hz, 2H), 4.17 (s, 3H), 3.87-3.77 (m, 2H), 2.89-2.76 (m, 4H), 2.05 (s, 3H), 1.90-1.88 (m, 4H), 1.79 (q, J=7.5Hz, 2H), 1.73-1.62 (m, 2H), 1.54 (t, J=7.0Hz, 3H), 1.30-1.18 (m, 2H), 0.94 (t, J=7.4Hz, 3H). 13CNMR(ö ppm, CDCI3i 100MHz) 159.0, 153.7, 146.9, 146.7, 138.4, 133.7, 130.6, 130.1, 124.4, 120.9, 113.0, 67.1,66.1,63.3, 41.1, 38.2, 29.7, 29.3, 24.5, 22.3, 14.5, 14.0. HRMS m/z 527.2439 (M+1).Yield: 93% MP: 172-174 ° C. 1HNMR (δ ppm, CDCI3, 400MHz) 10.85 (s wide, 1H), 8.77 (s, 1H), 7.80 (dd, J = 2.2Hz, J = 8.7Hz, 1H), 7.01 (d, J = 8.8Hz, 1H), 4.27 (q, J = 7.0Hz, 2H), 4.17 (s, 3H), 3.87-3.77 (m, 2H), 2.89-2.76 (m, 4H), 2.05 (s, 3H), 1.90-1.88 (m, 4H), 1.79 (q, J = 7.5Hz, 2H), 1.73-1.62 (m, 2H), 1.54 (t, J = 7.0Hz, 3H), 1.30-1.18 (m, 2H), 0.94 ( t, J = 7.4Hz, 3H). 13CNMR (δppm, CDCl3i 100MHz) 159.0, 153.7, 146.9, 146.7, 138.4, 133.7, 130.6, 130.1, 124.4, 120.9, 113.0, 67.1, 66.1, 63.3, 41.1, 38.2, 29.7, 29.3, 24.5, 22.3, 14.5, 14.0. HRMS m / z 527.2439 (M + 1).
TU001ATTU001AT
Beispiel 5 5-[2-Ethoxy-5-[(8-methyl-3,8-diazabicyclo[3.2.1]octanyl)sulfonyl]phenyl]-1,6-dihydro-1-methyl-3-propyl- 7H-pyrazolo[4,3-d]pyrimidin-7-onExample 5 5- [2-Ethoxy-5 - [(8-methyl-3,8-diazabicyclo [3.2.1] octanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl-3-propyl-7H- pyrazolo [4,3-d] pyrimidin-7-one
5 Ausbeute: 95 % MP: 129°C (Zers.) 1HNMR (δ ppm, CDCI3, 400MHz) 11.17 (s breit, 1H), 8,47-8.43 (m, 1H), 7.67 (dd, J=2.4Hz, J=8.7Hz, 1H), 7.03 (dd, J=1.7Hz, J=8.8Hz, 1H), 4.25-4.18 (m, 2H), 4.14 (d, J=2.5Hz, 3H), 3.31 (m, 2H), 3.05 (s breit, 2H), 7.80 (dot, J=2.4Hz, J=8.0Hz, 2H), 10 2.57 (d breit, J=10.5Hz, 2H), 2.09 (d, J=2.3Hz, 3H), 1.93-1.87 (m, 2H), 1.80-1.68 (m, 4H), 1.51-1.44 (m, 3H), 0.91 (dot, J=2.3Hz, J=7.4Hz, 3H). 13CNMR (δ ppm, CDCI3, 100MHz) 159.4, 154.0, 146.7, 138.4, 131.4, 130.6, 128.7, 124.4, 121.5, 112.9, 65.8, 60.5, 51.9, 40.7, 38.1, 27.6, 24.8, 22.5, 22.2, 14.4, 13.9. 155 Yield: 95% MP: 129 ° C (dec.) 1HNMR (δ ppm, CDCl 3, 400 MHz) 11.17 (s broad, 1H), 8.47-8.43 (m, 1H), 7.67 (dd, J = 2.4Hz , J = 8.7Hz, 1H), 7.03 (dd, J = 1.7Hz, J = 8.8Hz, 1H), 4.25-4.18 (m, 2H), 4.14 (d, J = 2.5Hz, 3H), 3.31 (m , 2H), 3.05 (s wide, 2H), 7.80 (dot, J = 2.4Hz, J = 8.0Hz, 2H), 10 2.57 (d wide, J = 10.5Hz, 2H), 2.09 (d, J = 2.3 Hz, 3H), 1.93-1.87 (m, 2H), 1.80-1.68 (m, 4H), 1.51-1.44 (m, 3H), 0.91 (dot, J = 2.3Hz, J = 7.4Hz, 3H). 13CNMR (δ ppm, CDCl 3, 100 MHz) 159.4, 154.0, 146.7, 138.4, 131.4, 130.6, 128.7, 124.4, 121.5, 112.9, 65.8, 60.5, 51.9, 40.7, 38.1, 27.6, 24.8, 22.5, 22.2, 14.4, 13.9 , 15
Beispiel 6 5-[2-Ethoxy-5-[([1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptanyl)sulfonyl] phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-onExample 6 5- [2-Ethoxy-5 - [([1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptanyl) sulfonyl] phenyl] -1,6-dihydro-1-methyl- 3-propyl-7H-pyrazolo [4,3-d] pyrimidin-7-one
20 Ausbeute: 96 % MP:140-143°C bei 98% HPLC Reinheit 1HNMR (δ ppm, CDCI3, 400MHz) 10.90 (s breit, 1H), 8.71 (s, 1H), 7.80 (dd, J=2.2Hz, J=8.8Hz, 1H), 7.07 (d, J=8.8Hz, 1H), 4.28 (q, J=7.0Hz, 2H), 3.17 (s, 3H),20 Yield: 96% MP: 140-143 ° C at 98% HPLC Purity 1HNMR (δ ppm, CDCl 3, 400 MHz) 10.90 (s wide, 1H), 8.71 (s, 1H), 7.80 (dd, J = 2.2Hz, J = 8.8Hz, 1H), 7.07 (d, J = 8.8Hz, 1H), 4.28 (q, J = 7.0Hz, 2H), 3.17 (s, 3H),
TU001AT • · 2.53 (d, J=9.7Hz, 1H), 3.34 (s breit, 1H), 2.99 (d, J=9.8Hz, 1H), 2.84 (t, J=7.6Hz, 2H), 2.81 (d J=2.3Hz, 1H), 2.65 (d, H=9.9Hz, 1H), 2.31 (s, 3H), 1.77 (sextet, J=7.5Hz, 2H), 1.70 (d breit, J=10.1Hz, 1H), 1.54 (t, J=6.9Hz, 2H), 1.19 (d breit, J=10.1Hz, 1H), 0.94 (t, J=7.4Hz, 3H). 13CNMR ( δ ppm, CDCI3, 100MHz) 159.3, 153.7, 146.8, 146.6, 138.3 131.8, 131.2, 130.5, 124.4, 121.3, 113.2, 66.0, 63.1, 61.5, 61.0, 50.0, 40.3, 38.2, 35.2, 27.7, 22.2, 14.5, 14.0. HRMS m/z 487.2125 (M+1).TU001AT • · 2.53 (d, J = 9.7Hz, 1H), 3.34 (s wide, 1H), 2.99 (d, J = 9.8Hz, 1H), 2.84 (t, J = 7.6Hz, 2H), 2.81 (i.e. J = 2.3Hz, 1H), 2.65 (d, H = 9.9Hz, 1H), 2.31 (s, 3H), 1.77 (sextet, J = 7.5Hz, 2H), 1.70 (d wide, J = 10.1Hz, 1H ), 1.54 (t, J = 6.9Hz, 2H), 1.19 (d wide, J = 10.1Hz, 1H), 0.94 (t, J = 7.4Hz, 3H). 13CNMR (δ ppm, CDCl 3, 100 MHz) 159.3, 153.7, 146.8, 146.6, 138.3 131.8, 131.2, 130.5, 124.4, 121.3, 113.2, 66.0, 63.1, 61.5, 61.0, 50.0, 40.3, 38.2, 35.2, 27.7, 22.2, 14.5, 14.0. HRMS m / z 487.2125 (M + 1).
Beispiel 7 2-[2-Ethoxy-5-[(9-ethyl-3,9-diazabicyclo[4.2.1 ]nonan-1 -yl)sulfonyl]phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1 H)-onExample 7 2- [2-Ethoxy-5 - [(9-ethyl-3,9-diazabicyclo [4.2.1] nonan-1-yl) sulfonyl] phenyl] -5-methyl-7-propylimidazo [5.1- f] [1,2,4] triazine-4 (1H) -one
Ausbeute: 86 % MP 169-170°C (Zers.) beige fest 1HNMR ( δ ppm, CDCI3, 400MHz) 8.32 (s, 1H), 7.79 (dd, J=2.0Hz, J=8.8Hz, 1H), 7.06 (d, J=8.8Hz, 1H), 4.24 (q, J=7.0Hz, 2H), 3.55 (dd, J=5.2Hz, J=13.6Hz, 1H), 3.49 (d, J=12.0Hz, 1H), 3.32 (t, J=7.8Hz, 1H), 3.25 (d, J=7.5Hz, 1H), 2.91 (t, J=7.6Hz, 3H), 2.70 (d, J=11.6Hz, 1H), 2.53 (s, 3H), 2.49 (q, J=7.1Hz, 2H), 2.21-2.06 (m, 1H), 2.02-1.89 (m, 1H), 1.89-1.72 (m, 4H), 1.73-1.63 (m, 1H), 1.63-1.52 (m, 1H), 1.48 (t, J=6.9Hz, 3H), 0.95 (t, J=7.3Hz, 6H). 13CNMR (δ ppm, CDCls, 100MHz) 159.5, 155.0, 146.3, 144.8, 140.1, 132.5, 131.6, 129.2, 118.7, 113.6, 113.0, 65.9, 63.4, 60.4, 56.1,49.3, 47.0, 36.0, 32.5, 29.7, 28.0, 26.7, 21.0, 14.9, 14.5, 14.0. HRMS m/z 529.2607 (M+1).Yield: 86% MP 169-170 ° C (dec.) Beige solid 1HNMR (δ ppm, CDCl3, 400 MHz) 8.32 (s, 1H), 7.79 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8Hz, 1H), 4.24 (q, J = 7.0Hz, 2H), 3.55 (dd, J = 5.2Hz, J = 13.6Hz, 1H), 3.49 (d, J = 12.0Hz, 1H ), 3.32 (t, J = 7.8Hz, 1H), 3.25 (d, J = 7.5Hz, 1H), 2.91 (t, J = 7.6Hz, 3H), 2.70 (d, J = 11.6Hz, 1H), 2.53 (s, 3H), 2.49 (q, J = 7.1Hz, 2H), 2.21-2.06 (m, 1H), 2.02-1.89 (m, 1H), 1.89-1.72 (m, 4H), 1.73-1.63 ( m, 1H), 1.63-1.52 (m, 1H), 1.48 (t, J = 6.9Hz, 3H), 0.95 (t, J = 7.3Hz, 6H). 13CNMR (δ ppm, CDCls, 100 MHz) 159.5, 155.0, 146.3, 144.8, 140.1, 132.5, 131.6, 129.2, 118.7, 113.6, 113.0, 65.9, 63.4, 60.4, 56.1, 49.3, 47.0, 36.0, 32.5, 29.7, 28.0 , 26.7, 21.0, 14.9, 14.5, 14.0. HRMS m / z 529.2607 (M + 1).
TU001AT • · * · «t Μ • I Μ · · * * « * * »··«** *TU001AT • · * · «t Μ • I Μ · · * *« * * »··« ** *
Beispiel 8 2-[2-Ethoxy-5-[(10-ethyl-3,10-diazabicyclo[4.3.1]decan-1-yl)sulfonyl]phenyl]-5-methy!-7-propylimidazo[5,1 -f][1,2,4]triazin-4(1 H)-onExample 8 2- [2-Ethoxy-5 - [(10-ethyl-3,10-diazabicyclo [4.3.1] decan-1-yl) sulfonyl] phenyl] -5-methyl-7-propylimidazo [5.1 -f] [1,2,4] triazine-4 (1H) -one
5 Ausbeute: 76 %5 Yield: 76%
MP: 178-181°C 1HNMR (δ ppm, CDCI3, 400MHz) 8.33 (d, J=2.2Hz, 1H), 7.83 (dd, J=2.2Hz, J=8.8Hz), 7.05 (d, J=8.8Hz, 1H), 4.23 (q, J=7.0Hz, 2H), 3.60-3.45 (m, 2H), 3.16-3.00 (m, 2H)t 3.00-2.82 (m, 4H), 2.70-2.56 (m, 1H), 2.53 (s, 3H), 2.53-2.41 (m, 1H), 2.09-10 1.91 (m, 2H), 1.79 (sextet, J=7.5Hz, 2H), 1.76-1.62 (m, 3H), 1.48 (t, J=7.0Hz, 3H), 1.46-1.37 (m, 2H), 0.94 (t, J=7.4Hz, 3H), 0.77 (t, J=7.0Hz, 3H). 13CNMR (δ ppm, CDCh, 100MHz) 159.5, 155.0, 146.3,145.0,140.1, 132.6, 131.8, 129.3, 118.7, 113.6, 112.8, 65.8, 54.1,52.3, 51.3,48.0, 47.1,32.6, 30.3, 28.0, 26.9, 25.1, 20.9, 15.9, 14.5, 14.4, 14.0. 15 HRMS m/z 543.2749 (M+1).MP: 178-181 ° C 1HNMR (δ ppm, CDCl3, 400 MHz) 8.33 (d, J = 2.2Hz, 1H), 7.83 (dd, J = 2.2Hz, J = 8.8Hz), 7.05 (d, J = 8.8 Hz, 1H), 4.23 (q, J = 7.0Hz, 2H), 3.60-3.45 (m, 2H), 3.16-3.00 (m, 2H) t 3.00-2.82 (m, 4H), 2.70-2.56 (m, 1H), 2.53 (s, 3H), 2.53-2.41 (m, 1H), 2.09-10 1.91 (m, 2H), 1.79 (sextet, J = 7.5Hz, 2H), 1.76-1.62 (m, 3H), 1.48 (t, J = 7.0Hz, 3H), 1.46-1.37 (m, 2H), 0.94 (t, J = 7.4Hz, 3H), 0.77 (t, J = 7.0Hz, 3H). 13CNMR (δ ppm, CDCh, 100 MHz) 159.5, 155.0, 146.3, 145.0, 140.1, 132.6, 131.8, 129.3, 118.7, 113.6, 112.8, 65.8, 54.1, 52.3, 51.3, 48.0, 47.1, 32.6, 30.3, 28.0, 26.9 , 25.1, 20.9, 15.9, 14.5, 14.4, 14.0. 15 HRMS m / z 543.2749 (M + 1).
Beispiel 9 2-[2-Ethoxy-5-[(8-ethyl-3,8-diazabicyclo[3.2.1]octan-1-yl)sulfonyl]phenyl]-5- methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1H)-onExample 9 2- [2-Ethoxy-5 - [(8-ethyl-3,8-diazabicyclo [3.2.1] octan-1-yl) sulfonyl] phenyl] -5-methyl-7-propylimidazo [5.1- f] [1,2,4] triazin-4 (1H) -one
Ausbeute: 61 % MP: 196-200X (Zers.) 1HNMR (δ ppm, CDCI3, 400MHz) 9.92 (s breit, 1H), 8.26 (d, J=2.0Hz, 1H), 7.75 (dd, J=2.0Hz, J=8.8Hz, 1H), 7.05 (d, J=8.8Hz, 1H), 2.23 (q, J=7.0Hz, 2H), 3.39 (dd,Yield: 61% MP: 196-200X (dec.) 1HNMR (δ ppm, CDCl3, 400MHz) 9.92 (s wide, 1H), 8.26 (d, J = 2.0Hz, 1H), 7.75 (dd, J = 2.0Hz , J = 8.8Hz, 1H), 7.05 (d, J = 8.8Hz, 1H), 2.23 (q, J = 7.0Hz, 2H), 3.39 (dd,
TU001ATTU001AT
J=0.8Hz, J=10.4Hz, 2H), 3.19 (s breit, 2H), 2.90 (t, J=7.6Hz, 2H), 2.58 (d, J=10.3Hz, 2H), 2.54 (s, 3H), 2.23 (q. J=7.2Hz, 2H), 1.92-1.72 (m, 6H), 1.49 (t, J=7.0Hz, 3H), 0.98-0.89 (m, 6H). 13CNMR (δ ppm, CDCI3, 100MHz) 159.8, 155.0, 146.3, 144.8, 140.1, 132.2, 130.0, 129.4, 118.9, 113.6, 112.9, 65.9, 58.3, 52.2, 46.6, 27.9, 25.1, 20.9, 14.5, 14.4, 14.0, 13.3. HRMS m/z 515.2445 (M+1).J = 0.8Hz, J = 10.4Hz, 2H), 3.19 (s wide, 2H), 2.90 (t, J = 7.6Hz, 2H), 2.58 (d, J = 10.3Hz, 2H), 2.54 (s, 3H ), 2.23 (q.J = 7.2Hz, 2H), 1.92-1.72 (m, 6H), 1.49 (t, J = 7.0Hz, 3H), 0.98-0.89 (m, 6H). 13CNMR (δ ppm, CDCl 3, 100 MHz) 159.8, 155.0, 146.3, 144.8, 140.1, 132.2, 130.0, 129.4, 118.9, 113.6, 112.9, 65.9, 58.3, 52.2, 46.6, 27.9, 25.1, 20.9, 14.5, 14.4, 14.0 , 13.3. HRMS m / z 515.2445 (M + 1).
Beispiel 10 2-[2-Ethoxy-5-[([1 S,4S] 5-ethyl-2,5-diazabicyclo[2.2.1]heptan-1-yl)sulfonyl] phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1 H)-onExample 10 2- [2-Ethoxy-5 - [([1S, 4S] 5-ethyl-2,5-diazabicyclo [2.2.1] heptan-1-yl) sulfonyl] phenyl] -5-methyl-7- propylimidazo [5,1-f] [1,2,4] triazine-4 (1H) -one
Ausbeute: 71 % MP: 135-140°C (Zers.) 1HNMR (δ ppm, CDCI3, 400MHz) 8.35 (d, J=2.2Hz, 1H), 7.86 (dd, J=2.2Hz, J=8.8Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 2.24 (q, J=7.0Hz, 2H), 3.49 (d, J=9.6Hz, 1H), 3.42 (s, 1H), 2.99-2.83 (m, 4H), 2.58 (d, J=10.1Hz, 1H), 2.52 (s, 3H), 2.51-2.38 (m, 1H), 1.79 (sextet, J=7.5Hz, 2H), 1.67 (d, J=9.9Hz, 1H), 1.48 (t, J=7.0Hz, 3H), 1.17 (d, J=9.4Hz, 1H), 1.00-0.88 (m, 6H). 13CNMR (δ ppm, CDCI3, 100MHz) 159.8, 155.1, 146.3, 144.8, 140.1, 132.0, 131.7, 129.8, 119.0, 113.6, 113.0, 65.9, 60.9, 60.6, 59.4, 50.1,47.4, 35.3, 27.9, 20.9, 14.5, 14.4, 14.1, 13.9. HRMS m/z 501.2280 (M+1).Yield: 71% MP: 135-140 ° C (dec.) 1HNMR (δ ppm, CDCl3, 400 MHz) 8.35 (d, J = 2.2Hz, 1H), 7.86 (dd, J = 2.2Hz, J = 8.8Hz, 1H), 7.08 (d, J = 8.8Hz, 1H), 2.24 (q, J = 7.0Hz, 2H), 3.49 (d, J = 9.6Hz, 1H), 3.42 (s, 1H), 2.99-2.83 ( m, 4H), 2.58 (d, J = 10.1Hz, 1H), 2.52 (s, 3H), 2.51-2.38 (m, 1H), 1.79 (sextet, J = 7.5Hz, 2H), 1.67 (d, J = 9.9Hz, 1H), 1.48 (t, J = 7.0Hz, 3H), 1.17 (d, J = 9.4Hz, 1H), 1.00-0.88 (m, 6H). 13CNMR (δ ppm, CDCl 3, 100 MHz) 159.8, 155.1, 146.3, 144.8, 140.1, 132.0, 131.7, 129.8, 119.0, 113.6, 113.0, 65.9, 60.9, 60.6, 59.4, 50.1, 47.4, 35.3, 27.9, 20.9, 14.5 , 14.4, 14.1, 13.9. HRMS m / z 501.2280 (M + 1).
Allgemeine Arbeitsvorschrift zur Herstellung von Citrat-SalzenGeneral procedure for the preparation of citrate salts
Die entsprechende freie Base und Citronensäure wurden im molaren Verhältnis 1:1 in Aceton gelöst und 5-30 Min. unter Rückfluß erhitzt und anschließend dasThe corresponding free base and citric acid were dissolved in acetone in a molar ratio of 1: 1 and refluxed for 5-30 minutes, and then the
TU001AT ·* · φ φ φ Φ φφ φ φ φφφφ φφ φ φφ· φ · φφ φφφφ # φ φ φ Φ φ φ φ # φ φ «οΦ Φ Φ Φ φ φ ΦΦ lil)'** ΦΦ ΦΦΦΦ ΦΦΦ Lösungsmittel im Vakuum entfernt. Falls das Citrat nicht als Feststoff vorlag wurde das Rohprodukt mit Methanol digeriert und so Feststoff erhalten.TU001AT * * * φφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφΦφφφφΦφ)) ** ΦΦΦΦΦΦΦΦΦ solvent in vacuum away. If the citrate was not present as a solid, the crude product was digested with methanol to obtain solid.
Bestimmung der in vitro Phosphodiesesterase Hemmung 5 Die Untersuchungen erfolgten durch Cerep in Frankreich an Lysaten aus humanen recombinanten HEK-293 Zellen entsprechend Weishaar, R.E et al. (1986) Biochem. Pharmacol., 35: 787-800. Die Aktivitäten an PDE5, PDE6 und PDE11A und PDE1B werden durch die erfindungsgemäßen Verbindungen gemäß nachfolgender Tabelle gehemmt, wobei zum Vergleich die Werte für Vardenafil und Sildenafil 10 angegeben werden:Determination of In Vitro Phosphodiesterase Inhibition 5 The investigations were carried out by Cerep in France on lysates from human recombinant HEK-293 cells according to Weishaar, R.E et al. (1986) Biochem. Pharmacol., 35: 787-800. The activities on PDE5, PDE6 and PDE11A and PDE1B are inhibited by the compounds according to the invention as shown in the following table, the values for vardenafil and sildenafil 10 being given for comparison:
Tabelle 1: PDE HemmungTable 1: PDE inhibition
Beispiel Nr. PDE5 %lnhibition bei 0.5 nM PDE5 EC50 [nM] PDE6 %lnhibition bei 5 nM PDE11A %lnhibition bei 500 nM PDE1B %lnhibition bei 500 nM 1 68 0,36 15 16 10 2 33 - - - - 3 32 - - - - 4 75 0,22 57 14 -1 5 38 - - - - 6 25 - - _ - 7 Θ6 0,11 70 54 15 8 81 0,16 60 42 31 9 90 0,09 59 58 28 10 81 0,13 57 62 26 Vardenafil 71 0,20 12 9 19 Sildenafil 24 1,52 19 -1 22Example No. PDE5% inhibition at 0.5 nM PDE5 EC50 [nM] PDE6% inhibition at 5 nM PDE11A% inhibition at 500 nM PDE1B% inhibition at 500 nM 1 68 0.36 15 16 10 2 33 - - - - 3 32 - - - - 4 75 0,22 57 14 -1 5 38 - - - - 6 25 - - _ - 7 Θ6 0,11 70 54 15 8 81 0,16 60 42 31 9 90 0,09 59 58 28 10 81 0 , 13 57 62 26 Vardenafil 71 0.20 12 9 19 Sildenafil 24 1.52 19 -1 22
Claims (14)
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| ATA1536/2011A AT512084A1 (en) | 2011-10-20 | 2011-10-20 | DIAZABICYCLO AND DIAZASPIRO ALKAN DERIVATIVES AS PHOSPHODIESTERASE-5 INHIBITORS |
| PCT/EP2012/070682 WO2013057205A1 (en) | 2011-10-20 | 2012-10-18 | Diazabicyclo- and diazaspiro-alkane derivatives as phosphodiesterase-5 inhibitors |
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