Nothing Special   »   [go: up one dir, main page]

DE19931206A1 - Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil - Google Patents

Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil

Info

Publication number
DE19931206A1
DE19931206A1 DE1999131206 DE19931206A DE19931206A1 DE 19931206 A1 DE19931206 A1 DE 19931206A1 DE 1999131206 DE1999131206 DE 1999131206 DE 19931206 A DE19931206 A DE 19931206A DE 19931206 A1 DE19931206 A1 DE 19931206A1
Authority
DE
Germany
Prior art keywords
imidazo
pyrimidin
pyrazolo
hexahydro
dimethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE1999131206
Other languages
German (de)
Inventor
Christian G Stief
Stefan Ueckert
Armin Becker
Udo Jonas
Wolf-Georg Forssmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to DE1999131206 priority Critical patent/DE19931206A1/en
Publication of DE19931206A1 publication Critical patent/DE19931206A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The use of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors (I) is claimed in the production of medicaments for the relaxation of smooth muscular tissue or for increasing the cAMP concentration in smooth muscular tissue. Independent claims are included for the following: (i) the use of the following compounds (II) as for (I) above: (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-2,5-dimethyl-3-benzyl-cyclopenta (4,5)-imidazo (2,1-b) purin-4(3H)-one; (6aR,9aS)-benzyl-5,6a,7,8,9,9a-hexahydro-5-methyl-3-benzyl-cyclopenta (4,5)-imidazo (2,1-b) purin-4(3H)-one; rac-(6aR asterisk ,9aS asterisk )-5,6a,7,8,9,9a-hexahydro-5-methyl-1-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; (6aR,9aS)-3,5-dimethyl-5,6a,7,8,9,9a-hexahydro-1-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; rac-(6a asterisk R,9aS asterisk )-5,6a,7,8,9,9a-hexahydro-1,5-dimethyl-3-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; rac-(6a asterisk R,9aS asterisk )-1,3-dibenzyl-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; rac-(6a asterisk R,9aS asterisk )-5,6a,7,8,9,9a-hexahydro-2,5-dimethyl-3-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one;(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-2,5-dimethyl-3-b enzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; 2',5'-dimethyl-3'-benzyl-spiro-(cyclopentane-1,7'(8'H)-(2H) imidazo (1,2-a) pyrazolo (4,3-e) pyrimidine)-4'(5'H)-one; 7,8-dihydro-3-benzyl-2,5,7,7-tetramethyl-(2H)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; (7R)-7,8-dihydro-2,5-dimethyl-7-isopropyl-3-benzyl-(2H)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-phenyl-2-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; rac-(6aR asterisk ,9aS asterisk )-5,6a,7,8,9,9a-hexahydro-5-methyl-3-benzyl-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; (6aR,9aS)-3,5-dimethyl-5,6a,7,8,9,9a-hexahydro-cyclopenta (4,5)-imidazo (1,2-a) pyrazolo (4,3-e) pyrimidin-4(1H)-one; 2-(2-propoxyphenyl)-8-azapurin-6-one (zaprinast); dipyridamole; 1-(3-chlorophenylamino)-4-phenylphthalazine; 2-(N-(4-carboxypiperidine)-6-chloro-4-(3,4-methylenedioxy)-benzyl)-ami no)-quinazoline; 2,3-dihydro-8-hydroxy-7-nitro-1,4-benzodioxin-2-methanol; 4-((3,4-methylenedioxy)-benzyl)-amino)-6,7,8-trimethoxy-quinazoline; 1-methyl-3'-propyl-6-(5-(N-(4-methylmorpholino)-sulfonyl)-2-ethoxyphen yl)-pyrazolo (4,5) pyrimidin-4(5H)-one (sildenafil); 2-n-butyl-5-chloro-1-(2-chlorobenzyl)-4-methylacetate-imidazole; 1-cyclopentyl-3-methyl-6-(4-pyridinyl)-pyrazolo (3,4-d) pyrimidin-4(5H)-one; 7-(3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-2-carboxy -2,3-didehydro-chroman-4-one; quinazolines or their trimethoxy derivatives; or pyrazolopyrimidines and (ii) the use of sildenafil, IC 351 or BAY-9456 for the production of medicaments for the treatment of diseases in which an increase of the cAMP concentration in smooth muscular tissue.

Description

Die Erfindung betrifft Arzneimittel zur Erhöhung des cAMP-Spiegels bzw. zur Inhibierung der cAMP-Hydrolyse im glatt-muskulären Gewebe und deren Verwendung zur Behandlung von Krankheiten, bei denen eine Inhibierung der cAMP-Hydrolyse in diesem Gewebe notwendig ist.The invention relates to medicaments for increasing the cAMP level or to inhibit cAMP hydrolysis in smooth muscle tissue and their use in the treatment of diseases in which inhibition of cAMP hydrolysis in this tissue is necessary is.

Überraschenderweise wurde gefunden, daß die folgenden Verbindungen, für die bisher eine cGMP-Inhibierung beschrieben würde, nämlich
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro--2,5-dimethyl-3- (phenylmethyl) cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-on;
(6aR,9aS)-(Phenylmethyl)-5,6a,7,8,9,9a-hexahydro-5- methylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-5-methyl-1- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]lpyrazolo[4,3- el]pyrimidin-4(1H)-on;
(6aR,9aS)-3,5-Dimethyl-5,6a,7,8,9,9a-hexahydro-1- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin- 4(1H)-on;
rac-(6aR*,9aS*)-5,6a,7, 8,9; 9a-Hexahydro-1,5-dimethyl-3- (phenylmethyl)cycloperit[4,5]imidazo[1,2-a]pyrazolo-[4,3- e]pyrimidin-4(1H)-on;
tac- (6aR*,9aS*)-1,3-Bis(phenylmethyl)-5,6a; 7,8,9; 9a-hexahydro-5- methylcyclopent[4,5]imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(1H)- on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin- 4(1H)-on;
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin- 4(1H)-on;
2',5'-Dimethyl-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)- [2H]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin]-4'-(5'H)-on;
7,8-Dihydro-3-(phenylmethyl)-2,5,7,7-tetramethyl-[2H]-imidazo[1,2- a]pyrazolo[4,3-e]pyrimidin-4(5H)-on;
(7R)-7,8-Dihydro-2,5-dimethyl-7-(1-methylethyl)-3-(phenylmethyl)- [2H]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-on;
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-phenyl-2- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo-[4,3- e]pyrimidin-4(1H) -on;
rac = (6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazaio[4,3- e]pyrimidin-4(1H)-on;
(6aR,9aS)-3,5-Dimethyl-5,6a,7,8,9,9a­ hexahydrocyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin- 4(1H)-on;
2-(2-Propoxyphenyl)-8-azapurin-6-on(Zaprinast);
Dipyridamol;
1-(3-Chlorphenylamino)-4-phenylphthalazin;
2-(N-(4-Carboxypiperidin)-6-chlor-4-(3,4-(methylendioxy)-benzyl)- amino)-quinazolin;
2,3-Dihydro-8-hydroxy-7-nitro-1,4-benzodioxin-2-methanol;
4-((3,4-(Methylendioxy)benzyl)amino)-6,7,8-trimethoxyquinazolin;
1-Methyl-3-propyl-6-(5-(N-(4-methylmorpholino)sulfonyl)-2- ethoxyphenyl)pyrazol[4,5]pyrimidin-4(5H)on(Sildenafil);
2-n-Butyl-5-chlor-1-(2-chlorbenzyl)-4-methylacetat-imidazol;
1-Cyclopentyl-3-methyl-6-(4-pyridinyl)pyrazolo(3,4-d)pyrimidin- 4(5H)-on;
7-(3-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-2- carboxy-2,3-didehydro-chronan-4-on;
Quinazoline und deren Trimethoxy-derivate; und
Pyrazolopyrimidone
die Hydrolyse von cAMP in glatt-muskulärem Gewebe inhibieren und damit zu einem Anstieg der Konzentration von cAMP in dem betreffenden Gewebe führen.Surprisingly, it has been found that the following compounds, for which cGMP inhibition has hitherto been described, namely
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro - 2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [2,1-b] purine-4 ( 3H) -on;
(6aR, 9aS) - (phenylmethyl) -5,6a, 7,8,9,9a-hexahydro-5-methylcyclopent [4,5] imidazo [2,1-b] purin-4 (3H) -one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-5-methyl-1- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] lpyrazolo [4 , 3-el] pyrimidin-4 (1H) -one;
(6aR, 9aS) -3,5-dimethyl-5,6a, 7,8,9,9a-hexahydro-1- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo- [4, 3-e] pyrimidin-4 (1H) -one;
rac- (6aR *, 9aS *) - 5.6a, 7, 8.9; 9a-hexahydro-1,5-dimethyl-3- (phenylmethyl) cycloperite [4,5] imidazo [1,2-a] pyrazolo- [4,3- e] pyrimidin-4 (1H) -one;
tac- (6aR *, 9aS *) - 1,3-bis (phenylmethyl) -5,6a; 7,8,9; 9a-hexahydro-5-methylcyclopent [4,5] imidazo [1,2-a] pyrazolo- [4,3-e] pyrimidin-4 (1H) - one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1H) -one;
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3 -e] pyrimidine-4 (1H) -one;
2 ', 5'-Dimethyl-3' - (phenylmethyl) spiro [cyclopentane-1,7 '(8'H) - [2H] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine] - 4 '- (5'H) -one;
7,8-dihydro-3- (phenylmethyl) -2,5,7,7-tetramethyl- [2H] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one ;
(7R) -7,8-Dihydro-2,5-dimethyl-7- (1-methylethyl) -3- (phenylmethyl) - [2H] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine -4 (5H) -on;
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-5-methyl-3-phenyl-2- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo- [ 4,3- e] pyrimidin-4 (1H) -one;
rac = (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-5-methyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazaio [4 , 3-e] pyrimidin-4 (1H) -one;
(6aR, 9aS) -3,5-dimethyl-5,6a, 7,8,9,9a hexahydrocyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine-4 (1H ) -on;
2- (2-propoxyphenyl) -8-azapurin-6-one (Zaprinast);
Dipyridamole;
1- (3-chlorophenylamino) -4-phenylphthalazine;
2- (N- (4-carboxypiperidine) -6-chloro-4- (3,4- (methylenedioxy) benzyl) amino) quinazoline;
2,3-dihydro-8-hydroxy-7-nitro-1,4-benzodioxin-2-methanol;
4 - ((3,4- (methylenedioxy) benzyl) amino) -6,7,8-trimethoxyquinazoline;
1-methyl-3-propyl-6- (5- (N- (4-methylmorpholino) sulfonyl) -2-ethoxyphenyl) pyrazole [4,5] pyrimidin-4 (5H) one (sildenafil);
2-n-butyl-5-chloro-1- (2-chlorobenzyl) -4-methyl acetate imidazole;
1-cyclopentyl-3-methyl-6- (4-pyridinyl) pyrazolo (3,4-d) pyrimidin-4 (5H) -one;
7- (3- (4-Acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy) -2-carboxy-2,3-didehydro-chronan-4-one;
Quinazolines and their trimethoxy derivatives; and
Pyrazolopyrimidones
inhibit the hydrolysis of cAMP in smooth muscle tissue and thus lead to an increase in the concentration of cAMP in the tissue in question.

Die genannten Verbindungen wurden bisher beschrieben als besonders wirksam zur Erhöhung von cGMP-Spiegeln.The compounds mentioned have so far been described as special effective for increasing cGMP levels.

Die überraschenden Befunde der Inhibierung des cAMP-Abbaus sind in den Abb. 1 bis 3 dargestellt.The surprising findings of inhibition of cAMP degradation are shown in Figs. 1 to 3.

Physiologischerweise spielt Stickoxid (NO) eine wesentliche Rolle. in der Relaxation des glattmuskulären Gewebes. NO induziert innerhalb dieses Gewebes die Bildung des Second Messengers cGMP wie in Abb. 1 dargestellt, der dann über eine komplexe Kaskade zu einer Relaxation der glatten Muskelzellen führt. Zur Verstärkung der Wirkung von NO wurden verschiedene Verbindungen entwickelt, die die Phosphodiesterasen hemmen, die zu einem Abbau von cGMP führen und dadurch den cGMP-Spiegel erhöhen.Physiologically, nitric oxide (NO) plays an important role. in the relaxation of smooth muscle tissue. NO induces the formation of the second messenger cGMP within this tissue as shown in Fig. 1, which then leads to a relaxation of the smooth muscle cells via a complex cascade. To increase the effect of NO, various compounds have been developed which inhibit the phosphodiesterases, which lead to a breakdown of cGMP and thereby increase the cGMP level.

Beispielhaft für derartige Verbindungen ist in Abb. 2 die Wirkung von Sildenafil auf den cGMP-Spiegel dargestellt.The effect of sildenafil on the cGMP level is shown in Fig. 2 as an example of such compounds.

Überraschenderweise zeigte sich, daß in glatt-muskulärem humanen Gewebe bei der Inkubation mit Sildenafil in Dosen, die normalerweise durch orale Einnahme erreicht werden, kein nennenswerter Anstieg von cGMP gemessen wurde. Erst in unphysiologisch hohen Dosierungen, die beim Menschen, nicht oder nur mit gravierendsten Nebenwirkungen wie z. B. Kreislaufversagen oder Herzflimmern, erreicht werden können, ließ sich eine Erhöhung von cGMP feststellen.Surprisingly, it was found that in smooth-muscular human Tissue when incubated with sildenafil in cans normally achieved through oral ingestion, none significant increase in cGMP was measured. Only in unphysiologically high doses that are not in humans or only with the most serious side effects such. B. Circulatory failure or cardiac fibrillation, an increase could be achieved from cGMP.

Völlig unerwartet wurde daher der in Abb. 3 dargestellte drastische Anstieg der cAMP-Spiegel gefunden.The drastic increase in cAMP levels shown in Fig. 3 was therefore found completely unexpectedly.

Gegenstand der Erfindung ist daher die Verwendung der genannten Verbindungen zur Herstellung von Arzneimitteln zur Inhibierung der glatt-muskulären zyklischen Adenosin-3',5'-monophosphatat­ phosphodiesterasen (cAMP PDEs).The invention therefore relates to the use of the abovementioned Compounds for the manufacture of medicaments for inhibiting the smooth-muscular cyclic adenosine-3 ', 5'-monophosphatate phosphodiesterases (cAMP PDEs).

Ein weiterer Gegenstand der Erfindung ist die Verwendung von Inhibitoren der cAMP PDEs zur Relaxation glatt-muskulären Gewebes.Another object of the invention is the use of Inhibitors of cAMP PDEs for relaxation of smooth muscular tissue.

Claims (5)

1. Verwendung von Inhibitoren der cAMP PDEs zur Herstellung von Arzneimitteln zur Relaxation glatt-muskulären Gewebes.1. Use of inhibitors of cAMP PDEs for the production of Medicines for relaxation of smooth muscular tissue. 2. Verwendung von Inhibitoren der cAMP PDEs zur Herstellung von Arzneimitteln zur Erhöhung der cAMP-Konzentration in glatt­ muskulärem Gewebe.2. Use of inhibitors of cAMP PDEs for the production of Medicines to increase the concentration of cAMP in smooth muscular tissue. 3. Verwendung von Verbindungen ausgewählt aus der Gruppe
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-on;
(6aR,9aS)-(Phenylmethyl)-5,6a,7,8,9,9a-hexahydro-5- methylcycloperit[4,5]imidazo[2,1-b]purin-4(3H)-on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-5-methyl-1- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]lpyrazolo[4,3- el]pyrimidin-4(1H)-on;
(6aR,9aS)-3,5-Dimethyl-5,6a,7,8,9, 9a-hexahydro-1- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo-[4,3- e]pyrimidin-4(1H)-on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-1,5-dimethyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo-[4,3- e]pyrimidin-4(1H)-on;
rac-(6aR*; 9aS*)-1,3-Bis(phenylmethyl)-5,6a,7,8,9,9a-hexahydro- 5-methylcyclopent[4,5]imidazo[1,2-a]pyrazoho-[4,3-e]pyrimidin- 4(1H)-on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3- e]pyrimidin-4(1H)-on;
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazoho[4,3- e]pyrimidin-4(1H)-on;
2',5'-Dimethyl-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)- [2H]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin]-4'-(5'H)-(5'H)-on;
7,8-Dihydro-3-(phenylmethyl)-2,5,7,7-tetramethyl-[2H]- imidazo[1,2-a]pyrazolo[4,3-e] pyrimidin-4(5H)-on;
(7R)-7,8-Dihydro-2,5-dimethyl-7-(1-methylethyl)-3- (phenylmethyl)-[2H]imidazo[1,2-a]pyrazalo[4,3-e]pyrimidin- 4(5H)-on;
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-phenyl-2- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a] pyrazolo-[4,3- e] pyrimidin-4(1H)-on;
rac-(6aR*,9aS*)-5,6a,7,8,9,9a-Hexahydro-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3- e]pyrimidin-4(1H)-on;
(6aR,9aS)-3,5-Dimethyl-5,6a,7,8,9,9a- hexahydrocyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin- 4(1H)-on;
2-(2-Propoxyphenyl)-8-azapurin-6-on(Zaprinast);
Dipyridamol;
1-(3-Chlorphenylamino)-4-phenylphthalazin;
2-(N-(4-Carboxypiperidin)-6-chlor-4-(3,4-(methylendioxy)- benzyl)-amino)-quinazolin;
2,3-Dihydro-8-hydroxy-7-nitro-1,4-benzodioxin-2-methanol;
4-((3,4-(Methylendioxy)benzyl)amino)-6,7,8-trimethoxy­ quinazolin ;
1-Methyl-3'-propyl-6-(5- N-(4-methylntorpholino)sulfonyl)-2- ethoxyphenyl)pyrazol[4,5] pyrimidin-4(5H)on(Sildenafil);
2-n-Butyl-5-chlor-1-(2-chlorbenzyl)-4-methylacetat-imidazol;
1-Cyclopentyl-3-methyl-6-(4-pyridinyl)pyrazolo(3,4-d)pyrimidin- 4(5H)-on;
7-(3-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-2- carboxy-2,3-didehydro-chronan-4-on;
Quinazolinen und deren Trimethoxy-derivaten; und
Pyrazolopyrimidonen
zur Herstellung von Arzneimitteln zur Relaxation glatt­ muskulären Gewebes.3. Use of compounds selected from the group
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [2,1-b] purine-4 (3H ) -on;
(6aR, 9aS) - (phenylmethyl) -5,6a, 7,8,9,9a-hexahydro-5-methylcycloperit [4,5] imidazo [2,1-b] purin-4 (3H) -one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-5-methyl-1- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] lpyrazolo [4 , 3-el] pyrimidin-4 (1H) -one;
(6aR, 9aS) -3,5-dimethyl-5,6a, 7,8,9,9a-hexahydro-1- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo- [4, 3-e] pyrimidin-4 (1H) -one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-1,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo - [4,3- e] pyrimidin-4 (1H) -one;
rac- (6aR *; 9aS *) - 1,3-bis (phenylmethyl) -5,6a, 7,8,9,9a-hexahydro-5-methylcyclopent [4,5] imidazo [1,2-a] pyrazoho - [4,3-e] pyrimidin-4 (1H) -one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3- e] pyrimidin-4 (1H) -one;
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-2,5-dimethyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazoho [4,3 - e] pyrimidin-4 (1H) -one;
2 ', 5'-Dimethyl-3' - (phenylmethyl) spiro [cyclopentane-1,7 '(8'H) - [2H] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine] - 4 '- (5'H) - (5'H) -one;
7,8-dihydro-3- (phenylmethyl) -2,5,7,7-tetramethyl- [2H] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one ;
(7R) -7,8-Dihydro-2,5-dimethyl-7- (1-methylethyl) -3- (phenylmethyl) - [2H] imidazo [1,2-a] pyrazalo [4,3-e] pyrimidine - 4 (5H) -on;
(6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-5-methyl-3-phenyl-2- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo- [ 4,3- e] pyrimidin-4 (1H) -one;
rac- (6aR *, 9aS *) - 5,6a, 7,8,9,9a-hexahydro-5-methyl-3- (phenylmethyl) cyclopent [4,5] imidazo [1,2-a] pyrazolo [4 , 3-e] pyrimidin-4 (1H) -one;
(6aR, 9aS) -3,5-dimethyl-5,6a, 7,8,9,9a-hexahydrocyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine-4 ( 1H) -on;
2- (2-propoxyphenyl) -8-azapurin-6-one (Zaprinast);
Dipyridamole;
1- (3-chlorophenylamino) -4-phenylphthalazine;
2- (N- (4-carboxypiperidine) -6-chloro-4- (3,4- (methylenedioxy) benzyl) amino) quinazoline;
2,3-dihydro-8-hydroxy-7-nitro-1,4-benzodioxin-2-methanol;
4 - ((3,4- (methylenedioxy) benzyl) amino) -6,7,8-trimethoxy quinazoline;
1-methyl-3'-propyl-6- (5- N- (4-methylntorpholino) sulfonyl) -2-ethoxyphenyl) pyrazole [4,5] pyrimidin-4 (5H) one (sildenafil);
2-n-butyl-5-chloro-1- (2-chlorobenzyl) -4-methyl acetate imidazole;
1-cyclopentyl-3-methyl-6- (4-pyridinyl) pyrazolo (3,4-d) pyrimidin-4 (5H) -one;
7- (3- (4-Acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy) -2-carboxy-2,3-didehydro-chronan-4-one;
Quinazolines and their trimethoxy derivatives; and
Pyrazolopyrimidones
for the production of medicines for relaxation of smooth muscular tissue. 4. Verwendung von Verbindungen gemäß Anspruch 3 zur Herstellung von Arzneimitteln zur. Erhöhung der cAMP-Konzentration in glatt­ muskulärem Gewebe.4. Use of compounds according to claim 3 for the preparation of medicines for. Increase in cAMP concentration in smooth muscular tissue. 5. Verwendung von Sildenafil, IC 351 oder BAY38-9456 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten bei denen eine Erhöhung der cAMP-Konzentration in glatt­ muskulärem Gewebe erforderlich ist.5. Use of Sildenafil, IC 351 or BAY38-9456 for Manufacture of medicines for the treatment of diseases where an increase in cAMP concentration in smooth muscular tissue is required.
DE1999131206 1999-07-07 1999-07-07 Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil Withdrawn DE19931206A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE1999131206 DE19931206A1 (en) 1999-07-07 1999-07-07 Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1999131206 DE19931206A1 (en) 1999-07-07 1999-07-07 Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil

Publications (1)

Publication Number Publication Date
DE19931206A1 true DE19931206A1 (en) 2001-01-11

Family

ID=7913849

Family Applications (1)

Application Number Title Priority Date Filing Date
DE1999131206 Withdrawn DE19931206A1 (en) 1999-07-07 1999-07-07 Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil

Country Status (1)

Country Link
DE (1) DE19931206A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006133261A3 (en) * 2005-06-06 2007-06-21 Intra Cellular Therapies Inc Organic compounds
US8273751B2 (en) 2007-12-06 2012-09-25 Takeda Pharmaceutical Company Limited Organic compounds
JP2013530956A (en) * 2010-05-31 2013-08-01 イントラ−セルラー・セラピーズ・インコーポレイテッド Organic compounds
US8536159B2 (en) 2008-12-06 2013-09-17 Intra-Cellular Therapies, Inc. Organic compounds
US8633180B2 (en) 2008-12-06 2014-01-21 Intra-Cellular Therapies, Inc. Organic compounds
US8664207B2 (en) 2008-12-06 2014-03-04 Intra-Cellular Therapies, Inc. Organic compounds
US8697710B2 (en) 2008-12-06 2014-04-15 Intra-Cellular Therapies, Inc. Optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo [3,4-d]pyrimidin-6(7H)-ones
US8846693B2 (en) 2007-12-06 2014-09-30 Intra-Cellular Therapies, Inc. Optionally substituted pyrazolo[3,4-d]pyrimidine-4,6-diones
US8859564B2 (en) 2008-12-06 2014-10-14 Intra-Cellular Therapies, Inc. Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase 1
US8927556B2 (en) 2008-12-06 2015-01-06 Intra-Cellular Therapies, Inc. 1H-pyrrolo[3,4-D]pyrimidin-2(6H)-one compounds
US9006258B2 (en) 2006-12-05 2015-04-14 Intra-Cellular Therapies, Inc. Method of treating female sexual dysfunction with a PDE1 inhibitor
US9073936B2 (en) 2013-03-15 2015-07-07 Intra-Cellular Therapies, Inc. Organic compounds
US9157906B2 (en) 2001-08-31 2015-10-13 The Rockefeller University Phosphodiesterase activity and regulation of phosphodiesterase 1B-mediated signaling in brain
US9198924B2 (en) 2006-11-13 2015-12-01 Intra-Cellular Therapies, Inc. Organic compounds
US9255099B2 (en) 2006-06-06 2016-02-09 Intra-Cellular Therapies, Inc. Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors
US9371327B2 (en) 2010-05-31 2016-06-21 Intra-Cellular Therapies, Inc. PDE1 inhibitor compounds
US9434730B2 (en) 2010-05-31 2016-09-06 Intra-Cellular Therapies, Inc. PDE1 inhibitor compounds
US9468637B2 (en) 2009-05-13 2016-10-18 Intra-Cellular Therapies, Inc. Organic compounds
US9545406B2 (en) 2013-03-15 2017-01-17 Intra-Cellular Therapies, Inc. Method of treating a CNS injury with a PDE1 inhibitor
US9546175B2 (en) 2014-08-07 2017-01-17 Intra-Cellular Therapies, Inc. Organic compounds
US9605041B2 (en) 2009-08-05 2017-03-28 Intra-Cellular Therapies, Inc. Regulatory proteins and inhibitors
US9763948B2 (en) 2010-05-31 2017-09-19 Intra-Cellular Therapies, Inc. PDE1 inhibitory compounds and methods
US9801882B2 (en) 2013-02-17 2017-10-31 Intra-Cellular Therapies, Inc. Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases
US9849132B2 (en) 2014-01-08 2017-12-26 Intra-Cellular Therapies, Inc. Products and pharmaceutical compositions
US9884872B2 (en) 2014-06-20 2018-02-06 Intra-Cellular Therapies, Inc. Organic compounds
US10105349B2 (en) 2014-12-06 2018-10-23 Intra-Cellular Therapies, Inc. Organic compounds
US10131671B2 (en) 2014-08-07 2018-11-20 Intra-Cellular Therapies, Inc. Organic compounds
US10150774B2 (en) 2014-09-17 2018-12-11 Intra-Cellular Therapies, Inc. Compounds and methods
US10285992B2 (en) 2014-08-07 2019-05-14 Intra-Cellular Therapies, Inc. Combinations of PDE1 inhibitors and NEP inhibitors and associated methods
US10300064B2 (en) 2014-12-06 2019-05-28 Intra-Cellular Therapies, Inc. Organic compounds
US10561656B2 (en) 2011-06-10 2020-02-18 Intra-Cellular Therapies, Inc. Organic compounds
US10682354B2 (en) 2016-03-28 2020-06-16 Intra-Cellular Therapies, Inc. Compositions and methods
US11291666B2 (en) 2016-09-12 2022-04-05 Intra-Cellular Therapies, Inc. Uses
US11464781B2 (en) 2009-02-25 2022-10-11 Intra-Cellular Therapies, Inc. PDE1 inhibitors for ophthalmic disorders
US11759465B2 (en) 2018-01-31 2023-09-19 Intra-Cellular Therapies, Inc. Uses

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9157906B2 (en) 2001-08-31 2015-10-13 The Rockefeller University Phosphodiesterase activity and regulation of phosphodiesterase 1B-mediated signaling in brain
WO2006133261A3 (en) * 2005-06-06 2007-06-21 Intra Cellular Therapies Inc Organic compounds
JP2008545783A (en) * 2005-06-06 2008-12-18 イントラ−セルラー・セラピーズ・インコーポレイテッド Organic compounds
JP2012180369A (en) * 2005-06-06 2012-09-20 Takeda Chem Ind Ltd Organic compound
US8273750B2 (en) 2005-06-06 2012-09-25 Takeda Pharmaceutical Company Limited Organic compounds
CN101248050B (en) * 2005-06-06 2013-07-17 武田药品工业株式会社 Organic compounds
US9624230B2 (en) 2005-06-06 2017-04-18 Intra-Cellular Therapies, Inc. Organic compounds
US9000001B2 (en) 2005-06-06 2015-04-07 Intra-Cellular Therapies, Inc. Organic compounds
JP2015007121A (en) * 2005-06-06 2015-01-15 武田薬品工業株式会社 Organic compound
US9255099B2 (en) 2006-06-06 2016-02-09 Intra-Cellular Therapies, Inc. Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors
US9198924B2 (en) 2006-11-13 2015-12-01 Intra-Cellular Therapies, Inc. Organic compounds
US9006258B2 (en) 2006-12-05 2015-04-14 Intra-Cellular Therapies, Inc. Method of treating female sexual dysfunction with a PDE1 inhibitor
US8846693B2 (en) 2007-12-06 2014-09-30 Intra-Cellular Therapies, Inc. Optionally substituted pyrazolo[3,4-d]pyrimidine-4,6-diones
US8273751B2 (en) 2007-12-06 2012-09-25 Takeda Pharmaceutical Company Limited Organic compounds
US9403836B2 (en) 2007-12-06 2016-08-02 Intra-Cellular Therapies, Inc. Organic compounds
US8829008B2 (en) 2007-12-06 2014-09-09 Takeda Pharmaceutical Company Limited Organic compounds
CN104370919A (en) * 2007-12-06 2015-02-25 武田药品工业株式会社 Organic compounds
CN104370920A (en) * 2007-12-06 2015-02-25 武田药品工业株式会社 Organic compounds
US8664207B2 (en) 2008-12-06 2014-03-04 Intra-Cellular Therapies, Inc. Organic compounds
US8859564B2 (en) 2008-12-06 2014-10-14 Intra-Cellular Therapies, Inc. Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase 1
US8633180B2 (en) 2008-12-06 2014-01-21 Intra-Cellular Therapies, Inc. Organic compounds
US8536159B2 (en) 2008-12-06 2013-09-17 Intra-Cellular Therapies, Inc. Organic compounds
US8697710B2 (en) 2008-12-06 2014-04-15 Intra-Cellular Therapies, Inc. Optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo [3,4-d]pyrimidin-6(7H)-ones
US9487527B2 (en) 2008-12-06 2016-11-08 Intra-Cellular Therapies, Inc. Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase I
US8927556B2 (en) 2008-12-06 2015-01-06 Intra-Cellular Therapies, Inc. 1H-pyrrolo[3,4-D]pyrimidin-2(6H)-one compounds
US11464781B2 (en) 2009-02-25 2022-10-11 Intra-Cellular Therapies, Inc. PDE1 inhibitors for ophthalmic disorders
US9468637B2 (en) 2009-05-13 2016-10-18 Intra-Cellular Therapies, Inc. Organic compounds
US10010553B2 (en) 2009-05-13 2018-07-03 Intra-Cellular Therapies, Inc. Organic compounds
US10238660B2 (en) 2009-05-13 2019-03-26 Intra-Cellular Therapies, Inc. Organic compounds
US9605041B2 (en) 2009-08-05 2017-03-28 Intra-Cellular Therapies, Inc. Regulatory proteins and inhibitors
US9371327B2 (en) 2010-05-31 2016-06-21 Intra-Cellular Therapies, Inc. PDE1 inhibitor compounds
JP2013530956A (en) * 2010-05-31 2013-08-01 イントラ−セルラー・セラピーズ・インコーポレイテッド Organic compounds
US9434730B2 (en) 2010-05-31 2016-09-06 Intra-Cellular Therapies, Inc. PDE1 inhibitor compounds
US9556185B2 (en) 2010-05-31 2017-01-31 Intra-Cellular Therapies, Inc. Organic compounds
US9763948B2 (en) 2010-05-31 2017-09-19 Intra-Cellular Therapies, Inc. PDE1 inhibitory compounds and methods
US10561656B2 (en) 2011-06-10 2020-02-18 Intra-Cellular Therapies, Inc. Organic compounds
US10398698B2 (en) 2013-02-17 2019-09-03 Intra-Cellular Therapies, Inc. Uses
US9801882B2 (en) 2013-02-17 2017-10-31 Intra-Cellular Therapies, Inc. Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases
US10682355B2 (en) 2013-03-15 2020-06-16 Intra-Cellular Therapies, Inc. Uses
US9598426B2 (en) 2013-03-15 2017-03-21 Intra-Cellular Therapies, Inc. Organic compounds
US9556186B2 (en) 2013-03-15 2017-01-31 Intra-Cellular Therapies, Inc. Organic compounds
US11504372B2 (en) 2013-03-15 2022-11-22 Intra-Cellular Therapies, Inc. Uses
US9545406B2 (en) 2013-03-15 2017-01-17 Intra-Cellular Therapies, Inc. Method of treating a CNS injury with a PDE1 inhibitor
US9073936B2 (en) 2013-03-15 2015-07-07 Intra-Cellular Therapies, Inc. Organic compounds
US10183023B2 (en) 2013-03-15 2019-01-22 Intra-Cellular Therapies, Inc. Uses
US9849132B2 (en) 2014-01-08 2017-12-26 Intra-Cellular Therapies, Inc. Products and pharmaceutical compositions
US9884872B2 (en) 2014-06-20 2018-02-06 Intra-Cellular Therapies, Inc. Organic compounds
US10285992B2 (en) 2014-08-07 2019-05-14 Intra-Cellular Therapies, Inc. Combinations of PDE1 inhibitors and NEP inhibitors and associated methods
US10131671B2 (en) 2014-08-07 2018-11-20 Intra-Cellular Therapies, Inc. Organic compounds
US11166956B2 (en) 2014-08-07 2021-11-09 Intra-Cellular Therapies, Inc. Combinations of PDE1 inhibitors and NEP inhibitors
US9546175B2 (en) 2014-08-07 2017-01-17 Intra-Cellular Therapies, Inc. Organic compounds
US10150774B2 (en) 2014-09-17 2018-12-11 Intra-Cellular Therapies, Inc. Compounds and methods
US10543194B2 (en) 2014-12-06 2020-01-28 Intra-Cellular Therapies, Inc. Organic compounds
US10300064B2 (en) 2014-12-06 2019-05-28 Intra-Cellular Therapies, Inc. Organic compounds
US10105349B2 (en) 2014-12-06 2018-10-23 Intra-Cellular Therapies, Inc. Organic compounds
US10682354B2 (en) 2016-03-28 2020-06-16 Intra-Cellular Therapies, Inc. Compositions and methods
US11291666B2 (en) 2016-09-12 2022-04-05 Intra-Cellular Therapies, Inc. Uses
US11759465B2 (en) 2018-01-31 2023-09-19 Intra-Cellular Therapies, Inc. Uses
US11839614B2 (en) 2018-01-31 2023-12-12 Intra-Cellular Therapies, Inc. Methods for treating or mitigating cardiotoxicity characterized by inhibition of adenosine A2 signaling and/or adenosine A2 receptor expression

Similar Documents

Publication Publication Date Title
DE19931206A1 (en) Relaxing, or increasing cyclic adenosine monophosphate concentration in smooth muscular tissue, e.g. by administration of cAMP phosphodiesterase inhibitors, dipyridamole or sildenafil
WO2010132127A1 (en) Organic compounds
US9006258B2 (en) Method of treating female sexual dysfunction with a PDE1 inhibitor
ES2334682T3 (en) NEW USE FOR PDE5 INHIBITORS.
DE69633860D1 (en) Oral aktive adenosinkinase-inhibitoren
US6225315B1 (en) Method of treating nitrate-induced tolerance
WO2008063505A1 (en) Organic compounds
US20120178915A1 (en) Pyrimidine derivatives and analogs, preparation method and use thereof
RU2011116928A (en) HETEROCYCLIC INHIBITORS JAK KINASES
AU2008276455A1 (en) Combinations for the treatment of B-cell proliferative disorders
RU2009140469A (en) Pyrrolopyrimidine-7-one derivatives and their use as pharmaceutical preparations
JP2007526285A5 (en)
IL122333A0 (en) Water-soluble adenosine kinase inhibitors
AU2008276451A1 (en) Treatments of B-cell proliferative disorders
HUP0500332A3 (en) Substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1h)-one derivatives, their use and pharmaceutical compositions containing them
RU2007102847A (en) COMBINATION OF NORADRENALINE AND NORADRENALINE RETURN INHIBITOR AND DEV INHIBITOR
DE102013104441A1 (en) Acne drug and process for its preparation
CN111297868A (en) Use of a composition comprising a heterocyclic compound for the manufacture of a medicament for the treatment of phosphodiesterase mediated diseases
CA2529007A1 (en) Composition comprising a pulmonary surfactant and a pde5 inhibitor for the treatment of lung diseases
DE69230891D1 (en) Medicines used to treat autoimmune diseases
MX2022014855A (en) Pyrazolo[1,5-a]pyrimidine derivatives having multimodal activity against pain.
US20110224128A1 (en) Methods and compositions for treatment of muscular dystrophy
FI953298A0 (en) 5-alkoxy (1,2,4) triazolo (1,5-c) pyrimidine-2 (3H) -thione compounds and their use in the preparation of 2,2'-dithiobis (5-alkoxy (1,2,4 triazolo) (1,5-C) pyrimidine) and 2-chlorosulfonyl-5-alkoxy (1,2,4) triazolo (1,5-C) pyrimidine compounds
JPWO2020068729A5 (en)
TR200000473T1 (en) Anticonvulsive and antiallergic / antiastimatic pyrazolo- [3,4-d] pyrimidines showing adenosine receptor and method of their preparation.

Legal Events

Date Code Title Description
8139 Disposal/non-payment of the annual fee