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
  • A61K31/33—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the field relates to the administration of inhibitors of phosphodiesterase 1 (PDE1) inhibitors for promoting the resolution of inflammation, for example through the polarization of Ml macrophages to M2 macrophages, and the treatment and prophylaxis of diseases or disorders related to inflammation.
• PDE1 phosphodiesterase 1
• PDEs phosphodiesterases
• CaM-PDEs Ca 2+ -calmodulin-dependent phosphodiesterases
• CaM-PDEs Ca 2+ -calmodulin-dependent phosphodiesterases
• PDEs are therefore active in stimulated conditions when intra-cellular calcium levels rise, leading to increased hydrolysis of cyclic nucleotides.
• the three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C are all expressed in central nervous system tissue.
• PDE1A In the brain, the predominant expression of PDE1A is in the cortex and neostriatum, PDE1B is expressed in the neostriatum, prefrontal cortex, hippocampus, and olfactory tubercle, and PDE1C is more ubiquitously expressed.
• PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells, and PDE4 inhibitors are of interest as anti-inflammatory drugs.
• PDE1 has not been thought to play a major role in the inflammatory response, although PDE-1 is induced in monocyte-to-macrophage differentiation mediated by the cytokine granulocyte-macrophage colony- stimulating factor (GM-CSF).
• GM-CSF cytokine granulocyte-macrophage colony- stimulating factor
• the PDE1 inhibitor vinpocetine has been shown to be anti inflammatory, but the anti-inflammatory action of vinpocetine is believed to be caused by a direct inhibition of the IKB kinase complex (IKK) rather than PDE blockade.
• IKK IKB kinase complex
• Macrophages have a central role in maintaining homeostasis and mediating inflammation in the body. Macrophages are capable of polarization by which a macrophage expresses different functional programs in response to microenvironmental signals. There are several activated forms of macrophages, but the two main groups are designated as Ml and M2. Ml macrophages, also referred to as“classically activated macrophages,” are activated by LPS and IFN-gamma, and secrete high levels of IL-12 and low levels of IL-10 for a pro-inflammatory effect.
• the M2 designation also referred to as“alternatively activated macrophages,” broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti inflammatory cytokines like IL-10.
• M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12. Prolonged Ml type of macrophages is harmful for the organism and that is why tissue repair and restoration is necessary.
• Macrophage polarization is also involved in virus infection, in which M2 phenotype macrophages can also suppress inflammation and promote tissue healing. Influenza virus augments the phagocytic function of human macrophages, which is a major feature of M2 phenotype, to clear apoptotic cells and accelerate the resolution of inflammation.
• SARS severe acute respiratory syndrome
• M2 phenotype macrophages are critical to regulate immune response and protect host from the long-term progression to fibrotic lung disease by a STAT dependent pathway.
• severe respiratory syncytial virus (RSV) induced bronchiolitis is closely associated with mixed Ml and M2 macrophages.
• Macrophage polarization has also been shown to play a significant role in various inflammatory diseases and disorders, such as nonalcoholic steatohepatitis (NASH),
• NASH nonalcoholic steatohepatitis
• Atherosclerosis metabolic disease
• systemic lupus erythematosus among many others.
• Figure 1 depicts the number of leukocytes detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 2A depicts the number of macrophages detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 2B depicts the number of macrophages expressed as percent of total leukocytes detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 3A depicts the number of neutrophils detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 3B depicts the amount of neutrophils expressed as percent of total leukocytes detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 4A depicts the amount of Ml macrophages expressed as a percentage of total macrophages detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 4B depicts the amount of M2 macrophages expressed as a percentage of total macrophages detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 5A depicts the number of Ml macrophages detected at the site of inflammation in the M2 activation state following sterile insult when treated with Compound 1.
• Figure 5B depicts the number of M2 macrophages detected at the site of
• Figure 6A depicts the mean fluorescent intensity (MFI) of CD38 expression on macrophage populations detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 6B depicts the mean fluorescent intensity (MFI) of CD38 expression on macrophage populations detected at the site of inflammation following sterile insult when treated with Compound 1.
• Figure 7 depicts cytokine production in plasma in test subjects following sterile insult when treated with Compound 1.
• Figure 8 depicts the number of macrophages in the Ml activation state detected at the site of inflammation following sterile insult when treated with Compound 2.
• Figure 9 depicts the number of macrophages in the M2 activation state detected at the site of inflammation following sterile insult when treated with Compound 2.
• Figure 10 depicts the results of Compound 1 on the motility of BV2 cells in a microglia chemotaxis assay.
• Figure 11 A depicts the amount of CD80+ macrophages expressed as a percentage of total macrophages detected at the site of inflammation.
• Figure 11B depicts the amount of iNOS+ macrophages expressed as a percentage of total macrophages detected at the site of inflammation.
• Figure 12A depicts the amount of Argl+ macrophages expressed as a percentage of total macrophages detected at the site of inflammation.
• Figure 12A depicts the amount of CD206+ macrophages expressed as a percentage of total macrophages detected at the site of inflammation.
• inhibition of PDE1 regulates inflammatory activity in macrophages, reducing expression of pro-inflammatory genes, thereby providing novel treatments for a variety of disorders and conditions characterized by macrophage mediation.
• cGMP also plays a role in modulation of inflammatory processes, such as inducible NO synthase induction and TNF-a release. Therefore, the marked up-regulation of PDE1B may be critical in the regulation of these processes in differentiated macrophages. This suggests that PDE1 inhibitors, such as those disclosed herein, may prove beneficial in diseases associated with, for example, inflammation disorders relating to macrophage activation.
• the invention provides using various PDE1 inhibitory compounds to treat inflammation, and/or diseases or disorders related to inflammation.
• PDE1B may affect macrophage activation in the blood and/or microglial activation in the CNS, so as to reduce Ml activation and the release of pro-inflammatory cytokines, and to promote the polarization of macrophages to M2 type through the up-regulation of anti-inflammatory cytokines such as IL-10. Discussion of the treatment of and prophylaxis of inflammation and/or diseases or disorders related to inflammation as they relate to the microglia e.g.,
• Ml to M2 polarization in macrophages is important in a number of inflammatory-related disorders including bacterial infections (e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes,
• Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium avium infections include viral infections (e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus-2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome
• viral infections e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus-2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial
• Coronavirus, West Nile Virus, Viral Hepatitis e.g., Hepatitis A, Hepatitis B, Hepatitis C
• parasitic infestations e.g., Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, Schistosoma mansoni infestations
• atopic dermatitis pneumonia
• cardiovascular diseases such as atherosclerosis; obesity and insulin resistance; asthma; pulmonary fibrosis; cardiac obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; nonalcoholic
• NASH steatoheptatitis
• SLE systemic lupus erythematosus
• wound healing pleurisy
• peritonitis and cystic fibrosis.
• Targeted inhibition of PDE1 with a compound of the present invention is believed to affect macrophage activation and promote production of anti-inflammatory cytokines and factors involved in resolution of macrophage mediated inflammation.
• the invention provides a method of promoting resolution of inflammation for the treatment or prophylaxis of inflammation or disease associated with inflammation, the method comprising administering a specific inhibitor of
• phosphodiesterase type I e.g., PDE1 inhibitor, e.g., a PDE1B inhibitor
• PDE1 inhibitor e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described.
• the invention provides a method of promoting macrophage activation to the M2 activation state, the method comprising administering a specific inhibitor of phosphodiesterase type I (e.g., PDE1 inhibitor, e.g., a PDE1B inhibitor) (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described).
• a specific inhibitor of phosphodiesterase type I e.g., PDE1 inhibitor, e.g., a PDE1B inhibitor
• a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described.
• the invention provides a method of treating inflammation and/or diseases or disorders associated with inflammation and/or microglial function, e.g., including bacterial infections (e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium avium infections); viral infections (e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus-2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome
• bacterial infections e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculos
• Coronavirus, West Nile Virus, Viral Hepatitis e.g., Hepatitis A, Hepatitis B, Hepatitis C
• parasitic infestations e.g., Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, Schistosoma mansoni infestations
• atopic dermatitis pneumonia
• cardiovascular diseases such as atherosclerosis; obesity and insulin resistance; asthma; pulmonary fibrosis; cardiac obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; nonalcoholic
• steatoheptatitis NASH
• autoimmune hepatitis NASH
• systemic lupus erythematosus SLE
• wound healing pleurisy
• peritonitis and cystic fibrosis
• a PDE1 inhibitor of the current invention e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described
• the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are optionally substituted 7,8-dihydro-imidazo[l,2-a]pyrazolo[4,3- e]pyrimidin-4-one compounds and 7,8,9-trihydro-[lH or 2H]-pyrimido [l,2-a]pyrazolo[4,3- e]pyrimidin-4(5H)-one compounds, in free or pharmaceutically acceptable salt form.
• the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis which are described herein are selected from any of the Applicant’s own publications: US 2008-0188492 Al, US 2010-0173878 Al, US 2010-0273754 Al, US 2010-0273753 Al, WO 2010/065153, WO 2010/065151, WO
• PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication WO2006133261A2; U.S. Patent 8,273,750; U.S. Patent 9,000,001; U.S. Patent 9,624,230; International Publication
• PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication W02018007249A1; U.S. Publication 2018/0000786; International Publication W02015118097A1; U.S. Patent 9,718,832;
• the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula I:
• Ri is H or C M alkyl (e.g., methyl);
• R 4 is H or Ci- 4 alkyl and R 2 and R 3 are, independently, H or Ci- 4 alkyl
• R 2 and R 3 are both methyl, or R 2 is H and R 3 is isopropyl
• aryl e.g., R 2 and R 3 are both methyl, or R 2 is H and R 3 is isopropyl
• aryl e.g., R 2 and R 3 are both methyl, or R 2 is H and R 3 is isopropyl
• aryl e.g., R 2 and R 3 are both methyl, or R 2 is H and R 3 is isopropyl
• R 2 is H and R 3 and R 4 together form a di-, tri- or tetramethylene bridge
• R5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl
• R 5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
• halogen e.g., Cl or F
• Rio is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoro methyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, or thiadiazolyl (e.g., l,2,3-thiadiazol-4- yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, R 9 , or Rio, respectively, is not present; and
• R 6 is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N- (arylakyl) amino (e.g., N-phenyl-N-(l,l’-biphen-4-ylmethyl)amino); and
• R 13 and R 14 are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy or (optionally hetero)arylalkyl;
• the invention provides that the PDE1 inhibitors for use in the methods as described herein are Formula la:
• R 2 and R5 are independently H or hydroxy and R 3 and R 4 together form a tri- or tetra- methylene bridge [pref. with the carbons carrying R 3 and R 4 having the R and S configuration respectively]; or R 2 and R 3 are each methyl and R 4 and R5 are each H; or R 2 , R 4 and R5 are H and R 3 is isopropyl [pref. the carbon carrying R 3 having the R configuration];
• R 6 is (optionally halo- or hydroxy-substituted) phenylamino, (optionally halo- or hydroxy-substituted) benzylamino, Ci- 4 alkyl, or Ci- 4 alkyl sulfide; for example, phenylamino or 4-fluorophenylamino ;
• (iii) Rio is Ci- 4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (for example 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl); and
• X and Y are independently C or N,
• the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula II:
• X is Ci- 6 alkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);
• Y is a single bond, alkynylene (e.g.,— CoC— ), arylene (e.g., phenylene) or
• heteroarylene e.g., pyridylene
• Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloCi- 6 alkyl (e.g., trifluoromethyl),— C(O)— R 1 ,— N(R 2 )(R 3 ), or C 3- 7cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);
• aryl e.g., phenyl
• heteroaryl e.g., pyridyl, e.g., pyrid-2-yl
• halo e.g., F, Br, Cl
• R 1 is Ci- 6 alkyl, haloCi- 6 alkyl,— OH or— OCi- 6 alkyl (e.g.,— OCH 3 );
• R 2 and R 3 are independently H or Ci- 6 alkyl
• R 4 and R 5 are independently H, Ci- 6 alky or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4 -hydroxyphenyl or 2-hydroxyphenyl) or Ci- 6 alkoxy;
• halo e.g., fluorophenyl, e.g., 4-fluorophenyl
• hydroxy e.g., hydroxyphenyl, e.g., 4 -hydroxyphenyl or 2-hydroxyphenyl
• Ci- 6 alkoxy e.g., Ci- 6 alkoxy
• X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C 1 6 al ky 1 (e.g., methyl), haloCi- 6 alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6- fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4- fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloCi- 6 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or Ci- 6 -alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl,
• the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula III:
• Rl is H or C 1-4 alkyl (e.g., methyl or ethyl);
• R 2 and R 3 are independently H or Ci- 6 alkyl (e.g., methyl or ethyl);
• R 4 is H or C M alkyl (e.g., methyl or ethyl);
• R 6 and R 7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from Ci -6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more Ci -6 alkyl and one or more halogen or phenyl substituted with one Ci -6 alkyl and one halogen, for example 4- fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and
• n is 1, 2, 3, or 4, in free or salt form.
• the invention provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula IV
• Ri is Ci- 4 alkyl (e.g., methyl or ethyl), or -NH(R 2 ), wherein R 2 is phenyl optionally
• halo e.g., fluoro
• 4-fluorophenyl e.g., 4-fluorophenyl
• X, Y and Z are, independently, N or C;
• R 3 , R 4 and R5 are independently H or Ci- 4 alkyl (e.g., methyl); or R 3 is H and R 4 and R5 together form a tri-methylene bridge (pref. wherein the R 4 and R5 together have the cis configuration, e.g., where the carbons carrying R 4 and Rshave the R and S
• R 6 , R7 and Rs are independently:
• Ci- 4 alkyl e.g., methyl
• Ri is -NH(R 4 ), wherein R 4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• halo e.g., fluoro
• R 2 is H or Ci-r,alkyl (e.g., methyl, isobutyl or neopentyl);
• R 3 is -SO2NH2 or -COOH
• the invention provides that the PDE1 inhibitors for use in the methods as described herein are Formula VI:
• Ri is -NH(R 4 ), wherein R 4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• R 2 is H or Ci-r,alkyl (e.g., methyl or ethyl);
• R 3 is H, halogen (e.g., bromo), C i 6 al ky 1 (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl),
• halogen e.g., bromo
• C i 6 al ky 1 e.g., methyl
• aryl optionally substituted with halogen e.g., 4-fluorophenyl
• heteroaryl optionally substituted with halogen e.g., 6-fluoropyrid-2-yl or pyrid-2-yl
• acyl e.g., acetyl
• the present disclosure provides for administration of a PDE1 inhibitor for use in the methods described herein (e.g., a compound according to Formulas I, la, II, III, IV, V, and/or VI), wherein the inhibitor is a compound according to the following:
• the invention provides administration of a PDE1 inhibitor for treatment or prophylaxis of inflammation or an inflammatory related disease or disorder, wherein the inhibitor is a compound according to the following:
• the invention provides administration of a PDE1 inhibitor for treatment or prophylaxis of inflammation or an inflammatory related disease or disorder, wherein the inhibitor is a compound according to the following:
• the invention provides administration of a PDE1 inhibitor for treatment or prophylaxis of inflammation or an inflammatory related disease or disorder, wherein the inhibitor is a compound according to the following:
• the invention provides administration of a PDE1 inhibitor for treatment or prophylaxis of inflammation or an inflammatory related disease or disorder, wherein the inhibitor is a compound according to the following:
• selective PDE1 inhibitors of the any of the preceding formulae are compounds that inhibit phosphodiesterase- mediated (e.g., PDE1 -mediated, especially PDE1B -mediated) hydrolysis of cGMP, e.g., the preferred compounds have an IC50 of less than ImM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5nM in an immohili zed-metal affinity particle reagent PDE assay, in free or salt form.
• phosphodiesterase- mediated e.g., PDE1 -mediated, especially PDE1B -mediated
• the preferred compounds have an IC50 of less than ImM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5nM in an immohili zed-metal affinity particle reagent PDE assay, in free or salt form.
• Alkyl as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• Cycloalkyl as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• the cycloalkyl optionally contains one or more atoms selected from N and O and/or S, said cycloalkyl may also be a heterocycloalkyl.
• Heterocycloalkyl is, unless otherwise indicated, saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein at least one carbon atom is replaced with N, O or S, which
• heterocycloalkyl may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• Aryl as used herein is a mono or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoro methyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).
• alkyl e.g., methyl
• halogen e.g., chloro or fluoro
• haloalkyl e.g., trifluoro methyl
• hydroxy carboxy
• an additional aryl or heteroaryl e.g., biphenyl or pyridylphenyl
• Heteroaryl as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy.
• Compounds of the Invention e.g., optionally substituted 7,8-dihydro-imidazo[l,2- a]pyrazolo[4,3-e]pyrimidin-4-one compounds and 7,8,9-trihydro-[lH or 2H]-pyrimido [1,2- a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds, in free or pharmaceutically acceptable salt form, e.g., Compounds of Formulas I, la, II, III, IV, V, and/or VI, may exist in free or salt form, e.g., as acid addition salts.
• salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their pharmaceutically acceptable salts, are therefore also included.
• Compounds of the Invention may in some cases also exist in prodrug form.
• a prodrug form is compound which converts in the body to a Compound of the Invention.
• these substituents may form physiologically hydrolysable and acceptable esters.
• physiologically hydrolysable and acceptable ester means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered.
• the Compound of the Invention contains a hydroxy group, for example, Compound-OH
• the acyl ester prodrug of such compound i.e., Compound- 0-C(0)-Ci- 4 alkyl
• the Compound of the Invention contains a carboxylic acid, for example, Compound- C(0)OH, the acid ester prodrug of such compound, Compound-C(0)0-Ci- 4 alkyl can hydrolyze
• the invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a Compound of the Invention, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable carrier, for use as an anti-inflammatory agent.
• Compounds of the Invention may in some cases also exist in prodrug form.
• a prodrug form is compound which converts in the body to a Compound of the Invention.
• these substituents may form physiologically hydrolysable and acceptable esters.
• physiologically hydrolysable and acceptable ester means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered.
• the Compound of the Invention contains a hydroxy group, for example, Compound-OH
• the acyl ester prodrug of such compound i.e., Compound- 0-C(0)-Ci- 4 alkyl
• the Compound of the Invention contains a carboxylic acid, for example, Compound- C(0)OH
• the acid ester prodrug of such compound Compound-C(0)0-Ci- 4 alkyl can hydrolyze to form Compound-C(0)OH and HO-Ci- 4 alkyl.
• the term thus embraces conventional pharmaceutical prodrug forms.
• the invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a Compound of the Invention, in free, pharmaceutically acceptable salt or prodrug form, in admixture with a pharmaceutically acceptable carrier, for use as an anti-inflammatory agent.
• the compounds of the Invention and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.
• the Compounds of the Invention include their enantiomers, diastereoisomers and racemates, as well as their polymorphs, hydrates, solvates and complexes.
• Some individual compounds within the scope of this invention may contain double bonds. Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond.
• some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.
• the Compounds of the Invention encompass their stable and unstable isotopes.
• Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs.
• the hydrogen atom at a certain position on the Compounds of the Invention may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but not limited to, deuterium, 13 C, 15 N, 18 O.
• unstable isotopes which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., 123 1, 131 I, 125 I, U C, 18 F, may replace the corresponding abundant species of I, C and F.
• Another example of useful isotope of the compound of the invention is the U C isotope.
• the Compounds of the Invention are useful in the treatment of inflammatory diseases or conditions, particularly inflammatory diseases or conditions. Therefore, administration or use of a preferred PDE1 inhibitor as described herein, e.g., a PDE1 inhibitor as hereinbefore described, e.g., a Compound of Formulas I, la, II, III, IV, V, and/or VI provides a means to regulate inflammation (e.g., prevent, reduce, and/or reverse inflammation, and diseases or disorders related to inflammation), and in certain embodiments provide a treatment for various inflammatory diseases and disorders.
• a preferred PDE1 inhibitor as described herein e.g., a PDE1 inhibitor as hereinbefore described, e.g., a Compound of Formulas I, la, II, III, IV, V, and/or VI provides a means to regulate inflammation (e.g., prevent, reduce, and/or reverse inflammation, and diseases or disorders related to inflammation), and in certain embodiments provide a treatment for various inflammatory diseases and disorders.
• the invention provides a method (Method 1) of promoting resolution of inflammation comprising administering an effective amount of a specific inhibitor of phosphodiesterase type I (PDE1), to a patient in need thereof, for example:
• the invention provides a method (Method 1) of promoting resolution of inflammation for the treatment or prophylaxis of inflammation or disease associated with inflammation comprising administering an effective amount of a specific inhibitor of phosphodiesterase type I (PDE1), to a patient in need thereof, for example: Method 1 wherein the patient is suffering from inflammation and/or a disease or disorder mediated by macrophage activation.
• Method 1 wherein the patient is suffering from inflammation and/or a disease or disorder mediated by macrophage activation.
• Method 1 or 1.1 wherein promoting resolution of inflammation comprises promoting activation of M2 macrophages.
• Method 1 or 1.1 wherein the disease or condition to be treated is selected from bacterial infections (e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerans, and
• bacterial infections e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerans, and
• viral infections e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus- 2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome Coronavirus, West Nile Virus, Viral Hepatitis (e.g., Hepatitis A, Hepatitis B, Hepatitis C));
• HIV Human Immunodeficiency Virus
• parasitic infestations e.g., Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, Schistosoma mansoni infestations
• atopic dermatitis pneumonia;
• cardiovascular diseases such as atherosclerosis; obesity and insulin resistance;
• asthma pulmonary fibrosis
• COPD cardiac obstructive pulmonary disease
• neuropathic pain stroke; diabetes; sepsis; nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.
• NASH nonalcoholic steatoheptatitis
• SLE systemic lupus erythematosus
• any foregoing method wherein the disease or condition to be treated is a bacterial infection.
• any foregoing method wherein the disease or condition to be treated is a Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium
• tuberculosis Mycobacterium ulcerans, or Mycobacterium avium infection.
• Method 1-1.3 wherein the disease or condition to be treated is a viral infection.
• HIV Immunodeficiency Virus
• HIV1 e.g., HIV1
• Influenza A Virus e.g., HIV1
• Porcine Circovirus- 2 Porcine Reproductive and Respiratory Syndrome Virus
• Porcine Pseudorabies Virus Porcine Pseudorabies Virus
• Respiratory Syncytial Virus Severe Acute Respiratory Syndrome Coronavirus, West Nile Virus
• Viral Hepatitis e.g., Hepatitis A, Hepatitis B, Hepatitis C.
• Method 1-1.3 wherein the disease or condition to be treated is a parasitic infestation.
• Method 1.8 wherein the parasitic infestation is a Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, or Schistosoma mansoni infestation.
• Method 1-1.3 wherein the disease or condition to be treated is atopic dermatitis; pneumonia; cardiovascular diseases, such as atherosclerosis; obesity and insulin resistance; asthma; pulmonary fibrosis; cardiac obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.
• cardiovascular diseases such as atherosclerosis; obesity and insulin resistance
• asthma pulmonary fibrosis
• COPD cardiac obstructive pulmonary disease
• COPD nonalcoholic steatoheptatitis
• SLE systemic lupus erythematosus
• Method 1-1.3 or 1.10 wherein the disease or condition to be treated is nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.
• NASH nonalcoholic steatoheptatitis
• SLE systemic lupus erythematosus
• any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) in an amount effective to (i) reduce or inhibit activation of Ml macrophages, and/or (ii) an amount effective to reduce levels of one or more pro-inflammatory cytokines (e.g., IL1 b, TNF- a, IL6 and Ccl2, or
• any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) to a patient in need thereof, in an amount effective to (i) promote activation of M2 macrophages, and/or (ii) an amount effective to promote anti-inflammatory cytokines (e.g., IL-10).
• a PDE1 inhibitor of the current invention e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described
• Any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) to a patient in need thereof, in an amount effective to reduce levels of macrophages of the Ml phenotype and/or enhance levels of macrophages of the M2 phenotype.
• a PDE1 inhibitor of the current invention e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described
• any foregoing method wherein the inflammation is associated with increased expression and/or activation of macrophages (e.g., Ml macrophages).
• macrophages e.g., Ml macrophages
• the PDE1 inhibitor blunts or inhibits the expression and/or activity of pro-inflammatory cytokines, e.g., selected from the group consisting of: IL1B, IL-6, TNF- a, Ccl2, Nitric Oxide (NO), and Reactive Oxygen Species (ROS).
• pro-inflammatory cytokines e.g., selected from the group consisting of: IL1B, IL-6, TNF- a, Ccl2, Nitric Oxide (NO), and Reactive Oxygen Species (ROS).
• PDE1 inhibitor in administered in combination with a PDE4 inhibitor (e.g., rolipram).
• a PDE4 inhibitor e.g., rolipram
• cytokines e.g., IL1B, IL6, TNF-alpha, Ccl2.
• PDE1 inhibitor describes a compound(s) which selectively inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated, especially PDE IB -mediated) hydrolysis of cGMP, e.g., with an IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immohili zed-metal affinity particle reagent PDE assay.
• PDE1 inhibitor describes a compound(s) which selectively inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated, especially PDE IB -mediated) hydrolysis of cGMP, e.g., with an IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immohili zed-metal affinity particle reagent PDE assay.
• PDE1 inhibitor inhibits the activity of PDE1 (e.g., bovine PDE1 in the assay described in Example 1) with an IC50 of less than 10 nM, e.g., wherein the PDE1 inhibitor does not inhibit the activity of PDE types other than PDE1, e.g., has an IC50 at least 1000 times greater for PDE types other than PDE1.
• PDE1 e.g., bovine PDE1 in the assay described in Example 1
• PDE1 inhibitor is the following:
• PDE1 inhibitor is the following:
• any of the foregoing method wherein the patient has elevated levels of one or more pro-inflammatory cytokines e.g., selected from IL1 b, TNFa, Ccl2, IL-6, and combinations thereof.
• the invention provides a method (Method 2) of promoting macrophage activation to the M2 activation state, the method comprising
• PDE1 phosphodiesterase type I
• the disease or condition to be treated is selected from bacterial infections (e.g., Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium avium infections); viral infections (e.g., African Swine Fever Virus, Classical Swine Fever Virus, Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus-2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome Coronavirus, West Nile Virus, Viral Hepatitis (e.g., Hepatitis A, Hepatitis B, Hepatitis C)); parasitic infestations (e.g., Taenia crassiceps, To
• SLE systemic lupus erythematosus
• tuberculosis Mycobacterium ulcerans, or Mycobacterium avium infection.
• Method 2 or 2.1 wherein the disease or condition to be treated is a viral infection.
• Swine Fever Virus Dengue Virus, Foot and Mouth Disease Virus, Human Immunodeficiency Virus (HIV) (e.g., HIV1), Influenza A Virus, Porcine Circovirus- 2, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Pseudorabies Virus, Respiratory Syncytial Virus, Severe Acute Respiratory Syndrome Coronavirus, West Nile Virus, or Viral Hepatitis (e.g., Hepatitis A, Hepatitis B, Hepatitis C). Method 2 or 2.1, wherein the disease or condition to be treated is a parasitic infestation.
• HIV Human Immunodeficiency Virus
• HIV1 Human Immunodeficiency Virus
• Influenza A Virus e.g., HIV1
• Porcine Circovirus- 2 Porcine Reproductive and Respiratory Syndrome Virus
• Porcine Pseudorabies Virus Porcine Pseudorabies Virus
• Method 2.7 wherein the parasitic infestation is a Taenia crassiceps, Toxoplasma gondii, Leishmania infantum, or Schistosoma mansoni infestation.
• Method 2 or 2.1 wherein the disease or condition to be treated is atopic dermatitis; pneumonia; cardiovascular diseases, such as atherosclerosis; obesity and insulin resistance; asthma; pulmonary fibrosis; cardiac obstructive pulmonary disease (COPD); neuropathic pain; stroke; diabetes; sepsis; nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.
• cardiovascular diseases such as atherosclerosis; obesity and insulin resistance
• asthma pulmonary fibrosis
• COPD cardiac obstructive pulmonary disease
• COPD nonalcoholic steatoheptatitis
• SLE systemic lupus erythematosus
• Method 2 or 2.8 wherein the disease or condition to be treated is nonalcoholic steatoheptatitis (NASH); autoimmune hepatitis; systemic lupus erythematosus (SLE); wound healing; pleurisy; peritonitis; and cystic fibrosis.
• NASH nonalcoholic steatoheptatitis
• SLE systemic lupus erythematosus
• any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) in an amount effective to (i) reduce or inhibit activation of Ml macrophages, and/or (ii) an amount effective to reduce levels of one or more pro-inflammatory cytokines (e.g., IL1 b, TNF- a, IL6 and Ccl2, or
• any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) to a patient in need thereof, in an amount effective to (i) promote activation of M2 macrophages, and/or (ii) an amount effective to promote anti-inflammatory cytokines (e.g., IL-10).
• a PDE1 inhibitor of the current invention e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described
• any foregoing method comprising administering an effective amount of a PDE1 inhibitor of the current invention (e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described) to a patient in need thereof, in an amount effective to reduce levels of macrophages of the Ml phenotype and/or enhance levels of macrophages of the M2 phenotype.
• a PDE1 inhibitor of the current invention e.g., a PDE1 inhibitor of Formulas I, la, II, III, IV, V, and/or VI as herein described
• PDE1 inhibitor is a Compound of Formulas I, la, II, III, IV, V, and/or VI.
• the PDE1 inhibitor blunts or inhibits the expression and/or activity of pro-inflammatory cytokines, e.g., selected from the group consisting of: IL1B, IL-6, TNF- a, Ccl2, Nitric Oxide (NO), and Reactive Oxygen Species (ROS).
• pro-inflammatory cytokines e.g., selected from the group consisting of: IL1B, IL-6, TNF- a, Ccl2, Nitric Oxide (NO), and Reactive Oxygen Species (ROS).
• PDE1 inhibitor in administered in combination with a PDE4 inhibitor (e.g., rolipram).
• a PDE4 inhibitor e.g., rolipram
• cytokines e.g., IL1B, IL6, TNF-alpha, Ccl2.
• PDE1 inhibitor describes a compound(s) which selectively inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated, especially PDE IB -mediated) hydrolysis of cGMP, e.g., with an IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immohili zed-metal affinity particle reagent PDE assay.
• PDE1 inhibitor describes a compound(s) which selectively inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated, especially PDE IB -mediated) hydrolysis of cGMP, e.g., with an IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immohili zed-metal affinity particle reagent PDE assay.
• PDE1 inhibitor inhibits the activity of PDE1 (e.g., bovine PDE1 in the assay described in Example 1) with an IC50 of less than 10 nM, e.g., wherein the PDE1 inhibitor does not inhibit the activity of PDE types other than PDE1, e.g., has an IC50 at least 1000 times greater for PDE types other than PDE1.
• PDE1 e.g., bovine PDE1 in the assay described in Example 1
• PDE1 inhibitor is the following:
• PDE1 inhibitor is the following: in free or pharmaceutically acceptable form.
• cytokines e.g., selected from IL1 b, TNFa, Ccl2, IL-6, and combinations thereof.
• the invention further provides the use of a PDE1 inhibitor, e.g., any of a Compound of Formulas I, la, II, III, IV, V, and/or VI in the manufacture of a medicament for use in any of Methods 1, et seq.
• a PDE1 inhibitor e.g., any of a Compound of Formulas I, la, II, III, IV, V, and/or VI in the manufacture of a medicament for use in any of Methods 1, et seq.
• the invention further provides a PDE1 inhibitor, e.g., any of a Compound of
• the invention further provides a pharmaceutical composition comprising a PDE1 inhibitor, e.g., any of a Formulas I, la, II, III, IV, V, and/or VI for use in any of Methods 1 et seq.
• a PDE1 inhibitor e.g., any of a Formulas I, la, II, III, IV, V, and/or VI for use in any of Methods 1 et seq.
• phrase“Compounds of the Invention” or“PDE 1 inhibitors of the Invention”, or like terms, encompasses any and all of the compounds disclosed herewith, e.g., a Compound of Formulas I, la, II, III, IV, V, and/or VI.
• treatment and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.
• the word“effective amount” is intended to encompass a therapeutically effective amount to treat or mitigate a specific disease or disorder, and/or a symptom thereof, and/or to reduce inflammatory cytokines, e.g., as produced by macrophages, and/or to reduce Ml macrophage activation, and/or to increase anti-inflammatory cytokines, e.g., as produced by macrophages, and/or to enhance M2 macrophage activation.
• the term“patient” includes a human or non-human (i.e., animal) patient.
• the invention encompasses both humans and nonhuman animals.
• the invention encompasses nonhuman animals.
• the term encompasses humans.
• Compounds of the Invention e.g., Formulas I, la, II, III, IV, V, and/or VI as hereinbefore described, in free or pharmaceutically acceptable salt form, may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents.
• the Compounds of the Invention e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g., the Compounds of the Invention, e.g.,
• Formulas I, la, II, III, IV, V, and/or VI as hereinbefore described, in free or pharmaceutically acceptable salt form may be administered in combination (e.g. administered sequentially or simultaneously or within a 24 hour period) with other active agents, e.g., with one or more antidepressant agents, e.g., with one or more compounds in free or pharmaceutically acceptable salt form, selected from selective serotonin reuptake inhibitors (SSRIs), ) serotonin- norepinephrine reuptake inhibitors (SNRIs), c) tricyclic antidepressants (TCAs), and atypical antipsychotics.
• SSRIs selective serotonin reuptake inhibitors
• SNRIs serotonin- norepinephrine reuptake inhibitors
• TCAs tricyclic antidepressants
• Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired.
• Compounds of the Invention may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally.
• satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg.
• an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg (depending on the drug to be administered and the condition to be treated, for example in the case of Compound 214, 0.5 to 25 mg, e.g., 1 to 10 mg, per diem, e.g., in monophosphate salt form, for treatment of inflammatory conditions), conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form.
• Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg (e.g., 1, 2.5, 5, 10, or 20 mg) of a Compound of the Invention, e.g., together with a pharmaceutically acceptable diluent or carrier therefor.
• compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art.
• oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
• Zymosan is injected into the pleural cavities of mice in order to induce sterile inflammation. Infiltration of leukocytes, neutrophils, and macrophages are monitored at days 3 and 7 following injection. Detection of various cell types are identified according to the gating strategy outlined in Table 1 below.
• Table 1 Cell types and identifiable markers for flow cytometry
• zymosan causes the recruitment of various waves of leukocytes, which are observed and recorded. Exudate volume increases to a maximum over a period of 24 hours, and neutrophils increase within 4 hours and reach a maximum by 48 hours. Lymphocytes of the adaptive immune system enter at a later stage, after three days, which is signaled by macrophages presenting antigens. A resolution phase is well documented in this model and is accompanied by decreased total macrophage number and transition into M2 phenotype.
• MFI for CD38+ showed an increase on day 3 for all animal groups, with the lowest value for the group treated with Compound 1, and decreased on day 7 for all groups.
• the MFI for Egr2+ was decreased on all animal groups on days 3 and 7, when compared to naive.
• BV2 cells were added to upper chamber of a 5 pm pore Transwell 96-well plate over a reservoir containing 100 pM ADP and incubated at 37°C with 5% C02 for 4 hours. After the incubation cells were harvested with pre-warmed cell detachment solution for 30 minutes in the same incubation conditions. 75 pl of this cell detachment solution was combined with 75 pl of culture medium in a new 96 well plate compatible with a fluorescence reader. Cell number in bottom chamber was determined by adding CyQuant® GR dye and reading in the Envision fluorescence reader at 480 nm EX /520 nm EM.
• CyQuant® GR dye exhibits strong fluorescence when bound to nucleic acid and is accurate enough to measure differences down to single cells. As shown in Figure 10, the presence of the PDE1 inhibitor Compound 1 showed a marked dampening effect on the motility of the BV2 cells across the membrane, providing additional evidence that Compound 1 dampens the release of pro-inflammatory markers.
• Zymosan was injected into the pleural cavities of mice in order to induce sterile inflammation by the methods discussed in Example 1.
• Compound 1 was administered to test subjects to observe the effects on a variety of inflammatory biomarkers. Results were recorded after 4 hours. The subjects showed a clear decrease in cytokine markers following
• IFNy, IL-Ib, MCPl-b and TNF-a decreased following administration of Compound 1 in all serum and plasma samples.
• IL10 showed a decrease in serum.
• Lipids are known to be involved in regulation of a multitude of cellular responses including cell growth and death, and inflammation/infection, via receptor- mediated pathways. Various lipids are involved in both the initiation and resolution of inflammation. Pro-resolving lipid mediators are produced naturally in the body from unsaturated fatty acids, such as arachidonic acid (AA) and docosahexaenoic acid (DHA). Further studies were carried out to identify metabolites of AA and DHA, which are summarized below in Tables 2 and 3.
• unsaturated fatty acids such as arachidonic acid (AA) and docosahexaenoic acid (DHA).

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