Elucidation of Novel 13-Series Resolvins that Increase with Atorvastatin and Clear Infections

A resolvin compound having the formula:

• wherein each of P1, P2 and P3, when present, individually is a protecting group or a hydrogen atom;
• , when present, represents a double bond and each double bond is independently in either the Z or the E configuration;
• wherein the carbon at the 7 and 13 positions or 8, 12 or 20, when present, is independently in the R or S configuration;
• Z is —C(O)ORd, —C(O)NRcRc, —C(O)H, —C(NH)NRcRc, —C(S)H, —C(S)ORd, —C(S)NRcRc, or —CN;
• each Ra, is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
• each Rc, is independently a protecting group or Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
• each Rb is independently selected from ═O, —ORd, (C1-C3) haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS (O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C( NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)N RcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc or —[NRaC(NRa)]nNRcRc;
• each n, independently is an integer from 0 to 3;
• and
• each Rd, independently is a protecting group or Ra;
• or a pharmaceutically acceptable salt thereof,
• provided when Z is —C(O)ORd, then Rd for Z is not a hydrogen when P1, P2 and/or P3, when present, are all hydrogen atoms.

A method to treat or prevent one or more of inflammasome activation, diabetes, nasopharyngitis, arthralgia, diarrhea, pain in the extremities, bacterial infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, pharyngolaryngia pain, inflammation, arterial inflammation, arthritis, psoriasis, urticara, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, cardiovascular diseases, recruitment of neutrophils, leukocytes and/or cytokines, allergy, Alzheimer's disease, asthma, atherosclerosis, cancer, cardiovascular diseases, diabetes, genitourinary disorders, hypertension, infectious diseases, neuromuscular disorders, renal disorders, oral infections or periodontal disease comprising the step of administering an effective amount of one or more of resolvin compounds having the formulae:

• wherein each of P1, P2 and/or P3, when present, individually is a protecting group or a hydrogen atom;
• , when present, represents a double bond;
• and wherein each double bond is independently in the Z or the E configuration;
• Z is —C(O)ORd , —C(O)NRcRc, —C(O)H, —C(NH)NRcRc, —C(S)H, —C(S)ORd, —C(S)NRcRc, or —CN;
• each Ra, is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
• each Rc, is independently a protecting group or Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
• each Rb is independently selected from ═O, —ORd, (C1-C3) haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS (O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C( NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)N RcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc or —[NRaC(NRa)]nNRcRc;
• each n, independently is an integer from 0 to 3;
• and
• each Rd, independently is a protecting group or Ra;
• or a pharmaceutically acceptable salt thereof,
• to a subject in need thereof, such that the disease or condition is treated or prevented.

A method for preparing a resolvin compound, the method comprising:

• (a) incubating n-3 DPA with a cyclooxygenase to produce a 13-HDPA compound;
• (b) isolating the 13-HDPA compound;
• (c) incubating the isolated 13-HDPA compound with a lipoxygenase to produce a first compound;
• (d) reducing the first compound with a reducing agent to produce the resolvin compound;
• and
• (e) isolating the resolvin compound.

A method for preparing a resolvin compound, the method comprising:

• (a) incubating endothelial cells with Interleukin-1β and tumor necrosis factor-α;
• (b) incubating the endothelial cells with atorvastatin, celecoxib, L-NAME, and 1400 W;
• (c) adding n-3 DPA to the endothelial cells to form a mixture;
• (d) incubating the mixture to produce the resolvin compound;
• and
• (e) isolating the resolvin compound.