MXPA06005109A - Use of the lipoxin receptor, fprl1, as a tool for identifying compounds effective in the treatment of pain and inflammation - Google Patents
Use of the lipoxin receptor, fprl1, as a tool for identifying compounds effective in the treatment of pain and inflammationInfo
- Publication number
- MXPA06005109A MXPA06005109A MXPA/A/2006/005109A MXPA06005109A MXPA06005109A MX PA06005109 A MXPA06005109 A MX PA06005109A MX PA06005109 A MXPA06005109 A MX PA06005109A MX PA06005109 A MXPA06005109 A MX PA06005109A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- straight
- group
- compound according
- aryl
- Prior art date
Links
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Abstract
Disclosed herein are compounds that selectively activate the FPRL1 receptor. Further disclosed are methods of alleviating inflammatory responses by regulating key steps in leukocyte trafficking and preventing neutrophil-mediated tissue damage by administering to a subject a therapeutically effective amount of the compounds disclosed herein. In addition, methods of modulating, or specifically agonizing, the FPRL1 receptor by administering an effective amount of the compounds disclosed herein are provided.
Description
USE OF THE LIPOXINE / FPRL1 RECEPTOR, AS A TOOL TO IDENTIFY EFFECTIVE COMPOUNDS IN THE TREATMENT
OF PAIN AND INFLAMMATION
Field of the Invention The aspects of the invention described below relate to the use of the Lipoxin Receptor, FPRL1, as a tool to identify effective compounds in the treatment of pain and inflammation. This tool can be used in the selection of compounds, but is not limited to this application of use. Specifically, compounds that are identified as active in this receptor would be effective therapeutic agents for alleviating symptoms of the immune response as a result of neutrophil activation, leading to: vasoconstrictive, inflammatory, myeloid-suppressive, cardiovascular and gastrointestinal diseases and subsequent pain associated with these conditions.
Additionally, compounds that are identified as active in this receptor would be effective therapeutic agents that are administered before an inflammatory attack that would result in the activation of neutrophils, leading to: vasoconstrictive, inflammatory, myeloid-suppressive, cardiovascular and gastrointestinal diseases and Subsequent pain associated with these conditions.
Background of the Invention The immune response in humans is a complex cascade of events that can be triggered by both endogenous and exogenous stimuli and once triggered, if not controlled, can result in significant tissue damage and eventual death. A diverse range of endogenous mediators is involved in this response, with the key roles being played by icosanoids such as prostaglandins and leukotrienes. These molecules exert their actions through the activation of receptors in diverse leukocyte populations that include neutrophils. Neutrophils are within the host's first line of defense and, because of their ability to devour microbes, can protect the host from infection. However, they can also give rise to a vascular lesion and may contribute to increased vascular permeability, edema and the subsequent release of chemoattractants. In an effort to balance the activation of neutrophils, humans and other organisms have developed a negative feedback loop that acts as a signal of rupture. The FPRL1 orphan receptor, which is expressed mainly in neutrophils and monocytes, could be a likely candidate to trigger this inflammatory balance and return the cells to their dormant state. The FPRL1 was first identified by Murphy et al as a structurally related homologue of the N-formyl peptide receptor (FPR, for its acronym in English). It has been shown that this. Peptide, when released by bacteria during infection, mediates chemotaxis and degranulation. Additionally, it has been shown that the WKYMVM hexapeptide acts as a FPRLl receptor agonist in vi tro in experiments seeking chemotaxis as well as in vitro assays designed to measure calcium mobilization. To date, no evidence has been provided to definitively support the role of the FPRLl receptor in vivo in inflammation. Here it is demonstrated, with the compounds selective for the FPRL1 receptor and active in vivo, the binding between the FPRL1 receptor and the relief of pain and inflammation; highlighting in this way the importance of the FPRLl receptor as a therapeutic target for the efforts in the discovery of drugs in this field of medical necessity. It has been shown that most icosanoids derived from the metabolism of arachidonic acid exacerbate pain and inflammation in diseases such as asthma, glomerulonephritis, rheumatoid arthritis and Alzheimer's disease. In contrast, it has been shown that the FPRL1 selective compounds described herein act prophylactically as inflammation alleviators and thus confirm that the FPRL1 receptor is a valuable target for the development of drugs in the reduction of inflammation in diseases such as such as asthma, glomerulonephritis, rheumatoid arthritis and Alzheimer's disease and subsequently in the relief of pain associated with these conditions.
Brief Description of the Invention In a first embodiment, the invention includes the use of the FPRL1 receptor as a tool to identify effective compounds in the treatment of inflammation and associated pain. In a second embodiment, the invention includes the use of the FPLR1 receptor as a screening tool to identify effective compounds in the treatment of inflammation and associated pain. In a third embodiment, the invention includes the use of compounds specifically active in the FPRL1 receptor as therapeutic agents to treat inflammation and associated pain. In a fourth embodiment, the invention includes the prophylactic use of compounds specifically active in the FPRL1 receptor as therapeutic agents to block inflammation and associated pain. In a fifth embodiment, the invention includes a method for selecting a compound capable of affecting one or more activities of an FPRL1 receptor comprising the steps consisting of, a) contacting a recombinant cell with a test compound, wherein the The recombinant cell comprises a recombinant nucleic acid expressing the FPRL1 receptor, provided that the cell does not have an expression of the endogenous functional nucleic acid FPRL1 receptor, and b) determining the ability of the test compound to affect one or more FPRLl receptor activities. and comparing the ability with that of the test compound to affect one or more activities of the FPRL1 receptor in a cell that does not comprise the recombinant nucleic acid; wherein the recombinant nucleic acid comprises a nucleic acid of the FPRL1 receptor selected from the group consisting of: i) nucleic acid of SEQ ID NO 1, ii) nucleic acid encoding SEQ ID NO 2 of amino acids, iii) a derivative of any nucleic acid molecule in i) or ii), wherein the derivative encodes a receptor having one or more FPRL1 receptor activities and comprises at least 20 contiguous nucleotides which can be hybridized under conditions of stringent hybridization for the complement of the acid nucleic of SEQ ID NO: l. In one aspect of the fifth embodiment, the FPRL1 receptor nucleic acid encodes the amino acid sequence of a SEQ ID: 2 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions with a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 2. In a sixth embodiment, the invention includes a method for treating acute and chronic inflammation of any kind comprising contacting an organism with an effective amount of at least a compound of Formula I, II or III, wherein the compound activates a subtype of the FPRL1 receptor. In one aspect of this modality, inflammation is associated with diabetes, viral infection, irritable bowel syndrome, amputation, cancer, bacterial infection, physical injury, including physical trauma and exposure to radiation, vasoconstriction as a result of asthma, anaphylactic reactions , allergic reactions, shock, diabetes, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome in adults, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, prosthetic hypertrophy benign, myocardial ischemia, myocardial infarction, circulatory shock, brain injury including ischemic stroke and hemorrhagic stroke, systemic lupus erythematosus, chronic kidney disease, cardiovascular disease and hypertension or chemical injury. In a seventh embodiment, the invention includes a method for identifying a compound which is an FPRL1 receptor agonist, the method comprising: contacting an FPRL1 receptor with at least one test compound of Formula I, II or III; and determining any increase in the activity level of the FPRL1 receptor to identify a test compound which is an FPRL1 receptor agonist. In an eighth embodiment, the invention includes a method for identifying a compound which is an agonist of an FPRL1 receptor, the method comprising: culturing cells expressing the FPRL1 receptor; incubating the cells or a component extracted from the cells with at least one test compound of Formula I, II or III; and determining any increase in FPRL1 receptor activity to identify a test compound which is an agonist of an FPRL1 receptor. In one aspect of the eighth embodiment, the cultured cells overexpress the FPRL1 receptor. In another aspect of the eighth embodiment, the identified agonist is selective for the FPRL1 receptor. In a ninth embodiment, the invention includes a method for treating inflammation comprising contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, II or III, thereby reducing one or more symptoms of inflammation. In one aspect of the ninth embodiment, the method further comprises the step of identifying an individual in need of the inflammatory treatment prior to the passage of the contact. In another aspect of the ninth embodiment, the compound of Formula I, II or III selectively activates the FPRL1 receptor subtype. In a further aspect of the ninth embodiment, the inflammatory response results from the activation of leukocytes, activation comprising the migration of leukocytes and the generation of reactive oxygen species to evoke a vascular leak or edema. In yet another aspect of the ninth modality, the inflammatory response is associated with rheumatoid arthritis, Alzheimer's disease or asthma. In another aspect of the ninth modality, the inflammatory response results from physical injury, including physical trauma and exposure to radiation. A tenth embodiment of the invention includes a method for treating or preventing inflammation or an inflammatory response in the subject, comprising: administering to a subject an anti-inflammatory, effective amount of a compound of Formula I, II or III. An eleventh embodiment of the invention includes a method for inducing vasodilation to treat or prevent a vasoconstrictive response or condition, comprising: administering to a subject a vasodilating, effective amount of a compound of Formula I, II or III. In one aspect of the eleventh modality, the response or vasoconstrictive condition is selected from the group consisting of a renal hemodynamic disease, including glomerular disease and cardiovascular disease, including hypertension, myocardial infarction and myocardial ischemia. A twelfth embodiment of the invention includes a method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, comprising: administering to the subject a composition of Formula I, II or III. In one aspect of the twelfth embodiment, the vasoconstrictive response to leukotriene is associated with a medical disorder selected from the group consisting of: asthma, anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, syndrome of respiratory distress in adults, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, injury cerebral, systemic lupus erythematosus, chronic kidney disease, cardiovascular disease and hypertension.
In another aspect of the twelfth embodiment, the vasoconstrictive response is a renal vasoconstrictive response, including mild vasoconstriction, such as chronic kidney disease and chronic severe vasoconstriction, such as glomerular renal disease. A thirteenth embodiment of the invention includes a method for stimulating cell proliferation in a subject to treat or prevent myeloid-suppressive disorders comprising: administering to the subject an effective amount of the compound of Formula I, II or III.
A fourteenth embodiment of the invention includes a compound of Formula I
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein i is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0 , C = S, C = NQ, S = 0, S (= 0) 2, C = N0Q, where Q is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, R4 and R5 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, alkynyl of straight or branched chain of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR7, - N (R7) 2, -CN, -C (= Z) R7, -C (= Z) OR7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by an aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms substituted optionally by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R3 and R4 and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring. R6 may be present 0-5 times and is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl, aryl or optionally substituted heteroaryl, hydroxy, nitro, amino, halogen, sulfonate, perhaloalkyl, -0R7, -N (R8) 2, -CN, -C (= Z) R8,
-C (= Z) 0R8, -C (= Z) N (R8) 2, -N (R8) -C (= Z) R8, -N (R8) -C (= Z) N (Rβ) 2, -0C (= Z) R8 and -SR8, wherein Z is oxygen or sulfur; and wherein each R8 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or UR6"forms a fused aryl or heteroaryl ring In one aspect of the fourteenth embodiment, Rx is hydrogen or straight-chain alkyl of 1 to 10 carbon atoms In another aspect of the fourteenth embodiment, Ri is straight-chain alkylene from 1 to 5 carbon atoms In still another aspect of the fourteenth embodiment, Ri is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene and isopentylene. In yet another aspect of the fourteenth embodiment, R is selected from the group consisting of hydrogen, hydroxy, nitro, amino, aryl, heteroaryl, -OR7 and -N (R7) 2 and wherein R7 is hydrogen or straight-chain alkyl of 1 to 10 carbon atoms. For example, in the above aspect, R7 may be hydrogen or straight chain alkyl of 1 to 3 carbon atoms. In a further aspect of the fourteenth embodiment, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, methoxy and ethoxy. In another aspect of the fourteenth embodiment, R3 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, amino, -0R7 and -N (R7) 2 and wherein R7 is hydrogen or straight chain alkyl of 1 to 10 carbon atoms. In yet a further aspect of the fourteenth embodiment, R7 is hydrogen or straight chain alkyl of 1 to 3 carbon atoms. In another aspect of the fourteenth embodiment, R3 is selected from the group consisting of hydrogen, nitro, aryl, heteroaryl. In a further aspect of the fourteenth embodiment, wherein R4 is selected from the group consisting of hydrogen, straight chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, -0R7 and -N (R7) 2 and wherein R7 is straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl. In a further aspect of the fourteenth embodiment, R4 is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, -0R7 and -N (R7) 2 and R7. is straight chain alkyl of 1 to 3 carbon atoms optionally substituted by aryl. In still another aspect of the fourteenth embodiment, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino and benzyloxy. In still another additional aspect of the fourteenth embodiment, R5 is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR7 and -N (R7) 2 and wherein R7 is straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl. In a further aspect of the fourteenth embodiment, R5 is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR7 and -N (R7) 2 and wherein R7 is straight chain alkyl of 1 to 3 carbon atoms. In another aspect of the fourteenth embodiment, R5 is selected from the group consisting of hydrogen, hydroxy, chlorine, bromine, trifluoromethyl, and methoxy. In some aspects of the fourteenth embodiment, R6 is hydrogen. In another aspect of the fourteenth embodiment, R2 and R3 and the nitrogen atom to which they are attached form a heteroaryl ring or fused heterocyclic alkyl. For example, in the above aspect, the ring can be a heterocyclic alkyl ring. In some cases, the heterocyclic alkyl ring may be selected from the group consisting of N-morpholine and pyrrole. A fifteenth embodiment of the present invention includes a compound selected from the group consisting of
A sixteenth embodiment of the present invention includes a compound of Formula II
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein each of X x and X 2 is independently oxygen or sulfur; Ri is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0, C = S, C = NQ, S = 0, S (= 0 ) 2, C = N0Q, wherein Q is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 atoms carbon optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, straight chain alkynyl or branched from 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR7, -N (R ) 2, -CN, -C (= Z) R7, -C (= Z) OR7 / -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N ( R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by an aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms substituted optionally by an aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms. In one aspect of the sixteenth embodiment, Rx is selected from the group consisting of oxygen and NQ, wherein Q is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 5 carbon atoms optionally substituted by aryl or heteroaryl.
For example, in some versions of the prior aspect of the sixteenth embodiment, Q is straight or branched chain alkyl of 1 to 3 carbon atoms. In other versions of the prior aspect of the sixteenth embodiment, Q is selected from the group consisting of methyl, ethyl and propyl. In additional versions of the previous aspect of the sixteenth modality, Q is methyl. In another aspect of the sixteenth embodiment, R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms and optionally substituted aryl. For example, in a version of the above aspect, R2 is substituted aryl. In another version of the above aspect, R2 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, 4-alkoxycarbonylphenyl. In another version of the above aspect, R2 is selected from the group consisting of 4-methylphenyl, 4-ethoxyphenyl and 4-ethoxycarbonylphenyl. In another aspect of the sixteenth embodiment, R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms and optionally substituted aryl. For example, in a version of the above aspect, R3 is substituted aryl. In another version of the above aspect, R3 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl and 4-halophenyl. For example, in some cases, R3 may be selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-methoxyphenyl. A seventeenth embodiment of the present invention includes a compound of Formula III
or a .sal, ester, pharmaceutically acceptable amide or prodrug thereof, wherein each of R 1 t R 2, R 3, R 4, R 5 and R 6 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, alkenyl straight or branched chain of 2 to 5 10 carbon atoms, straight or branched chain alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 10 substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR7, -N (R7) 2, -CN, -C (= Z) R7, -C (= Z) OR7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7, 15 where Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight-chain or branched alkynyl of 2 to 10 carbon atoms optionally substituted by an aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R3 and R and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring; RB and R-6 and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring, - or Ri R2 the carbon atom to which Rx is attached and the nitrogen atom to which R2 is attached form a ring of heteroaryl or fused heterocyclic. In one aspect of the seventeenth embodiment, R x is selected from the group consisting of hydrogen and straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted. In a version of the prior aspect of the seventeenth embodiment, Rx is straight chain alkyl of 1 to 5 carbon atoms optionally substituted by an aryl or heteroaryl ring. For example, in some cases, the aryl ring is phenyl. In other cases, the heteroaryl ring comprises nitrogen.
In some cases, the heteroaryl ring is indole. In a further aspect of the seventeenth embodiment, R x is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In a further aspect of the seventeenth embodiment, R x is selected from the group consisting of methyl, indolylmethyl, benzyl and sec-butyl. In another aspect of the seventeenth embodiment, Rx, R2, the carbon atom to which Rx is attached and the nitrogen atom to which R2 is attached form a fused heteroaryl or heterocyclic ring. In some versions of the above aspect, the heterocyclic ring is pyrrolidine. In a further aspect of the seventeenth embodiment, R2, R3 and R5 are each independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 5. carbon atoms and straight or branched chain alkynyl of 2 to 5 carbon atoms. In some versions of the above aspect, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In other versions of the previous aspect, R2, R3 and R5 are hydrogen. In another aspect of the seventeenth embodiment, R 4 is optionally substituted aryl. For example, in some versions of the previous aspect, aryl is phenyl. In other versions of the above aspect, aryl is optionally substituted by halo, alkoxy, alkyl, alkylthio and perhaloalkyl. In some versions of the above aspect, aryl is optionally substituted by chlorine, bromine, methyl, ethyl, isopropyl, methoxy, methylthio and trifluoromethyl. In other versions of the above aspect, R 4 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 2,6-diisopropylphenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-methylmercaphophenyl Y . 4-trifluoromethylphenyl. In another aspect of the seventeenth embodiment, Rs is selected from the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted and an optionally substituted heterocyclic ring. In some versions of the above aspect, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and 1-methylbutyl. For example, in some cases, alkyl is substituted by a heterocyclic ring or a substituted amine. In some cases, the heterocyclic ring is morpholine. In other cases, the heterocyclic ring is piperidine or morpholine. In another aspect of the seventeenth embodiment, Rs is selected from the group consisting of l-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin-4-yl. In a further aspect of the seventeenth embodiment, R5 and R6 and the nitrogen atom to which they are attached form a fused, optionally substituted or heterocyclic ring optionally substituted. In some versions of the above aspect, the heterocyclic ring is piperidine or benzopiperidine. In a further aspect of the seventeenth embodiment, R5 and R6 and the nitrogen atom to which they are attached form a substituent selected from the group consisting of
A eighteenth embodiment of the present invention includes a compound selected from the group consisting of
In certain embodiments, the FPRL1 receptor is used as a tool to identify effective compounds in the treatment of inflammation and subsequent pain associated with an inflammatory state. This receptor may be of animal origin but in a preferred embodiment it would be of human origin. This receptor can be used in a cell-based transfection system that would be able to detect molecules that interact with the FPRL1 receptor by comparing the response produced by the cells transfected with FPRL1 against those devoid of the FPRL1 receptor. This comparison may be through examination of receptor binding properties or through functional responses produced by cells when cells express FPRL1 and are determined to exhibit a new phenotypic characteristic either in the presence or in the absence of an additional compound . It can be determined, in this way, that this compound is an agonist, antagonist or inverse agonist of the FPRL1 receptor. In certain embodiments, a method for identifying a compound which is an agonist of an FPRL1 receptor is described herein, the method comprises cultivating cells expressing the FPRLl receptor.; incubating the cells with at least one compound and determining any increase in FPRLl receptor activity to identify a compound of which is an agonist of an FPRL1 receptor. In certain embodiments, the cultured cells overexpress the FPRL1 receptor. In 'other modalities, the identified agonist is selective for the FPRL1 receptor. In another aspect, the invention relates to a method for identifying a mutation in the FPRL1 receptor gene, a mutation which is suspected to confer constitutive activity on the receptor, the method comprising: a) extracting nucleic acid from a biological sample obtained from an individual having a disorder or condition putatively associated with the constitutive activity of the FPRL1 receptor; b) preparing cDNA of the extracted nucleic acid;
c) selecting from the cDNA of step (b) the cDNA encoding the FPRL1 receptor; d) transfecting a cell with an expression vector comprising the selected cDNA; e) selecting a cell that expresses the constitutively active FPRLl receptor; and f) sequencing the cDNA in the selected cell to detect the mutation (s). In a further aspect, the invention relates to a method for diagnosing a disorder or condition, or a susceptibility to a disorder or condition, associated with the constitutive activity of the FPRL1 receptor, the method comprising: a) obtaining a biological sample from an individual putatively affected by or susceptible to a disorder or condition associated with the constitutive activity of the FPRL1 receptor; b) isolating from the biological sample a nucleic acid sequence encoding the receptor or a portion of the nucleic acid sequence corresponding to the portion of the gene identified to include the mutation (s) by means of the identification method of mutations described above; and c) detecting the presence or absence of the mutation (s) in the nucleic acid sequence or a portion thereof. The presence of one or more mutations in the nucleic acid sequence can be detected, for example, by sequencing the nucleic acid sequence and comparing it with a previously known or identified sequence containing mutation (s). In another aspect, the present invention relates to a test kit for detecting mutation (s) in the gene encoding the FPRL1 receptor, mutations that give rise to the constitutive activity of the FPRL1 receptor, the test kit comprising a sequence of nucleic acid corresponding to a portion of the gene identified by the mutation identification method described above to include at least one mutation. In certain embodiments, a method for identifying a compound which is an agonist of an FPRL1 receptor is described in this document, the method comprising cultivating cells expressing the FPRL1 receptor; incubating the cells with at least one compound and determining any increase in FPRLl receptor activity to identify a compound of which is an agonist of an FPRL1 receptor. In certain embodiments, the cultured cells overexpress the FPRL1 receptor. In other embodiments, the identified agonist is selective for the FPRL1 receptor.
In certain embodiments, a method for identifying a compound which is an antagonist or inverse agonist of an FPRL1 receptor is described, the method comprising culturing cells expressing the FPRL1 receptor; incubating the cells with at least one compound and determining any decrease in FPRLl receptor activity to identify a compound of which is an agonist of an FPRL1 receptor. In certain embodiments, the cultured cells overexpress the FPRL1 receptor. In other embodiments, the identified antagonist or inverse agonist is selective for the FPRL1 receptor. It will be understood by those skilled in the art that numerous and diverse modifications can be made without departing from the spirit of the present description. Therefore, it should be clearly understood that the forms described in this document are illustrative only and are not intended to limit the scope of the present disclosure. The compounds of Formula I, Formula II or Formula III are further described herein.
as defined herein, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, which selectively activates the FPRL1 receptor. Methods for alleviating inflammatory responses by regulating key steps in leukocyte trafficking and for preventing neutrophil-mediated tissue damage are also described when administering to a subject a therapeutically effective amount of a compound of Formula I,
Formula II or Formula III. In addition, methods for modulating, or agonizing specifically, the FPRL1 receptor by administering an effective amount of a compound of Formula I, Formula II or Formula III are also described. Other embodiments of the present invention are described below.
Brief Description of the Drawings Figure 1 illustrates the effects of varying dosages of Compound 7 on thermal hyperalgesia at various time points. Figure 2 illustrates the effects of varying dosages of Compound 7 on thermal hyperalgesia. Figure 3 illustrates the% hyperalgesia observed in varying dosages of Compound 7. Figure 4 illustrates the effects of varying dosages of Compound 7 on edema formation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT In a first aspect, a compound of Formula I is described herein.
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein Ri is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0, C = S, C = NQ, S = 0, S (= 0) 2, C = N0Q, where Q is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms substituted optionally by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, R4 and R5 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to
carbon atoms, straight or branched chain alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino,. halogen, perhaloalkyl, -OR7, -N (R7) 2, -CN, -C (= Z) R7, -C (= Z) 0R7, -C (= Z) N (R7) 2, -N (R7) - C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -0C (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R4 and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring. it can be present 0-5 times and is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl, aryl or optionally substituted heteroaryl, hydroxy, nitro, amino, halogen, sulfonate , perhaloalkyl, -0R7, -N (R8) 2, -CN, -C (= Z) R8, -C (= Z) 0R8, -C (= Z) N (R8) 2, -N (R8) - C (= Z) R8, -N (R8) -C (= Z) N (R8) 2, -OC (= Z) R8 and -SR8, wherein Z is oxygen or sulfur; and wherein each R8 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or RS "forms a fused ring of aryl or heteroaryl In certain embodiments, Ri in the compound of Formula I is straight chain alkylene of 1 to 10 carbon atoms In some embodiments, Ri is straight or branched chain alkylene. 1 to 5 carbon atoms In further embodiments, Rx is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene and isopentylene.
In some embodiments, R2 in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, -0R7 and -N (R7) 2 Y wherein R7 is hydrogen, aryl, heteroaryl or alkyl straight chain of 1 to 10 carbon atoms. In certain embodiments, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, halogen and -OR 7 and wherein R 7 is hydrogen or straight chain alkyl of 1 to 3 carbon atoms. In other embodiments, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, methoxy and ethoxy. In certain embodiments, R3 in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, -0R7 and -N (R7) 2 and wherein R7 is hydrogen, aryl, heteroaryl or alkyl straight chain of 1 to 10 carbon atoms. In some embodiments, R3 is selected from the group consisting of hydrogen, hydroxy, nitro and -0R7 and wherein R7 is hydrogen or straight-chain alkyl of 1 to 3 carbon atoms. In other embodiments, R3 is selected from the group consisting of hydrogen, nitro, hydroxy, methoxy and ethoxy. Modalities include those in which R4 in the compound of Formula I is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, -0R7 and -N ( R7) 2 and wherein each R7 is independently straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl. In some embodiments, R is selected from the group consisting of hydrogen, straight chain alkyl of 1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, -OR7 and ~ N (R7) 2 and wherein each R7 is independently straight chain alkyl of 1 to 3 carbon atoms optionally substituted by aryl. In still other embodiments, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino and benzyloxy. In further embodiments, R5 in the compound of Formula I is selected from the group consisting of hydrogen, aryl, heteroaryl, straight-chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -0R7 and -N (R7) 2 and wherein each R7 is independently straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl
0 heteroaryl. In other embodiments, R5 is selected from the group consisting of hydrogen, straight chain alkyl of
1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -0R7 and -N (R7) 2 and wherein each R7 is independently straight chain alkyl of 1 to 3 carbon atoms. In certain embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, chlorine, bromine, trifluoromethyl, and methoxy. In some embodiments, R6 is hydrogen. As mentioned above, in some embodiments, R 2 and R 3 and the nitrogen atom to which they are attached form a fused heteroaryl ring or heterocyclic alkyl. In some embodiments, the ring is a fused heterocyclic alkyl ring, which may be an N-morpholine or pyrrole. In certain embodiments, the compound of Formula I is selected from the group consisting of
In another aspect, a compound of Formula II is described herein.
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and each of Xx and X2 is independently oxygen or sulfur, - Ri is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0, C = S,
C = NQ, S = 0, S (= 0) 2, C = NOQ, wherein Q is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, straight chain alkynyl or branched from 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -0R7, -N (R7 ) 2, -CN, -C (= Z) R7, - C (= Z) 0R7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7 # -N ( R7) - C (= Z) N (R7) 2 / -OC (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms. In certain embodiments, the compound of Formula II is selected from the group consisting of
In still another aspect, a compound of Formula III or a pharmaceutically acceptable salt, ester, amide or prodrug thereof is described herein, wherein each of Rx, R2, R3, R4, R5 and R6 is independently selected from group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, straight or branched chain alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -0R7, -N (R7) 2, -CN, -C (= Z) R7,
-C (= Z) 0R7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -0C (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R3 and R4 and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring; Rs and Rs and the nitrogen atom to which they are attached form a heteroaryl or fused heterocyclic ring; or i R the carbon atom to which i is attached and the nitrogen atom to which R2 is attached form a fused heteroaryl or heterocyclic ring. In certain embodiments, Ri of the compound of the
Formula III is selected from the group consisting of hydrogen and straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted. In other embodiments, Rx may be straight chain alkyl of 1 to 5 carbon atoms optionally substituted by an aryl or heteroaryl ring. In some embodiments, the aryl ring is phenyl, while still other embodiments, the heteroaryl ring comprises nitrogen. Some embodiments include those in which the heteroaryl ring is indole. In some embodiments, the alkyl group of i is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In certain embodiments, Ra is selected from the group consisting of methyl, indolylmethyl, benzyl and sec-butyl. In some embodiments, RX / R2 and the carbon atom to which i is attached and the nitrogen atom to which R2 is attached form a fused heteroaryl or heterocyclic ring. The heterocyclic ring can be pyrrolidine. In certain embodiments, R / R3 and R5 of the compound of Formula III are each independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms and straight or branched chain alkynyl of 2 to 5 carbon atoms. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In further embodiments, R2, R3 and R5 are hydrogen. In some embodiments, R 4 of the compound of Formula III is optionally substituted aryl. In certain embodiments, the aryl is phenyl. In some of these embodiments, the aryl is optionally substituted by halo, alkoxy, alkyl, alkylthio and perhaloalkyl. In further embodiments, the aryl is optionally substituted by chlorine, bromine, methyl, ethyl, isopropyl, methoxy, methylthio and trifluoromethyl. In some embodiments, R is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 2,6-diisopropylphenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-methylmercaphophenyl and 4- trifluoromethylphenyl. The embodiments of the present disclosure include those in which R6 of the compound of Formula III is selected from the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted and an optionally substituted heterocyclic ring. In some modalities, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and 1-methylbutyl. In further embodiments, the alkyl is substituted by a heterocyclic or an amine-substituted ring. In some embodiments, the heterocyclic ring with which the alkyl is substituted is morpholine. In certain embodiments, R6 is an optionally substituted heterocyclic ring, which may be piperidine or morpholine. In further embodiments, Rg is selected from the group consisting of 1-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl and N-benzylpiperidin-4-yl. In some embodiments, R5 and Rg of the compound of Formula III and the nitrogen atom to which they are attached form an optionally substituted fused heteroaryl ring or optionally substituted heterocyclic ring. In certain embodiments, the heterocyclic ring is piperidine or benzopiperidine. In other embodiments, R5 and Rs and the nitrogen atom to which they are attached form a substituent selected from the group consisting of
In certain embodiments, the compound of Formula III is selected from the group consisting of
25
The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and which does not negate the biological activity and the properties of the compound.Pharmaceutical salts can be obtained by reacting a compound described herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like Pharmaceutical salts can also be obtained by reacting a compound described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylam ina and salts with amino acids such as arginine, lysine and the like. The term "ester" refers to a chemical moiety with the formula - (R) n-C00R ', wherein R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a carbon atom of the ring) and a heteroalicyclic group (linked through a ring carbon atom) and where n is 0 or 1. An "amide" is a chemical moiety with the formula ~ (R) nC (0) NHR 'or - (R) n-NHC (0) R', wherein R and R 'are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon atom) and a heteroalicyclic group (linked through a ring carbon atom) and where n is 0 or 1. An amide may be an amino acid or a peptide molecule that is attached to a molecule described herein, thereby forming a prodrug. Any amine, hydroxy or carboxyl side chains in the compounds described herein may be esterified or branched. The specific methods and groups to be used to achieve this purpose are known to those skilled in the art and can be easily found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999, which is incorporated in this document as a reference in its entirety. A "prodrug" refers to an agent that becomes the precursor drug in vivo. Prodrugs are often useful because, in some situations, it may be easier to administer them than the precursor drug. They can be, for example, bioavailable by means of oral administration while the precursor drug is not. The prodrug may also have improved solubility in pharmaceutical compositions on the precursor drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmission through a cell membrane where solubility in water is harmful to mobility but which is then hydrolyzed metabolically to the carboxylic acid, the complete entity, once inside the cell where it is beneficial to the solubility in water. A further example of a prodrug could be a short peptide (polyamino acid) linked to an acid group wherein the peptide is metabolized to recover the active portion. The term "aromatic" refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl groups (for example, phenyl) and heterocyclic aryl groups (for example, pyridine). The term includes monocyclic or polycyclic ring-fused groups (i.e., rings that share adjacent pairs of carbon atoms). The term "carbocyclic" refers to a compound that contains one or more covalently closed ring structures and the atoms that form the main structure of the ring are all carbon atoms. The term thus distinguishes carbocyclic rings from heterocyclic rings in which the main structure of the ring contains at least one atom which is different from a carbon atom. The term "heteroaromatic" or "heteroaryl" refers to an aromatic group which contains at least one heterocyclic ring. Examples of an aryl ring include, but are not limited to benzene and substituted benzene, such as toluene, aniline, xylene and the like, naphthalene and substituted naphthalene and azulene. Examples of a heteroaryl ring include, but are not limited to, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyrano. , pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,
where R is as defined in this document. As used herein, the term "alkyl" refers to a hydrocarbon, aliphatic group. The alkyl portion may be a "saturated alkyl" group, which means that it does not contain any portion of alkene or alkyne. The alkyl portion may also be an "unsaturated alkyl" portion, which means that it contains at least a portion of alkene or alkyne. A "alkene" portion refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond and an "alkyne" portion refers to a group consisting of at least two carbon atoms. carbon and at least one triple carbon-carbon bond. The alkyl portion, whether saturated or unsaturated, can be branched, straight or cyclic chain. The alkyl group can have from 1 to 20 carbon atoms (each time it appears in this document, a numerical range such as "1 to 20" refers to an integer in the given range, for example, "1 to 20 atoms" "carbon" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where a numerical range is designated). The alkyl group may also be an alkyl group of intermediate size having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl group having from 1 to 5 carbon atoms. The alkyl group of the compounds described herein can be designated as "C 1 -C 4 alkyl" or similar designations. By way of example only, "alkyl of 1 to 4 carbon atoms" indicates that there are from one to four carbon atoms in the alkyl chain, ie, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group (s) is (are) one or more groups selected individually and independently of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio , cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate , thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl and amino, including mono- and di-substituted amino groups and protected derivatives thereof. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Each time a substituent is described as "optionally substituted" that substituent can be substituted by one of the above substituents. The term "alkylene" refers to an alkyl group, as defined herein, which is a biradical and is connected to two other portions. In this way, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2-CH (CH3) -) and isobutylene (-CH2-CH (CH3) -CH2-) are examples, without limitation, of an alkylene group. The substituent "R" appearing alone and without any numerical designation refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon atom) and a heteroalicyclic group (linked to through a ring carbon atom). An "O-carboxy" group refers to a group RC (= 0) 0-, where R is as defined in this document. A "C-carboxy" group refers to a group -C (= 0) OR-, where R is as defined herein. An "acetyl" group refers to a group -C (= 0) CH3. A "trihalomethanesulfonyl" group refers to a group X3CS (= 0) 2- where X is a halogen. A "cyano" group refers to a -CN group. An "isocyanate" group refers to a -NCO group. A "thiocyanate" group refers to a -CNS group. An "isothiocyanate" group refers to a group
-NCS. A "sulfinyl" group refers to a group -S (= 0) -R, with R as defined herein. An "S-sulfonamido" group refers to a group -S (= 0) 2NR, with R as defined herein. A group "N-sulfonamido" refers to a group RS (= 0) 2NH-, with R as defined herein. A "trihalomethanesulfonamido" group refers to a group X3CS (= 0) 2NR-, with X and R as defined herein.
An "O-carbamyl" group refers to a group -0C (= 0) -NR, with R as defined herein. A "N-carbamyl" group refers to a group R0C (= 0) NH-, with R as defined herein. An "O-thiocarbamyl" group refers to a group
-OC (= S) -NR, with R as defined in this document. A "N-thiocarbamyl" group refers to a group -ROC (= S) NH-, with R as defined herein. A "C-amido" group refers to a group -C (= 0) -NR2, with R as defined herein. An "N-amido" group refers to a group RC (= 0) NH, with R as defined herein. The term "perhaloalkyl" refers to an alkyl group where all hydrogen atoms are replaced by halogen atoms. When two substituents and the carbon atoms to which they are attached form a ring, it means that the following structure .-
It is representative of the following structure:
In the previous example, Rx and R2 and the carbon atoms to which they are attached form a six-membered aromatic ring. When two substituents and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring; means that the following structure:
is representative of, for example, the following structures:
Unless otherwise indicated, when a substituent is considered to be "optionally substituted" it means that the substituent is a group that can be substituted by one or more groups selected individually and independently of cycloalkyl, aryl, heteroaryl, heterocyclic , hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N sulfonamide, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl and amino, including mono- and di-substituted amino groups and the protected derivatives thereof. The protecting groups that can form the protective derivatives of the above substituents are known to those of experience in the field and can be found in references such as Greene and Wuts, above. Certain compounds described herein may exist as stereoisomers, including optical isomers. The scope of the present disclosure includes all stereoisomers and both racemic mixtures of these stereoisomers as well as the individual enantiomers that can be separated according to methods that are well known to those of ordinary skill in the art. In yet another aspect, a compound selected from the group consisting of:
The schemes, discussed below, provide the general scheme for the synthesis of the compounds described in this document. Scheme 1 represents the synthesis of the compounds of Formula I.
Scheme 1
overnight solvent R4 R3 base t.a. 3h
Scheme 2 represents the synthesis of the compounds of Formula II.
Scheme 2
LG = Outgoing group / reactive protective group of t.a., during PG = Protective group coupling all night
R2
Scheme 3 represents the synthesis of the compounds of Formula III.
Scheme 3
Rs' RY1? N? s 'Rj R' 2 H
alkylation
In another aspect, the use of the FPRL1 receptor as a selection tool to identify effective compounds in the treatment of inflammation is described herein. In some modalities, this use can be carried out through a method for selecting a compound that is capable of affecting one or more activities of a FPRL1 receptor comprising the steps consisting of a) contacting a recombinant cell with a test compound, where the The recombinant cell comprises a recombinant nucleic acid expressing the FPRL1 receptor, provided that the cells do not have an expression of the functional FPRL1 receptor of the endogenous nucleic acid, and b) determining the ability of the test compound to affect one or more FPRLl receptor activities. and comparing that capacity with that of the test compound to affect one or more activities of the FPRL1 receptor in a cell that does not comprise the recombinant nucleic acid; wherein the recombinant nucleic acid comprises a nucleic acid of the FPRL1 receptor selected from the group consisting of: i) nucleic acid of SEQ ID NO: 1; ii) nucleic acid encoding amino acid SEQ ID NO: 2, iii) a derivative of any nucleic acid molecule in i) or ii), wherein the derivative encodes a receptor having one or more FPRLl receptor activities and comprises minus 20 contiguous nucleotides which can hybridize under stringent hybridization conditions with the nucleic acid complement of SEQ ID NO: 1. In certain embodiments, the FPRLl receptor nucleic acid encodes the amino acid sequence of a derivative of SEQ ID NO: 2 comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions with a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO: 2. In some embodiments, the derivative comprises at least 50, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, minus 400, at least 450, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500 at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400 or at least 2500, contiguous nucleotides which can be hybridized under conditions of rigorous hybridization with a nucleotide complement cont iguos that encode the amino acid sequence of the S? Q ID N0: 2. In another aspect, the present disclosure relates to a method for treating acute and chronic inflammation of any type comprising contacting an organism with an effective amount of at least one compound of Formula I, II or III, wherein the compound activates a subtype of the FPRLl receptor. In still another aspect, the present disclosure relates to a method for treating inflammation comprising contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, II or III, thereby One or more symptoms of inflammation are reduced. In certain embodiments, the above method further comprises the step of identifying an individual in need of the inflammatory treatment before the contact step. In other embodiments, the compound of Formula I, II or III selectively activates the FPRL1 receptor subtype. In another aspect, the present disclosure relates to a method for treating or preventing inflammation or an inflammatory response in the subject, comprising: administering to a subject an anti-inflammatory, effective amount of a compound of Formula I, II or III. In certain embodiments, the inflammatory response results from the activation of leukocytes, activation comprising the migration and generation of leukocytes from reactive oxygen species to evoke a vascular leak or edema. In other modalities, the inflammatory response is associated with rheumatoid arthritis, Alzheimer's disease or asthma. In still other modalities, the inflammatory response results from physical injury, including physical trauma and exposure to radiation. In another aspect, the present disclosure relates to a method for inducing vasodilation to treat or prevent a vasoconstrictive response or condition comprising: administering to a subject an effective vasodilating amount of a compound of Formula I, II or III. In certain modalities, the vasoconstrictive response or condition is selected from the group consisting of a renal hemodynamic disease, including glomerular disease and cardiovascular disease, including hypertension, myocardial infarction, and myocardial ischemia. In a further aspect, the present disclosure relates to a method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, which comprises: administering to the subject a compound of Formula I, II or III. In some embodiments, the vasoconstrictive response to leukotriene is associated with a medical disorder selected from the group consisting of: asthma, anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome in adults , Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, brain injury, systemic lupus erythematosus , chronic kidney disease, cardiovascular disease and hypertension. In other embodiments, the vasoconstrictive response is a renal vasoconstrictive response, including mild vasoconstriction, such as chronic kidney disease and chronic severe vasoconstriction, such as glomerular renal disease. In yet another aspect, the present disclosure relates to a method for stimulating cell proliferation in a subject to treat or prevent myeloid-suppressive disorders comprising: administering to the subject an effective amount of the compound of Formula I, II or III. In certain embodiments, the methods described herein are also directed to methods of treating acute and chronic inflammation. Preferred, particular embodiments of the compounds for use with the methods described herein are represented by COMPOUNDS 1, 2, 3, 4, 5, 6 and 7.
Compound 1 Compound 2 Compound 3 Compound 4
Compound 5 Compound 6
Compound 7 In another aspect, a method for treating acute and chronic pain comprising identifying an individual in need thereof and contacting the individual with an effective amount of at least one compound of Formula I is described herein. Formula II or Formula III as defined herein, thereby reducing one or more pain symptoms. Another aspect described in this document is the discovery that the FPRL1 compounds described are agonists specific for the FPRL1 receptor. Therefore, it is expected that these agonists bind to the FPRL1 receptor and induce anti-inflammatory responses. The FPRL1 receptor agonists described herein can be used to treat acute or chronic inflammation. Thus, in some embodiments, the compound of Formula I, Formula II or Formula III activates the FPRL1 receptor. In certain embodiments, the compound may selectively activate the FPRL1 receptor subtype, but not the FPR or FPRL2 receptor. The term "activate" refers to increasing the cellular function of the FPRL1 receptor. The function of the receptor is preferably the interaction with a natural binding partner. The term "natural binding partner" refers to a molecule that binds to an FPRL1 receptor in a cell. In certain embodiments, the inflammation treated by the methods described herein is associated with a bacterial infection, viral infection, physical injury, including physical trauma and radiation exposure, vasoconstriction as a result of asthma, anaphylactic reactions, allergic reactions, shock, diabetes, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome in adults, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel, myocardial ischemia, myocardial infarction, circulatory shock, brain injury including ischemic stroke and hemorrhagic stroke, systemic lupus erythematosus, chronic kidney disease, cardiovascular disease and hypertension or chemical injury. In another aspect, a method for identifying a compound that alleviates inflammation in a subject, which comprises identifying a subject suffering from inflammation, is described herein; providing the subject with at least one compound of Formula I, Formula II or Formula III, as defined herein; and determining whether at least one compound reduces inflammation in the subject. In yet another aspect, a method for identifying a compound of Formula I, Formula II or Formula III which is an FPRLl 'receptor agonist is described herein, the method comprising contacting an FPRL1 receptor with at least one compound of Formula I, Formula II or Formula III, as defined herein; and determining any increase in the level of FPRLl receptor activity to identify a compound of Formula I, Formula II or Formula III, which is an FPRLl receptor agonist. In the context of the present disclosure, an "agonist" is defined as a compound that increases the basal activity of a receptor (i.e., signal transduction mediated by the receptor). An "antagonist" is defined as a compound, which blocks the action of an agonist on a receptor. A "partial agonist" is defined as an agonist that exhibits limited, or less than complete, activity such that it fails to activate an in vitro receptor, functioning as an antagonist in vivo. The term "subject" refers to an animal, preferably a mammal and more preferably a human, who is the object of treatment, observation or experiment. The mammal can be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees and apes and humans. The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that produces the indicated biological or medical response. This response can occur in a tissue, system, animal or human, which is being sought by a researcher, veterinarian, doctor or other clinician and includes relief of the symptoms of the disease being treated. In a further aspect, a method for identifying a compound which is an agonist of an FPRL1 receptor is described herein, the method comprises culturing cells expressing the FPRLl receptor.; incubating the cells with at least one compound of Formula I, Formula II or Formula III as defined herein; and determining any increase in FPRLl receptor activity to identify a compound of Formula I, Formula II or Formula III which is an agonist of an FPRL1 receptor. In certain embodiments, the cultured cells overexpress the FPRL1 receptor. In other embodiments, the identified agonist is selective for the FPRL1 receptor. In another aspect, a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III as described above and a physiologically acceptable carrier, diluent or excipient or a combination thereof is described herein.
The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. In the field there are multiple techniques for administering a compound that include, but are not limited to, oral, injection, aerosol, parenteral and topical administration. The pharmaceutical compositions can also be obtained by reacting the compounds with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. . The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier since it facilitates the uptake of many organic compounds in the cells or tissues of an organism. The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are used as diluents in the field. A commonly used buffered solution is phosphate buffered saline because it mimics the saline conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. The term "physiologically acceptable" defines a carrier or diluent that does not cancel out the biological activity and properties of the compound. The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, such as in combination therapy, or suitable carriers or excipients. Techniques for the formulation and administration of the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990. Suitable routes of administration may include, for example , oral, rectal, transmucosal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal or infraocular injections.
Alternatively, one can administer the compound in a local rather than systemic manner, for example, by injection of the compound directly into the pain area, often in a depot or sustained release formulation. In addition, one can administer the drug in a targeting drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and selectively taken by the organ. The pharmaceutical compositions described herein can be made in a manner that is known per se, for example, by means of conventional mixing, dissolving, granulating, confectioning, levigating, emulsifying, eneapsulating, entrapping or manufacturing processes. tablets In this manner, pharmaceutical compositions for use in accordance with the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which are They can be used pharmaceutically. The appropriate formulation is dependent on the selected route of administration. Any of the suitable techniques, carriers and excipients that are well known and understood in the field can be used.; for example, in Remington's Pharmaceutical Sciences, above. For injection, the agents described herein can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, appropriate penetrants are used in the formulation so that the barrier is penetrated. These penetrants are generally known in the field. For oral administration, the compounds can be formulated easily by combining the active compounds with pharmaceutically acceptable carriers that are well known in the art. These carriers make it possible for the compounds described herein to be formulated as tablets, pills, confections, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient being treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with a pharmaceutical combination described herein, optionally grinding the resulting mixture and processing the granule mixture, after adding suitable auxiliaries, if desired, to obtain tablets or confectionery cores Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, starch rice, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP), if desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar or acid Alginic or a salt thereof, such as sodium alginate.The confectionery cores are provided with suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or candy coatings for identification or to characterize different combinations of active compound doses. The pharmaceutical preparations, which can be used by the oral route, include easy-swallow capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Easy to swallow capsules may contain the active ingredients in a mixture with a filler such as lactose, binding substances such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for this administration. For buccal administration, the compositions may take the form of tablets or rhombic tablets formulated in conventional manner. For administration by inhalation, the compounds for use according to the present disclosure are conveniently supplied in the form of an aerosol spray presentation from pressurized packings or a nebulizer, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane. , dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for the delivery of a measured quantity. Capsules and cartridges, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in a unit dosage form, for example, in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active compounds can be prepared as suspensions for oily, appropriate injections. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or suitable agents, which increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in the form of powder for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds can also be formulated as a depot preparation. These long-acting formulations can be administered by means of the implant
(for example by the subcutaneous or intramuscular route) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for the hydrophobic compounds described herein is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w / v of benzyl alcohol, 8% w / v of the non-polar surfactant Polysorbate 80MR and 65% p / v of polyethylene glycol 300, completed to a volume in pure ethanol. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the co-solvent components can be varied: for example, other non-polar surfactants of low toxicity can be used instead of POLYSORBATE 80 ™; the size of polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example polyvinyl pyrrolidone; and other sugars or polysaccharides can replace dextrose. Alternatively, other delivery systems for the hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of carriers or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used, although usually at the cost of increased toxicity. Additionally, the compounds can be delivered using a sustained release system, such as semipermeable matrices of hydrophobic, solid polymers containing the therapeutic agent. Several sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules can release, depending on their chemical nature, the compounds for a few weeks or up to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. Many of the compounds used in the pharmaceutical combinations described herein can be provided as salts with pharmaceutically compatible counterions. The pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. The salts tend to be more soluble in aqueous solvents or other protonic solvents than the free acids or corresponding basic forms. Pharmaceutical compositions that are suitable for use in the methods described herein include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of compound that is effective to prevent, alleviate or ameliorate the symptoms of a disease or prolong the survival of the subject being treated. The determination of a therapeutically effective amount is within the ability of those skilled in the art, especially in view of the detailed description provided in this document. The exact formulation, route of administration and dosage for the pharmaceutical compositions described herein can be selected by the individual physician in view of the condition of the patient. (See, for example, Fingí et al 1975, in "The Pharmacological Basis of Therapeutics," Ch. 1 p.1). Typically, the dose range of the composition administered to the patient may be from about 0.5 to 1000 mg / kg of the patient's body weight or from 1 to 500 mg / kg, or from 10 to 500 mg / kg, or from 50 to 100 mg / kg of the patient's body weight. The dosage can be an individual dosage or a series of two or more dosages administered in the course of one or more days, as the patient needs. It should be noted that for almost all of the specific compounds mentioned in the present disclosure, dosages for humans have been established for use in the treatment of at least some condition. In this way, in most cases, the methods described in this document will use those same dosages or dosages that are between approximately 0.1% and 500% or between approximately 25% and 250% or between 50% and 100% of the dosage established human Where a dosage for humans is not established, as will be the case for newly discovered pharmaceutical compounds, a suitable dosage for humans can be deduced from the ED50 or ID? 0 values or other appropriate values that are derived from in vi tro studies. or in vivo, qualified by toxicity studies and efficacy studies in mammals. Although the exact dosage will be determined on a drug-in-drug basis, in most cases, some generalizations can be made with respect to dosing. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, for example, 5 to 200 mg or an intravenous dose, subcutaneous or intramuscular of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, for example 1 to 40 mg of each ingredient of the pharmaceutical compositions described herein or a pharmaceutically acceptable salt thereof calculated as the Free base, the composition is administered 1 to 4 times a day. Alternatively, the compositions described herein can be administered by means of continuous intravenous infusion, preferably in a dose of each ingredient up to 400 mg per day. In this manner, the total daily dosage by means of oral administration of each ingredient will typically be in the range of 1 to 2000 mg and the total daily dosage by means of parenteral administration will typically be in the range of 0.1 to 400 mg. Suitably, the compounds will be administered during a period of continuous therapy, for example for a week or more or for months or years. The dosage amount and range can be adjusted individually to provide levels in the plasma of the active portion that are sufficient to maintain the modulating effects or a minimum effective concentration (MEC, for its acronym in English). The MEC will vary for each compound but can be estimated from the in vitro data. The dosages necessary to achieve the MEC will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine concentrations in plasma. The dosing intervals can also be determined using a MEC value. The compositions should be administered using a regimen, which maintains the levels in the plasma over the MEC for 10-90% of the time, preferably between 30-90% and more preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the concentration in the plasma. The amount of composition administered will, of course, be dependent on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. The compositions can be presented, if desired, in a package or dispensing device, which may contain one or more unit dosage forms containing the active ingredient. The package may comprise, for example, a thin sheet of metal or plastic, such as a blister-type package. The package or dispensing device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice associated with the package in the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical products, notice that reflects the agency's approval of the drug's form for administration human or veterinary This notice may be, for example, the label approved by U.S. Food and Drug Administration for prescription drugs or the approved product insert. Compositions comprising a compound described herein which are formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for the treatment of an indicated condition. It will be understood by those skilled in the art that numerous and varied modifications can be made without departing from the spirit of the present description. Therefore, it should be clearly understood that the forms described in this document are illustrative only and are not intended to limit the scope of the present disclosure.
Example 1: Receptor Selection and Amplification Technology Assay The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used to investigate the pharmacological properties of known FPRL1 agonists and new. The R-SAT is described in U.S. Patents Nos. 5,707,798, 5,912,132 and 5,955,281, all of which are hereby incorporated herein by reference in their entirety, including any drawings. In summary, NIH3T3 cells were grown in 96-well tissue culture plates at 70-80% confluence. The cells were transfected for 16-20 hours with plasmid DNAs using Polyfectmr (Qiagen Inc.) according to the manufacturer's protocols. R-SATs were generally performed with 3 ng / well of receptor and 20 ng / well of β-galactosidase plasmid DNA. All the G protein and receptor constructs used were in the mammalian expression vector derived from pSI (Promega Inc) as previously described. The FPRL1 receptor gene was amplified by PCR from the genomic DNA using oligodeoxynucleotide primers based on the published sequence (GenBank Access # M84562). For large-scale transfections, the cells were transfected for 16-20 hours, then treated with trypsin and frozen in DMSO. The frozen cells were subsequently thawed, placed at ~ 10,000 cells per well of a 96-well medium-area plate containing a drug. With both methods, the cells were then grown in a humidified atmosphere with 5% environmental C02 for five days. The media was then removed from the plates and the activity of the marker gene was measured by means of the addition of the β-galactosidase substrate or-nitrophenyl-β-D-galactopyranosidase (ONPG, in PBS with 0.5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nm. All data were analyzed using the XLFit computational program (IDBSm). Efficacy is the percentage of maximum activation compared to activation by a control compound (WKYMVm in the case of FPRLl). The pEC50 value is the negative value of log (EC50) where EC50 is the concentration calculated in a molar ratio that produces 50% maximum activation. These experiments have provided a molecular profile, or fingerprint, for each of these agents in the human FPRLl receptor. As can be seen in Table 1, these compounds selectively activate the FPRL1 receptors relative to cells transfected with false solutions.
The efficacy is relative to the ligand WKYMVm.
Example 2: FPRLl Receptor Linkage Assay Using the following reagents, supplies and methods, the ability of the compounds described herein to bind to FPRLl receptors can be easily determined in a receptor binding assay. 1. Develop COS cells transfected with the FPRL1 receptor (or can be replaced by another transfected cell line that does not endogenously express FPRL1 receptors) in a suitable growth medium in 24-well culture plates.
2. Prepare radiolabelled test solutions by mixing 245 μl of a working solution of [125I] WKYMVm 0.25 nM with 5 μl of the following mixture (one per solution): unlabelled WKYMVm working solution 50 μM, working solution of [125I ] WKYMVm 0.25 nM, only HEPES buffer or 50x test compound. 3. Aspirate the medium from the 24-well plates using a Pasteur pipette attached to a vacuum source. Do not wash the cells. 4. Add 250 μl of radiolabeled assay solution from step 2 to each test well and incubate the plates for 60 minutes at room temperature (~ 22 ° C) on an orbital shaker at low speed. 5. Finish the incubation by aspirating the radioactive solution with a 24-well Brandel cell harvester. Wash the wells three times with 0.5 ml of ice-cold HEPES buffer using the cell harvester. 6. Aspirate the solution from the wells with a micropipettor and transfer to 12 x 75-mm polystyrene test tubes. Analyze with a gamma counter (Packard, Cobra II). 7. Determine the specific binding and calculate the ICS0 values -Example 3: Determination of Changes in Cytosolic Calcium in Transfected HL-60 Cells 1. HL-60 cells transfected with the FPRL1 receptor or a control receptor at a density of 1-3 x 106 cells / ml are washed with phosphate buffered saline. 2. Cells are loaded with 2 μM Fura-2 and analyzed for elevation in intracellular calcium in the presence or absence of a variant concentration of the ound. 3. The response is ared to that produced by the application of the standard reference ligand WKYMVm when tested at 100 nM. The intracellular free calcium concentrations are calculated using the formula:
where Ka for Fura-2 is 224 nM, Fmax is the fluorescence in the presence of Triton-XlOO 0.04% and Fmin is the fluorescence obtained after the addition of 5 mM EGTA in 30 mM Tris-HCl, pH 7.4.
Example 4: Determination of the anti-inflammatory and analgesic properties of the specific compounds for FPRLl 1. Baseline responses were determined for natural male Sprague-Dawley rats
(175 - 200 g, n = 6 per group) towards a thermal, noxious stimulus which were measured using the hot plate test at 52 ° C. 2. The animals were injected intraperitoneally with a vehicle, ibuprofen (100 mg / kg) or several doses of the FPRLl-specific compounds of Formula I, II or III. 3. Acute inflammatory pain was created by the injection of 0.10 ml of β-carrageenan 2% (type IV, isolated from two species of algae Gigartina aciculaire and G. pisata) on the dorsal surface of the left hind paw 15 minutes after the administration of the compound. 4. The response latencies were then measured at 60, 90, 120 and 180 minutes after the administration of the compound in order to detect possible changes in thermal sensitivity. A significant decrease in latency of the hot plate was interpreted as the presence of thermal hyperalgesia. 5. Additionally, the thickness of the paw was determined, in order to quantify the local edema, immediately after the test at the 180 minute time point. The results are indicated in Figures 1-4.
As shown in Figures 1-3, the administration of
Compound 7 reduced thermal hyperalgesia. As shown in Figure 4, administration of Compound 7 also prevents the formation of edema.
Example 5: Sequences for FPRL1 SEQ ID NO: 1, below, is the DNA sequence encoding the FPRL1 receptor. SEQ ID NO: 2, below, is the polypeptide sequence for the FPRL1 receptor.
SEQ ID N?: L: 1 ggcacgagga acaacctatt tgcaaagttg gcgcaaacat tcctgcctga caggaccatg
61 gacacaggtt gtagagatag agatggctct ggctgtgcat tcagcagatt ctgtagafcag
121 aattaatagg acttggatgg gattgtggtg agagaaagtg aaatgaaaga taagttctag
181 tttggaag t ttaacaactg aatgtttaaa ctcaaataga cacaaaatafc tggaagagtg 2 1 gcaggtttgg gaggatgaga caatcaactg tttggttgag ccacgttagg tttgaaatgfc
301 ctacgggata ccgtggggag aggttatatc agactggagc acaagagaga ggscaaggct
361 gatagtttag atgaaaagag agcatgatat tttaagccat gagactggat aatatcacct
421 atagaaagac tatatagaga taagagaggfc ggggaacaag fcaaaagctgc gggacactcc
481 taaatttaga gtcaaattta gagcagaaaa tactagcaaa ggggactgaa aagcggtggc
541 caattgagct tcaaatgsaa gtgaaagfcgt gttgtgtgta catttatcat ctcatggcac
601 aggaaaaacg tgatttaagg agaaggaagc gatccaatgg gaagaagaga tccaatggat
661 c? Tctatcac gaagatattg agataagaac caatatggat ttgsacccac tgcatttgca
721 gccttgaggt cataagcatc ctcaggaaaa tgcaccaggt gctgstggca agatggaaas
781 caacttctcs acfccctctga atgaatatga agaagtgtcc tatgag ctg atggcfcacac
841 tgttctgcgg atcsfcccsat tggtggtgct tggggtcacc tttgtcctcg gggtcctggg
901 caatgggcfct gtgatctggg tggctggafct ccggatgaca cgcacagtca ccaccatctg 961 ttacctgaac ctggccctgg ctgacttttc tttcacggcc acattaccat tcctcattgt
1021 ctccatggcc atgggagaaa aatggccttt tggctggttc ctgtgtaagt taattcacat
1081 cgtggtggac atcaaactct ttggaagtgt cttcttgatt ggtttcattg cactggaccg
1141 ctgcatttgt gtsctgcatc cagtctgggc ccagaaccac cgcactgtga gtctggccat
1201 gaaggtgats gtcggacstt ggatfccttgc tctagtcctt accttgccag ttttcctctt
1261 tttgactaca gtaactattc caaatgggga cacatactgt actttcaast ttgcatsctg
1321 gggtggcacs cctgaggaga ggctgaaggt ggccattacc atgctgacag scagagggat
1381 tatccggttt gtcattggct ttagcttgca gatgtccatt gttgccatct gctatgggct
1441 cattgcagca aagatcsaca aaaagggcat gattaaatcc agccgtccct tacgggtcct
1501 cactgstgtg gtggcttctt tcttcafcctg ttggtttccc tttcaactgg ttgsccttct
1561 gggsaccgtc tggstcaaag agatgttgtt ctatggcaag tacaaaatca ttgacatcct
1621 ggttaacsca acgagstccc tggccttctt caacagctgc ctcaacccca tgctttacgt
1681 ctttgtgggs caagacttcc gagagagact gatccactcc stgcccacca gtctggagag 1741 ggccctgtct gaggastcag ccscaactaa tgacacggcfc gccaattctg cttcacctcc
1801 tgcagagact gagttacagg caatgtgagg atggggtcag ggatattfctg agttctgttc 1861 atcctacccfc aatgccagtt ccagcttcat stacccttga gtcatattga ggcattcaag
1921 gatgcacagc tcaagtattt attcaggaaa aatgcttttg tgtscctgat ttggggctaa
1981 gaaatagaca gtcaggctac taaaatatta gtgttatttt ttgttttttg acttctgsct
2041 ataccctggg gtaagtggag ttgggaaata caagaagaga aagaccagtg gggatttgta
2101 agacttagat gagatagcgc ataataaggg gaagacttta aagtataaag taaaatgttt
2161 gctgtaggtt ttttatagct attaaaaaaa atcagattat ggaag tttc ttctattttt
2221 agtttgctaa gagttttctg tttctttttc ttacatcatg agtggacttt gcattttatc
2281 aaatgcattt tctacatgta ttaagatggt catattattc ttcttctttt atgtaaatca
2341 ttataaataa tgttsattaa gttctgaatg ttaaactact cttgaattcc tggaataaac
2401 cacasttagt cctgatgtac tttaaatatt tatatctcac aggagttggt tagaatttct
2461 gtgtttatgt ttatatactg ttatttcact ttttctacta tccttgctaa gttttsatag
2521 aaaataagga acaaagagaa acttgtaatg gtctctgaaa aggaattgag aagtaattcc
2581 tctgattctg ttttstggtg ttatatcttt attaaatatt cagaaaaatt c
SEQ ID N?: 2 :. ? METNFSTPLN YEEVS "raSAGYTVLRILPl-VVLGV VLGVLGN VVDIN FGSVFLIGFIAI DRCICVLHPVWAQiraRTVS-_AMKVIVGPWIl aLVTJTLPV FLFLTTVTIPNGDTYCTF FASWGGTPEERIiKVAITMTTARGIIRFVIGFSr-P SIVA ICYGLIAAKIH KGMIKSSRP RVLTAVVASFFIC FPFQLVALLGTVWLKEM F GK YKIIDILVNPTSSI-AFFNSCLNPlyc VFVGQDFRERr) RHS -!?!? PTSIERAr SEDSAPTÍID TAANSASPPAETELQAM?
Claims (87)
- CLAIMS 1. The use of FPRLl receptor as a tool to identify effective compounds in the treatment of inflammation and associated pain.
- 2. The use of the FPRLl receptor as a screening tool to identify effective compounds in the treatment of inflammation and associated pain.
- 3. The use of compounds specifically active in the FPRL1 receptor as therapeutic agents to treat inflammation and associated pain.
- 4. The prophylactic use of compounds specifically active in the FPRL1 receptor as therapeutic agents to block inflammation and associated pain.
- 5. A method for selecting a compound capable of affecting one or more activities of an FPRL1 receptor, characterized in that it comprises the steps consisting in: a) contacting a recombinant cell with a test compound, wherein the recombinant cell comprises a recombinant nucleic acid expressing the FPRL1 receptor, provided that the cell does not have an expression of the endogenous functional nucleic acid FPRL1 receptor, and b) determining the ability of the test compound to affect one or more FPRL1 receptor activities and compare the capacity with that of the test compound to affect one or more activities of the FPRL1 receptor in a cell that does not comprise the recombinant nucleic acid; wherein the recombinant nucleic acid comprises a nucleic acid of the FPRL1 receptor selected from the group consisting of: i) nucleic acid of SEQ ID NO 1, ii) nucleic acid encoding SEQ ID NO 2 of amino acids, iii) a derivative of any nucleic acid molecule in i) or ii), wherein the derivative encodes a receptor having one or more FPRL1 receptor activities and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions with the nucleic acid complement of SEQ ID NO: 1.
- 6. The method according to claim 5, characterized in that the nucleic acid of the FPRL1 receptor encodes the amino acid sequence of a derivative of SEQ ID NO 2 comprising at least 20 contiguous nucleotides which they can hybridize under stringent hybridization conditions with the complement of at least 20 contiguous nucleotides encoding the amino acid sequence of the S EQ ID NO 2.
- 7. A method for treating acute and chronic inflammation of any type, characterized in that it comprises contacting an organism with an effective amount of at least one compound of Formula I, II or III, wherein the compound activates a subtype of the FPRLl receiver.
- The method according to claim 7, characterized in that the inflammation is associated with diabetes, viral infection, irritable bowel syndrome, amputation, cancer, bacterial infection, physical injury, including physical trauma and radiation exposure, vasoconstriction as asthma result, anaphylactic reactions, allergic reactions, shock, diabetes, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome in adults, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, benign prostatic hypertrophy, myocardial ischemia, myocardial infarction, circulatory shock, brain injury including ischemic stroke and hemorrhagic stroke, systemic lupus erythematosus, chronic kidney disease, cardiovascular disease and hypertension or chemical injury.
- 9. A method for identifying a compound that is an FPRL1 receptor agonist, the method is characterized in that it comprises: contacting a FPRL1 receptor with at least one test compound of Formula I, II or III; and determining any increase in the activity level of the FPRL1 receptor to identify a test compound which is an FPRL1 receptor agonist.
- 10. A method for identifying a compound which is an agonist of an FPRL1 receptor, the method is characterized in that it comprises: culturing cells expressing the FPRLl receptor; incubating the cells or a component extracted from the cells with at least one test compound of Formula I, II or III; and determining any increase in FPRL1 receptor activity to identify a test compound which is an agonist of an FPRL1 receptor.
- 11. The method according to claim 10, characterized in that the cultured cells overexpress the FPRL1 receptor.
- 12. The method according to claim 9 or 10, characterized in that the identified agonist is selective for the FPRL1 receptor.
- A method for treating inflammation, characterized in that it comprises contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, II or III, thereby reducing one or more symptoms of the inflammation. 1 .
- The method according to claim 13, characterized in that it also comprises the step that consists in identifying an individual in need of the inflammatory treatment before the contact step.
- 15. The method according to claim 13, characterized in that the compound of the Formula I, II or III selectively activates the FPRL1 receptor subtype.
- The method according to claim 13, characterized in that the inflammatory response results from the activation of leukocytes, activation comprising the migration of leukocytes and the generation of reactive oxygen species to evoke a vascular leak or edema.
- 17. The method according to claim 13, characterized in that the inflammatory response is associated with rheumatoid arthritis, Alzheimer's disease or asthma.
- 18. The method according to claim 13, characterized in that the inflammatory response results from a physical injury, including physical trauma and exposure to radiation.
- 19. A method for treating or preventing inflammation or an inflammatory response in the subject, characterized in that it comprises: administering to a subject an anti-inflammatory, effective amount of a compound of Formula I, II or III.
- 20. A method for inducing vasodilation to treat or prevent a vasoconstrictive response or condition, characterized in that it comprises: administering to a subject a vasodilating, effective amount of a compound of Formula I, II or III.
- 21. A method according to claim 20, characterized in that the response or vasoconstrictive condition is selected from the group consisting of a renal hemodynamic disease, including a glomerular disease and a cardiovascular disease, including hypertension, myocardial infarction and myocardial ischemia.
- 22. A method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, characterized in that it comprises: administering to the subject a composition of Formula I, II or III.
- 23. The method according to claim 22, characterized in that the vasoconstrictive response to leukotriene is associated with a medical disorder selected from the group consisting of: asthma, anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid arthritis, gout, psoriasis , allergic rhinitis, respiratory distress syndrome in adults, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, ischemic bowel shock, renal glomerular disease, benign prosthetic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction , circulatory shock, brain injury, systemic lupus erythematosus, chronic kidney disease, cardiovascular disease and hypertension.
- 24. The method according to claim 22, characterized in that the vasoconstrictive response is a renal vasoconstrictive response, including mild vasoconstriction, such as chronic kidney disease and chronic severe vasoconstriction, such as glomerular renal disease.
- 25. A method for stimulating cell proliferation in a subject to treat or prevent myeloid-suppressive disorders, characterized in that it comprises: administering to the subject an effective amount of the compound of Formula I, II or III.
- 26. A compound of Formula I or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, characterized in that Ri is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0, C = S, C = NQ, S = 0, S (= 0) 2, C = NOQ, wherein Q is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms substituted optionally by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, R and R5 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, alkynyl of straight or branched chain of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR7, - N (R7) 2, -CN, -C (= Z) R7, -C (= Z) 0R7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring. R6 may be present 0-5 times and is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl, aryl or optionally substituted heteroaryl, hydroxy, nitro, amino, halogen, sulfonate , perhaloalkyl, -OR7, -N (R8) 2, -CN, -C (= Z) R8, -C (= Z) OR8, -C (= Z) N (R8) 2, -N (R8) - C (= Z) R8, -N (R8) -C (= Z) N (R8) 2, ~ 0C (= Z) R8 and -SR8, wherein Z is oxygen or sulfur; and wherein each R8 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or "Re" forms a fused aryl or heteroaryl ring.
- 27. The compound according to claim 26, characterized in that Ri is hydrogen or straight chain alkyl of 1 to 10 carbon atoms.
- 28. The compound according to claim 26, characterized in that Ri is straight chain alkylene of 1 to 5 carbon atoms.
- 29. The compound according to claim 28, characterized in that Rx is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene and isopentylene.
- 30. The compound according to claim 26, characterized in that R2 is selected from the group consisting of hydrogen, hydroxy, nitro, amino, aryl, heteroaryl, -0R7 and -N (R7) 2 and wherein R7 is hydrogen or alkyl straight chain of 1 to 10 carbon atoms.
- 31. The compound according to claim 30, characterized in that R7 is hydrogen or straight chain alkyl of 1 to 3 carbon atoms.
- 32. The compound according to claim 26, characterized in that R2 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, methoxy and ethoxy.
- 33. The compound according to claim 26, characterized in that R3 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, amino, -0R7 and -N (R7) 2 and wherein R7 is hydrogen or alkyl straight chain of 1 to 10 carbon atoms.
- 34. The compound according to claim 33, characterized in that R7 is hydrogen or straight chain alkyl of 1 to 3 carbon atoms.
- 35. The compound according to claim 26, characterized in that R3 is selected from the group consisting of hydrogen, nitro, aryl, heteroaryl.
- 36. The compound according to claim 26, characterized in that R is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, -OR7 and -N (R 2 and wherein R7 is straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl.
- 37. The compound according to claim 26, characterized in that R is selected from the group consisting of hydrogen, straight chain alkyl of 1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, -0R7 and -N (R7) 2 and wherein R7 is straight chain alkyl of 1 to 3 carbon atoms optionally substituted by aryl .
- 38. The compound according to claim 26, characterized in that R4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino and benzyloxy.
- 39. The compound according to claim 26, characterized in that R5 is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 10 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -0R7 and -N (R7) 2 and wherein R7 is straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl.
- 40. The compound according to claim 26, characterized in that R5 is selected from the group consisting of hydrogen, straight-chain alkyl of 1 to 3 carbon atoms, hydroxy, nitro, amino, halogen, perhaloalkyl, -0R7 and -N (R7) 2 and wherein R7 is straight chain alkyl of 1 to 3 carbon atoms.
- 41. The compound according to claim 26, characterized in that R5 is selected from the group consisting of hydrogen, hydroxy, chloro, bromo, trifluoromethyl and methoxy.
- 42. The compound according to claim 26, characterized in that R6 is hydrogen.
- 43. The compound according to claim 26, characterized in that R2 and R3 and the nitrogen atom to which they are attached form a heteroaryl ring or fused heterocyclic alkyl.
- 44. The compound according to claim 43, characterized in that the ring is a heterocyclic alkyl ring.
- 45. The compound according to claim 44, characterized in that the heterocyclic alkyl ring is selected from the group consisting of N-morpholine and pyrrole.
- 46. A compound, characterized in that it is selected from the group consisting of
- 47. A compound of Formula II or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, characterized in that each of Xx and X2 is independently oxygen or sulfur; Ri is selected from the group consisting of straight or branched chain alkylene of 1 to 10 carbon atoms, oxygen, sulfur, NQ, CHCN, C = 0, C = S, C = NQ, S = 0, S (= 0 ) 2, C = N0Q, wherein Q is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 atoms carbon optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; each of R2, R3, is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, straight chain alkynyl or branched from 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -0R7, -N ( R7) 2, -CN, -C (= Z) R7, -C (= Z) OR7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7, wherein Z is oxygen or sulfur; and wherein each R7 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight or branched chain alkynyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms.
- 48. The compound according to claim 47, characterized in that Rx is selected from the group consisting of oxygen and NQ, wherein Q is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 5 carbon atoms optionally substituted by aryl or heteroaryl.
- 49. The compound according to claim 48, characterized in that Q is straight or branched chain alkyl of 1 to 3 carbon atoms.
- 50. The compound according to claim 48, characterized in that Q is selected from the group consisting of methyl, ethyl and propyl.
- 51. The compound according to claim 48, characterized in that Q is methyl.
- 52. The compound according to claim 47, characterized in that R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms and optionally substituted aryl.
- 53. The compound according to claim 52, characterized in that R is substituted aryl.
- 54. The compound according to claim 53, characterized in that R2 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, 4-alkoxycarbonylphenyl.
- 55. The compound according to claim 53, characterized in that R2 is selected from the group consisting of 4-methylphenyl, 4-ethoxyphenyl and 4-ethoxycarbonylphenyl.
- 56. The compound according to claim 47, characterized in that R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms and optionally substituted aryl.
- 57. The compound according to claim 56, characterized in that R3 is substituted aryl.
- 58. The compound according to claim 57, characterized in that R3 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl and 4-halophenyl.
- 59. The compound according to claim 58, characterized in that R3 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-methoxyphenyl.
- 60. A compound of Formula III or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, characterized in that each of Ri, R2, R3, R, R5 and Rs is independently selected from the group consisting of hydrogen, straight or branched chain alkyl of from 1 to 10. carbon atoms, straight or branched chain alkenyl of 2 to 10 carbon atoms, straight or branched chain alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted, substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, 10-amino, halogen, perhaloalkyl, -OR7, -N (R) 2, -CN, -C (= Z) R7, -C (= Z) 0R7, -C (= Z) N (R7) 2, -N (R7) -C (= Z) R7, -N (R7) -C (= Z) N (R7) 2, -OC (= Z) R7 and -SR7 / wherein Z is oxygen or sulfur; and where each R7 is selected 15 independently of the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted by aryl or heteroaryl, straight chain or branched alkenyl of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, alkynyl straight or branched chain of 2 to 10 carbon atoms optionally substituted by aryl or heteroaryl, cycloalkyl of 3 to 10 carbon atoms and cycloalkenyl of 5 to 10 carbon atoms; or R3 and R and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring; R5 and Rs and the nitrogen atom to which they are attached form a fused heteroaryl or heterocyclic ring; or i / R2 / the carbon atom to which Rx is attached and the nitrogen atom to which R2 is attached form a fused heteroaryl or heterocyclic ring.
- 61. The compound according to claim 60, characterized in that Rx is selected from the group consisting of hydrogen and straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted.
- 62. The compound according to claim 61, characterized in that Ri is straight chain alkyl of 1 to 5 carbon atoms optionally substituted by an aryl or heteroaryl ring.
- 63. The compound according to claim 62, characterized in that the aryl ring is phenyl.
- 64. The compound according to claim 62, characterized in that the heteroaryl ring comprises nitrogen.
- 65. The compound according to claim 64, characterized in that the heteroaryl ring is indole.
- 66 The compound according to claim 61, characterized in that Ra is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.
- 67. The compound according to claim 60, characterized in that R is selected from the group consisting of methyl, indolylmethyl, benzyl and sec-butyl.
- 68. The compound according to claim 60, characterized in that R, R2, the carbon atom to which R is attached and the nitrogen atom to which R2 is attached form a fused heteroaryl or heterocyclic ring.
- 69 The compound according to claim 68, characterized in that the heterocyclic ring is pyrrolidine.
- 70. The compound according to claim 60, characterized in that R2, R3 and R5 are each independently selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl. of 2 to 5 carbon atoms and straight or branched chain alkynyl of 2 to 5 carbon atoms.
- 71. The compound according to claim 70, characterized in that alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.
- 72. The compound according to claim 60, characterized in that R2, R3 and R5 are hydrogen.
- 73. The compound according to claim 60, characterized in that R4 is optionally substituted aryl.
- 74. The compound according to claim 73, characterized in that aryl is phenyl.
- 75. The compound according to claim 73, characterized in that aryl is optionally substituted by halo, alkoxy, alkyl, alkylthio and perhaloalkyl.
- 76. The compound according to claim 73, characterized in that aryl is optionally substituted by chlorine, bromine, methyl, ethyl, isopropyl, methoxy, methylthio and trifluoromethyl.
- 77. The compound according to claim 73, characterized in that R is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 2,6-diisopropylphenyl, 3,4-dichlorophenyl, -methoxyphenyl, 4-methylmercaphophenyl and 4-trifluoromethylphenyl.
- 78. The compound according to claim 60, characterized in that R6 is selected from the group consisting of straight or branched chain alkyl of 1 to 10 carbon atoms optionally substituted and an optionally substituted heterocyclic ring.
- 79. The compound according to claim 78, characterized in that alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and 1-methylbutyl.
- 80. The compound according to claim 79, characterized in that alkyl is substituted by a heterocyclic ring or a substituted amine.
- 81. The compound according to claim 80, characterized in that the heterocyclic ring is morpholine.
- 82. The compound according to claim 80, characterized in that the heterocyclic ring is piperidine or morpholine.
- 83. The compound according to claim 60, characterized in that Re is selected from the group consisting of l-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl and N-benzylpiperidin-4-yl.
- 84. The compound according to claim 60, characterized in that Rs and Rs and the nitrogen atom to which they are attached form a fused, optionally substituted or heterocyclic ring optionally substituted.
- 85. The compound according to claim 84, characterized in that the heterocyclic ring is piperidine or benzopiperidine.
- 86. The compound according to claim 60, characterized in that R5 and R6 and the nitrogen atom to which they are attached form a substituent selected from the group consisting of
- 87. A compound, characterized in that it is selected from the group consisting of
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/518,476 | 2003-11-07 | ||
| US60/519,085 | 2003-11-10 | ||
| US60/592,926 | 2004-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06005109A true MXPA06005109A (en) | 2006-10-17 |
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