MX2008010474A - Phenyl-cycloalkyl and phenyl-heterocyclic derivatives as sip receptor agonists - Google Patents

Abstract

Compounds I and II that have agonist activity at one or more of the SIP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.

Description

DERIVATIVES OF PHENYL-CICLOALQUILO AND FENIL- HETEROCICLILO AS AGENTS OF THE SIP RECEIVER Cross Reference to Related Requests This application claims priority for the Request Provisional Serial No. 60 / 775,309, filed on February 21, 2006, the description of which is incorporated as a reference in its entirety. Right of the Government of the United States This invention was made with the support of the Government of the United States under Grant No. R01 GM067958, granted by the National Institutes of Health. The Government of the United States may have certain rights in the invention. Background of the Invention Sphingosine-1-phosphate (S1P) is a mediator of lysophosphid lipid that avocates a variety of cellular responses by stimulating five members of the cell endothelial cell differentiation (EDG) gene receptor family. The EDG receptors are receptors coupled to the G protein (GPCRs) and, in the stimulation, they propagate signals of the second messenger via the activation of subunits of the heterotrimeric G alpha protein and beta-gamma dimers (GPy). Finally, this signaling driven by S1P results in cell survival, increased cell migration and, frequently, mitogenesis The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiological homeostasis. For example, the immunomodulator, FTY720 (2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol), which, after phosphorylation, is an agonist in 4 of 5 S1P receptors , reveals that increasing the tone of S1P influences lymphocyte traffic. In addition, S1P type 1 receptor antagonists (S1Pi) cause loss of pulmonary capillary endothelium, which suggests that S1P may be involved in maintaining the integrity of the endothelial barrier in some tissue beds. Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator that avocates a variety of cellular responses by stimulating five members of the cell endothelial cell differentiation (EDG) gene receptor family. Sphingosine phosphate (S1P) has been shown to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, S1P receptors are good targets for therapeutic applications such as wound healing and inhibition of tumor growth. Sphingosine-phosphate signals cells in part via a set of G protein-coupled receptors named YES PL S1P2, SIP3, SIP4, and SIP5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8). The EDG receptors are receptors coupled to the G protein (GPCRs) and in the second stimulation propagation messenger point via the activation of heterodimeric G alpha (Ga) protein subunits and beta-gamma dimers (GPy). These receptors distribute 50-55% identity of the amino acid sequence and are grouped with three distinct receptors (LPA- ?, LPA2, and LPA3 (formerly EDG2, EDG4 and EDG7) for structurally related lysophosphatidic acid (LPA). change as induced in the Protein G Coupled Receptor (GPCR) when the ligand binds to that receptor, causing the GDP to be replaced by GTP in the a subunit of the associated G proteins and subsequent release of the G proteins in the The subunit to then dissociates from the β subunit and each subunit can then be associated with the effector proteins, which activate the second messengers that lead to a cellular response, and eventually, GTP in the G proteins is hydrolyzed to GDP and the subunits of the G proteins re-anneal with each other and then with the receptor.Amplification plays a major role in the general GPCR sequence.The binding of a ligand to a receptor eva to the activation of many G proteins, each capable of associating with many effector proteins that lead to an amplified cellular response.

S1P receptors make good drug targets because individual receptors are both tissue-specific and responsive. The tissue specificity of S1P receptors is desirable because the development of a selective agonist or antagonist for a receptor localizes the cellular response to tissues containing that receptor, limiting undesirable side effects. The specificity of response of S1P receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the specificity of response of S1P receptors could allow for a mimetic S1P to initiate platelet aggregation without affecting cell morphology. Sphingosine-1-phosphate is formed as a metabolite of sphingosine in its reaction with sphingosine kinase and is stored in platelets where high levels of sphingosine kinase exist and S1P lyase is lacking. S1P is released during platelet aggregation, accumulates in the serum, and is also found in malignant ascites. The reversible biodegradation of S1P most likely proceeds via hydrolysis by ectophosphohydrolases, specifically the phosphohydrolases of sphingosine-1-phosphate. The irreversible degradation of S1P is catalyzed by S1P lyase producing ethanolamine and hexadecenal phosphate.

Currently, there is a need for potent and selective agents that are S1P receptor agonists. There is also a need for pharmacological tools for further study of the physiological processes associated with the agonism of S1P receptors. Brief Description of the Invention The present invention provides, in one aspect, sphingosine-1-phosphate analogues that are potent and selective agonists in one or more S1P receptors, specifically the S1Pi receptor type. In another aspect, the compounds may have a phosphate moiety as well as a hydrolysis-resistant phosphate substitute such as phosphonate, a / a-substituted phosphonate (particularly where the alpha substitution is a halogen), and phosphothionates. In addition, the invention provides pro-drugs, such as primary alcohol-containing compounds that can be activated or converted, (eg, phosphorylated) in vitro, for example, by the enzyme sphingosine kinase, most particularly sphingosine kinase type 2 (SPHK2 ). The present invention provides in one aspect sphingosine-1-phosphate analogs having formula I or formula II: wherein R4 and R7 are independently CH, or CH2; R5 is C, CH, or N, R6 is CH, CH2, O, S or NR3; R3 is hydrogen, or (d-Cio) alkyl; X is hydroxyl (-OH), phosphate (-OP03H2), phosphonate (-CH2PO3H2), or alpha-substituted phosphonate; R1 is hydrogen, haloalkyl (Ci-C10), or (Ci-C10) alkoxy; R2 is a group having the formula III, IV, V, or VI: VI wherein R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 and R18 are independently O, S, C, CR19, CR20R21, C = 0, N or NR22; R19, R20 and R21 are independently hydrogen, halo, (C1-C10) alkyl, (C1-C10) alkyl substituted with halo, hydroxy, (C1-C10) alkoxy, or cyano; R22 is hydrogen or (C-i-C10) alkyl; and at least one ring of the groups of formula III, IV, V, or VI includes a heteroatom (O, S or N); Z2 is alkyl of (C ^ -C6), cycloalkyl of (C3-C8), alkenyl of (C2-C6), alkynyl of (C2-C6), aryl of (C6-C10), alkaryl of (C7-Ci6) , or (C7-Ci6) arylalkyl; wherein the Z2 alkyl groups are optionally substituted with 1, 2, 3 or 4 substituent groups, wherein the substituent groups are independently halo, alkoxy (C1-C10) or cyano; indicates one or more optional double links; Y2 is a link, -O-, or > C = 0; W and W2 are -CH2-, where m is o, 1, 2 or 3; or W2 is - (C = 0) (CH2) i-5-, where m is 1; n is 0, 1, 2, 3 or 4; i is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3. The alkyl groups of R1 can be optionally substituted with 1., 2, 3 or 4 substituent group, wherein the substituent groups are aryl, (CrC10) alkoxy or cyano. Any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R2 are optionally substituted with 1, 2, 3 or 4 substituent groups, where the substituent groups independently are oxo (= 0), imino (= NRd) ), alkyl (CT-CIO), alkoxy (CT-CK)), or C6-aryl, or wherein one or more of the carbon atoms in the alkyl groups of R2 can be independently replaced with oxygen without peroxide, Sulfur or NRC; the alkyl groups of R3 are optionally substituted with 1, or 2 hydroxy groups; and Rc and Rd are independently hydrogen, or alkyl of The invention includes pharmaceutically acceptable salts or esters of the compounds of formula I or formula II. In another aspect, the present invention also provides esters of any of the compounds of the formula I or of the formula II, for example phosphate esters or phosphonate esters. In another aspect, the invention provides compounds of Formula I or Formula II which are phosphate esters, having the formula VII.

In another aspect, the invention provides pro-drugs of the compounds of formula I or formula II. In another aspect, the invention also provides compounds of formula I or formula II for use in medical therapy. In another aspect, the present invention provides a method for inhibiting angiogenesis in a tumor, comprising contacting the cancer cells with an effective amount of a compound of the formula I or of the formula II. In another aspect, the invention provides a method for modulating the immune system by altering lymphocyte trafficking for the treatment of autoimmune diseases or prolongation of allograft transplantation survival, the method comprising administering an effective amount of at least one compound of formula I or from formula II to a subject who needs it. In another aspect, the invention provides a method for preventing, inhibiting or treating neuropathic pain, wherein the method comprises administering an effective amount of less a compound of formula I, formula II or a compound of formula I or formula II with a pharmaceutically acceptable carrier to a subject in need thereof. Pain can be nociceptive or neuropathic by nature. Neuropathic pain is characterized by its chronic nature, an absence of a direct, obvious cause (for example, tissue damage), hyperalgesia or allodynia. Hyperalgesia is an exaggerated response to a painful stimulus. Allodynia is the perception of normal as painful stimuli (examples include touch or rubbing with clothing, heat or cold air, etc.). Neuropathic pain can be a sequelae to nerve damage in a limb such as an arm, or more frequently a leg. Precipitating events can include trauma, for example, motor vehicle accidents or amputations (eg, phantom limb pain). Neuropathic pain may occur due to an adverse drug therapy rectum, for example, vincristine or paclitaxel (TAXOLMR) or may occur as a component of disease pathologies, such as type 1 or type 2 diabetes, herpes, HIV-infections 1, etc. Typically, neuropathic pain is not responsible for opiate or nonsteroidal anti-inflammatory drugs such as aspirin. In another aspect, the invention provides a method for repairing vascular injury after catheterization, comprising contacting the lumen of the affected vessel with an effective amount of the compound of the formula I or of the formula II. In another aspect, the invention includes coating resident stents (devices) with a compound of formula I or formula 11. In another aspect, the present invention provides compositions and methods for the use of S1P analogs to prevent and inhibit restenosis. vascular after a vascular injury. For example, the injury may be due to balloon angioplasty. In another aspect, the present invention includes a method for treating subjects to prevent vascular restenosis.

In another aspect, the present invention provides compositions and methods for the use of sphingosine analogues (including S1P pro-drugs) to prevent asthma attacks. In another aspect, asthma could be due to the overproduction of cysteinyl leukotrienes. In another aspect, the present invention includes a method for treating asthma. In another aspect, the present invention provides compositions and methods for the use of sphingosine analogues of formula I or formula II (including prodrugs of S1P) to treat obesity. In another aspect, the present invention provides compositions and methods for the use of sphingosine analogues (including S1P pro-drugs) to normalize the composition of lipids in the blood. In one aspect, levels low-density lipoprotein (LDL or "bad cholesterol") could be decreased. In another aspect, triglyceride levels in the blood can be decreased by administering an effective amount of a compound having formula I or formula II. In another aspect, the present invention provides compositions and methods for the use of S1P analogs and S1P pro-drugs for the prevention and treatment of arteriosclerosis. In another aspect, the present invention provides compositions and methods for the use of S1P analogs and S1P pro-drugs for the treatment of a neoplastic disease. In one aspect, this treatment is effected by the application of S1P receptor antagonists having the formula I or formula II which are effective by virtue of their anti-angiogenic properties. In another aspect, the treatment is effected by the administration of sphingosine analogs of the formula I or of the formula II which inhibit the multiple substrate lipid kinase. In another aspect, the present invention provides compositions and methods for the use of S1P analogs and S1P pro-drugs for the treatment of neurodegenerative diseases. In one aspect, the treatment is for senile dementia of the Alzheimer type. In another aspect, the invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof for use in medical treatment (eg, treatment of a neoplastic disease, treatment of neuropathic pain, treatment of an autoimmune disease, prolongation of allograft survival) . In another aspect, the invention provides for the use of a compound of formula I or formula II to prepare a medicament for inhibiting tumor growth, metastasis or tumor angiogenesis in a mammalian species (eg, a human). In another aspect, the invention provides for the use of a compound of formula I or formula II to prepare a medicament for treating an autoimmune disease or prolonging allograft survival in a mammalian species (eg, a human). In another aspect, the invention provides for the use of a compound of formula I or formula II to prepare a medicament for treating neuropathic pain in a mammalian species (eg, a human). In another aspect, the invention provides a method for titrating a compound of formula I or formula II (eg, S1P receptor pro-drugs) as a substrate for sphingosine kinase types 1 or 2, in vitro and in vitro. alive. In another aspect, the invention includes a method for titrating a compound of formula I or formula II to bind sites of the designated receptor comprising in vivo or in vitro, with an amount of a compound of formula I or formula II effective to bind the receptors. The tissue comprising S1P receptor sites designated to bind the ligand can be used to measure the selectivity of test compounds for specific receptor subtypes, or they can be used as a tool to identify potential therapeutic agents for the treatment of diseases, by contact the agents with the receptor-ligand complexes, and measure the degree of displacement of the ligand or bond of the agent. In another aspect, the invention provides novel intermediates and processes described herein that are useful for preparing compounds of formula I or formula II, including the generic and specific intermediates as well as the synthetic processes described herein. In another aspect, the present invention provides synthetic schemes and methods of using compounds having the formula I, formula II, analogs or derivatives thereof. In another aspect, the invention provides synthetic and modification schemes for preparing analogs and derivatives of the compounds of formula I or formula II, as well as compositions and methods for the use of such analogs and derivatives. The previous summary of the present invention is not intended to describe each described embodiment or each implementation of the present invention. The description that follows more particularly exemplifies illustrative modalities. In various places throughout the application, a guide is provided through lists of examples, examples of which can be used in various combinations. In each example, the cited list serves only as a representative group and should not be interpreted as an exclusive list. The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects and advantages of the invention would be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-3 illustrate the syntheses of the described compounds. Detailed Description of the Invention The following abbreviations are used herein: S1P, sphingosine-1-phosphate; S1P receiver types are S1Pi. 5; GPCR, receptor coupled to the G protein; SAR, structure-activity relationship; EDG, endothelial cell differentiation gene; EAE, experimental autoimmune encephalomyelitis; NOD, non-obese diabetic; TNFa, tumor necrosis factor alpha; HDL, high density lipoprotein; and RT-PCR, reverse transcriptase polymerase chain reaction.

Describing and claiming the invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art for which this invention pertains. Although any similar or equivalent materials and methods for those described herein may be used in the practice or testing of the present invention, preferred materials and methods are described herein. Each of the following terms has the meaning associated with it in this section. Specific and preferred values listed below for radicals, substituents and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. The terms "ones", "an", "he or she", "at least one", and "one or more" are used interchangeably. Thus, for example, a composition comprising "an" element means an element or more than one element. The term "receptor agonists" are compounds that mimic the action of S1P on one or more of its receptors but may have different potency or efficacy. The term "receptor antagonists" are compounds that 1) lack intrinsic agonist activity and 2) block the activation of the agonist (eg, S1P) of the receptor S1P, often in a way that is both fully surmountable and reversible ("competitive antagonist"). The term "affected cell" refers to a cell of a subject afflicted with a disease or disorder, whose affected cell has an altered phenotype relative to a subject not afflicted with a disease or disorder. Cells or tissues are "afflicted" by a disease or disorder if the cells or tissues have an altered phenotype relative to the same cells or tissues in a subject not afflicted with a disease or disorder. A disease or disorder is "relieved" if the severity of a symptom of the disease or disorder, the frequency with which a symptom is experienced by a patient, or both, is reduced. An "analog" of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (for example, 5-fluorouracil is a thymine analog). The terms "cell", "cell line", and "cell culture" can be used interchangeably. A cell, tissue, sample, or "control" subject is a cell, tissue, sample, or subject of the same type as a cell, tissue, sample or test subject. The control can, for example, be examined accurately or at about the same time that the cell, tissue, sample or test subject is examined.

The control can also, for example, be examined at a time distant from the time at which the cell, tissue, sample or test subject is examined, and the results of the control examination can be recorded so that the recorded results can be compared with the results obtained by the examination of a cell, tissue, sample or test subject. The control can also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a disease or disorder for which the test is being performed. . A cell, tissue, sample or subject of "proof" is one that is examined or treated. A "patoindicative" cell, tissue or sample is one that, when present, is an indication that the animal in which the cell, tissue or sample is located (or from which the tissue is obtained) is afflicted with a disease or disorder. By way of example, the presence of one or more breast or breast cells in a lung tissue of an animal is an indication that the animal is afflicted with metastatic breast cancer. A tissue "normally comprises" a cell if one or more than one cell is present in the tissue in an animal not afflicted with a disease or disorder. The use of the word "detect" and its variants Grammatical means that it refers to the measurement of species without quantification, while the use of the word "determine" or "measure" with its grammatical variants are meant to refer to the measurement of species with quantification. The terms "detect" and "identify" are used interchangeably herein. A "detectable label" or a "reporter molecule" is an atom or molecule that allows specific detection of a compound comprising the label in the presence of similar compounds without a label. Detectable labels or reporter molecules include, for example, radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, chemo-luminescent molecules, electrochemically detectable molecules, and molecules that provide altered fluorescence-polarization or altered light scattering. A "disease" is a state of health of an animal where the animal may not maintain homeostasis, and where the disease is not improved after the animal's salute continues to deteriorate. A "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's condition is less favorable than it could be in the absence of the disorder. Leave untreated, a disorder does not necessarily cause an additional decrease in the condition of animal health. An "effective amount" means an amount sufficient to produce a selected effect. For example, an effective amount of an S1P receptor antagonist is an amount that decreases the cellular signaling activity of the S1P receptor. A "functional" molecule is a molecule in a form in which it has a property by which it is characterized. By way of example, a functional enzyme is one that exhibits the characteristic catalytic activity by which the enzyme is characterized. The term "inhibit" refers to the ability of a described compound to reduce or prevent a function described. Preferably, the inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%. "Instructional material" includes a publication, a record, a diagram, or any other means of expression that can be used to communicate the usefulness of the compounds described in the kit to effect the improvement of the various diseases or disorders cited herein. Optionally, or alternatively, the instructional material may describe one or more methods for alleviating diseases or disorders in a cell or a tissue of a mammal. The equipment instruction material may, for example, be attached to a container containing a described compound or be sent together with a container containing the identified compound. Alternatively, the instructional material may be sent separately from the container with the intention that the instructional material and compound be used cooperatively by the container. The term "parenteral" means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intrathecal, or intravenous. The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers, such as phosphate buffered saline, water and emulsions such as an oil / water or water / oil emulsion, and various types of wetting agents. The term also covers any of the agents tested by a regulatory agency of the United States Federal Government or listed in the United States Pharmacopeia for use in animals, including humans. The term "purified" and similar terms refer to the isolation of a molecule or compound in a form that is substantially free (at least 75% free, preferably 90% free, and most preferably at least 95% free) of other components normally associated with the molecule or compound in a native environment. The term "purified" does not it necessarily indicates that complete purity of the particular molecules is achieved during the process. A "very pure" compound refers to a compound that is greater than 90% pure. A "highly purified" compound refers to a compound that is greater than 95% pure. A "sample" preferably refers to a biological sample of a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine. A sample can also be any other source of material obtained from a subject, which contains cells, tissues or fluid of interest. A sample can also be obtained from cell or tissue culture. The term "standard" refers to something used for comparison. For example, a standard can be a known standard or compound agent that is administered or added to a control sample and used to compare results when measuring the compound in a test sample. "Standard" refers to an "internal standard", such as an agent or compound that is added to known amounts in a sample and is useful for determining such matters as purification or recovery rates when proceeding or submitting a sample to purification or screening procedures. extraction before a marker of interest is measured. A "subject" of analysis, diagnosis or treatment is a animal. Such animals include mammals, preferably a human. A "therapeutic" treatment is a treatment administered to a subject who shows signs of pathology for the purpose of diminishing or eliminating those signs. A "therapeutically effective amount" of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered. The term "treating" includes prophylaxis of the specific disorder or condition, or improvement of symptoms associated with a specific disorder or condition, or preventing or eliminating symptoms. The described compounds are generally named according to the IUPAC or CAS nomenclature system. Abbreviations that are well known to one of ordinary skill in the art can be used (eg, "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hour, "ta" for room temperature, and "rae" by racemic mixture). The values listed below for radicals, substituents and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. The disclosed compounds include compounds of formula I or formula II having any combination of the values, specific values, more specific values, and preferred values described herein. The term "halogen" or "halo" includes bromine, chlorine, fluorine and iodine. The term "haloalkyl" refers to an alkyl radical bearing at least one halogen substituent, non-limiting examples include, but are not limited to, chloromethyl, fluoroethyl or trifluoromethyl and the like. The term "(Ci-C10) alkyl" refers to a branched or linear alkyl group having from one to ten carbons. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. The term "(C2-C6) alkenyl" refers to an olefinically unsaturated linear or branched group having from two to six carbon atoms and at least one double bond Typically, (C2-C6) alkenyl groups include, but are not limited to 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, hexenyl, and the like The term (C2-C6) alkynyl may be ethynyl, 1-propynyl, -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or hexinyl, and the like The carbon atoms of the alkenyl or alkynyl groups that are not linked multiplied are considered to be carbon atoms of alkyl for purposes of substitution or replacement.The term "(Ci-C10 alkoxy)" refers to a alkyl group attached through an atom of oxygen. Examples of (C1-C10) alkoxy may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy and the like. The term "(C3-C8) cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "optionally substituted" refers to zero, one, two, three or four substituents, wherein the substituents are each independently selected. Each of the independently selected substituents may be the same or different from other substituents. The term "(C6-C0) aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and similar. The term "(C7-C16) arylalkyl" or "(C7-C16) aralkyl" refers to an alkyl group substituted with a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, such a group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Non-limiting examples of arylalkyl include benzyl, phenylethyl, and the like.

The term "optionally substituted aryl" includes aryl compounds having zero, one, two, three or four substituents, and a substituted aryl includes aryl compounds having one, two, three or four substituents, wherein Substituents include groups such as, for example, alkyl, halo, or amino substituent. The "(C2-C-10) heterocyclic group" refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing one, two or three heteroatoms (optionally in each ring) wherein the heteroatoms are oxygen, sulfur and nitrogen. The term "(C4-C10 heteroaryl)" refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing one, two or three heteroatoms (optionally in each ring) wherein the heteroatoms are oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl groups include furyl, thienyl, pyridyl, and the like. The term "phosphate analog" and "phosphonate analog" comprises phosphate and phosphonate analogs wherein the phosphorus atom is in the +5 oxidation state and one or more of the oxygen atoms is replaced with a portion without oxygen, including for example, the phosphorothioate phosphate analogs, phosphorothioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, phosphoramidate, boronophosphates, and the like, including associated contractions, for example, H, NH 4, Na, K and the like if such counterions are present. A "derivative" of a compound refers to a chemical compound that can be produced from another compound of similar structure in one or more stages, such as replacement of hydrogen by an alkyl, acyl or amino group. The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers, such as phosphate buffered saline, hydroxypropyl beta-cyclodextrins (HO-propyl beta-cyclodextrins), water, emulsions such as an oil / water emulsion or water / oil, and various types of wetting agents. The term also covers any of the agents approved by a regulatory agency of the Federal Government of the United States or listed in the United States Pharmacopeia for use in animals, including humans. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable. In many cases, the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto. An "effective amount" means an amount sufficient to produce a selected effect. For example, an effective amount of an S1P receptor agonist is an amount that decreases the cellular signaling activity of the S1 P receptor.

The disclosed compounds may contain one or more asymmetric centers in the molecule. In accordance with the present disclosure any structure that does not designate stereochemistry is to be understood as encompassing all the various optical isomers, as well as mixtures thereof. The disclosed compounds can exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. For example, the following structure: N ^ NH \ / is understood to represent a mixture of structures: \ = as well as \ = J. The hydrocarbon terms of 16: 0, 18: 0, 18: 1, 20: 4 or 22: 6 refer to a branched or linear alkyl or alkenyl group, wherein the first integer represents the total number of carbons in the group and the second integer represents the number of double bonds in the group. An "S1P modulating agent" refers to a compound or composition that is capable of inducing a detectable change in S1P receptor activity in vivo or in vitro (eg, at least 10% increase or decrease in S1P activity). as measured by a given trial such as the bioassay described in the examples and known in the art. The "S1P receptor" refers to all of the subtypes of the S1P receptor (for example, the SIP ^ S1P2, S1P3, S1P4 and S1P5 receptors of S1P), unless the specific subtype is indicated. It will be appreciated by those skilled in the art that the described compounds having chiral centers may exist in and be isolated in optically active and racemic forms. It is to be understood that the disclosed compounds encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the compound, which possesses the useful properties described herein, such as the diastereomers S, R; H.H; R, R; or R, S. It is well known in the art how to prepare such optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine the S1P agonist activity using the standard tests described herein, or using other similar tests that are well known in the art. In addition, some compounds may exhibit polymorphism. Potential uses of S1P receptor agonist pro-drugs (selective S1P! Receptor-like receptor agonists) include, but are not limited to, altering lymphocyte trafficking as a method of treatment for pathologies autoimmune diseases such as uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, and, more particularly, multiple sclerosis. "Treatment" of multiple sclerosis includes the various forms of the disease including relapse-remission, chronic progressive, etc., and S1P receptor agonists can be used alone or in conjunction with other agents with signs of relief and symptoms of the disease as well. as well as prophylactically. In addition, the described compounds can be used to alter lymphocyte trafficking as a method for prolonging allograft survival, for example solid organ transplants, graft versus treatment. host disease, bone marrow transplantation, and the like. In addition, the disclosed compounds can be used to inhibit autotaxin. Autotaxin, a plasma phosphodiesterase, has been shown to be subject to inhibition of the terminal product. Autotaxin hydrolyzes various substrates to produce lysophosphatidic acid and sphingosine-1-phosphate, and has been implicated in the progression of cancer and angiogenesis. Therefore, S1P receptor agonist prodrugs of the described compounds can be used to inhibit autotaxin. This activity may be combined with agonism in S1P receptors or may be independent of such activity. In addition, described compounds may be useful for inhibition of S1P Mass. The S1P Mass is an intracellular enzyme that irreversibly degrades S1P. Inhibition of S1P Mass disrupts lymphocyte trafficking with concomitant lymphopenia. Accordingly, S1P Mass inhibitors may be useful for modulating the function of the immune system. Therefore, the described compounds can be used to inhibit the S1P Mass. This inhibition could be in accordance with the activity of the S1P receptor, or be independent of the activity in any S1P receptor. In addition, disclosed compounds may be useful as CB receptor antagonists! cannabinoid The antagonism of CBi is associated with a decrease in body weight and an improvement in blood lipid profiles. Antagonism of CB-t could be in accordance with the activity of the S1P receptor, or be independent of the activity in any S1P receptor. In addition, described compounds may be useful for the inhibition of a cytosolic PLA2 group IV A (cPLA2). cPLA2 catalyzes the release of eicosanoic acids (eg, arachidonic acid). Eicosanoic acids are transformed into pro-inflammatory eicosanoids such as prostaglandins and leukotrienes. In this way, disclosed compounds may be useful as anti-inflammatory agents. This inhibition could be in accordance with the activity of the S1P receptor, or be independent of the activity in any S1P receptor.

In addition, disclosed compounds may be useful for the inhibition of multiple substrate lipid kinase (MuLK). MuLK is highly expressed in many human tumor cells and in this way its inhibition may be possible to decrease the growth or dilation of tumors. "Treatment" of multiple sclerosis includes the various forms of the disease including relapse-mitigation, chronic progressive, etc., and S1P receptor agonists can be used alone or in conjunction with other agents with signs of relief and symptoms of the disease as well. as well as prophylactically. The present invention also includes pharmaceutical compositions comprising the compounds of formula I or formula II. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition comprising a compound of the formula or formula II, or analog, derivative, or modification thereof, as described herein, is used to administer the appropriate compound to a subject. The compounds of formula I or formula II are useful for treating a disease or disorder including administering to a subject in need thereof a quantity Therapeutically acceptable of a compound of the formula I or of the formula II, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I or of the formula II, and a pharmaceutically acceptable carrier. The disclosed compounds and methods are directed to sphingosine-1-phosphate analogues (S1P) having activity as receptor agonists or antagonists in one or more S1P receptors, specifically the S1Pi, S1P4 and SIP5 receptor types. The disclosed compounds and method include both compounds having a phosphate moiety as well as compounds with hydrolysis-resistant phosphate substitutes such as phosphonates, alpha substituted phosphonates particularly where the alpha substitution is a halogen and phosphothionates. The values listed below for radicals, substituents and ranges are for illustration only; they do not exclude other defined values or other values within the ranges defined for the radicals and substituents. A preferred value for n is 0, 1, 2 or 3. A preferred value for R6 is CH, CH2, O, N or NH. A preferred value for R4, R5, R6 and R7 are CH or CH2. A preferred value for lower alkyl group is methyl, ethyl or propyl. A preferred value for halo is fluorine or chlorine.

A preferred value for X is hydroxy or OP03H2. Phosphonate substituted with alpha includes -CHFP03H2, -CF2P03H2, -CHOHPO3H2, -C = OP03H2 or thiophosphate (OP02SH2). A preferred value for R1 is hydrogen. Preferred cyclic groups including a double bond include: A preferred compound of the invention has the group R1 placed ortho or meta to R2. Additional preferred compounds have the group R2 placed for the cyclic group (eg, 1.4). Non-limiting examples of esters of the compounds include compounds wherein the group X is; -c-where Y is O, CH2) CHOH, CHF, CF2, or 20; and R and R21 are alkoxy, alkenyloxy, alkynyloxy, aryloxy, wherein R22 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl) or optionally substituted aryl. Preferred groups R20 and R21 are alkoxy, Preferred compounds of formula I include: Additional preferred compounds of formula I include: Additional compounds of formula I are illustrated in 1, below.

Table 1 Without wishing to be bound by any particular theory, it is expected that the compounds described herein are prodrugs, for example, are activated by phosphorylation of the primary alcohol to form the mono-phosphorylated analog. Additionally, the active drugs are expected to be agonists in the S1P type 1 receptor. In cases where the compounds of the formula I are sufficiently basic or acidic to form stable non-toxic acid or base salts, the preparation and administration of the Compounds such as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, a- and glycerophosphate. Inorganic salts can also be formed, including salts of hydrochloride, sulfate, nitrate, bicarbonate, and carbonate. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid which produces a physiologically acceptable anion. Alkali metal salts (eg, sodium, potassium or lithium) or alkaline earth metal (eg calcium) can also be made from carboxylic acids. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.

Salts of inorganic bases, include but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary amines, secondary and tertiary such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di (substituted alkyl) amines, tri (to Iq ui I or substituted) amines, alkenyl amines, dialkenyl, trialkenyl, substituted alkenyl, di (substituted alkenyl) amines, tri (substituted alkenyl) amines, cycloalkylamines, di (cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkyl, disubstituted cycloalkyl amine, trisubstituted cycloalkyl, cycloalkenyl, di (cycloalkenyl) amines, tri (cycloalkenyl) amines, substituted cycloalkenylamines, disubstituted cycloalkenylamine, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituent s in the amine are different and are alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic heteroaryl group. Non-limiting examples of amines include, isopropylamine, trimethylamine, diethylamine, tri (iso-propyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, Usin, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromo, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful, for example, carboxylic acid amides, including carboxamides, lower alkylcarboxamides, dialkylcarboxamides, and the like. The compounds of the formula I can be formulated as pharmaceutical compositions and administered to a mammal, such as a human patient in a variety of forms adapted for the chosen route of administration, for example, orally or parenterally, by intravenous, intramuscular routes. , topical or subcutaneous. In this way, the present compounds can be administered systematically, for example, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an edible assimilable carrier. They can be enclosed in soft or hard shell gelatin capsules, can be compressed into tablets, or can be incorporated directly with the patient's diet foods. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingested tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least about 0.1% active compound. The percentage of the compositions and preparations can, of course, be varied and conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level would be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: buffers such as gum tragacanth, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various different materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules they can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl- and propyl-parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and devices. The active compound can also be administered intravenously or intraperitoneally by infusion or injection. The solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or sterile dispersions or powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or a liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters , and mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it would be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be caused by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the amount required in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization of the filter. In the case of sterile powders for preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients present in previously sterile filtered solutions. For topical administration, the present compounds can be applied in pure form, for example, when they are liquid. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Exemplary solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol mixtures, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties of a given use. The resulting liquid compositions can be applied from absorbent pads, used to impregnate bandages and other bandages or dressings, or sprayed into the affected area using pump or spray type sprinklers. Thickeners such as synthetic polymers, acids Fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be used with liquid carriers to form expandable pastes, gels, ointments, soaps, and the like, for application directly to the wearer's skin. Examples of useful dermatological compositions that can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157) and Wortzman (U.S. Patent No. 4,820,508). Useful dosages of the compounds of the formula I can be determined by comparing their in vitro activity and activity in vivo in animal models. Methods for extrapolating effective dosages in mice, and other animals, to human are known to the art; for example, see United States Patent No. 4,938,949. Generally, the concentration of the compounds of the formula I in a liquid composition, such as a lotion, will be from about 0.1 to about 25 weight percent, preferably about 0.5-10 weight percent. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5% by weight, preferably about 0.5-2.5% by weight. weight based on the total weight of the composition. The amount of the compound, or an active salt or derivative thereof, required for use in the treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the condition. patient and will finally be the discretion of the doctor or clinician who attends. In general, however, a dose would be in the range of about 0.1 to about 10 mg / kg of body weight per day. The compound is conveniently administered in unit dosage form; for example, containing from 5 to 1000 mg, conveniently 10 to 750 mg, more conveniently, 50 to 500 mg of active ingredient per unit dosage form. Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 1.0 to about 1000 nM, preferably, from about 10 to 500 nM, more preferably, from about 25 to about 200 nM. This can be achieved, for example, by intravenous injection of a solution of 0.05 to 5% of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels can maintained by continuous infusion to provide approximately 0.01-5.0 mg / kg / hr or by intermittent infusions containing approximately 0.4-15 mg / kg of the active ingredients. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-dose itself may be further divided, for example, into a variety of freely discrete spaced administrations; such as multiple inhalations of an insufflator or by application of a plurality of drops in the eye. The method described includes a kit comprising an inhibitor compound of formula I and instructional material that describes administering the inhibitor compound or a composition comprising the inhibitor compound to a cell or a subject. This should be constructed to include other embodiments of equipment that are known to those skilled in the art, such as a kit comprising a solvent (preferably sterile) for dissolving or suspending the inhibitor compound or composition prior to administering the compound or composition to a cell or a subject. Preferably, the subject is a human. According to the compounds and methods described, as described above or as discussed in the Examples later, conventional chemistry, cell chemistry, histochemistry, biochemistry, molecular biology, microbiology, and in vivo techniques are known to those of skill in the art. Such techniques are fully explained in the literature. Without further description, it is believed that one of ordinary skill in the art can, utilize the foregoing description and the following illustrative examples, make and use the disclosed compounds. Processes for preparing compounds of the formula I or for preparing intermediates useful for preparing compounds of the formula I are provided as additional embodiments. Useful intermediates for preparing compounds of the formula I are also provided as additional embodiments. The processes are provided as additional modalities and are illustrated in the schemes, where the meanings of the generic radicals are as given above unless they are otherwise qualified. The invention is now described with reference to the following Examples and Modalities. Without further description, it is believed that one of ordinary skill in the art can use the foregoing description and the following illustrative examples make and use the described compounds. The following work examples are therefore provided for the purpose of illustration only and specifically they indicate the preferred modalities, and are not to be constructed as limiting in any way the rest of the description. Therefore, the examples should be constructed to encompass any and all variations that become apparent as a result of the teaching of the specification.

The compounds described above presented in Table 1 can be synthesized by the routes illustrated in either Scheme 1 (Fig. 1) or Scheme 2 (Fig. 2). In Scheme 1, key steps in the synthesis involve initial coupling of a 4-cyanophenyl-boronic acid, 1, with cyclopentenone, 2, and subsequently converting the nitrile of compound A, shown in compound C. Compound C can be converted to to compound VIII. In a similar manner, the intermediate of cyclopentanone to XI can be prepared. Additional alterations in this sequence could produce precursors for intermediaries to XII and XIII. Using the phenol derived from modifications to the synthetic scheme observed in Example 2, below, suitable cyclopentanone intermediates for IX and X can be synthesized. In Scheme 2 the key steps involve the preparation of a phenolic cyclopentanone using 4-tert-butyldimethylsilyloxyphenylboronic acid. After the generation of the desired cyclopentanone intermediate, the carbonyl function is elaborated in unit 1-amino-1-hydroxymethyl as described later. Examples Example 1: 3- (4'-Cyanophenyl) cyclopentanone (Compound A). Palladium (II) acetate (0.23 g, 0.1 eq.) And antimony (III) chloride (0.23 g, 0.1 eq.) Were added to a solution of 80 mL of acetic acid containing 2-cyclopenten-1 -one, 2, (0.82 g, 10 mmol), sodium acetate (1.6 g, 20 mmol) and 4-cyanophenyl-boronic acid, 1, (1.46 g, 10 mmol) under nitrogen. The reaction was stirred for 24 hours at 25 ° C, the black precipitate was removed by filtration and the filtrate was diluted with 250 mL of brine, extracted twice with 50 mL of methylene chloride. The organic layer was stirred with saturated bicarbonate solution for 30 minutes, washed with brine and dried over magnesium sulfate. The solvent was removed and subjected to chromatography to provide compound A. Example 2: 3- (4'-hydroxyphenyl) cyclopentanone. Palladium (II) acetate (0.23 g, 0.1 eq.) And antimony (III) chloride (0.23 g, 0.1 eq.) Were added to a solution of 80 mL of acetic acid containing 2-cyclopenten-1 -one, 2, (0.82 g, 10 mmol), sodium acetate (1.6 g, 20 mmol) and 4-tert-butyldimethylsilyloxyphenyl-boronic acid, 4, (2.54 g, 10 mmol) under nitrogen. The reaction was stirred for 24 hours at 25 ° C, the black precipitate was removed by filtration and the filtrate was diluted with 250 mL of brine, extracted twice with 50 mL of methylene chloride. The organic layer was stirred with a solution of saturated bicarbonate for 30 minutes, washed with brine and dried over magnesium sulfate. The solvent was removed and subjected to chromatography to provide 3- (4'-hydroxyphenyl) cyclopentanone. Example 3: 3- (4'-Aldoximinophenyl) cyclopentanone (Compound B).

Compound A (1.0 mmol) was dissolved in 95% ethanol (1.5 ml_). Triethylamine (2.3 mmol) and hydroxylamine hydrochloride (2.2 mmol) were added and the reaction mixture was heated to about 75 ° C for 3 hours. The progress of the reaction can be monitored by CCF (thin layer chromatography). Generally, after about 3 hours, no starting nitrile remained and the solution was concentrated to a suspension and from water, or an organic solvent. The solid was filtered and washed with cold water, and dried under vacuum to provide the crude product, which can be used in the next step without further purification. Example 4: 3-H- \ 5- (4-1 so bu ti lf in i? -? .2.41 oxadiazol-3-M1-phenyl-cyclopentanone (Compound C) To a solution of 4-isobutylbenzoic acid, 3, (0.150 mmol) in dry methylene chloride (4 ml_) were added (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.150 mmol) and diisopropylethylamine (0.150 mmol), followed by the aldoximinophenyl derivative (compound B) ( 0.150 mmol) The reaction was stirred at room temperature for approximately 12-16 hours. The mixture was diluted with diethyl ether (15 ml_), washed with saturated aqueous ammonium chloride (2 X 5 ml_), brine (5 ml), and concentrated in vacuo. The title compound was purified by column chromatography. Example 5: Conversion of the Intermediates of 3- (4'-substituted phenyl) cyclopentanone to Compounds VIII-XIII. The cyclopentanone intermediates synthesized through the sequences described in Scheme 1 can be converted to the 1-hydroxymethyl-3- (4'-substituted phenyl) cyclopentanes (compounds VIII-XIII) through a procedure of step 3 described in International Patent Application WO 2006/088944 A1, pages 37-39. This procedure is illustrated for the synthesis of compound VIII in Figure 3. Cyclopentanone precursors to IX-XIII can be converted by analogous methods. Step 1: 1 -Amino-3- (4'-substituted phenyl) cyclopentanecarbonitrile (Scheme 3: Compound D). The intermediate of cyclopentanone (11.8 mmol), sodium cyanide (0.15 g, 23.5 mmol) and ammonium chloride (1.25 g, 23.5 mmol) were added to 20 mL of aqueous ammonium hydroxide solution. The mixture was vigorously stirred overnight. After completion the reaction mixture was extracted twice with 10 mL of methylene chloride afterwards. The organic extraction was dried over magnesium sulfate, concentrated to provide the amino-nitrile, D. The crude product is used for the next step without further purification. (See, for example, J. Med. Chem., 1986, 29, 1988-1995). In a similar manner, the cyclopentanone intermediate can be prepared to XI. Alterations in this sequence can produce intermediary precursors to XII and XIII. Using the phenol derived from the modifications for the synthetic scheme observed above, suitable cyclopentanone intermediary compounds for IX and X can be synthesized. Step 2j 1-amino-3- (4'-substituted phenyl) cyclopentanecarboxylic acid (Scheme 3; Compound E ). The crude product of step 1 (-11.2 mmol) and 50 ml_ of concentrated hydrochloric acid were heated to about 70 ° C and stirred overnight under an argon or nitrogen atmosphere. The resulting aqueous solution was evaporated to dryness. 10 ml_ of water were added and the solution was dried again. This process was repeated twice. The crude product was washed with cold water and acetone to provide compound E. Step 3: 1-amino-3- (4'-phenyl) -cyclopentanill-methanol (Scheme 3: Compound R. The product of step 2 (0.20 mmol) and borohydride Sodium (27 mg, 0.6 mmol) was dissolved in 3 ml_ of tetrahydrofuran. After the solution was cooled to approximately 0 ° C, 51 mg (0.2 mmol) of iodide dissolved in 1 ml_ of THF were added dropwise. The vessel was fitted with a condenser and the reaction mixture was heated to reflux under argon for 5 hours. Excess sodium borohydride was warmed with methanol. After removal of the solvent by evaporation in vacuo, 2 ml_ of water and 5 ml_ of methylene chloride were added and the mixture was stirred for about 1 hour. The organic phase was collected and the aqueous phase was extracted twice with methylene chloride. The combined organic extracts were dried and concentrated to provide the crude product. Additional purification by column chromatography provides the purified compound. Step 4: Conversion to phosphate (Scheme 3: Compound G). The alcohols, VIII-X 111 can be converted to the corresponding phosphates by the following procedure. Slowly add 1 mL of 85% aqueous phosphoric acid to 0.5 g of phosphorus pentoxide, heat at 100 ° C for 1 hour under nitrogen. Another 0.5 g of phosphorus pentoxide and 30 mg of the alcohol VIII (or IX-XIII) were added to the mixture and the reaction was heated for an additional 5 hours. After cooling to room temperature, 10 mL of ice water was added to the reaction mixture. The product was collected as a precipitate. The product was collected and washed with water, then dried under vacuum. The tests below are assays reported in the standard literature known in the art to confirm and quantify the activity of the described compounds. Example 6: Sphingosine-Kinase Assay Recombinant type 2 sphingosine kinase (SPHK2) was prepared by forcing the expression of the recombinant mouse or human enzyme by transfecting the relevant plasmid DNA into HEK293T or CHO K1 cells. After about 60 hours, the cells were harvested, divided and the non-microsomal (eg soluble) fraction retained. The divided cell supernatant fluid containing the recombinant enzyme was mixed with the test compounds (FTY720, AA151, VIII and XVIII) (5-50 micromolar) and? -32? - ??? and incubated for 0.5-2.0 hours at 37 ° C. The lipids in the reaction mixture were extracted in an organic solvent and presented by normal phase thin layer chromatography. Radiolabelled bands are detected by autoradiography, scraped from the plate and quantified by scintillation counting. The test compounds are used in a concentration of approximately 50 μ ?, the incubation time is approximately 20 minutes. Example 7: GTPyS-35 binding assay This assay illustrates the agonist activation of the receptors coupled with the G protein (GPCRs) in isolation. The assay forces the expression concomitantly of a recombinant GPCR (e.g., the S1P1-5 receptor) and each of the three subunits (typically, α-i2, β-1, and α -2) of a heterotrimeric G protein in a HEK293T cell when transfecting the cell with four plasmid DNAs that encode the respective proteins. Approximately 60 hours after the transfection, the cells were harvested, divided, the nucleus was discarded, and the crude microsomes were prepared from the rest. Agonist stimulation (eg, S1P) of the G protein complex of the receptor in the microsomes results in the exchange of GTP by GDP in the a subunit in a dose-dependent manner. The GTP-linked subunit was detected using a GTP analog (GTPyS-35), which is a radionuclide-labeled phosphothionate (sulfur-35) that is not hydrolysed to GDP. The microsomes with the adherent G proteins are collected by filtration and the GTPyS-35 binding is quantified in a liquid scintillation counter. The assay produces relative potency (EC50 values) and maximum effect (efficacy, Emax). Antagonist activity is detected as changes to the right in the agonist dose response curve in the presence of a fixed amount of antagonist. If the antagonist behaves competitively, the affinity of the receptor / antagonist pair (K) can be determined. The assay is described in Davis, M.D., J.J. Clemens, T.L. Macdonald and K.R.

Lynch (2005) "S1P Analogs as Receptor Antagonists" Journal of Biological Chemistry, vol. 280, pp. 9833-9841. Example 8: Lymphopenia Assay Compounds (e.g., primary alcohol test compounds) were dissolved in 2% hydroxypropyl beta-cyclodextrin and introduced into groups of mice by oral gavage at doses of 0.01, 1.0 and 10 mg / kg of body weight. At intervals, for example, 24 hours, 48 hours or 96 hours the mice are lightly anesthetized and approx. 0.1 ml_ of blood was drawn from the orbital sinus. The number of lymphocytes (in thousands per microliter of blood, normal is 4-11) was determined using a Hemavet blood analyzer. Example 9: Cardiac Rate Test Mice were dosed with test compounds (intravenous, 3 mg / kg) or vehicle (2% hydroxypropyl beta-cyclodextrin) and heart rate was measured at 1 hour post-dosing. The heart rate was captured in conscious animals, unbridled using the ECGenieMR system. The invention should not be constructed to be limited only to the tests and methods described above, but should be constructed to include other methods and assays as well. Other methods that are used but not described above are well known and are within the competence of one of ordinary skill in chemistry, biochemistry, molecular biology and clinical medicine. One of ordinary skill in the art will know that other assays and methods are available to perform the procedures described above. The abbreviations used above have their conventional meaning within clinical, chemical and biological techniques. In the case of any inconsistencies, the present description, including any definitions herein shall prevail. The descriptions of each and each patent, patent application, and publication cited in the specification are hereby expressly incorporated by reference in their entirety in this description. Illustrative modes of this description are discussed and reference has been made to possible variations within the scope of this description. These and other variations and modifications in the description will be apparent to those skilled in the art without departing from the scope of the description, and it should be understood that this specification and the claims shown below are not limited to the illustrative embodiments indicated.

Claims (5)

1. CLAIMS 1. A compound of the formula I or of the formula II: ? characterized in that R4 and R7 are independently CH, or CH2; R5 is C, CH, or N, R6 is CH, CH2, O, S or NR3; R3 is hydrogen, or alkyl of X is hydroxyl (-OH), phosphate (-OP03H2), phosphonate (-CH2PO3H2), or alpha-substituted phosphonate; R1 is hydrogen, halo (C-1-C10) alkyl, or (Cr) alkoxy C 1 o); R2 is a group having the formula III, IV, V, or VI: V VI wherein R8, R9, R10, R11, R12, R13, R14, R15, R16, R7 and R18 are independently O, S, C, CR19, CR 0R21, C = 0, N or NR22; R19, R20 and R21 are independently hydrogen, halo, (C1-C-10) alkyl, (d-C10) alkyl substituted with halo, hydroxy, (C-i-C10) alkoxy, or cyano; R is hydrogen or (d-C10) alkyl; and at least one ring of the groups of formula III, IV, V, or VI includes a heteroatom (O, S or N); Z2 is (C ^ -C6) alkyl, (C3-C8) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-Ci0) aryl, (C7-C6) alkaryl ), or (C7-C6) arylalkyl; wherein the Z2 alkyl groups are optionally substituted with 1, 2, 3 or 4 substituent groups, wherein the substituent groups are independently halo, (C1-C-10) alkoxy or cyano; indicates one,.; more optional double links; Y2 is a link, -O-, or > C = 0; W1 and W2 are -CH2-, where m is o, 1, 2 or 3; or W2 is - (C = 0) (CH2) 1-5-, where m is 1; n is 0, 1, 2, 3 or 4; i is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3, wherein the alkyl groups of R1 may be optionally substituted with 1, 2, 3 or 4 substituent group, wherein the substituent groups are aryl, (C1-C10) alkoxy or cyano; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R2 are optionally substituted with 1, 2, 3 or 4 substituent groups, where the substituent groups independently are oxo (= 0), min (= NRd ), alkyl of (CrC10), alkoxy of (CrC10), or aryl of C6, or wherein one or more of the carbon atoms in the alkyl groups of R2 can be independently replaced with oxygen without peroxide, sulfur or NRC; the alkyl groups of R3 are optionally substituted with 1, or 2 hydroxy groups; and Rd is hydrogen, or (Ct-C ^ o) alkyl; or a pharmaceutically salt acceptable or ester thereof.
2. 2. The compound according to claim 1, characterized in that R1 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methoxy, alkyl of (C-i-C6), haloalkyl of (C6-C6), or substituted with alkoxy, cyano or aryl.
3. 3. The compound according to claim 2, characterized in that R1 is hydrogen, trifluoromethyl, or -C H 2 C F 3.
4. 4. The compound according to claim 2, characterized in that R1 is benzyl, phenylethyl, or methyl-benzyl.
5. 5. The compound according to any of claims 1-4, characterized in that R2 is 6. The compound according to claim 5, characterized in that R2 is: wherein Y3 is (CH3) 3C-, CH3CH2 (CH3) 2C-, CH3CH2CH2-, CH3 (CH2) 2 CH2, CH3 (CH2) 4C H 2-, (CH3) 2CHCH2-, (CH3 ) 3CCH2-, CH3CH20-, (CH3) 2CHO-, or CF3CH2CH2- or a group having the formula: » 7. The compound according to claim 6, characterized in that R2 is: 8. The compound according to claim 7, characterized in that R2 is: 10. The compound according to claim 9, characterized in that R2 is: 11. The compound according to any of claims 1-4, characterized in that R2 has the formula IV 12. The compound according to claim 11, characterized in that R2 is: 13. The compound according to any of claims 1-12, characterized in that each of X1, Y1 and Z1 is C or CH2. The compound according to any of claims 1-13, characterized in that R3 is hydrogen, methyl, hydroxymethyl, ethyl, hydroxyethyl, propyl or isopropyl. 15. The compound according to claim 14, characterized in that R3 is hydrogen, methyl, hydroxymethyl, ethyl or hydroxyethyl. 16. The compound according to any of claims 1-15, characterized in that it has the formula: 17. The compound in rdance with the claim 16, characterized in that it has the formula: 18. A method for the prevention or treatment of a pathological condition or symptom in a mammal, characterized in that the activity of the sphingosine-1-phosphate receptors is involved and the agonism of such activity is desired, which comprises administering to the mammal an effective amount of a compound rding to any of claims 1-17. 19. The method rding to claim 18, characterized in that the pathological condition is an autoimmune disease. The method rding to claim 19, characterized in that the autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, inflammatory diseases of the intestine, or multiple sclerosis. 21. The method rding to claim 20, characterized in that the autoimmune disease is multiple sclerosis. 22. The method rding to claim 21, characterized in that the pathological condition is to alter the lymphocyte trafficking. 23. The method rding to claim 22, characterized in that the treatment is the alteration of the lymphocyte traffic. 24. The method rding to claim 23, characterized in that the lymphocyte trafficking provides prolonged allograft survival. 25. The method rding to claim 24, characterized in that the allograft is for transplantation. 26. A method for the prevention or treatment of a pathological condition or symptom in a mammal, characterized in that the activity of S1P lyase is involved and the inhibition of S1P lyase is desired, which comprises administering to the mammal an effective amount of a compound of S1P lyase. rding to any of claims 1-17.