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  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to compounds that have activity as S 1 P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate SlP receptor activity.
• Sphingosine-1-phosphate has been demonstrated to induce many cellular effects, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and endothelial cell in vitro angiogenesis.
• SlP receptors are therefore good targets for therapeutic applications such as wound healing and tumor growth inhibition.
• SlP signals cells in part via a set of G protein-coupled receptors named SlPl, S1P2, S1P3, S1P4, and S1P5 (formerly called EDG-I, EDG-5, EDG-3, EDG-6, and EDG-8, respectively).
• LPA structurally-related lysophosphatidic acid
• SlP receptors make good drug targets, because individual receptors are both tissue- and response-specific. Tissue specificity of the SlP receptors is important, because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the SlP receptors is also important because it allows for development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other things. For example, the response specificity of the SlP receptors could allow for an SlP mimetic that initiates platelet aggregation without affecting cell morphology.
• S 1 P is formed as a metabolite of sphingosine in its reaction with sphingosine kinase, and is abundantly stored in platelet aggregates where high levels of sphingosine kinase exist and sphingosine lyase is lacking. SlP is released during platelet aggregation, accumulates in serum and is also found in malignant ascites. SlP biodegradation most likely proceeds via hydrolysis by ectophosphohydrolases, specifically the sphingosine 1-phosphate phosphohydrolases.
• the present invention relates to the use of new compositions which include SlP modulators, e.g., agonists, partial agonists, inverse agonists and antagonists, and their use in treating, preventing or curing various SlP receptor-related conditions.
• SlP modulators e.g., agonists, partial agonists, inverse agonists and antagonists
• the invention features compounds which are SlP receptor modulators; in an embodiment, such compounds include those having the formula
• the present invention relates to compounds of formula I.
• A may be an aryl or heteroaryl group, optionally substituted with one, two or three substituents which may include halogen, hydroxyl, SR 2 , S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO2R 2 , cyano, amino, Ci_s alkylamino/arylamino/heteroarylamino, Q -6 alkyl, Ci -S alkylthio, C 1 - S alkoxy, halogen-substituted C 1-6 alkyl, and halogen-substituted Ci_s alkoxy.
• R 2 may be selected independently from hydrogen, hydroxyl, amino, alkylamino/arylamino, Q. s alkyl, d-s alkoxy, C 1 - 5 alkylthio, halogen-substituted C] -6 alkyl and halogen-substituted C 1 . 5 alkoxy; or aryl/heteroaryl.
• A may desirably be a Ci-6 cyclic ring (alicyclic or aromatic) optionally having one or more heteroatoms.
• B and C are an at least partially aromatic bicyclic ring system, e.g., bicycloaryl, bicycloheteroaryl, dihydrobicyclic or tetrahydrobicyclic aryl and heteroaryl.
• the bicyclic ring system may be substituted with 1 to 5 substituents, e.g., C 1 ⁇ alkyl, Ci -S alkylthio, Ci -S alkoxy, halogen, hydroxyl, cyano, halogen-substituted Ci-galkyl and halogen-substituted C 1 . 5 alkoxy.
• Z 1 and Z 2 may be independently selected from O, NR 3 , S, S(O), S(O) 2 ,
• R 3 may be hydrogen, hydroxyl, Q. 6 alkyl, Ci_s alkoxy, C1.5 alkylthio, halogen-substituted Ci. ⁇ alkyl and halogen-substituted C ⁇ .s alkoxy; aryl or heteroaryl.
• R 4 and R 5 may independently be hydrogen, halogen, hydroxyl, cyano, C]_ 6 alkyl, C 1 .
• R 3 may be a C 3 -C 6 ring optionally containing a heteroatom.
• R 1 may be Cj -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, Ci_ 5 alkoxy, Ci -5 alkylamino, aryl or heteroaryl.
• R 1 may optionally be substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, heteroarylamino groups, and the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents, e.g., hydroxyl, halogen, cyano, Q- ⁇ alkyl, Ci -S alkylthio, C 1 - 5 alkoxy, C 3 -6 cycloalkyl.
• X may be WC(O)OR 63 , WP(O)R 6b R 6c , WS(O) 2 OH, WCONHSO 3 H or 1 H- tetrazol-5-yl.
• W may be a direct bond, oxygen or Q- 4 alkyl with substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C 1-4 alkoxy and;
• R 6a may be hydrogen or Ci ⁇ alkyl;
• R 6b and R 6c may be hydrogen, hydroxyl, Ci ⁇ alkyl or halogen substituted Ci ⁇ alkyl.
• Y may be a residue of formula (a) where the left and right asterisks indicate the point of attachment:
• R 7 and R 8 may be joined together with the atoms to which they are attached to form a 4 to 7- membered ring, optionally having a hetero atom.
• R 9 may be hydrogen, halogen, hydroxyl, cyano, Ci-e alkyl, C 1 .
• R 10 and R ⁇ may individually be hydrogen, halogen, hydroxyl, cyano, Ci- 6 alkyl, Ci-s alkoxy, Ci -S alkylthio, halogen-substituted Ci -6 alkyl or halogen-substituted Ci-s alkoxy.
• the invention includes compounds having the formula
• A may be a Ci_ 6 cyclic ring (alicyclic or aromatic) that may have one or more heteroatoms. Where A is an aryl or heteroaryl group, A may be optionally substituted with one, two or three substituents which may include halogen, hydroxyl, S, S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, Ci-5 alkylamino/arylamino/heteroarylamino, Cj- 6 alkyl, C 1 - 5 alkylthio, C 1 -5 alkoxy, halogen-substituted C 1 - 6 alkyl, and halogen-substituted C 1 - 5 alkoxy.
• R 2 may be hydrogen, hydroxyl, amino, alkylamino/arylamino, alkyl and halogen-substituted C 1-S alkoxy; or aryl/heteroaryl.
• B and C are an at least partially aromatic bicyclic ring system, e.g., bicycloaryl, bicycloheteroaryl, dihydrobicyclic ortetrahydrobicyclic aryl and heteroaryl.
• the bicyclic ring system may be substituted with 1 to 5 substituents, e.g., Ci -6 alkyl, C 1 - 5 alkylthio, C 1-S alkoxy, halogen, hydroxyl, cyano, halogen-substituted Ci-ealkyl and halogen-substituted C1.
• R 1 may be C 1 ⁇ alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C3-6 cycloalkyl, C 1-S alkoxy, C1. 5 alkylamino, aryl or heteroaryl.
• Ri may optionally be substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, heteroarylamino groups, and the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents, e.g., hydroxyl, halogen, cyano, Q_ 6 alkyl, C 1 - 5 alkylthio, C 1 - S alkoxy, Ca -6 cycloalkyl.
• X may be WC(O)OR , WP(O)R 6b R 6c , WS(O) 2 OH, WCONHSO 3 H or lH-tetrazol-5-yl.
• W may be a direct bond, oxygen or C M alkyl with substituents independently selected from the group consisting of: halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, CM alkoxy and COO 2 H;
• R 4a may be hydrogen or Q ⁇ alkyl;
• R 6b and R 6c may be hydrogen, hydroxyl, Q- 4 alkyl or halogen substituted C ⁇ alkyl.
• Y has the formula:
• R 9 may be hydrogen, halogen, hydroxyl, cyano, Q -6 alkyl, C 1 - 5 alkylthio, C 1 - 5 alkoxy, halogen-substituted C]_ 6 alkyl or halogen-substituted C 1 - 5 alkoxy;
• R 10 and R 11 may individually be hydrogen, halogen, hydroxyl, cyano, Ci - 6 alkyl, Cj . 5 alkoxy, C 1 . 5 alkylthio, halogen-substituted Ci -6 alkyl or halogen-substituted C1-5 alkoxy.
• the present invention relates to a compound having the formula
• A is an optionally substituted aryl or heteroaryl group
• B and C are an at least partially aromatic bicyclic ring system;
• X is selected from the group consisting of WC(O)OR 6 ⁇ WP(O)R 6b R 6c ,
• W is a direct bond, oxygen or C M alkyl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, Q -4 alkoxy and COO 2 H;
• R 6a is hydrogen or C ⁇ aHcyl; and
• R 6b and R 6c are independently hydrogen, hydroxyl, C ⁇ alkyl or halogen substituted Q ⁇ alkyl;
• Y is residue of formula (a) where the left and right asterisks indicate the point of attachment
• m 0, 1, 2 or 3;
• R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, amino, C 1 - 5 alkylamino, hydroxyl, cyano, Q -6 alkyl, Cue hydroxyalkyl (e.g., hydroxy- terminated alkyl), C 1-5 alkylthio, C 1 - 5 alkoxy, halogen-substituted Ci- ⁇ alkyl and halogen- substituted C 1 . 5 alkoxy; or R 7 and R 8 may be joined together with the atoms to which they are attached to form a 4 or 5-membered ring; and
• R 9 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano,
• R 10 and R 1 * are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1. 6 alkyl, C 1 . 5 alkoxy, C 1 - 5 alkylthio, halogen-substituted Ci -6 alkyl or halogen-substituted C 1 . 5 alkoxy and
• n 0, 1 , 2 or 3;
• R 1 is selected from the group consisting of Q -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3 - 6 cycloalkyl, C 1 - 5 alkoxy, Ci -5 alkylamino, aryl or heteroaryl.
• the invention includes compounds of formula (II):
• A may be an aryl or heteroaryl group
• X is -C(O)OR 6a , where
• R 6a is hydrogen or Q ⁇ alkyl
• Y is a residue of formula (a)
• Q is (CR 10 R 1 *) m ; m is 0, 1 , 2, 3 or 4; R 7 and R 8 may independently be hydrogen, hydroxyl, lower alkyl; or R 7 and R 8 , taken with the atoms to which they are attached, form a ring; R 9 is selected from, e.g., hydrogen, halogen, hydroxyl, or cyano; and Z 1 and Z 2 are independently O or (CR 4 R 5 ) n , where R 4 and R 5 are independently hydrogen, halogen, hydroxyl, cyano, Q. 6 alkyl, C 1 .5 alkoxy; n is 0, 1, 2 or 3; and R 1 is selected from, e.g., Ci.
• alkyl C 2 - 6 alkenyl, C 2-6 alkynyl, C 3 _6 cycloalkyl, C1.5 alkoxy, C1.5 alkylamino, aryl or heteroaryl; or a pharmaceutically acceptable salts thereof.
• the aryl or heteroaryl group may be substituted with one, two or three substituents such as halogen, hydroxyl, S, S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1 - 5 alkylamino/arylamino/heteroarylamino, Q- 6 alkyl, Ci -5 alkylthio, Ci. 5 alkoxy, halogen-substituted Ci.
• substituents such as halogen, hydroxyl, S, S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1 - 5 alkylamino/arylamino/heteroarylamino, Q- 6 alkyl, Ci -5 alkylthio, Ci. 5 alkoxy, halogen-substitute
• R 2 is, e.g., of hydrogen, hydroxyl, amino, alkylamino/arylamino, Q- ⁇ alkyl, Ci -S alkoxy, Ci -5 alkylthio, halogen-substituted Ci -6 alkyl and halogen-substituted C 1 . 5 alkoxy; or aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z 1 and the ring to which they are attached, form an alicyclic or heterocyclic ring.
• R 2 may be selected from hydrogen, hydroxyl, amino, alkylamino/arylamino, C 1-6 alkyl, Ci-S alkoxy, C 1 -5 alkylthio, halogen-substituted Cj-g alkyl and halogen-substituted Ci. 5 alkoxy; or aryl/heteroaryl.
• the benzofuranyl ring may be substituted with 1 to 5 substituents, e.g., of C1.6 alkyl, Ci -S alkylthio, C 1-S alkoxy, halogen, hydroxyl, cyano, halogen-substituted Ci-6alkyl or halogen-substituted C 1-S alkoxy.
• substituents e.g., of C1.6 alkyl, Ci -S alkylthio, C 1-S alkoxy, halogen, hydroxyl, cyano, halogen-substituted Ci-6alkyl or halogen-substituted C 1-S alkoxy.
• R 1 may be Ci-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 3 -6 cycloalkyl, C 1-S alkoxy, C 1-S alkylamino, aryl or heteroaryl; Ri may optionally substituted with, e.g., hydroxyl, halogen, cyano, amino, alkylamino, arylamino, or heteroarylamino groups.
• the aryl and heteroaryl groups may be substituted with one to five substituents such as hydroxyl, halogen, cyano, Ci -6 alkyl, C1. 5 alkylthio, C] -5 alkoxy, and C 3-6 cycloalkyl.
• the present invention relates, in one embodiment, to compounds according to
• A is a substituted or unsubstituted aryl or heteroaryl group, which may be one illustrated below, where R 12 is hydrogen or Ci- ⁇ alkyl; and the left and right asterisks indicate the point of attachment in formula (I);
• R 12 may be hydrogen, hydroxyl, amino, alkylamino or arylamino, Q.g alkyl, C 1 . 5 alkoxy, C 1 - 5 alkylthio, halogen-substituted C 1-6 alkyl and halogen-substituted Cj-s alkoxy; aryl or heteroaryl; more preferably hydrogen.
• B and C preferably are substituted or unsubstituted aryl or heteroaryl, e.g.,
• R 12 is hydrogen or Q -6 alkyl; and the left and right asterisks indicate the point of attachment in formula (I); Wi, W 2 , W 3 or W 4 may be C, N, C-OH, C-OR 13 or C- R 13 ; R 13 is hydrogen or Ci- ⁇ alkyl, Ci. 5 alkylthio, C1.5a.koxy, halogen, hydroxyl, cyano, halogen- substituted C h alky! and halogen-substituted Ci-salkoxy.
• Z 1 and Z 2 are preferably CH 2> O 5 S or a direct bond.
• R 3 is preferably methyl.
• R 4 and R 5 are preferably hydrogen or methyl, n is preferably lor 2.
• X may be combined with Y, e.g.,
• two adjacent substituents on the ring A with Z 1 to form a fused ring that may contain one or more hetero atoms, and wherein X may be combined with Y, e.g.,
• A is an aryl or heteroaryl group, optionally substituted with one, two or three substituents selected from halogen, hydroxyl, SR 2 , S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, Q -5 alkylamino, arylamino, heteroarylamino, Cj -6 alkyl, C 1-S alkylthio, C 1 .
• R 2 is selected independently, in each instance, from hydrogen, hydroxyl, amino, alkylamino, arylamino, C 1-6 alkyl, C1- 5 alkoxy, C1- 5 alkylthio, halogen-substituted C 1-6 alkyl, halogen-substituted C 1-5 alkoxy, aryl and heteroaryl.
• A is 1 ,4-disubstituted phenyl, additionally optionally substituted with one, two or three substituents selected from halogen, hydroxyl, SR 2 , S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C1. 5 alkylamino, arylamino, heteroarylamino, Cj -6 alkyl, C 1 - S alkylthio, C1.
• R 2 is selected independently, in each instance, from hydrogen, hydroxyl, amino, alkylamino, arylamino, Ci -6 alkyl, C 1-5 alkoxy, C1.5 alkylthio, halogen-substituted Ci-e alkyl, halogen-substituted C 1 - 5 alkoxy, aryl and heteroaryl.
• A is an aryl or heteroaryl group, optionally substituted with one, two or three halogen atoms.
• A is an phenyl, optionally substituted with one, two or three halogen atoms.
• A is an phenyl, optionally substituted with one, two or three fluorine atoms.
• A is fluorophenyl.
• A is a heteroaryl group, optionally substituted with one, two or three halogen atoms.
• A is a heteroaryl group.
• B and C together are bicycloheteroaryl optionally substituted with 1 to 5 substituents selected from Ci_ 6 alkyl, C 1 - S alkylthio, Ci-s alkoxy, halogen, hydroxyl, cyano, halogen-substituted C ⁇ alkyl and halogen-substituted C 1-5 alkoxy.
• B and C together are a bicycloheteroaryl selected from: [0062] any of which are optionally substituted with 1 to 5 substituents selected from Q- 6 alkyl, Ci -5 alkylthio, C 1 -5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted Ci ⁇ alkyl and halogen-substituted C 1-5 alkoxy.
• B and C together are a bicycloheteroaryl selected from:
• any of which are substituted with 1 to 5 substituents selected from Ci -6 alkyl, halogen, and halogen-substituted Ci- ⁇ alkyl.
• B and C together are a bicycloheteroaryl selected from:
• B and C together are a bicycloheteroaryl selected from:
• R 1 is selected from Cj_ 6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3 .6 cycloalkyl, C 1-5 alkoxy, Ci -S alkylamino, aryl and heteroaryl; any of which are optionally substituted with hydroxyl, halogen, cyano, amino, alkylamino, arylamino orheteroarylamino, wherein the aryl and heteroaryl groups may optionally be substituted with 1-5 substituents independently selected from hydroxyl, halogen, cyano, Q. 6 alkyl, Ci -5 alkylthio, C1-5 alkoxy and C3-6 cycloalkyl.
• R 1 is selected from phenyl and heteroaryl; both of which are optionally substituted with halogen.
• R 1 is phenyl optionally substituted with halogen.
• R 1 is heteroaryl optionally substituted with halogen.
• R 1 is phenyl
• R 1 is heteroaryl.
• R 1 is 5- or 6-membered unsaturated ring including one atom selected from N, O and S, and 0, 1, 2 or 3 additional N atoms.
• R 1 is selected from pyridinyl, pyrimidine, thiazolyl, oxazolyl, furanyl and thiophenyl.
• X is WC(O)OR 63 , WP(O)R 6b R 6c , WS(O) 2 OH, WCONHSO 3 H or IH- tetrazol-5-yl.
• W is a direct bond, oxygen or Ci -4 alkyl with substituents independently selected from halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylaminoand Ci ⁇ alkoxy; and
• R 6a is hydrogen or Q ⁇ alkyl;
• R 6b and R 6c are independently selected from hydrogen, hydroxyl, C ⁇ aUcyl and halogen substituted C 1-4 alkyl.
• X is CO 2 H.
• R 9 is selected from hydrogen, halogen, hydroxyl, cyano, Ci .6 alkyl, C1. 5 alkylthio, C 1-S alkoxy, halogen-substituted C 1 ⁇ alkyl and halogen-substituted Ci -S alkoxy.
• R 9 is selected from hydrogen, halogen and hydroxyl.
• R 9 is hydrogen.
• R 9 is hydroxyl.
• Z 1 is CR 4 R 5 ; wherein R 4 and R 5 are independently hydrogen, halogen, hydroxyl, cyano, Q. 6 alkyl, C 1-S alkoxy, C] -S alkylthio, halogen-substituted C 1 ⁇ alkyl or halogen-substituted C 1 . 5 alkoxy.
• Z 1 is CR 4 R 5 ; wherein R 4 and R 5 are independently hydrogen, halogen, Q-g alkyl or halogen-substituted C 1-6 alkyl.
• Z is CH 2 .
• R 3 is hydrogen, hydroxyl, Ci ⁇ alkyl, C 1 -5 alkoxy, C1- 5 alkylthio, halogen- substituted Ci- 6 alkyl or halogen-substituted C>. 5 alkoxy;
• R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, cyano,
• Ci- 6 alkyl, C 1 . 5 alkoxy, C 1 . 5 alkylthio, halogen-substituted C 1- ⁇ alkyl and halogen-substituted Ci- 5 alkoxy, or together form "C O";
• n is i, 2 or 3.
• R 3 is hydrogen, hydroxyl, Ci -6 alkyl, Ci - 5 alkoxy, C 1 - 5 alkylthio, halogen- substituted C 1-S alkyl or halogen-substituted C 1 . 5 alkoxy;
• R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, cyano,
• R 3 is hydrogen, hydroxyl, Ci -6 alkyl, C 1 - 5 alkoxy, C M alkylthio, halogen- substituted C i-6 alkyl or halogen-substituted C 1.5 alkoxy; and [0097] R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, cyano,
• the present invention provides methods for modulating SlP-I receptor mediated biological activity.
• the present invention also provides methods for using SlP-I modulators ⁇ i.e., agonists or antagonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostate cancer; acute lung diseases, adult respiratory distress syndrome ("ARDS”), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury such as transcorneal freezing or cutaneous burns, and cardiovascular diseases such as ischemia in a subject in need of such treatment or prevention.
• ARDS adult respiratory distress syndrome
• the invention provides methods for using SlP-I modulators in treating or preventing disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma.
• disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psori
• the invention provides methods for using SlP-I modulators to treat or prevent a disease or disorder in a subject, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of an SlP-I modulator, e.g., an agonist, that stimulates the immune system.
• an SlP-I modulator e.g., an agonist
• the subject is afflicted by an infectious agent.
• the subject is immunocompromised.
• the present invention provides a method of modulating an
• the present invention provides a method for modulating an SlP-I receptor-mediated biological activity in a cell.
• a cell expressing the SlP-I receptor is contacted with an amount of an SlP-I receptor modulator sufficient to modulate the SlP-I receptor mediated biological activity.
• SlP-I receptor mediated biological activity in a subject.
• an amount of a modulator of the SlP-I receptor effective to modulate an SlP-I receptor-mediated biological activity is administered to the subject.
• the present invention provides a method for treating, preventing or ameliorating an SlP-I receptor mediated condition in a subject.
• an amount of a modulator of the SlP-I receptor effective to modulate an SlP-I receptor-mediated biological activity is administered to the subject.
• the SlP-I receptor mediated condition may be, e.g., transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas.
• transplant rejection solid organ transplant and islet cells
• transplant rejection tissue
• cancer autoimmune/inflammatory diseases
• rheumatoid arthritis lupus
• insulin dependent diabetes Type I
• non-insulin dependent diabetes Type II
• multiple sclerosis psoriasis
• ulcerative colitis inflammatory bowel disease
• Crohn's disease acute and chronic lymphocytic leukemias and lymphomas.
• Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
• Alkyl includes saturated aliphatic groups, e.g., straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and dasyl; branched-chain alkyl groups ⁇ e.g., isopropyl, tert-butyl, and isobutyl); cycloalkyl (alicyclic) groups like cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); alkylsubstituted cycloalkyl groups; and cycloalkyl-substituted alkyl groups.
• straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nony
• Alkyl groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound.
• Straight or branched alkyl groups may have six or fewer carbon atoms in their backbone (e.g., Ci-C ⁇ for straight chain, C 3 -C 6 for branched chain), and more preferably four or fewer.
• Preferred cycloalkyl groups have from three to eight carbon atoms in their ring structure, and more preferably five or six carbons in the ring structure.
• C]-C 6 includes alkyl groups containing one to six carbon atoms.
• Substituted alkyls refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
• substituents can include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, •sulfhydryl, alkylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sul
• Aryl includes groups with aromaticity, including 5- and 6-membered unconjugated ⁇ i.e., single-ring) aromatic groups that may include from zero to four heteroatoms, as well as conjugated (i.e., multicyclic) systems having at least one ring that is aromatic.
• aryl groups include benzene, phenyl, tolyl and the like.
• Multicyclic aryl groups include tricyclic and bicyclic systems, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine, tetralin, and methylenedioxyphenyl.
• tricyclic and bicyclic systems e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine, tetralin, and methylenedi
• Aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”; e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine.
• aryl heterocycles e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine.
• the aromatic ring can be substituted at one or more ring positions with, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoy
• alkylaryl or an “aralkyl” moiety is an alkyl substituted with an aryl group
• alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
• alkenyl includes straight-chain alkenyl groups ⁇ e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl), branchedchain alkenyl groups, cycloalkenyl groups such as cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl; alkyl or alkenyl-substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl-substituted alkenyl
• Alkenyl groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound.
• Straight or branched alkenyl groups may have six or fewer carbon atoms in their backbone (e.g., C 2 -Ce for straight chain, C 3 -Ce for branched chain.)
• Preferred cycloalkenyl groups have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure.
• the term "C 2 -C 6 " includes alkenyl groups containing two to six carbon atoms.
• Substituted alkenyls refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
• substituents can include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, aylcarbonyloxy, alkoxycarbonyloxy, ary ⁇ oxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulf
• Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
• alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), brmched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
• Alkynyl groups may also optionally include heteroatoms, i.e., where oxygen, nitrogen, sulfur or phosphorous atoms replaces one or more hydrocarbon backbone carbon atoms, particularly where the substitution does not adversely impact the efficacy of the resulting compound
• Straight or branched chain alkynyls group may have six or fewer carbon atoms in their backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
• C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
• Substituted alkynyls refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
• substituents can include alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamo
• lower alkyl includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure.
• Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
• Acyl includes compounds and moieties which contain the acyl radical
• Substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, syloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
• Acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
• the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
• Alkylamino includes moieties wherein an alkyl moiety is bonded to an amino group; "dialkylamino”, “arylamino”, “diarylamino”, and “alkylarylamino” are analogously named.
• "amino” may include acylamino and/or alkylamino groups.
• alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.
• Alkoxy includes alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
• alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
• substituted alkoxy groups include halogenated alkoxy groups.
• Substituted alkoxy groups can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, • alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamirocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, or heterocycly
• halogen-substituted alkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy .
• heterocyclyl or “heterocyclic group” include closed ring structures, e.g., 3- to 10-, or 4- to 7-membered rings which include one or more heteroatoms.
• Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperizine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
• Heterocyclic rings may be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety.
• substituents as described above, as for example, halogen,
• thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
• ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
• alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
• esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
• ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
• alkyl, alkenyl, or alkynyl groups are as defined above.
• thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms.
• examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
• alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
• alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
• hydroxy or "hydroxy 1" includes groups with an -OH or -O ' .
• halogen includes fluorine, bromine, chlorine, iodine, etc.
• perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
• Heteroatom includes atoms of any element other than carbon or hydrogen.
• heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
• At least partially aromatic bicyclic ring system means a bicyclic ring system where either or both of the rings forming the bicycle are aromatic.
• the structure of some of the compounds of the invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
• Alkenes can include either the E- or Z-geometry, where appropriate.
• Combination therapy includes the administration of a SlP receptor modulator of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
• the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
• Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
• “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
• Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
• Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
• Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
• all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
• the sequence in which the therapeutic agents are administered is not narrowly critical.
• “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.)
• the combination therapy further comprises a non-drug treatment
• the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
• anionic group refers to a group that is negatively charged at physiological pH.
• Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof.
• "Functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents.
• a particularly preferred anionic group is a carboxylate.
• heterocyclic group is intended to include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, or oxygen or sulfur.
• Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine.
• Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF 3 , -CN, or the like.
• S IP-modulating agent includes compound or compositions capable of inducing a detectable change in SlP receptor activity in vivo or in vitro, e.g., at least 10% increase or decrease in SlP activity as measured by a given assay such as the bioassay described hereinbelow.
• EC 50 of an agent included that concentration of an agent at which a given activity, including binding of sphingosine or other ligand of an SlP receptor and/or a functional activity of a SlP receptor (e.g., a signaling activity), is 50% maximal for that SlP receptor.
• the EC50 is the concentration of agent that gives 50% activation, when 100% activation is set at the amount of activity of the SlP receptor which does not increase with the addition of more ligand/agonist and 0% activation is set at the amount of activity in the assay in the absence of added ligand/agonist.
• an "effective amount” includes an amount sufficient to produce a selected effect.
• an effective amount of an SlP receptor antagonist is an amount that decreases the cell signaling activity of the SlP receptor.
• Immunomodulation includes effects on the functioning of the immune system, and includes both the enhancement of an immune response as well as suppression of the immune response.
• the compounds of the invention and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term “combination” further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. [00149] The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
• the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
• An appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
• a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.01 to 1 mg/kg per day.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• the amount of the compound of the invention required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
• compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein.
• compositions of the present invention comprise an effective amount of the compounds of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.
• “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
• “Pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents. isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into. the compositions.
• compositions and combination therapies of the invention will then generally be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
• parenteral administration e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
• the preparation of an aqueous composition that contains a composition of the invention or an active component or ingredient will be known to those of skill in the art in light of the present disclosure.
• compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
• Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• compositions of the present invention will generally comprise an effective amount of the component(s) of the combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium.
• pharmaceutically acceptable media or carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the therapeutic compositions of the present invention.
• compositions will be known to those of skill in the art in light of the present disclosure.
• such compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including cremes, lotions, mouthwashes, inhalants and the like.
• injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• the preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) or agent(s) to a small area.
• sterile formulations such as saline-based washes, by surgeons, physicians or health care workers to cleanse a particular area in the operating field may also be particularly useful.
• Therapeutic formulations in accordance with the present invention may also be reconstituted in the form of mouthwashes, or in conjunction with antifungal reagents. Inhalant forms are also envisioned.
• the therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as in cremes and lotions.
• Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like.
• Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5.
• Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%.
• Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like.
• Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
• Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.
• therapeutics Upon formulation, therapeutics will be administered in a manner compatible with the dosage formulation, and in such amount as is pharmacologically effective.
• the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
• the quantity of active ingredient and volume of composition to be administered depends on the host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual.
• a minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but would be typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals.
• a suitably buffered, and if necessary, isotonic aqueous solution would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration.
• One dosage could be dissolved in 1 mL of isotonic NaCl solution and either added to 1000 mL of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, Remington 's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580).
• active compounds may be administered orally. This is contemplated for agents which are generally resistant, or have been rendered resistant, to proteolysis by digestive enzymes. Such compounds are contemplated to include chemically designed or modified agents; dextrorotatory peptides; and peptide and liposomal formulations in time release capsules to avoid peptidase and lipase degradation.
• the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
• Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum-drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
• the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
• aqueous solutions for parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
• sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
• other pharmaceutically acceptable forms include, e.g., tablets or other solids for oral administration; liposomal formulations; time-release capsules; and any other form currently used, including cremes.
• suppositories include suppositories.
• traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%.
• Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. [00177] In certain defined embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
• the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%.
• the amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, 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, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
• a binder as gum tragacanth, acacia, cornstarch, 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
• a sweetening agent such as sucrose, lactose or saccharin may be added or a flavor
• tablets, pills, or capsules may be coated with shellac, sugar or both.
• a syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
• compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
• the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
• the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
• the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
• the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
• a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
• preformulation compositions when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
• compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
• Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
• the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• the compounds of the present invention are high affinity agonists (or antagonists) at various SlP receptors.
• the compounds of the invention are also expected to evoke lymphopenia when introduced into rodents, non human primate or humans.
• the compounds of the invention can be used as immune modulators, and are useful in treating or preventing pathologies mediated by lymphocyte actions, including acute or chronic rejection of tissue grafts such as organ transplants, and autoimmune diseases.
• Autoimmune diseases that may be treated with compounds of the invention include: systemic lupus erythematosus, multiple sclerosis, Behcet's disease, glomerulonephritis, rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis ⁇ psoriasis, myasthenia gravis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, hepatitis and Wegner's granuloma.
• the compounds of the invention are useful also in treating inflammatory disorders, including atopic asthma, inflammatory glomerular injury and ischemia-reperfusion injury.
• Lysophospholipids, SlP and lysophosphatidic acid (LPA) stimulate cellular proliferation and affect numerous cellular functions by signaling through G protein-coupled endothelial differentiation gene-encoded (SlP) receptors.
• SlP receptor modulators of the invention are anticipated to have utility in immunomodulation, e.g., in anti- angiogenesis therapy, such as in neoplastic disease treatment.
• a pharmaceutical composition comprising one or more of the SlP receptor agonists of the present invention is administered to a mammalian species, including humans, to enhance wound repair, improve neuronal function or enhance an immune response of that species. It has also been reported that SlP inhibits fibrosis in various organs. Accordingly, the SlP receptor agonists of the invention can be used to prevent/treat diseases associated with organ fibrosis, such as pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, hepatic cirrhosis, chronic renal insufficiency or kidney glomerular sclerosis.
• organ fibrosis such as pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, hepatic cirrhosis, chronic renal insufficiency or kidney glomerular sclerosis.
• a composition comprising an SlP receptor agonist of the present invention is used to treat wounds, including burns, cuts, lacerations, surgical incisions, bed sores, and slow-healing ulcers such as those seen in diabetics.
• SlP modulating compounds of the invention are believed to mobilize lymphocytes and increase their homing to secondary lymphoid tissues.
• the present compounds can be used to direct lymphocytes away from transplanted organs, e.g., allografts, or healthy cells, e.g., pancreatic islets as in type I diabetes, myelin sheathing (multiple sclerosis), or other tissues that may be subjected to an undesirable imrnunoresponse, and thus decrease damage to such tissues from the immune system.
• the SlP receptor-modulating compounds of the invention are administered to a subject to treat or prevent a disorder of abnormal cell growth and differentiation. These disorders include Alzheimer's disease, aberrant corpus luteum formation, osteoporosis, anovulation, Parkinson's disease, and cancer.
• an SlP antagonist is administered to a patient to treat a disease associated with abnormal growth.
• the compounds of the invention are used as immunomodulators to alter immune system activities and prevent damage to healthy tissue that would otherwise occur in autoimmune diseases and in organ transplantation.
• the compounds can be administered to patients as part of the treatment associated with organ transplantation, including pancreas, pancreatic islets, kidney, heart and lung transplantations.
• the SlP modulators can be administered alone or in combination with known immunosuppressants such as cyclosporine, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate and corticosteroids such as cortisone, des-oxymetasone, betametasone, desametasone, flunisolide, prednisolone, prednisone, amcinomide, desonide, methylprednisolone, triamcinolone, and alclometasone.
• immunosuppressants such as cyclosporine, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate and corticosteroids
• corticosteroids such as cortisone, des-oxymetasone, betametasone, desametasone, flunisolide, prednisolone, prednisone, amcinomide
• SlP also acts as a survival factor in many cell types.
• compounds of the invention having SlP antagonistic activity are anticipated to be useful in protecting cells and tissues from hypoxic conditions.
• compounds of the invention are administered to a patient judged to be or actually in need of treatment, to treat cells and tissues exposed to hypoxic conditions, including injury sustained as a result of ischemia.
• compounds of the invention that show SlP receptor antagonist activity can be used to treat ischemia reperfusion type injury. Interference with the supply of oxygenated blood to tissues is defined as ischemia. The effects of ischemia are known to be progressive, so that over time cellular vitality continues to deteriorate and tissues become necrotic.
• compositions comprising the compounds of the invention may be administered to an individual in need by any number of routes, including topical, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
• the oral route is typically employed for most conditions requiring the compounds of the invention. Preference is given to intravenous injection or infusion for the acute treatments. For maintenance regimens the oral or parenteral, e.g., intramuscular or subcutaneous, route is preferred.
• composition comprising a compound of invention and albumin, e.g., a compound of the present invention, a pharmaceutically acceptable carrier and 0.1-1.0% albumin.
• Albumin functions as a buffer and improves the solubility of the compounds.
• kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
• a kit is provided for treating a patient in need of immunomodulation, including instructions for use of the kit.
• the kit comprises one or more of the SlP modulators of the invention, and may also include one or more known immunosuppressants.
• These pharmaceuticals can be packaged in a variety of containers, e.g., vials, tubes, microliter well plates, bottles, and the like.
• Other reagents can be included in separate containers and provided with the kit; e.g., positive control samples, negative control samples, buffers, cell culture media, etc.
• the kits will also include instructions for use.
• the activity of compounds of the invention may be determined by using an assay for detecting SlP receptor activity (such as the [ ⁇ -35 S]GTP binding assay) and assaying for activity in the presence of SlP and the test compound. More particularly, in the method described by Traynor et al., 1995, MoL Pharmacol. 47: 848-854, incorporated herein by reference, G-protein coupling to membranes can be evaluated by measuring the binding of labeled GTP. [00195] For example, samples comprising membranes isolated from cells expressing an
• SlP polypeptide can be incubated in a buffer promoting binding of the polypeptide to ligand (i.e. SlP), in the presence of radiolabeled GTP and unlabeled GDP ⁇ e.g., in 20 mM HEPES, pH 7.4, 100 mM NaCl, and 10 mM MgCl 2 , 80 pM 35 S-GTP 7 S and 3 ⁇ M GDP), with and without a candidate modulator.
• the assay mixture is incubated for a suitable period of time to permit binding to and activation of the receptor (e.g., 60 minutes at 30 0 C), after which time unbound labeled GTP is removed (e.g., by filtration onto GF7B filters).
• labeled GTP can be measured by liquid scintillation counting.
• a similar GTP-binding assay can be performed without the presence of the ligand (SlP) to identify agents that act as agonists.
• ligand-stimulated GTP binding is used as a standard.
• An agent is considered an agonist if it induces at least 50% of the level of GTP binding induced by SlP when the agent is present at 10 ⁇ m or less, and preferably will induce a level which is the same as or higher than that induced by the ligand.
• GTPase activity can be measured by incubating cell membrane extracts containing an SlP receptor with ⁇ 32 P-GTP. Active GTPase will release the label as inorganic phosphate, which can be detected by separation of free inorganic phosphate in a 5% suspension of activated charcoal in 20 mM H 3 PO4, followed by scintillation counting. Controls would include assays using membrane extracts isolated from cells not expressing an SlP receptor ⁇ e.g., mock-transfected cells), in order to exclude possible non-specific effects of the candidate modulator.
• cell membrane samples can be incubated with the ligand (SlP), with and without the modulator, and a GTPase assay can be performed as described above.
• SlP ligand
• a change (increase or decrease) of 10% or more in the level of GTP binding or GTPase activity relative to samples without modulator is indicative of SlP modulation by a candidate modulator.
• SlP receptor activity may also be measured by an SlP receptor (e.g., hSIPl , hSlP3, rSlPl, rS ⁇ P3 and parental cell) Ca 2+ Flux protocol as described below: 1.
• SlP receptor e.g., hSIPl , hSlP3, rSlPl, rS ⁇ P3 and parental cell
• Ca 2+ Flux protocol as described below: 1.
• Cell growth media i. human and rat SlPl and S1P3: F12-Ham's media; 10% FBS (qualified);
• FBS FBS (qualified); Ix Pen/Strep/Glu; 300ug/mL Hygromycin; c. Cell seeding media; F12-Ham's media; 10% FBS (Charcoal/dextran stripped); Ix Pen/Strep/Glu; d. Cell dissociation buffer: Versene from Invitrogen e. Agonist (SlP) dissolving buffer: 0.4% (w/v) fatty-acid free BSA (Sigma #
• FLIPR dye BD PBX Calcium assay kit; Cat#641077 is composed of Calcium indicator (Cat#850000) and 10Ox PBX signal enhancer (cat#850001).
• the 10Ox PBX signal enhancer is diluted into FLIPR buffer 1 :100 and the calcium indicator is then added at 1 : 1000 ratio.
• SlP stock solution preparation SlP is purchased from CalBioChem (Catalog # 970471; lmg vial; custom prep using methanol, & nitrogen gas drying inside glass vial; Storage @ -20 0 C).
• hSIPl and hSlP3 were established as stable clones and rSIPl and rSlP3 were sorted by anti V5 tag and established as stable pools after sorting.
• c Parental cell line CHO/K1 Gqi5 is used as the control.
• d All the cells are maintained in cell growth media and splitted twice a week using Versene.
• e All the cell lines are used under passage 30. 3.
• b. Cell loading Cell seeding media is discarded.
• Cells are loaded with 50ul of FLIPR dye at RT for 90 min. Signal is stable for up to 5 h after dye loading.
• Agonist (SlP) preparation Frozen stock of SlP is thawed out and sonicated at 37c for 30 minutes every time before use. The stock is then diluted into FLIPR buffer at proper concentration.
• Compound preparation Compounds are dissolved in DMSO. A 3x, 10 point dilution of the compounds are carried out in DMSO. Then the compounds are diluted into assay buffer 133x so that the DMSO concentration is 0.75%.
• Activity measurement The fluorescence signal change of the cells upon compound addition is monitored in FLIPRtetra.
• A is the minimum (EC50min or IC50min)
• B is the maxmum (EC50max or IC50max)
• C is the inflection point (EC50IP or IC50IP)
• D is the hill slope (EC50 slope or IC50 slope).
• Identified SlP receptor agonists and antagonists can be used to treat a variety of human diseases and disorders, including, but not limited to the treatment of infections such as bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-I or HIV-2; pain; cancers; diabetes, obesity; anorexia; bulimia; asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; stroke; ulcers; asthma; allergy; benign prostatic hypertrophy; migraine; vomiting; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, depression, delirium, dementia, and severe mental retardation.
• infections such as bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-I or HIV-2
• infections such as bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-I or HIV-2
• pain such as bacterial, fungal, protozoan and viral infections
• cancers such
• Pain is a complex subjective sensation reflecting real or potential tissue damage and the affective response to it.
• Acute pain is a physiological signal indicating a potential or actual injury.
• Chronic pain can either be somatogenetic (organic) or psychogenic.
• Chronic pain is frequently accompanied or followed by vegetative signs, which often result in depression.
• Somatogenetic pain may be of nociceptive origin, inflammatory or neuropathic.
• Nociceptive pain is judged to be commensurate with ongoing activation of somatic or visceral pain-sensitive nerve fibers.
• Neuropathic pain results from dysfunction in the nervous system; it is believed to be sustained by aberrant somatosensory processes in the peripheral nervous system, the CNS 3 or both.
• Chronic pain results in individual suffering and social economic costs of tremendous extent.
• Existing pharmacological pain therapies are widely unsatisfying both in terms of efficacy and of safety.
• SlP modulators of the present invention are used as immunomodulators to suppress the immune system and prevent damage to healthy tissue that would otherwise occur in autoimmune diseases and in organ transplantation.
• the compounds can be administered to patients as part of the treatment associated with organ transplantation, including pancreas, pancreatic islets, kidney, heart and lung transplantations.
• the SlP modulators can be administered alone or in combination with known immunosuppressants such as cyclosporine, tacrolimus, azatioprine, desoxymetasone, cyclophosphamide, cortisone, betametasone, FK 506 (a fungal macrolide immunosuppressant), desametasone, flunisolide, prednisolone, prednisone, amcinomide desonide, methylprednisolone, triamcinolone, alclometasone and methotrexate.
• immunosuppressants such as cyclosporine, tacrolimus, azatioprine, desoxymetasone, cyclophosphamide, cortisone, betametasone, FK 506 (a fungal macrolide immunosuppressant), desametasone, flunisolide, prednisolone, prednisone, amcinomide desonide,
• the dosage to be used is, of course, dependent on the specific disorder to be treated, as well as additional factors including the age, weight, general state of health, severity of the symptoms, frequency of the treatment and whether additional pharmaceuticals accompany the treatment.
• the dosages are in general administered several times per day and preferably one to three times per day.
• the amounts of the individual active compounds are easily determined by routine procedures known to those of ordinary skill in the art
• SlP also acts as a survival factor in many cell types.
• SlP receptor modulators are anticipated to have activity in protecting cells and tissues from hypoxic conditions.
• compounds of the invention are administered to treat cells and tissues exposed to hypoxic conditions, including injury sustained as a result of ischemia.
• the SlP modulators having antagonistic activity can be used to treat ischemia reperfusion type injury. Interference with the supply of oxygenated blood to tissues is defined as ischemia.
• the effects of ischemia are known to be progressive, such that over time cellular vitality continues to deteriorate and tissues become necrotic. Total persistent ischemia, with limited oxygen perfusion of tissues, results in cell death and eventually in coagulation-induced necrosis despite reperfusion with arterial blood.
• the compounds of the invention and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term “combination” further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
• the compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
• An appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day, which may be administered in single or multiple doses.
• the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
• a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.01 to 1 mg/kg per day.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• the amount of the compound of the invention required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
• compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein.
• Aqueous compositions of the present invention comprise an effective amount of the compounds of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.
• “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
• “Pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• compositions and combination therapies of the invention will then generally be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
• parenteral administration e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
• the preparation of an aqueous composition that contains a composition of the invention or an active component or ingredient will be known to those of skill in the art in light of the present disclosure.
• compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
• Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• compositions of the present invention will generally comprise an effective amount of the component(s) of the combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium.
• pharmaceutically acceptable media or carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the therapeutic compositions of the present invention.
• compositions will be known to those of skill in the art in light of the present disclosure.
• such compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including cremes, lotions, mouthwashes, inhalants and the like.
• injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• the preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) or agent(s) to a small area.
• sterile formulations such as saline-based washes, by surgeons, physicians or health care workers to cleanse a particular area in the operating field may also be particularly useful.
• Therapeutic formulations in accordance with the present invention may also be reconstituted in the form of mouthwashes, or in conjunction with antifungal reagents. Inhalant forms are also envisioned.
• the therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as in cremes and lotions.
• Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like.
• Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5.
• Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%.
• Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like.
• Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
• Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.
• formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
• quantity of active ingredient and volume of composition to be administered depends on the host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual.
• a minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but would be typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals.
• a suitably buffered, and if necessary, isotonic aqueous solution would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration.
• One dosage could be dissolved in 1 mL of isotonic NaCl solution and either added to 1000 mL of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, Remington 's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580).
• active compounds may be administered orally. This is contemplated for agents which are generally resistant, or have been rendered resistant, to proteolysis by digestive enzymes. Such compounds are contemplated to include chemically designed or modified agents; dextrorotatory peptides; and peptide and liposomal formulations in time release capsules to avoid peptidase and lipase degradation.
• Pharmaceutically acceptable salts include acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric, hydrobromic, boric, phosphoric, sulfuric acids or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, maleic, fumaric, citric, succinic, mesylic, mandelic, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric. a-glycerophosphoric, glucose- 1 -phosphoric acids and the like.
• inorganic acids such as, for example, hydrochloric, hydrobromic, boric, phosphoric, sulfuric acids or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, maleic, fumaric, citric, succinic, mesylic, mandelic, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric. a-gly
• Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, magnesium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
• inorganic bases such as, for example, sodium, potassium, ammonium, calcium, magnesium, or ferric hydroxides
• organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.
• Other examples of pharmaceutically acceptable salts include quaternary derivatives, and internal salts such as N-oxides.
• the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
• Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum-drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
• the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
• aqueous solutions for parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
• sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
• other pharmaceutically acceptable forms include, e.g., tablets or other solids for oral administration; liposomal formulations; time-release capsules; and any other form currently used, including cremes.
• suppositories include suppositories.
• traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%.
• Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
• oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
• the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%.
• the amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, 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, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
• a binder as gum tragacanth, acacia, cornstarch, 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
• a sweetening agent such as sucrose, lactose or saccharin may be added or a flavor
• tablets, pills, or capsules may be coated with shellac, sugar or both.
• a syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
• compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
• the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
• the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
• the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
• the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
• a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
• preformulation compositions when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
• compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
• Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
• the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• reaction mixture Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with IN HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system) to give a pure product.
• Example Compound 1 (step 2 Scheme 1) in the general method described above (65% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.63 (d, IH), 7.45 (d, IH) 5 7.29 (m, 2H), 7.22 (d, IH) 3 7.00-7.08 (m, 4H), 6.71 (m IH).
• Example Compound 1 (step 4 in Scheme 1) in the general method described above except using 5-bromothiophene-2-carbaldehyde (32% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 9.92 (s, IH), 7.73 (d, IH), 7.51 (dd, IH), 7.39 (d, IH), 7.96 (m, 2H), 6.94 (dd, IH), 3.98 (dd, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.01 (t, 3H). l-((5-(5-butoxybenzofuran-2-yl)thiophen-2-yl)methyl)azetidine-3-carboxylic acid:
• Example Compound 6 (step 1 in Scheme 2) in the general method described above except using thiophen-2-ylboronic acid (55% yield).
• Trifluoroacetic anhydride (4.6 mL, 27.2 mmol) was added dropwise to a solution of ethyl 3-chloro-4-hydroxybenzoate (5.02 g, 25.0 mmol) and pyridine (2.2 mL, 27.5 mmol) in DCM (31 mL) at -10 0 C.
• the reaction mixture was stirred for 1 h at -10 0 C 5 allowed to warm up to rt and stirred for an additional 2 h.
• the reaction mixture was quenched with H 2 O, and the resulting biphasic mixture was stirred for 15 min. The layers were separated and the organic layer was washed with 0.2 N HCl, water and brine.
• Trifluorosulfonic anhydride (87 ⁇ L, 0.52 mmol) was added to the solution of tert-butyl 3-(6-hydroxy-3 5 4-dihydroisoquinolin-2(lH)-yl)propanoate (111 mg, 0.4 mmol) in pyridine (5 mL) at 0 0 C.
• the reaction mixture was stirred for 1 hour at room temperature , concentrated, purified on ISCO column (2% to 5% MeOH/CH 2 Cl 2 ) to provide the title compounds (93 mg, 57%).
• DEAD (362 mg, 2.09 rnmol) was slowly added to a solution of 5- hydroxybenzofuran (200 mg, 1.49 mmol), triphenylphosphine (547 mg, 2.09 mmol) and cycl ⁇ pentyl- methanol (203 mg, 2.02mmol) in 3 mL of THF. The mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by ISCO column chromatography using 0-5% AcOEt in Hexanes.
• Example Compound 40 (step 2, Scheme 5) in the general method described above (52% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.89 (m, 2H), 7.61 (d, IH) 3 7.42-7.17 (m, 8H), 6.95 (s, IH), 4.06 (s, 2H), 3.82 (s, 3H), 2.61 (s, 3H).
• Example Compound 40 (step 3, Scheme 5) in the general method described above (86% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.94 (s, IH), 7.82 (d, IH), 7.48-7.07 (m, 9H), 6.85 (s, IH), 4.67 (brs, IH), 4.06 (s, 4H), 2.58 (s, 3H).
• Example Compound 40 (step 4, Scheme 5) in the general method described above (90% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 10.03 (s, IH) 5 8.07 (d, IH), 7.81 (m, 2H), 7.46-7.17 (m, 8H), 7.01 (s, IH), 4.08 (s, 2H), 2.63 (s, 3H).
• Example Compound 1 (step 4 in Scheme 1) in the general method described above (56% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 10.04 (s, IH) 5 8.21 (d, IH) 5 7.77 (d, IH), 7.59-7.19 (m 5 5H), 4.04 (s, 3H), 3.11 (m, IH) 5 2.15-1.77(m, 4H), 1.58-1.56 (m, 4H).
• Example Compound 1 (step 1 in Scheme 1) in the general method described above (70% yield): 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.07 (d 5 2H), 6.82 (d, 2H), 4.81 (t, IH), 3.96 (d, 4H), 3.90 (t, 2H), 3.79-3.72 (m, 2H), 3.67-3.59 (m, 2H), 2.81 (S 5 3H), 2.77 (t, 2H), 2.61 (m, IH), 1.77-1.70 (m, 2H), 1.21 (t, 6H).
• Example Compound 1 (step 4 in Scheme 1) in the general method described above (62% yield): 1 H NMR (400 MHz 5 CDCl 3 ) ⁇ 10.03 (s, IH), 8.21 (t, IH), 7.79 (d, IH), 7.72 (d, IH), 7.51-7.21 (m, 4H) 5 3.98 (m, 4H) 5 2.84 (s, 3H) 5 2.76 (m, IH), 2.05-1.81 (m, 4H).
• Example Compound A (step 3) in the general method described above and used without further purification for the next step: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.72 (m, IH), 7.52 (m, IH), 7.32 (m, IH), 7.21 (m, IH) 5 4.62 (s, 2H) 3.37 (d, 2H), 1.41 (m, IH), 0.58 (m, 2H), 0.21 (m, 2H).
• Example Compound A [00466] The title compound was prepared as Example Compound A (step 4) in the general method described above.
• 1 H NMR 400 MHz, CDCl 3 ): ⁇ 10.02 (s, IH), 8.24 (t, IH), 7.78 (d, IH), 7.69 (d, IH), 7.63 (s, IH), 7.54 (d, IH), 7.36 (m, 2H), 4.62 (s, 2H) 3.38 (d, 2H), 1.41 (m, IH), 0.58 (m, 2H), 0.21 (m, 2H).
• Example Compound A (step 4) in the general method D described above (67% yield in two steps): 1 H NMR (400 MHz 5 CDCl 3 ): ⁇ 10.01 (s, IH), 8.21 (t, IH), 7.76 (d, IH) 5 7.63 (d 5 IH) 5 7.61 (s, IH) 5 7.46 (d 5 IH) 5 7.39 (m, 2H) 5 4.51 (s 5 2H) 4.04 (m, IH) 5 2.22 (m, 2H) 5 2.01 (m, 2H) 5 1.74 (m, IH) 5 1.53 (m, IH).
• Example Compound A (step 4) in the general method D described above.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 10.01 (s, IH) 5 8.22 (t, IH), 7.78 (d, IH), 7.75 (s, IH), 7.69 (d, IH) 5 7.58 (d, IH) 5 7.42-7.27 (m, 2H), 7.02 (m, 5H), 5.18 (s, 2H).
• Example Compound A [00494] The title compound was prepared as Example Compound A (step 4) in the general method D described above.
• 1 H NMR 400 MHz, CDCl 3 ): ⁇ 10.01 (s, IH), 8.21 (t, IH), 7.78 (d, IH), 7.64 (d, IH) 5 7.61 (s 5 IH) 5 7.54 (d, IH) 5 7.39 (m 5 2H) 5 4.63 (s, 2H) 3.39 (m, IH) 5 1.98 (m, 2H), 1.78 (m 5 2H) 5 1.34 (m, 2H) 5 1.21 (m, 4H).
• Example Compound A step 5 in the general method E described above.
• Example Compound A [00502] The title compound was prepared as Example Compound A (step 4) in the general method D described above.
• 1H NMR 400 MHz, CDCl 3 ): ⁇ 10.01 (s, IH), 8.23 (t, IH), 7.86 (d, IH), 7.66 (d, IH), 7.61 (s, IH), 7.52 (d, IH), 7.39 (m, 2H), 4.73 (s, 2H) 4.03 (m, IH), 1.78 (m, 4H) 3 1.61 (m, 2H), 1.21 (m, IH), 0.95 (m, IH).

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