Title of Invention

5-PHENOXYALKOXYPSORALENS AND METHODS FOR SELECTIVE INHIBITION OF THE VOLTAGE GATED KV1.3 POTASSIUM CHANNEL

Abstract Compositions o matter comprising f-phenoxalkovypsoralen compounds and their method of synthesis and use. The compounds are useable to treat diseases or disorders in human or animal subjects, including autoimmune diseases. The compounds inhibit potassium channels, including the Kvl.3 channel and at least some of the therapeutic effects of such compounds may be due at least in part to potassium channel inhibition. In some embodiments, the compounds are more selective for certain potassium channels (e.g., Kvl.3 channels) than other potassium channels (e.g., Kvl.5 channels).
Full Text

5-PHENCXYA_K0XYPSORA’ENS AND methods FOR Selective [N’HIBITION OF THE VOLTAGE GATED Kv1.3
POTASSIUM CHANNEL
FIELD OF THE INVENTION
The present invention provides a) novel compositions of matter comprising or consisting of 5-phenoxyaikoxypsoralens, b) methods for treating and/or preventing diseases or disorders in human or animal subjects, c) methods and kits for in vivo and/or in vitro inhibition of the selected types of potassium channels and d) the use of 5-phenoxyalkoxypsoralen compositions in the manufacture of pharmaceutical preparations for the treatment and/or prevention of diseases of disorders in human or animal subjects.
BACKGROUND OF THE INVENTION
and Their Functions:
T cells are lymphocytes that have receptors capable of recognizing protein fragments (antigens) derived from foreign, potentially harmful proteins or organisms such as bacteria and viruses or from proteins present in the body of the host. Each T Celt receptor recognizes a different string of amino acids, which comprise the antigen. Essentially there will always be at least one T cell receptor in the total repertoire of T cells, which vl recognize any given antigen, which is in the body.
There are two main types of T cells, namely CD4+ helper T cells and CD8+ killer T cells. Helper T Cells (Th) carry receptors that engage antigens present on the surfaces of an antigen-presenting ceil (APC) such as dendritic cells and sometimes macrophages. It is only by engagement with an antigen present on an APC and a subsequent process known as co-stimulation that a Th Celt can become activated so that it may attack that specific antigen. Before the

destroyed, most of the effector T ceils die. However, some effector T cells remain in a resting or quiescent state and are then known as "memory T ceils/ At least two types of Memory T cells exist, each having different migratory characteristics and effector functions. The first type of memory T cells are known as "effector memory T cells" (I’M) and produce IFN-y, TNF-a and IL-2 or pre-stored person (in the case of CD8s) when they encounters an antigen. The second type of memory T ceils, known as "central memory T cells" (TCM), express the chemokine receptor CCR7 similar to naive T cells and lack immediate effector function. When TEM cells encounter the same antigen that initially caused their activation, they quickly convert back to effector T cells without the need for co-stimulation. Such rapid redeployment of effector T cells without the need for co-stimulation allows the immune system to attack the antigen in a very efficient manner.
ion Channels: Molecular Targets for Pharmacological Intervention
Ion channels are proteins embedded within the eel! membrane that control the selective flux of ions across the membrane, thereby allowing the rapid movement of ions during electrical signaling processes. Because ion concentrations are directly involved in the electrical activity of excitable cells (e.g., neurons), the functioning (or malfunctioning) of ion channels can substantially control the electrical properties and. behavior of such cells. Indeed, a variety of disorders, broadly termed as "chahnelopathies," are believed to be linked to ion channel insufficiencies or dysfunctions.
Ion channels are referred to as "gated" if they can be opened or closed. The basic types of gated ion channels include a) ligand-gated channels, b) mechanically gated channels and c) voltage-gated channels. In particular, voltage-gated channels are found in neurons and muscle cells. They open or


In recent years, drug development "efforts have included work aimed at identifying and characterizing various ion channels and designing agents that increase or decrease the flux of ions through those ion channels to bring about desired therapeutic’ effects.
Kv1,3 Channels and Their Roll in T Cell Physiology.
The predominant voltage-gated potassium ion channel in human T-lymphocytes is encoded by Kvt.S, a S/7a/cer-re!ated gene. Kv1.3 channels have been characterized extensively at the molecular and physiological level and are known to play a vital role in controlling T-iymphocyte proliferation, mainly by maintaining the membrane potential of resting T-lymjSiiocytes. For example, encephalitogenic and anthropogenic rat T cells that have been chronically activated with myelin antigens have been shown to express a unique channel phenotype (high Kv1.3 channels and low IKCa1 channels), distinct from that seen in quiescent and acutely activated T cells (Beeton et ai., 2001, Selective blockade of T lymphocyte K{+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc. Natl. Acad. Set. USA 98:13942) and such findings have been confirmed in myelin antigen specific T cells from human patients suffering from multiple sclerosis (MS). Contrary to myelin-reactive T cells from healthy controls and to amidogen or control antigen activated T cells from MS patients, myelin reactive T cells from MS patients predominantly expressed surface markers of terminally differentiated effector memory T ceils (CCR7-CD45RA') and exhibited the Kv1.3’'9’lKCal"' phenotype (Wolff et ai., The voltage-gated Kvl .3 K(+) channel in effector memory T cells as new target for MS. 2003, J. Clin. Invest, 111:1703). In the same study, it was shown that this special K"‘ channel phenotype made the proliferation of effector memory T cells highly sensitive to inhibition by Kv1.3 blockers. Naive and central memory T cefts were only affected at 10-fold higher concentrations of Kvl.3 blockers and could escape Kvl.3 inhibition during subsequent stimulation through the up-regulation of the calcium-activated potassium channel Inca.

"
Kv1.3 and IKCa1 Expression and Functional Roles in Naive and Memory T-cells
Naive, central! memory (TCM) and effector memory T (TEM) cells are classified based on the expression of the chemokine receptor CCR7 and the phosphatase CD45RA. Naive (CCR7XD45RA’) and TCM (CCR7XD45RA") cells migrate to the lymph node using CCR7 as an entry code, before migrating to sites of inflammation. In contrast. TEM cells have the ability to home directly to sites of inflammation, where they can secrete high amounts of interferon (IFN-y) and tumor necrosis factor-a (TNF-a) and exhibit immediate effector function. The expression patterns of Kv1.3 and IKCa1 change dramatically as naive cells become memory cells. At rest, CD4' and CDS'" T-cells of all three subsets exhibit - 200 to 400 Kv1.3 channels, and 0 to 30 IKCa1 channels (Wulff et al., The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. 2003, J. Clin. Invest. 111:1703). Activation has diametrically opposite effects on channel expression; as naive and TCM cells move from resting to proliferating blast cells, they transcription ally up-regulate IKCal to -500 channels per cell. In contrast, activation of TEM cells enhances Kv1.3 expression without any change in IKCal levels (Wulff et al., 2003, J. Clin, invest 111:1703). Functional Kv1.3 expression increases dramatically within 15 h of activation to a level of 1500 Kvl3 channels/ceil, remains elevated for the following 48 to 72 h, and then returns to baseline over the next five days (Beeton et al.. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes. 2003, J. Bioi. Chem. 278:9928)
The subset-specific channel expression has important functional consequences, since Kv1.3 and IKCal regulate Ca’"" entry into T-ceils through Ca’*-release-activated Ca’"" channels that exhibit 'upside-down' voltage-dependence compared with voltage-gated Ca’"" channels. A negative membrane


Depolarization resulting from Kv1.3 and IKCa1 blockade is inhibitory for Ca’"" influx, signaling and lymphocyte activation. As Kv1.3 channels predominate in resting T-cities of the three subsets, the Kv1.3 blocker She, but not the IKCa1 blocker TRAM-34, suppress antigen or amidogen-driven activation. , She is 10-fold more effective on TEM cells than on naive and TCM cells (IC50 values of 400 pM and 4 nM, respectively), due to the fact that the latter cells rapidly up-regulate IKCal after stimulation and become less sensitive to Kv1.3 inhibitors (Wulff et al., The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. 2003, J. Clin. Invest. 111:1703). Once IKCal is up-regulated in naive and TCM cells, the reactivation of these cells is sensitive to IKCal but not Kv1.3 blockade. cells can up-regulate IKCal following mitogen or antigen stimulation, even if their initial activation is suppressed by Kv1.3 blockade; and can consequently escape further inhibition by Kv1.3 inhibitors (Wulff et aL, 2003, J. Clin. Invest 111:1703). Early in vivo studies support these in vitro findings. The Kv1.3 blockers MgTX (Koo et al., Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. 1997, J. Immunol. 158:1520) and correlate (Koo et al., Correlate and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels. 1999. Cell Immunol. 197:99) effectively suppress the primary delayed-type hypersensitivity (DTH) response in mini-pigs, but are much less effective in suppressing the secondary DTH response, presumably to the fact that the activated naive or TCM cells involved have up-regulated IKCal expression. In contrast, TEM cells exclusively up-regulated Kv1.3 channels, and are persistently suppressed by Kv1.3 inhibitors.

Kv1.3 and IKCa1 Expression and Functional Roles in Naive and Memory B-cells
A similar change in potassium channel expression takes place during the differentiation from naive into class-switched memory B cells. While naive (lgD'CD27') and "early" memory B cells (igD'CD27’) rely on IKCa1 for their proliferation, class-switched (igD"CD271 memory B cells rely on Kv1.3 and their proliferation is therefore potently inhibited by the Kv1.3 blockers She and Psora-4 (Wulff et al. K+ channel expression during B cell differentiation: implications for Immunomodulation and autoimmunity. 2004. J. Immunol. 173:776-86). Thus, Kv1.3 blockers selectively target "late" memory responses in both the T- and B-cell lineage should be useful for the treatment of autoimmune disorders.
Kv1,5 Channels and Repulation/DereQulation of Cardiac Rhythm
Ion flux through voltage gated potassium channels also plays a role in regulation of cardiac rhythms. Atrial fibrillation (AF) is a common cardiac rhythm disturbance. AF can be treated or prevented by agents that prolong the atrial action potential duration and refractoriness. Indeed, drugs such as dovetailed, almokalant, amiodarone and d-sotalol can effectively suppress AF. However, such drugs may also prolong the ventricular action potential duration, thereby giving rise to life threatening or lethal ventricular arrhythmias. This potential for antiarrhythmic drugs to actually cause certain types of an'hythmias while preventing others is sometimes referred to as the drug's "proarrhythmic potential." Proarrhythmic potential is an important dose-limiting factor in the use of antiarrhythmic drugs. In fact, a common proarrhythmic event reported to result from the use of traditional antiamhythmic drugs that prolong ventricular depolarization (QT intent/al) to treat AF is a condition known as tirades de pointes, which is a rapid polymorphic ventricular tachycardia.

channels could prove to be a viable new approach for the treatment of AF with minimal or no proan’hythmic potential. However’ it is also possible that, untoward inhibition of Kv1.5 channels in patients who have normal heart rhythms could induce an electrical imbalance and actually cause arrhythmias in such patients. Thus, when developing drugs that are intended to inhibit potassium channels other than Kv1.5 (e.g., drugs intended to inhibit Kv1.3 channels to treat T cell mediated diseases), it may be desirable to design these drugs to display selectivity for the target potassium channels (e.g., Kv1.3 channels) over the heart-affecting Kv1.5 channels.
In view of the foregoing, there remains a need for the synthesis and development of new potassium channel inhibitors that are specific for certain potassium channels over other potassium channels, thereby providing specific therapeutic effects with minimal side effects.
SUMMARY OF THE INVENTION
The present invention provides 5-Phenoxyalkoxypsoraiens, a new class of small-molecules that block the Kv1.3 channel in the low nummular range and preferentially suppress the proliferation of effector memory T cells and affect knife and central! memory T cells only at much higher concentrations. Given the known m vitro and in vivo effects of peptide and non-peptide inhibitors of the Kv1.3 channel, the present invention further comprises the therapeutic and/or diagnostic use of these 5-phenoxyalkoxypsoralens for any diagnosis or treatment that results from or is facilitated by blocking or inhibiting of the Kv1.3 channel, including but not limited to the use of 5-phenoxyalkoxypsoralens as immunosuppressants and/or for the treatment of


in accordance with the invention there are provided compositions of matter comprising or consisting of 5-phenoxyalkoxypsoraiens of general

wherein:
n is 1 through 10, cyclic or acyclic and optionally substituted or unsubstituted;
IsO, S, N, Chirp; and
R1 is arch heterocyclyl or cycloalkyl and is optionally substituted one or more substituents selected from alkyl, alkoxy, amino and its alkyl derivatives, acylamino, carboxyl and its alkyl ester, cyano, halo, hydroxy, nitro and sulfonamide groups.
Further in accordance visit the present invention, there are provided pharmaceutical preparations for administration to human or veterinary patients, said preparations comprising a 5-Phenoxyaikoxypsoralen of General Formula I above or a pharmaceutically acceptable salt thereof alone or in combination pharmaceutically acceptable carriers, exciplents and other ingredients commonly used in pharmaceutical preparations for oral, rectal, intravenous, intraarterial, intradermally, subcutaneous, intramuscularly, intrathecal, sublingual, buccal, intranasal, trans-mucosal, trans-dermal, topical, other enteral, other parenteral and/or other possible route(s) of administration.

administering to the subject a therapeutic or preventative amount of a composition of General Formula I above or a pharmaceutically acceptable salt or derivative thereof. Various diseases and disorders may be treated or prevented by inhibiting selected types of potassium channels. For example, compositions of the present invention that inhibit Kv1.3 channels on human T ceils may be used to treat or prevent T ceil mediated diseases or disorders, such as various autoimmune diseases and disorders. The following are some non-limiting examples of some T cell mediated autoimmune diseases or disorders that may be prevented or treated by the methods of the present invention, categorized p’th respect to the target organ that is principally affected by each such disease:





Irrespective of the particular organ(s) affected, T-lymphocytes are believed to contribute to the development of autoimmune diseases. The currently available therapies for these diseases are largely unsatisfactory and typically involve the use of glucocorticoids (e.g. methylprednisolone, prednisone), non-steroidal anti-inflammatory agents, gold salts, methotrexate, antimalarials, and other immunosuppressants such as cyclosporin and FK-506. Also, another T cell mediated disorder that may be prevented or treated by the methods of the present invention is graft vs. host disease and/or rejection of transplanted organs. T-lymphocytes play a central role in the immune response and they are responsible, in large measure, for the rejection of many transplanted organs. They are also responsible for the so-called graft-versus host disease in which transplanted bone marrow cells recognize and destroy MHC-mismatched host tissues. Accordingly, drugs such as cyclosporin and FK506 that suppress T-cell immunity are used to prevent transplant rejection and graft-versus-host disease. However, immunosuppressive therapy with cyclosporin A is limited by severe side effects such as liver and renal damage. Selective inhibitors of the Kv1.3 potassium channel, such as the 5-Phenoxyalkoxypsoraiens of Genera! Formula I above, may be less likely to cause such side effects and, thus, may be used alone or in combination with other agents (e.g., cyclosporin and/or FK506) to treat or prevent rejection of transplanted tissues or organs and/or

Preventing or treating diseases that are associated with effector memory T cells, such as; bone resorption and periodontal disease, psoriasis, rheumatoid arthritis, type-1 diabetes mellitus and multiple sclerosis. In addition to T ceil mediated diseases, the Kv1.3 channel has been determined to regulate energy homeostasis, body weight and peripheral insulin sensitivity. Thus, the methods of the present invention may be used to treat other diseases and disorders that involve abnormal homeostasis, body weight and peripheral insulin sensitivity by inhibiting Kv1.3 channels on cell membranes, such other diseases and disorders include but are not necessarily limited to bone resorption in periodontal disease, Type 2 diabetes, metabolic syndrome and obesity. Additionally, for Multiple Sclerosis in particular, the current therapy with interferon-beta and Coaxing only benefits about 60% of patients. The appearance of neutralizing antibodies in around 40% of patients treated with interferon-beta makes interferon-beta treatment less effective over time in the responsive patients. Thus, the 5-Phenoxya!koxypsoralens disclosed herein may provide substantial improvements in the treatment of MS.
Still further in accordance with the present invention, there are provided methods for causing a desired inhibition of a first type of potassium channel (e.g., Kv1.3 channels) while not causing undesired inhibition of a second type of potassium channel (e.g., Kv1.5 channels) in a human or animal subject. Such methods generally comprise the step of administering to the human or animal subject a compound of General Formula ! in an amount and form that a) causes the desired inhibition of potassium channels of the first type but b) does not cause the undesired inhibition of potassium channels of the second type. The "desired inhibition of a first type of potassium channel" can be, for example, any inhibition of any type of potassium channel that causes an intended therapeutic or preventative effect, such as inhibition of Kv1.3 potassium channels to treat or prevent a T cell mediated disorder in the human or animal

Effect untoward effect or any effect other than the desired therapeutic or preventative effect, such as the inhibition of Ki/15 potassium channels in a vary that causes a proarrhythmic effect or increases the potential for cardiac arrhythmia in the human or animal subject.
Still further in accordance p’th the present Invention, there are provided methods for inhibiting potassium channels in vitro by contacting ceils with one or more compounds of General Formula !. Such methods may be useful in pharmacological research and/or for screening of drug candidates. Specific compounds of General Formula 1 may be selected for use in these methods on the basis of their relative inhibitory selectivity for certain type(s) of potassium channels over other type(s) of potassium channels.
Still further aspects, objects and advantages of the invention will become apparent to persons of skill in the art upon reading and understanding of the detailed descriptions of the preferred embodiments set forth here below.
DETAILED DESCRIPTION AND EXAMPLES
The following detailed description and the accompanying drawings are intended to describe some, but not necessarily all, examples or embodiments of the invention only and does not limit the scope of the invention in any way.
Set forth herebelow are some examples of substituted 5-phenoxyalkoxypsoralens of the present invention that inhibit the Kv1.3 channel and suppress the proliferation of effector memory T cells in the low Nan molar concentrations.

Example 1
5-(4-PhenoxvbLftoxv)p5orafe'n (PAP 1)
4-(4-Pheno>Py/ 7H-furo[3’2-Q][1]Denzopyran-7-on

700 mg (3.462 mmol) of 5-hydroxypsoralen (crystallized) and 600 mg (3.462 mmol) of 4-phenoxybutyl bromide was refluxed in 30 ml of 2-butanone in the presence of an excess (2 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The spurn/ was stirred for 15-20 min and extracted with 3 x 100 ml of dichioromethane. The dichloromethane layer was extracted with 25 mi of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoraien. The dichloromethane layer w’as washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The solid residue was dissolved in a methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.
Yield: 733.6 mg (60.48%)
Melting point: 104°C
‘H-NMR (500 MHz, CDCI3): 5 [ppm] - 8.13 (d, 1H, ‘J = 9.7 Hz, 3-H), 7.59 (d, 1H, ‘J = 2.0 Hz, 2'-H), 7.30 (m. 5H, 5-OCH2CH2CH2CH2OC6H5), 7.15 (s, 1H, 8-H). 6.91 (d, 1H, ‘J = 2.0 Hz, 3’-H), 6.25 (d, 1H, ‘J = 9.8 Hz, 4-H), 4.56 (t, 2H, ‘J = 6.14 Hz. 5-OCH2CH2CH2CH2OC6H5). 4.09 (t, 2H, ‘J = 5.80 Hz, 5-

03-2CH23HjC-::OCt.-::l 2.09 (n, 4H. -j = 4,2-’ Hz 5-
"C-NMR (DMSO-de, 75 MHz): 6 [ppm] ‘ 25,26 and 26/.8 (5-0-CH2(CH2)2CH2-O-CBHS); 66.91 and 72.29 (5-0-CH2(CH2)2CH2-0-C6H5); 93.18 (C-8); 105.62 (C-4'); 105.98 (C-4a); 112.29 (C-3); 112.92 {C-6); 114.39 (C-3" and C-5"); 120.39 (C’"); 129.41 (C-2" and C-6"); 139.44 (C-4); 145.89 (C-5'); 148.72 (C-5); 152.11 (C-8a); 157.63 (C-1"); 158.48 (C-7); 160.07 (C-2).
MS (70 eV) m/z : 350 (20%, M*), 202 (9%, [M-doHizOf). 201 (5%), 174 (13%, [202-COf), 173 (4%), 150 (11%), 149 (100%), 145 (8%), 107 (100%, [149-CsHef), 94 (9%, CeHgO), 89 (4%), 77 (37%, CgHs), 65 (6%, C5H5).
Combustion analysis: (FW: 350.37) % C71.92, %H 5.08.
(Calc.%C 71.99, %H 5.18)

700 mg (3.5 mmol) of 5-hydroxypsoralen and 750 mg (3.5 mmol) of 3-phenoxypropyl bromide were refluxed in 30 ml of 2-butanone in {he presence of an excess of anhydrous potassium carbonate (3.0 g) and catalytic amounts of potassium iodide for 36 liars. The progress of the reaction was monitored by thin layer chromatography. After 36 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1.


Yield: 390 mg (33.48%).
welting point: 108.4'C
‘H-NMR (500 MHz, CDCI3): 5 [ppm] = 8.13 (d, 1H, ‘J = 9.8 Hz, 3-H), 7.59 (d, 1H, ‘J = 2.3 Hz, 2'-H), 7.31 (t, 3H, 3"-H, 4"'-H, S'-H), 7.16 (s, 1H, 8-H), 6.99 (d, 1H, ‘J = 2.4 Hz, 3'-H), 6.93 (d, 2H, 2"-H, 6"-H), 6.24 (d, 1H, ‘J = 9.5 Hz, 4-H), 4.66 (t, 2H, ‘J = 5.9 Hz, S-OCHZCHJCHZOCBHS), 4.26 (t, 2H, ‘J = 6.0 Hz, 5-OCH2CH2CH2OC6H5), 2.38 (p, 2H, ‘J = 6.0 Hz, 5-OCH2CH2CH2OC6H5).
IVIS (70 eV) m/z : 336 (91%, M"), 203 (7%), 202 (57%, [M-CgHioOf), 201 (11%), 174 (16%, [202-COr), 173 (11%), 145 (14%). 135 (90%), 134 (9%), 108 (8%), 107 (100%), 95 (8%), 89 (9%), 77 (62%, CgHs), 65 (9%, C5H5).
Combustion analysis: (FW: 336.35) %C 71.09, %H 4.74
(Calc.%C 71.42, %H 4.79) Example 3
5-(2-Benzvloxvethoxv)spiraled (PAP 5)
4-(2-Benzyloxyethoxy)-7H-furo[3,2-g][1]benzopyran-7-on


of anhydrous potassium carbonate (2.0 g) and catalytic amounts of potassium iodide for 16 hours. The progress of the reaction was monitored by thin layer chromatography. After 16 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting oily residue was dissolved in methanol, treated charcoal and re-crystallized from 70% methanol.
Yield: 123 mg (12.33%)
Melting point: 90.9°C
‘H-NMR(500 MHz, CDCI3): 6 [ppm] = 8.19 (d, 1H, ‘J = 9.7 Hz, 3-H), 7.59 (d. 1H, ‘J = 2.2 Hz, 2'-H), 7.37 (m, 5H, 5-OCH2CH2OCH aCsHs), 7.19(s, 1H. 8-H), 6.95 (d, 1H. ‘J = 2.0 Hz, 3'-H), 6.25 (d, 1H, ‘J = 9.7 Hz, 4-H). 4.64 (s. 2H, 5-OCH2CH2OCH2C6H5), 4.58 (t, 2H, ‘J = 4.62 Hz, 5-OCH2CH2OCH2C6H5), 3.88 (t, 2H, ‘J = 4.56 Hz, 5-OCH2CH2OCH2C6H5).
MS (70 eV) m/z: 336 (35%, M""), 105 (5%), 91 (100%, [CTHyD-
Combustion analysis: (FW: 336.35) %C 70.65, %H 4,73
(Calc.%C 71.42, %H 4.79)

Example 4 5-(4-Benzv[o>:vbutoxv)psoraten (PAP 6)
4-(4-Benzyloxybutoxy)-7/-/-furo[3,2-g][1]benzopyrari-7-on

700 mg (3.5 mmol) of 5-hydroxypsoral’n and 850.5 mg (3.5 mmol) of benzyl-4-bromobutyi ether was refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (2.0 g) and catelytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The oily residue was dissolved in methanol, treated with charcoal and re-crystallized from 80% methanol.
Yield: 171 mg (13.41%)
Melting point: 78.4°C
‘H-NMR (500 MHz, CDCI3): 5 [ppm] = 8.14 (d, 1H, ‘J - 9.8 Hz, 3-H), 7.55 (d, 1H, ‘J = 2.5 Hz. 2'-H). 7.34 (m, 5H. 5-OCH2CH2CH2CH2OCH2C6H5), 7.13 (s. 1H, 8-H), 6.91 (d. 1H, ‘J = 2.4 Hz, 3'-H), 6.25 (d, 1H, ‘J= 9.8 Hz, 4-H), 4.54 (s, 2H, 5-OCH2CH2CH2CH2OCH2C6H5), 4.49 (t, 2H, ‘J = 6.5 Hz, 5-


1.0 g (4.946 mmol) of S-hydroxypsoraten and 1.36 g (5.936 mmol) of benzyl-3-bromopropyl ether were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (3.4 g) and catalytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid solution,


Yield: 700 mg (40.39%)
Melting point: 75.2°C
‘H-NMR (500 MHz, CDCI3): 6 [ppm] = 8.06 (d, 1H, ‘J = 9.7 Hz, 3-H), 7.57 (d, 1H, -J = 2.2 Hz, 2'-H), 7.29 (m, 5H, ‘J = 6,3 Hz, 5-OCH2CH2CH7GCH2C6H5), 7.15 (s, 1H, 8-H), 6.98 (d, 1H, 'j = 2.2 Hz, 3'-H), 6.21 (d, 1H, ‘J= 9.8 Hz, 4-H), 4.58 (t, 2H, ‘J = 6.1 Hz, 5-OCH2CH2CH2OCH2C6H5), 4.55 (s, 2H, 5-OCH2CH2CH2OCH2C6H5), 3.73 {t, 2H, ‘J = 5.7 Hz, 5-OCH2CH2CH2OCH2C6H5), 2.18 (p, 2H, "'j = 6.1 Hz, 5-OCH2CH2CH2OCH2C6H5).
MS (70 e\J) m/z : 350 (25%. M*), 202 (9%, [M-C10H12O]*), 174 (5%, [202-CO]*), 91 (100%, [CTHTD.
Combustion analysis: (i’W: 350.37) %C 71.54, %H 5.34
(Calc.%C 71.99, %H 5.18)
Example 6 5-(4-Chlorobutoxv)psoralen (I 1)
4-(4-Chlorobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on

817 mg (4.041 mmol) of 5-hydroxypsoralen and 1.413 g (6.47mmol) of 4-chlorobutyl iodide were refluxed in 80 ml of acetone in the presence of an excess of (3.0 g) anhydrous potassium carbonate for 30 hours. The progress of the reaction was monitored by thin layer chromatography. After 30 hours the

Dichloromethane. The dichloromethane layer was extracted with 1 x 25 mi of 1% sodium hydroxide to separate trace amounts of un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid and further washed with water to neutral pH. The dichloromethane layer was dried , over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was then suspended in petroleum ether and filtered to wash out the excess 4-chtorobutyl iodide. The resulting 5-(4-chlorobutoxy)psoralen was used for the synthesis of various derivatives v’thout furbisher purification.
Yield: 1.10 g (92.98%)
Melting point: 115.4-115.6°C
■•H-NMR (500 MHz. CDCI3): 6 [ppm] = 8.15 (d, 1H, ‘J = 9.75 Hz, 3-H). 7.60 {d, 1H/J= 2.62 Hz, 2"-H). 7.17(s, 1H, 8-H), 6.95 (d, 1H, ‘J = 2.15 Hz, 3'-H), 6.29 (d, 1H, ‘J = 9.79 Hz, 4-H). 4.52 (t, 2H, ‘J=5.44 Hz, 5-OCH2CH2CH 2CH2CI), 3.68 (t, 2H, ‘J = 5.89 Hz, 5-OCH2CH2CH2CH2CI), 2.08 (p, 4H, ‘J = 3.06 Hz, 5-OCH2CH2CH2CH2CI).


anhydrous acetonitrile and the resulting mixture was refluxed for 72 hours. The progress of the reaction was monitored by thin layer chromatography. After 72 hours the reaction mixture was concentrated under reduced pressure. The residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 2 x 35 ml of 1% sodium hydroxide to separate the excess of 4-nitroguaicol. The dichloromethane layer was washed with 30 mi of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting solid was dissolved in methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.
Yield: 381.9 mg (52.56%)
Melting point: 170.5'C
‘H’NMR (500 MHz, CDCI3): 5 [ppm] = 8.15 (d, 1H, ‘J = 9.8 Hz, 3-H), 7.91 (d, 1H, ‘J = 2.6 Hz, 3"-H), 7.75 (dd, 1H, ‘J = 2.65 Hz, 5"-H), 7.60 (d, 1H. ‘J= 2.2 Hz, 2'-H), 7.16 (s, 1H. 8-H), 6.98 (d, 1H.. ‘J=2.4 Hz, 3'-H), 6.93 (d, 1H. ‘J = 2.2 Hz, e’-H). 6.26 (d, 1H, ‘J = 9.7 Hz , 4-H), 4.59 (t, 2H, 'j = 6.0 Hz, 5-OCH2CH2CH2CH20C6H3[4-N02-2-CH30]), 4.23 (t, 2H. ‘J = 5.7 Hz, 5-OCH2CH2CH2CH20C6H3[4-N02-2-CH30]), 3.915 (s, 3H, 2"-OCH3). 2.14 (m. 4H, 5-OCH2CH2CH2CH2OC6H3K-NO2-2-CH3O]).


NO.,


0 "0

6" ‘4"-083

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, and 741 mg (4.946 mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrile for 60 min to obtain the iodo derivative. To this solution were added 523.2 mg (3.416 mmol) of 2-nitro-p-cresol, an excess of anhydrous potassium carbonate (4.0 g), 10 m! anhydrous acetonitrile and the resulting mixture was refluxed for 69 hours. The progress of the reaction was monitored by thin layer chromatography. After 69 hours the reaction mixture was concentrated under reduced pressure. The residue was cooled and diluted within water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 2 x 30 ml of 1% sodium hydroxide to separate the excess of 2-nitro-p-cresol. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.
Yield: 447.2 mg (63.95%)
Melting point: 124.5°C
‘H"NMR {500 MHz, CDCI3): 5 [ppm] = 8.14 (d, 1H. ‘J = 9.7 Hz, 3-H). 7.63 (d, 1H, ‘J = 18 Hz, 3"-H), 7.59 (d, 1H, ‘J = 2.4 Hz. 2*-H), 7.31 (d, 1H, ‘J = 8.2 Hz, S-'-H), 7.14 (s. 1H, 8-H), 6.98 (d. 1H, ‘J = 2.5 Hz, 3'-H). 6.96 (d, 1H, ‘J = 8.76 Hz,


500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, and 512 mg (3.416 mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrile for 60 min to obtain the iodo derivative. To this solution were added 475 mg (3.416 mmol) of 2-nitrophenol, an excess (4.0 g) of anhydrous potassium carbonate, 15 ml of anhydrous acetonitrile and the resulting mixture Vvas refluxed for 29 hours. The progress of the reaction was monitored by thin layer chromatography. After 29 hours the reaction mixture was concentrated under reduced pressure. The residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 2 x 20 ml of 1% sodium hydroxide solution to separate the excess of 2-nitrophenoL The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated. The solid residue obtained was dissolved in methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.

V:aid: 3BJ.5 n: (56 Z2%)
Melting point: 121.6-’'21.8’C
'H-NMR (500 MHz, CDCI3): 0 [ppm] = 8.14 (d, 1H, ‘J = 9.7 Hz.. 3-H). 7.82-7.86 (overlapping dd, 2H, "‘J = 1.6 Hz, ‘J = 8.3 Hz, ‘J = 7.91 Hz, 3"-H, 6"-H), 7.60 (d. 1H, ‘J = 2.5 Hz, 2'-H), 7.52-7.55 (t, 2H, ‘J ‘ 7.57 Hz, 'J = 1.0 Hz/T-H. 4'-H), 7.15 (s, 1H, 8-H), 6.99 (d. 1H, ‘'j = 2.35 Hz, 3'-H), 6.26 (d, 1H, ‘J = 9.7 Hz , 4-H), 4.57 (t, 2H, ‘J = 5.8 Hz, 5-OCH2CH2CH2CH20C6H4[2-N02]), 4.23 (t, 2H, ‘J = 2.74 Hz, 5-OCH2CH2CH2CH2O C6H42-NO2]), 2-09-2.16 (m, 4H, 5-OCH2CH2CH2CH20C6H4[2-N02])-

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen and 512 mg (3.416 mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrile for 60 min to obtain the iodo derivative. To this solution were added 475 mg (3.416 mmol) of 3-nitrophenol, an excess (4.0 g) of anhydrous potassium carbonate, 15 ml anhydrous acetonitrile and the resulting mixture was refluxed for 29 hours. The progress of the reaction was monitored by thin layer chromatography. After 29 hours the reaction mixture was concentrated under reduced pressure. The residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stinted for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 2 x 20 ml of 1% sodium hydroxide to separate the excess of 3-nitrophenoi. The dichloromethane layer was washed

.
Yield: 286.4 mg (42.41%)
Melting point: 140.3°C
‘H-NMR (500 MHz, CDCI3): 5 [ppm] = 8.15 (d. 1H, ‘J = 9.7 Hz, 3-H). 7.84 (dd, 1H, ‘J==8.1 Hz/j = 16Hz. 4'-H), 7.61 (d, 1H, ‘J =: 2.3 Hz, 2'-H). 7.42 (t, 1H, ‘J = 8.3Hz, 5"-H), 7.41 (t, 1H, ‘J = 2.2 Hz, 2'-H), 7.22 (dd, 1H, ‘J = 8.1 Hz/j - 2.3 Hz, 6"-H) 7.16 (s, 1H, 8-H), 6.97 (d, 1H, ‘J = 2.2 Hz, 3'-H), 6.27 (d. 1H, ‘J = 9.8 Hz, 4-H), 4.56 (t, 2H, ‘J = 5.8 Hz, 5-OCH2CH2CH2CH2OC6H4I3-NO2]), 4.16 (t. 2H, ‘J = 5.6 Hz, 5-OCH2CH2CH2 CH2OC6H43-NO2]), 2.12 (m, 4H, 5’ OCH2CH2CH2CH20C6H4[3-N02]).

500 mg (1.708 mmol) of 5-(4-chiorobutoxy)psoralen, 512 mg (3.416 mmol) of sodium iodide and 629 mg (3.416 mmol) of 2,4-dinitrophenol were refluxed in 30 ml of anhydrous acetonitrile in the presence of an excess (3 g) of anhydrous potassium carbonate for 50 hours. The progress of the reaction was monitored by thin layer chromatography. After 50 hours the reaction mixture was concentrated under reduced pressure. The residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric


Yield: 82.4 mg (10.96%)
Melting point: 134.2°C
‘H-NMR (500 MHz, Cocoa): 5 [ppm] = 8.78 (d, 1H/J = 2.8 Hz, 3"-H), 8.45 (dd’ 1H, ‘J = 9.0 Hz, ‘J = 2.8 Hz. 5"-H). 8.15 (d, 1H/J = 9.7 Hz. 3-H), 7.61 (d. 1H, ‘J = 2.0 Hz, 2'-H). 7.22 (d, 1H. ‘J = 9.5 Hz. 6"-H),_7.17 (s, 1H, 8-H), 6.98 (d, 1H. ‘J = 2.1 Hz, 3'-H), 6.29 (d, 1H, ‘J = 9.8 Hz, 4-H), 4.57 (t, 2H, ‘J = 5.3 Hz, 5-OCH2CH2CH2CH20C6H3[2,4-(N02)2]), 4.36 (t, 2H. ‘J ‘ 5.1 Hz. 5-OCH2CH2CH2CH20C6H3[2,4-(N02)2]), 2.2 (m, 4H, 5-OCH2CH2CH2CH20C6H3[2,4-(N02)2]).
The following Examples 12-47 describe compounds that may be ~ synthesized by methods that sure similar to those described above with respect to Examples 1-11 and. thus, only physical data is being provided for the compounds of Examples 12-47.


Melting point: 111.5°C
Combustion analysis: C22H20O6 (380.4)
calculated: C 69,46 H
5.30
found: C 69.52 H
5.39
‘H-NMR (DMSO-ds, 300 MHz): 5/ppm (TMS) = 1.91-1.99 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 3,69 (s, 3H, -OCH3); 4,00 (t, 2H, ‘J = 5,8 Hz, 5-0-CH2{CH2)2CH2-0-C6H4-OCH3); 4,57 (t, 2H, ‘J=5.7 Hz, 5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 6.30 (d, 1H, ‘J = 9,8 Hz, H-3); 6,81-6,87 (m. 4H, 5-0-CH2{CH2)2CH2-0-C6H4-OCH3); 7,32-7,34 (m, 2H, H-8 and H-4'); 8.03 (d, 1H, ‘J = 2.3 Hz, H-5'); 8.18 (d, 1H, ‘J = 9.8 Hz, H-4).
"C-NMR (DWlSO-ds, 75 MHz): 5/ppm (TMS) = 25.30 and 26.18 (5-0-CH2(CH2)2CH2-0-C6H5); 55,3 (-OCH3); 67,49 and 72,29 (5-0-CH2(CH2)2CH2-0-CeHs); 93,17 (C-8); 105,61 (0-4'); 105,97 (C-4a); 112,27 (C-3); 112,91 (C-6); 114,54 and 115,29 (C-2", C-3", 0-5" and C-6"); 139,42 (C-4); 145,88 (C-5'); 148,71 (C-5); 152.10 (C-8a):i52,47 and 153,25 (C-l" and C-4"); 157,62 (C-7); 160,06(0-2).
IR (KBr): = 3126, 2958, 1722, 1626, 1508, 1233, 1130.
MS (El): m/z (%) = 380 M’ (14), 257 (8), 215 (7), 202 [M-CuHi’Ozf (5), 179 [CnHisOzf (69), 145 (6), 137 [CH3-0-C6H40-CH2r (100), 109 (29), 107 [C6H5O-CH2]* (18), 77 [OgHsr (23), 55 [C4H7r (61), 41 (15).


Melting point: 102.5°C
Combustion analysis; C22H20O6 (380.4)
calculated: C 69.46 H 5.30
found: C 68.89 H5.38
‘H-NMR (DMSO-ds, 300 MHz): 6/ppm (TMS) = 1.91-1,99 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 3.71 (s, 3H, -OCH3); 4.05 (t, 2H, ‘J = 5.4 Hz, 5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 4.58 (t, 2H, ‘J’5A Hz, 5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 6.29 (d, 1H, ‘J= 9.8 Hz, H-3); 6.45-6.51 (m, 3H, H-2", H-4" and H-6"); 7.15 (t, 1H, ‘J = 8.14 Hz, H-5"); 7.33 (s, 2H, H-8 and H-4'); 8.02 (d, 1H, ‘J = 1.9 Hz, H-5"); 8.18 (d, 1H, ‘J = 9.8 Hz, H-4).
‘‘C-NMR (DMSO-dg, 75 MHz): 5/ppm (TMS) = 25.21 and 26.17 (5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 54.98 (-OCH3); 67.04 and 72.24 (5-0-CH2(CH2)2CH2-0-C6H4-OCH3); 93.15 (C-8); 100.62 (C-5"); 105.61 (C-4'); 105.95 (C-4a); 106.14 and 106.57 (C-4" and C-6"); 112.25 (C-3); 112.89 (C-6); 129.86 (C-2"); 139.42 (C-4); 145.86 (C-5'); 148.69 (C-5); 152.09 (C-8a); 157.61 (C-7); 159.73 and 160.44 (C-1" and C-3"); 160.05 (C-2).
IR(KBr): v/cant' = 3128, 2948, 1728, 1626, 1604, 1454, 1348, 1154.



Melting point: 139°C
Combustion analysis: C23H22O7 (410.43)
calculated: C 67,31 H
5.40
found: C 66.92 H
5.60
‘H-NIMR (DMSO-de, 300 MHz): 5/ppm (IMS) = 1.93-1.97 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H3-(OCH3)2); 3.69 (s, 3H, -(OCH3)2); 4.05 (t, 2H, ‘J= 5.4 Hz, 5-0-CHz(CH2)2CH2-0- C6H3-(OCH3)2); 4.58 (t, 2H, ‘J = 5.4 Hz, 5-0-CH2(CH2)2CH2-0-C6H3-(OCH3)2); 6.07 (s. 3H, H-2", H-4" and H-6"); 6.31 (d, 1H, ‘J=9.& Hz, H-3); 7.34 (s, 2H, H-8 and H-4'); 8.03 (d, 1H, ‘J = 2.1 Hz, H-5'); 8.19 (d, 1H,’J=9.8Hz, H-4).
"C-NMR {DMSO-de, 75 MHz): 5/ppm (TMS) = 25.15 and 26.18 (5-0-CH2(CH2)2CH2-0-C6H3-(OCH3)2); 55.05 (-(OCH3)2); 67.10 and 72:20 (5-0-

CH2’Ch2'Ohr-0-C6K,-(OC-v..;- 22.7S 'C-4"): 12M :G-8): 33.2' 0-2' and C-6";: 105.?-: (C-4'); 135.94 ;>4£ . 112.22 (0-2;; 112.S6 ■0-5); ‘39,42 (C-4K 145,84 (C-5'); 148.68 (C-5); 152.09 (C-Sa); 157.61 (C-7); 150.05 {C-2); 150.34 (C-1"); 161.09 {C-3" and C-5").
IR (KBr): v/cm"' = 3158, 2954, 1716, 1600, 1456, 1354, 1152.
MS (El): m/z (%) = 410 M' (12), 209 [CiaHirOaf (100), 202 [M-lCizHiyOar (5), 167 [(CH3-0)2-CBH30-CH2]' (75), 137 [CH3-0-C6H40-CH2r (34), 122 (15), 107 [CeHsO-CHz]' (10), 77 [CeHs]' (11), 55 [C4H7]’ (46), 41 (6).

Combustion analysis: C21H17O7 (395.34)
calculated: C 63.80 H 4.33
N3.54
found: C 63.79 H 4.46
N3.60
‘H-NMR (DWISO-dB, 300 MHz): 5/ppm (TMS) = 1.99 (s, 4H, 5-0-CH2(CH2)2CH2-O-C6H4-NO2); 4.05 (s, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-N02); 4.56 (s, 2H, 5-0-Cid2(CH2)2CH2-0-C6H4-N02); 6.27 (d, 1H, ‘J = 9.8 Hz, H-3); 7.10 (d, 2H, ‘J = 9.2 Hz, H-2" and H-6"); 7.28 (s. 1H, H-8); 7.30 (d, 1H, ‘J = 1.9 Hz, H-4'); 8.00 (d, 1H,


"C-NMR (DWISO-ds, 75 MHz): 5/ppm (TMS) = 24,95 and 25.36 (5-0-CH2(CH2)2CH2-0-C6H4-N02); 68.25 and 72.04 {5-0-CH2(CH2)2CH2-0-C6H4-NO2); 93.07 (C-8); 105,56 (C-4"); 105.84 (C-4a); 112.17 (C-3); 112.78 (C-6); 114.87 and 125.74 (C-2", C-3", C-5" and C-6"); 139.28 (C-4); 140.65 (C-4"); 145.80 (C-5'); 148.58 (C-5); 152.03 (C-8a); 157.57 (C-7); 159.99 (C-2); 163.80 (C-1").
IR(KBr): v/cm"‘ =2960, 2881, 1728, 1593, 1498, 1455, 1327, 1270.
MS (El): m/z (%) = 395 M’ (25), 202 [M-CioHi403Nf (30), 194 [doHizOsNf (100), 174 [202-COf (26), 152 [02N-C6H40-CH2r (82), 133 (17), 106 (17), 89 (13), 75(12), 55[C4H7r (84), 41 (11).


Combustion analysis: C-n--C:D5 (3?-4.S2)
calculated: C 65.55 H
4.45
found: C 65.23 H
4.57
‘H-NMR (DMSO-dg, 300 MHz): 5/ppm (TMS) = 1.95-1.96 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H4-CI); 4.05 (m. 2H, 5-0-CH2(CH2)2CH2-0-C6H4-CI); 4.55 (m, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-CI); 6.28 (d, 1H, =J = 9.8 Hz, H-3); 6.93 (d, 2H, "J = 8.9 Hz, H-2" and H-6"); 7.29 (d, 2H, ‘J == 8.9 Hz, H-3" and H-5"); 7,31 (s, 2H, H-8 and H-4'); 8.01 (d, 1H, ‘J = 2.0Hz, H-5'); 8.15 (d, 1H. ‘J=9.8Hz, H-4).
"C-NMR (DMSO-cafe, 75 MHz): 5/ppm (TMS) = 25.12 and 26.08 (5-0-CH2(CH2)2CH2-0-C6H4-CI); 67.44 and 72.17 (5-0-CH2(CH2)2CH2-0-C6H4-Ci); 93.10 (C-8); 105.59 (0-4'); 105.89 (C-4a); 112.21 (0-3); 112.83 (C-6); 116.14 (C-2" and C-6"); 124.08 (C-4"); 129.13 (C-3" and C-5" ); 139.34 (C-4); 145.83 (G-5'); 148.65 (C-5); 152.07 (C-8a); 157.32 (C-7); 157.60 (C-1"); 160.03 (C-2).
IR (KBr): v/cm"‘ = 3090, 2929, 2882, 1718, 1618, 1577, 1491, 1346, 1246.
MS (El): m/z (%) = 384 M* (10), 202 [M-CioHMdOf (14), 183 [doHizOClf (80), 174 [202-COr (11), 141 [CI-CeH’O-CHzr (100), 113 (18), 111 (23), 89 (7), 77 [CeHsf (9), 55 [C4H7]" (72), 41 (5).


Melting point: 13’ °C
Combustion analysis: C27H22O5 (442.47)
calculated: C 73.29 H
5.01
found: C 73.24 H
5.09
‘H-NMR (Disso-de, 300 MHz): 5/ppm (TMS) = 1.97 (s, 4H, 5-0-CH2{CH2)2CH2-O-C6H4-O-C6H5); 4.05 (s, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-0-C6H5); 4.57 (s, 2H, 5-0-CH!2(CH2)2CH2-0-C6H4-0-C6H5); 6.29 (d, 1H,/J = 9.7 Hz, H-3); 6.89-6.96 (m, 6H, -O-C6H4-O-C6H5); 7,06 (t, 1H, H-4'"); 7.31-7.35 (m, 4H, H-8, H-4' and -O-C6id4-0-C6H5); 8.02 {s, 1H, H-5'); 8.17 (d, 1H, ‘J = 9.8 Hz, H-4),
‘‘C-NMR (DMSO-de. 75 MHz): 5/ppnn (TMS) = 25.28 and 26.14 (5-0-CH2(CH2)2CH2-0-C6H4-0-C6H5); 67.46 and72.23 (5-0-CHz(CH2)2CH2-0-C6H4-0-CeHs); 93.11 (C-8); 105.59 (C-4'); 105.91 (C-4a); 112.22 (C-3); 112.85 (C-6); 139.36 (C-4); 145.83 (C-5'); 148.67 (C-5); 152.07 (C-8a); 157.60 (C-7); 160,03 (C-2); 115.60, 117.23, 120.57, 122.49, 129.78, 149.32, 154.85 and 157.92 (-0-C6H4-O-C6H5).
IR(KBr): = 3119, 2930, 1724, 1626, 1578, 1506, 1456, 1349, 1221,
MS (El): m/z (%) = 442 M' (25), 257 (16), 241 [C6H5-OCioHi20r (100), 215 (12), 199 [CsHs-OCsHsOr (100), 186 [CeHs-OC-Hoof (100), 171 (12), 148 (38), 129 (13), 115 (17), 93 (10), 77 [CQHST (49), 55 [C4H7r (70), 41 (7),


Melting point: 128 "C
Combustion analysis: C22H20O5 (364.40)
calculated: C 72,51 H
5.53
found: C 72.59 H
5.65
‘H-NNIR (DMSO-dg, 300 MHz): 5/ppm (TMS) = 1.92-2.01 (m, 4H, 5-0-
CH2(CH2)2CH2-0-C6H4-CH3); 2.22 (s, 3H, -CH3); 4.02 (t, 2H, ‘J = 5.7 Hz, 5-0-CH2(CH2)2CH2-0-GBH4-CH3); 4.56 (t. 2H, ‘J = 5.6 Hz, 5-0-GH2(CH2)2CH2-0-G6H4-CH3); 6.28 (d, 1H, ‘J - 9.8 Hz. H-3): 6.80 (d, 2H, ‘J = 8.5 Hz, H-3" and H-5"); 7.06 (d, 2H, ‘J = 8.4 Hz, H-2" and H-6"); 7.31 (s, 2H, H-8 and H-4'); 8.02 (d, 1H,’J = 2.1 Hz, H-5');8,15(d, 1H, ‘J = 9.8Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 6/ppm (TMS) = 19.97 (-CH3); 25.25 and 26.16 (5-0-CH2(CH2)2CH2-0-C6H4-CH3); 66.96 and 72.21 (5-0-CH2(CH2)2CH2-0-C6H4-CH3); 93.06 (C-8); 105.56 (C-4'); 105.87 (C-4a); 112.16 (C-3); 112.79 (0-6); 114.19 (C-3" and 0-5"); 128.95 (0-4"); 129.69 (C-2" and 0-6"); 139.32 (0-4); 145.78 (0-5'); 148.63 (0-5); 152.05 (0-8a); 156.33 (0-1"); 157.57 (C-7); 160.01 (0-2).
IR(KBr): v/cnT' = 3091, 2915, 1717, 1619, 1576, 1509, 1456, 1346, 1244.

WIS ;=[): rr,'- (%; = 3S- i’’ (IC;, 2C2 iM-C-.-iisOr (5). 53 '_Z-M’e’{' (8", 12' iCHr-sH.O-CHsr (1’-;. 91 [C7H7J". ‘33), 55 (9), 55 [C’n-r {35), 41 (4).

Melting point: 104 °C
Combustion analysis: C23H22O5 (378.43)
calculated: C 73.00
H5.86
found; C 71.74
H 5.89
‘H-NMR (DlVISO-de, 300 MHz): 6/ppm (TMS) = 1.14 (t, 3H, ‘J =■ 7.6 Hz, -CHzCHa); 1.95-1.99 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H4-CH2CH3); 2.52 (q, 2H, ‘J = 7.6 Hz -CH2CH3); 4.03 (t, 2H, ‘J = 5.7 Hz, 5-0-CH2(CH2)2CH2-0-C6H4-CH2CH3); 4.57 (t, 2H, ‘J = 5.7 Hz, 5-0-CH2(CH2)2CH2-0-C6H4-CH2CH3); 6.28 (d, W,’J = 9.8 Hz, H-3); 6.82 (d, 2H, ‘J = 8.6 Hz, H-3" and H-5"); 7.09 (d, 2H, ‘J = 8.5 Hz, H-2" and H-6"); 7.33 (s, 2H, H-8 and H-4'); 8.02 (d, 1H, ‘J = 2.3 Hz, H-5');8.18{d, 1H, ‘J = 9.8Hz, H-4).
"C-NMR (DMSO-ds, 75 MHz): 6/ppm (TMS) = 15.82 (-CH3); 25.27 and 26.17 (5-0-CH2(CH2)2CH2-0-C6H4-C2H5); 27.20 (-CH2CH3); 66.98 and 72.26 (5-0-CH2(CH2)2CH2-0-CeH4-C2H5); 93.13 (C-8); 105.59 (C-4'); 105.93 (C-4a); 112.22 (C-3); 112.87 (C-6); 114.22 (C-3" and C-5"); 128.51 (C-4"); 135.55 (C-2" and C-

-

Melting point: 121 °C
Combustion analysis: C21H17FO5 (368.37)
calculated: C 68.47 H
4.65
found: C 68.15 H
4.65
‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 1.94-1.96 (m, 4H, 5-0-CH2(CH2)2CH2-0-C6H4-F); 4.01-4.05 (m, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-F); 4,53-4.55 (m, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-F); 6,27 (d, 1H, ‘J = 9.8 Hz, H-3); 6.89-6.94 (m, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-F); 7,30 (s, 2H, H-4' and H-8); 8,01 (d, 1H, ‘J = 2.0Hz, H-5');8,14(d, 1H, ‘J = 9.8Hz, H-4),
"C-NMR (DMSO-c/s, 75 MHz): 5/ppm (TMS) = 25,20 and 26,10 (5-0-GH2(CH2)2CH2-0-G6H4-F); 67,60 and 72,17 (5-0-CH2(CH2)2CH2-0-C6H4-F); 93,07 (C-8); 105,56 (C-4'); 105.87 (C-4a); 112.18 (0-3); 112.80 (C-6); 115.53,

-;-:5.63 ana "‘SS ?C-2'\ C-3", :-5" and C-S"); '3..32 (C-4); '45.B: (C-£';: '45,63 (C-5); '52.05 ;C-8aj: 154."'2 (C-5"); 157.55 (:-7); 157.91 (0-1"; '60.D2 (C-2).
IR (KBr): vlcm'‘ = 2947, 1722, 1625. 1503, 1457, 1346, 1203.
MS (EI): m/z (%) = 368 M"" (11), 202 [M-CioHuFOr (11), 174 [202-00)* (11), 167 [C10H12OF]' (83), 125 [F-C6H40-CH2r (100), 95 (23), 89 (5), 55 [C4H7r (46), 41 (3).

Melting point: 118 °C
Combustion analysis: C22H17F3O5 (418.37)
calculated: 0 63.16 H
4.10
found: C 63.19 H
4.09
‘H-NMR (DMSO-dg, 300 MHz): 5/ppm (TMS) = 1,98 (s, 4H, 5-0-OH2(CH2)2CH2-O-C6H4-CF3); 4.15 (s, 2H, 5-0-CH2(CH2)2CH2-0-C6H4-CF3); 4.57 (s, 2H, 5-0-CH2(CH2)2CH2-0-06H4-CF3); 6.26 (d, 1H, ‘J = 9.8 Hz, H-3); 7.18-7.32 (m, 5H, H-2", H-4", H-6", H-8 and H-4'); 7.49 (t, 1H, ‘J = 7,93 Hz, H-5"); 8.01 (d, 1H, ‘J = 2.3 Hz, H-5'); 8.15 (d, 1H, ‘J = 9.8 Hz, H-4).




‘‘C-NMR (DMSO-ds, 75 MHz): 5/ppm (TMS) = 25,28 and 26.39 (5-0-CH2(CH2)2CH2-0-CioH7); 67.37 and 72,20 (5-0-CH2(CH2)2CH2-0-CioH7); 93,06 (C-8); 105,07, 119,73, 121.28, 124.86, 125.03, 126.13, 126.29, 127.36 and 133.95 (5-0-CH2(CH2)2CH2-0-CioH7); 105.61 (C-4'); 105.87 (C-4a); 112.14 (C-3); 112.78 (C-6); 139.34 (C-4); 145.79 (C-5"); 148.61 (C-5); 152.06 (C-8a); 157.60 (C-7): 153.88 (C-1"); 160.02 (C-2).
IR (KBr): v/cm'' = 2956, 1728, 1624, 1578, 1456, 1344, 1268, 1128.
MS (El): m/z (%) = 400 M' (35), 257 (42), 215 (26), 199 [CuHisOf (100), 157 [CnHgOf (96), 127 (40), 89 (12), 55 [C.HJT (97).

Melting point: 122 "C
Combustion analysis: C25H20O5 (400.44)
calculated: C 74.99 H 5.30
found: C 75.28 H 5.22
‘H-NMR (DMSO-de, 300 MHz): 6/ppm (TMS) = 2.04 (s, 4H, 5-0-CH2(CH2)2CH2-O-C10H7); 4.21 (s, 2H, 5-0-CH2(CH2)2CH2-0-CioH7); 4.60 (s, 2H, 5-0-CH2(CH2)2CH2-0-CioH7); 6.22 (d, 1H, ‘J = 9.8 Hz, H-3); 7.14 (dd, 1H, ‘J = 8.9 Hz, ‘J=2.4 Hz, H-3"); 7.27-7.36 (m, 4H, H-8, H-4' and5-0-CH2(CH2)2CH2-0-

CoH- 7At \ 1M’ 'J = " 5 f-;- S--Z’~CHrS’’:_:20'--0-C.;-’): -,76-".S5 ijn, 3y\. 5-0-Ch2{C-:}2CH2-0-Cionv). i.JO (d’ iH, ‘ = 2,’ -\z., h-5'); Hz B,"‘" vci, 1H’ ‘J = 9.8 Hz, H-4i.
"C-NMR (DMSO-cfs, 75 MHz): S/ppm (IMS) = 25.21 and 26.22 (5-0-CH2{CH2)2CH«-0-CioH7); 67.16 and 72 26 (5-0-CH2(CH2)2CH2-0-CioH7); 93.13 (C-8); 105,65 (C-4'); 105.92 (C-4a); 106.74, 118.64, 123.47. 126.32, 126.58, 127.46, 128.41, 129.22 and 134.27 (5-0-CH2(CH2)2CH2-0-CioH7); 112.21 (C-3); 112.86 (C-6); 139.38 (C-4); 145.86 (C-5'); 148.71 (C-5); 152.11 (C-8a); 156.38 (C-1"); 157,64 (C-7); 160,04 (C-2).
IR (KBr): v/cnT’ = 1732, 1626, 1600, 1460, 1354, 1260.
MS (El): m/z (%) = 400 M* (20), 257 (5), 215 (5), 199 [CMHisOf (97), 157 [CnHgOr (100), 127 (49), 89 (8), 55 [C’Hit (72).

calculated: C 68,85 H 4,95
found: C 68,56 H 5,07
‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 2.24 (t, 2H, ‘J = 6.0 Hz, 5-0-CH2CH2CH2-O-C6H4-OCH3); 3,68 (s, 3H, -OCH3); 4,15 (t, 2H, ‘J = 6,0 Hz, 5-0-

OCHj;; 6.25 (d. 'H. 'j = B.8 --. --3;; S.B2-6.9C ;rn. ‘n, S-D-CHzCHsC-r-O-CsH4-OCH3)i 7.31-7.32 (m. 2H. H-8 and H-4'); S,C2 (s. 1H, H-5'); 8.20 (d, 1H, 'j = 9.8Hz, H-4).
"C-NMR (DMSO-C/B, 75 MHz): 5/ppm (TMS) = 29.30 (5-O-CH2CH2CH2-O-C6H4OCH3); 55.29 (-OCH3); 64.55 und 69.52 (5-O-CH2CH2CH2-O-C6H4OCH3); 93.33 (C-8); 105.38 (C-4'); 106.08 (C-4a); 112.30 (C-3); 113.02 (C-6); 114.56 and 115.35 (C-2", C-3", C-5" and C-6"); 139.42 (C-4); 145.96 (C-5'); 148.54 (C-5); 152.05 (C-8a); 152.40 and 153.37 (C-1" and C-4"); 157.55 (C-7); 160.02 (C-2).
IR(KBr): v/cm"' = 3125, 2952, 2828, 1721, 1622, 1508, 1456, 1352, 1233, 1129.
MS (El): m/z (%) = 366 M’ (32), 243 (18), 215 (17), 202 [CiiH604r (18), 165 [CioHisOzf (100), 145 (10), 137 [CH3-0-C6H40-CH2r (94), 109 (30), 92 (17), 77 [C6H5]' (35), 51 (14), 44 (40).
Example 25 5-r3-(3-Methoxvphenoxv)i3ropoxv]psoralen (AS64)
4-[3-(3-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on


calculated: C 58.85 H
4-95
found: C 68.57 H
5,05
‘H-NMR (DMSO-ds, 300 MHz): 5/ppm (TMS) ‘ 2.27 (quilt 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2-O-C6H4-OCH3); 3.72 (s, 6H, -OCH3); 4.22 (t, 2H, ‘J = 6.2 Hz, 5-0-CH2CH2CH2-O-C6H4-OCH3); 4.66 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2-O-C6H4-OCH3); 6.30 (d, 1H, ‘J = 9.8 Hz, H-3); 6.50-6,55 (m, 3H, H-2", H~4" and H-6"); 7.17 (t, 1H, ‘J = 8.5 Hz, H-5"); 7.33 (d, 1H, ‘J = 2.2 Hz, H-4'); 7.36 (s, 1H, H-8); 8.04 (d, 1H, ‘J = 2.2 Hz, H-5"); 8.24 (d, 1H, ='J = 9.8 Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 29.20 (S-O-CHzCHzCHz-O-CeH*-OCH3); 55.01 (-OCH3); 64.10 and 69,49 (5-O-CH2CH2CH2-O-C6H4-OCH3); 93.35 (C-8); 100.70 (C-5"); 105.41 (C-4'); 106.09 (C-4a): 106.30 and 106.61 {C-4" and C-6"); 112.31 (C-3); 113.01 (C-6); 129.91 (C-2"): 139.49 (C-4); 145.99 (C-5'); 148.55 (C-5); 152.06 (C-8a); 157,56 (C-7); 159.65 and 150,46 (C-1" and C-3"); 150.02 (C-2).
IR (KBr): v/cm"‘ = 3125, 2956, 1724, 1618, 1455, 1352, 1270, 1175.
MS (El): m/z (%) = 366 M"" (16), 202 [CiiHB04r (7), 165 [C-ioHisOz]’ (100), 137 [CH3-0-C6H40-CH2r (80), 124 (8), 107 [CeHsO-CHzf (30), 92 (16), 77 [CeHsf (32),64(8),51(10),41[C3H5r(24).


Combustion analysis: C22H20O7 (396.40)
calculated; C 66.66 H 5.09
found: C 66.43 H 5.06
‘H-NIV!R (DMSO-ds, 300 WHz): 5/ppm (TMS) = 1.97 (t, 2H, ‘J = 5.7 Hz, 5-0-
CH2CH2CH2-0-C6H3-(OCH3)2); 3.70 (s, 3H, -(OCH3)2); 4.20 (t, 2H, ‘J = 5.8 Hz, 5-0-CH2CH2CH2-0-C6H3-(OCH3)2); 4.65 (t, 2H, ‘J = 5.6 Hz, 5-O-CH2CH2CH2-O-C6H3-(OCH3)2); 6.09-6.12 (m, 3H, H-2", H-4" and H-6"); 6.29 (d, 1H, ‘J= 9.8 Hz, H-3); 7.33 (s, 2H, H-8 and H-4'); 8.03 (s, 1H, H-5'); 8.24 (d, 1H, ‘J = 9.8 Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 29.17 (5-0-CH2CH2CH2-0-C6H3-(OCH3)2); 55.07 (-(OCH3)2); 64.16 and 69.44 (5-O-CH2CH2CH2-O-C6H3-(OCH3)2); 92.92 (C-8); 93.29 (C-2", C-4" and C-6"); 105.40 (C-4'); 106.05 (C-4a); 112.26 (C-3); 112.96 {C-6); 139.48 (C-4); 145.95 (C-5'); 148.53 {C-5); 152.05 (C-8a); 157.56 (C-7); 160.01 (0-2); 160.27 (0-1"); 161.11 (C-3" and C-5").
IR (KBr): ylcm'‘ = 3082, 2939, 1727, 1605, 1456, 1387, 1156.


Melting point: 179 °C
Combustion analysis: C20H15NO7 (381,35)
Calculated; C 62,99 H 3.96 N 3,67
Found:
‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 2.32-2.36 (m, 2H, 5-0-CH2CH2CH2-O-C6H4-NO2); 4.40 (t, 2H, ‘J = 6.1 Hz, 5-O-CH2CH2CH2-O-C6H4-NO2); 4.68 (t, 2H, ‘J=5.7 Hz, 5-O-CH2CH2CH2-O-C6H4-NO2); 6.31 (d, 1H, ‘J = 9.8 Hz, H-3); 7.18 (d, 2H, V= 9,0 Hz, 5-O-CH2CH2CH2-O-C6H4-NO2); 7,34 (s, 2H, H-B and H-4'); 8,04 (s, 1H, H-5'); 8.19-8.27 (m, 3H, H-4 and 5-0-CH2CH2CH2-O-C6H4-NO2),
"C-NMR (DMSO-c/e, 75 MHz): 5/ppm (TMS) = 28,93 (5-O-CH2CH2CH2-O-C6H4-NO2); 65.44 and 69.29 (5-O-CH2CH2CH2-O-C5H4- NO2); 93,36 (C-8); 105,40 (C-4'); 106,05 (C-4a); 112,33 (C-3); 112.96 (C-6); 114,99 (C-2" and C-6"); 125,82 (C-3" and G-5" ); 139.48 (C-4); 140.80 (C-4"); 146.00 (C-5'); 148.46 (C-5); 152.04 (C-8a); 157.55 (C-7); 160.01 (C-2); 163.72 (C-1").

IRfKBr); v/cm-' =3'f’3’ 29’5,235r 1~-L 1521 1351 12’: i13l,
MS (El): miz (%) = 381 M" (49). 2D2 [C:,H£04" (100), 174 :202-COr (31), 152 [O2N-CSH4O-CH2]' (52), 119 (35), 106 (16), 75 (23), 51 (2S), 41 [CsHsf (55).

Melting point: 137.5 °C
Combustion analysis: C20H15CIO5 (370 79)
calculated.: C 64.79 H 4.08
found.: C 64.47 H4.18
‘H-NMR (DMSO-ds, 300 MHz): 5/ppm (TMS) = 2.28 (quint, 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2-O-C6H4-CI); 4.23 (t, 2H, ‘J = 6.2 Hz, 5-O-CH2CH2CH2-O-C6H4-CI); 4.65 (t, 2H, ‘J = 6.1 Hz, 5-O-CH2CH2CH2-O-C6H4-CI); 6.30 (d, 1H, ‘J = 9.8 Hz, H-3); 6.96-7.02 (m, 2H, 5-O-CH2CH2CH2-O-C6H4-CI); 7.29-7.34 (m, 4H, H-8, H-4' and 5-O-CH2CH2CH2-O-C6H4-CI); 8.03 (d, 1H, ‘J = 2.4 Hz, H-5'); 8.23 (d, 1H, ‘J = 9.7Hz, H-4).
"C-NMR (DMSO-ds, 75 MHz): 5/ppm (TMS) = 29.09 (5-O-CH2CH2CH2-O-C6H4-Cl); 64.54 and 69.40 (5-O-CH2CH2CH2-O-C6H4-CI); 93.33 (C-8); 105.37 (C-4'); 106.05 (C-4a); 112.30 (C-3); 112.98 (C-6); 116.17 (G-2" and C-6"); 124.23 (C-

(C-Sa); 157.24 [Z-T): IST.S’i .o-V; 159.9£ (C-2,,.
!R(KBr):v/cm-' = 3129, 2953, 1715, 1621, 1578, 1492, 1353,1251.
MS (El): m/z (%) = 370 M' (38), 202 [CnHsO’r (88), 169 [CgHioOCir (69), 141 [CI-CsH’O-CHaf (100), 111 (39), 75 (23), 41 [C3H5]" (88).

Melting point: 133.5 X
Combustion analysis: CaeHaoOe (428.45)
calculated: C 72.89 H 4.71
found: C 73.23 H 4.81
‘H-NIVIR (DiVISO-c/e, 300 MHz): 5/ppm (TMS) = 2.29 (quint, 2H, ‘J=6.0 Hz, 5-0-CH2CH2CH2-O-C6H4-O-C6H5); 4.23 (t, 2H, ‘J = 6.1 Hz, 5-O-CH2CH2CH2-O-C6H4-O-CgHs); 4.67 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2-O-C6H4-O-C6H5); 6.30 (d, 1H, ‘J = 9.7 Hz, H-3); 6.91 (d, 2H, ‘J = 8.1 Hz, -O-C6H4-O-C6H5); 6.96-7.02 (m, 4H, 5-O-CH2CH2CH2-O-C6H4-O-C6H5); 7.07 (t, 1H, ‘J = 7.3 Hz, H-4'"); 7.32-7.37 (m, 4H, H-8, H-4' and -O-C6H4-O-C6H5); 8.04 (d, 1H, ‘J = 19 Hz, H-5'); 8.24 (d, 1H, ‘J = 9.8Hz, H-4).

•’C-NMR (DMSO-d’, 75 MKz): S ppm (IMS) = 29.2’ !;5-OOH2C-:2CHrO-C6K’-O-CeHs); 54,52 unci 69,47 (S-O-CHzCHzCHz-O-CsH’-O-CgHe;: 93,33 {C-8); 105,42 (C-4'); 106.06 (C-4a); 112,31 {C-3); 112,98 (C-6); 139.47 (C-4); 145.97 (.C-5'); 148,54 (C-5); 152,05 (C-8a); 157,57 (C-7); 150,02 (C-2); 115,68, 117,23, 120.62, 122.52, 129.80, 149.45, 154.76 and 157.91 (-O-C6H4-O-C6H5).
IR (KBr): vlcm’ = 3124, 2954, 1716, 1578, 1506, 1456, 1348, 1222.
MS (El): m/z (%) = 428 M’ (50), 227 {19}, 199 (57), 171 (6), 134 (100), 77 [C6H5r(43),51(15).

Combustion analysis: C21H18O5 (350.37)
calculated; C 71.99 H
5.18
found: C 72.27 H
5.24
‘H-NWIR (DMSO-dg, 300 MHz): S/ppm (TMS) = 2.22-2.30 (m, 5H, 5-0-CH2CH2CH2-0-C6H4-CH3 and -CH3); 4.18 (t, 2H, ‘J = 6.2 Hz, 5-O-CH2CH2CH2-O-C6H4-CH3); 4.63 (t, 2H, ‘J=6.1 Hz, 5-O-CH2CH2CH2-O-C6H4-CH3); 6.28 (d, 1H,

"C-NWIR (DMSO-de, 75 MHz): 5/ppm (TMS) = 20.01 (-CH3); 29.27 (5-0-CH2CH2CH2-O-CSH4-CH3); 64.06 and 69.54 (5-O-CH2CH2CH2-O-C6H4-CH3); 93.35 (C-8); 105.39 (C-4'); 106.11 (C-4a); 112.33 (C-3); 113.04 (C-6); 114.29 (C-3" and C-5"); 129.20 (C-4"); 129.78 (C-2" and C-6"); 139.45 (C-4); 145.98 (C-5'); 148.55 (C-5); 152.07 (C-8a); 156,30 (0-1"); 157.57 (C-7); 160.04 (C-2).
IR (KBr): v/cm'‘ = 3126, 2954, 1720, 1622, 1511, 1454, 1351, 1240, 1129.
MS (El): m/z {%) = 350 M* (37), 215 (5), 202 [CiiH604r (38), 174 (6), 149 [CioHi30r (87), 121 lCH3-C6H40-CH2r (100), 91 [CyHyf (58), 41 [CsHsf (22).


"C-NMR (DWISO-de, 75 MHz): 6/ppm (TMS) =: 15.80 (-CH3); 27,17 (-CH2CH3); 29.21 (5-O-CH2CH2CH2-O-C6H4-C2H5); 64.00 and 69.49 (5-O-CH2CH2CH2-0-C6H4-C2H5); 93,31 (C-8); 105,36 (C-4'); 106.06 (C-4a); 112,28 (C-3); 112.98 (C-6); 114,26 (C-3" and C-5"); 128,53 (C-2" and C-6"); 135.73 (C-4"); 139,42 (C-4); 145,94 (C-5'); 148,51 (C-5); 152,02 (C-8a); 156.41 (C-1"); 157.52 (C-7); 159.98 (C-2).


‘H-NMR (DMSO-dg, 300 MHz): 5/ppm (IMS) - 2.28 (quint, 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2-O-C6H4-F); 4.21 (t, 2H, ‘J = 6.2 Hz, 5-O-CH2CH2CH2-O-C6H4-F); 4.65 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2-O-C6H4-F); 6.30 (d, 1H, ‘J = 9.8 Hz, H-3); 6.95-7.00 (m, 2H, 5-O-CH2CH2CH2-O-C6H4-F); 7.07-7.14 (m, 2H, 5-0-CH2CH2CH2-O-C6H4-F); 7 33 (d, 1H, ‘J = 2.1 Hz, H-4'); 7.35 (s, 1H, H-8); 8.04 (d, 1H, ‘J = 2.3 Hz, H-5'); 8.23 (d, 1H, ‘J = 9.8 Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 29.18 (5-O-CH2CH2CH2-O-C6H4-F); 64.71 and 69.45 (5-O-CH2CH2CH2-O-C6H4-F); 93.34 (C-8); 105.38 (C-4'); 106.07 (C-4a); 112.31 (C-3); 113.00 (C-6); 115.60, 115.72 and 115.90 (C-2", C-3", C-5" and C-6"); 139.45 (C-4); 145.97 (C-5'); 148.51 (C-5); 152.04 (C-8a); 154.72 (C-4"); 157.55 (C-7); 158.01 (C-1"); 160.01 (C-2).
IR (KBr): velum’ = 3128, 2954, 1717, 1620, 1508, 1455, 1353, 1213.
MS (EI): m/z (%) = 354 M* (26), 202 [CiiH604r (46), 153 [C10H12OF]* (48), 125 [F-C6H40-CH2r (100), 95 (36), 83 (13), 41 [CgHsr (64).


Melting point: 157 °C
Combustion analysis: C2iH’5F305 (404.35)
calculated: C 62.38 H
3.47
found; C 62.13 H
3.78
‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 2.30 (t, 2H, ‘J = 5.5 Hz, 5-0-
CH2CH2CH2-0-CeH4-CF3); 4.32 (s, 2H, 5-O-CH2CH2CH2-O-C6H4-CF3); 4.67 (s, 2H, 5-O-CH2CH2CH2-O-C6H4-CF3); 6.27 (d, 1H, ‘J = 9.6 Hz, H-3); 7.23-7.33 (m, 5H, H-2", H-4", H-6", H-8 and H-4'); 7.51 (t, 1H, ‘J = 7.7 Hz, H-5"); 8.03 (s, 1H, H-5'); 8.23 (d, IN, ‘J = 10.0 Hz, H-4).
"C-NMR (DMSO-ds, 75 MHz): 5/ppm (TWIS) = 29.08 (5-O-CH2CH2CH2-O-C6H4-CF3); 64.75 and 69.36 (5-O-CH2CH22CH2-O-C6H4-CF3); 93.31 (C-8); 105.44 (C-4'); 106.02 (C’a); 110.93, 110.98, 117.06, 117,06, 130.48 and 130.67 (5-0-CH2(CH2)2CH2-0-C6H4-CF3); 112.26 (C-3); 112.94 (C-6); 118.73 (-CF3); 139.51 (C-4); 145.97 (C-5'); 148.53 (G-5); 152.06 (C-8a); 157.58 (C-7); 158.72 (C-1"); 160.01 (C-2).
IR (KBr): v/cm"‘ = 3126, 2924, 1724, 1622, 1454, 1342, 1242, 1130.
MS (El): m/z (%) = 404 M’ (56), 216 (2), 175 [CizHisOf (100), 145 (56), 127 (12), 89 (14), 41 [CsHsf (84).


Combustion analysis: C24H18O5 (386.41)
calculated: C 74.60 H
4.70
found: C 75.33 H
4.81 ‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 2.43 (quint, 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2-O-C10H7); 4.43 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2-O-C10H7); 4.79 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2-O-C10H7); 6.21 (d, 1H, V = 9.8 Hz, H-3); 7.03 (d, 1H, ‘J = 7.3 Hz, H-2"); 7.34 (s, 1H, H-8); 7.36 (d, 1H, ‘J = 2.2 Hz, H-4'); 7.39-7.53 (m, 4H, 5-O-CH2CH2CH2-O-C10H7); 7.86 (d, 1H, ‘J = 7.9 Hz, H-5"); 8.03 (d, 1H, ‘J = 2.3 Hz, H-5'); 8.14 (d, 1H, ‘J = 8.1 Hz, H-8"); 8.24 (d, 1H, ‘J = 9.8 Hz, H-4).
"C-NMR (DWlSO-ds, 75 MHz): 5/ppm (TMS) = 29.25 (5-O-CH2CH2CH2-O-C10H7); 64.45 and 69.66 (5-0-CH2CH2CHrO-CioH7); 93.32 (C-8); 105.07 (C-2"); 105.39 (C-4'); 106.06 (C-4a); 112.20 (C-3); 113.01 (C-6); 119.73 (C-4"); 121.28 (C-8"); 124.86, 125.03, 126.13, 126.29 and 127.36 (C-3", C-5", C-6", C-7" and C-8a"); 133.95 (C-4a"); 139.39 (C-4); 145,94 (C-5"); 148.55 (C-5); 152.03 (C-8a); 153.84 (C-1"); 157.54 (C-7); 159.97 (C-2).
IR(KBr):v/cm-' = 3126, 2949, 1721, 1622, 1580, 1454, 1351, 1129.

MS (E!): m/z {%) = 333 M" (33), 243 (25>, 215 '24), '35 iO’H.sJr (103). 15" [Ci-HgOr (65). 115 (36), 89 (12), 41 [CsHsf (15).

Combustion analysis: C25H20O5 (400.44)
calculated: C 74.60 H
4.70
found; C 75.11 H
4.81
‘H-NMR {DMSO-de, 300 MHz): 5/ppm (TMS) = 2.35 (quint, 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2-O-C10H7); 4.35 (t, 2H, ‘J = 6.2 Hz, 5-O-CH2CH2CH2-O-C10H7); 4.68 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH26H2-O-C10H7); 6.25 (d, 1H. ‘J = 9.8 Hz, H-3); 7.17 (dd, 1H, ‘J=9.0 Hz, "J = 2.4 Hz, H-3"); 7.30-7.35 (m, 4H, H-B, H-4' and 5-0-CH2CH2CH2-0-CioH7); 7.44 (t, 1H, ‘J = 7.0 Hz, H-7"); 7.76-7.82 (m, 3H, 5-0-CH2CHjCH2-0-CioH7); 8.01 (d, m,’J= 2.2 Hz, H-5'); 8.22 (d. 1H, ""J = 9.8 Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 29.22 (5-O-CH2CH2CH2-O-C10H7); 64.26 and 69.52 (5-O-CH2CH2CH2-O-C10H7); 93.31 (C-8); 105.42 (C-4'); 106.05 (C-4a); 105.80 (C-1"); 112.28 (C-3); 112.96 (C-6); 118.60 (C-3"); 123.53

fC-S"); 125,32 126.51 12"-4. -.25.45 and -2;.27 'Z-A", G-’a". 2-5". 2.7" and C-3"); 154.23 :C-5a",; 139.45 (G-’;; 145.96 (C-5'): '45.52 '0-5); '52.05 :C-8s;; 155.32(0-2"); 157.57 (C-7): 160.02(0-2).
IR (KBr): v/cm'‘ = 3133, 3046, 1720, 1452, 1349, 1130.
MS (EI): m/z (%) = 386 M' (59), 215 (6), 185 [C13H13O]* (100), 157 [CuHi’Ozf (59), 127(41), 89 (8), 41 [CsHsr (8).

Combustion analysis: C22H20O5 (364.40)
calculated: C 72.51 H
5.53
found: C 72.74 H
5.68
‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TMS) = 1.63-1.71 (m, 2H, 5-0-CH2CH2CH2CH2CH2-O-C6H5); 1.77-1.93 (m, 4H, 5-0-CH2CliCH2CH2CH2-0-CeHs); 4.00 (t, 2H, ‘J=6.2 Hz, 5-O-CH2CH2CH2CH2CH2-O-C6H5); 4.52 (t, 2H, ‘J = 6.0 Hz, 5-O-CH2CH2CH2CH2CH2-O-C6H5); 630 (d, 1H, ‘J = 9.7 Hz, H-3); 6.90-6.93 (m, 3H, 5-0- OH2CH2CH2CH2CH2-O-C6H5); 7.25-7.33 (m, 4H, H-8, H-4' and

-1-4).
"C-NMR (DMSO-dB, 75 MHz): 5/ppm (TMS) = 22.02 (5-O-CH2CH2CH2CH2CH2-O-CsHs); 28.31 and 29.01 (5-O-CH2CH2CH2CH2CH2-O-C6H5); 67.06 and 72.49 (5-O-CH2CH2CH2CH2CH2-O-C6H5); 93.20 (C-8); 105.55 (C-4'); 106.04 (C-4a); 112.30 (C-3); 113.01 (C-6); 114.34 (C-3" and C-5"); 120.32 (C-4"); 129.39 (C-2" and C-6"); 139.38 (C-4); 145.88 (C-5'); 148,74 (C-5); 152.08 (C-8a); 157.59 (C-1"); 158.58 (C-7); 160.05 (C-2).
IR (KBr): v/cm'' = 3130, 2946, 2872, 1716, 1602, 1496, 1350, 1242, 1134.
MS (El): m/z (%) = 364 M" (9), 202 [CnHsO’f (22), 163 [CnHisOr (44), 107 [CsHsO-CHzr (40), 69 [CsHsf (100), 41 [CgHsf (52).


'H-Heir (DMSO-ds, 3QC MHz): bipod '"MS) = '.r'-IS; (m. 3H, c-D-CH2CH2CH2CH2CH2-0-C?n4-OCH3): 3.33 (s, 3H, -OCH3;: 3.S3 ‘t. 2K ‘J = 5,1 Hz, S-O-CHjCHzCHzCHzCHj-O-CeHz-OCHj); 4.52 (t, 2n, 'J = 6.2 Hz, 5-0-CHsCHzCHzCHzCHrO-CsH’-OCHs); 6.31 (d, 1H, ‘J = 9.8 Hz, H-3); 6.84 (s, 4H, 5-0-CH2CH2CH2CH2CH2-0-C6H4-OCH3)i 7.32 (d, 1H, -J = 2.3 Hz, H-4'); 7.35 (s, 1H, H-8); 8.03 (d. 1H, ‘J = 2.4 Hz, H-5'); 8.20 (d, 1H, ‘J = 9.8 Hz, H-4).
‘‘C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 22.03 (5-O-CH2CH2CH2CH2CH2-O-C6H4-OCH3); 28.39 und 29.03 {5-0-CH2CH2CH2CH2CHrO-C5H4-OCH3); 55.31 (-OCH3); 64.55 and 69.52 {5-O-CH2CH2CH2CH2CH2-O-CSH4-OCH3); 93.24 (C-8); 105.57 (C-4'); 106.08 (C-4a); 112.34 (C-3); 113.05 (C-6); 114.54 and 115.26 (C-2", C-3", C-5" and C-6"); 139.42 (C-4); 145.91 (C-5'); 148.77 (C-5); 152.10 (C-8a); 152.61 and 153,22 (C-l" and C-4"); 157.61 (C-7); 160.08 (C-2).
IR (KBr):v/cm-' = 3123, 2932, 2866, 1725, 1628, 1508, 1457, 1343, 1232, 1130.





■■H-NMR (DMSO-de, 300 MHz): 5/ppnn (TMS) = 1.52-1.57 (m, 2H, 5-0-CH2CH2CH2CH2CH2-0-C6H4-N02); 1.66-1.68 (m, 4H, 5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 4.17 (s, 2H, 5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 4.52 (s, 2H, 5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 6.32 (d, 1H, "J = 9.9 Hz, H-3); 7.14 (d, 2H, ‘J = 7.7 Hz, 5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 7.32 (s, 2H, H-8 and H-4'); 8.02 (s, 1H, H-5'); 8.17-8.20 (m, 3H. H-4 and 5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2).
‘‘C-NMR (CDCI3, 75 MHz): 5/ppm (TNIS) = 22.66 (5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 28.78 and 29.76 (5-O-CH2CH2CH2CH2CH2-O-C6H4-NO2); 68.47 and 72.66 (5-0-CH2CH2CH2CH2CH2-0-C6H4-N02)i 94.02 (C-8); 105.06 (C-4'); 106.80 (C-4a); 112.68 (C-3); 113.35 (C-6); 114.39 (C-2" and C-6"); 125.95 (C-3" and C-5"); 139.18 {C-4); 141.54 (C-4"); 144.89 (C-5'); 148.91 (C-5); 152.75 (C-8a); 158.29 (C-7); 161.13 (C-2); 164.00 (C-1").
IR (KBr): vicm'' = 3126, 2959, 1729, 1594, 1507, 1339, 1264,
MS (Ei): m/z (%) = 409 M* (19), 202 [CiiH604r (58), 174 [202-00}* (21), 152 [O2N-C6H4O-CH2]* (17), 69 (100), 41 [Chars (79).


Wetting point: '25.5 '"Z
Combustion analysis: CZ2H19CIO5 (398.85)
calculated: C 66.25 H
4.80
found: C 66.62 H
4.91 ‘H-NMR (DWISO-de, 300 MHz): 5/ppm (TMS) = 1 58-1,68 (m, 2H, 5-0-CH2CH2CH2CH2CH2-O-C6H4-CI); 1.75-1.92 (m, 4H, 5-O-CH2CH2CH2CH2CH2-O-CfiH’-Cl); 3.99 (t, 2H, ‘J = 6.3 Hz, 5-O-CH2CH2CH2CH2CH2-O-C6H4-CI); 4.50 (t, 2H, ‘J = 6.2 Hz, 5-0-CH2CH2CH2CH2CH2-0-C6H4-Ci); 6.30 (d, 1H, ‘J = 9.8 Hz, H-3); 6.92-6.95 (m, 2H, 5-0-CH2CH2CH2CH2CH2-0-C6H4-CI); 7.28-7.32 (m, 4H, H-8, H-4' and 5-0-CH2CH2CH2CH2CH2-0-C6H4-CI); 8.01 (d, 1H, ‘J = 2.3 Hz, H-5');8.17(d, 1H, ‘J=9,8Hz, H’).
"C-NMR (DMSO-Qfe, 75 MHz): 5/ppm (TWS) = 21.93 (5-O-CH2CH2CH2CH2CH2-O-CBHA-CI); 28.17 and 28.96 (5-O-CH2CH2CH2CH2CH2-O-C6H4-CI); 67.59 and 72.43 (5-O-CH2CH2CH2CH2CH2-O-C6H4-CI); 93.16 (C-8); 105.53 (C-4"); 106.00 (C-4a); 112.27 (C-3); 112.97 (C-6); 116.09 (C-2" and C-6"); 123.99 (C-4"); 129.11 {C-3" and C-5" ); 139.34 (C-4); 145.84 (C-5'); 148.70 {C-5); 152.06 (C-8a); 157.42 (0-7); 157.57 (C-1"); 160.03 (C-2).
!R (KBr): v/cm"' = 3155, 2940, 1719, 1622, 1579, 1451, 1350, 1246.
MS (El): m/z (%) =-398 M" (10), 197 [CiiHi40Cir (30), 174 (11), 141 [CI-G6H4O-CH2Y (22), 111 (10), 69 [CsHg]" (100), 41 [CsHsf (50).


Combustion analysis: C28H24O6 (456.50)
calculated: C 73.67 H
5.30
found: C 73.49 H
5.36
‘H-NWIR (DMSO-de, 300 MHz): 5/ppm (TMS) = 1.61-1.68 (m. 2H, 5-0-
CH2CH2CH2CH2CH2-O-C6H4-O-C6H5); 1,77-1.94 (m, 4H, 5-0-
CH2CH2CH2CH2CH2-O-C6H4-O-C6H5); 4.00 (t. 2H, 'j = 6.2 Hz. 5-0-CH2CH2CH2CH2CH2-O-CBH4-O-C5H5); 4.52. (t, 2H, ‘J = 6.2 Hz, 5-0-CH2CH2CH2CH2CH2-O-C6H4-O-C6H5); 6.31 (d, 1H, ‘J = 9.8 Hz, H-3); 6.91-7.00 (m, 6H, -O-C6H4-O-C6H5); 7.07 (t, 1H, ‘J = 7,4 Hz, H’'"); 7.31-7.37 (m, 4H, H-8, H-4' and -O-C6H4-O-C6H5); 8.02 (d, 1H, ‘J = 2.2 Hz, H-5'); 8.18 (d, 1H, ‘J = 9.8 Hz, H-4).
"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 22.01 (5-O-CH2CH2CH2CH2CH2-O-C6H4-O-C6H5); 28,34 and 29.01 (5-O-CH2CH2CH2CH2CH2-O-G6H4-O-C6H5); 67.63 and 72.46 (5-O-CH2CH2CH2CH2CH2-O-C6H4-O-C6H5); 93.16 (C-8); 105.54 (C-4'); 106.01 (C-4a); 112.27 (C-3); 112.97 (C-6); 139.33 (C-4); 145.84 (C-5'); 148.71 (0-5); 152.07 (C-8a); 157.58(0-7); 160.04 (C-2); 115,57, 117.23, 120.58, 122.48, 129.79, 149.28, 154.97 and 157.95 (-O-C6H4-O-C6H5).

iR (K5r): v/c- ' =25’9. 1725, ' f25. -’550, 'S’:. '2_2.
MS (El): m/z (%) = 456 M" (59), 255 (28), -99 (27). 186 (32). 141 (13), 69 [C5H9r(100), 41[C3H5r(65).

Melting point: 83 X
Combustion analysis: C23H22O5 (378.43)
calculated: C 73.01 H
5.86
found: C 73.41 H
6.09
‘H-NMR (DMSO-ds, 300 MHz): 5/ppm (TMS) = 1.64-1.69 (m, 2H, 5-0-CH2CH2CH2CH2CH2-0-C6H4-CH3); 1.75-1.90 (m, 4H, 5-O-CH2CH2CH2CH2CH2-O-C6H4-CH3); 2.51 (s, 3H, -CH3); 3.95 (t, 2H, ‘J = 6.2 Hz, 5-0-CH2CH2CH2CH2Cii-0-C6H4-CH3); 4.51 (t, 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2CH2CH2-O-C6H4-CH3); 6.30 (d, 1H, ‘J = 9.8 Hz, H-3); 6.80 (d, 2H, ‘J = 8.4 Hz, H-3" and H-5"); 7.06 (d, 2H, ‘J=8.2 Hz, H-2" and H-6"); 7.31 (d, 1H, ‘J = 1.6 Hz, H-4'); 7.33 (s, 1H, H-8); 8.02 (d, 1H, ‘J = 2.2 Hz, H-5'); 8.18 (d, 1H, ‘J = 9.8 Hz, H-4).

•"-C-NMR (DM30-ds, 75 MHzi: 5/ppm (IMS) = .9,9: -Ch:. ; 22 JO {5-D-CH2CH2CH2CH2CnrO-C5-;,-CHj;; 2£.32 anc 29,03 (‘-C-CHaC-ijCKsCHzCHz-O-C6H4-CH3); 67.12 and 72.47 (5-0-CH2CH2CH2CH2CH2-0-C6H,-CH3): -93.17 (C-8): 105.54 (C-4'); 105.02 (C-4a); 112.28 (C-3); 112.99 {C-6); 114,15 (C-3" andC-5"); 128.90 (C-4"); 129.69 (C-2" and C-6"); 139.36 (C-4); 145.85 (C-5'); 148.72 (C-5); 152.07 (C-8a); 156.45 (C-1"); 157.58 (C-7); 160.03 (C-2).
IR{KBr):v/cm-' = 3154, 2939, 1722,1625, 1511, 1457, 1345, 1243, 1131.
MS (El): m/z (%) = 378 M* (12), 202 [CnHgO.r (14), 177 [CizHiyOf (53). 121
[CH3-C6H40-CH2r (49), 69 [CsHg]’ (100), 41 [CsHsf (45).

Combustion analysis: C24H24O5 (392.46)
calculated; C 7S.45 H6.16
found; C 73.36
H 6.28
‘H-NMR (DMSO-ds, 300 MHz): 5/ppm (TMS) = 1.14 (t, 3H, ‘J = 7.6 Hz, -CHzCHa); 1.61-1.69 (m, 2H, 5-O-CH2CH2CH2CH2CH2-O-CBH4-CH2CH3); 1.75-1.93 (m, 4H, 5-O-CH2CH2CH2CH2CH2-O-C6H4-CH2CH3); 2.54 (q, 2H, ‘J = 7,5


"C-NMR (DMSO-de, 75 MHz): 5/ppm (TMS) = 15.82 (-CH3); 22.01 (5-0-CH2CH2CH2CH2CH2-O-C6H4-C2H5): 27.21 {-CH2CH3); 28.33 and 29.00 (5-0-GH2CH2CH2CH2CH2-0-C6H4-C2H5); 67.12 and 72.46 (5-O-CH2CH2CH2CH2CH2-O-C6H4-C2H5); 93.15 (C-8); 105.53 (C-4'); 106.00 (C-4a); 112.26 (C-3); 112.97 (C-6); 114.19 (C-3" and C-5"); 128.50 (0-2" and 0-6"); 135.49 (C-4"); 139.34 (0-4); 145.84 (0-5'); 148.71 (0-5); 152.07 (0-8a); 156.63 (0-1"); 157.58 (C-7); 160.03 (0-2).
IR(KBr):v/cm"' = 3150, 2933, 2866, 1721, 1626,1511, 1458, 1344,1241.
MS (El): m/z (%) = 392 M' (13), 191 [CisHisOr (52), 135 [CH3-CH2C6H40-OH2r
(45), "107 [OaHnf (24), 69 [CsHsf (100), 41 [OsHsf (46).



‘H-NMR (DMSO-de, 300 MHz): 5/ppm (TWIS) = 1.60-1.66 (m, 2H, 5-0-CH2CH2CH2CH2CH2-O-C5H4-F); 1.76-1.91 (ITK 4H, 5-0-CH2CH2CH2CH2CH2-0-C6H4-F); 3.96 (t, 2H, ‘J = 6.2 Hz, 5-0-CH2CH2CH2CH2CH2-0-C6H4-F); 4.50 (t, 2H, ‘J = 6.2 Hz, 5-O-CH2CH2CH2CH2CH2-O-C6H4-F); 6.29 (d, 1H, 'J = 9.8 Hz, H-3); 6.89-6.95 (m, 2H, 5-O-CH2CH2CH2CH2CH2-O-CSH4-F); 7.04-7.12 (m, 2H, S-O-CHZCHZCHZCHZCHZ-O-CSHA-F); 7.29 (d, 1H, ‘J = 2.3 Hz, H-4'); 7.31 (s, 1H, H-8); 8.01 (d, 1H, ‘J=2.3 Hz, H-5'); 8.17 (d, 1H, ‘J= 9.8 Hz, H-4).
"C-NWIR (DMSO-ds, 75 MHz): 5/ppm (TMS) = 21.97 (S-O-CHzCHzCHzCHzCHr O-C6H4-F); 28.27 and 28.99 {5-O-CH2CH2CH2CH2CH2-O-C6H4-F); 67.78 and 72.44 (5-O-CH2CH2CH2CH2CH2-O-C6H4-F); 93.15 (C-8); 105.53 (C-4'); 105.99 (C-4a); 112.27 (C-3); 112.96 (C-6); 115.49, 115.52, 115.59 and 115.83 (C-2", C-3', C-5" and C-6"); 139.33 (C-4); 145.84 (C-5'); 148.70 (C-5); 152.06 (C-8a); 154.77 (C-4"); 157.58 (C-7); 157.89 (C-1"); 160.03 (C-2).
IR (KBr): v/cnT' = 3136, 2944, 2872, 1720, 1626, 1504. 1452, 1351, 1134.
MS (El): m/z (%) = 382 M' (8), 202 [CiiH604f (21), 181 [CizHieOFf (37), 125 [F-C6H40-CH2r (30), 69 [CsHgf (100), 41 [CsHsf (42).


Melting point: 103 "C
Combustion analysis: C26H22O5 (414.46)
calculated: C 75.35 H 5.35
found: C 75.56 H 5.43
‘H-NMR {DMSO-ds, 300 MHz): 6/ppm (TMS) = 1.71-1.81 (m, 2H, 5-0-CH2CH2CH2CH2CH2-0-CnciH7); 1.89-2.00 (m, 1H, 5-O-CH2CH2CH2CH2CH2-O-C10H7); 4.18 (t 2H, ‘J = 6.1 Hz, 5-0-CH2CH2CH2CH2CH2-0-CioH7): 4.54 (t, 2H, 'j = 6.0 Hz, 5-O-CH2CH2CH2CH2CH2-O-C10H7); 6.21 (d, 1H, ‘J=9.8 Hz, H-3); 6.94 (d, 1H, ‘J = 7.2 Hz, H-2"); 7.30 (s, 2H, H-8 and H-4'); 7.36-7.53 (m, 4H, 5-O-CH2CH2CH2CH2CH2-O-C10H7); 7.84 (d, 1H,’J = 7.7 Hz, H-5"); 8.00 (d, 1H, ‘J = 2.2 Hz, H-5'); 8.14 (d, 1H, ‘J = 8.0 Hz. H-8"); 8.16 (d, 1H, ‘J = 9.8 Hz, H-4).
‘‘C-NMR (DMSO-rfs, 75 MHz): 6/ppm (TMS) = 22.23 (5-O-CH2CH2CH2CH2CH2-O-C10H7); 28.33 and 29.05 {5-O-CH2CH2CH2CH2CH2-O-C10H7); 67.48 and 72.43 (5-0-CH2CH2CH2CH2CH2-0-CioH7); 93.12 (C-8); 105.01 (C-2"); 105.57 (C-4'); 105.93 (C-4a); 112.20 (C-3); 112.89 (C-6); 119.69 (C-4"); 121.35 (C-8"); 124.91, 125.08, 126.17, 126.30 and 127.39 (C-3", C-5", C-6", C-7" and C-8a"); 133.97 (C-4a"); 139.30 (C-4); 145.82 (C-5'); 148.73 (C-5); 152.07 (C-8a); 154.02 (C-l"); 157.60 (C-7); 160.02 (C-2).
IR (KBr): v/cm"‘ = 2946, 2870, 1733, 1591, 1458, 1345.

■ MS (E!): m/z (%) = 4-4 f’’" (32): 2"-: (IB,, 213 [C:iH-:-:DY '54), U’ (58; r
Combustion analysis: C26H22O5 (414.46)
calculated; C 75,35 H 5.35
found: C 75.00 H 5.52
‘H-NMR (DWJSO-de, 300 MHz): 5/ppm (TMS) = 1.66-1.75 (m, 2H, 5-0-CH2CH2CH2CH2CH2-O-C10H7); 1.84-1.96 (m, 1H, 5-O-CH2CH2CH2CH2CH2-O-CIDH-); 4.14 (t, 2H, ‘J = 6.3 Hz, 5-0-CH2CH2CH2CH2Cil2-0-CioH7); 4.53 (t, 2H, ‘J = 6.1 Hz, 5-O-CH2CH2CH2CH2CH2-O-C10H7); 6.31 (d, 1H, ‘J = 9.8 Hz, H-3); 7.15 (dd, 1H, ‘J = 8.9 Hz, "J = 2.4 Hz, H-3"); 7.31-7.36 (m, 4H, H-8, H-4' und 5-O-CH2CH2CH2CH2CH2-O-C10H7); 7.45 (t, 1H, ‘J=7.2 Hz, H-7"); 7.77-7-82 (m, 3H, 5-O-CH2CHZCH2CH2CH2-O-C10H7); 8.02 (d, 1H, ‘J = 2.3 Hz, H-5'); 8.20 (d, 1H,’J = 9.8Hz, H-4).




500 mg (2.473 mmol) of 5-hydroxypsoralen and 893 mg (4.088 mmol) of 4-iodo-1-chlorobutane were stirred at 25°C in 30 ml of anhydrous acetone in the presence of an excess (2.0 g) of anhydrous potassium carbonate for 28 hours. The progress of the reaction was monitored by thin layer chromatography. After 28 hours the reaction mixture was concentrated under reduced pressure and distilled off the solvent almost completely. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and filtered. The solids were washed with water to neutral pH and dried. The dried solids were suspended in petroleum ether, filtered and dried under vacuum. To the solids were added 400 mg (5.875 mmol) of pyrazole, 2.0 g anhydrous potassium carbonate, catalytic amounts of potassium iodide, 30 ml of 2-butanone and the

pH 1 with concentrated hydrochloric acid. The separated oily organic layer was extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was then washed with 0.75% aqueous sodium hydroxide to separate the un-reacted 5-hydroxypsoraien followed by washing with acidic water. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in an acetone-methanol mixture, treated with charcoal and re-crystallized from an ethyl acetate-petroleum ether (20:80) mixture.
Yield: 108.6 mg (13.54%)
Melting point: 145.6°C
‘H-NMR (500 MHz, DMSOKie): 5 [ppm] = 8.17 (d, 1H, ‘J= 9,1 Hz, 3-H), 8.02 (s,
1H, 2'-H), 7.74 (s, 1H, 5-OCH2CH2CH2CH2C3H3N2), 7.43 (s, 1H, 5-OCH2CH2CH2CH2-C3H3N2). 7.34 (s, 1H, 8-H), 7.29 (s, 1H, 3'-H), 6.32 (d. 1H, ‘J = 9.1 Hz, 4-H), 4.47 (s, 2H, 5-OCH2CH2CH2CH2C3H3N2), 4.20 (s, 2H, 5-OCH2CH2CH2CH2C3H3N2). 2.0 (s, 2H, 5-OCH2CH2CH2CH2C3H3N2), 1.75 (s, 2H, S-OCHzCHsCHsCHsCgHsNz).
MS (70 eV) m/z : 324 (29%, M’), 202 (6%, [M-doHiaOD, 174 (6%, [202-COn. 123 (99%), 81 (26%), 69 (13%).
Combustion analysis: (FW: 324.34) %C 65.83, %H 4.96, %N 7.36
(Calc. %C 66.66, %H 4.97, %N 8.64)



390 mg (1.334 mmol) of 5-(4-ch!orobutoxy)psoralen and 628 mg (6.67 mmol) of 4-aminopyridine were refluxed in 20 ml of anhydrous acetonitrile in the presence of catalytic amounts of potassium iodide for 45 hours. The progress of the reaction was monitored by thin layer chromatography. After 45 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled, diluted with water arxi acidified with 10% aqueous hydrochloric add to pH 7-7.5. The slurry was stirred for 15-20 min and filtered. The solids were dissolved in methanol, treated with charcoal and re-crystallized from 2% acidic acetone.
Yield: 171.5 mg (30.37%)
Melting point: 133.9°C
‘H-NMR (500 MHz, DMSO-dg): 5 [ppm] = 8.272 (s, 1H, 5-OCH2CH2CH 2CH2NHC5H4N), 8.25 (d, 2H, ‘J = 7.41 Hz, 5-OCH2CH2CH 2CH2NHC5H4N), 8.18 (d, 1H, 'j = 9.8 Hz, 3-H). 8.05 (d, 1H, ‘J=2.6 Hz, 2'-H), 7.36 (s, 1H, 8-H), 7.33 (d, 1H, ‘J = 2.3 Hz, 3’H), 6.85 (d, 2H, ‘J = 7.32 Hz, 5-OCH2CH2CH 2CH2NHC5H4N), 6.32 (d, 1H, ‘J = 9.8 Hz, 4-H), 4.514 (t, 2H, 'J = 6.06 Hz, 5-OCH2CH2CH 2CH2NHC5H4N), 4.22 (t, 2H. ‘J = 6.98 Hz, 5-OCH2CH2CH 2CH2NHC5H4N), 1.99 (p, 2H, 5-OCH2CH2CH2CH2NHe5H4N), 1.77 (p, 2H, 5-OCH2CH2CH 2CH2NHC5H4N).

WrS (j: eV) m/2 ; 350 ('2%, I/'";. 202 ;&?7: [M-C.H,2Ki"). "‘ (60%, [201-COf). 154 (20%). 145 (11%;, 120 (15%). 107 ',’5%), 94 (7%. Cessna).
Combustion analysis: (FW: 423.38) %C 55.69. %H 4.S4, %Ni 6.3S
(Calc. %C 56.68, %H 4.72, %N 5.61)

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen and 361 mg (2.733 mmol) of 2-mercapto-1,3,4-thtadia2ole were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (2.0 gm) and catalytic amounts of potassium iodide for 66 hours. The progress of the reaction was monitored by thin layer chromatography. After 66 hours the reaction mixture was concentrated under reduced pressure and distilled off the solvent almost completely. The oily residue was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 100 ml of dichloromethane. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated. The oily residue obtained was dissolved in methanol, treated with charcoal and re-crystallized from a petroleum ether-ethyl acetate (80:20) mixture.
Yield: 107 mg (16.13%)

Melting point: 92/°C
'H-NMR (500 MHz, CDCb): 5 Ipprr,] - 8.15 (d. 1H, 'j ‘ 9.79 Kz, 3-H)’ 7.59 (d, 1H, "j = 2.48 Hz, 2'-H), 7.16 (s, 1H, 8-H). 6.95 (d, 1H, ‘J = 2.45 Hz, 3'-H), 6.29 (d, 1H, ‘J = 9.76 Hz, 4-H). 4.51 (t 2H, ‘J = 5.81 Hz, 5-OCH2CH2CH2CH2S-), 3.43 (t, 2H, ‘J ‘ 6.88 Hz, 5-OCH2CH2CH2CH2S-), 2.74 (s. 3H, S'XHs), 2.09 (m, 4H, ‘J = 3.00 Hz, 5-OCH2CH2CH2CH2S-).
MS (70 eV) m/z : 388 (62%, M’), 202 (14%.. {M-C7HioN2S2r). 187 (96%, C7H11N2S2), 174 (12%, [202-COf ), 145 (10%), 133 (32%). 99 (34%, CSH3N2S), 87 (8%, C4H7S), 55 (28%, C4H7).
Combustion analysis: (FW: 388.47) %C 53.44, %H 4.45, %N 7.59. %S 16.77
(Calc. %C 55.65, %H 4.15, %,N 7.21, %S 16.51)

500 mg (1.708 mmol) of 5-(4-chiorobutoxy)psoralen and 443 mg (2.733 mmol) of 7-hydroxycoumarin were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (2.0 g) and catalytic amounts of potassium iodide for 68 hours. The progress of the reaction was monitored by thin iayer chromatography. After 68 hours the reaction mixture was concentrated under reduced pressure. The oiiy residue was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3 x 50 ml of dichloromethane. The dichloromethane layer was extracted with 3 x 25 ml of 1% sodium hydroxide to separate the un-reacted 7-hydroxycoumarin. The dichloromethane layer was wgshed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate


Yield: 134.0 mg (18.75%) Melting point: 147°C
‘H-NWIR (500 MHz, CDCI3): 5 [ppm] = 8,15 (d, 1H, ‘J= 9.80 Hz, 3-H), 7.64 (d, 1H, ‘J = 9.5 Hz, 5-OCH2CH2CH2CH2OC9H5O2), 7.61 (d, IN, ‘J = 2.1 Hz, 2'-H), 7.36 (dd, 1H, ‘J = 8.6 Hz. ‘J = 2.5 Hz, 5-OCH2CH2CH2CH2OC9H5O2), 7.16 (s, 1H, 8-H), 6.99 (d, 1H, ‘J = 2.1 Hz, 3'-H), 6.83 (m, 2H, 5-OCH2CH2CH2CH2OC9H5O2), 6.26 (d, 1H, ‘J = 9.50 Hz, 4-H), 6.20 (d, 1H, ‘J = 9.8 Hz, 5-OCH2CH2CH2CH2OC9H5O2), 4.57 (t, 2H, ‘J = 5.4 Hz, 5-OCH2CH2CH2CH2OC9H5O2), 4.15 (t, 2H, ‘J = 5.0 Hz, 5-OCH2CH2CH2CH2OC9H5O2), 2.11 (m, 4H, ‘J = 2.6 Hz, 5-OCH2CH2CH2CH2OC9H5O2).
MS (70 eV) m/z : 418 (34%, M*), 378 (68%), 217 (89%), 202 (20%, [M-
CiaHizOsD, 175 (100%), 174 (14%, [202-00]"), 187 (16%), 145 (32%), 134 (26%), 89 (30%), 55 (48%, C4H7).
Combustion analysis: (FW: 418.41) %C 69.08, %H 4.46.
(Calc. %C 68.90, %H 4.34)

539 mg (2.733 mmol) of 2-mercapto-5-methoxy-1,3-benzothiazole and 161 mg (2.869 mmol) of potassium hydroxide were refluxed in 25 ml of methanol until a

was monitored by thin layer chromatography. After 69 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1- The slurry was stemmed for 15-20 min and extracted with 100 m! of dichloromethane. The dichloromethane layer was washed with 30 ml of 1% sodium hydroxide to separate the un-reacted 2-mercaptobenzothiazole followed by 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting oily residue was dissolved in methanol, treated with charcoal and re-crystallized from a petroleum ether-acetone (80:20) mixture.
Yield: 599.8 mg (77.09%)
Melting point: 134.8°C.
'H-NMR (500 MHz, CDCI3): 5 [ppm] = 8.09 (d, 1H, ‘J - 9.76 Hz, 3-H), 7.61 (d, 1H, ‘J = 8.9 Hz benzothiazole), 7.58 (d, 1H, 'j = 2.24 Hz’ 2'-H), 7.35 (d, 1H, ‘J = 2.2 Hz, benzothiazole), 7.14(s, 1H. 8-H). 6.97 (dd, 1H, ‘J = 8.9 Hz, ‘J = 2.1 Hz. benzothiazole), 6.95 (d, 1H, ‘J=2J6 Hz, 3'-H), 6.18 (d, 1H, ‘J = 9.78 Hz. 4-H). 4.53 (t 2H, ‘J = 5.78 Hz, 5-OCH2CH2CH2CH2S-), 3.87 (s, 3H, O-CH3), 3.48 (t, 2H, ‘J=6.61 Hz, 5-OCH2CH2CH2CH2S-), 2.11 (m, 4H, 5-OCH2CH2CH2CH2S-).
MS (70 eV) m/z: 455 (6%. M"), 453 (44%), 328 (28%), 252 (100%, C12H14NOS2),
201 (6%), 196 (12%, CeHeNOSs), 174 (14%, [202-00]" ), 145 (8%), 89 (6%), 55 (28%, C4H7).
Combustion analysis: (FW: 455.56) %C 60.70, %H 4.49, %N 3.09, %S 13.94
(Calc. %C 60.70, 7oH 4:65, %N 3.07, %S 14.08


306 mg (2.733 mmol) of 2-mercaptopyrimidine and 163 mg (2.87 mmol) of potassium hydroxide were refluxed in 50 ml methanol until a clear solution was obtained. The solution was concentrated to dryness under reduced pressure. To the solid potassium salt was then added 30 ml of anhydrous acetonitrile, 500 mg (1.708 mmol!) of 5-(4-chlorobutoxy)psoriases, 333 mg (2.220 mmol) of sodium iodide and the resulting mixture was refluxed for 67 hours. The progress of the reaction was monitored by thin layer chromatography. After 67 hours the reaction mixture was concentrated unclear focused pressure and distilled off the solvent almost completely. The oily residue was cooled and diluted with water and then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 100 ml of dichloromethane. The dichloromethane layer was washed with 30 ml of 1% sodium hydroxide to separate the un-reacted 2-mercaptopyrimidine followed by 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The oily residue was dissolved in methanol, treated with charcoal and re-crystallized from methanol.
Yield: 244 mg (38.78%)
Melting point: 107-107.1°C
‘H-NMR {500 MHz, CDCI3): 5 [ppm] = 8.51 (d, 2H; pyrimidine), 8.14 (d, 1H, 'J = 10.1 Hz, 3-H), 7.59 (d, 1H, ‘J = 2.4 Hz, 2'-H), 7.16 (s, 1H, 8-H), 7,0 (t, 1H, ‘J = 4.89 Hz, pyrimidine), 6.96 (d, 1H, ‘J = 1.5 Hz, 3'-H), 6.25 (d, 1H, ‘J = 9.8 Hz, 4-

H). 4.52 :: 2H. ‘J = 5.5 Hz, 5--D::i2CH.CH2G-.’S-: 1.29 {i 2'H., "‘=5.: -Iz. 5-OCH2CH2CH2C’S-). 2.01 (m, 4r. S-OCH2CH2C-i2Cn25-).
MS (70 eV) m/2 : 358 (27%, M’), 202 (8%, M-CBH10N2S), 167 (100%, C6Hi-;N2S), 125 (34%). 113 (37%), 55 (26%, C4H7).
Combustion analysis: (FW: 368.41) %C 61.55, %H 4.24, %N 7.41, %S 8.46
(Calc. %C 61.94, %H 4.38, %N 7.60, %,S 8.70)

800 mg (3.956 mmo!) of 5-hycIroxypsoralen and 0.7 mt (655.5 mg, 6.33 mmol) of 4-chlorobutyronitrile were refluxed in 50 ml of 2-butanone in the presence of an excess (2.6 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 48 hours. The progress of the reaction was monitored by . thin layer chromatography. After 48 hours the reaction mixture was concentrated under reduced pressure. The residual oily layer was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and then filtered. The solids were washed with water to neutral pH, dried by suction and then further washed with petroleum ether. The dried solids were dissolved in refluxing methanol, treated with charcoal and recrystallized from methanol.
Yield: 710.2 mg (66.67%) Melting point: 155.2°C




Yield: 295.2 mg (34.27%)
Melting point: Ize.l’'C
‘H-NMR (500 MHz, CDCI3): 6 [ppm] = 8.13 (d, 1H, ‘J = 9.9 Hz, 3-H), 8.01 (d, 2H, ‘J = 7.9 Hz, -"J- 0.95 Hz, 2'-H, 6"-H), 7.62 (t, 1H, ‘J = 7A Hz, 3"-H, 5"-H), 7.60 (d, 1H, ‘J = 2.4 Hz, 2'-H), 7.50 (t, 2H, ‘J=7.7 Hz, 4"-H). 7.15 (5, 1H. B-H), 6.99 (d, 1H, ‘J=2.5 Hz, 3'-H), 6.26 (d, 1H, ‘J = 9.8 Hz, 4-H) 4.59 (t, 2H, ‘J = 6.2 Hz, 5-OCJdzCHzCHsCOCsHs), 3.28 (t, 2H, ‘J = 6.8 Hz, S-OCHiCHsCHzCOCeHs), 2.38 (p, 2H, ‘J = 6.5 Hz. 5-OCH2CH2CH2COC6H5).
MS (70 eV) m/2 : 348 (347o. M’), 202 (5%, M'-CioHioO), 147(99%, C-,oHioO), 174, (5%, [202-COf). 105 (71%, CaHg), 77 (33%, C5H5).
Combustion analysis: (FW: 348.36) %C 71.68. %H 5.25
(Calc.%C 72.41. %H 4.63)
Example 55 5-(4-Pentvnvloxv)P5oraien (AP1)
4-(4-Pentynyloxy)-7H-furo[3,2-g][1]benzopyran-7-on































What is claimed is;
1. A composition of matter comprising a compound having the formula:

Wherein;
n is 1 through 10, cyclic or acyclic and optionally substituted or unsubstituted;

R1 is aryl, heterocydyi or cydoalkyl and is optionally substituted with one or more substituents selected from alkyl, alkoxy, amino and its alkyl derivatives, acylamino, carboxy and its alkyl ester, cyano, halo, hydroxy, nitro and sulfonamide groups.
2. A composition according to Claim 1 wherein the compound comprises 4-
(4-Phenoxybutoxy)-7/-/-furo[3,2-g][1]benzopyran-7-on.
3. A composition according to Claim 1 herein the compound comprises 4-
(3-Phenoxypropoxy>-7H-furo[3,2-g][1]benzopyran-7-on.


5. A composition according to Claim 1 wherein the compound comprises 4-(4-Benzyioxybutoxy)-7H-furo[3,2-g][1]ben2opyran-7-on.
6. A composition according to Claim 1 wherein the compound comprises 4-(3-Benzyloxypropoxy)-7/-/-furo[3,2-gj[1]benzopyran-7-on.
7. A composition according to Claim 1 wherein the compound comprises 4-
(4-Ch!orobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
8. A composition according to Claim 1 wherein the compound comprises 4-
(4-{2"-Methoxy-4'-nitrophenoxy}butoxy)-7H-furo[3,2-g][1)benzopyran-7-on.
9. A composition according to Claim 1 wherein the compound comprises 4-
(4-{4"-Methyl-2"-nitrophenoxy}butoxy}-7H-furo[3.2-g][1]ben2opyran-7-on.
10. A composition according to Claim 1 wherein the compound comprises 4-(4-{2"-Nitrophenoxy}butoxy)-7W-furo{3,2-g][1]benzopyran-7-on.
11. A composition according to Claim 1 wherein the compound comprises 4-(4-{3"-Nitrophenoxy}butoxy)-7/-/'furoI3,2-g][1]benzopyran-7-on.
12. A composition according to Claim 1 wherein the compound comprises 4-
(4-{2",4"-Dinitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.

13. A composition according :o Clair: 1 wherein the compound comprises (4’[4-Methoxyphenoxylbutcxy)-7h'-furo[32-g][1]benzopyran-7-on
14. A composition according to Claim 1 wherein the compound comprises 4-(4-[3-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]ben2opyran-7-on
15. A composition according to Claim 1 wherein the compound comprises 4-(4-[3,5-Dimethoxyphenoxy]butoxy)-7/-/-furo[3,2-g][1]benzopyran-7-on
16. A composition according to Claim 1 wherein the compound comprises 4-(4-[4-Nitrophenoxy]butoxy)-7/-/-furo[3,2-g]{1]benzopyran-7-on.
17. A composition according to Claim 1 wherein the compound comprises 4-(4-[4-Chlorphenoxy]butoxy)-7/-/-furo[3,2-g][1]benzopyran~7-on.
18. A composition according to Claim 1 wherein the compound comprises 4-(4-[4.phenoxyphenoxy]butoxy)-7W-furo[3..2-gJ[1]benzopyran-7-on.
19. A composition according to Claim 1 wherein the compound comprises 4-(4-[4-l\/lethyiphenoxy]butoxy)-7/V-furo[3,2-g][1]ben2opyran-7-on.
20. A composition according to Claim 1 wherein the compound comprises 4-{4-[4-Ethylphenoxy]butoxy)-7H-furo[3 2-g][1]benzopyran-7-on.
21. A composition according to Claim 1 wherein the compound comprises 4-{4-[4-Fiuorphenoxy]butoxy)-7H-furo{3,2-g][1]benzopyran-7-on
22. A composition according to Claim 1 wherein the compound comprises 4-(4-[3-TrifluonDethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.

23. A composition according to Clair; ': the compound composes 4-(4-[1-Naphthylox>']butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
24. A composition according to Claim 1 herein the compound comprises 4-(4-[2-Naphthyloxy]butoxy)-7’/-furo[3,2-g][1]benzopyran-7-on.
25. A composition according to Claim 1 wherein the compound comprises 4-[3-(4-Methoxyphenoxy)propoxy]-7/-/-furo[3,2-g][1]benzopyran-7-on.
26. A composition according to Claim 1 wherein the compound comprises 4-[3-(3-Methoxyphenoxy)propoxy]-7f/-furo{3,2-g][1]benzopyran-7-on.
27. A composition according to Claim 1 wherein the compound comprises 4-
[3-(3,5-Dimethoxypheno>cy)propoxy]-7H-furo[3,2-g][1]ben2opyran-7-on.
28. A composition according to Claim 1 wherein the compound comprises 4-[3-(4-Nitrophenoxy)propoxy]-7H-furo[3,2-g]t1]benzopyran-7-on.
29. A composition according iso Claim 1 wherein the compound comprises 4-[3-(4-Chlorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
30. A composition according to Claim 1 wherein the compound comprises 4-[3-(4-Phenoxyphenoxy)propoxy]-7/T'-furo[3,2-g][1]benzopyran-7-on,
31. A composition according to Claim 1 herein the compound comprises 4-[3-(4-Methylphenoxy)prQpoxyl-7/-/-furo[3,2-g][1]benzopyran-7"On.

-Etny!phe’o>‘';DropoxyV7’7'-fJ'D[3,2-7][1]D5’2op/’a--7-D’.
33. A composition according to Claim 1 wherein the compound comprises 4-[3-(4-Fluorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
34. A composition according to Claim 1 wherein the compound comprises 4-[3-(3-Triftuomnethylphenoxy)propoxy]-7H-furo[3,2-g][1]ben2opyran"7-on.
35. A composition according to Claim 1 wherein the compound comprises 4-[3-(1-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
36. A method according to Claim 31 wherein the compound comprises 4-[3-(2-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]ben2opyran-7-on.
37. A composition according to Claim 1 wherein the compound comprises 4-
(5-Phenoxypentoxy)-7W-furo[3,2-g][1]benzopyran-7-on
38. A composition according to Claim 1 wherein the compound comprises 4-[5-(4-Methoxyphenoxy)pentoxy]-7H"furo[3,2-g][1]benzopyran-7-on
39. A composition according to Claim 1 wherein the compound comprises 4-[5-(3,5-Dimethoxyphenoxy)pentoxy]-7H-furo[3,2-g)[1]ben2opyran-7-on.
40. A composition according to Claim 1 'herein the compound comprises 4-[5-(4-Nitrophen6xy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
41. A composition according to Claim 1 wherein the compound comprises 4-[5-(4-Chlorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on


43. A composition according to Claim 1 wherein the compound comprises 4-[5-(4-Methylphenoxy)pentoxy]-7H-furo[3,2-gl[1]benzopyran-7-on.
44. A composition according to Claim 1 wherein the compound comprises 4-[5-{4-Ethylphenoxy)pentoxy]-7W-furo[3,2-g][1]benzopyran-7-on.
45. A composition according to Claim 1 wherein the compound comprises 4-[5-(4-Fluorphenoxy)pentoxy]-7/-/-furo[3,2-g][1]benzopyran-7-on.
46. A composition according to Claim 1 wherein the compound comprises 4-[5-(1-Naphthyloxy)pentoxy]-7H-furo[3.2-g][1]benzopyran-7-on.
47. A composition according to Claim 1 wherein the compound comprises 4-[5-(2-Naphthyloxy)pentoxy]-7H-furo[3,2-g}[1]benzopyran-7-on.
48. A composition according to Claim 1 wherein the compound comprises 4-{4-(1-N-Pyra2oiyi)butoxy}-7/’-furo[3,2-g][13benzopyran-7-on.
49. A corfiposition according to Claim 1 wherein the compound comprises 4-{4-(4-N~Pyridinyl)aminobutoxy}-7/-/-furo[3,2-g][1]benzopyran-7-on.
50. A composition according to Claim 1 wherein the compound comprises 4-{4-(5"-Methy!-r\3",4"-thiadiazol-2"-thioiy!) butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
51. A composition according to Claim 1 wherein the compound comprises 4-{4-(7-Coumarinyloxy)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.


52. ‘ c;
{4-(5-Kte:hcxy-1,3-benzoth;azo--2-tnio[y:)botch)'}-7'---furof3.2-g][1]Denr3"y’’ on.

53. A composition according to Claim 1 wherein the compound comprises 4-{4-(Pyrimidin-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
54. A composition according to Claim 1 wherein the compound comprises 4-(3-Cyanopropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
55. A composition according to Claim 1 wherein the compound comprises 4-(4-Phenyl-3-oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.

56. A composition according to Claim 1 wherein the compound comprises 4-(4-Pentynyloxy)-7H-furo[3,2-’l1]benzopyran-7-on.
57. A composition according to Claim 1 wherein the compound comprises 4-[4-(N-Phthalimide)butoxy]-7/-/-furo[3,2-g][1]benzopyran-7-on.
58. A method for treating or preventing, in a human or animal subject, a
disease or disorder that can be treated or prevented by inhibition of potassium
channels, said method comprising the step of administering to the subject, in
an amount and form that is effective to treat or prevent the disease or
disorder, a composition of matter comprising a compound having the formula:
R1


wherein;

General Formula 1



R1 is aryl. heterocyciyi or cycloalkyi and is optionally substituted with one or more substituents selected from alkyd, alkoxy, amino and its alky! derivatives, acylamino, carboxy and its alkyI ester, cyano, halo, hydroxy, nitro and sulfonamide groups;
or a pharmaceutically acceptable salt or derivative of said compound.
59. A method according to Claim 58 wherein the disease or disorder is a T cell mediated autoimmune disease or disorder.
60. A method according 59 wherein the compound inhibits Kv1.3 channels.
61. A method according to Claim 60 wherein the compound has a substantially greater affinity for inhibition of Kv1.3 than for inhibition of K'vf.5 channels.
62. A method according to Claim 60 wherein the subject does not suffer from atrial fibrillation and wherein the compound inhibits Kv1.3 channels sufficiently to treat or prevent the disease or disorder but does not inhibit Kv1,5 channels sufficiently to cause cardiac arrhythmias.
63. A method according to Claim 61 wherein the compound has an affinity for inhibition of Kv1.3 channels that is at least 10 times greater than its affinity for inhibition of channels.

34
65. A method according to Claim 60 wherein the compound is administered parenterally.
66. A method according to Claim 60 wherein the compound is administered topically.
67. A method according to Claim 58 wherein the compound comprises 4-(4-Phenoxybutoxy)-7W-furo[3,2-g][1]benzopyran-7-on.
68. A method according to Claim 58 wherein the compound comprises 4-(3-Phenoxypropoxy)-7W-furo[3,2-gJ[1]ben2opyran-7-on.
69. A method according to Claim 58 wherein the compound comprises 4-(2-
Benryloxyethoxy)-7H-furo[3,2-g]{1]benzopyran-7"Cn.
70. A method according to Claim 58 wherein the compound comprises 4-(4-Benzy(oxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
71. A method according to Claim 58 wherein the compound comprises 4-(3-Benzyloxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
72. A method according to Claim 58 wherein the compound comprises 4-(4-Chlorobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
73. A method according to Claim 58 wherein the compound comprises 4-(4-{2'-Methoxy-4'-nitrophenoxy}butoxy)-7W-furo[3,2-g][1]benzopyran-7-on.


75. A method according to Claim 58 Vv’herein the compound comprises 4-(4-(2"-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]ben2opyran-7-on.
76. A method according to Claim 58 wherein the compound comprises 4-(4-{3"-Nitrophenoxy}butoxy)-7H-furo[3,2-g][13benzopyran-7-on.
77. A method according to Claim 58 wherein the compound comprises 4-(4-{2",4"-Dinitrophenoxy}butoxy)-7H-furo[3.2-g][1]benzopyran-7-on.
78. A method according to Claim 58 wherein the compound comprises 4-(4-l4-Methoxyphenoxy]butoxy)-7/-/-furo[3,2-g)[1]benzopyran-7-on
79. A method according to Claim 58 wherein the compound comprises 4-(4-[3-Methoxyphenoxy]butoxy)-7/-/-furo[3,2-g][1lbenzopyran~7-on
80. A method according to Claim 58 wherein the compound comprises 4-(4-[3,5-Dimethoxyphenoxy]butoxy)-7H-furo[3.2-g][1]ben2opyran-7-on
81 A method according to Claim 58 wherein the compound comprises 4-{4-[4-Nitrophenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
82. A method according to Claim 58 wherein the compound comprises 4-(4-[4-Chlorphenoxy3butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
83. A method according to Claim 58 wherein the compound comprises 4-(4-[4-Phenoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.

84
85, A method according to Claim 58 wherein the compound comprises 4-(4-[4-Ethylphenoxy)butoxy)-7/-/-furo[3,2-g][1]ben2opyran-7-on.
86. A method according to Claim 58 wherein the compound comprises 4-(4-[4-Fluorphenoxy]butoxy)-7/-/-furo[3,2-g][1]benzopyran-7-on
87. A method according to Claim 58 wherein the compound comprises 4-(4-[3-Trifluormethylphenoxy]butoxy)-7/-/-furo[3,2-g][1]ben2opyran-7-on.
88. A method according to Claim 58 wherein the compound comprises 4-(4-[1-Naphthy!oxy]butoxy)-7H-furo[3,2-g][1]ben2opyran-7-on.
89. A method according to Claim 58 wherein the compound comprises 4-(4-[2-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
90. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Methoxyphenoxy)propoxy]"7H-furo[3,2-g][1]benzopyran-7-on.
91. A method according to Claim 58 wherein the compound comprises 4-[3-(3-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
92. A method according to Claim 58 wherein the compound comprises 4-[3-{3,5-Dimethoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.


94. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Chlorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
95. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Phenoxyphenoxy)propoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
96. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Methylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
97. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Ethylphenoxy)propoxy]-7/-/-furo[3.2-g][1]benzopyran-7-on.
98. A method according to Claim 58 wherein the compound comprises 4-[3-(4-Fluorphenoxy)propoxy]-7H-furo[3,2-g][1]ben2opyran-7-on.
99. A method according to Claim 58 wherein the compound comprises 4-[3-(3-Trifluormethylphenoxy)propoxy}-7H-furo[3,2-g][1]benzopyran-7-on
100. A method according to Claim 58 wherein the compound comprises 4-[3-(1-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
101. A method according to Claim 31 wherein tlie compound comprises 4-[3-(2-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
102. A method according to Claim 58 wherein the compound comprises 4-(5-Phenoxypentoxy)-7/-/-furo[3,2-g][1]benzopyran-7-on
103. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Methoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on


105. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Nitrophenoxy)pentoxy]-7H-furo[3,2-g][1]ben2opyran-7-on.
106. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Chlorphenoxy)pentoxy]-7/-/-furo[3,2~g}[1]benzopyran-7-on
107. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Phenoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]ben2opyran-7-on
108. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Methylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
109. A method according to Claim 58 wherein the compound comprises 4-[5-(4-Ethylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-oh.
110. A method according to Claim 58 wherein the compound comprises 4-[5' (4-Fluorphenoxy)pentoxy]-7/-/-furo[3,2-g][1]benzopyran-7-on.
111. A method according to Claim 58 wherein the compound comprises 4-[5-(1-Naphthyloxy)pentoxy]-7/-/-furo[3,2-g][1]ben2opyran-7-on.
112. A method according to Claim 58 wherein the compound comprises 4-[5-(2-Naphthyloxy)pentoxy]-7H'-furo[3,2-g][1]benzopyran-7-on.


114. A method according to Claim 58 wherein the compound comprises 4-{4-(4-N-Pyridinyi)amincbutoxy}-7H-furo[3,2-g][1]ben2opyran-7"On.
115. A method according to Claim 58 wherein the compound comprises 4-{4-(5'-Methyl-1".3",4"-thiadiazol-2"-thiolyi) butoxy}-7H-furo[3,2--g][1]benzopyran-7-on.
116. A method according to Claim 58 wherein the compound comprises 4-{4-
(7-Coumarinyloxy)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
117. A method according to Claim 58 wherein the compound comprises 4-{4-
(5-Methoxy'1,3-benzothiazol-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
118. A method according to Claim 58 wherein the compound comprises 4-{4-
(Pyrimidin-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
119. A method according to Claim 58 wherein the compound comprises 4-(3-
Cyano propoxy)-7/-/-furo[3,2-g][1]benzopyran-7-on.
120. A method according to Claim 58 wherein the compound comprises 4-(4-
Phenyl-3-oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
121. A method according to Claim 58 wherein the compound comprises 4-(4-Pentynyloxy)-7/-/-furo[3,2-g][1]benzopyran-7-on.
122. A method according to Claim 58 wherein the compound comprises 4-[4-(N-Phthalimide)butoxy]-7/-/-furo[3,2-g][1]benzopyran-7-on.


Documents:

1901-CHENP-2007 CORRESPONDENCE OTHERS 02-12-2013.pdf

1901-CHENP-2007 CORRESPONDENCE OTHERS 04-12-2012.pdf

1901-CHENP-2007 CORRESPONDENCE OTHERS 26-11-2013.pdf

1901-CHENP-2007 AMENDED CLAIMS 01-11-2013.pdf

1901-CHENP-2007 AMENDED CLAIMS 04-12-2013.pdf

1901-CHENP-2007 AMENDED PAGES OF SPECIFICATION 01-11-2013.pdf

1901-CHENP-2007 ASSIGNMENT 01-11-2013.pdf

1901-CHENP-2007 CORRESPONDENCE OTHERS 04-12-2013.pdf

1901-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 01-11-2013.pdf

1901-CHENP-2007 FORM-3 01-11-2013.pdf

1901-CHENP-2007 OTHER PATENT DOCUMENT 01-11-2013.pdf

1901-CHENP-2007 OTHER PATENT DOCUMENT 1 01-11-2013.pdf

1901-CHENP-2007 POWER OF ATTORNEY 01-11-2013.pdf

1901-chenp-2007-abstract.pdf

1901-chenp-2007-claims.pdf

1901-chenp-2007-correspondnece-others.pdf

1901-chenp-2007-description(complete).pdf

1901-chenp-2007-form 1.pdf

1901-chenp-2007-form 3.pdf

1901-chenp-2007-form 5.pdf

1901-chenp-2007-pct.pdf


Patent Number 258801
Indian Patent Application Number 1901/CHENP/2007
PG Journal Number 07/2014
Publication Date 14-Feb-2014
Grant Date 07-Feb-2014
Date of Filing 04-May-2007
Name of Patentee THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Applicant Address 1111 Franklin Street, 5th floor, Oakland, California 94607-5200
Inventors:
# Inventor's Name Inventor's Address
1 SCHMIDT-LASSEN, Kristina Tonniesstr. 4, 24106 Kiel
2 WULFF, Heike 3302 Victoria Place, Davis, California 95616
3 SANKARANARAYANAN, Ananthakrishnan 920 Cranbrook Court #158, Davis, California 95616 (US).
4 HAENSEL, Wolfram Eichkoppel Weg 20, 24 119 Kronshagen
5 SCHMITZ, Alexander Kirchhofallee 28, 24103 Kiel
PCT International Classification Number A61K 31/506
PCT International Application Number PCT/US2005/035572
PCT International Filing date 2005-10-04
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/958,997 2004-10-04 U.S.A.