KR100542841B1 - Dialkylaminoalkoxy substituted fluorenones and their use as protein kinase C inhibitors - Google Patents

Abstract

The present invention provides not only certain alkyloxyamino substituted fluorenones that inhibit protein kinase C, but also pharmaceutical compositions comprising these compounds, and methods of using these compounds to modulate protein kinase C activity in mammals, including humans. Describe. More specifically, the compounds of the present invention include neoplastic disease states, disorders associated with abnormal blood flow (including hypertension, ischemia, atherosclerosis, coagulation disorders) and inflammatory diseases (immune disorders, asthma, pulmonary fibrosis and psoriasis) Is useful for the treatment of).

Description

Dialkylaminoalkoxy substituted fluorenones and their use as protein kinase C inhibitors}

The present invention relates to compounds having protein kinase C inhibitory activity. More specifically, the present invention relates to alkyloxyamino substituted fluorenones that inhibit protein kinase C, pharmaceutical compositions comprising these compounds and methods of using these compounds for modulating protein kinase C activity in mammals, including humans. will be. More specifically, the present invention relates to neoplastic disease states, disorders associated with abnormal blood flow (including hypertension, ischemia, atherosclerosis, coagulation disorders) and inflammatory diseases (including immune disorders, asthma, pulmonary fibrosis, psoriasis) It is useful for treatment.

Protein kinase C (PKC) constitutes a family of enzymes called protein kinases. Activation of protein kinases catalyzes the transfer of γ-phosphate of MgATP to one of the serine and threonine residues of a particular protein substrate. Protein kinases regulate almost all cellular functions through the phosphorylation of proteins and the regulation of cellular responses that are responsible for signal transduction. Thus, inhibitors of protein kinases can function as pharmacological components because they alter cellular activity. Protein kinase C is first a phospholipid-dependent, calcium-activated serine / threonine protein kinase characterized in the brain (Y. Nishizuka, Science 233 : 305-312 (1986)). Subsequently, PKC has also been characterized as a family of 11 or more enzymes (see A. Azzi et al ., Eur. J. Biochem . 208 : 547-557 (1992); all of which are incorporated herein by reference; DS Lester and RM Epand, Current Concepts and Future Perspectives , Ellis Horward, New York (1992); H. Hug and TF Sarre, Biochem. J. 291 : 329-343 (1993); C. Tanaka and Y. Nishizuka, Annu Rev. Neurosci 17 : 551-67 (1994); SE Wilkinson, TJ Hallam, Trends Pharm.Sci. 15 : 53-57 (1994); EO Harrington and AJ Ware, Trends Cardiovas.Med . 5 : 193-199. (1995); AC Newton, J. Biol. Chem . 270 : 28495-28498 (1995)].

The protein kinase group C component consists of a single polypeptide having an N-terminal regulatory end and a C-terminal catalytic end. The regulatory region for all isozymes requires phospholipids for enzyme activity, but only some of them require calcium for activation and some of these are long components associated with phorbol myristate acetate (PMA) and PKC activation. Is not activated by On the other hand, the catalytic moieties of PKC enzymes are quite similar, but they share limited homology with other kinase species. For example, only 40% of the domains with another well characterized protein kinase, protein kinase A (PKA), exist. Analysis of the catalytic site also revealed a unique acidic residue cluster for the protein kinase C group of enzymes (JW Orr, AC Newton, J. Biol. Chem . 269 : 8383-8367 (1994)). Thus, inhibitors or pharmaceutical components acting at the catalytic sites of the enzyme are expected to be specific for the protein kinase C group of the enzyme. Because of the potential therapeutic value of inhibitors of PKC, considerable efforts are made to identify such substances (see, HH Grunick, F. Ueberall, Sem. In Cancer Biol . 3 : 351-, all of which are incorporated by reference herein). 360 (1992); D. Bradshaw et al., Agents Actions 38 : 135-147 (1993); W. Harris et al., Drugs Future 18 : 727-735 (1993); A. Levitzi, Eur. J. Biochem . 226 : 1 -13 (1994); KJ Murray and WJ Coates, Annu Reports Med Chem 29 :.. 255-264 (1994); PC Gordge and WJ Ryves, Cell Signal 6:. . 871-882 (1994); PM Blumberg et al., Agents Action Suppl . 47 : 87-100 (1995); JC Lee and JL Adams, Curr. Opp. Biotech . 6 : 657-661 (1995)].

PKCs regulate critical steps in cell proliferation and cell growth. Potential activators of PKCs such as phorbol esters are well known carcinogenic substances. Thus, inhibitors of PKC are also expected to be anticancer agents. The anticancer activity of some PKC inhibitors is well known, including activity against tumors expressing a phenotype of multiple drug resistance (I. Utz et al. , Int. J. Cancer 57 : 104-110 (1994)). See: Grunick, supra, Levitzi, supra, Lee et al. , Supra, T. Meyer et al. , Int. J. Cancer 43 : 851-856 (1989); S; Akinagaka et al., Cancer Res . 51 : 4888-4992 (1991)]. PKC inhibitors have been specifically shown in the inhibition of CDC2 kinase activity and in the inhibition of cell circulation (see, J. Hoffman et al. , Biochem. Biophys. Res. Commun . 199 : 937-943, which is incorporated herein by reference . 1994)]). Inhibition of protein kinase C has been shown to inhibit tumor metastasis (JA Dumont et al. , Cancer Res . 52 : 1195-1200 (1992), JA Dumont et al. , Biochem. Biophys. Res. Comm . 204 : 264-272 (1994)]. Angiogenesis, ie, new angiogenesis, is associated with tumor formation and growth, which promotes its formation and growth, in which case new angiogenesis is a pathological event.

Protein kinase C activation has been associated with mechanisms that establish intravascular flow rates. Excessive PKC activity is similarly included in hypertension, ischemia and atherosclerosis; These reactions all contribute to impaired blood flow and can lead to ischemic heart disease, myocardial infarction or seizures. Phorbol esters will increase the arterial contractility of hypertensive rats with elevated PKC activity, which is essential for their vasculature and platelets (EO Harrington and AJ Ware, supra; D. Bradshaw et al., Supra). Platelet coagulation is performed by PKC activation, which contributes to aberrant clot formation and blood flow obstruction (MA Evans et al . , Br. Heart J. 68 : 109), which is incorporated herein by reference. Hyperplasia and proliferation of vascular smooth muscle play an important role in atherosclerotic plaque formation. PKC activation is involved in smooth muscle proliferation (EO Harrington and AJ Ware, supra).

Tissues and organs become infected as a result of invasion of certain activated white blood cells. Prolonged results can damage tissue and result in fibrosis. Both infected cell activation and fibrosis response have been associated with excessive protein kinase C activity. T lymphocytes (T cells) are modulators of the immune response. PKCs play an important role in the activation of these cells, and PKC inhibitors will inhibit their activation and growth (see, D. Bradshaw et al., Supra, W. Harris, all of which are incorporated herein by reference). Et al ., Supra, SS Alkkan et al ., Cell. Immunol . 150 : 137-148 (1993)]. Naturally, PKC inhibitors have been shown to be active in diseases in which T cells play a major role, such as transplant rejection (JP Demers et al. , Bioorg. Med. Chem. Lett . 4 : 2451-56) and psoriasis (see :....... L. Hegemann , etc., Arch Dermatol Res 284 -179-183 (1992 ); and so on JJ Tegeler, Bioorg Med Chem Lett 5 : 2477-2482 (1995)). Leukocytes such as monocytes (macrophages), neutrophils and eosinophils can be activated by phorbol esters, and their activities such as free radical generation, phagocytosis, chemotaxis and secretion can be inhibited by inhibitors of PKC (CK Huang and RI Sha'afi, Protein kinases in blood cell function , CRC press, Boca Raton, Ch. 3, 4, 5). These granulocytes participate in and are a major cause of acute infection reactions that occur in diseases such as asthma, allergies and gouty arthritis. Thus, inhibitors of PKC are expected to have general anti-inflammatory activity. The consequence of chronic infection is fibrosis. In particular, it is well known that the compound (fluorenone) described herein, which the inventors have identified as an inhibitor of PKC, is expected to have anti-inflammatory and antifibrotic activity of the lung because it inhibits alveolar macrophage activation and fibroblast proliferation. (JYC Ma et al . , Exp. Lung Res . 21 : 771-790 (1995)), incorporated herein by reference.

Regarding the inclusion of PKC in some human disease responses, including neoplastic disease states, vascular perfusion disorders and infections, inhibition of the enzyme is expected to be of significant value in the treatment of these disorders. In addition, PKC inhibitors that are highly specific for the PKC class of protein kinases that have minimal effects on other metabolic pathways, such as those associated with the stimulation of protein kinase A by cAMP, are highly desirable. Neoplastic disease states, vascular perfusion disorders and infections are common conditions where the demand for new and more decisive treatment is still considerable.

<Overview of invention>

The present invention relates to compounds of Formula 1, their pharmaceutically acceptable salts and pharmaceutical compositions:

Where

B is O, S or NH,

R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino;

R ⁵ is C _1-5 alkylene;

V is hydrogen, methoxy, ethoxy, n-propoxy or n-butoxy;

X is hydrogen, methoxy, ethoxy, n-propoxy, fluoro or chloro;

Y is hydrogen, NH ₂ , NHR or NHCOR, where R is C _1-5 alkyl or phenyl;

Z is H, C _1-5 alkyl, fluoro, chloro or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only,

Z can be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X; Also,

When Z is BR ⁵ N (R ⁴ ) ₂ , at least one of Y, V and X is not hydrogen and is not substituted by Z.

The invention also relates to the use of a compound of formula 2 and pharmaceutically acceptable salts thereof for the treatment of disorders mediated by PKC

Where

B is O, S or NH,

R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino;

R ⁵ is C _1-5 alkylene;

V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy;

X is hydrogen, methoxy, ethoxy, n-propoxy, fluoro or chloro;

Y is hydrogen, NH ₂ , NHR or NHCOR, where R is C _1-5 alkyl or phenyl;

Z is H, C _1-5 alkyl, fluoro, chloro or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; Also,

Z may be present at the 1, 2, 3 or 4 position, provided that when present at the 1, 2 or 4 position each substitutes for Y, V or X.

These disorders include, for example, neoplastic disease states, abnormal blood flow disorders (including hypertension, ischemia, atherosclerosis, coagulation disorders) and inflammatory disorders (including immune disorders, asthma, pulmonary fibrosis and psoriasis). do. Compounds of the invention are also useful in therapeutic inhibition of angiogenesis and inhibition of alveolar macrophage activation.

In addition, the present invention is a chemical formula Thionyl, wherein R ¹ and R ² are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl; m, n and p are each independently 0 or 1 A reaction with chloride followed by reaction in situ with an amine of formula (R ₆ ) (R ₇ ) NH, wherein R ₆ and R ₇ are each independently ethyl or propyl Wherein R ¹ and R ² are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl; R ₆ and R ₇ are each independently ethyl or propyl; m, n and p Each independently represents 0 or 1).

In addition, the present invention is a chemical formula Wherein R ¹ and R ² are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl; m, n and p are each independently 0 or 1). Benzotriazol-1-yl- in the presence of an amine and a tri- (Ci_ ₅ alkyl) amine of R ₆ ) (R ₇ ) NH, wherein R ₆ and R ₇ are each independently ethyl or propyl Formula comprising reacting with oxy-tris (pyrrolidino) phosphonium hexafluorophosphate Wherein R ¹ and R ² are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl; R ₆ and R ₇ are each independently ethyl or propyl; m, n and p Each independently represents 0 or 1).

In addition, the present invention is a chemical formula Wherein R ² and R ³ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl) Wherein R ² and R ³ are each independently a method for the preparation of a compound of methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl.

Finally, the present invention provides chemical formulas useful as intermediates for the preparation of compounds Wherein R ¹ and R ² are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or allyl; R ₆ and R ₇ are each independently ethyl or propyl; m, n and p Are each independently 0 or 1, provided that at least one of R ¹ and R ² is allyl.

As used herein, the term "pharmaceutically acceptable salt" means any organic or inorganic acid salt capable of forming a nontoxic acid addition salt suitable for use as a medicament. Exemplary inorganic acids that form suitable salts include acid metal salts such as hydrochloride, hydrobromic acid, sulfuric acid and phosphoric acid, and sodium orthophosphoric acid monohydrochloride and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tri-carboxylic acids. For example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid , Salicylic acid, glutamic acid, gluconic acid, formic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Further examples of suitable pharmaceutically acceptable salts are listed in Berge, SM et al . , J. Pharm. Sci . 66 : 1, 1 (1977). Such salts may be present in either hydrated or substantially anhydrous form.

As used herein, the term “patient” means a warm blooded animal, such as a mammal with a particular disease. Obviously, it is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are examples of animals within the scope of the term.

As used herein, the term “effective protein kinase C inhibitory amount” is an amount in which an enzyme inhibitory effect sufficient to induce a therapeutic effect of a patient when a single or multiple administration to the patient is achieved. The exact amount of the compound of formula 1 or 2 to be administered can be readily determined by the diagnostician's participation as a person of ordinary skill in the art, using conventional techniques, and observing the results obtained under similar circumstances. Significant factors in determining the dosage include dosage; Animal type, animal size, age and general health; Specific disease, degree of disease, degree of onset, or disease depth involved; Response of each patient; The particular compound administered; Mode of administration; Bioavailability characteristics of the administered agent; Selected dosage regimens; The use of collateral medications; And other related environments.

An effective protein kinase C inhibitory amount of the compound of formula 1 or 2 will typically be from about 0.5 to about 200 mg / kg body weight / day. A daily dosage of about 0.625 to 100 mg / kg body weight / day is preferred.

Compounds of the invention are inhibitors of protein kinase C. It is believed that the compounds of the present invention exert their inhibitory effects through the inhibition of protein kinase C, thereby preventing or alleviating symptoms such as neoplastic disease states, abnormal blood flow disorders, infectious diseases and the like. However, it is understood that the present invention is not limited by any particular theory or proposed mechanism for explaining its effect in the field of end use.

As used herein, the term “neoplastic disease state” means an abnormal condition or condition characterized by cell growth or rapid proliferation of neoplasms. Neoplastic disease states for treatment with compounds of Formula 1 or 2 that will be particularly useful include leukemias such as acute lymphoblasts, chronic lymphocytes, acute myelocytes and chronic myeloids; Carcinoma and adenocarcinoma, such as those of the cervix, esophagus, stomach, small intestine, colon, lung (both small and large cells), chest and prostate; Sarcomas such as osteomas, osteosarcomas, lipomas, liposarcomas, hemangiomas and angiosarcomas; Melanoma, including melanin deficiency and melanoma; And complex neoplastic forms such as carcinosarcomas, lymphoid tissue types, reticulomegaloids, cell sarcomas, and Hodgkin's disease. Neoplastic disease conditions for treatment with the compounds of formula (I) or (II) which will be particularly preferred include carcinomas and adenocarcinomas of the chest, prostate and lungs, among others. An effective protein kinase C inhibitory amount of a compound of formula (1) or (2) is one or more administrations to a patient, effective in regulating the growth of neoplasms beyond the expectations of such treatment or prolonging the survival of the patient. Means quantity. As used herein, the term "growth control" of a neoplasm means that it delays, hinders, stops or stops its growth and metastasis and does not necessarily indicate complete elimination of the neoplasm.

As used herein, the term “C _1-5 alkylene” means a linear or branched saturated hydrocarbyldiyl radical having 1 to 5 carbon atoms. Within the scope of this term, methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, n-pentylene and the like are included.

As used herein, the term "C _1-5 alkyl" refers to a linear or branched saturated hydrocarbyl radical having 1 to 5 carbon atoms. Within the scope of this term are included methyl, ethyl, propyl, isopropyl, n-butyl, secondary butyl, n-pentyl and the like.

As used herein, the term "C _1-4 alkyl" refers to a linear or branched saturated hydrocarbyl radical having 1 to 4 carbon atoms. Within the scope of this term are included methyl, ethyl, propyl, isopropyl, n-butyl, secondary butyl and the like.

As used herein, the term “PyBOP” or benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate is a benzotriazol-1-yl-oxy-tris of the formula Dino) phosphonium hexafluorophosphate.

<Composition>

The compound of formula 1 or 2 may be administered in a pharmaceutical composition or pharmaceutical form prepared by mixing the compound of formula 1 or 2 with a pharmaceutically acceptable carrier or excipient, the ratio and nature of which is determined by the route of administration chosen and standard pharmaceutical practice. Can be.

Pharmaceutical compositions of the present invention are prepared by methods well known in the pharmaceutical art. Carriers or excipients can be solid, semisolid or liquid substances which can function as vehicles or media for the active ingredient. Suitable carriers or excipients are well known in the art. Pharmaceutical compositions may be applied for oral, inhalation, parenteral or topical use and may be administered to a patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, powders, syrups and the like. The term "pharmaceutical carrier" as used herein may include one or more excipients.

In preparing the compositions of the compounds of the present invention, care should be taken to ensure the bioavailability of inhibitory effective amounts, including oral, parenteral and subcutaneous routes. For example, effective routes of administration may include subcutaneous, intramuscular, transdermal, nasal, rectal, and the like, including release from the graft as well as direct injection of the active ingredient and / or composition into the tissue or tumor site. have. Suitable pharmaceutical carriers and composition techniques are found in standard literature such as Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pennsylvania.

For oral administration, the compounds may be formulated in solid or liquid formulations, such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions, with or without inert diluents or edible carrier (s). have. Tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, tragacanth rubber or gelatin; Excipients such as starch or lactose; Disintegrants such as alcinic acid, Primogel ^R , corn starch and the like; Lubricants, such as stearic acid, magnesium stearate or Sterotex ^R ; Glidants, such as colloidal silicon dioxide; Sweeteners such as sucrose or saccharin; And flavorings such as peppermint, methyl salicylate or fruit flavoring. If the unit dosage form is a capsule, the unit dosage form may also contain a liquid carrier such as polyethylene glycol or fatty oil. The material used is pharmaceutically pure and nontoxic in use. These formulations should contain at least 0.05% by weight of the active ingredient of the compound of formula 1 or 2, but may vary depending on the particular formulation and may conveniently be from 0.05 to about 90% by weight of the unit. The amount of active ingredient present in the composition is that amount which will yield a unit dosage form suitable for administration.

For parenteral administration, the compounds of formula 1 or 2 may be incorporated into solutions or suspensions. These formulations should contain at least 0.1% of the compounds of the present invention but can vary from 0.1 to about 50% by weight. The amount of active ingredient present in such compositions is the amount from which a suitable dosage will be obtained.

Liquids or suspensions may also include one or more of the following auxiliaries, depending on the solubility and other properties of the compound of formula 1 or 2: water for injection, saline solution, hardened oil, polyethylene glycol, glycerin, propylene glycol or other synthesis Sterile diluents such as solvents; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium disulfite; Chelating agents such as ethylene diaminetetraacetic acid; Buffers such as acetates, citrate or phosphates; And toxicity modifiers such as sodium chloride or dextrose. Parenteral preparations can be placed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

The compounds may be administered in the form of graft preparations that may be formulated in a skin patch, depot injection, or in a manner that allows sustained release of the active ingredient. The active ingredient may be compressed into pellets or small syringes and implanted subcutaneously or intramuscularly as accumulation injections or grafts. Grafts may use inert materials such as biodegradable polymers and synthetic silicones. Additional information and formulation techniques regarding suitable pharmaceutical carriers are found in standard literature such as Remington's Pharmaceutical Sciences .

Chemical Synthesis

Starting compounds in the synthesis of the dibasic fluorenone compounds of the present invention are known or combined with Meyers & Mihelich, J. Amer. Chem. Soc ., 97 (25), 7383 (1975). : Meyers et al ., J. Org. Chem ., Et al ., 39 (18), 2787 (1974)).

The following examples illustrate particular synthesis that was partially adopted from the available literature.

Scheme 1 describes a method for synthesizing some compounds of the present invention, including both dibasic and certain monobasic compounds, with dialkoxy oxazoline (1) as starting material. OR 'in dialkoxy oxazoline (1) is at one of 3, 4 and 5 as shown in Scheme 1, and R' can be any straight or branched C _1-4 alkyl radical. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl and the like, while methyl and isopropyl are preferred. R 'is chosen to be readily removed upon reaction of the halo-phenyl ether (2) with the Grignard reagent to form biphenyl oxazoline (3). The reaction can be carried out in a manner consistent with the reaction shown in Meyers and Mihelich, J. Amer. Chem. Soc ., Supra. X in halo-phenyl ether (2) is typical Grignard halogen such as bromo, chloro, iodo and the like, while bromo is preferred. OR "is present as ortho, meta or para to magnesium substituents and represents a similar range of radicals as described by OR 'where R' is preferably methyl and n-propyl. Compounds 1 and 2 represent Both reactants and product biphenyl oxazolines react under typical Grignard conditions (anhydrous solvents) in solvents that are both soluble and non-reactive, for example diethyl ether, tetrahydrofuran (THF), glame, diggle Lime, etc.

The biphenyl oxazoline (3) is then converted to biphenyl acid (5) in one of two ways. First, it can be converted by the addition of acid and heat in one step, which is the preferred selection method for the preparation of dibasic compounds. Acid hydrolysis conversion is equally available when the ether bonds in OR 'and OR "are relatively immune to acid hydrolysis, such as when R' and R" are both methyl. Alternatively, the conversion can proceed via base hydrolysis as reported in Ladd et al ., J. Med. Chem . 29 (10), 1904 (1986). The conversion can be carried out by first methylating and forming a quaternary ammonium salt (4), such as with methyl iodide, and then base hydrolyzing under conditions suitable to obtain the corresponding biphenyl acid (5). For example, sodium hydroxide and methanol can be used and then acidified.

The biphenyl acid (5) is then treated according to the position of the OR 'and OR "alkoxy substituents. If rings A and B of compound 5 correspond to rings C and D of compound 7, respectively, 1,5 (a small amount of Product), 2,5 or 3,5 fluorenone (7) is prepared by route A, while 4,5 and 1,5 (main product) fluorenone (7) is prepared by route B. As an example , Path A corresponds to said biphenyl acid (5) wherein OR "is at one of the 4 'and 3' positions, wherein path B is a substituent where OR" is at one of the 2 'and 3' positions R'O may be present at positions 3, 4, 5 or 6. The placement of one substituent, ie R'O and R''O, will affect the position of the remaining substituents as described below.

It will also be understood that compound 7 is represented by R ¹ and R ² instead of R ′ and R ″, respectively. This occurs because the 6 position of compound 5 may correspond to the 5 position of compound 7 but is not necessary. This is because the 2 'position may also result as a 5 position substitution of compound 7. As a result, R ¹ may be ^one of R' and R "but R ² may be one of R" and R ' Wherein ring B of compound 5 also corresponds to ring C of compound 7, while ring A corresponds to ring D. To illustrate, 1,5 fluorenone (7) is 3 ′, 6 And 2 ′, 3-substituted biphenyl acid (5), however, since R 5 of compound 7 must contain an alkoxy substituent, R ¹ O is substituted for ring A of biphenyl acid (5). Whenever a substitution is made at a position other than position 6, R ² O will always be present at position 2 'and path B must be followed. For example, 2,5-fluorenone is formed from 4 ', 6 biphenyl acid (5) via route A or from 2', 4 biphenyl acid (5) through route B Can be.

To continue, para or 4 ′ substituted ring B biphenyls (5) may be subjected to any suitable Friedel-Crafts conditions, for example thionyl chloride, oxalyl chloride, PCl ₅ followed by tin tetrachloride (preferably Ring) under TFAA or the like to form a para or bisubstituted fluorenone (7). Accurate selection of suitable Friedel-Crafts conditions and reaction parameters can be readily determined by one of ordinary skill in the art. These suitable Friedel-Crafts conditions applied to meta or 3 'substituted ring B biphenyls will yield a mixture of both 1 and 3 substituted fluorenones (7) with excess 3 substituted products.

As reported in J. Fu et al ., J. Org. Chem ., 56 (5), 1683-1685 (1991), the carboxamides (6) are subject to ring-specific ring From the substituted biphenyl acid (5) form a monosubstituted fluorenone (7). In addition, the 2 'substituted biphenyl acid must be closed with fluorenone via LDA condensation of the carboxamide (path B), because typical Friedel-Crafts conditions would form biphenylpyrans instead of the desired fluorenone. (T. Sala & MV Sargent, .J. Chem. Soc., Perkin Trans. 1 , 2593 (1979); MV Sargent, J. Chem. Soc., Perkin Trans. 1 , 2553 (1987) ).

The inventors have found that the acid chloride (prepared from biphenyl acid (5) by applying thionyl chloride) without the significant formation of biphenylpyrans as reported by Sargent, supra, has the formula HN (R ₆ ) (R ₇ ) the carboxamide intermediate 6 can be prepared by immediate reaction with an excess of amine, wherein R ₆ and R ₇ are as defined above and preferably R ₆ and R ₇ are ethyl. Found out. Acid chlorides and subsequent carboxamides can be formed in the reaction system, wherein the carboxamides are isolated and then reacted with LDA to give fluorenone (7).

The inventors also note that amines and tri- of formula HN (R ₆ ) (R ₇ ), wherein R ₆ and R ₇ are as defined above, acting as bislic acid (5) as an acid scavenger It has been found that the carboxamide intermediate 6 can be prepared by immediate reaction with PyBOP (Nova Biochem, San Diego, Calif.) In the presence of (C _1-5 alkyl) amine. The reaction is typically a suitable organic solvent such as chlorinated hydrocarbons such as methylene chloride or carbon tetrachloride; Chlorinated aromatic solvents such as 1,2,4-trichlorobenzene; Tetrahydrofuran; Or in an aromatic solvent such as benzene, methylene chloride is the preferred solvent. Examples of suitable tri- (C _1-5 alkyl) amines include triethylamine, N, N-diisopropylethylamine and the like, with N, N-diisopropylethylamine being preferred. The reaction is typically carried out over 6 to 25 hours. The carboxamide intermediate 6 is isolated and purified by any suitable technique, such as filtration, evaporation and flash chromatography.

Subsequently, as in the case of preparing the dibasic compound of the present invention, or optionally as in the case where a monobasic fluorenone compound is desired, the fluorenone (7) is dealkylated to give 5-phenol (8). Can be obtained. R "'is defined as R ² or H. R"' will be hydrogen in the case of complete dealkylation as in the case of dibasic fluorenone. Dealkylation conditions will vary with R ¹ and R ² and are readily known to those skilled in the art. For example, complete dealkylation can be carried out by application of hydrogen bromide and heat in glacial acetic acid. Methoxy groups can be optionally dealkylated by diphenyl phosphine and n-butyl lithium, while isopropoxy groups can be dealkylated by boron trichloride (Re, Ireland & DM Walba, Organic Synthesis , 56 , p. 44 (1977); T. Sala & MV Sargent, J. Chem. Soc., Perkin Trans. I , 2593 (1979)). Then, the 5-phenol (8) U.S. Patent No. 3,592,819 (Fleming, etc.) and literature (see: Andrews, etc., J. Med Chem 17 (8), 882 (1974)) as described by the general formula XR ⁵ - It can be alkylated with a reagent of N (R ⁴ ) ₂ . Wherein X is halogen and R ⁵ is C _1-5 alkylene and R ⁴ is C _1-3 alkyl, or R ⁴ is taken together to form pyrrolidinyl, piperidinyl or morpholino. Typically, the alkylation reaction is carried out in the presence of sodium methoxide in chloro-benzene and methanol to give the product fluorenone (10).

Alternatively, unless otherwise stated, the substituents can produce the carboxamide intermediate 6 according to Scheme 1a as defined above.

The acid (6a) in Scheme 1a is converted to PyBOP and the appropriate tri- (Ci_ ₅ alkyl) amine, in particular N, N-diisopropylethylamine (DIEA), at ambient temperature according to the procedure described in route B Condensation of an amine of the formula HN (R ₆ ) (R ₇ ), wherein R ₆ and R ₇ are as defined above, affords amide 6b. The reaction is preferably carried out in the presence of a suitable organic solvent, preferably methylene chloride, as described above. The amide 6b is then coupled with aryl boronic acid 6c using Suzuki coupling to obtain a carboxamide intermediate 6 (N. Miyarura et al ., J. Org. Chem . 51, 5467-5471 (1986); Y. Hoshino et al. , Bull. Chem. Soc. Japan 61, 3008-3010; N. Miyaura et al. , J. Am. Chem. Soc . 111, 314-321 (1989); WJ Thompson et al ., J. Org. Chem . 53, 2052-2055 (1988); and TI Wallow and BM Novak, J. Org. Chem . 59, 5034-5037 (1994)).

For example, amide 6b is contacted with a suitable aryl boronic acid 6c. Suzuki coupling reactions are carried out in a suitable solvent, such as 1,2-dimethoxyethane (glyme). The reaction is carried out using about 1.1 to about 3 molar equivalents of an appropriate arylboronic acid. The reaction is carried out in the presence of about 1 to about 3 molar equivalents of a suitable base such as potassium carbonate or sodium carbonate. Coupling is carried out using a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium [Pd (PPh ₃ ) ₄ ]. The coupling reaction is carried out at 0 ° C. to the reflux temperature of the solvent. The coupling reaction shown in Scheme 1a may require a reaction time of 6 hours to 14 days. Carboxamide intermediate 6 is isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.

Suitable arylboronic acids (6c) are prepared by techniques and procedures well known and understood in the art (WJ Thompson and J. Gaudino, J. Org. Chem ., 49, 5237-5243 (1984)). Arylboronic acids are often contaminated by their corresponding anhydrides that do not perform well in Suzuki coupling. Substances contaminated with adverse amounts of anhydride can be converted to the corresponding acids by hydrolysis. Hydrolysis is carried out by simple boiling in water, if necessary, and arylboronic acid is recovered by filtration.

A possible preparation of the starting material dialkoxy oxazoline (1) is described in Scheme 2. A ¹ is as defined in Scheme 6a. Route C then indicates that diphenolic acid (12) available herein was prepared from a common chemical source such as Aldrich Chemical Co. (Milwaukee, WI) and converted to diphenolic methyl ester (13) in methanolic hydrogen chloride. Indicates. For example, hydrogen chloride may be used to carry out any known technique such as saturating the methanol boiling solution of diphenol 12 (King et al. , J. Chem. Soc ., 4206 (1955)). The diphenolic methyl ester is then alkylated with a dialkyl methyl ester 14, such as by reaction with haloalkanes under typical conditions and solvents known in the art, wherein the alkyl moiety is defined as R ', as previously defined. Indicates. Halogen may also be any of those typically used in alkyl substitution reactions, for example bromo, chloro or iodo. While the alkylation technique can be used for the entire R 'range, we have found it particularly preferred if R' is acid sensitive, such as isopropyl. Dialkyl methyl ester 14 is reacted with 2-amino-2-methylpropan-1-ol in the presence of sodium hydride in a suitable non-reactive solvent to give hydroxy amide 15. For example, Dodd et al., Synthetic Communications , 23 (7), 1003 (1993) describe tetraalkylation in the presence of potassium carbonate in toluene (corresponding to the conversion of compound 13 to 14 of Scheme 2), tetra Amidation with amino-alcohol in hydrofuran is described. The hydroxy amide 15 can then be converted to dialkoxy oxazoline 1 by any known means. For example, two equivalents of triphenyl phosphine and N- (1,1-dimethyl-2), respectively, by application of thionyl chloride as described in Sargent, supra, or as described in Dodd et al., Supra. -Hydroxyethyl) -4'-dimethoxymethylbenzamide (DEAD).

Route D in Scheme 2 illustrates a simplified preparation procedure for dialkoxy oxazoline (1) when R 'is methyl. To explain, if dimethoxy benzoic acid 16 is already readily available (also purchased from Aldrich Chemical Co.), there is no need to synthesize these 16 by forming methyl ethers from biphenolic acid 12. . Dimethoxy benzoic acid (16) is converted to acid chloride by reaction with thionyl chloride and then reacted with at least 2 molar equivalents of 2-amino-2-methylpropan-1-ol to give dimethoxycarboxamide (17). do. The dimethoxycarboxamide can then be converted to dialkoxy oxazoline (1) by reaction with thionyl chloride. The formation of oxazoline 1 can also be mediated by oxalyl chloride, phosphoryl chloride, as well as other condensation reagents such as Friedel-Crafts and the like.

Scheme 3 describes the preparation of halo-dialkyl phenyl ethers (21) and the corresponding Grignard (22), starting compounds used in the preparation of dialkoxy substituted monobasic fluorenone compounds of the present invention. X is as defined under Scheme 1. The mono-alkyl substituted ethers (2) used in Scheme 1 can be prepared by alkylation of the corresponding halo-phenols, as known. Reaction conditions for the halo-biphenol (18) conversion to halo-dialkoxy phenyl ether (21) by selective alkylation of hydroxy groups in the preparation of dialkyl ethers (21) are also known in the art. For example, as described in Bose et al. , J. Am. Chem. Soc ., 1991, 113 , 9293, halo-diphenol (18) is an inert solvent such as acetone, 2-butanone, and the like. Protected by alkylation with para-toluene sulfonyl chloride in the presence of potassium carbonate. The protected phenol is then reacted with a suitable halo-alkyl compound, wherein the halogen moiety is as previously defined and the alkyl moiety is defined by R ² , to form the protected halo-phenyl alkoxy ether 19. . The protected ether 19 is then first deprotected under basic conditions followed by acidic conditions to give an alkoxy phenol 20. For example, potassium hydroxide in aqueous ethanol followed by acetic acid. The alkoxy phenol 20 can then be alkylated under similar conditions as in the alkylation of Scheme 1, wherein alkyl is defined by R ³ to give halo-dialkoxy phenyl ether 21. R ³ is defined similarly to R ¹ and R ² . Halo-dialkoxy phenyl ether 21 can be converted to the corresponding Grignard 22 by reaction with magnesium in a suitable non-reactive solvent such as diethyl ether, tetrahydrofuran and the like, as is known.

Scheme 4 illustrates the first part of the preferred synthesis of the trialkoxy substituted 5-fluorenone of the present invention. Scheme 4 is similar to route B of Scheme 1 using a number of the same reagents as Scheme 4, but in principle (as compared to monoalkoxy Grignard (2)) halo-dialkoxy phenyl ether Grignard prepared in Scheme 3 Not only in the use of (22) but also in the restriction of R 'to isopropyl only, it is different from Scheme 1. R ² and R ³ are as previously defined when under reaction conditions. The compound of Scheme 4 is represented similarly as in Scheme 1 (as “a”) to indicate the corresponding reaction conditions.

Scheme 5 illustrates the second part of the trialkoxy substituted 5-fluorenone synthesis of the present invention. Tri-ether 28 can be modified in two ways to yield the compounds of the present invention. Route E in Scheme 5 selectively dealkylated 5-isopropoxy groups by treatment with boron trichloride in a suitable non-reactive solvent, such as methylene chloride, to provide 5-phenol (29) as described in Sargent, supra. The formation method is demonstrated. Subsequently, 5-phenol (29) is added to a compound of formula XR ⁵ -N (R ⁴ ) ₂ , wherein X, R ⁵ and R ⁴ are as defined in Scheme 1 in the presence of chlorobenzene and sodium methoxide. Alkylation to give 2,4-alkoxy-5-alkoxy-dialkylamine (30), which may be not only the final compound but also an intermediate for 1-nitro compound (32). Compound 1 is obtained upon nitriding compound 30 with nitronium tetrafluoroborate in methylene chloride at -70 [deg.] C. (warming to ambient temperature). The 1-nitro compound 32 is then reduced to 1-amine 33 by any effective means known in the art, but stannous chloride in ethanol is preferred. Further reducing systems include, for example, chemically 1) zinc metal in acetic acid, 2) zinc metal in methanol with or without ammonium chloride, and 3) iron and acetic acid in ethanol.

Route F of Scheme 5 illustrates the 1-amine synthesis of the present invention. In the case where the nitriding step is first applied, the method of applying nitronium tetrafluoroborate to tri-ether 28 has the effect of selectively dealkylating 5-isopropoxy groups as well as nitriding (31). Found that The conditions of this reaction are similar to those used in route E. Path F is preferred because the result is to eliminate the synthetic step compared to path E. The nitro-phenol (31) is then alkylated with appropriate 2-chloroethyl-dialkyl amine under conditions similar to those already described to give 1-nitro compound (32). To explain, the 1-nitro compound shows the convergence of Schemes E and F and then is reduced to 1-amine as described under Path E.

Alternatively, the 2,5-dibasic fluorenone compounds of the present invention can be prepared from US Pat. No. 3,592,819 (Fleming et al.) As well as from Andrews et al ., J. Med. Chem ., 17 : 8, 882 (1974). It can be obtained by the method described in the above, wherein these compounds are obtained by reduction, diazotization and hydrolyzable substitution of the corresponding 2,5-dinitro compounds. Di-nitro compounds can be obtained by nitriding fluorenone as is known.

In addition, suitable 2,5-dimethoxyfluoren-9-ones may be prepared according to Scheme 1a to afford the appropriate intermediates of Formula 6 and then to the desired final product according to Scheme 1.

Scheme 6a illustrates the synthesis of a dibasic alkoxy compound of the present invention starting from one of dialkoxy oxazoline (1) and trialkoxyoxazoline (34). Scheme 6a is similar to Scheme 1 describing the synthesis of compounds 3 to 7 and similar reaction conditions may be employed herein. R ¹ , R ² , R ₆ , R ₇ , R 'and R "are as defined in Scheme 1. R ⁸ is methyl, ethyl, n-propyl, isopropyl, n-butyl or secondary butyl. A ₁ And A ₂ represents an alternative route for obtaining R ⁸ O in compound 40. That is, R ⁸ O can be obtained from the alkoxy substituent of ortho to the removed R′O substituent (A ₁ ), or phenyl From an alkoxy substituent of ortho to the magnesium bond (A ₂ ) A ₁ and A ₂ are mutually exclusive, ie A ₂ is absent if A ₁ is present and vice versa.

Scheme 6b is a continuation of the synthesis starting from Scheme 6a, starting from tri-alkoxy fluorenone 40. Reagents and reaction conditions are similar to those used in Scheme 5. Path F of Scheme 5 is similar to Path H of Scheme 6b, utilizing similar reagents and reaction conditions. Path E of Scheme 5 utilizes reagents and reaction conditions corresponding to those described in Path G of Scheme 6b. Compounds similar to those of Scheme 5 are identified as "a" and follow the compound of Scheme 5. The compounds of Scheme 6b also have many novel identifications of the compounds themselves. The variability definitions through Schemes 6a and 6b are as previously defined.

Compound examples of the present invention include the following:

3,5-bis- (2-diethylamino-ethoxy) -fluoren-9-one,

1,5-bis- (2-diethylamino-ethoxy) -fluoren-9-one,

3,5-bis- (2-dimethylamino-ethoxy) -fluoren-9-one,

1,5-bis- (2-dimethylamino-ethoxy) -fluoren-9-one,

3,5-bis- (3-diethylamino-propoxy) -fluoren-9-one,

1,5-bis- (3-diethylamino-propoxy) -fluorene-9-one,

3,5-bis- (4-diethylamino-n-butoxy) -fluorene-9-one,

1,5-bis- (4-diethylamino-n-butoxy) -fluoren-9-one,

3,5-bis- (2-pyrrolidinyl-ethoxy) -fluoren-9-one,

1,5-bis- (2-pyrrolidinyl-ethoxy) -fluoren-9-one,

3,5-bis- (pyrrolidinyl-methoxy) -fluoren-9-one,

1,5-bis- (pyrrolidinyl-methoxy) -fluoren-9-one,

3,5-bis- (3-pyrrolidinyl-propoxy) -fluorene-9-one,

1,5-bis- (2-pyrrolidinyl-propoxy) -fluorene-9-one,

3,5-bis- (4-pyrrolidinyl-n-butoxy) -fluorene-9-one,

1,5-bis- (4-pyrrolidinyl-n-butoxy) -fluorene-9-one,

3,5-bis- (2-piperidinyl-ethoxy) -fluoren-9-one,

1,5-bis- (2-piperidinyl-ethoxy) -fluoren-9-one,

3,5-bis- (piperidinyl-methoxy) -fluoren-9-one,

1,5-bis- (piperidinyl-methoxy) -fluoren-9-one,

3,5-bis- (3-piperidinyl-propoxy) -fluorene-9-one,

1,5-bis- (3-piperidinyl-propoxy) -fluorene-9-one,

3,5-bis- (4-piperidinyl-n-butoxy) -fluorene-9-one,

1,5-bis- (4-piperidinyl-n-butoxy) -fluorene-9-one,

3,5-bis- [2- (morpholino-4-yl) -ethoxy] -fluorene-9-one,

1,5-bis- [2- (morpholino-4-yl) -ethoxy] -fluorene-9-one,

3,5-bis-[(morpholino-4-yl) -methoxy] -fluorene-9-one,

1,5-bis-[(morpholino-4-yl) -methoxy] -fluorene-9-one,

3,5-bis- [3- (morpholino-4-yl) -propoxy] -fluorene-9-one,

1,5-bis- [3- (morpholino-4-yl) -propoxy] -fluorene-9-one,

3,5-bis- [4- (morpholino-4-yl) -n-butoxy] -fluoren-9-one,

1,5-bis- [4- (morpholino-4-yl) -n-butoxy] -fluoren-9-one,

1,5-bis- (2-diethylamino-ethoxy) -4-methoxy-fluoren-9-one,

1,5-bis- (2-diethylamino-ethoxy) -4-ethoxy-fluoren-9-one,

1,5-bis- (2-diethylamino-ethoxy) -4-propoxy-fluorene-9-one,

1,5-bis- (2-diethylamino-ethoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- (3-diethylamino-propoxy) -4-methoxy-fluorene-9-one,

1,5-bis- (3-diethylamino-propoxy) -4-ethoxy-fluorene-9-one,

1,5-bis- (3-diethylamino-propoxy) -4-propoxy-fluorene-9-one,

1,5-bis- (3-diethylamino-propoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- (2-pyrrolidinyl-ethoxy) -4-methoxy-fluoren-9-one,

1,5-bis- (2-pyrrolidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

1,5-bis- (2-pyrrolidinyl-ethoxy) -4-propoxy-fluoren-9-one,

1,5-bis- (2-pyrrolidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- (3-pyrrolidinyl-propoxy) -4-methoxy-fluoren-9-one,

1,5-bis- (3-pyrrolidinyl-propoxy) -4-ethoxy-fluoren-9-one,

1,5-bis- (3-pyrrolidinyl-propoxy) -4-propoxy-fluoren-9-one,

1,5-bis- (3-pyrrolidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- (2-piperidinyl-ethoxy) -4-methoxy-fluoren-9-one,

1,5-bis- (2-piperidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

1,5-bis- (2-piperidinyl-ethoxy) -4-propoxy-fluoren-9-one,

1,5-bis- (2-piperidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- (3-piperidinyl-propoxy) -4-methoxy-fluoren-9-one,

1,5-bis- (3-piperidinyl-propoxy) -4-ethoxy-fluoren-9-one,

1,5-bis- (3-piperidinyl-propoxy) -4-propoxy-fluoren-9-one,

1,5-bis- (3-piperidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

1,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-fluoren-9-one,

1,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-ethoxy-fluoren-9-one,

1,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-propoxy-fluoren-9-one,

1,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-n-butoxy-fluoren-9-one,

1,5-bis- [3- (morpholino-4-yl) -propoxy] -4-methoxy-fluoren-9-one,

1,5-bis- [3- (morpholino-4-yl) -propoxy] -4-ethoxy-fluoren-9-one,

1,5-bis- [3- (morpholino-4-yl) -propoxy] -4-propoxy-fluorene-9-one,

1,5-bis- [3- (morpholino-4-yl) -propoxy] -4-n-butoxy-fluorene-9-one,

2,5-bis- (2-diethylamino-ethoxy) -4-methoxy-fluoren-9-one,

2,5-bis- (2-diethylamino-ethoxy) -4-ethoxy-fluoren-9-one,

2,5-bis- (2-diethylamino-ethoxy) -4-propoxy-fluorene-9-one,

2,5-bis- (2-diethylamino-ethoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- (3-diethylamino-propoxy) -4-methoxy-fluorene-9-one,

2,5-bis- (3-diethylamino-propoxy) -4-ethoxy-fluorene-9-one,

2,5-bis- (3-diethylamino-propoxy) -4-propoxy-fluorene-9-one,

2,5-bis- (3-diethylamino-propoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- (2-pyrrolidinyl-ethoxy) -4-methoxy-fluoren-9-one,

2,5-bis- (2-pyrrolidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

2,5-bis- (2-pyrrolidinyl-ethoxy) -4-propoxy-fluoren-9-one,

2,5-bis- (2-pyrrolidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- (3-pyrrolidinyl-propoxy) -4-methoxy-fluoren-9-one,

2,5-bis- (3-pyrrolidinyl-propoxy) -4-ethoxy-fluoren-9-one,

2,5-bis- (3-pyrrolidinyl-propoxy) -4-propoxy-fluoren-9-one,

2,5-bis- (3-pyrrolidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- (2-piperidinyl-ethoxy) -4-methoxy-fluoren-9-one,

2,5-bis- (2-piperidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

2,5-bis- (2-piperidinyl-ethoxy) -4-propoxy-fluoren-9-one,

2,5-bis- (2-piperidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- (3-piperidinyl-propoxy) -4-methoxy-fluoren-9-one,

2,5-bis- (3-piperidinyl-propoxy) -4-ethoxy-fluoren-9-one,

2,5-bis- (3-piperidinyl-propoxy) -4-propoxy-fluoren-9-one,

2,5-bis- (3-piperidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-fluoren-9-one,

2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-ethoxy-fluoren-9-one,

2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-propoxy-fluoren-9-one,

2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-n-butoxy-fluoren-9-one,

2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-methoxy-fluoren-9-one,

2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-ethoxy-fluoren-9-one,

2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-propoxy-fluorene-9-one,

2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (2-diethylamino-ethoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (2-diethylamino-ethoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (2-diethylamino-ethoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (2-diethylamino-ethoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (3-diethylamino-propoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (3-diethylamino-propoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (3-diethylamino-propoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (3-diethylamino-propoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (2-pyrrolidinyl-ethoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (2-pyrrolidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (2-pyrrolidinyl-ethoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (2-pyrrolidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (3-pyrrolidinyl-propoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (3-pyrrolidinyl-propoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (3-pyrrolidinyl-propoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (3-pyrrolidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (2-piperidinyl-ethoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (2-piperidinyl-ethoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (2-piperidinyl-ethoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (2-piperidinyl-ethoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- (3-piperidinyl-propoxy) -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- (3-piperidinyl-propoxy) -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- (3-piperidinyl-propoxy) -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- (3-piperidinyl-propoxy) -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-propoxy-fluoren-9-one,

1-amino-2,5-bis- [2- (morpholino-4-yl) -ethoxy] -4-n-butoxy-fluoren-9-one,

1-amino-2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-methoxy-fluoren-9-one,

1-amino-2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-ethoxy-fluoren-9-one,

1-amino-2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-propoxy-fluorene-9-one,

1-amino-2,5-bis- [3- (morpholino-4-yl) -propoxy] -4-n-butoxy-fluorene-9-one,

5- (2-diethylamino-ethoxy) -2-methoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2-methoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-methoxy-fluoren-9-one,

5- (3-pyrrolidinyl-propoxy) -2-methoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-methoxy-fluoren-9-one,

5- (2-piperidinyl-propoxy) -2-methoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-methoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -propoxy] -2-methoxy-fluorene-9-one,

5- (2-diethylamino-ethoxy) -2-ethoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2-ethoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-fluoren-9-one,

5- (3-pyrrolidinyl-propoxy) -2-ethoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-ethoxy-fluoren-9-one,

5- (2-piperidinyl-propoxy) -2-ethoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -propoxy] -2-ethoxy-fluorene-9-one,

5- (2-diethylamino-ethoxy) -2-propoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2-propoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-propoxy-fluoren-9-one,

5- (3-pyrrolidinyl-propoxy) -2-propoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-propoxy-fluoren-9-one,

5- (2-piperidinyl-propoxy) -2-propoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-propoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -propoxy] -2-propoxy-fluorene-9-one,

5- (2-diethylamino-ethoxy) -2-n-butoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2-n-butoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-n-butoxy-fluoren-9-one,

5- (3-Pyrrolidinyl-propoxy) -2-n-butoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-n-butoxy-fluoren-9-one,

5- (3-piperidinyl-propoxy) -2-n-butoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-n-butoxy-fluoren-9-one,

5- [3- (morpholino-4-yl) -propoxy] -2-n-butoxy-fluoren-9-one,

4- (2-diethylamino-ethoxy) -5-methoxy-fluoren-9-one,

4- (3-diethylamino-propoxy) -5-methoxy-fluoren-9-one,

4- (2-pyrrolidinyl-ethoxy) -5-methoxy-fluoren-9-one,

4- (3-pyrrolidinyl-propoxy) -5-methoxy-fluoren-9-one,

4- (2-piperidinyl-ethoxy) -5-methoxy-fluoren-9-one,

4- (3-piperidinyl-propoxy) -5-methoxy-fluoren-9-one,

4- [2- (morpholino-4-yl) -ethoxy] -5-methoxy-fluoren-9-one,

4- [3- (morpholino-4-yl) -propoxy] -5-methoxy-fluoren-9-one,

4- (2-diethylamino-ethoxy) -5-ethoxy-fluoren-9-one,

4- (3-diethylamino-propoxy) -5-ethoxy-fluoren-9-one,

4- (2-pyrrolidinyl-ethoxy) -5-ethoxy-fluoren-9-one,

4- (3-pyrrolidinyl-propoxy) -5-ethoxy-fluoren-9-one,

4- (2-piperidinyl-ethoxy) -5-ethoxy-fluoren-9-one,

4- (3-piperidinyl-propoxy) -5-ethoxy-fluoren-9-one,

4- [2- (morpholino-4-yl) -ethoxy] -5-ethoxy-fluorene-9-one,

4- [3- (morpholino-4-yl) -propoxy] -5-ethoxy-fluoren-9-one,

4- (2-diethylamino-ethoxy) -5-propoxy-fluoren-9-one,

4- (3-diethylamino-propoxy) -5-propoxy-fluorene-9-one,

4- (2-pyrrolidinyl-ethoxy) -5-propoxy-fluoren-9-one,

4- (3-pyrrolidinyl-propoxy) -5-propoxy-fluorene-9-one,

4- (2-piperidinyl-ethoxy) -5-propoxy-fluoren-9-one,

4- (3-piperidinyl-propoxy) -5-propoxy-fluorene-9-one,

4- [2- (morpholino-4-yl) -ethoxy] -5-propoxy-fluoren-9-one,

4- [3- (morpholino-4-yl) -propoxy] -5-propoxy-fluorene-9-one,

4- (2-diethylamino-ethoxy) -5-n-butoxy-fluoren-9-one,

4- (3-diethylamino-propoxy) -5-n-butoxy-fluoren-9-one,

4- (2-pyrrolidinyl-ethoxy) -5-n-butoxy-fluorene-9-one,

4- (3-pyrrolidinyl-propoxy) -5-n-butoxy-fluoren-9-one,

4- (2-piperidinyl-ethoxy) -5-n-butoxy-fluoren-9-one,

4- (2-piperidinyl-propoxy) -5-n-butoxy-fluorene-9-one,

4- [2- (morpholino-4-yl) -ethoxy] -5-n-butoxy-fluoren-9-one,

4- [3- (morpholino-4-yl) -propoxy] -5-n-butoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-ethoxy-4-propoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-ethoxy-4-n-butoxy-fluorene-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-4-methoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-4-ethoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-ethoxy-4-ethoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-4-ethoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-4-propoxy-fluorene-9-one,

5- (2-piperidinyl-ethoxy) -2-ethoxy-4-propoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-4-propoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-methoxy-4-ethoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-methoxy-4-propoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-methoxy-4-n-butoxy-fluorene-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-methoxy-4-ethoxy-fluorene-9-one,

5- (2-piperidinyl-ethoxy) -2-methoxy-4-ethoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-methoxy-4-ethoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-methoxy-4-propoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-methoxy-4-propoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-methoxy-4-propoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-propoxy-4-ethoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2-propoxy-4-n-butoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-propoxy-4-ethoxy-fluorene-9-one,

5- (2-piperidinyl-ethoxy) -2-propoxy-4-ethoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-propoxy-4-ethoxy-fluoren-9-one,

5- (2-pyrrolidinyl-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2-propoxy-4-methoxy-fluoren-9-one,

5- (3-diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2,4-dimethoxy-fluorene-9-one,

5- (2-pyrrolidinyl-ethoxy) -2,4-dimethoxy-fluorene-9-one,

5- (3-pyrrolidinyl-propoxy) -2,4-dimethoxy-fluorene-9-one,

5- (2-piperidinyl-ethoxy) -2,4-dimethoxy-fluoren-9-one,

5- (3-piperidinyl-propoxy) -2,4-dimethoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2,4-dimethoxy-fluoren-9-one,

5- [3- (morpholino-4-yl) -propoxy] -2,4-dimethoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2,4-diethoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2,4-diethoxy-fluorene-9-one,

5- (2-pyrrolidinyl-ethoxy) -2,4-diethoxy-fluorene-9-one,

5- (3-pyrrolidinyl-propoxy) -2,4-diethoxy-fluorene-9-one,

5- (3-piperidinyl-propoxy) -2,4-diethoxy-fluorene-9-one,

5- (2-piperidinyl-ethoxy) -2,4-diethoxy-fluorene-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2,4-diethoxy-fluoren-9-one,

5- [3- (morpholino-4-yl) -propoxy] -2,4-diethoxy-fluoren-9-one,

5- (2-diethylamino-ethoxy) -2,4-dipropoxy-fluoren-9-one,

5- (3-diethylamino-propoxy) -2,4-dipropoxy-fluorene-9-one,

5- (2-pyrrolidinyl-ethoxy) -2,4-dipropoxy-fluorene-9-one,

5- (3-pyrrolidinyl-propoxy) -2,4-dipropoxy-fluoren-9-one,

5- (2-piperidinyl-ethoxy) -2,4-dipropoxy-fluoren-9-one,

5- (3-piperidinyl-propoxy) -2,4-dipropoxy-fluoren-9-one,

5- [2- (morpholino-4-yl) -ethoxy] -2,4-dipropoxy-fluoren-9-one,

5- [3- (morpholino-4-yl) -propoxy] -2,4-dipropoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-ethoxy-4-propoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-ethoxy-4-n-butoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2-ethoxy-4-methoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-4-methoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2-ethoxy-4-propoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2-ethoxy-4-propoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2-ethoxy-4-propoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-methoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-methoxy-4-propoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-methoxy-4-n-butoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2-methoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2-methoxy-4-ethoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2-methoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-propoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2-propoxy-4-n-butoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2-propoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2-propoxy-4-ethoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2-propoxy-4-ethoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2-propoxy-4-methoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2-propoxy-4-methoxy-fluorene-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one,

1-amino-5- (3-diethylamino-propoxy) -2,4-dimethoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2,4-dimethoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2,4-dimethoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2,4-dimethoxy-fluoren-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2,4-diethoxy-fluoren-9-one,

1-amino-5- (3-diethylamino-propoxy) -2,4-diethoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2,4-diethoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2,4-diethoxy-fluoren-9-one,

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2,4-diethoxy-fluorene-9-one,

1-amino-5- (2-diethylamino-ethoxy) -2,4-dipropoxy-fluoren-9-one,

1-amino-5- (3-diethylamino-propoxy) -2,4-dipropoxy-fluoren-9-one,

1-amino-5- (2-pyrrolidinyl-ethoxy) -2,4-dipropoxy-fluoren-9-one,

1-amino-5- (2-pyridinyl-ethoxy) -2,4-dipropoxy-fluoren-9-one and

1-amino-5- [2- (morpholino-4-yl) -ethoxy] -2,4-dipropoxy-fluoren-9-one.

Compound examples of the method of use of the invention include all compounds already listed and the following compounds:

2,5-bis- (2-diethylamino-ethoxy) -fluoren-9-one,

2,5-bis- (2-dimethylamino-ethoxy) -fluoren-9-one,

2,5-bis- (2-dipropylamino-ethoxy) -fluoren-9-one,

2,5-bis- (3-dimethylamino-propoxy) -fluorene-9-one,

2,5-bis- (3-diethylamino-propoxy) -fluoren-9-one and

2,5-bis- (3-dipropylamino-propoxy) -fluoren-9-one.

The following definitions were used throughout the experimental examples:

Room temperature or ambient temperature: 18-25 ° C .;

Overnight: 8-12 hours.

Brine: saturated aqueous sodium chloride (NaCl) solution.

THF: tetrahydrofuran.

LDA: lithium diisopropylamine.

MgSO ₄ : magnesium sulfate.

EtOAc: ethyl acetate.

CH ₂ Cl ₂ : methylene chloride.

NH ₄ Cl: ammonium chloride.

NaOH: sodium hydroxide.

Where reference is made to references in detail, it is intended that these references be interpreted as citing by reference.

I. Dibasic Fluorenone:

<Example 1>

The synthesis of Examples 1A-1D below was taken from Meyers, AI and Mihelitch ED, J. Am. Chem. Soc ., 97 , 7383 (1975).

<Example 1A>

2- (2,3-dimethoxy-phenyl) -4,4-dimethyl-4-oxazoline

Thionyl chloride (66 mL, 107.6 g, 0.9 mol) at room temperature is added dropwise with 2,3-dimethoxy benzoic acid (54.63 g, 0.3 mol) and stirred overnight until benzoyl chloride is fully formed. Excess thionyl chloride and any gas released on the rotary evaporator are removed. Additional toluene is added to remove any remaining thionyl chloride from the reaction vessel. The already formed 2,3-dimethoxy benzoic acid chloride is dissolved in methylene chloride (150 mL) and 2-amino-2-methyl-propanol (53.40 g, 57.2 mL, 0.6 mol) in chloroform (150 mL) at 0 ° C. The reaction temperature is maintained at 10 DEG C or lower while adding a stirred solution of. Once addition is complete, stir overnight to filter off any remaining amino-alcohol as a white solid. The filtrate is washed and extracted twice with 300 ml of water. Dry over magnesium sulfate, filter and concentrate to give a yellow oil. The product is left under vacuum until it solidifies (N- (2-hydroxy-1,1-dimethyl-ethyl) -2,3-dimethoxy-benzamide). Additional thionyl chloride (64 mL) is added dropwise to note the formation of the exothermic reactants and the yellow solution. Stir for about 1 hour, then add about 500 ml of anhydrous diethyl ether and stir overnight to precipitate the product oxazoline as hydrochloride. Pre-added ether was decanted from the reaction to add an additional amount (300 mL) and stirred vigorously. While the remaining solid is dissolved in a cooled ether: NaOH (aqueous) (80:20) solution, it is confirmed that the aqueous phase is basic. The organic phase is washed with brine and dried over MgSO ₄ . The remaining ether is stripped and dried under near vacuum to afford the title compound. Yield: 43.1 g (61%), Melting point: 48-50 ° C. (grey-white crystals). The structure of the compound is as follows:

<Example 1B>

2- (6,4'-dimethoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline

4-Bromoanisole (41.1 g, 27.5 mL, 0.22 mole) was added dropwise under stirring to prepare a solution of magnesium (5.5 g, 0.22 mole) in about 45 mL of diethyl ether. Heat gently and add iodine and / or 1,2-dibromoethane as needed to initiate the reaction. 4-Bromoanisole is continuously added at a rate sufficient to maintain reflux. Once the addition is complete, additional ether (100 mL) is added and heated to reflux for about 1 hour. Cool down to room temperature and add 2- (2,3-dimethoxy-phenyl) -4,4-dimethyl-4-oxazoline (17.6 g, 0.075 mol) dissolved in 90 ml of THF dropwise followed by stirring overnight to Note the exotherm and the dark brown color of the solution. Quench with 150 ml ammonium chloride. The organic layer is separated and the aqueous phase is extracted with 100 ml of THF. The combined organic phases are washed twice with 200 ml brine. Dry over MgSO ₄ , filter and rotary evaporate to give a dark yellow semisolid. Dissolve in 10% HCl (30 mL concentrated acid diluted to 120 mL) and wash twice with 100 mL ether. Hydrogen chloride of the title compound precipitates in the aqueous layer. The aqueous layer and the solids are made basic with 50% NaOH solution. Extract twice with 250 ml of ethyl acetate. The organic phase is dried over MgSO ₄ , filtered and rotary evaporation to afford 24.2 g (0.08 mole) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 1.43 (s, 6H), 3.89 (s, 3H), 3.86 (s, 3H), 4.66 (s, 2H), 7.05 (d, 2H), 7.22 (d, 2H) , 7.48 (dd, 2H), 7.60 (dd, 1H).

The structure of this compound is as follows:

<Example 1C>

2,5-dimethoxy-fluorene-9-one

2- (6,4'-dimethoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline (24.2 g, 0.08 mole) and 4.5N hydrochloric acid (750 mL) were combined and stirred at reflux Heat overnight. Cool to room temperature under stirring. The solidified resulting brown oil is filtered through sintered glass and washed three times with 100 ml of water to air dry. Transfer to pestel to grind to a tan powder to afford 6,4'-dimethoxy-biphenyl-2-carboxylic acid (16.4 g, 77%).

A suspension of 6,4'-dimethoxy-biphenyl-2-carboxylic acid (15.5 g, 0.060 moles) in 300 ml of anhydrous methylene chloride is prepared under argon at room temperature. Thionyl chloride (6.5 g, 0.078 mol, 4.0 mL) is added dropwise and heated at reflux for about 1 hour to confirm the conversion to acid chloride. Cool down to 0 ° C. and add dropwise tin chloride (SnCl ₄ ) (20.6 g, 0.079 mol, 9.1 mL) to ensure the temperature is maintained at 0-5 ° C. Once addition is complete, stirring is continued at 0 ° C. for 2 hours. The dark reaction mixture is poured onto ice and observed to turn orange. The organics are separated and the aqueous phase is extracted twice with 200 ml of methylene chloride. Any solid is dissolved with additional methylene chloride if necessary. The combined extracts are extracted twice with 200 ml of NaHCO ₃ . Wash again with brine. Dry over MgSO ₄ , filter and concentrate on rotary evaporator. Filter through separation chromatography and elute with methylene chloride to remove the baseline material. Yield: 9.0 g (62%).

Recrystallization from ethyl acetate gives a reddish orange solid that is 2,5-dimethoxy-fluorene-9-one. Melting point: 125 to 127 ° C.

<Example 1D>

2,5-dihydroxy-fluorene-9-one

A solution of 2,5-dimethoxy-fluorene-9-one (7.5 g, 0.031 mmol) in 50 ml of glacial acetic acid is prepared and warmed to 80 ° C. Once all fluorenone is in solution, 150 ml of hydrogen bromide (48% solution) is added. Continue heating to reflux to redissolve any precipitate formed and reflux overnight. Cool to room temperature and filter. Wash the filtrate with water. The solid is dissolved in ethyl acetate and dissolved by heating in a steam bath. Filter through a short column of silica eluting with warm ethyl acetate. The ethyl acetate eluted on the rotary evaporator is concentrated to give a dark red solid. Heating in warm methylene chloride dissolves and filters unwanted solids to afford 2,5-dihydroxy-fluorene-9-one. Melting point: 298-301 ° C. (decomposition). Yield: 9.4 g (97%).

<Example 2>

2,5-bis [(2-diethylamino) ethoxy] -fluoren-9-one

<Example 2A>

N, N-diethyl-2-bromo-5-methoxybenzamide

Diethylamine (0.951 g, 0.013) in a stirred suspension of 2-bromo-5-methoxy benzoic acid (2.31 g, 0.010 mol) and PyBOP (5.20 g, 0.010 mol) in CH ₂ Cl ₂ (30 mL) at ambient temperature Mole) is added. Watch the solution warm slightly and turn brown. To the brown solution is added diisopropylethylamine (3.83 mL, 0.022 mol) and the resulting mixture is stirred at rt overnight. The reaction mixture was extracted with H ₂ O (100 mL), 5% HCl (2 × 100 mL) and NaHCO ₃ (2 × 100 mL), washed with brine (100 mL), dried (MgSO ₄ ) and filtered Evaporate to give a brown oil. Chromatography eluting the oil with EtOAc-hexane (4: 6) affords 2.45 g (90%) of the title compound as a pale yellow liquid. R _f = 0.24. EtOAc-hexane (4: 6); ¹ H NMR (CDCl ₃ ) d 7.40 (1H, d), 6.79 (1H, s), 6.77 (1H, d), 3.78 (4H, m), 3.41-3.28 (1H, m), 3.18-3.15 (2H m), 1.27 (3H, s), 1.08 (3H, s).

<Example 2B>

N, N-diethyl-6,4'-dimethoxy-biphenyl-2-carboxamide

To a stirred solution of 2-bromo-5-methoxy-diethylbenzamide (2.43 g, 8.2 mmol) in DME (50 mL) Pd (PPh ₃ ) ₄ (0.55 g, 0.5 mmol), 2-methoxy phenyl Boronic acid (1.52 g, 10 mmol) and Na ₂ CO ₃ (2M, 7.0 mL) are added at ambient temperature, respectively. The resulting mixture is heated and stirred at reflux under an argon atmosphere for 7 hours and then overnight at ambient temperature. The solvent is evaporated and the residue is partitioned between H ₂ O—EtOAc. The organic layer is washed with brine, dried (MgSO ₄ ) and chromatographed with EtOAc-hexane to afford the title compound as off white solid. Recrystallization (cyclohexane) yields 1.91 g (69%) of white plate. Melting point: 117 to 118 ° C.

Elemental Analysis for C ₁₉ H ₂₃ NO ₃ :

Calc .: C, 72.82; H, 7. 40; N, 4.47.

Found: C, 72.57; H, 7. 34; N, 4.41.

<Example 2C>

2,5-dimethoxy-fluorene-9-one

To a stirred solution of freshly distilled diisopropylamine (1.90 mL, 13.5 mmol) in dry THF (20 mL) at −50 ° C. is added n-BuLi (2.5M, 5.5 mL, 13.5 mmol). The solution is allowed to warm to 0 ° C and then immediately cooled to -20 ° C and N, N-diethyl-6,4'-dimethoxy-biphenyl-2-carboxamide (1.70 g, 5.4 mmol) in THF (20 mL). Add). The resulting solution is stirred overnight. The red reaction mixture was quenched with saturated NH ₄ Cl solution and separated, the organic layer was washed with brine, dried (MgSO ₄ ) and filtered to evaporate the filtrate. The remaining solid is recrystallized (CH ₃ OH) to give the title compound as a red needle. Melting point: 125 to 127 ° C.

<Example 2D>

2,5-dihydroxy-fluorene-9-one

A 2,5-dimethoxy-fluoren-9-one (0.031 mmol) solution in glacial acetic acid (50 mL) is prepared and warmed up to 80 ° C. Hydrogen bromide (150 mL, 48% solution) was added and prepared according to the procedure described in Example 1D to give 2,5-dihydroxy-fluoren-9-one.

<Example 2E>

2,5-bis [(2-diethylamino) ethoxy] -fluoren-9-one

In a procedure similar to that reported in Andrews, Fleming et al ., J. Med. Chem . 17 (8), 882 (1974), 0.138 g of Na was reacted with 5.0 ml of anhydrous CH ₃ OH to give NaOCH ₃ Prepare a solution. To this solution is added 2,5-dihydroxy-fluorene-9-one (dried overnight at 100 ° C. under high vacuum) dissolved in chlorobenzene (20.0 mL). The stirred reaction mixture is heated under argon atmosphere until the methanol is evaporated (130 ° C.). 1.8 g (10.4 mmol) of 2-chloroethyldiethylamine hydrochloride basified with aqueous NaOH solution, extracted with chlorobenzene (20.0 mL), dried over MgSO ₄ and decanted to free base of 2-chloroethyldiethylamine To prepare. The resulting dark brown reaction mixture is heated and stirred at reflux overnight. The reaction mixture is cooled to ambient temperature, poured into 1% NaOH (100 mL) and extracted with CH ₂ Cl ₂ (100 mL). The organic layer is dried (MgSO ₄ ) and filtered to evaporate the filtrate on a rotary evaporator. The resulting dark brown oil is dissolved in anhydrous Et ₂ O (50 mL) and filtered. The filter is washed with additional anhydrous Et ₂ O (100 mL). To this solution is added ethereal HCl under an argon blanket. Precipitated hydrochloride (CH ₃ OH / EtOAc) is recrystallized to give the title compound as an orange solid (0.94 g, 75%). Melting point: 235 to 237 ° C.

The structure of the compound is as follows:

<Example 3>

3,5-bis- (2-diethylamino-ethoxy) -fluoren-9-one

<Example 3A>

2- (6,3'-dimethoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline

In a similar manner to Example 1B, Grignard reagent of magnesium (2.7 g, 0.11 mole) in 20 ml of anhydrous diethyl ether was prepared by dropwise addition of 3-bromoanisole (20.6 g, 0.11 mole) to 2- ( 2,3'-dimethoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline is obtained. Yield: 12.5 g (100%). EtOAc-hexane (4: 6), R _f = 0.26.

¹ H-NMR (CDCl ₃ ) δ 1.20 (6H, s, CH ₃ ), 3.70 (2H, s, CH ₂ ), 3.77 (3H, s, OCH ₃ ), 3.80 (3H, s, OCH ₃ ), 6.84 -6.93 (2H, m, Ar-H), 6.94 (1H, d, Ar-H), 7.05 (1H, d, Ar-H), 7.26-7.38 (3H, m, Ar-H).

The structure of the compound is as follows:

<Example 3B>

3,5-dimethoxy-fluorene-9-one, 1,5-dimethoxy-fluorene-9-one

In a manner similar to Example 1C, 2- (6,3'-dimethoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline (11 g, 0.035 mol) and 4.5N hydrochloric acid (about 350 117 mL diluted to mL) are combined to yield 8.2 g (91%) of carboxylic acid (6,3'-dimethoxy-biphenyl-2-carboxylic acid).

6,3'-dimethoxy-biphenyl-2-carboxylic acid (8.2 g, 0.032 mol) and thionyl chloride (3.3 g, 0.04 mol, 2.1 ml) were reacted in a similar manner to Example 1C, followed by tin chloride (11.2 g, 0.043 mol) is reacted. After 3 days, the reaction is quenched with aqueous HCl. The organic layer is separated, dried over MgSO ₄ and filtered to evaporate the solvent. Fractional crystallization from EtOAc / hexanes affords the 3,5-isomer (melting point: 122-124 ° C.) of the dimethoxy-fluorene-9-one as well as the 1,5-isomer (melting point: 118-121 ° C.). Yield: (3,5 isomer): 4.24 g, 55%; (1,5 isomer): 0.73 g, 9.5%.

¹ H-NMR (CDCl ₃ ) (3,5-isomer) δ 3.74 (3H, s, OCH ₃ ), 3.79 (3H, s, OCH ₃ ), 6.80-6.89 (3H, m, Ar-H), 7.12 (1H, d, Ar-H), 7.27 (1H, d, Ar-H), 7.37 (1H, 7.48 (1H, d, Ar-H).

The structure of the compound is as follows:

<Example 3C1>

3,5-dihydroxy-fluorene-9-one

In a similar manner to Example 1D, a solution of 3,5-dimethoxy-fluorene-9-one (4.0 g, 16.6 mmol) in 25 ml of glacial acetic acid was prepared and reacted with 75 ml of hydrogen bromide to give the title compound ( Melting point: 301-303 ° C. (decomposition), 54%).

<Example 3C2>

1,5-dihydroxy-fluorene-9-one

In a similar manner to Example 1D, a solution of 1,5-dimethoxy-fluorene-9-one (0.65 g, 2.7 mmol) in 15 ml of glacial acetic acid was prepared and reacted with 15 ml of hydrogen bromide to give the title compound ( Melting point: 236 to 238 ° C. (decomposition), yield: 0.50 g, 2.3 mmol, 87%).

<Example 3D1>

3,5-bis [(2-diethylamino) ethoxy] -fluoren-9-one

A solution of 3,5-dihydroxy-fluoren-9-one (1.06 g, 5 mmol) in 8 mL methanol and sodium methoxide (0.59 g, 11 mmol) in 24 mL chlorobenzene is prepared. Heat under stirring to evaporate methanol. 15 mL of aqueous amine chloride (2.1 g, 12 mmol) solution was made basic using an aqueous NaOH solution, and then sodium chloride was added to the free base of 2-chloroethyldiethyl amine hydrochloride until the solution was saturated and the amine precipitated. Prepared individually. Extract twice with 20 mL of chlorobenzene, then dry over MgSO ₄ and filter.

When the methanolic fluorenone solution temperature reaches 130 ° C., it is cooled to 100 ° C. and the pre-made free base of 2-chloroethyl-diethyl amine is added and stirring is continued overnight. The mixture is poured into 200 ml of 1% sodium hydroxide and extracted twice with 100 ml CH ₂ Cl ₂ . Dry over MgSO ₄ , filter through celite and remove solvent. The remaining solvent is removed by placing under vacuum. The remaining orange oil is dissolved in ether and filtered through celite. Ethereal hydrogen chloride is added until a precipitate forms. Wash with diethyl ether and dry the orange-yellow solid at 80 ° C. under almost vacuum for 24 h to afford the title compound. Melting point: 198 to 201 ° C. (decomposition). Yield: 1.27 g, 52%.

Elemental Analysis for C ₂₅ H ₃₄ N ₂ O ₃ · 2HCl · 3H ₂ O:

Calc .: C, 62.10; H, 7.51; N, 5.79.

Found: C, 61.06; H, 7.79; N, 5.63.

The structure of the compound is as follows:

<Example 3D2>

1,5-bis [(diethylamino) ethoxy] -fluoren-9-one

In a similar manner to Example 3D1, a solution of 1,5-dihydroxy-fluorene-9-one (0.5 g, 2.3 mmol) in 4 ml of methanol and 12 ml of chlorobenzene was prepared, followed by sodium methoxide (0.28 g , 5.1 mmol) is added. Free base 2-chloro-ethyl-diethyl amine (1.1 g, 6 mmol) in 20 mL chlorobenzene is added. The reaction is worked up in a conventional manner to afford the title compound. Melting point: 180 to 184 ° C. (decomposition). Yield: 0.68 g, 61%.

Elemental Analysis for C ₂₅ H ₃₄ N ₂ Cl ₃ 2HCl3H ₂ O:

Calc .: C, 62.10; H, 7.51; N, 5.59.

Found: C, 61.86; H, 7.53; N, 5.68.

The structure of the compound is as follows:

<Example 4>

2,5-bis- (2-diethylamino-ethoxy) -4-methoxy-fluoren-9-one

<Example 4A>

2,5-bis- (2-diethylamino-ethoxy) -4-methoxy-fluoren-9-one

2,5-dihydroxy-4-methoxy-fluoren-9-one (0.22 g, 0.9 mmol), 2-chloroethylamine hydrochloride (1.7 g, 0.10 mol) and sodium methoxide (0.20 g, 3.6 mmol ) Is reacted as described in Example 9B to afford the title compound as a hemihydrate (0.10 g, 22%). Melting point: 236 to 238 ° C.

Elemental Analysis for C ₂₆ H ₃₆ N ₃ O ₄ · 2HCl · 1/5 · H ₂ O:

Calc .: C, 60.39; H, 7. 49; H, 5. 42.

Found: C, 60.24; H, 7. 36; N, 5.39.

The structure is as follows:

The following synthesis is adopted from MV Sargent, J. Chem. Soc. Perkin Trans. I , 2553 (1987) and W. Wang, V. Snieckus, J. Org. Chem ., 57, 424 (1992). It was.

<Example 4B>

2,5-dihydroxy-4-methoxy-fluoren-9-one (dengibsin, Dengibsin)

6,4'-Diisopropyloxy-2'-methoxy-biphenyl-2-diethylcarboxamide (1.30 g, 3.3 mmol) in THF (15.0 mL) was treated with THF (30 mL) under argon at -50 ° C. To a stirred solution of LDA (0.013 mol) in. The resulting pale yellow solution is warmed to ambient temperature and stirred for 48 hours. Quench with saturated NH ₄ Cl (30 mL) solution and dilute with THF (150 mL). The organic layer is separated and washed, then washed with brine, separated, dried over MgSO ₄ and filtered. Concentrate the filtrate to give red oil (1.07 g). Flash chromatography eluting with EtOAc / hexanes (15:85) gave 0.57 g of the title compound as a red solid. Melting point: 71 to 72 ° C.

<Example 4C>

6,4'-Diisopropyloxy-2'-methoxy-biphenyl-2-diethyl-carboxamide

Thionyl chloride (0.1793 g, 2.1 mmol) in 6,4'-diisopropyloxy-2'-methoxy-biphenyl-2-carboxylic acid (0.315 g) in CH ₂ Cl ₂ (14.00 mL) under argon atmosphere. , 0.9 mmol) and 1,2,4-trimethoxybenzene (0.1576 g, 0.9 mmol) in dropwise addition. The resulting yellow solution is stirred at ambient temperature for 15 minutes and then heated at 41 ° C. for 15 minutes. The resulting light brown solution is cooled to 0-5 ° C. in an ice bath and diethylamine (0.848 g, 11.6 mmol) is added dropwise to confirm that the temperature is maintained at 15 ° C. or lower. After the addition is complete the solution is warmed to ambient temperature and stirred for 4 hours. Dilute with CH ₂ Cl ₂ (75 mL), extract with water (2 × 50 mL), separate, extract with 5% NaHCO ₃ (2 × 50 mL), separate, wash with brine (50 mL), and separate then dried over MgSO _4. The concentrate is filtered and the resulting residue is chromatographed (EtOAc / hexane 4: 6) to afford the title compound as a white solid. Melting point: 74 to 75 ° C.

<Example 4D>

6,4'-Diisopropyloxy-2'-methoxy-biphenyl-2-carboxylic acid

2- (6,4'-diisopropyloxy-2'-methoxy-biphenyl-2-yl) -3,4,4-trimethyl-oxa in 20% NaOH (140 mL) and methanol (140 mL) A solution of zolinium iodide (13.20 g, 0.0245 mol) is prepared and stirred at reflux overnight. The resulting colorless solution is concentrated on a rotary evaporator until precipitation begins. The resulting suspension is diluted to 300 ml with water and acidified to pH 1 with concentrated HCl. The precipitate is extracted with CH ₂ Cl ₂ (400 mL), washed with brine, separated and dried over MgSO ₄ . Filtration, concentration and recrystallization from cyclohexane (˜175 mL) afforded the title compound (7.10 g, 84%). Melting point: 117 to 119 ° C.

<Example 4E>

2- (6,4'-Diisopropyloxy-2'-methoxy-biphenyl-2-yl) -3,4,4-trimethyl-oxazolinium iodide

Iodomethane (12.43 g, 0.0875 mol) was added to 2- (6,4'-diisopropyloxy-2'-methoxy-biphenyl-2-yl) -4,4-dimethyl in anhydrous DMSO (30 mL). To a stirred solution of oxazoline (5.80 g, 0.0146 mol) is added. The resulting mixture is stirred for about 72 hours and then diluted with ether (600 mL). The precipitated solid is collected by filtration, then triturated with CHCl ₃ (400 mL) and filtered. Discard the insoluble solid and concentrate the filtrate to afford the title compound as off white solid. Melting point: 213 to 214 ° C.

<Example 4F>

2- (6,4'-Diisopropyloxy-2'-methoxy-biphenyl-2-yl) -4,4-dimethyloxazoline

2- (2,3-Diisopropyloxy-phenyl-2-yl) -4,4-dimethyl-oxazoline (8.74 g, 0.030 mol) in THF (30 mL) was dried at ambient temperature, with dry THF (175 mL). To Grignard reagent prepared from 1-bromo-2methoxy-4-isopropoxy-benzene (7.35 g, 0.030 mol) and magnesium (0.7240 g, 0.030 mol) in. After the addition is complete, stir overnight at ambient temperature. The reaction is quenched with saturated NH ₄ Cl solution, separated, washed with brine, separated, dried over MgSO _4, filtered and concentrated on a rotary evaporator. The residue is chromatographed (EtOAc / hexane 4: 6) to give 6.52 g (64%) as a viscous liquid. R _f = 0.29. The structure corresponds to:

<Example 4G>

3-methoxy-4-bromophenol

4-Bromo-resorcinol (17.75 g, 0.0896 mol) and potassium carbonate (K ₂ CO ₃ , 80.0 g, 0.58 mol) are stirred in acetone (1 L) under argon. Para-toluenesulfonyl chloride (17.12 g, 0.0896 mol) is added and heated to reflux for about 20 hours. The mixture is cooled to room temperature and methyl iodide (CH ₃ I, 34.20 g, 15.00 mL, 0.24 mol) is added. Cool to ambient temperature, dilute with ether (800 mL) and filter through celite. Concentrate to give 31.70 g of semi-solid, transfer to 3 L flask with ethanol (1 L), add 8% aqueous potassium hydroxide solution (1 L), and stir at reflux until all solids are in solution. Continue heating under argon for 2 hours and stir overnight at ambient temperature under argon. The reaction mixture is acidified with HOAc (100 mL) in an ice bath and then extracted with ether (3 x 400 mL). The ether extract is washed with brine, separated, dried over MgSO ₄ and filtered. The resulting yellow liquid is concentrated in vacuo overnight to give 18.0 g (99%) of the waxy solid of the title compound.

II. Monobasic, alkoxy fluorenone:

<Example 5>

5- (2-Diethylamino-ethoxy) -2-methoxy-fluoren-9-one

<Example 5A>

5- (2-Diethylamino-ethoxy) -2-methoxy-fluoren-9-one

5-hydroxy-2-methoxy-fluoren-9-one (0.35 g, 1.5 mmol), 3 mL of methanol and sodium methoxide (0.12 g, 2.1) in 10 mL of chlorobenzene in a similar manner as in Example 3D1 Mole). After cooling, specially prepared free base 2-chloroethyldiethyl amine is added to give the hydrochloride of the title compound as a yellow-orange powder. Melting point: 196-199 ° C. (decomposition). Yield: 0.387 g (72%).

Elemental Analysis for _{C 20 H 23 NO 3 · HCl} :

Calc .: C, 66.38; H, 6. 69; N, 3.87.

Found: C, 66.16; H, 6. 69; N, 3.80.

<Example 5B>

5-hydroxy-2-methoxy-fluoren-9-one

5-Isopropoxy-2-methoxy-fluoren-9-one (0.78 g, 2.9 mmol) is combined with boron trichloride (1.0M in methylene chloride, 6.50 mL) in 20 mL of methylene chloride at 0 to -5 ° C. . The reaction is stirred at 5 ° C. for 1 hour and then quenched with 20 ml of water to maintain the temperature below 20 ° C. The solution turns red from dark brown solution as a hairy solid precipitate. Melting point: 245 to 248 ° C. The precipitate is filtered off to yield 0.296 g of a red solid. Melting point: 245 to 248 ° C.

Elemental Analysis for C ₁₄ H ₂ O ₃ :

Calc .: C, 74.33; H, 4.46.

Found: C, 74.33; H, 4.58.

<Example 5C>

5-isopropoxy-2-methoxy-fluoren-9-one

N-butyl lithium (2.5 M 22.00 ml, 0.055 mol) and diisopropylamine (6.07 g, 0.060 mol) in 150 ml tetrahydrofuran (THF) are combined at -50 ° C under stirring. Wait about 5 minutes and then dropwise add N, N-diethyl-2'-isopropoxy-4-methoxy-biphenyl-2-carboxamide (3.80 g, 0.011 mol) dissolved in 50 ml of THF. . The cooling source is removed and the reaction is brought to ambient temperature and stirred for 5 hours while heating at 65 ° C. The reactant turns orange and then dark brown. The reaction is continued to stir overnight at ambient temperature, then cooled in an ice bath and neutralized with about 100 ml of saturated ammonium chloride solution. The reactant turns orange. The THF solvent is washed separately with brine (saturated sodium chloride) and dried over magnesium sulfate. Filtration and concentration yields a red liquid. This material (20% ethyl acetate: 80% hexane) was purified by chromatography to give an orange liquid which solidified when drying under high vacuum to give an orange solid (1.60 g, 50%). Melting point: 89-90 ° C.

Elemental Analysis for C ₁₇ H ₁₆ O ₃ :

Calc .: C, 76.10; H, 6.06.

Found: C, 76.31; H, 6.0.

<Example 5D>

N, N-diethyl-2'-isopropoxy-4-methoxy-biphenyl-2-carboxamide

A solution of 2'-isopropoxy-4-methoxy-biphenyl-2-carboxylic acid (4.80 g, 0.0168 mol) in 125 ml methylene chloride (dichloromethane) is prepared. Thionyl chloride (2.99 g, 0.0356 moles, 1.835 mL) is added under ambient conditions under argon. Continue stirring for about 45 minutes to observe the color change to light brown. The reaction mixture is cooled to 0 ° C. and diethylamine (22.00 mL, 15.627 g, 0.21 mole) is added dropwise to ensure that the temperature does not exceed 25 ° C. Stirring is continued for 30 minutes after the amine addition is complete. The reaction is diluted with 150 ml of methylene chloride and the organic phase is washed with water and then separated and washed twice with 100 ml of 5% sodium bicarbonate. Separate, wash with brine (saturated NaCl) and dry over magnesium sulfate. Filtration through celite and evaporation on a rotary evaporator yielded a viscous light brown liquid. Chromatography (30% ethyl acetate: 70% hexanes) yields a pale yellow liquid. Placed in near vacuum to give a waxy solid of the title compound (3.80 g, 66%).

<Example 5E>

2'-isopropoxy-4-methoxy-biphenyl-2-carboxylic acid

A solution of sodium hydroxide (20%, 60 mL) and methanol (60 mL) was prepared and 2- (2'-isopropoxy-4-methoxy-biphenyl-2-yl) -3,4,4-trimethyl 4-oxazolinium iodide salt (8.30 g, 0.0172 mol) is added. The reaction mixture is stirred and heated at reflux under an argon atmosphere for about 20 hours. The reactant is cooled to ambient temperature and the reactant volume is lowered on a rotary evaporator to the point where the reactant becomes cloudy. The reaction mixture is diluted to 500 ml with water and then acidified with concentrated hydrochloric acid. A gummy precipitate is formed. Extract with methylene chloride (150 mL) and wash the organic phase twice with 100 mL sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filtration through celite gave an off white solid (4.85 g, 98%).

The structure of the compound is as follows:

<Example 5F>

2- (2'-isopropoxy-4-methoxy-biphenyl-2-yl) -3,4,4-trimethyl-4-oxazolinium iodide

Iodomethane (22.8 g, 10.00 mL) was added to 2- (2'-isopropoxy-4-methoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxa in nitromethane (60 mL). To a stirred solution of sleepy (7.40 g, 0.0218 mL) is added and the resulting mixture is stirred overnight under argon. The solution is diluted with anhydrous ether (400 mL) and the resulting white precipitate is collected by filtration and air dried to give a white solid (8.30 g, 79%).

The structure of the compound is as follows:

<Example 5G>

2- (2'-isopropoxy-4-methoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline

A Grignard solution of 1-bromo-2-isopropoxy benzene (16.13 g, 0.075 mL) and magnesium (1.82 g, 0.075 mole) in anhydrous THF (150 mL) was prepared. Carefully add a 2- (2,5-dimethoxyphenyl) -4,4-dimethoxy-4-oxazoline (7.07 g, 0.030 mol) solution dissolved in THF (30 mL). The reaction temperature is raised to 32 ° C. during the addition. After the addition is complete the reaction is stirred overnight at ambient temperature. Neutralize with NH ₄ Cl (75 mL). The THF layer was separated, washed with brine, concentrated again, concentrated, dissolved in 5% HCl (300 mL), basified with solid potassium carbonate (K ₂ CO ₃ ) to pH 8.0, and the resulting precipitate collected and collected with EtOAc. Extract.

The EtOAc mixture is separated, washed with brine, separated, dried over MgSO _4, filtered and the filtrate is concentrated to a yellow crude oil. The oil is eluted with 20% EtOAc / 80% hexanes to give 7.40 g (63%) of the title compound.

The structure of the compound is as follows:

<Example 5H>

2- (2,5-dimethoxy-phenyl) -4,4-dimethyl-4-oxazoline

Thionyl chloride (97.97 g, 60.00 mL, 0.823 mol) is added dropwise to 2,5-dimethoxybenzoic acid (50.00 g, 0.2745 mol) under ambient temperature and argon atmosphere and stirred overnight. Excess thionyl chloride is evaporated on the rotary evaporator followed by addition of toluene (˜50 mL) and concentrated on the rotary evaporator. The resulting acid chloride was dissolved in methylene chloride (about 180 mL) and added to a stirred solution of 2-amino-2-methyl-1-propanol (26.74 g, 28.63 mL, 0.30 mol) in methylene chloride (270 mL) at 0 ° C. Be careful not to exceed 20 ° C by the addition. After precipitation, the mixture is stirred at ambient temperature for 2 hours. Extract twice in 200 mL of water, wash with brine, dry over magnesium sulfate, filter and concentrate to give amide (N- (1-hydroxy-1-methyl-ethyl) -2,5-dimethoxy-benzamide). To obtain.

The amide is ground and placed in a flask with a magnetic stir bar. Additional thionyl chloride (54.00 mL, 88.07 g, 0.7403 mol) is added slowly under stirring to observe the exothermicity of the product. After the addition is complete the solution is kept stirring for about 20 minutes, then diluted with anhydrous ether and stirred overnight. The precipitate is collected, washed with anhydrous ethyl acetate and air dried. The resulting gum solid is dissolved in H ₂ O and neutralized with 20% NaOH. The resulting oil is extracted with EtOAc (500 mL). The ethyl acetate layer is washed with brine and dried over MgSO ₄ . Filtration and concentration affords the title compound (50.40 g, 77%).

The structure of the compound is as follows:

<Example 6>

5- (2-Diethylamino-ethoxy) -2-propoxy-fluoren-9-one

<Example 6A>

5- (2-Diethylamino-ethoxy) -2-propoxy-fluoren-9-one

2-Chloroethyldiethylamine hydrochloride (0.60 g, 3.5 mmol) is dissolved with water (20 mL) and made basic with aqueous NaOH. Extract with chlorobenzene (2 × 10 mL) and dry the organic layer over MgSO ₄ and filter. 5-hydroxy-2-propoxy-9-fluoren-9-one (0.42 g, 1.6 mmol) is dissolved in a solution of methanol (2.0 mL) and chlorobenzene (10 mL). Sodium methoxide (0.10 g, 1.8 mmol) is added to the MeOH / chlorobenzene mixture and the resulting mixture is heated to 130 ° C. The dark brown suspension is cooled to 100 ° C. and 2-chloroethyldiethylamine solution is added dropwise. The combined mixture is heated at reflux overnight. Work up the reaction as described in Example 2E to afford the title compound as a hydrate (0.28 g, 44%). Melting point: 190-193 ° C. CI-MS [M + H] ⁺ = 354.

Elemental Analysis for _{C 22 H 27 NO 3 · HCl} · (2.5) H 2 O:

Calc .: C, 66.99; H, 7. 28; N, 3.55.

Found: C, 66.73; H, 7.47; N, 3.56.

¹ H- (CDCl ₃ ) δ 0.97 (3H, t, CH ₃ ), 1.26 (6H, t, CH ₃ ), 1.73 (2H, m, CH ₂ ), 3.27 (4H, q, CH ₂ ), 3.65 ( 2H, NCH ₂ ), 4.00 (2H, t, OCH ₂ ), 4.58 (2H, t, OCH ₂ ), 7.09 (1H, d, ArH), 7.14 (1H, s, ArH), 7.23 (1H, d, ArH), 7.30 (1H, t, ArH), 7.36 (1H, d, ArH), 7.75 (1H, d, ArH).

The structure of the compound is as follows:

<Example 6B>

5-hydroxy-2-propoxy-fluoren-9-one

N-butyl-lithium (4.80 mL, 0.012 mol) in THF (60 mL) is added dropwise to diphenylphosphine (Ph ₂ PH, 2.34 g, 0.012 mol) at -20 ° C. The resulting red solution is allowed to warm to ambient temperature and then stirred for 30 minutes. A 5-methoxy-2-propoxy-fluoren-9-one (0.88 g, 3.3 mmol) solution in THF (20 mL) was prepared and added to the dark red Ph ₂ PH stirred solution and added while changing from dark red to brown Stir for 1 hour then heat at reflux for 15 minutes. Cool to ambient temperature and then quench with saturated NH ₄ Cl solution. The THF layer is separated, washed with brine, dried over MgSO _4, filtered and the filtrate is concentrated to orange oil. The oil is dissolved in CH ₂ Cl ₂ and extracted with 5% aqueous NaOH (50 mL) to form a purple solid in the aqueous layer.

The aqueous layer is separated in a separatory funnel and the precipitated solid is collected by filtration. The solid in the aqueous phase is acidified to pH 1 with HCl and dissolved with EtOAc (150 mL). EtOAc solvent is dried over MgSO _4, filtered and evaporated to afford 0.450 g (44%) of the title phenol. Melting point: 224 to 226.

The structure of the compound is as follows:

<Example 6C>

5-methoxy-2-propoxy-fluoren-9-one

In a similar manner to the second paragraph of Example 1C, 6-methoxy-4'-propoxy-biphenyl-2-carboxylic acid (2.85 g, 0.0106 mol) in anhydrous methylene chloride (-50 mL) was identified by thionyl chloride. (2.10 g, 1.10 mL) and tin chloride (5.21 g, 2.30 mL, 0.030 mole) to give 5-methoxy-2-propoxy-fluoren-9-one. Yield: 2.24 g, 83%. Melting point: 96 to 97 ° C.

¹ H-NMR (CDCl ₃ ) δ1.04 (t, 3H, CH ₃ ), 1.81 (q, 2H, CH ₂ ), 3.94 (m, 5H, OCH, OCH ₃ ), 6.91 (d, 1H), 7.21 -7.15 (m, 2H), 7.25 (d, 1H), 7.65 (d, 1H).

<Example 6D>

6-methoxy-4'-propoxy-biphenyl-2-yl-2-carboxylic acid

Similar to Example 5E, 2- (6-methoxy-4'-propoxy-biphenyl) -3,4,4-trimethyl-4-oxazoli in 50 ml of 20% sodium hydroxide and 50 ml of methanol Reaction of iodide (5.10 g, 0.0106 mol) affords the title compound (2.80 g, 98%). Melting point: 118 to 120 ° C.

<Example 6E>

2- (6-methoxy-4'-propoxy-biphenyl) -3,4,4-trimethyl-4-oxazolinium iodide

2- (6-methoxy-4'-propoxy-biphenyl) -4,4-dimethyl-4-oxazoline (6.10 g, 0.018 mole), methyl iodide (5.00 mL) in a similar manner to Example 5F ) And nitromethane to give the title compound (7.10 g, 82%). Melting point: 222 to 224 ° C.

<Example 6F>

2- (6-methoxy-4'-propoxy-biphenyl) -4,4-dimethyl-4-oxazoline

In a similar manner to Example 1A, 4-bromo-1-n-propoxybenzene (10.75 g, 0.050 mol) and magnesium (1.22 g, 0.050 mol) in diethyl ether (100 mL) were converted into 1,2-dibro The reaction is initiated if necessary by reaction with the parent ethane (three drops) and iodine (crystal). Additional diethyl ether (-50 mL) is added and then heated to reflux for about 1 hour. Cool to ambient temperature and add 2- (2,3-dimethoxy-phenyl) -4,4-dimethyl-4-oxazoline (4.70 g, 0.020 mol) dissolved in tetrahydrofuran (60 mL) dropwise. The reaction temperature is raised to about 36 ° C. during the addition. The light brown reaction mixture is kept stirring overnight and then quenched with saturated ammonium chloride solution. The organic layer is separated, washed with brine, separated again, dried over MgSO _4, filtered and concentrated. The remaining oil is dissolved in ethyl acetate and extracted with about 200 ml of 9% hydrochloric acid. The aqueous layer is separated and then made alkaline with solid potassium carbonate. Extract with EtOAc, separate, dry over MgSO ₄ and concentrate to give the title compound (4.70 g, 70%).

<Example 6G>

1-bromo-4-propoxy-benzene

A solution of 4-bromo-phenol (17.30 g, 0.10 mole) and potassium carbonate (13.80 g, 0.1 mole) in isopropanol (175 mL) is prepared. The resulting mixture is heated at reflux and stirred overnight. Cool to ambient temperature and filter to concentrate the filtrate on a rotary evaporator. The remaining oil is dissolved in ethyl acetate (250 mL), extracted twice with 5% sodium hydroxide (100 mL), separated and washed with brine. Kugelrohr distillation at 100-120 ° C. (0.05 mm) affords the title compound (12.86 g, 60%) as a clear liquid.

<Example 7>

4- (2-Diethylamino-ethoxy) -5-methoxy-fluoren-9-one

<Example 7A>

4- (2-Diethylamino-ethoxy) -5-methoxy-fluoren-9-one

In a similar manner to Example 2B, a free base of 2-chloroethyl-dimethylamine hydrochloride (0.60 g, 3.5 mmol) is prepared. As before, a solution of 4-hydroxy-5-methoxy-fluorene-9-one (0.54 g, 2.4 mmol) in methanol (4 mL) and chlorobenzene (12 mL) was separately prepared and stirred for 30 minutes While heating to 130 ℃. The reaction is cooled to 100 ° C. and then free base of 2-chloroethyl-dimethylamine prepared in 15 ml of chlorobenzene is added. Proceed as in Example 2B above to afford the title compound as an orange-yellow powder (0.79 g, 91%). Melting point: 188-191 ° C. (decomposition).

Elemental Analysis for C ₂₀ H ₂₃ NO ₃ :

Calc .: C, 66.38; H, 6. 69; N, 3.87.

Found: C, 66.58; H, 6.51; N, 3.79.

The structure of the compound is as follows:

<Example 7B>

4-hydroxy-5-methoxy-fluoren-9-one

A solution of 4-isopropoxy-5-methoxy-fluorene-9-one (0.78 g, 2.9 mmol) in methylene chloride (15 mL) is prepared and stirred at 0 ° C. under argon atmosphere. 9 ml (9.0 mmol) of boron trichloride (1.0 M) in methylene chloride are added dropwise and the mixture is stirred for 1 hour to observe a darkening change. The reaction was quenched with 20 mL of water to observe the mild exothermic reactants and the orange precipitate. The solid is filtered off and washed twice with 100 ml of methylene chloride. The organic layer is separated from the filtrate and washed with brine. Dry over magnesium sulfate and filter to remove solvent. The solid is recrystallized from chloroform / hexanes (20:80, R _f = 0.2) to afford the title compound. Yield: 0.55 g, 84%.

The structure of the compound is as follows:

<Example 7C>

4-isopropoxy-5-methoxy-fluoren-9-one

LDA reagents are prepared by combining 4.1 ml of n-butyl lithium (2.5M in hexane) and 1.4 ml of diisopropylamine dropwise under argon in 40 ml of tetrahydrofuran (THF) at -50 ° C. The reaction was warmed to 0 ° C. and N, N-diethyl-2′-isopropoxy-6-methoxy-biphenyl-2-carboxamide (1.4 g, 4.1 mmol) dissolved in THF (15 mL). Add dropwise with stirring. The temperature is maintained at 0 ° C. for 10 minutes and then the reaction is brought to room temperature as it slowly changes to yellow. Heat the reaction at reflux for about 2 hours and observe that the yellow solution darkens. The reaction is quenched with saturated ammonium chloride, extracted with ether and the organic layer is washed with water. Recrystallization from ether / methanol yields the orange title compound solid (0.34 g, 1.3 mmol, 31%). Melting point: 118 to 120 ° C.

The structure of the compound is as follows:

<Example 7D>

N, N-diethyl-2'-isopropoxy-6-methoxy-biphenyl-2-carboxamide

A stirred solution of 2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid (1.432 g, 0.0050 mol) in methylene chloride (50 mL) was prepared under argon at -50 ° C. Warm to ambient temperature and then add thionyl chloride (0.8415 g, 0.516 mL). Continue stirring for about 45 minutes and observe the change to light brown. Cool to 0 ° C and add diethylamine (6.00 mL, 4.242 g, 0.058 mole) dropwise to maintain the temperature of the reaction at 26 ° C or less. Once addition is complete, continue stirring for about 30 minutes. Dilute to 150 ml with additional methylene chloride. The methylene chloride layer is washed with water, separated and extracted with 100 ml of 5% sodium bicarbonate. Separate, wash again with brine, separate and dry over MgSO ₄ . Filter through celite and concentrate to a viscous light brown liquid on a rotary evaporator. Elution with chromatography using 30% ethyl acetate / 70% hexanes yields a clear viscous liquid (1.90 g). Concentration under high vacuum gives the waxy title compound solid (1.40 g, 82%).

<Example 7E>

2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid

2- (2'-isopropoxy-6-methoxy-biphenyl) -4,4-dimethyl-4-oxazolium methyl iodide (7.10 g, 0.0127 mol) and 20% NaOH in methanol (60 mL) (60 mL) of a stirred mixture is prepared and heated at reflux for 20 h under argon. The resulting solution is cooled to ambient temperature and then methanol is evaporated on a rotary evaporator until the solution becomes cloudy. This fine suspension is diluted to 200 ml with water and then acidified with concentrated HCl to pH 1 to precipitate the title compound. Extract with CH ₂ Cl ₂ (200 mL), separate, wash with brine, separate again, dry over MgSO _4, filter and concentrate the filtrate to give the purified title compound as off white solid (3.67 g, 87%). Melting point: 139 to 140 ° C.

The structure of the compound is as follows:

<Example 7F>

2- (2'-isopropoxy-6-methoxy-biphenyl) -4,4-dimethyl-4-oxazolium methyl iodide

Of 2- (2'-isopropoxy-6-methoxy-biphenyl) -4,4-dimethyl-4-oxazoline (6.10 g, 0.0180 mol) in nitromethane (CH ₃ NO ₂ , -50 mL) Prepare a stirred solution and add iodomethane (11.40 g, 0.080 mol) and continue stirring overnight. Dilution with ether (400 mL) and filtration give the title compound (7.10 g, 82%) as off-white solid. Melting point: 222 to 224 ° C.

<Example 7G>

2- (2'-isopropoxy-6-methoxy-biphenyl) -4,4-dimethyl-4-oxazoline

In a manner similar to Examples 6F and 1A, 2- (2,3-dimethoxyphenyl) -4,4-dimethyloxazoline (4.70 g, 0.020 mol) was dissolved in THF (50 mL) and this was dried with anhydrous ether (75 mL). To Grignard prepared from 1-bromo-2-isopropoxybenzene (10.75 g, 0.050 mol) and Mg (1.22 g, 0.050 mol). Work up as in Example 6F to afford the title compound as pale yellow oil (6.30 g, 81%).

The structure of the compound is as follows:

<Example 7H>

1-bromo-2-isopropoxy-benzene

A stirred mixture of ortho-bromo-phenol (25.951 g, 17.4 mL, 0.15 mole) and potassium carbonate (20.70 g, 0.16 mole) in 175 mL of isopropanol is prepared under argon at ambient temperature. Isopropyl iodide (22.2 g, 16.00 mL) is added slowly and heated at reflux and the mixture is stirred overnight. Cool to ambient temperature then filter and concentrate the filtrate on a rotary evaporator. The remaining oil is dissolved in diethyl ether (300 mL) and extracted twice with 100 mL of 50% sodium hydroxide. Separate, wash with brine and concentrate on rotary evaporator to give a pale yellow liquid. Distillation on Kugelroer (0.05 mm, 100-120 ° C.) affords the title compound as an oil (24.21 g, 75%).

<Example 8>

5- (2-Diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one

<Example 8A>

5- (2-Diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one

2,4-dimethoxy-5-hydroxy-fluoren-9-one (0.33) in 24 ml of chlorobenzene with methanol (8 ml) and sodium methoxide (0.11 g, 2.0 mmol) similar to Example 3D1 g, 1.3 mmol) and a free base of 2.1 g (12 mmol) of 2-chloro-ethyl-diethylamine hydrochloride are obtained to give 0.30 g of the title compound as a reddish orange powder. Melting point: 178 to 180 ° C.

Elemental Analysis for _{C 21 H 25 NO 4 · HCl} :

Calc .: C, 64.36; H, 6. 69; N, 3.58.

Found: C, 63.99; H, 6.75; N, 3.62.

<Example 8B>

2,4-dimethoxy-5-hydroxy-fluoren-9-one

A 5-isopropoxy-2,4-dimethoxy-fluoren-9-one (0.48 g, 1.6 mmol) solution in 25 mL CH ₂ Cl ₂ is prepared and stirred at 0 ° C. under argon. Boron trichloride (1.0 M in 1.8 mL CH ₂ Cl ₂ , 1.8 mmol) is added dropwise and the reaction is stirred for 1 hour. Quench with 20 mL of water and stir vigorously. It is filtered and the resulting precipitate is washed twice with 100 ml of methylene chloride. The organic layer is separated from the filtrate and washed with brine. Dry with MgSO ₄ and filter to strip the solvent. The solid is recrystallized from CH ₂ Cl ₂ / hexanes (4: 6) to give the title compound (0.28 g, 1.1 mmol, 69%). R _f = 0.35.

The structure of the compound is as follows:

<Example 8C>

5-isopropoxy-2,4-dimethoxy-fluorene-9-one

Similar to Example 7C, n-butyl lithium (8.2 mL, 21 mmol 2.5 M) under argon at −50 ° C. was diluted with diisopropyl amine (2.0 g, 2.8 mL / d = 50 mL of tetrahydrofuran (THF)). 0.722, 20.3 mmol) to prepare LDA reagent. The reaction was allowed to warm to 0 ° C. and then N, N-diethyl-6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-carboxamide (3.0 g, 8.1 mmol) in 50 mL of THF. Drop it off. The reaction is further warmed to room temperature and stirred overnight. The procedure from Example 7C is continued to yield 2.0 g (6.7 mmol, 83%) of the title compound. (EtOAc / hexane 4: 6, R _f = 0.50).

The structure of the compound is as follows:

<Example 8D>

N, N-diethyl-6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-carboxamide

A stirred solution of 6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-carboxylic acid (8.60 g, 0.0276 mol) in CH ₂ Cl ₂ (200 mL) was prepared under argon at ambient temperature. . Thionyl chloride (4.6 g, 54 mmol, 2.8 mL) is added dropwise. Continue stirring for about 60 minutes. The reaction is cooled to 0 ° C. and diethylamine (19.7 g, 28 mL, 0.27 mol) is added dropwise to ensure the temperature does not exceed 25 ° C. The reaction is continued stirring for about 30 minutes after the addition is complete. The organic layer is washed with water, separated and washed twice with 100 ml of 5% sodium bicarbonate. Separated again, washed with brine (saturated NaCl) and dried over magnesium sulfate. Filter through celite and concentrate on a rotary evaporator to give a viscous light brown liquid. Dissolve (partly) in methylene chloride (20 mL) and filter. Flash chromatography in 30% ethyl acetate / 70% hexane removes solid impurities. A mixture of the desired product is obtained that can continue to elute. Further chromatography isolates the title compound as a pale yellow liquid (6.80 g, 68%). (EtOAc / hexanes 30:70; R _f = 0.15).

The structure of the compound is as follows:

<Example 8E>

2-Isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-carboxylic acid

2- (2-isopropoxy-2 ', 4'-methoxy-biphenyl-2-yl) -2,4,4-trimethyl-4-oxazolinium iodide (14.9 g, under argon at room temperature) 29.1 mmol), 100 ml of 20% sodium hydroxide and 100 ml of methanol are prepared. Heated and stirred overnight, then cooled to room temperature and methanol is evaporated on a rotary evaporator. Dilute to about 300 mL with water, cool to 0 ° C in an ice bath, and acidify to pH about 1.0 with concentrated hydrochloric acid. Extract with CH ₂ Cl ₂ , wash with brine, separate and dry over MgSO ₄ . Filtration and evaporation gave the title compound (8.3 g, 26.3 mmol, 90%) as a brown glass. Melting point: 121 to 122 ° C.

<Example 8F>

2- (2-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -2,4,4-trimethyl-4-oxazolinium iodide

2- (2-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -2,4,4-trimethyl-4- in 40 ml of dimethylsulfoxide (DMSO) under argon at room temperature Prepare an oxazoline (13.2 g, 30.9 mmol) solution. Methyl iodide (CH ₃ I, 20.9 g, 0.21 mol) is added, stirred overnight and poured into anhydrous ether (about 1.5 L). Stirring is continued until the off-white solid is completely precipitated. The solid is filtered off, washed with anhydrous diethyl ether, filtered and evaporated to afford the title compound (14 g, 88%). Melting point: 192-193 ° C.

<Example 8G>

2- (2-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -2,4,4, -trimethyl-4-oxazoline

A magnesium (2.1 g, 86 mmol) solution in anhydrous diethyl ether (20 mL) is prepared. The reaction is initiated by gentle heating to add 1-bromo-2,4-dimethoxy-benzene (18.7 g, 12.4 mL, 86.1 mmol) dropwise. Once the addition is complete, 70 ml of anhydrous diethyl ether are added and heated to reflux for about 1 hour. Cool to room temperature and add dropwise 2- (2,3-diisopropoxy-phenyl-2-yl) -4,4-dimethyl oxazoline (9 g, 30.9 mmol) in 50 mL of anhydrous tetrahydrofuran. Stir overnight and then quench with saturated aqueous NH ₄ Cl solution (75 mL). The organic layer is separated, separated by washing with brine and dried over magnesium sulfate. Filter and concentrate on rotary evaporator. The resulting purple liquid is dissolved in ethyl acetate (250 mL) and extracted with 210 mL of 5% hydrochloric acid. The aqueous layer is separated, washed with brine, separated and dried over magnesium sulfate. Filtration through celite and evaporation on a rotary evaporator gave 13.20 g of the title compound as a green oil.

¹ H-NMR δ 1.11 (6H, d, CH ₃ ), 1.21 (3H, s, CH ₃ ), 1.22 (3H, s, CH ₃ ), 3.63 (1H, d, CH ₂ ), 3.70 (3H, s , OCH ₃ ), 3.74 (1H, d, CH ₂ ), 3.83 (3H, s, OCH ₃ ), 4.32 (1H, m, CH), 6.45-6.49 (2H, m, ArH), 7.00-7.05 (2H , m, ArH), 7.26 (1H, t, ArH), 7.33 (1H, d, ArH).

<Example 8H>

2- (2,3-diisopropoxy-phenyl-2-yl) -4,4-dimethyl oxazoline

Prepare a solution of N- (2-hydroxy-1,1-dimethyl-ethyl) -2,3-diisopropoxy-benzamide (9.30 g, 0.030 mol) in methylene chloride (8.00 mL) under argon at 0 ° C. Then thionyl chloride (6.80 mL / d = 1.632, 11.08 g, 0.131 mol) is added dropwise. The reaction temperature is kept below 5 ° C. during the addition and then warmed to ambient temperature and stirred for about 1.5 hours. Dilute to 150 mL or less with ethyl acetate and pour into water cooled to 0 ° C. The aqueous layer is separated and it is neutralized with solid potassium carbonate to pH 9.0 and further extracted with ethyl acetate. Ethyl acetate (about 300 mL) is washed with brine, separated and dried over magnesium sulfate. Filtration and concentration on a rotary evaporator yields 6.7 g (82%) of the title compound. (R _f = 0.24; EtOAc / hexanes 3: 7).

<Example 8I>

N- (2-hydroxy-1,1-dimethyl-ethyl) -2,3-diisopropoxy-benzamide

60% sodium hydride (9.20 g, 0.23 mol) is added in portions to a stirred solution of 2-amino-2-dimethyl-propanol (9.20 g, 0.23 mol) dissolved in THF (200 mL). Stirring is continued under argon at ambient temperature for 1 hour, followed by dropwise addition of 2,3-diisopropoxy-methyl benzoate (25.35 g, 0.100 mol) dissolved in THF (60 mL). The resulting mixture is stirred at ambient temperature overnight and then water (4.00 mL) is added carefully. The brown paste oil is evaporated on a rotary evaporator. The residue is dissolved in an ethyl acetate / water mixture and the EtOAc phase is separated. Wash with brine, separate and dry over magnesium sulfate. Filtration and evaporation yields the title amide.

The structure of the compound is as follows:

<Example 8J>

2,3-diisopropyl methyl benzoate

A stirred solution of isopropyl iodide (72.19 g, 0.425 mol) and 2,3-dihydroxy methyl benzoate (23.80 g, 0.1415 mol) in 2-butanone (300 mL) under argon was prepared and potassium carbonate ( 55.2 g, 0.400 mole) is added and the mixture is heated under reflux until reflux. Cool the mixture to ambient temperature and filter. The filtrate is concentrated to give a yellow liquid. Extract with ether / water (100 mL) and separate ether phase. Extract with 5% NaOH (2 × 250 mL), separate, wash with brine, dry over MgSO _4, filter and evaporate to give 25.60 g (72%) of yellow liquid.

<Example 8K>

Methyl 2,3-dihydroxy-benzoate

A reaction flask with 300 mL of methanol is prepared and 30 mL of acetyl chloride is added under argon in an ice bath. 2,3-Dihydroxy-benzoic acid (21.70 g, 0.1418 mol) is added and stirred at reflux overnight under heating. Cool in an ice bath and bubble for about 10 minutes through hydrogen chloride gas. The mixture is heated and stirred at reflux overnight. Cool to ambient temperature and then concentrate to an off-white solid. Dissolve and separate with diethyl ether and water. The ether portion is isolated and extracted twice with 250 ml of 5% sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filtration and concentration on a rotary evaporator gave the title compound as off white solid (21.1 g, 99%). Melting point: 79 to 81 ° C.

Example 9

1-amino-5- (2-diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one

<Example 9A>

1-amino-5- (2-diethylamino-ethoxy) -2,4-dimethoxy-fluoren-9-one hydrochloride

5- (2-diethylamino-ethoxy) -2,4-dimethoxy-1-nitro-fluoren-9-one (0.08 g, 0.18 mmol) in 20 mL ethanol and stannous chloride dihydrate ( SnCl ₂ .2H ₂ O, 0.80 g, 3.5 mmol) is prepared. Heat overnight at 70 ° C. under argon. Dilute with about 60 mL of water and make it slightly basic by adding 5% sodium bicarbonate. The precipitate is extracted with ethyl acetate and dried over magnesium sulfate. Filter to evaporate the solvent. Acidify (to pH 2) with 5% hydrochloric acid and extract organics. The aqueous phase is made basic (up to pH 8) and extracted with methylene chloride. Dry over magnesium sulfate. Filtration and evaporation of the solvent gave a red oil. Chromatron with 7% methanol in methylene chloride and concentrate under high vacuum to give the free base (0.48 g) of the title compound. Melting point: 208 to 210 ° C.

The free base obtained above is dissolved in ether (-20 mL) and acidified with excess etheric HCl. The precipitated red solid is collected and dried to afford the title compound. Melting point: 208 to 210 ° C.

The structure of the compound is as follows:

<Example 9B>

5- (2-Diethylamino-ethoxy) -2,4-dimethoxy-1-nitro-fluoren-9-one

A solution of 5-hydroxy-2,4-dimethoxy-1-nitro-fluoren-9-one (0.5 g, 1.6 mmol) in 4 mL of dry methanol and 20 mL of chlorobenzene is prepared. Sodium methoxide (0.11 g, 2.0 mmol) is added and heated under argon to evaporate methanol. When the temperature reaches 130 ° C., cool to 100 ° C. and add the free base of 2-chloro-ethyl-diethyl amine in 25 ml of chlorobenzene (prepared similarly to Example 2B). Once addition is complete, heat to reflux overnight. After cooling to room temperature the red colored mixture is poured into 100 ml of 1% sodium hydroxide. The organic layer was dried over magnesium sulfate by separation and washing with brine. Filtration strips the solvent. Drying under high vacuum then dissolving in ether and dropwise addition of ethereal HCl precipitates the product. Chromatography eluting with methanol / CH ₂ Cl ₂ (10:90) affords the title compound (0.10 g, 16%).

MS CI (M + H) ⁺ 401.

<Example 9C>

5-hydroxy-2,4-dimethoxy-1-nitro-fluoren-9-one

A 5-isopropoxy-2,4-methoxy-fluorene-9-one (1.5 g, 5.0 mmol) solution in 70 mL of anhydrous methylene chloride under argon at -78 ° C was prepared and nitrotetrafluoroborane (0.72) g, 5.4 mmol) is added. Stir for about 5 hours, then warm to room temperature and stir overnight. The reaction is quenched with water and extracted with methylene chloride. Wash with brine and dry the organic layer using magnesium sulfate. Filtration and stripping of the solvent yielded a black solid as a pasty oil. Triturate with EtOAc and filter out the red solid to afford the title compound (0.5 g).

<Example 9D>

5-isopropoxy-2,4-methoxy-fluorene-9-one

LDA reagent by dropwise addition of n-butyl-lithium (2.5 mL 8.2 mL, 21 mmol) at -50 ° C to diisopropyl amine (2.0 g, 2.8 mL, 20.2 mmol) in 50 mL anhydrous tetrahydrofuran (THF) To prepare. Warm up to 0 ° C. under stirring when the addition is complete. Cool down to −10 ° C. and add N, N-diethyl-6-isopropoxy-1 ′, 4′-dimethoxy-biphenyl-2-carboxamide (3.0 g, 8.1 mmol) in 20 mL THF dropwise. do. Warm to room temperature and stir overnight. When quenching the reaction with saturated ammonium chloride, the clear orange solution turns dark red. Purification by chromatography with 40% ethyl acetate / hexanes and evaporation under high vacuum yields the title compound as a red solid (1.9 g, 6.3 mmol, 79%).

<Example 9E>

N, N-diethyl-6-isopropoxy-1 ', 4'-dimethoxy-biphenyl-2-carboxamide

6-isopropoxy-2 ', 4'-dimethoxy-biphenyl in CH ₂ Cl ₂ (200 mL) and diethylamine (19.0 g, 27 mL, 260 mmol) in a similar manner as described in Example 8D 2-carboxylic acid (8.3 g, 26.2 mmol) and thionyl chloride (4.5 g, 2.7 mL, 52 mmol) are reacted together. Continued as in Example 8D to afford the title compound (7.9 g, 81%).

<Example 9F>

6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-carboxylic acid

2- (6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -3,4,4-trimethyl-4-oxazolinium urine in a similar manner as described in Example 8E Odide (14.9 g, 29.1 mmol), 20% sodium hydroxide (100 mL) and methanol (100 mL) are reacted together. The title compound is obtained as a brown glass (8.3 g, 90%) as in Example 8E except dilution with water to 300 mL and acidification to pH 2.

<Example 9G>

2- (6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -3,4,4, -trimethyl-4-oxazolinium iodide

In a similar manner as described in Example 8F, 2- (6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -3,4,4-trimethyl-4 in anhydrous dimethyl sulfoxide Oxazoline (2.73 g, 0.0074 mole) and methyl iodide (9.9887 g, 0.0074 mole) are reacted together to yield the title compound. Yield: 14.2 g, 88%. The structure of the compound is as follows:

<Example 9H>

2- (6-isopropoxy-2 ', 4'-dimethoxy-biphenyl-2-yl) -3,4,4-trimethyl-4-oxazoline

A mixture of anhydrous diethyl ether (20 mL) and magnesium (2.1 g, 86 mmol) is prepared. 1-bromo-2,4-dimethoxybenzene (4.1 g, 27.5 mL, 0.22 mol) is added dropwise under stirring. Heat gently to initiate the reaction. Iodine crystals and / or 1,2-bromoethane are added if necessary to initiate the reaction. Continue adding ether at a rate sufficient to maintain reflux. After complete addition diethyl ether (100 mL) is added and heated to reflux for about 1 h. Cool to room temperature and add 2- (2,3-diisopropoxy-2-yl) -4,4-dimethyl-4-oxazoline (9 g, 30.9 mmol) in 50 ml of anhydrous tetrahydrofuran (THF). Add it down. Stir overnight and then quench with aqueous ammonium chloride (75 mL saturated solution). The organic layer is separated and the aqueous layer is extracted with 100 ml of THF. The combined organic layers are washed twice with brine, dried over magnesium sulfate, filtered and rotovap. The residue is dissolved in 10% hydrochloric acid (conc. 30 ml diluted to 120 ml) and washed twice with 100 ml diethyl ether to precipitate the chloride salt of the title compound. The aqueous layer is made basic with 50% sodium hydroxide to prepare a free base and extracted twice with 250 ml of ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and rotovap to afford 13.2 g of green oil.

<Example 10>

1-amino-5- (2-diethylamino-ethoxy) -4-methoxy-2-propoxy-fluoren-9-one

<Example 10A>

1-amino-5- (2-diethylamino-ethoxy) -4-methoxy-2-propoxy-fluoren-9-one

5- (2-diethylamino-ethoxy) -4-methoxy-1-nitro-2-propoxy-fluoren-9-one (0.52 g, 1.2 mmol) and chloride in 60 ml of ethanol under argon A solution of tin (SnCl ₂ , 1.3 g, 6 mmol) is prepared. Reflux overnight. Lower the volume on the rotary evaporator. 200 mL of deionized water is added and basified with sodium bicarbonate. Extract with methylene chloride. The organic layer is dried over magnesium sulfate. Filtration and evaporation on a rotary evaporator yielded a red oil. Dissolve in anhydrous diethyl ether and filter through celite. Etheric HCl is added to precipitate the hydrochloride. The resulting red solid is filtered off and washed with diethyl ether. Place at 100 ° C. under high vacuum overnight to obtain purified hydrochloride of the title compound. Melting point: 163 to 165 ° C. Yield: 0.338 g, 70%. R _f = 0.33; 5% Methanol / CH ₂ Cl ₂ .

Elemental Analysis for C ₂₃ H ₃₀ N ₂ O ₄ · HCl:

Calc .: C, 63.51; H, 7. 18; N, 6.44.

Found: C, 63.42; H, 7. 27; N, 6.31.

The structure of the compound is as follows:

<Example 10B>

5- (2-Diethylamino-ethoxy) -4-methoxy-1-nitro-2-propoxy-fluoren-9-one

5- (2-diethylamino-ethoxy) -4-methoxy-2-propoxy-fluoren-9-one (1.1 g, 2.9 mmol) in 100 mL of anhydrous methylene chloride under stirring at -72 ° C under argon. ) To prepare a solution. Nitronium tetrafluoroborate (0.42 g, 3.2 mmol) is added once in succession. The solution becomes dark while the mixture is warmed to room temperature for 3 hours. Stir for an additional 2 hours and then check the reaction progress by thin layer chromatography. The reaction is quenched with water and transferred to an individual funnel. The organic layer is maintained and the insoluble red solid is filtered off from the interface. Wash with water and methylene chloride. The solid is dissolved in 5% sodium hydroxide and stirred vigorously. Extract with methylene chloride and organics chromatograph and combine CH ₂ Cl ₂ fractions, dry over MgSO _4, filter and concentrate on rotary evaporator. The resulting residue is chromatographed, eluting with methanol / CH ₂ Cl ₂ (5:95) to afford 0.52 g (52%) of the title compound. CI-MS [M + H] ⁺ = 429.

<Example 10C>

5- (2-Diethylamino-ethoxy) -4-methoxy-2-propoxy-fluoren-9-one

In a similar manner to Example 9B, 5-hydroxy-2-propoxy-4-methoxy-fluoren-9-one (1.75 g, 6.1) in 5 ml of methanol and 100 ml of chlorobenzene was converted to 2-chloroethyl. Reaction with diethyl amine hydrochloride (4.4 g, 25 mmol) and sodium methoxide (0.51 g, 9.5 mmol) and reflux for 2 hours followed by 1.1 g of the title compound (2.9 mmol, 47%) as in Example 9B. ). Melting point: 127 to 129 ° C.

<Example 10D>

5-hydroxy-2-propoxy-4-methoxy-fluoren-9-one

A stirred solution of 5-isopropoxy-2-propoxy-4-methoxy-fluorene-9-one (2.2 g, 6.7 mmol) in 100 ml of methylene chloride is prepared at 0 ° C. under argon. Boron trichloride (15.4 ml of 1.0 M) in methylene chloride (15.4 mmol) is added dropwise. The reaction is monitored by TLC on a partial sample in 40% ethyl acetate / hexanes, where the reaction is quenched with saturated ammonium chloride. After 1 hour the reaction is quenched with saturated ammonium chloride. Filter and wash twice with 100 ml methylene chloride. The organic layer is separated from the filtrate and washed with brine. Dry over magnesium sulfate and filter to strip the solvent. The crude product is first dissolved in methylene chloride and then chromatographed eluting in 30% ethyl acetate / hexanes to give the title compound as red powder (1.75 g, 6.1 mmol, 92%). R _f = 0.54 (EtOAc / hexanes, 40:60).

The structure of the compound is as follows:

<Example 10E>

5-isopropoxy-2-propoxy-4-methoxy-fluoren-9-one

LDA reagent is prepared by reacting n-butyl lithium and diisopropylamine as in Example 7C to yield 0.05 mole in THF (50 mL) at 0 ° C. N, N-diethyl-6-isopropyloxy-2'-methoxy-4'-propyloxy-biphenyl-2-carboxamide (4.3 g, 0.011 mol) in THF (20 mL) at 0 ° C. Add it down. The mixture is warmed to ambient temperature and stirred for 1 hour and then heated to reflux for 1.5 hours. The mixture is worked up as in Example 7C and chromatographed eluting with 50% / 50% EtOAc / hexanes to give the title compound as a red solid (2.6 g, 63%). Melting point: 114 to 116 ° C.

<Example 10F>

N, N-diethyl-6-isopropoxy-2'-methoxy-4'-propoxy-biphenyl-2-carboxamide

A stirred solution of 6-isopropoxy-1-methoxy-4-propoxy-biphenyl-2-carboxylic acid (5.8 g, 16.8 mmol) in CH ₂ Cl ₂ (100 mL) under argon at ambient temperature was prepared. do. Thionyl chloride (2.8 g, 0.516 mL / d = 1.632) is added and stirring is continued for about 60 minutes. Reaction progress is checked by TLC. After about 1.3 hours it is cooled to 0 ° C. and diethylamine (9.9 g, 0.135 moles, 14.00 mL) is added dropwise, taking care not to exceed the temperature of 26 ° C. After the addition is complete, the mixture is stirred for another 30 minutes and then diluted to 100 ml with methylene chloride. Wash with water and separate and wash twice with 100 ml of 5% sodium bicarbonate. Separate, wash with brine, separate and dry over magnesium sulfate. Filter through celite and concentrate on rotary evaporator. Chromatography eluting with 40% ethyl acetate-60% hexanes yields 4.3 g (0.011 mol, 64%) of the title compound. R _f = 0.33.

¹ H-NMR (CDCl ₃ ) δ 0.68 (3H, t, CH ₃ ), 0.84 (3H, t, CH ₃ ), 1.02 (3H, t, CH ₃ ), 1.05 (3H, d, CH ₃ ), 1.18 (3H, d, CH ₃ ), 1.80 (2H, m, CH ₂ ), 2.65 (1H, m, CH ₂ ), 2.82 (1H, m, CH ₂ ), 3.19 (1H, m, CH ₂ ), 3.70 (3H, s, OCH ₃ ), 3.72 (1H, m, CH ₂ ), 3.91 (2H, t, OCH ₂ ), 4.35 (1H, m, CH), 6.44 (1H, s, ArH), 6.46 (1H , d, ArH), 6.91 (2H, d, ArH), 7.15 (1H, d, ArH), 7.27 (1H, t, ArH).

The structure of the compound is as follows:

<Example 10G>

6-isopropoxy-1'-methoxy-4-propoxy-biphenyl-2-carboxylic acid

In a manner similar to Example 9F, 2- (6-isopropoxy-1'-methoxy-4'-propoxy-biphenyl-2-yl) -3,4,4-trimethyl- in methanol (50 mL) Reaction of 4-oxazolinium iodide (9.2 g, 17 mmol) and 20% aqueous sodium methoxide (50 mL) yields 5.8 g (16.8 mmol, 99%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 1.10 (3H, t, CH ₃ ), 1.11 (3H, d, CH ₃ ), 1.19 (3H, d, CH ₃ ), 1.87 (2H, m, CH ₂ ), 3.68 (3H, s, OCH ₃ ), 4.00 (2H, t, OCH ₂ ), 4.30 (1H, m, CH), 6.50 (1H, s, ArH), 6.52 (1H, d, ArH), 7.10 (1H, d, ArH), 7.16 (1H, d, ArH), 7.33 (1H, t, ArH), 7.53 (1H, d, ArH).

<Example 10H>

2- (6-isopropoxy-1'-methoxy-4'-propoxy-biphenyl-2-yl) -3,4,4-trimethyl-4-oxazolinium iodide

In a manner similar to Example 9G, 2- (6-isopropoxy-1'-methoxy-4'-propoxy-biphenyl-2-yl) -4,4-dimethyl-4 in 20 ml of dimethylsulfoxide Oxazoline (8.1 g, 20 mmol) and methyl iodide (12.8 g, 5.6 mL, 90 mmol) are reacted. After the reaction is diluted with 500 ml of anhydrous diethyl ether and the mixture is poured into additional 1.5 liter of diethyl ether and stirred for about 15 minutes. Filter and wash with diethyl ether. The solid is dissolved in methylene chloride and filtered to remove the white precipitate. Strip the solvent under high vacuum to afford the title compound (9.2 g, 85%). Melting point: 198 to 201 ° C.

<Example 10I>

2- (6-isopropoxy-1'-methoxy-4'-propoxy-biphenyl-2-yl) -4,4-dimethyl-4-oxazoline

In a similar manner to Example 9H, 30 ml of magnesium (0.73 g, 30 mmol) and 2- (2,3-diisopropoxy) -4,4-dimethyl-4-oxazoline (8.0 g, 27.5 mmol) Reaction with 1-bromo-2-methoxy-4-propoxy-benzene (6.9 g, 28 mmol) in diethyl ether and 30 mL tetrahydrofuran gave the title compound (8.1 g, 20.4 mmol, 74%). To obtain. (R _f = 0.25; EtOAc-hexane 40:60)

The structure of the compound is as follows:

<Example 10J>

1-bromo-2-methoxy-4-propoxy-benzene

A solution of 4-bromo-3-methoxyphenol (6.5 g, 32 mmol) and potassium carbonate (15 g) in acetone (250 mL) is prepared under argon. n-propyl iodide (9.0 g, 5.2 mL, 53 mmol) is added and heated to reflux overnight. Cool to room temperature and filter. Concentrate by rotary evaporation and evaporate the solvent. Check by thin layer chromatography (25% ethyl acetate / 75% hexane). Wash three times with 100 ml of 3% potassium hydroxide. The organic layer is dried over magnesium sulfate. Filtration and rotary evaporation. Purification by chromatography and placing under high vacuum yields the title compound (6.9 g, 88%). R _f = 0.60 (EtOAc / hexanes; 25:75).

<Example 11>

5- (2-Pyrrolidinyl-ethoxy) -1-amino-4-methoxy-2-propyloxy-fluoren-9-one hydrochloride

<Example 11A>

5- (2-Pyrrolidinyl-ethoxy) -4-methoxy-2-propyloxy-fluorene-9-one hydrochloride

Examples of 5-hydroxy-4-methoxy-2-propyloxy-fluoren-9-one (0.83 g, 2.9 mmol) and 2-chloroethylpyrrolidine and sodium methoxide (0.20 g, 3.5 mmol) Reaction as described in 9B yields a red powder which is recrystallized from 2-butanone to give the title compound (0.222 g, 18%). Melting point: 147 to 149 ° C.

Elemental Analysis for _{C 23 H 27 NO 4 · HCl} :

Calc .: C, 66.10; H, 6.75; N, 3.35.

Found: C, 65.82; H, 6.65; N, 3.09.

The structure of the compound is as follows:

<Example 11B>

5- (2-Pyrrolidinyl-ethoxy) -4-methoxy-2-propyloxy-1-nitro-fluoren-9-one

5- (2-Pyrrolidinyl-ethoxy) -4-methoxy-2-propyloxy-fluoren-9-one (0.35 g, 0.92 mmol) and nitronium tetrafluor in CH ₂ Cl ₂ (20 mL) Roborate (0.13 g, 0.92 mmol) is reacted as described in Example 9C to afford the title compound.

<Example 11C>

5- (2-Pyrrolidinyl-ethoxy) -1-amino-4-methoxy-2-propyloxy-fluoren-9-one hydrochloride

5- (2-Pyrrolidinyl-ethoxy) -4-methoxy-2-propoxy-1-nitro-fluoren-9-one (0.30 g, 0.7 mmol) and stannous chloride dihydrate (1.0 g) , 0.7 mmol) is reacted as described in Example 9A to give the title compound (0.10 g, 33%). Melting point: 122-124 ° C.

The structure of the compound is as follows:

<Example 12>

5- [2- (morpholino-4-yl) -ethoxy] -1-amino-4-methoxy-2-propyloxy-fluoren-9-one hydrochloride

<Example 12A>

5- [2- (morpholino-4-yl) -ethoxy] -1-amino-4-methoxy-2-propyloxy-fluoren-9-one hydrochloride

5- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-2-propyloxy-1-nitro-fluoren-9-one hydrochloride (0.20 g, 0.45 mmol) and chloride Monotin dihydrate (SnCl ₂ · H ₂ O; 1.0 g, 4.4 mmol) is reacted as described in Example 9A to give the hemihydrate (0.765 g, 38%) of the title compound as a dark red solid. Melting point: 128-131 ° C.

Elemental Analysis for C ₂₃ H ₂₈ N ₂ O ₅ HCl ₅ H ₂ O:

Calc .: C, 60.46; H, 6. 40; N, 6.13.

Found: C, 60.15; H, 6. 37; N, 6.04.

The structure of the compound is as follows:

<Example 12B>

5- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-2-propyloxy-1-nitro-fluoren-9-one

5- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-2-propyloxy-fluoren-9-one (0.18 g, 0.45 mmol) in CH ₂ Cl ₂ (20 mL) ) And nitronium tetrafluoroborate (0.5 M in sulfolane; 1.0 mL, 0.5 mmol) are stirred together at -78 ° C for 2 hours and then warmed to ambient temperature and stirred again for about 60 hours. The reaction was quenched with saturated NH ₄ Cl solution and then separated. The organic layer is extracted three times with water, separated, washed with brine and separated. The CH ₂ Cl ₂ layer is diluted with additional CH ₂ Cl ₂ and dried over MgSO ₄ . Filtration and evaporation affords the title compound as a red oil (0.2 g). R _f = 0.45 (MeOH / CH ₂ Cl ₂ ; 5:95).

<Example 12C>

5- [2- (morpholino-4-yl) -ethoxy] -4-methoxy-2-propyloxy-fluoren-9-one hydrochloride

5-hydroxy-4-methoxy-2-propoxy-fluoren-9-one (0.40 g, 1.4 mmol), 2-chloroethyl-morpholine (0.84 g, 5.6 mmol) and sodium methoxide (0.10 g , 1.8 mmol) is reacted as described in Example 9B. The chlorobenzene is removed on a rotary evaporator and the residue is mixed with water if necessary to redissolve the residue and heated on a steam bath. Filter on a sintered glass funnel to remove insoluble solids, wash with water and dry to afford 0.187 g of free base corresponding to the title compound. The free base is converted to hydrochloride with etheric HCl and dried to give the title compound as an orange powder. Melting point: 184 to 186 ° C.

Elemental Analysis for _{C 27 H 27 NO 5 · HCl} :

Calc .: C, 63.66; H, 6. 50; N, 3.23.

Found: C, 63.48; H, 6.57; N, 2.99.

<Example 12D>

5-hydroxy-4-methoxy-2-propoxy-fluorene-9-one

See Example 11A.

III. Dibasic Alkoxy Fluorenone:

Example 13

1-amino-2,5-bis- (diethylamino-ethoxy) -4-methoxy-fluoren-9-one

<Example 13A>

1-amino-2,5-bis- (diethylamino-ethoxy) -4-methoxy-fluorene-9-one hydrochloride

2,5-bis- (2-diethylamino-ethoxy) -1-nitro-4-methoxy-1-nitro-fluoren-9-one hydrochloride (0.37 g, 0.70 mmol) and stannous dichloride Water (SnCl ₂ · 2H ₂ O; 1.0 g, 0.7 mmol) was reacted as described in Example 9A to afford the title compound, whose structure is as follows:

<Example 13B>

2,5-bis-2- (diethylamino-ethoxy) -4-methoxy-1-nitro-fluoren-9-one

2,5-bis-2- (diethylamino-ethoxy) -4-methoxy-fluoren-9-one (0.476 g, 0.92 mmol) and nitronium tetrafluoro in CH ₂ Cl ₂ (20 mL) Borate (0.13 g, 0.92 mmol) is reacted as described in Example 9C to afford the title compound.

<Examples 13C to H>

2,5-bis-2- (diethylamino-ethoxy) -4-methoxy-fluoren-9-one

Starting materials for Example 13B can be prepared as in Example 4A and synthesized as in Examples 4B to 4F.

For Examples 14 and 15, the melting point is not corrected. ¹ H-NMR spectra and ¹³ C NMR were obtained at 300 MHz and 75 MHz, respectively. Chemical shifts are reported as d values for Me ₄ Si (d = 0.00) as internal reference to the ¹ H spectrum.

<Example 14>

Alternative preparation of 2,5-dihydroxy-4-methoxy-fluoren-9-one (dengibine)

<Example 14A>

1-bromo-2-methoxy-4- (1-methylethoxy) benzene

Isopropyl urine in a stirred suspension of 4-bromo-3-methoxyphenol (2.03 g, 10 mmol) and K ₂ CO ₃ (1.38 g, 10 mmol) in 2-butanone (70 mL) at ambient temperature under argon. Odide (2.21 g, 13.3 mmol) is added dropwise. The resulting mixture is heated and stirred for 17 hours under reflux. The mixture is cooled to ambient temperature, filtered and the solvent is concentrated by evaporation. The residue is partitioned between Et ₂ O and H ₂ O. The Et ₂ O layer is extracted with 5% NaOH (2 × 50 mL), washed with brine and dried over MgSO ₄ . The solvent is evaporated and the resulting residue is purified by flash chromatography (5% EtOAc / hexanes) to afford the desired compound as a pale yellow oil (2.13 g, 87%).

UV (MeOH) 1 max = 283 nm, e = 9,510; ¹ H NMR (CDCl ₃ ) (d, 1H, J = 8.6 Hz), 6.47 (1H, d, J = 2.7 Hz), 6.38 (1H, dd, J = 8.5, 2.7 Hz), 4.5 (1H, hept. , J = 6.3 Hz), 3.85 (3H, s), 1.33 (6H, d, J = 6.3 Hz);

¹³ C-NMR (CDCl ₃ ) d 158.4, 156.6, 133.0, 107.7, 102.0, 101.8, 70.3, 56.0, 21.9; Elemental Analysis for C ₁₀ H ₁₃ BrO ₂ :

Calc .: C, 49.00; H, 5.35.

Found: C, 48.87; H, 5.12.

<Example 14B>

4,5-dihydro-2- [2,3-bis (1-methylethoxy) -1-phenyl] -4,4-dimethyloxazole

Sodium hydride (8.25 g, 60%, 0.205 mol) is added in portions to a stirred solution of 2-amino-2-methyl propanol (17.52 g, 0.196 mol) in anhydrous THF (200 mL). The mixture is stirred at ambient temperature for 1 hour. To this solution is added methyl 2,3-di-isopropoxybenzoate (24.82 g, 0.098 mol) dissolved in THF (50 mL). The mixture is stirred under argon overnight, quenched with H ₂ O (4 mL) and the solvent is concentrated by evaporation. The residue is dissolved in CH ₂ Cl ₂ extracted with H ₂ O, washed with brine and dried over MgSO ₄ . Filtration and evaporation of the solvent gave 33.3 g of a yellow liquid. To this crude product dissolved in CH ₂ Cl ₂ (30 mL) at 0-5 ° C. is added dropwise SOCl ₂ (19 mL, 0.37 mol). After addition the reaction mixture is warmed to ambient temperature and stirred for 1.5 h. The mixture is diluted with EtOAc (300 mL) and poured into ice water (500 mL) and the aqueous layer is separated and neutralized to solid pH ₂ with solid K ₂ CO ₃ . EtOAc is washed with brine, dried over MgSO ₄ and filtered. The solvent is evaporated and the final traces of solvent are removed under high vacuum to afford the title compound as a yellow liquid (total 23.6 g, 83%).

¹ H-NMR (CDCl ₃ ) d 7.29-7.27 (1H, m), 6.99-6.98 (2H, m), 4.55 (1H, sept., J = 6.1 Hz), 4.44 (1H, sept., J = 6.1 Hz), 4.09 (2H, s), 1.38 (6H, s), 1.31 (3H, d, J = 6.1 Hz), 1.27 (6H, d, J = 6.1 Hz).

<Example 14C>

4,5-dihydro-2- [2'-methoxy-4 ', 6-bis (1-methylethoxy) 1,1'-biphenyl-2-yl] -4,4-dimethyloxazole

Mg (0.917 g, 37.7 mmol), crystals of I ₂ and 1-bromo-2-methoxy-4- (1-methylethoxy) dissolved in THF (30 mL) in a stirred suspension of 3 drops of ethylene dibromide A benzene (8.51 g, 34.7 mmol) solution is added dropwise. The mixture is warmed up to 40 ° C. and 1-bromo-2-methoxy-4- (1-methylethoxy) benzene, prepared beforehand, is added. After adjusting the reaction, the mixture is heated at 50 ° C. for 40 minutes. To this solution is added dropwise oxazoline (11.27 g, 38.0 mmol) prepared above in THF (30 mL) at ambient temperature. The reaction mixture is warmed to 10 ° C during the addition. The reaction mixture is heated and stirred at 50 ° C. overnight. The mixture is cooled in an ice bath and quenched with saturated NH ₄ Cl. The THF layer is washed with brine, dried over MgSO ₄ and filtered. The solvent is evaporated and the residue is purified by flash chromatography (40% EtOAc / hexanes) to afford the title compound as pale yellow oil (11.34 g, 81%).

¹ H-NMR (CDCl ₃ ) d 7.32 (1H, dd, J = 7.8, 1.3 Hz), 7.28 (1H, dd, J = 8.0, 7.8 Hz), 7.02 (1H, dd, J = 8.0, 1.2 Hz) , 7.00 (d, 1H, J = 8.8, 2.4 Hz), 6.47 (1H, dd, J = 7.0, 2.3 Hz), 6.46 (1H, d, J = 2.4 Hz), 4.58 (1H, sept., J = 6.1 Hz), 4.29 (1H, sept., J = 6.2 Hz), 3.74 (1H, d, J = 8.0 Hz, 3.69 (3H, s), 3.62 (1H, d, J = 8.1 Hz), 1.36-1.35 (6H, m), 1.19-1.18 (6H, m), 1.12-1.11 (6H, m);

¹³ C-NMR (CDCl ₃ ) d 163.6, 158.2, 155.9, 131.2, 131.0, 129.3, 127.7, 122.1, 119.0, 117.6, 105.7, 110.1, 79.3, 71.5, 69.9, 67.0, 55.4, 28.0, 22.1, 22.0, 21.9 .

Elemental Analysis for C ₂₄ H ₃₁ NO ₄ :

Calc .: C, 72.52; H, 7.86; N, 3.52.

Found: C, 72.82, H, 8.07; N, 3.52.

<Example 14D>

4,5-dihydro-2- [2'-methoxy-4 ', 6-bis (1-methylethoxy) -1,1'-biphenyl] -2-yl-3,4,4-trimethyl Oxazolium iodide

4,5-dihydro-2- [2'-methoxy-4 ', 6-bis (1-methylethoxy) 1,1'-biphenyl) -2' in dry DMSO (30 mL) at ambient temperature MeI (12.42 g, 87.5 mmol) is added to a stirred solution of -yl] -4,4-dimethyloxazod (5.80 g, 14.6 mmol) (see HJ Meyers and J. Slade, J. Org. Chem). 45: 2785 (1980)). The resulting mixture is stirred overnight and diluted with anhydrous Et ₂ O. The precipitate is removed by filtration. The solid is triturated with CHCl ₃ (400 mL) and filtered. The filtrate is evaporated and then recrystallized from MeOH / EtOAc to give the title compound as a white solid (7.40 g, 94%). Melting point: 213 to 214 ° C;

¹ H-NMR (CDCl ₃ ) d 7.8 (1H, dd, J = 8.0, 1.1 Hz), 7.47 (1H, dd, J = 8.0, 8.0 Hz), 7.18 (1H, br d, J = 8.2 Hz), 6.94 (1H, d, J = 8.4 Hz), 6.52 (1H, dd, J = 8.4, 2.3 Hz), 6.47 (1H, d, J = 2.3 Hz), 5.09 (1H, d, J = 9.5 Hz), 4.85 (1H, d, J = 9.4 Hz), 4.57 (1H, sept., J = 6.2 Hz), 4.44 (1H, sept., J = 6.0 Hz), 3.68 (3H, s), 2.87 (3H, s ), 1.63 (3H, s), 1.33-1.31 (6H, m), 1.28 (3H, s), 1.16-1.15 (6H, m).

¹³ C (CDCl ₃ ) d 172.8, 159.8, 157.6, 155.9, 131.9, 120.5, 128.1, 122.5, 122.4, 118.9, 114.9, 106.4, 100.5, 82.3, 71.2, 70.0, 67.57, 55.7, 30.36, 24.2, 23.4, 21.9 , 21.8, 21.7, 21.6. Elemental Analysis for C ₂₅ H ₃₄ NO ₄ :

Calc .: C, 55.66; H, 6. 35; N, 2.60.

Found: C, 55.82; H, 6. 42; N, 2.55.

<Example 14E>

2'-methoxy-4 ', 6-bis (1-methylethoxy) -1,1'-biphenyl-2-carboxylic acid

4,5-dihydro-2- [1'-methoxy-4 ', 6-bis (1-methylethoxy)-(1,1'-biphenyl) -2-yl] -3,4,4 Trimethyloxazolium iodide (13.2 g, 24.5 mmol) is heated and stirred in a mixture of 20% aqueous NaOH / MeOH (1: 1, 280 mL) overnight under reflux. The reaction is evaporated until turbid and diluted with H ₂ O (300 mL). The solution is acidified with concentrated HCl and the precipitated acid is extracted with CH ₂ Cl ₂ . Evaporate the solvent to give a glass. Crystallization of the glass from cyclohexane affords the title compound as a white solid (7.10 g, 84%). Melting point: 118 to 120 ° C; IR (KBr) 1697 (C = 0).

¹ H NMR (CDCl ₃ ) d 7.52 (1H, dd, J = 7.7, 1.2 Hz), 7.30 (1H, dd, J = 8.0 Hz), 7.13 (1H, dd, J = 8.3, 1.2 Hz), 7.06 ( 1H, d, J = 8.3 Hz), 6.56 (1H, dd, J = 8.4, 2.4 Hz), 6.46 (1H, J = 2.3 Hz), 4.59 (1H, sept., J = 6.1 hz), 4.26 (1H , sept., J = 6.3 Hz), 3.66 (3H, s), 1.37 (6H, J = 6.2 Hz), 1.08 (3H, d, J = 6.0 Hz).

¹³ C-NMR (CDCl ₃ ) d 171.8, 158.7, 157.7, 156.1, 132.4, 131.6, 129.6, 127.8, 122.6, 119.9, 117.4, 105.9, 100.2, 71.9, 69.9, 55.3, 22.2, 22.1, 21.9, 21.9.

Elemental Analysis for C ₂₀ H ₂₄ O ₅ :

Calc .: C, 69.75; H, 7.02.

Found: C, 69.83; H, 6.90.

<Example 14F>

N, N, -diethyl- [2'-methoxy-4 ', 6-bis (1-methylethoxy) -1,1'-biphenyl] -2-carboxamide

2'-methoxy-4 ', 6-bis (1-methylethoxy) -1,1'-biphenyl-2-carboxylic acid (3.40 g, 9.9 mmol) in CH ₂ Cl ₂ (30 mL), To a mixture of PyBOP (5.15 g, 9.9 mmol) and Et ₂ NH (0.88 g, 12.1 mmol), N, N-diisopropylethyl amine (2.82 g, 21.8 mmol) is added. The resulting mixture is stirred overnight under argon. The solvent is evaporated and the residue is dissolved in EtOAc (250 mL). The EtOAc solution is extracted with 5% HCl (3 × 70 mL), washed with brine, extracted with NaHCO ₃ (3 × 70 mL) and dried over MgSO ₄ . Filtration and evaporation of the solvent gave a light brown oil. The oil is purified by flash chromatography (40% EtOAc / hexanes) to afford the desired amide as a solid. The solid is recrystallized from hexane (50 mL) to give the title compound as a white solid (3.35 g, 85%). Melting point: 73 to 74 ° C. IR (pure) 1629 cm ^-1 (C = 0).

¹ H-NMR (CDCl ₃ ) d 7.28 (1H, dd, J = 8.0 Hz), 7.15 (1H, d, J = 8.2 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.46 (1H, dd J = 8.2, 2.3 Hz), 6.43 (1H, d J = 2.1 Hz), 4.55 (1H, sept., J = 6.1 Hz), 4.32 (1H, sept., J = 6.1 Hz), 3.77 (1H, m ), 3.68 (3H, s), 3.19 (1H, m), 2.76 (1H, m), 2.63 (1H, m), 1.3-1.31 (6H, m), 1.18 (3H, d, J = 6.1 Hz) , 1.09 (3H, d, J = 6.0 Hz), 0.84 (3H, t, J = 7.1 Hz), 0.67 (3H, t, J = 7.2 Hz).

¹³ C-NMR (CDCl ₃ ) d 170.0, 158.5, 156.0, 139.4, 132.2, 128.4, 126.0, 118.2, 117.5, 114.7, 105.5, 100.0, 71.1, 69.8, 55.1, 41.6, 37.6, 22.2, 22.1, 21.9, 21.7 , 13.7, 11.8.

Elemental Analysis for C ₂₄ H ₃₃ NO ₄ :

Calc .: C, 72.15; H, 8.33; N, 3.51.

Found C, 72.20; H, 8.56; N, 3.56.

<Example 14G>

4-methoxy-2,5-bis (1-methylethoxy) -9H-fluorene-9-one

To a stirred solution of LDA (15.0 mmol) in THF (30 mL) at 50 ° C. was added N, N- [diethyl-2'-methoxy-4 ', 6-bis (1-methylethoxy) in THF (15.0 mL). ) -1,1'-biphenyl] -2-carboxamide (1.28 g, 3.2 mmol) is added. The resulting yellow solution is warmed to ambient temperature and stirred for 48 h under argon. During this time the solution turns to brilliant red. The red solution is quenched with saturated NH ₄ Cl (30 mL). The mixture is diluted with THF (150 mL) and separated. The NH ₄ Cl layer is extracted with THF (150 mL) and the combined organic extracts are dried over MgSO ₄ . THF is evaporated and the resulting red oil is purified by flash chromatography (15% EtOAc / hexanes) to give a red solid. Recrystallization from hexanes affords the title compound as red flakes (0.65 g, 62%). Melting point: 74 to 75 ° C. IR (KBr) 1712 cm ^-1 (C = 0). UV (MeOH) 1 max = 476 nm, e = 1,570, 1 max = 339 nm, e = 3,489 1 max = 276 nm, e = 40,200.

¹ H-NMR (CDCl ₃ ) d 7.27 (1H, dd, J = 6.9 Hz, J = 1.2 Hz), 7.1 (1H, dd, J = 8.3, 6.8 Hz), 7.04 (1H, dd, J = 8.2, 1.2 Hz) 6.86 (1H, d, J = 2.2 Hz), 6.57 (1H, d, J = 2.2 Hz), 4.59 (1H, m), 3.88 (3H, s) 1.38 (6H, d, J = 6.1 Hz ), 1.35 (6H, doublet, J = 6.1 Hz).

Elemental Analysis for C ₂₀ H ₂₂ O ₄ :

Calc .: C, 73.60; H, 6.79.

Found: C, 73.46; H, 6.83.

<Example 14H>

2,5-dihydroxy-4-methoxy-9H-fluorene-9-one (dengibine)

To a stirred solution of 4-methoxy-2,5-bis- (1-methylethoxy) -9H-fluorene-9-one (0.58 g, 1.8 mmol) in CH ₂ Cl ₂ (15.0 mL) at 0 ° C. BCl ₃ (7.2 mL, 7.2 mmol) (1.0 M) is added. The green mixture is warmed to ambient temperature and stirred under argon for 2 hours. The mixture is cooled to 0 ° C. and quenched with H ₂ O (20 mL). The precipitated red solid is removed by filtration to recrystallize from MeOH / H ₂ O to afford 0.331 g (76%) of the title compound as a red solid. Melting point: 235 to 237 ° C (lit., 238 to 240 ° C). IR (KBr) 1697, 1614, 1597 cm ^-1 ; UV (EtOH) 1 max = 265, 274 and 338 nm (e = 32,576, 36,000 and 3,406 nm).

¹ H-NMR (CD ₃ COCD ₃ ) d 9.22 (1H, wide s), 9.92 (1H, s), 7.16-7.09 (2H, m), 6.96 (1H, dd, J = 7.02, 2.1 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.78 (1H, d, J = 2.1 Hz);

Elemental Analysis for C ₁₄ H ₁₀ O ₄ :

Calc .: C, 69.42; H, 4.16.

Found: C, 69.03; H, 4. 26.

<Example 15A>

1-bromo-2-methoxy-4-allyloxybenzene

Add allyl bromide (3.60 g, 0.030 mol) to a stirred mixture of K ₂ CO ₃ (3.45 g, 0.025 mol) and 3-methoxy-4-bromo-phenol (6.09 g, 0.030 mol) at ambient temperature under argon do. The resulting mixture is heated and stirred overnight. The mixture is filtered and the filtrate is concentrated on a rotary evaporator. The residue is partitioned between Et ₂ O and H ₂ O. The Et ₂ O layer is separated and extracted with 2 × 70 mL of 5% NaOH, washed with brine, dried (MgSO ₄ ) and filtered. Flash evaporation on a rotary evaporator followed by flash chromatography (EtOAc-hexane 1: 9) afforded 5.93 g (81%) of the title compound. R _f = 0.41 (EtOAc-hexane 25:75) H-NMR (CDCl ₃ ) d 7.38 (d, 1H), 6.38 (dd, 1H), 6.1-5.9 (m, 1H), 5.41 (d, 1H), 5.29 (d, 1 H), 4.51-4.48 (m, 2 H), 3.84 (s, 3 H).

<Example 15B>

4,5-dihydro-2- [2'-methoxy-4'-allyloxy-6- (1-methylethoxy) -1'-biphenyl] -2-yl-4,4-dimethyl-oxa Sol

THF (30) was added to a stirred solution of Grignard reagent prepared from Mg (0.803 g, 0.033 mol) and 1-bromo-2-methoxy-4-allyloxybenzene (6.83 g, 0.028 mol) in THF (45 mL). 4,5-dihydro-2- [2,3 bis (1-methylethoxy) -phenyl-2-yl-4,4-dimethyl-oxosol (8.15 g, 0.0280 mol) in ml) is added. The temperature rises from 24 ° C. to 42 ° C. during the addition. After adjusting the reaction, the mixture is stirred at ambient temperature for 72 hours. NH ₄ Cl (75 mL) saturated solution is then added and the THF layer is separated, washed with brine, dried (MgSO ₄ ) and filtered. The filtrate is evaporated to yield 9.2 g of viscous oil. Flash chromatography (EtOAc-hexane 40:60) afforded 6.90 g (62%) of a pale yellow liquid.

Elemental Analysis for C ₂₄ H ₂₉ NO ₄ :

Calc .: C, 72.89; H, 7.39; N, 3.34.

Found: C, 72.94; H, 7.56; N, 3.55.

<Example 15C>

2'-methoxy-4'-allyloxy-6- (1-methylethoxy) -1,1'-biphenyl-2-carboxylic acid

Iodomethane (8.56 mL) was added to 4,5-dihydro-2- [2'methoxy-4'-allyloxy-6- (1-methylethoxy) -1 in dry DMSO (19.00 mL) at ambient temperature. To a stirred solution of, 1'-biphenyl] -2-yl-4,4-dimethyl-oxazole (5.70 g, -0.0144 mol). The resulting yellow solution is stirred overnight and then poured into anhydrous Et ₂ O (400 mL). The resulting white precipitate is collected on a Buchner funnel, washed with fresh Et ₂ O and then partially dissolved in CHCl ₃ (300 mL). The mixture is filtered and the filtrate is evaporated to yield a white solid. Heat the solid and stir methanol (100 mL) overnight in 20% NaOH (100 mL). The resulting clear solution is evaporated on a rotary evaporator until cloudy and then diluted with H ₂ O (200 mL), acidified to pH 1 with aqueous HCl and extracted with CH ₂ Cl ₂ (400 mL). The CH ₂ Cl ₂ phase is washed with brine and dried (MgSO ₄ ). Filtration and evaporation yielded 5.77 g (98%) of a tan solid. Recrystallization (cyclohexane) yields a sample for analysis. Melting point: 101-103 ° C.

Elemental Analysis for C ₂₀ H ₂₂ O ₅ :

Calc .: C, 70.46; H, 6.48.

Found: C, 70.08; H, 6.75.

<Example 15D>

N, N-diethyl-2'-methoxy-4'-allyloxy-6- (1-methylethoxy)-[1,1'-biphenyl] -2-carboxamide

(A) Thionyl chloride Procedure I: 2'-methoxy-4'-allyloxy-6- (1-methylethoxy) -1,1'-biphenyl)-in anhydrous CH ₂ Cl ₂ (33 mL)- To a stirred solution of 2-yl-2-carboxylic acid (3.57 g, 0.014 mol) is added dropwise SOCl ₂ (1.30 mol) at ambient temperature. The solution is stirred at ambient temperature for 45 minutes, then cooled to 0 ° C. and diethylamine (10.75 mL, 0.104 mol) is added dropwise. The temperature is kept below 25 ° C. during the addition. The resulting mixture is stirred at ambient temperature for 2 hours and then diluted with CH ₂ Cl ₂ (50 mL). CH ₂ Cl ₂ is washed with H ₂ O (2 × 200 mL), extracted with 5% NaHCO ₃ (200 mL), washed with brine, dried (MgSO ₄ ) and filtered. The filtrate was concentrated and chromatographed (EtOAc / hexane 1/1) to give lactone [compound 2,3-allyloxy-10- (1-methylethoxy) -benzo- [c] chromen-6-one] ( 0.082 g) is followed by 1.60 g (39%) of the desired fluorenone [Compound 3,2-allyloxy-4- (1-methylethoxy) -fluoren-9-one].

(B) thionyl chloride II: 2'-methoxy-4'-allyloxy-6- (1-methylethoxy) -1,1'-biphenyl-2- in anhydrous CH ₂ Cl ₂ (30 mol) To a stirred solution of il-2-carboxylic acid (2.53 g, 0.0074 mol) is added SOCl ₂ (0.88 mL, 0.017 mL) and the resulting mixture is stirred for 20 minutes and then heated at reflux for 15 minutes. The resulting tan solution is cooled to 0 ° C. and diethylamine (7.66 mL, 0.074 mol) is added dropwise. After addition of diethylamine the resulting mixture is diluted with CH ₂ Cl ₂ (15 mL) and then treated as described above to yield 2.18 g (74%) of a clear oil.

HRMS (HRFAB): Elemental Analysis for C ₂₄ H ₃₂ NO ₄ :

Calc .: 398.233134.

Found: 398.230815.

(C) PyBOP procedure: 2'-methoxy-4'-allyloxy-6- (1-methylethoxy) -1,1'-biphenyl-2-yl- _{2 in} CH ₂ Cl ₂ (20 mL) Add diisopropylethylamine (2.43 ml, 0.0140 mol) to a stirred solution of carboxylic acid (2.17 g, 0.0063 mol), PyBOP (3.27 g, 0.0063 mol) and diethylamine (0.83 ml, 0.0080 mol). . The solution turns brown and becomes exothermic (temperature rises to -10 ° C). The mixture is stirred overnight at ambient temperature, diluted with CH ₂ Cl ₂ (˜100 mL) and evaporated on a rotary evaporator. The residue is dissolved in EtOAc (200 mL). EtOAc is extracted with 5% HCl (3 × 70 mL), separated, washed with brine, then extracted with 5% NaHCO ₃ (3 × 70 mL), washed with brine, dried (MgSO ₄ ) and evaporated. The residue is chromatographed as described above to yield 3.03 g (78%) of the title compound as a clear oil.

IV. Biological data

Protein Kinase C Purification:

Protein kinase C (PKC) is described by Salama, SE, Thromb. Res . 44 : 649-660, 1986, partially purified from the cytosol of the rat brain. After brain recovery, all manipulations were performed at 4 ° C. Briefly, the cerebellum was recovered from 8-10 rat brains and then each brain was homogenized in 9 ml sucrose / EDTA (0.32M sucrose, 1 mM EDTA, 5 mM Tris, pH 7.4). Pooled equivalents were then centrifuged at 1000 × g for 10 minutes at 4 ° C., and pellets were resuspended in the same volume of fresh sucrose / EDTA and centrifuged at 1000 × g for 10 minutes at 4 ° C. Supernatants from each of these spins were pooled and centrifuged at 25,700 × g for 30 minutes at 4 ° C. and the resulting pellet was 20 ml of Buffer A (20 mM Tris pH 7.5, 0.1 mM calcium chloride, 0.4 mM leupeptin at 4 ° C.). Homogenization). The PKC linked membrane was then pelleted by centrifugation at 45,700 × g for 15 minutes at 4 ° C. and resuspended in 20 ml Buffer A. This step was repeated for a total of three centrifugations and the supernatant was discarded and finally the pellet was resuspended in 20 mL of buffer B (20 mM Tris pH 7.5, 1 mM EGTA, 1 mM EDTA and 0.01 mM leupeptin) and stirred for 30 minutes on ice. It was. Dissociated PKC was then collected by centrifugation at 45,700 × g at 4 ° C. for 15 minutes. The pellet was discarded and the supernatant centrifuged at 100,000 xg for 60 minutes at 4 ° C. The pellet was discarded again and the supernatant was adjusted by adding sufficient volumes of stock solution containing 100 mM CaCl ₂ and MgCl ₂ , respectively to remove all EDTA and EGTA to obtain final concentrations of 1 mM Ca ⁺⁺ and 1 mM Mg ⁺⁺ . The resulting slurry was then applied to a 12 cm × 1 cm DE-52 (DEAE cellulose, Whatman ^R ) column already equilibrated with Buffer B. The flow rate of all column chromatography was 0.75 ml / min. The column was washed with 70 ml of buffer B to remove unbound protein and then the undesired protein was eluted with 40 ml of buffer B containing 40 mM NaCl and the fraction containing PKC was 20 ml of buffer containing 150 mM NaCl. Eluted with B. The PKC eluate was then concentrated to about 5 ml using Amicon ^R ultracells equipped with a PM-10 membrane, followed by addition of 30 ml of 5 mM Tris (pH 7.4) and to a final volume of about 5 ml. Excess NaCl was removed by reconcentration. The concentrated and desalted PKC formulation was then adjusted to contain 10% glycerol and 0.5% Triton X-100 and then aliquoted to store a volume of 200 μl at −70 ° C. Frozen formulations were stable for at least 3 months at -70 ° C.

<Analysis procedure>

Protein kinase C is described by Aftab, DT and WN Hait., Anal Biochem . 187 : 84-88. 1990; And Parant, MR and Vial, HJ, Anal Biochem . 184 : 283-290. And analyzed using a semi-automatic 96 well plate procedure based on the procedure of [1990]. In short, each well of a 96 well "u" well microtiter plate has a final concentration of 30 mM Tris (pH 7.4), 10 mM MgSO ₄ , 1 mM EGTA, 200 μg H1 histone (Sigma Type III-S H5505), 30 μl of PKC extract diluted in 5 mM Tris (pH 7.4) containing 50 μM of ATP, 0.5 μCi 30 Ci / mmol of ³² P-ATP, and 1 mg of leupeptin, pepstatin and chimastin per ml, And a total of 100 μl of analyte volume consisting of 1 mM phenylmethylsulfonylfluoride. The reaction was initiated by the addition of PKC extract and the reaction was stopped by adding 50 μl of 40% trichloroacetic acid followed by the addition of 25 μl of 50 mM unlabeled ATP and 25 μl of 0.5% bovine serum albumin, followed by Skatron (Skatron). ) Were collected on a glass fiber filter using an ^R automatic micro cell harvester. Samples were washed with 5% trichloroacetic acid for 30 seconds, dried for 5 seconds on a harvester and then transferred to scintillation vials for counting and analysis of data. The reaction was carried out at room temperature for 5-7 minutes.

<Data analysis procedure>

Data were fed to competitive binding curves using the ENZFITTER ^R program (Biosoft). The error evaluated for IC ₅₀ values was less than 10%. The results are summarized in Table 1.

Claims (31)

A compound of the formula: or a pharmaceutically acceptable salt thereof. Where B is O or S, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or n-butoxy; X is hydrogen, methoxy, ethoxy or n-propoxy; Y is NH ₂ ; Z is hydrogen or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z can be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X; Also, When Z is BR ⁵ N (R ⁴ ) ₂ , at least one of Y, V and X is not hydrogen and is not substituted by Z. The compound of claim 1, wherein B is O, R ⁵ is ethylene, X is hydrogen, methoxy, ethoxy or n-propoxy and Z is hydrogen or OCH ₂ CH ₂ N (R ⁴ ) ₂ . The compound of claim 1, wherein B is O, R ⁴ is methyl or ethyl, R ⁵ is ethylene, V is hydrogen, methoxy, ethoxy or n-propoxy, X is hydrogen or methoxy, Y Is NH ₂ and Z is hydrogen or OCH ₂ CH ₂ NR ⁴ . The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. A compound of the formula: or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound of claim 1 or a pharmaceutically acceptable salt thereof. Treating a disease selected from the group consisting of neoplastic disease states, disorders associated with abnormal blood flow and inflammatory diseases, comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Pharmaceutical composition for. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is hydrogen, methoxy or ethoxy; Y is hydrogen or NH ₂ ; Z is hydrogen or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. A pharmaceutical composition for treating a neoplastic disease state comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. The pharmaceutical composition of claim 15, wherein the neoplastic disease state is carcinoma. The pharmaceutical composition of claim 15, wherein the neoplastic disease state is leukemia. A pharmaceutical composition for inhibiting angiogenesis, comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. A pharmaceutical composition for treating abnormal blood flow conditions, comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. The pharmaceutical composition of claim 19 for the treatment of hypertension. The pharmaceutical composition of claim 19 for the treatment of ischemia. The pharmaceutical composition of claim 19 for the treatment of atherosclerosis. A pharmaceutical composition for inhibiting platelet aggregation, comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. A pharmaceutical composition for inhibiting inflammation comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. The pharmaceutical composition of claim 24 for the treatment of transplant rejection. The pharmaceutical composition of claim 24 for the treatment of psoriasis. The pharmaceutical composition of claim 24 for the treatment of asthma. The pharmaceutical composition of claim 24 for the treatment of gouty arthritis. The pharmaceutical composition of claim 24 for the treatment of pulmonary fibrosis. A pharmaceutical composition for inhibiting alveolar macrophage activation, comprising an effective protein kinase C inhibitory amount of a compound of the formula: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Where B is O, S or NH, R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together may form pyrrolidinyl, piperidinyl or morpholino; R ⁵ is C _1-5 alkylene; V is hydrogen, methoxy, ethoxy, n-propoxy or butoxy; X is H, methoxy or ethoxy; Y is H or NH ₂ ; Z is H or BR ⁵ N (R ⁴ ) ₂ , wherein R ⁴ , R ⁵ and B are as defined above; only, Z may be present at the 1, 2, 3 or 4 position, and when present at the 1, 2 or 4 position, respectively, replaces Y, V or X. The compound of any one of claims 14, 15, 18, 19, 23, 24 and 30, wherein B is O and R ⁴ is methyl, ethyl or n-propyl, or two R ⁴ together are pyrrolidinyl or Can form piperidinyl, R ⁵ is ethylene, V is hydrogen, methoxy, ethoxy or n-propoxy, X is hydrogen, methoxy or ethoxy, Y is hydrogen or NH ₂ , Pharmaceutical composition wherein Z is hydrogen or OCH ₂ CH ₂ NR ⁴ .