Among the problems faced in certain types of drug therapy, including cancer chemotherapy and malaria drug therapy, is the phenomena of resistance to treatment regimens. The resistance means, for example, that cancerous tumors that responded well initially to a particular drug or drugs, later develop a tolerance to the drug(s). Drug resistance is the name given to the circumstance when a disease does not respond to a treatment drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been responsive to the drug(s), or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously been responsive to. Multidrug resistance is a specific type of drug resistance that is characterized by cross-resistance of a disease to more than one functionally and/or structurally unrelated drugs. Multidrug resistance in the field of cancer, is discussed in greater detail in Kuzmich and Tew, xe2x80x9cDetoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,xe2x80x9d particularly section VII xe2x80x9cThe Multidrug-Resistant Phenotype (MDR),xe2x80x9d Medical Research Reviews, Vol. 11, No. 2, 185-217, particularly 208-213 (1991); and in Georges, Sharom and Ling, xe2x80x9cMultidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,xe2x80x9d Advances in Pharmacology, Vol. 21, 185-220 (1990).
Treatment of drug and multidrug resistance typically involves the coadministration of a drug suitable for treatment of the disease and a compound which acts through various mechanisms to cause the drug suitable for treatment of a disease to begin and/or continue to function as a therapeutic agent.
U.S. Pat. No. 5,654,304 (""304), incorporated by reference herein, discloses a series of 10,11-(optionally substituted)methanodibenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-Difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride is disclosed in ""304 and is currently under development as a pharmaceutical agent.
A crystalline form of this compound, which can be conveniently formulated for administration to patients, is highly desirable. Thus, there is a need to prepare (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride as a pure, highly crystalline solid in order to fulfill exacting pharmaceutical requirements and specifications.
Preferably, such a crystalline compound will be readily formed and have favorable bulk or pharmaceutical characteristics. Examples of favorable bulk characteristic are drying times, filterability, solubility, intrinsic dissolution, thermal stability, and hygroscopicity. Examples of favorable pharmaceutical characteristics are purity and potency. Decreased organic solvents in the crystalline structure is favorable, due in part to potential solvent toxicity to the recipient as a function of the solvent. Furthermore, the process for preparing crystalline compounds also needs to be conveniently carried out on commercial scale.
Although the 10,11-methanedibenzosuberanes prepared by the procedures taught in ""304 could be used as a pharmaceutical, xe2x80x9cone cannot predict which compounds will be polymorphicxe2x80x9d (Florence and Attwood, Physicochemical Principles of Pharmacy, 2nd Ed., Chapman and Hall, New York, N.Y., 1988, pages 23-24), it would be highly desired and advantageous to find a more crystalline form of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride having the advantageous properties described above. The preparation of the new crystalline form of the present invention fulfills these desirable features.
Additionally, there is need for an improved process for the preparation 10,11-(optionally substituted)methanodibenzosuberane derivatives which is more efficient and adaptable to large scale processing than those previously employed, for example in ""304. Advantages of an improved process may include, for example, improved stereoselectivity, purity, and yield.
The present invention provides a process for preparing a compound of formula (1) 
wherein
A is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHRaxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHRaxe2x80x94CH2xe2x80x94CH2xe2x80x94, and
Ra is OH;
R1 is H, F, Cl, or Br;
R2 is H, F, Cl, or Br; and
R3 is heteroaryl or phenyl, each optionally substituted with F, Cl, Br, CF3, CN, NO2, or OCHF2;
or the pharmaceutically acceptable salts thereof, comprising the steps of:
(a) reacting a compound of formula (4) 
with a nucleophile source to form a compound of formula (5) 
wherein X is a leaving group;
(b) reacting a compound of formula (5) with pyrazine to provide a compound of formula (6) 
(c) reducing the compound of formula (6) to provide a compound of formula (8): 
(d) reacting a compound of formula (8) with either:
(i) an epoxy compound of formula (9) 
wherein R3 is as defined above, and n is an integer 1 or 2; or
(ii) a halo compound of formula (10)
X1xe2x80x94(CH2)mxe2x80x94Oxe2x80x94R3xe2x80x83xe2x80x83(10)
wherein R3 is as defined above, X1 is halo, and m is 2, 3 or 4; and
(e) optionally forming a pharmaceutically acceptable salt from the compound produced in step (d).
The present invention also provides an improved process for preparing a compound of formula (4): 
comprising reacting dibenzosuberenone with an alkali trihaloacetate to produce an intermediate 10,11-(optionally substituted)methanodibenzosuberone and reducing said intermediate, wherein both reactions are performed in one operational step.
The ability to perform both reactions in one operational step is an advantage over the prior art. U.S. Pat. No. 5,654,304 teaches a step-wise preparation of the 10,11-(optionally substituted)methanodibenzosuberol, beginning with preparation and isolation of 10,11-(optionally substituted)methanodibenzosuberone from dibenzosuberenone (2) in diglyme and sodium trihaloacetate (e.g., sodium chlorodifluoroacetate) in diglyme at a temperature of 160xc2x0 C. to 165xc2x0 C. followed by reduction of the intermediate 10,11-(optionally substituted)methanodibenzosuberone (3) to afford the corresponding 10,11-(optionally substituted)methano dibenzosuberol.
Additionally, the present invention contemplates a compound of formula (6) 
wherein R1 and R2 are independently H, F, Cl or Br and X is leaving group selected from the group consisting of Br, Cl, OMs, and OTs.
Moreover, the present invention provides a novel hydrate crystal form of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (xe2x80x9cHydrate Ixe2x80x9d), having an X-ray diffraction pattern which comprises the following peaks corresponding to d spacings: 7.95+/xe2x88x920.04 xc3x85 when obtained at 22xc2x12xc2x0 C. and 31xc2x110% relative humidity from a copper radiation source.
The present invention also provides the novel hydrate a characterized above, having an X-ray diffraction pattern further comprising the following peaks: 9.93, 4.45, and 3.36+/xe2x88x920.04 xc3x85 when obtained at 22xc2x12xc2x0 C. and 31xc2x110% relative humidity from a copper radiation source.
The present invention further provides a method of treatment for a drug resistant disease comprising coadministering to a mammal in need thereof a resistance modulating amount of Hydrate I and an effective amount of a treatment drug for said drug resistant disease.
The present invention further provides a method of treatment for a multidrug resistant disease comprising coadministering to a mammal in need thereof a multidrug resistance modulating amount of Hydrate I and an effective amount of a treatment drug for said multidrug resistant disease.
The present invention further provides a method for enhancing bioavailability of a drug to the brain, comprising coadministering to a mammal in need thereof a therapeutically effective amount of said drug and Hydrate I sufficient enough to allow said drug to cross the blood-brain barrier and enter the brain.
The present invention further provides a method for enhancing oral bioavailability of a drug comprising administering to a mammal in need thereof a therapeutically effective amount of said drug and Hydrate I sufficient enough to allow said drug to be transported across the gastrointestinal tract and enter the bloodstream.
The present invention further provides a solvate of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride.