MXPA98010785A - Compounds and methods to provide pharmacologically active preparations and uses of mis - Google Patents

Abstract

The invention relates to pharmacologically active compounds that are capable of binding to nuclear hormone receptors and are useful for the stimulation of osteoblast proliferation and ultimately the growth of bone. This invention also relates to the use of such compounds for the treatment or prevention of diseases and / or disorders associated with families of nuclear hormone receptors.

Description

COMPOUNDS AND METHODS TO PROVIDE PHARMACOLOGICALLY ACTIVE PREPARATIONS AND USES THEREOF FIELD OF THE INVENTION The present invention relates to compounds and their uses for the treatment of the family of the nuclear hormone receptor (NHR) associated with disorders. More specifically, the present invention relates to compounds having a particular 3-dimensional spatial orientation that are capable of binding to and thus altering the function of the NHR. Such compounds would be useful as therapeutic agents for disorders associated with NHRs such as the retinoid receptor x (RXR). The invention also relates to compositions and methods for the treatment or prophylaxis of osteoporosis, bone loss, arthritis, inflammation, cancer and skin conditions.

REF .: 29136 BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PREVIOUS ART Current modern methods for the discovery of therapeutic agents for the amelioration of major diseases focus on interdisciplinary approaches of molecular biology, enzymology, crystallography, drug synthesis, molecular modeling and pharmacology. The typical approach involves: identification, isolation, purification, and crystallization of a white protein associated with the disease (s) of interest; modeling of the protein link and active sites; and modeling, synthesis and evaluation of compounds to optimize their pharmacological activity. Even with the advanced state of the art, drug discovery and, in particular, prediction of structure-activity relationships, significant effort continues to be required in the part of the pharmaceutical industry. Thus, there remains a need to develop efficient and cost-effective methods for the identification of pharmacologically active compounds for the treatment of specific diseases.

Osteoporosis is a condition characterized by a decrease in bone mass with decreased density and lengthening of bone spaces, producing porosity and fragility. This condition afflicts men and women, particularly menopausal women, of advanced age. This condition is mainly a disorder in the formation of the bone matrix. Osteoblasts, a population of cells that form bone, are typically reduced in number. Osteoblasts are derived from adjacent mesenchymal precursors in a process regulated by factors derived from the local bone. Osteoclasts, a population of cells that break the bone and that are associated with bone resorption, are not reduced in number. The osteoclasts are large, usually multinuclear cells found on the resorbed surfaces of mineralized bone. Osteoclasts are formed by fusion of mononuclear precursors, which originate from precursors born from extra-skeletal blood.

All known and local stimulators of osteoclastic bone resorption, including parathyroid hormone, 1.25D, IL-2, and TNF, modulate their stimulatory effects on the osteoclast through an initial effect on osteoblasts. Osteoblasts are therefore believed to play a major role in the regulation of bone transfer by controlling the rate of new bone formation, as well as serving to generate signals that stimulate osteoclastic bone resorption.

NHR families are associated with the modulation of the proliferation and differentiation of mammalian cells. These cellular processes are controlled by signal molecules that regulate gene expression. NHRs such as retinoid receptors are associated with many diseases and disorders such as osteoporosis, cancer, acne, AIDS, arthritis, psoriasis, lupus erythematosus and the like. The retinoid x receptor (RXR) serves to modulate cellular transcriptional activity thus controlling cell proliferation.

It is recognized in art that osteoblasts play a very complex role in bone formation. It is generally believed that osteoclasts serve to dissolve (resorb) bone such that osteoblasts can then deposit more bone. It is then reasonable that compounds that can inhibit excessive bone resorption or stimulate the proliferation of osteoblasts will be useful for the prevention of bone loss or the stimulation of bone growth.

Takashi et al. (Jopn Kokai Tokyo Koho JP03130216 A2, 4/6/94) exhibits diphenyl compounds having the following general structure where X is -CH2- or -C (= 0) -, for the treatment and prophylaxis of osteoporosis.

Labroo (US 5,389, 646 published on 2/14/95) discloses compounds having the following general structure wherein R1 is H, OH, C1-C17 alkoxy, alkylcarbonyloxy (C1-C17), alkylcarbonylamino (C1-C17) or alkylcarbonyl (C1-C17); R2 is - (CH2) (1.6) -CH2-heterocycle; and R3 is H, OH, C1-C17 alkoxy, (C1-C17) alkylcarbonyl, (C1-C17) alkylcarbonylamino or (C1-C17) alkylcarbonyl, for the treatment and prevention of bone loss.

Other compounds such as the following have been proposed for the treatment of osteoporosis. Even so, these compounds have not found general use due to their limited efficiency. Thus, there remains a need for more effective compounds for the treatment of osteoporosis.

Kamala et al. (Indian J. Chem. (1983), 22B, 1194-96) and Waisser et al. (Collect. Czech, Chem. Commun. (1991), 56. 2978-2985) state the synthesis of and its uses as a synthetic intermediate and antituberculous agent, respectively.

Bis-aromatic compounds are widely known for their use in the treatment of cancer and tumors. In general such compounds effectively inhibit DNA replication thus exerting their cytotoxic effects on mammalian cells. Here too, no compound has been found that is generally applicable for the treatment of a broad spectrum of cancers and tumors. Thus, there still remains a need for more effective anticancer and tumoricide compounds of broader spectrum.

It is an object of the present invention to overcome the limitations inherent in the art of modeling pharmaceutical agents by providing a method for selecting candidate chemical agents that use defined 3-dimensional spatial characteristics. These spatially defined chemical compounds in some aspects overcome more limitations associated with available osteogenic agents by providing agents that stimulate the production of morphogenic bone proteins, and thus provide useful compositions for stimulating osteoblast proliferation and diseases that result in bone loss.

A further objective of the invention is to provide agents that bind other receptors in the nuclear hormone receptor (NHR) family that are associated with diseases.

It is another object of the present invention to provide a method for using particular pharmacologically active compounds for the treatment or prophylaxis of physiological disorders or diseases associated with NHRs such as osteoporosis, arthritis, cancer, tumors and the like.

It is another object of the invention to provide a method for the selection of pharmacologically active compounds that are capable of stimulating the proliferation and differentiation of the osteoblast and are useful for the treatment of physiological disorders associated with NHR and in particular diseases associated with bone loss.

Another objective of the present invention is to provide methods for screening and screening for pharmacologically active compositions which are capable of stimulating the proliferation and differentiation activity of the osteoblast. Such selected composition will be used for the treatment or prophylaxis of osteoporosis and other physiological disorders associated with NHR.

Brief Description of the Invention The present invention provides methods for stimulating osteoblast proliferation, as well as methods for screening pharmacologically active compounds. In one embodiment, the method for stimulating osteoblast proliferation comprises selecting substances of general formula I X-L-Z, where: X is selected from the group consisting of: L is selected from the group consisting of: Or v% v < s ^ 0 -R7 a simple link Á6 ¿o Z is selected from the group consisting of: wherein R 1 is selected from the group consisting of: H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, and (C 1 -C 12) alkylcarbonyloxy; R 2 is selected from the group consisting of: H, OH, halo, Cl 6 alkyl, C 1 -C 6 alkenyl, Cl 6 alkoxy, and C 1 -C 12 alkylcarbonyloxy; R3 is selected from the group consisting of: H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, Cl-C6 alkenyl, and (C1-C12) alkylcarbonyloxy; R "is selected from the group consisting of: H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, and alkyl (Cl-C12) -carbonyloxy; R is selected from the group consisting of: H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC (= 0) Me, phthalimide and (C 1 -C 12) alkylcarbonyloxy; R6 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, and C1-C4 alkoxy; R7 is selected from the group consisting of: H, C1-C4 alkyl, (C1-C) alkylcarbonyl, and arylalkyl (C7-C10); RB is selected from the group consisting of: H, OH, halo, -CF3, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, -NHC (= 0) Me and -N (Cl-C4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C4 haloalkyl, -CF3, C1-C8 alkyl, C1-C8 alkoxy, -NHC (= 0) Me and -0C ( = 0) Me; R10 is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C4 haloalkyl, -C02H, alkyl C1-C12, C1-C12 alkoxy, phenyl, C1-C12 alkenyl, alkoxycarbonyl (C1-C4), -NHC (= 0) Me, alkylcarbonyl (C1-C4), alkylcarbonyloxy (C1-C12) and heteroaryl; R11 is selected from the group consisting of: H, OH, halo, C1-C4 haloalkyl, -CF3, C1-C4 alkyl, -NH2, C1-C4 alkoxy, -NHC (= 0) Me, C1-C4 alkenyl, (C1-C4) alkoxycarbonyl, alkylcarbonyl (C1) -C4), and alkylcarbonyloxy (C1-C14; R 12 is selected from the group consisting of: H, OH, -NH 2, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and (C 1 -C 4) alkylcarbonyl; Y R13 is selected from the group consisting of: H, OH, halo, -NH2, C1-C4 alkyl, C1-C4 alkoxy, -N (C1-C4 alkyl); Y exposure of cells comprising osteoblast cells for an effective amount of the pharmacologically active compound.

These methods are expected to result in the stimulation of osteoblast proliferation, and therefore a useful application in the prevention of bone loss and / or promotion of bone growth.

In further defined embodiments, the substance selected as part of the method is more particularly defined in that R10 and Rn could be brought together to form a 5-7 membered carbocycle or oxacarbocycle fused to a ring to which they are bound, where the carbocycle and oxacarbocycle are substituted with one or more groups selected independently of the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, OH, halo, carboxyl, H and aryl, to provide a pharmacologically active compound.

It is also contemplated and is within the scope of the invention that the pharmacologically active compound of formula I could bind more than one different type of nuclear hormone receptor (NHR), and therefore be useful in the treatment of other NHR-related diseases. .

While not being limited to any particular mechanism of action, it is contemplated that the pharmacologically active compound of formula I could promote the growth of the osteoblast or enrich the population of osteoblasts by increasing the activity of the BMP-2 promoter.

It is also contemplated and is within the scope of the present invention that the pharmacologically active compounds of formula I could be used in combination with other compounds for the stimulation or promotion of osteoblast growth. They could also be used for the stimulation of bone growth or the inhibition of bone loss and / or resorption.

Another aspect of the present invention provides a method for selecting a pharmacologically active compound or pharmacologically active candidate compounds. In one embodiment, the pharmacological activity of the compounds is a capacity to stimulate the activity of the BMP-2 promoter. The method in one modality comprises: select candidate compounds having a spatially defined 3-dimensional structure as in formula II W-L-Y where: W contains an aromatic group having a centroid indicated by the letter "A"; And it contains a carbocyclic group having a centroid indicated by the letter "B"; L is a group that links X and Z; a plane? F 'is formed by the aromatic atoms of the aromatic group in W; the centroid WB "falls within approximately 1, or approximately 0.7 angstroms above or below the plane the centroid, "A" and the centroid WB "are separated approximately 6, or approximately 6.6, to approximately 8, or approximately 8.5 angstroms; to provide the spatially defined molecules; and selecting spatially defined molecules capable of stimulating the activity of the BMP-2 promoter.

The molecules spatially defined in the above method are further defined in some embodiments since they have at least two groups that accept hydrogen bonds located within or close to L, the hydrogen bond acceptor groups are defined more as follows: 1) the hydrogen bond acceptor groups are at about 2, or about 2.3, at about 5, or about 5.4 angstroms apart; 2) a hydrogen bond acceptor group is about 4, or about 4.5, to about 7, or about 7.7 angstroms from the centroid?, A "and about 2, or about 2.7, to about 3, or about 3.8 angstroms from the MB centroid "; Y 3) a hydrogen bond acceptor group is about 2, or about 2.6, to about 3, or about 3.8 angstroms, from the centroid "A" and about 4, or about 4.6, to about 7, or about 6.9 angstroms from the centroid " B ".

In some embodiments of the method, L is further defined as occupying a space that outside the boundary is less than or equal to about 3, preferably about 3.1 angstroms, as measured by the distance of the heavy atom, above and below and normal to the plane T as measured along and normal to the WP plane. "In other embodiments L could be further defined as occupying a space that outside the boundary is about 4, preferably about 4.7 to about 6.0 angstroms, as measured by the distance of the heavy atom, perpendicular to a line that connects the centroid "A" to the centroid WB "and into the plane" P ".

Pharmaceutically acceptable preparations of these compounds are also claimed, and are used to provide a pharmacologically active preparation for stimulating osteoblast proliferation and / or bone resorption reduction.

It is contemplated and is within the scope of the present invention that the pharmacologically active compound of formula II could possess different activities of stimulation of osteoblast proliferation and inhibition of bone resorption. Such activities would be associated in general with the binding to one or more nuclear hormone receptors, and thus provide a treatment for several diseases that are associated with receptor activity.

It is also contemplated and is within the scope of the present invention that many pharmacologically active compounds not specifically listed herein could, however, fall within the spatially defined structure of formula II. Such spatially defined molecules would also fall within the scope of the method, where they are capable of stimulating the activity of the BMP-2 promoter, or stimulating the proliferation of the osteoblast, or some other desired pharmacological activity. These compounds would thus be useful in stimulating bone formation or reducing the loss of bone tissue.

It should be understood that a compound of formula II could also contain other structural parameters not recited here, yet falls within the defined scope of the invention. Such structural parameters are generally secondary to recitations. That is, although the addition of a particular substituent a or Y could make a compound of formula II more or less active than without the particular substituent, the compound having the substituent is within the scope of the present method at all times comprising the features recited above. for the compound of formula II, or any of the formula as described herein.

Another embodiment of the present invention provides a method for treating and / or preventing cell proliferation of malignant tumors. One modality of the method comprises: administering to a population of cells comprising malignant tumor cells an amount that inhibits malignant tumor cell proliferation of a pharmacologically active compound having a spatially defined structure as defined by formula II W-L-Y; and Formula II which inhibits malignant tumor cells, wherein the pharmacologically active compound is further defined by means of a 3-dimensional structure wherein: W contains an aromatic group having a centroid indicated by the letter WA "; And it contains a carbocyclic group having a centroid indicated by the letter "B"; L is a group that links X and Z; a "P" plane is formed by the aromatic atoms of the aromatic group in W; the centroid "B" falls within approximately 1, or approximately 0.7 angstroms above or below the WP plane "; the centroid WA "and the centroid" B "are separated by approximately 6, or 6.6 to approximately 8, or approximately 8.5 angstroms.

The pharmacologically active compound of the above method could be further defined as having a spatially defined structure wherein at least two hydrogen bond acceptor groups are located within or near the vicinity of L, with the hydrogen bond acceptor groups being defined also as follows: 1) the hydrogen bond acceptor groups are separated by about 2, or about 2.3, to about 5, or about 5.4 angstroms; 2) A hydrogen bond acceptor group is about 4, or about 4.5, to about 7, or about 7.7 angstroms from the centroid, "A" and about 2, or about 2.7, to about 3, or about 3.8, angstroms of the centroid "B"; 3) a hydrogen bond acceptor group is about 2, or about 2.6, to about 3, or about 3.8, angstroms of the centroid WA "and about 4, or about 4.6 to about 6, or about 6.9 angstroms of the centroid" B " .

In some embodiments of the method, L is further defined as a space that outside the limit is less than or equal to about 2.5, or about 3 or 3.1 angstroms, as measured by the distance of the heavier atom, up or down and normal to the flat WP "as measured with a normal to the" P "plane Still in another embodiment, the pharmacologically active compound is further defined wherein L occupies a space that outside the limit is approximately 4, or preferably approximately 4.7 to approximately 5, or preferably 6.0 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" and within the plane Other aspects of the present invention provide methods for stimulating the activity of the BMP-2 promoter or the proliferation of the osteoblast and the pharmacologically active compounds of formula III Formula III where: R1 is selected from the group consisting of: aryl, naphthyl, heteroaryl, cycloalkyl, cycloalkenyl, azacycloalkyl, oxacycloalkyl, azacycloalkenyl, oxacycloalkenyl, substituted cycloalkyl keto, and substituted keto cycloalkenyl, wherein each of the above substituents is substituted by one or more of the groups independently selected from the group consisting of : C1-C7 alkyl, C1-C7 alkoxy, benzyloxy, hydroxy, C1-C2 haloalkyl, halo, cyano, carboxyl, hydrogen, (C1-C4) alkoxycarbonyl, -N (ClC4 alkyl) 2, (C1-C4) alkylcarbonyloxy , aryl, alkylcarbonylamino (C 1 -C 4), alkylcarbonyl (Cl-C 4), alkyl (C 1 -C 4) -aryl, and -NH 2; R2 is selected from the group consisting of: H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy and -NH 2; R3 and R6 are selected from the group consisting of: H, hydroxy, halo, (C1-C5) alkylcarbonyloxy, cyano, C1-C4 alkyl, C1-C4 alkenyl, and C1-C4 alkoxy; R4 and R5 are selected from the group consisting of: H, halo, hydroxy, (C1-C4) alkylcarbonyloxy, cyano, C1-C2 haloalkyl, C1-C4 alkoxy, benzoyl, alkyl (Cl-C4) -aryl, alkylaminocarbonyloxy (C1-C6), phenylaminocarbonyloxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, (C1-C4) alkenyl-aryl, alkynyl (Cl-C4) -aryl, (C1-C4) alkyl-cycloalkyl (C6-C10), (C1-C4) alkenyl-cycloalkyl (C6-C10), alkynyl (Cl-C4) -cycloalkyl (C6-C10), alkyl (C1-C4) -cycloalkenyl (C6-C10), alkenyl (C1-C4) -cycloalkenyl (C6-C10), alkynyl ( C1-C4) - (C6-C10) cycloalkenyl, carboxy and (C1-C4) alkoxycarbonyl.

The method generally comprises administering an effective amount of a compound of formula III to cells comprising osteoblasts or osteoblast precursor cells.

More method modalities defined to stimulate BMP-2 promoter activity or osteoblast proliferation employ compounds of the type described above wherein R3 and R4 together form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, where The carbocycle or oxacarbocycle is substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl.

In alternative embodiments of the method, the pharmacologically active compound is defined as follows: R4 and R5 together form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, wherein the carbocycle or oxacarbocycle is substituted by one or more of the groups selected from the group consisting of: C1-C4, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl.

In yet another alternative embodiment of the invention, the pharmacologically active compound is further defined wherein: R5 and R6 together form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, wherein the carbocycle or oxacarbocycle is substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1 alkoxy -C4, hydroxy, halo, carboxyl, hydrogen and aryl.

Another aspect of the present invention comprises a pharmacologically active composition possessing osteoblast proliferation activity. In some embodiments, the composition is defined by reference to a particular defined process comprising: oxidize a compound of formula VI Formula VI with heat or Cr03 / H20 / AcOH for a sufficient period of time to form the pharmacologically active composition. This preparation could be further purified and most active fractions selected. The compositions provided as a result of the above process and having an ED50 of from about 1 to about 50 μg / ml, as measured using the test as described in Example 1, are expected to possess osteoblast proliferation activity and a capacity of to stimulate the activity of the BMP-2 promoter.

It is contemplated and is within the scope of the present invention that the above process could comprise other similar or equivalent processes that will effect the conversion of the compound of formula VI to a desired composition having the defined pharmacological activity. Such methods do not deviate from the spirit or scope of the present invention.

It is also contemplated and is within the scope of the present invention that the pharmacologically active composition thus prepared will be useful in the treatment or prophylaxis of diseases or disorders associated with the proliferation of tumor cells, arthritis, inflammation, bone resorption, skin conditions. , and diseases that could be treated using therapies directed to the recipient.

Other features, advantages and embodiments of the invention will be apparent to those skilled in the art from the following description, accompanying results and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS The present drawings are part of the present specification and are included to further demonstrate certain aspects of the invention. The invention could be better understood by reference to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.

Fig. 1. A graph showing the results obtained from a retinoic acid displacement test.

Fig. 2. A top view of a space filling model of a modality of a compound of formula II.

Fig. 3. A side view of a space filling model of a modality of a compound of formula II.

DETAILED DESCRIPTION OF THE INVENTION Method for the Selection of Pharmacologically Active Compounds.

The present invention relates, inter alia, to methods for the selection of a pharmacologically active compound or compounds from a group of compounds. The selected compounds will possess the spatial chemistry structure defined herein, and will have an observable capacity to stimulate the proliferation of the osteoblast or maintain the growth of the osteoblast in culture.

The chemical structure of the selected compound can be defined using the following structural and spatial parameters. The spatial parameters could be obtained by determining the 3-dimensional structure of the selected compounds. Useful methods for the determination of the 3-dimensional structure include: simple crystal x-ray diffraction or 2-dimensional to 3-dimensional algorithmic conversion such as CONCORD or molecular mechanics (MM2). The selected compound will possess two hydrophobic groups exemplified by an aromatic and a carbocyclic group, or alternatively a heterocyclic group. Each of these two hydrophobic groups can be described by means of a centroid, the position of which is simply the average position of all the atoms in the hydrophobic group. For compounds that possess the desired activity, the distance between these two centroids will fall in the range of about 7, or about 7.9 to about 8, or about 8.5 Á. In addition to these two hydrophobic groups, the compounds having the desired activity will possess a chemical grouping or substituent that is capable of forming a hydrogen bond or serving as a Lewis base. One can be formally associated with this hydrogen bond acceptor or Lewis basic site in the molecule, a hydrogen bond donor or Lewis acid group that is external to the molecule. This donor group of the external hydrogen bond or Lewis acid group will be oriented with respect to the molecule in such a way that it makes chemical contact with the complementary site in the molecule.

In this way, the external site will be placed at a distance between 2 and 4? from the complementary site in the molecule, and in such a way that a hydrogen bond or Lewis acid / base associations are formed. A certain geometric relationship must be maintained between the two hydrophobic groups and the donor site of the external hydrogen bond / Lewis acid. This geometric relationship can be described in terms of distances and angles. The external site will be arranged asymmetrically with respect to the two hydrophobic groups, such that one hydrophobic group (the distal hydrophobic group) moves farther from the external site than the other hydrophobic group (proximal). For compounds possessing the desired activity, the distance between the external hydrogen bond donor / Lewis acid group and the centroid describing the distal hydrophobic group will fall within the range of about 6, or about 6.7 to about 7, or about 7.7 Á and will fall optimally within the range of about 6, or about 6.8 to about 7, or about 7.7 Á. For compounds possessing the desired activity, the distance between this external site and the centroid that describes the proximal hydrophobic site will fall within the range of about 4, or about 4.6, to about 6, or about 6.3, Á, and will be optimally within the range from about 4, or about 4.9, to about 6.0 Á. In addition to the groups already described, the compounds possessing the desired activity will also possess a second group capable of serving as a hydrogen bond donor or as a Lewis base.

An angle can be used to describe the orientation with respect to this second acceptor site of the hydrogen / Lewis base link in the molecule. This angle is formed between the centroid that describes the distal hydrophobic group, this second hydrogen bond acceptor group and the external donor hydrogen / Lewis acid donor group. For compounds that possess the desired activity, this angle will fall within the range of 74 to 112 degrees, and will be optimally within the range of 85 to 89 degrees.

The spatial definition of some embodiments of the compound of formula II can be further understood by Figures 2 and 3 which are representations of a space filling model of the central rings in Y and the group of the compound of formula II. Observe the positioning and filling of the space of each of W, L and Y as represented by the white regions. The shaded regions indicate hydrogen bond acceptor regions found within or near the vicinity of L. For the purpose of simplification, substituents that could be attached from the central rings in and Y are not shown. The 3-dimensional structure shown requires a compound that possesses the pharmacological activities recited herein. It should be understood that the compounds contemplated and encompassed by the scope herein can be adapted to other conformations that could produce pharmacological activity. Such conformations could involve link distortions, link angle distortions, spatial variations in size, variations in group spatial orientation and the like and are within the scope of the present invention.

In one embodiment, the selected compound will possess osteoblast proliferation stimulating activity and / or be able to maintain or increase the growth of the osteoblast in vi tro. Such an activity could be determined using any of a number of methods known to the person skilled in the art, such as using the luciferase promoter test described in Example 1. In that assay, a compound possessing the ability to stimulate proliferation or growth of the osteoblast will stimulate the luciferase activity. Since the BMP-2 luciferase promoter constructs were transfected into immortalized murine osteoblasts (2T3 cells), the stimulation of the luciferase activity reasonably correlates to a stimulation activity of the osteoblast proliferation as recognized by those skilled in the art. art.

This method contemplates compounds having an osteoblast proliferation stimulating activity at least about that of the reference compound 2- (4-methoxybenzoylamino) -1,3-benzothiazole. By the phrase "at least about" is meant an activity of not less than about 100X of the activity of the reference compound and preferably an activity at least equal to or greater than that of the reference compound as determined by the ED50 in the test of promoter. Under the conditions of the test of Example 1, the reference compound has an ED50 of about 0.1 micromolar; therefore, the compounds selected by this method should have an ED50 of no greater than 10 micromolar.

Method to Stimulate Bone Growth The present invention in one aspect provides a method directed to the use of compounds of formulas II and III for the stimulation of osteoblast proliferation. It is projected that these compounds will possess the ability to stimulate osteoblast proliferation and therefore bone growth.

This method could be practiced in vivo or in vi tro. When in vivo, it is contemplated that all vertebrate animals, particularly those suffering from osteoporosis, will exhibit at least some stimulation of osteoblast proliferation when treated with compounds of formula II or III.

When practicing in vitro, it is contemplated that the compounds of formula II or III could be tested by any number of techniques known to the person skilled in the art to determine the stimulation activity of the osteoblast proliferation. Such a technique is described as the osteoblast proliferation test of Example 1.

Without being bound by the mechanism, it is believed that the compounds of formula II or III exert their bone growth stimulation activity by stimulating osteoblast proliferation which is a result of the ability of the compounds to modulate cellular transcription by binding to one. or more different types of NHR.

The evidence that these compounds of formulas II and III possess the ability to bind NHRs could be obtained using the test described in Example 6. In that test, a compound is tested for its ability to displace tritiated retinoic acid (RA). of a retinoid receptor. The displaced RA is quantified by scintillation. Figure 1 shows the results obtained when a compound displaces RA. Compounds that possess the ability to displace RA from the retinoic acid receptors can be used to treat or prevent disorders or diseases associated with the receptors. Such diseases and disorders include, by the way or example, osteoporosis, arthritis, acne, cancer, diabetes, leukemia, cardiac hypertrophy, inflammation, lymphomas, carcinomas, other oncological diseases, cervical dysplasia, melanoma, psoriasis, pityriasis rubra pilaris, palmoplantar pustulosis, non-genital warts, cirrhosis, oral lichen planus, xeroderma pigmentosum, immunosuppression and lupus erythematosus.

Preparation of a Composition that Poses Pharmacological Activity - Oxidation Product.

In some embodiments, the present invention relates to a method for the preparation of a pharmacologically active composition of 4-isopropoxybenzoic acid, or any intermediate compound that provides isopropoxyantrone that possesses activity such as could be found in compositions useful for the inhibition of bone loss or stimulation of bone growth.

Shown in Scheme 1 and described in Example 4 is a multistage synthesis for the conversion of 4-isopropoxybenzoic acid to a pharmacologically active composition possessing the desired stimulatory activity of the osteoblast. However, one could start with any of the intermediates in Scheme 1 and always prepare the desired composition by following the appropriate synthetic steps set forth herein. Thus it is contemplated that this pharmacologically active composition is a product of a single to multi-step synthesis where the key step is the oxidative conversion of an oxyanthone to the desired composition by heating or treatment with Cr03 / H20 / AcOH. It should be understood that other reaction conditions and / or similar reagents or equivalents not mentioned herein could be used to carry out the oxidative conversion to arrive at the composition having antiproliferative capacity. Thus, such reaction conditions and / or reagents are considered within the scope and spirit of the present invention.

Scheme 1 The activity of the fractionated material that has been through the oxidative passage possesses the stimulation activity of the osteoblast proliferation as described in the test set forth in Example 1. In that test, an increase in the production of the luciferase action was observed. compared to control, indicating the promotion of gene expression by the composition of the candidate. In that test, the present composition, pharmacologically active composition provided by the process defined above had ED50 of about 10 μg / ml. Compositions that demonstrate an ED50 of from about 1 to about 50 μg / ml, or within the range of about 5 to about 40 μg / ml, or even more particularly from about 10 to about 40 μg / ml constitute the preparations contemplated by the present invention.

Method to Avoid v / o Treat Cellular Malignant Tumor Disorders.

This method is for the treatment and / or prophylaxis of malignant tumor cells associated with disorders and diseases which comprises administering an amount that inhibits the growth of the malignant tumor cell of one or more of the pharmacologically active compounds of formulas I, II, III and VI as defined above.

It is believed that these compounds are capable of binding to NHRs and would therefore be useful to inhibit or prevent the proliferation of malignant tumor cells. The pharmacologically active compounds of malignant tumor cell disorders will be selected as described in Example 3, where spatially defined molecules that inhibit or prevent the proliferation of malignant tumor cells are discerned. The active compounds in that test would be able to inhibit or prevent cell growth or melanoma proliferation. An amount that inhibits malignant tumor cells is defined as an amount capable of inhibiting tumor cell growth in 50% of the control cells. general The pharmacological activities associated with the compounds provided in the present disclosure could be described as providing the enhancement or stimulation of osteoblast proliferation, as providing the delay or inhibition of the malignant tumor or the proliferation of the malignant tumor cells, or as they provide the improvement of skin conditions, such as acne. The pharmacological activity of these compounds could be described in other aspects of the invention as having an anti-arthritic, anti-aging and / or anti-wrinkle activity of the skin.

As used herein, "nuclear hormone receptor" (NHR) is intended to indicate cellular receptors located in the cell nucleus that is involved in the modulation of hormone-mediated physiological responses. Examples of such receptors include, by way of example and without limitation: steroid hormone receptors such as estrogen, androgen, progesterone, glucocorticoid and mineralocorticoid receptors; retinoic acid receptors such as families and subtypes of retinoid A and retinoid X receptors; and orphan receivers such as ROR and RZR.

As used herein, "alkyl" is intended to include branched, cyclic, and branched chain aliphatic hydrocarbon groups having specified the number of carbon atoms; "haloalkyl" is intended to include groups of saturated aliphatic hydrocarbons branched, cyclic or linear chain having specified the number of carbon atoms, substituted with one or more halogens (for example -CvFw where v = 3 and w = the (2v + l)); "alkoxy" represents an alkyl group of indicated number of carbon atoms linked by an oxygen bridge; "alkylthio" represents an alkyl group of indicated number of carbon atoms attached via a sulfur bridge; and "cycloalkyl" is intended to include saturated ring groups, including mono-, bi- polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and cyclooctyl. "Alkenyl" is intended to include hydrocarbon chains of a linear, cyclic or branched configuration and one or more unsaturated carbon-carbon bonds that could occur at any stable point along the chain, such as ethenyl, propenyl, and the like; "cycloalkenyl" is intended to include partially unsaturated cyclic ring groups; and "alkynyl" is intended to include linear, cyclic or branched hydrocarbon chains and one or more triple carbon-carbon bonds that could occur at any stable point along the chain, such as ethynyl, propynyl and the like.

"Alkylcarbonyl" is intended to include an alkyl group of a number of carbon atoms indicated attached via a carbonyl group to the residue of the compound at the designated location; "alkoxycarbonyl" is intended to include an alkoxy group of an indicated number of carbon atoms attached via a carbonyl group to the residue of the compound at the designated location; "alkylcarbonylamino" is intended to include an alkyl group of an indicated number of carbon atoms attached via a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location; "alkylcarbonyloxy" "alkoxycarbonylamino" is intended to include an alkyl group of a number of carbon atoms indicated attached to a carbonyl group, wherein the carbonyl group is attached via an oxygen atom to the residue of the compound at the designated location; "alkoxycarbonylamino" is intended to indicate an alkoxy group having the indicated number of carbon atoms and which is attached to a carbonyl group which is then attached via an amino group to the residue of the compound at the designated location; an "alkylamino" is intended for indicate an alkyl group having the indicated number of carbon atoms attached to an amino group which is then attached to the residue of the compound at the designated location.

"Halo" or "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine; and "counterion" is used to represent a small negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "aromatic group" is intended to indicate aryl or heteroaryl; "aryl" is intended to indicate phenyl or phenyl with substituted rings; "Arylalkyl" represents an aryl group linked by an alkyl bridge. By way of example, the term "C7-C10 arylalkyl" is intended to refer to an aryl group linked via a Cj-C4 alkyl bridge to the residue of the indicated compound; the term "(C: -C3 alkyl) aryl" is intended to refer to a CX-C3 alkyl group which is attached via an aryl ring to the residue of the indicated compound; the term "aryl (C 1 -C 3 alkyl)" is intended to refer to an aryl group linked by a Ci-C-j alkyl group to the residue of the indicated compound.

As used herein, "carbocycle" or "carbocyclic" is intended to mean any stable carbon ring monocycle or 3- to 7-membered bicyclic or 7- to 14-membered bicyclo or tricycle or a polycycle of up to 26-members , any of which could be saturated (cycloalkyl), partially unsaturated (cycloalkenyl), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, "azacycloalkyl" is intended to mean a cycloalkyl group having at least one carbon embedded in the ring replaced by a nitrogen; "oxacycloalkyl" is intended to mean a cycloalkyl group having at least one carbon atom embedded in the ring replaced by an oxygen; "azacycloalkenyl" is intended to mean a cycloalkenyl group having at least one carbon embedded in the ring replaced by a nitrogen; and "oxacycloalkenyl" is intended to indicate a cycloalkenyl group having at least one carbon embedded in the ring replaced by an oxygen.

The compounds described herein could have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds, and the like can also occur in the compounds described herein, and all stable isomers are contemplated in the present invention unless the stereochemistry or specific isomer form is specifically indicated. It will be apparent that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and could be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, of optically active starting materials. Also, it is perceived that the cis and trans geometric isomers of the compounds of the present invention are described and could be isolated as a mixture of isomers or as separate isomeric forms.

Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive the isolation to a degree of useful purity from the reaction mixture, and the formulation into an effective therapeutic agent.

The term "substituted", as used herein, means that one or more hydrogens in the designated atom or group are replaced with a selection of an indicated group, with the proviso that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound.

As used herein, the term "heteroaryl" is intended to indicate a completely unsaturated heterocycle; "heterocycle" is intended to indicate a 5- to 7-membered or 7- to 10-membered monocyclic or bicyclic heterocyclic stable ring that is saturated or unsaturated, and consisting of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms could optionally be oxidized, and the nitrogen could be quaternized, and include any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. The heterocyclic ring could join its pending group at any heteroatom or carbon atom resulting in a stable structure. The heterocyclic rings described herein could be substituted at the carbon or one nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1,5,2-thiadiazinyl, acridinyl, azocinyl, benzofuranyl, benzothiophenyl, carbazole, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl or, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, fenantridinyl, phenanthroline, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxyntinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl , pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl or, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuran, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiantrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl. Fused ring and spiro compounds containing, for example, the above heterocycles are also included.

The following abbreviations are used here and are defined as follows: RXR receptor x retinoid RAR receptor A retinoid NHR nuclear hormone receptor BMP morphogenic bone protein ROR orphan receptor related to retinoid RZR receptors related to Z retinoid PR progesterone receptor ER estrogen receptor AR androgen receptor GR glucocorticoid receptor MR mineralocorticoid receptor TR thyroid receptor VDR vitamin D receptor l, 25 (HO) 2D 1,25-dihydroxy vitamin D IL-2 interleukin 2 TNF tumor necrosis factor Pharmaceutical Formulation As used herein, the term "pharmacologically active compounds" is taken to mean any compound of formulas I, II, III, IV, V or VI having the desired beneficial pharmacological or therapeutic activity such as a pharmacological activity to stimulate or maintain the proliferation of the osteoblast.

The pharmacologically active compounds contemplated within the scope of the invention could be in their free acid, free base, or pharmaceutically acceptable salt forms. They could be derivatives or prodrugs of any of the given compounds.

The loading of pharmacologically active compounds in a pharmaceutical formulation could be carried out following well known techniques such as those described by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, the disclosure of which is incorporated herein by reference. reference.

The loading of the pharmacologically active compound in the formulation may need to be varied according to the pharmacological activity of the compound, the indication being treated, the targeted dosage regimen, the method of projected administration, the integrity or stability of the final formulation or other reasons .

The pharmaceutical formulation of the present invention could be administered by a variety of methods. Such methods include by way of example and without limitation: intraperitoneal, intra-articular, intra-arterial, intracardiac, intracavity, intracartilage, intradermal, intrathecal, intraocular, intraspinal, intrasynovial, intrathoracic, intratracheal, intrauterine, epidural, percutaneous, intravascular, injection. intravenous, intracoronary, intramuscular or subcutaneous; inhalation; or oral, nasal, buccal, rectal, ophthalmic, otic, urethral, vaginal, or sublingual dosing administration. Such methods of administration and others contemplated within the scope of the present invention are known to those skilled in the art.

The pharmaceutical formulation of the present invention could be provided in a variety of ways. Any ingredient used in the present formulation should not degrade or decompose a significant portion of the pharmacologically active compound used prior to administration.

For injection, the pharmaceutical formulation could be a suitable powder for reconstitution with an appropriate solution, such as, for example and without limitation: freeze-dried, spin-dried or spray-dried powders; amorphous powders; or granules, precipitates or particulates. For injection, the pharmaceutical formulation could also be a suspension in the appropriate solutions, such as, by way of example and without limitation, water, aqueous solvents, non-protic solvents, protic solvents, hydrophilic solvents, hydrophobic solvents, polar solvents, solvents not polar and / or combinations thereof, optionally containing stabilizers, pH modifiers, surfactants, bioavailability modifiers and / or combinations thereof.

The pharmaceutical formulation could be administered in the form of a depot injection or implant preparation which could be formulated in such a way as to allow a sustained release of the pharmacologically active compound. The formulation can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as injections or depot implants. The implants could employ inert materials such as biodegradable polymers or synthetic silicones, for example, silastic, silicone made with rubber by Dow-Corning Corporation.

For nasal administration, the pharmaceutical formulation could be a sprayable or aerosol containing the appropriate solvents (such as water, aqueous, non-aqueous, polar, non-polar, hydrophobic, hydrophilic and / or combinations thereof) and optionally other compounds (stabilizers) , antimicrobial agents, antioxidants, pH modifiers, surfactants and / or bioavailability modifiers). A propellant such as compressed air, nitrogen, carbon dioxide or hydrocarbon based on low melting solvents (such as butane, propane or others) would be used in an aerosol formulation. In addition, pastes, ointments or creams containing micelles of the invention could also be used. It is contemplated that bioavailability enhancers such as alcohols or other compounds that increase the penetration of the pharmacologically active compound of the pharmaceutical formulation into the nasal mucosa may be needed to prepare formulations suitable for nasal administration.

For oral, buccal, and sublingual administration, the pharmaceutical formulation could be in the form of a gel capsule, lozenge, tablet, capsule, suspension or powder. For rectal administration, the pharmaceutical formulation could be in the form of a suppository, ointment, enema, tablet and cream for the release of the compound in the intestines, sigmoid and / or rectus flexure.

In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders, such as acacia, corn starch or gelatin; disintegrating agents, such as, corn starch, guar gum, potato starch or alginic acid; lubricants, such as, stearic acid or magnesium stearate; and inert fillers, such as lactose, sucrose or corn starch.

The term "unit dosage form" is used herein to indicate a single or multiple dose form containing an amount of the pharmacologically active compound containing the formulation, said amount being such that one or more predetermined units are normally required for therapeutic administration simple. In the case of multiple dose forms, such as suspensions or cut tablets, said predetermined unit will be a fraction such as 5 ml (teaspoon) amount of a suspension or a half or quarter of a cut tablet, in the multiple dose form.

The pharmaceutical formulations could also be administered as liquid suspensions or solutions using a sterile liquid, such as an oil, water, an alcohol, or mixtures thereof, with or without the addition of a pharmaceutically suitable surfactant, suspending agent, or agent emulsifier for oral or parenteral administration.

For suspension preparations, the pharmaceutical formulation could include oils, for example, fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid, stearic acid and isostearic acid; and esters of fatty acids, such as ethyl oleate, isopropyl myristate, glycerides of fatty acids and glycerides of acetylated fatty acids; with alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l, 3-dioxolan-4-methanol; with ethers such as poly (ethylene glycol) 450, with petroleum hydrocarbons, such as mineral oil and petrolatum; with water, or with mixtures thereof; with or without the addition of a pharmaceutically suitable surfactant, suspending agent or emulsifying agent.

The oils can also be used in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and sugar-related solutions, and glycerols could be used in the preparation of suspension formulations that could adequately contain suspending agents, such as pectin, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as shock absorbers and condoms. Soaps and synthetic detergents could be used as surfactants and as vehicles for detergent compositions. Suitable soaps include alkali metal salts of fatty acid, ammonium, and triethanolamine. Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene) -block-poly (oxypropylene) copolymers; and amphoteric detergents, for example, alkyl β-aminopropionates and quaternary ammonium salts of 2-alkylimidazoline; and mixtures thereof.

It is contemplated that one or a combination of fast or short acting dosage forms, fast release, slow acting, sustained release, controlled release or slow release could be used in the present invention. The course and duration of the administration of and dosing requirements for the formulation of the present invention will vary according to the subject to be treated, the compound to be administered, the formulation used, the method of administration used, the severity and type of indication to be treated, co-administration of other drugs and other factors.

The pharmacologically active compounds contained within the formulation could be formulated as their pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the exposed compounds wherein the original pharmacologically active compound is modified by making acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the original compound formed, for example, of non-toxic inorganic or organic acids. For example, such conventional non-toxic ales include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, -acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the original pharmacologically active compound containing a basic or acidic radical by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a predetermined amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In general, non-aqueous media are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, 1985, p. 1418, the exhibition of which is incorporated herein by reference.

The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and animals without toxicity. excessive, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / irrigation ratio.

PREFERRED MODALITIES Following the patent law convention that has prevailed for a long time, the terms "one" and "one" mean "one or more" when used in this specification.

METHODS TO STIMULATE ACTIVITY BMP-2: PROLIFERATION OF OSTEOBLASTO The present invention provides a method for stimulating the activity of the BMP-2 promoter and therefore the proliferation of the osteoblast. In some embodiments, the method comprises exposing osteoblast-containing cells or osteoblast precursor cells to a pharmacologically active compound of formula I X-L-Z formula I where: X is selected from the group consisting of: L is selected from the group consisting of: * A and a simple link R < 5 Z is selected from the group consisting of; R1 is selected from the group consisting of: H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo and C 1 -C 12 alkylcarbonyloxy; R2 is selected from the group consisting of: H, OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkoxy and C 1 -C 12 alkylcarbonyloxy; R3 is selected from the group consisting of: H, OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkenyl and (C 1 -C 12) alkylcarbonyloxy; R4 is H; R5 is selected from the group consisting of: H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC (= 0) Me, phthalimide and (C 1 -C 12) alkylcarbonyloxy; R6 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, and C1-C4 alkoxy; R7 is selected from the group consisting of: H, C1-C4 alkyl, (C1-C) alkylcarbonyl and arylalkyl (C7-C10); R8 is selected from the group consisting of: H, OH, halo, -CF3, C1-C4 alkyl, C1-C4 alkoxy, -NCH (= 0) Me and -N (Cl-C4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, -CN, -N02, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, - NHC (= 0) Me, and -OC (= 0) Me R10 is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C4 haloalkyl, -C02H, C1-C12 alkyl, C1-C12 alkoxy, phenyl, C1-C12 alkenyl, (C1-C4) alkoxycarbonyl, -NHC (= 0) Me, (C1-C4) alkylcarbonyl, (C1-C12) alkylcarbonyloxy, and heteroaryl; R11 is selected from the group consisting of: H, OH, halo, C 1 -C 4 haloalkyl, -CF 3, C 1 -C 4 alkyl, -NH 2, C 1 -C 4 alkoxy, -NHC (= 0) Me, (C 1 -C 4) alkenyl, (C 1 -C 4) alkoxycarbonyl; (C 1 -C 4) alkylcarbonyl, and (C 1 -C 4) alkylcarbonyloxy; R12 is selected from the group consisting of: H, OH, -NH 2, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl; Y R13 is selected from the group consisting of: H, OH, halo, -NH2, 'C1-C4 alkyl, C1-C4 alkoxy, -N (alkyl? Cl-C4) 2.

In some embodiments of the method, the pharmacologically active compound of formula I could be further defined as follows: R10 and R11 are joined to form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, wherein the carbocycle and oxacarbocycle are substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-6 alkoxy C4, OH, halo, carboxyl, H and aryl; with the condition of: 1) L is Z is when X is selected from:) when X is then L is selected from the group consisting of: a simple link; ando X is: Z is: so L is A ando X is: and Z is so L is ando X is: ; so Z is ; and L is, R7 ndo X is: then Z is: L is: These methods could comprise a second step of stimulating the activity of the BMP-2 promoter to provide stimulation of osteoblast proliferation and bone growth. It is expected that bone resorption could also be reduced or inhibited.

Farmacophore Model Another aspect of the present invention provides a method for selecting a pharmacologically active compound or pharmacologically active candidate compounds. In some modalities, the method comprises: select candidate compounds having a spatially defined 3-dimensional structure as defined in formula II W-L-Y Formula II to provide spatially defined candidate compounds, wherein, W contains an aromatic group having a centroid indicated by the letter "A"; And it contains a carbocyclic group having a centroid indicated by the letter "B"; L contains a group that links X and Z; a plane "F" is formed by the aromatic atoms of the aromatic group in W; the centroid "B" falls within about 0.7 angstroms above or below the "F" plane; the centroid "A" and the centroid "B" are separated approximately 6, or approximately 6.6, to approximately 8, or approximately 8.5 angstroms; Y select spatially defined candidate compounds that have pharmacological activity.

In some embodiments, the 3-dimensional structure of the spatially defined candidate compounds is further defined as follows: L occupies a space that outside the limit is less than or equal to about 3, or about 3.1 angstroms, as measured by the distance of the heavier atom, up or down and normal to the "F" plane as measured by a normal flat "F" In other embodiments, L occupies a space that outside the boundary is approximately 4, or approximately 4.7, to approximately 6.0 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" "and within the" F "plane.

The compound of formula II in other embodiments of the method is defined as comprising at least two groups that accept hydrogen bonds located within or close to the vicinity of L, the hydrogen bond acceptor groups are defined as follows: 1) the hydrogen bond acceptor groups are at about 2, or about 2.3, at about 5, or about 5.4 angstroms apart; 2) a hydrogen bond acceptor group is about 4, or about 4.5, to about 7, or about 7.7 angstroms from the centroid "A" and about 2, or about 2.7, to about 3, or about 3.8 angstroms of the centroid "B" "; Y 3) a hydrogen bond acceptor group is about 2, or about 2.6, to about 3, or about 3.8 angstroms, from the centroid "A" and about 4, or about 4.6, to about 6, or about 6.9 angstroms from the centroid " B ".

In some embodiments, the method is further defined in that the compound of formula II is defined as: 1) no compound of formula X Formula X where Ra is H, OH, C1-C17 alkoxy, alkylcarbonyloxy (Cl-C17), alkylcarbonylamino (C1-C17) or alkylcarbonyl (C1-C17); R2 is (CH2) (1_6) -CH2- heterocycle; and R3 is H, OH, C1-C17 alkoxy, (C1-C17) alkylcarbonyl, (C1-C17) alkylcarbonylamino or (C1-C17) alkylcarbonyl; Y 2) no compound of formula XI Formula XI The invention also provides methods for using spatially defined molecules that are defined by formula II to stimulate BMP-2 promoter activity, osteoblast proliferation, tumor inhibition, skin conditions or arthritis. The candidate substances that satisfy the above spatial characteristics will be selected on the basis of the specific pharmacological activity desired using the tests described herein.

The aromatic ring having the centroid "A" could be substituted independently with one or more of the group consisting of: H, halo, hydroxy, amino, carboxyl, cyano, C1-C6 alkyl, C1-C2 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, -0C (= 0) - (C1-C6 alkyl) and -NHC (= 0) - (C1-C6 alkyl).

In other additional embodiments of the above preparations having the substitution or substitution of the centroid "A", the carbocyclic group having the centroid "B" is independently substituted with one or more of the group consisting of: H, halo, hydroxy, amino, carboxyl, cyano, nitro, trifluoromethyl, C1-C6 alkyl, haloalkyl C1-C2, alkoxy Cl-C6, alkenyl C1-C6, aryl, heteroaryl, -OC (= 0) - (alkyl Cl -C6) and -NHC (= 0) - (C1-C6 alkyl).

BENZOTIAZOL - METHODS IN THE PROLIFERATION OF OSTEOBLASTO Another aspect of the present invention comprises a method for stimulating osteoblast proliferation or BMP-2 promoter activity by employing a pharmacologically active compound of formula III Formula III where: R1 is selected from the group consisting of: aryl, naphthyl, heteroaryl and cycloalkyl, wherein each of the substituents R1 is substituted by one or more of the groups consisting of: C1-C7 alkyl, C1-C7 alkoxy, -N02, -CF3, aryl, benzyloxy, hydroxy, C1-C2 haloalkyl, halo, cyano, carboxyl, hydrogen, aryl, alkylcarbonylamino (C1-C4), alkylcarbonyl (C1-C4) , (C 1 -C 4) alkyl-aryl, and NH 2; R2 is H, C1-C4 alkoxy, amino, or C1-C4 alkyl; R3 and R6 are independently selected from the group consisting of: H, hydroxy, (C 1 -C 5) alkylcarbonyloxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkenyl and C 1 -C 4 alkoxy; Y R4 and R5 are independently selected from the group consisting of: H, halo, hydroxy, (C 1 -C 4) alkylcarbonyloxy, cyano, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, benzoyl, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkyl - aryl, (C1-C4) alkenyl-aryl, (C1-C4) alkynyl-aryl, (C1-C4) alkyl-cycloalkyl (C6-C10), (C1-C4) alkenyl-cycloalkyl (C6-C10), alkynyl (C1-C4) -cycloalkyl (C6-C10), carboxy and alkoxycarbonyl (C1-C4).

In some embodiments of the method, the pharmacologically active compound of formula III is further defined as follows: R4 and R5 are joined to form a 5-6 membered carbocycle or oxacarbocycle fused to the ring to which they are bound, wherein the carbocycle or oxacarbocycle is substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1 alkoxy -C4, hydroxy, halo, carboxyl, hydrogen and aryl.

The methods comprise administering an effective amount of the compound of formula III to cells containing osteoblasts.

In a particular embodiment, the method comprises stimulating the activity of the BMP-2 promoter which comprises administering a pharmacologically active preparation of 2- (2-methoxybenzamido) -1,3-benzothiazole. A method for stimulating the proliferation of osteoblasts using the above-mentioned compound is also specifically visualized.

BENZOTIAZOL AND RELATED COMPOUNDS Another aspect of the present invention relates to benzothiazole compounds and refers to compounds of formula III as pharmacologically active preparations. These pharmacologically active preparations are expected to be useful for stimulating osteoblast proliferation, stimulating the activity of the BMP-2 promoter, inhibiting or reducing bone resorption and inhibiting tumor cells. Formula III is as follows: Formula III where: R1 is selected from the group consisting of: aryl, naphthyl, heteroaryl and cycloalkyl, wherein each of the above substituents is replaced by one or more of the groups selected independently from the group consisting of: C1-C7 alkyl, C1-C7 alkoxy, -CF3, -N02, benzyloxy, hydroxy, C1-C2 haloalkyl, halo, cyano, carboxyl, hydrogen, aryl, alkylcarbonylamino (C1-C4), alkylcarbonyl (C1-C4), alkyl (C1-C4) -aryl, and -NH2; R2 is selected from the group consisting of: H, C 1 -C 4 alkoxy, amino, and C 1 -C 4 alkyl; R3 and R6 are independently selected from the group consisting of: H, hydroxy, (C 1 -C 2) alkylcarbonyloxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, and C 1 -C 4 alkoxy; Y R4 and R5 are independently selected from the group consisting of: H, halo, hydroxy, (C 1 -C 4) alkylcarbonyloxy, cyano, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, benzoyl, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkyl - aryl, (C 1 -C 4) alkenyl-aryl, (C 1 -C 4) alkynyl-aryl, alkyl (Cl-C 4) -cycloalkyl (C 6 -C 10), alkenyl (C 1 -C 4) -cycloalkyl (C 6 -C 10), alkynyl (C1-C4) -cycloalkyl (C6-C10), carboxy and alkoxycarbonyl (C1-C4).

These compounds are further defined in other embodiments of the invention as follows: R4 and Re join to form a 5-6 membered carbocycle or oxacarbocycle fused to the ring to which they are bound, where the carbocycle or oxacarbocycle is substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl; on condition that: 1) when R2, R3, R4, R5, R6 are all H, then R1 can not be phenyl, naphthyl, mono-substituted phenyl in which the substitution pattern is any of: 2-azido, 2-nitro, 2-chloro, 2-bromo, 2-fluoro, 2-hydroxy, 2-carboxy, 2- (2-carboxy-5-chlorofeni 1), 2- (4'-acetylbenzsulfonyloxy) , 2- (4 '- (cyanoacetyl) benzsulfonyloxy), 3- (4, -ethoxyphenyl) amino, 2-di (4'-hydroxyphenyl) methyl, 2-di (4'-acetoxyphenyl) methyl, 2- (2, 3-carboxypropenoyl) amino, 3-bromo, 3-chloro, 3-methoxy, 4-chloro, 4-bromo, 4-fluoro, 4-methyl, 4-nitro, 4-methoxy, 4-ethoxy, 4-n- propoxy, 4-i-propoxy, 4-n-butoxy, 4-i-butoxy, 4-n-pentoxy, 4-benzyloxy, 4-allyloxy, 4-acetoxy, 4- (2'-diethylamino) ethoxy, 4- amino, 4-dimethylamino, 4-guanidino, 4-thiomethyl, 4- (4'-methylbenzsulfonyl) amino, 4- (diethylphosphono) methyl, 4- (di-i-propylphosphono) methyl, 4- 4- where R is either H or Me where R 'is benzyl, 2-phenylethyl, alpha-naphthylmethyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 2- (3', 4'-dichlorophenyl) tyl, where R "is either H or Me where R "'is 2-chlorophenyl, 2-fluorophenyl, or 3-chlorophenyl where R "'' 'is either phenyl or 2-pyridyl, where R "'' * * is taken from the group: 4-sulfophenyl, 3,6-disulfophenyl, 4-methoxy-3-sulfophenyl, 6-chloro-3-sulfophenyl, or 2,5-dichloro-4-sulfophenyl where R7 is benzyl or hydrogen where R9 is hydroxy, R10 is a group '"i X where R11, R12, R13 and R14 are all hydrogen or wherein R12 and R14 equal hydrogen and R12 and R13 both equal hydrogen, methyl, methoxy or chloro, or where R11 and R13 both equal hydrogen and R12 and R14 both equal to chlorine, where Rn is methyl and R12, R13 and R14 are all hydrogen where R15 is a bond and R16 is hydrogen or chloro, or where R15 is 4-azophenyl and R16 is chloro; where R9 is hydrogen, R10 is and Rs is wherein Ru and R13 equal chlorine and R12 and R14 equal hydrogen or wherein R9 is hydroxy, R10 is hydroxy and R8 is where R12 and R14 both equal to hydroxy and R11 and R13 both equal to methyl, methoxy or chloro, or where Rn and R: 3 both equal to hydrogen and R12 and R14 both equal to chlorine, or where R12, R13 and R14 they are all hydrogen and Ru is methyl or wherein R11, R12, and R14 are all hydrogen and R13 is methyl; where R is taken from the group where R18 is either phenyl or 3-thienyl, where R19 is either a -CH = CH- bond; 2) when R3, R4, R5, R6 are all H, and R2 is phenyl, then R1 can not be phenyl; 3) when R3, R4, R5, R6 are all H, and R2 is methyl, then R1 can not be phenyl; 4) when R3, R4, R5, R6 are all H, and R2 is amino, then R1 can not be 4-methoxyphenyl; ) when R3, R4, R5, R6 are all H, and R2 is then R1 can not be 3-chlorophenyl; 6) when R3, R4, R5, R6 are all H, and R2 is then R1 can not be cyclopropyl; 7) when R3, R4, R5, R6 are all H, and R2 is either 2- (dimethylamino) ethyl or 3- (dimethylamino) propyl, then R1 can not be phenyl; 8) when R3, R4, R5, R6 are all H, and R2 is N, N'-diphenylamidino, then R1 can not be phenyl; 9) when R3, R \ R5, R6 are all H, and R2 is then R1 can not be 2-furyl, 2-thiazolyl, 4-methoxyphenyl, 4-tetrafluoromethylphenyl, 3,4-dimethoxyphenyl; ) when R3, R4, R5, R6 are all H, and R2 phenyl, then R1 can not be: where R20 is any of H, benzoyl, or nitro, "-" - CQ, - 11) when R3, R4, R5, R6 are all H, and R2 is then R1 can not be 2-furyl or 3-furyl; 12) when R2, R4, R5, R6 are all hydrogen and R3 is methoxy, then R1 can not be: phenyl, 2-carboxyphenyl, 4-guanidinophenyl, 4-nitrophenyl, 3, 5-dinitrophenyl, 4 - (diphenylphosphomethyl) phenyl, 4- (2'-diethylphosphinoxy) phenyl, 4- (3'-diethylphosphonopropoxy) phenyl , 4- (ethylphosphonomethyl) phenyl, 4- (ethyl, met i lphosf onomethyl) phenol, 4 - (benzyl, ethylphosphonomethyl) phenyl, 4- (ethyl, i- propylphosphonomethyl) phenyl, 4- (diethylphosphonomethyl) phenyl, 4- (dimethylphosphonomethyl) phenyl, 4- (di-n-butylphosphonomethyl) phenyl, T tOEOi - > - '- HH ,,? CC8_ - O O? "EEtt0 Ma Ph 13) when R4, R5, and R6 are all hydrogen, R2 is benzyl or methyl, and R3 is methoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 14) when R2, R4, R5 and R6 are all hydrogen and R3 is ethoxy, then R: can not be phenyl, 4-n-butoxyphenyl, 4-i-propylphenyl, 4-methoxyphenyl or 4-ethoxyphenyl; ) when R2, R4, R5 and R6 are all hydrogen and R3 is n-propoxy, then R1 can not be 4-ethoxyphenyl; 16) when R2, R4, R5 and R6 are all hydrogen and R3 is methyl, then R1 can not be phenyl, 4-guanidinophenyl, 4- (diethylphosphonomethyl) phenyl, or 17) when R2, R4, R5 and R6 are all hydrogen and R3 is trifluoromethyl, then R1 can not be 4-guanidinophenyl or 2,6-difluorophenyl; 18) when R2, R4, R5 and R6 are all hydrogen and R3 is nitro, then R1 can not be phenyl or 4-guanidinophenyl; 19) when R2, R4, R5 and R6 are all hydrogen, R2 is ethyl and R3 is chloro, then R1 can not be phenyl; ) when R2, R4, R5 and R6 are all hydrogen, and R3 is chlorine, then R1 can not be 4- (diethylphosphonomethyl) phenyl, phenyl, 3,5-dibromo-2-hydroxyphenyl, or tcncc 21) when R2, R4, R5 and R6 are all hydrogen and R3 is trifluoromethoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 22) when R2, R3, R5 and R6 are all hydrogen and R4 is sulfo, then R1 can not be 23) when R2, R3, R5 and R6 are all hydrogen and R4 is carboxy, then R1 can not be 24) when R2, R3, R5 and R6 are all hydrogen and R4 is carbamoyl, then R1 can not be 4-guanidinophenyl; ) when R2, R3, R5 and R6 are all hydrogen and R4 is fluoro, then R1 can not be 4- (guanidinomethyl) phenyl or 26) when R2, R3, R5 and R6 are all hydrogen and R4 is chloro, then R1 can not be phenyl, 4-chlorophenyl, 27) when R2, R3, R5 and R6 are all hydrogen and R4 is nitro, then R1 can not be phenyl; 28) when R2, R3, R5 and R6 are all hydrogen and R4 is trifluoromethyl, then R1 can not be 2,6-difluorophenyl; 29) when R2, R3, R5 and R6 are all hydrogen and R4 is methyl, then R1 can not be phenyl; ) when R2, R3, R5 and R6 are all hydrogen and R4 is phenyl, then R1 can not be 31) when R2, R3, R5 and R6 are all hydrogen and R4 is 4- (trifluoromethyl) benzoyl, then R1 can not be 2,6-difluorophenyl or 2-chloro-6-fluorophenyl; 32) when R2, R3, R5 and R6 are all hydrogen and R4 is methoxy, then R1 can not be phenyl; 33) when R2, R3, R5 and R6 are all H and R4 = R1 can not be. 34) when R2, R3, R5 and R6 are all hydrogen and R4 is ethoxy, then R1 can not be ) when R2, R3, R4 and R6 are all hydrogen and R5 is fluoro, then R1 can not be phenyl, 2-aminophenyl, 4-nitrophenyl, 4- (diethylphosphonomethyl) phenyl, or 36) when R2, R3, R4 and R6 are all hydrogen and R5 is chloro, then R1 can not be phenyl, 2-aminophenyl, 4-aminophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 4-nitrophenyl, 3.5 -dinitrophenyl, 4-guanidinophenyl, 4- (guanidinomethyl) phenyl, 37) when R2, R3, R4 and R6 are all hydrogen and R5 is bromine, then R1 can not be phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-butoxyphenyl, 4-i-butoxyphenyl, 4-n-propoxyphenyl , 4-i-propoxyphenyl, 4-nitrophenyl, 4-guanidinophenyl, 4- (diethylphosphonomethyl) phenyl or 38) when R2, R3, R4 and R6 are all hydrogen and R5 is iodo, then R1 can not be phenyl or 4-nitrophenyl; 39) when R2, R3, R4 and R6 are all hydrogen and R5 is amino, then R1 can not be 4-guanidinophenyl; 40) when R2, R3, R4 and R6 are all hydrogen and R5 is acetamido, then R1 can not be phenyl; 41) when R2, R3, R4 and R6 are all hydrogen and Rb is diethylamino, then R1 can not be phenyl; 42) when R2, R3, R4 and R6 are all hydrogen and R5 is nitro, then R1 can not be phenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-butoxyphenyl, 4-guanidinophenyl, 4- ( guanidinomethyl) phenyl, 3- (guanidinomethyl) phenyl, 4- (diethylphosphonomethyl) phenyl, 3,5-dinitrophenyl, 43) when R2, R3, R4 and R6 are all hydrogen and R5 is carboxy, then R: can not be phenyl; 44) when R2, R3, R4 and R6 are all hydrogen and R5 is carbamoyl, then R1 can not be 4-guanidinophenyl, 4- (diethylphosphonomethyl) phenyl, or 4- (guanidinomethyl) phenyl; 45) when R2, R3, R4 and R6 are all hydrogen and R5 is cyano, then R1 can not be 4-guadinophenyl or 46) when R2, R3, R4 and R6 are all hydrogen and R5 is carbetoxymethoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 47) when R2, R3, R4 and R6 are all hydrogen and R5 is carbetoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 48) when R2, R3, R4 and R6 are all hydrogen and R5 is 2-hydroxyethyl, then R1 can not be 4-guanidinophenyl; 49) when R2, R3, R4 and R6 are all hydrogen and R5 is methyl, then R1 can not be phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-guanidinophenyl, 4- (diethylphosphonomethyl) phenyl, 4- hydroxy-3-iodo-5-nitrophenyl 50) when R2, R3, R4 and R6 are all hydrogen and R5 is n-butyl, then R1 can not be 5-guanidinophenyl; 51) when R2, R3, R4 and R6 are all hydrogen and R5 is thiomethyl, then R1 can not be 4-guanidinophenyl or 4- (diethylphosphonomethyl) -phenyl; 52) when R2, R3, R4 and R6 are all hydrogen and R5 is methylsulfinyl, then R1 can not be 4-guanidinophenyl; 53) when R2, R3, R4 and R6 are all hydrogen and R5 is methylsulfonyl, then R1 can not be 4-guanidinophenyl; 54) when R2, R3, R4 and R6 are all hydrogen and R5 is sulphamoyl, then R1 can not be phenyl, 4-guanidinophenyl or 3, 5-dinitrophenyl; 55) when R3, R4 and R6 are all hydrogen, R2 is phenyl, and R5 is sulfo, then R1 can not be 56) when R2, R3, R4 and R6 are all hydrogen, and R5 is SCH2CF3, then R1 can not be 2.6-difluorophenyl; 57) when R2, R3, R4 and R6 are all hydrogen, and R5 is SOCF, then R1 can not be 2,6-difluorophenyl; 58) when R2, R3, R4 and R6 are all hydrogen and R5 is SCF3, then R1 can not be 2, 6-difluorophenyl or 2-chlorophenyl; 59) when R2, R3, R4 and R6 are all hydrogen and R5 is i-propyl, then R1 can not be 4-guanidinophenyl; 60) when R2, R3, R4 and R6 are all hydrogen and R5 is trifluoromethyl, then R1 can not be 4-guanidinophenyl, 4- (diethylphosphonomethyl) phenyl, 4- (guanidinomethyl) phenyl, 2-fluorophenyl, 2-methylphenyl, 2 -chloro-6-fluorophenyl, 2-chlorophenyl or 2,6-difluorophenyl; 61) when R2, R3, R4 and R6 are all hydrogen and R5 is trifluoromethoxy, then R1 can not be 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-bromophenyl, 2-chlorophenyl, 2-methylphenyl, 2-chloro-6-fluorophenyl , 2,4-dichlorophenyl, 2,6-difluorophenyl or 3,5-dichlorophenyl; 62) when R2, R3, R4 and R6 are all hydrogen and R5 is OCHF2, then R1 can not be 2.6-difluorophenyl; 63) when R2, R3, R4 and R6 are all hydrogen and R5 is OCF2CHF2, then R1 can not be 2.6-difluorophenyl; 64) when R2, R3, R4 and R6 are all hydrogen and R5 is OCF2CHFCF3, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 65) when R2, R3, R4 and R6 are all hydrogen and R5 is 2-chloro-4- (trifluoromethoxy) phenoxy, then R1 can not be 2-chlorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl; 66) when R2, R3, R4 and R6 are all hydrogen and R5 is 2, 3, 4, 5-tetrabromo-6-cyanobenzamido, then R1 can not be 2,3,4, 5-tetrabromo-6-cyanophenyl; 67) when R2, R3, R4 and R6 are all hydrogen and R5 is methoxy, then R1 can not be phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- (n-propoxy) phenyl, 4- (i-propoxy) phenyl , 4- (n-butoxy) phenyl, 4- (i-butoxy) phenyl, 4- (n-pentoxy) phenyl, 4- (3-methylbutoxy) phenyl, 4-methylphenyl, 4-chlorophenyl, 3,4-diaminophenyl , 4-amino-3-nitrophenyl, 4-acetamido-3- (diethylphosphonomethyl) phenyl, 68) when R2, R3, R4 and R6 are all hydrogen and R5 is n-propoxy, then R1 can not be phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- (n-propoxy) phenyl, 4- (i-propoxy) ) phenyl or 4- (n-butoxy) phenyl; 69) when R2, R3, R4 and R6 are all hydrogen and R5 is ethoxy, then R1 can not be phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- (n-propoxy) phenyl, 4- (i) - propoxy) phenyl, 4- (n-butoxy) phenyl, 4- (i-butoxy) phenyl, 2 f luorofeni lo, 4-guanidinophenyl, 4 (diethylphosphonomethyl) phenyl, 2 - (d i - (4-hydroxy phenyl) methyl) phenyl, 70) when R2, R3, R4 and R6 are all hydrogen and R5 is i-propoxy, then R1 can not be phenyl, 4-methoxyphenyl or 4-ethoxyphenyl; 71) when R2, R3, R4 and R6 are all hydrogen and R5 is n-butoxy, then R1 can not be phenyl, 4-methoxyphenyl, 4-ethoxyphenyl or 4- (n-butoxy) phenyl; 72) when R2, R3, R4 and R6 are all hydrogen and R5 is i-butoxy, then R1 can not be 4-methoxyphenyl; 73) when R2, R3, R4 and R6 are all hydrogen and R5 is benzyloxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 74) when R2, R3, R4 and R6 are all hydrogen and R5 is phenyl, then R1 can not be 3- (guanidinomethyl) phenyl, 4- (guanidinomethyl) phenyl, 2,6-difluorophenyl, '^ V * "hi _» ^^ NMßg wherein R is hydrogen, methyl, ethyl, n-propyl or i-propyl; 75) when R2, R3, R4 and R6 are all hydrogen and R5 is 4-fluorophenyl, then R1 can not be NH * - «- _ NH ,. 76) when R2, R3, R4 and R6 are all H, R5 is phenylazo, then R1 can not be phenyl; 77) when R2, R3, R4 and R5 are all hydrogen and R5 is nitro, then R1 can not be phenyl; 78) when R2, R3, R4 and R5 are all hydrogen and R5 is phenyl, then R1 can not be 79) when R2, R3 and R4 are all hydrogen, R5 is 2-chloro-4- (trifluoromethyl) phenoxy and R6 is methyl or hydrogen, then R1 can not be 2-chlorophenyl, 2-chloro-6-fluorophenyl or 2, 6-difluorophenyl; 80) when R2, R4 and R5 are all hydrogen, R3 is methyl and R5 is SCH2C02Et, then R1 can not be 4-cyanophenyl; 81) when R2, R3, R6 are all H, R4 and R5 are both equal to Me, then R1 can not be 4-guanidinophenyl, 2-hydroxyphenyl, 4- (diethoxyphosphonylmethyl) phenyl, in which R is either Cl or Me and R "is H or OH; 82) when R2, R5, R6 equal to H and R3 and R4 together equal to -CH = CH-CH = CH-, then R1 can not be phenyl, 4- (3 '- (dietary ilf os f ono) propi l ox i) f in ilo, 4- (diethylphosphonomethyl) phenyl, 4-methylphenyl, 4-nitrophenyl, 4-chlorophenyl, 83) when R2, R3 and R6 are all hydrogen and R4 and R5 are equal to carbomethoxy, then R1 can not be 84) when R2, R4 and R6 are all hydrogen, R3 is methoxy, and R5 is phenyl, then R1 can not be: 85) when R2, R3 and R6 are all hydrogen and R4 and R5 are equal to methoxy, then R1 can not be: 86) when R2, R3 and R6 are all hydrogen, R4 is chlorine, and R5 is nitro, then R1 can not be: 87) when R2, R4 and R6 are all hydrogen, R3 is benzoyl, and R5 is chloro, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 88) when R2, R4 and R6 are all hydrogen, R3 is phenyl, and R5 is bromine, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 89) when R2, R4 and R6 are all hydrogen and R5 and R6 together equal to CH = CH-CH = CH-, then R1 can not be 2-hydroxyphenyl 90) when R2, R3 and R4 are all hydrogen and R5 and R6 together equal to -CO-CH = C (Ph) -0-, then R1 can not be phenyl, 4-methylphenyl, 4-chlorophenyl or 4-methoxyphenyl; 91) when R2, R3 and R4 are all hydrogen, R5 and R6 together equal to -S-C (NHCOPh) = N-, then R1 can not be phenyl; 92) when R2, R3 and R5 are all hydrogen and R4 and R5 together equal to CH = CH-CH = CH-, then R1 can not be phenyl; 93) when R2, R3 and R5 are all hydrogen and R4 and R5 together equal to OCF2CF20-, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 94) when R2, R3 and R4 are all hydrogen and R5 and R6 together equal to 0CF2CF20-, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 95) when R2, R4 and R6 are all hydrogen and R3 and R5 together equal to chlorine, then R1 can not be phenyl or 4-nitrophenyl; 96) when R2, R4 and R6 are all hydrogen and R3 and R5 together equal to bromine, then R1 can not be phenyl or 4-nitrophenyl; 97) when R2, R4 and R6 are all hydrogen and R3 and R5 together equal to methoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 98) when R2, R4 and R6 are all hydrogen, R3 is methoxy and R5 is nitro, then R1 can not be 4-guanidinophenyl or 4- (guanidinomethyl) phenyl; 99) when R2, R4 and R6 are all hydrogen, R3 is COCH3 and R5 is bromine, then R1 can not be equal to 4- (diethylphosphonomethyl) phenyl; 100) when R2, R4 and R5 are all hydrogen, R3 is methoxy and R6 is chloro, then R1 can not be 4-guanidinophenyl; 101) when R2, R3 and R6 are all hydrogen, R4 is fluoro and R5 is thiocyano, then R1 can not be 4-nitrophenyl; 102) when R2, R3 and R6 are all hydrogen, R4 is chlorine and R5 is methoxy, then R1 can not be equal to 4- (diethylphosphonomethyl) phenyl; 103) when R2 and R3 are equal to hydrogen and R4, R5 and R6 are all bromine, then R1 can not be phenyl or 4-nitrophenyl; 104) when R2 and R3 are equal to hydrogen and R4, R5 and R6 are all methoxy, then R1 can not be phenyl; 105) when R2 and R3 are equal to H, R4 and R6 are both chloro and R5 is phenoxy, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 106) when R2 and R3 are equal to H, R4 and R6 are both chloro and R5 is 4- (trifluoromethyl) phenoxy, then R1 can not be 2,6-difluorophenyl; 107) when R2 and R4 are equal to hydrogen, R4 and R6 are both chlorine, and R5 is: then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 108) when R2 and R3 both equal to hydrogen, R4 and R6 are both chloro, and R5 is 4- (trifluoromethylthio) phenoxy, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 109) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine, and R5 is 4- (chloro) phenoxy, then R1 can not be 2-chlorophenyl, 2-methylphenyl, 2-chloro-6-fluorophenyl, 2-chloro-3-pyridyl or 2,6-difluorophenyl; 110) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine, and R5 is (2-chloro-4-trifluoromethyl) phenoxy, then R1 can not be 2,6-difluorophenyl; 111) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine, and R5 is: then R1 can not be 2, 6-difluorophenyl; 112) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine, and R5 is 2,4-dichlorophenoxy, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 113) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine, and R5 is 4-trifluoromethylphenoxy, then R1 can not be 2-chlorofenyl or 2,6-difluorofenyl; 114) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine and R5 is: then R1 can not be 2-chlorophenyl; 115) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine and R5 is: then R1 can not be 2, 6-difluorophenyl; 116) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine and R5 is fluoro, then R1 can not be 2,6-difluorophenyl; 117) when R2 and R3 both equal to hydrogen, R4, R5 and R6 are all chlorine, then R1 can not be 4-nitrophenyl or phenyl; 118) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine and R5 is OCF2CF2H, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 119) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine and R5 is methoxy, then R1 can not be 4-sulfamoylphenyl; 120) when R2 and R3 both equal hydrogen, R4 and R6 both equal to chlorine and R5 is ethoxy, then R1 can not be 2.6-difluorophenyl; 121) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine and R5 is dimethylamino, then R1 can not be 2-chlorophenyl or 2,6-difluorophenyl; 122) when R2 and R3 both equal to hydrogen, R4 and R6 both equal to chlorine and R5 is SCH2CF3, then R1 can not be 2.6-difluorophenyl; 123) when R2 and R6 both equal hydrogen, R3 and R4 together equal to CH = CH-CH = CH-, and R5 is nitro, then R1 can not be phenyl or 4-chlorophenyl; 124) when R2 and R4 both equal hydrogen, R3 is COCH3, R5 and R6 both equal to methoxy, then R1 can not be 4- (diethylphosphonomethyl) phenyl; 125) when R2 is hydrogen, R3, R4 and R6 are all methyl, and R5 is hydroxy, then R1 can not be phenyl, 4-carboxyphenyl or 4-sulfamoylphenyl; Y 126) when R2 is hydrogen, R3, R4 and R6 are all methyl, and R5 is methoxy, then R1 can not be 4-sulfamoylphenyl.

Unless otherwise indicated, all chemicals were purchased from Aldrich Chemicals (Milwaukee, Wl); EXEMPJ.Q 1 TECHNIQUE TO IDENTIFY CHEMICAL COMPOUNDS OUE STIMULATE OSEO GROWTH This technique has been described in the scientific literature [Ghosh-Choudhury, N .; Windle, J; J .; Koop, B. A .; Harris, M.A .; Guerrero, D. L .; Wozney, J. M .; Mundy, G. R .; Harris, S. E .; "Immortalized Murine Osteoblasts Derived from BMP 2-T-Antigen Expressing Transgenic Mice" Endocrinologv (1996) 137. 331-339]. These techniques are specifically incorporated herein by reference. This method could be used only to identify or select a library of candidate compounds with pharmacological activity to promote, stimulate or maintain osteoblast growth, or in conjunction with the technique provided to select spatially defined molecules and candidate substances that have proliferative activity of osteoblast.

Immortalized murine osteoblasts (2T3 cells) containing a promoter fragment of bone morphogenetic protein 2 (BMP-2) are isolated from the bald of transgenic mice and cloned. These 2T3 cells are reclonable and can be stably transfected with luciferase constructs of the BMP-2 promoter. The activity of the BMP-2 promoter can then be stimulated by recombinant human BMP-2 (rhBMP-2) or chemical compounds that stimulate osteoblast proliferation. Using this BMP-2 promoter test as an additional screening technique, the ED50 of the compounds that stimulate luciferase activity can also be tested, and, by implication, the proliferation of osteoblast. Other in vitro cellular tests for testing the activity of screened and selected candidate compounds well known to those of ordinary skill in the art could be used in place of the promoter test described above and provide additional measurement of the pharmacological activity of the compound that stimulates proliferation. of osteoblast. For example, a culture of osteoblast cells could be used. 2T3 cells in 10 cm tissue culture plastic plates are stably transfected with 10 micrograms of the plasmid containing the luciferase reporter gene driven by -2736/114 bp of the BMP-2 promoter and 12 micrograms of the plasmid pSV2neo for selection of the clone resistant to G418.

The transfection is carried out by the calcium phosphate precipitation technique. Stable clonal cell lines are generated using MEM containing 7% FCS and 200 microgram / mL G418. The activity of the luciferase enzyme can be measured in 15 different clonal cell lines. A cell line (2T3-BMP-2-LUC) is chosen here because using this test for luciferase has shown little variability over 20 steps. For a control group, a stable cytoponal cell line (2T3-basic LUC) is established as above, using the non-promoted luciferase vector, pGL2basic (Promega Corp., Madison, Wl) in place of the BMP-promoter luciferase plasmid 2. Both cell lines are plated on 35 mm tissue culture plates and treated with 0, 2, 5, 10 and 20 nanograms / mL of rhBMP-2 for 48 hr in MEM containing 2% FCS. Each concentration of rhBMP-2 is used in triplicate and each experiment is repeated three times. Luciferase activity is measured using a Promega kit and a luminometer.

E.JP_PtQ 2 PRODUCTION OF MULTI-GRAM AMOUNTS OF 2- (2- METOXYBENZOYLAMINO) BENZTIAZOL The present group of examples establishes a method wherein the benzthiozole compounds could be obtained. However, other methods could be used in the practice of the present invention. A solution of 4.5 g of 2-aminobenzthiazole in 40 mL of dichloromethane and 10 mL of pyridine was cooled in an ice bath. To this cooled solution was slowly added a solution of 2-methoxy benzoyl chloride in 10 mL of dichloromethane. The resulting mixture was stirred for 3 hours while the ice bath was slowly heated to room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with IN HCl (2 x 50 mL), saturated NaHCO 3 (1 x 40 mL) and saturated NaCl (1 x 50 mL). After drying with Na 2 SO 4, the solution containing the crude product was filtered and evaporated to dryness. The resulting 8.0 g of white solid was recrystallized from ethyl acetate to provide 4.0 g of 2- (2-methoxybenzoylamino) benzthiazole as white crystals, mp 196-197 ° C, as harvest.

Other synthetic chemical techniques well known to those skilled in the art such as those described in Kamala et al. Could be used. (Indian J. Chem. (1983), 22B, 1194-96) and Waisser et al. (Collect. Czech, Chem. Commun. (1991), 5_ £, 2978-2985) and the appended list of references which are hereby incorporated by reference in their entirety. gJEMPLQ 3 General Method for the Evaluation of Pharmacologically Active Compounds - Cell Culture of Anti Tumor Activity The murine B16 melanoma cell line is grown in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum, 2 mM L-glutamine, 50 units / ml penicillin, 50 μg / ml streptomycin, 25 μg / ml gentamicin , 0.75% sodium bicarbonate, 10 mM HEPES buffer (pH 7.4) and AntiPPLO 0.06 mg / ml. Murine P388 cell line and human HT-29 colon adenocarcinoma line are maintained in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum. P338 / CPT (cantothecin-resistant cell line) was maintained in RPMI-1640 medium supplemented with 20% heat-inactivated fetal bovine serum, 10 μM β-mercaptoethanol, 10 μM L-glutamine, 100 IU penicillin / ml, 100 streptomycin μg / ml and gentamicin 50 μg / ml. The human breast adenocarcinoma MCF-7M was maintained in IMEM medium supplemented with 5% non-heat activated fetal bovine serum and 1 nM insulin.

In Vitro Growth Inhibitory Activity Cells that grow exponentially (1-2 X 103 cells, unless otherwise specified) in 0.1 ml medium were seeded on day 0 in a 96-well microtiter plate. On day 1, aliquots of 0.1 ml of the medium containing the graduated concentrations of the test analogs were added in duplicate to the cell plates. After incubation at 37 ° C in a humidified incubator for 3 days (P388, P388 / CPT, B16) or 6 days (HT-29, MCF-7M), the plates were centrifuged briefly and 100 μl of the medium was removed. increase. Cell cultures were incubated with 50 μl of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide [MTT, 1 mg / ml in Dulbecco's phosphate buffered saline (PBS) ] for 4 hr at 37 ° C. The resulting purple formazan precipitate is solubilized with 200 μl of 0.04 N HCl in isopropyl alcohol. The absorbance was monitored in a BioRad Model 3550 Microplate Reader at a test wavelength of 570 nm and a reference wavelength of 630 nm. The absorbance is transferred to a PC 486 computer. The IC5C values are determined by a computer program (EZ-ED50) that corrects all the results to the four parameter logistic equation: where A ^ is the absorbance of the control cells, A ^ n, is the absorbance of the cells in the presence of the highest agent concentration, and is the observance observed, X is the concentration of the agent, IC50 is - the concentration of the agent that inhibits cell growth by 50% of the control cells (based on absorbance) and n is the slope of the curve.

EXAMPLE 4 Synthesis of the Pharmacologically Active Compound of Antrone The present example demonstrates the synthesis of a pharmacologically active anthrone compound, a compound that was found to have reduced pharmacological activity as determined by a test for the activity of the BMP-2 promoter. To 6.9 grams of 4-isopropoxy benzoic acid (commercially available from Aldrich) in a round bottom flask connected to a reflux condenser equipped with a drying tube filled with calcium chloride was added 20 mL of thionyl chloride. The resulting mixture was refluxed for 30 min and the excess thionyl chloride was removed under reduced pressure. The remaining liquid was mixed with 20 mL of freshly distilled benzene and treated dropwise with 2.79 mL of diethylamine. An additional 20 mL of benzene was added, and the resulting mixture was heated to reflux for one hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1% HCl (2 x 50 mL), 5% HaOH (3 x 50 mL), 1% HCl (2 x 50 mL), 5% NaOH (1 x 50 mL) and brine (1 x 50 mL). The resulting organic solution was dried with MgSO 4, filtered and evaporated to provide 6.22 g of N, N-diethyl-4-i-propoxybenzamide as a colorless oil. A solution of this material and TMEDA (4.8 mL) in THF in a round bottom flask under argon was cooled to -78 ° C and a solution of s-BuLi in hexanes was slowly added., (30.5 mL, 1.3 M). The reaction mixture was stirred an additional hour at -78 ° C, then a cooled solution (-78 ° C) of freshly distilled benzaldehyde (3.58 g) in THF was added. The reaction mixture was slowly allowed to warm to room temperature for 12 hours. The reaction mixture was treated with saturated aqueous NH 4 Cl (50 mL) and 1% HCl (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a solution prepared of equal volumes of saturated NH4C1 and 1% HCl (1 x 50 mL) and brine (3 x 50 mL). The organic layer was dried with Na 2 SO 4, filtered and evaporated. The residue was dissolved in 200 mL of toluene and 1 g of TsOH was added. The reaction mixture was heated to reflux for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with 5% K2CO3 (3 x 50 mL), 1% HCl (2 x 50 mL), saturated NH4C1 ( 1 x 50 mL), and brine (2 x 50 mL). The organic layer was dried with MgSO 4, filtered and evaporated. The residue was recrystallized from ethyl acetate / hexanes to give 5.0 g of lactone as colorless needles: XH NMR (CDC13) d 1.27 (d, J = 7.8 Hz, 6H), 4.56 (hept, J = 7.8 Hz, ), 6.26 (s, ÍH), 6.67 (s, ÍH), 6.95 (d, J = 10.8 Hz, ÍH), 7.25 (m, 5H), 7.79 (d, J = 10.8 Hz, 1H). This material was dissolved in acetic acid and treated with 500 mg of 10% Pd on carbon under a hydrogen atmosphere. The reaction mixture was heated at 85 ° C for 2 hours. After cooling to room temperature, the catalyst was removed by filtration, and the solvent was evaporated. The residue was dissolved in toluene (50 mL) and the solvent was evaporated. The residue was dissolved in chloroform (25 mL) and treated with trifluoroacetic anhydride (2.5 mL) at room temperature overnight. The solvent was removed and the product was recrystallized from ethyl acetate to provide 2.27 g of 3-i-propoxyanthrone as white crystals, mp 123-124 ° C. lH NMR (CDC13) d 1.29 (d, J = 7.8 Hz, 6H), 4.42 (s, 2H), 4.53 (hept, J = 7.8 Hz, ÍH), 6.63 (d, J = 3.4 Hz), 6.73 (dd) , J = 3.4, 10.8 Hz, ÍH), 7.20 (m, 4H), 8.04 (d, J = 10.8 Hz, ÍH); 13C NMR (CDC13) d 21.86, 39.93, 69.90, 112.50, 118.72, 119.93, 125.93, 128.30, 128.41, 129.08, 134.36, 140.64, 161.66, 172.45, 193.78; HRMS (Cl) MH + (C17H1702) Found 253.1208, Cale d. Oxytrone was converted to a material with increased pharmacological activity by three different methods: Method 1: The crystalline material was placed in a glass jar and heated by placing the flask on a hot plate at 250 ° C for 1-10 minutes.

Method 2: The 3-i-propoxyantrone was dissolved in toluene and heated in a sealed tube in an oil bath at 310 ° C for 14 hours. Evaporation of the solvent provided the active material.

Method 3: A solution of 159 mg of 3-i-propoxyanthrene in acetic acid (25 mL) was treated with chromium trioxide (180 mg) at room temperature. After 20 hours, the acetic acid was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic solution was washed with 5% Na 2 CO 3 (2 x 30 mL) and brine (2 x 30 mL) and then dried with MgSO 4. Filtration and evaporation gave a residue which was subjected to chromatography (Si02, 8: 1 hexanes / ethyl acetate) to give a fraction consisting mainly of a spot by thin layer chromatography (SiO2, 3: 1 hexanes / ethyl acetate , Rf approximately 0.6).

Example 5 Cell Differentiation Test This method will be used to select the spatially defined candidate compounds useful in the stimulation of osteoblast proliferation and the enrichment of a population of osteoblast cells. Eckhardt, S. G .; Dai, A; Davidson, K.K .; Fprseth, B. J.; Wahl, G. M .; Von Hoff, D.D. in Proc. Nati Acad. Sci. USA (1994), 1, 6674-6678 which incorporates here by reference, details of the proliferation test.

The HL60 promyelocytic leukemia cells were grown in RPMI 1640 medium with 10% fetal bovine serum and 2mM glutamine. Several of the compounds were added on day 0 of each culture at the indicated concentrations and replaced each time the cells were passed. All cells were passed to maintain a density of < 2 million cells per mL. Differentiation was tested using a functional test for mature myelocytes. For the reduction of nitroblue tetrazolium, 300,000 cells were suspended in 0.2 mL of RPMI 1640 medium supplemented with 10% fetal bovine serum and incubated for 20 min at 37 ° with an equal volume of 0.1% nitroblue tetrazolium (Sigma) and 50 ng of forbal freshly diluted 12-myristate 13-caetate (Sigma). The cytospin slides were prepared and counted for the percentage of cells containing intracellular reduced blue-black formazan deposits counting at least 500 cells and correcting for viability.

Example 6 Retinoid Acid Displacement Test This method is the same as the one indicated by Eyrolles, L .; Kagechika, H .; Kawachi, Y .; Fukasawa, H .; Iijima, T .; Matsushima, Y. Hashimoto, Y .; Shudo, K. J. Med.

Chem. (1994), 7, 1508-1517 which is incorporated herein by reference. The cells used in this test may be the same as those used in Example 1 or may be another appropriate cell line. The method could be used as an additional screening step in the selection of the chemically defined molecules herein, or the chemical molecules spatially defined herein, which possess a pharmacological activity to bind a biological receptor, such as a receptor that is a nuclear hormone receptor. .

The pelleted and used COS-1 cells are adjusted to ca 1-2 mg / mL by dilution in the buffer (0.3 M KCl, 20 mM Tris-HCl, pH 8.0, 1.5 mM EDTA, 1 mM PMSF, 1 microgram pepstatin / mL, bacitracin 0.1 mg / mL, leupeptin 0.1 mM and aprotinin 0.1 mg / mL). The suspension is homogenized with a Teflon-glass homogenizer and centrifuged at 100000 g, 4 ° C. The supernatant is used in the displacement test. The supernatant is incubated in the presence of 6 nM [3H] -cis-retinoic acid (Amersham) and several concentrations are added to the ligand for 16 hrs at 4 ° C in the dark. The incubation mixture is absorbed by suction on a nitrocellulose membrane. The membrane is washed three times with wash buffer (20 mM Tris-HCl, pH 8.0, 0.15 M NaCl) and then with 25% ethanol in distilled water. The radioactivity that remains in the filter is measured by liquid scintillation.

Example 7 Determination of Bone Growth This method could be used to select spatially and / or chemically defined molecules that would have an expected utility to promote bone growth.

Mineralization / bone growth test 2T3 cells are plated at 10,000 cells / well in a 24-well tissue culture plate (1.5 cm diameter / well) using 1.0 mL of MEM containing 7% PCS. These are allowed to grow to confluence (day 0), and the medium is then changed to the differentiation medium (7% FCS in MEM containing 100 micrograms / mL of ascorbic acid and 5mM beta-glycerophosphate). Recombinant human BMP-2 (rhBMP-2) and / or 1,25-dihydroxyvitamin D3 [1,25- (OH) 2D3] are added at various concentrations to triplicate wells. The means are changed every 2-3 days. At several times (4, 9, 12, 16, days), the plates are fixed in 10% formalin for 20 minutes, washed with distilled water followed by ethanol, and air dried. The plates are then stained with Van Giesen stain (matrix-collagen) and tempted by Von Kossa (mineral). The mineralized bone nodes are then quantified for the average area of the mineralized nodule, the total number of mineralized nodes per square centimeter, and the total area of the mineralized nodules per square centimeter using JAVA Image Analysis Programming Elements (Jandel Scientific , Corte Madera, CA).

Quantification cíej, (growth) multilayer dyrgnte ia 2T3 bone cell differentiation Duplicate 24-well plates are established as described above. The number of cells in triplicate wells is then determined at various time points as previously described. The cell layer is washed with PBS, and the cells are then incubated with 0.1-0.5 mL 0.05% trypsin 25 mM EDTA (GIBCO, Gaithersburg, MD) at 37 ° C for 10-40 min (until the cells in the wells they came together visibly). Then an equal volume of FCS is added, and the cells are dispersed to a single cell dispersion with up / down shocks using a 1.0 mL automatic pipetting device. The number of cells is determined using a hemocytometer.

Example 8 Preparation of 3-Benzamidoauinoline Compounds This method could be used to prepare a wide range of compounds of the formula IV indicated in Table 1 below. In general, the 3-aminoquinoline, in the presence of a basic catalyst or an acid precipitator such as pyridine, is reacted with the activated form of a particular benzoic acid derivative or analogue in an appropriate organic solvent. Depending on the reaction conditions employed, an appropriate isolation procedure will be used.

For example, a solution of 3-aminoquinoline (40 mg, 0.28 mmol) in methylene chloride (1.0 ml) was completely mixed with pyridine (25 μl). Subsequently, a slight molar excess of benzoyl chloride was added and the reaction was stirred at 25 ° C for 30 min. to form the condensation product 3-benzamidoquinoline in acceptable yield.

Table 1 below summarizes some of the compounds of formula IV made according to this example. The yields of the reaction are based on 0.56 mmol of 3-aminoquinoline. These compounds are exemplary of the compounds and methods of synthesis of the invention and should not be taken to limit the full scope to which the present inventor is designated.

Table 1 Formula IV For the present compounds in Table 1, R1, R2, R3, R4, R5 and R6 are all hydrogen. The remaining substituents are defined later. The performance of each compound is also indicated.

Example 9 Preparation of 2-Benzamido-1,3-benzthiazole Compounds The following general procedures can be used to prepare the 2-benzamido-1,3-benzthiazole compounds of Formula V indicated in Table 2 below. In general, 2-amino-1,3-benzthiazole, in the presence of a base catalyst or an acid precipitator such as pyridine, is reacted with a particular carboxylic acid chloride. The white compound 2-benzamido-1,3-benzthiazole can be isolated as the free base or as the alkali metal salt of nitrogen amido.

Procedure A: A solution of 2-amino-1,3-benzthiazole (700 mg, 4.7 mmol) in methylene chloride (20 ml) and pyridine (80 μl) was treated with 2,4-dimethoxybenzoyl chloride and stirred at 25 ° C. for 30 minutes. After this time, the reaction was treated with HCl (10 ml of 5% by weight) and the resulting precipitate was collected by filtration. The solid was recrystallized from ethanol to give 2- (2,4-dimethoxybenzamido) -1,3-benzthiazole as colorless needles. (1,185 mg, 80% yield).

Procedure B. alkali metal salt form A solution of 2-amino-1, 3-benzthiazole (40 mg, 0.27 mmol in methylene chloride (1 ml) and pyridine (100 μl) was treated with 4-n-butylbenzoyl chloride and stirred at 25 ° C for 30 minutes After this time, the reaction was treated with NaOH (0.5 ml, 5.0 M) and the resulting mixture was stirred overnight.The resulting precipitate was collected by filtration and recrystallized from water to give 2- ( 4-n-butylbenzamido) -1,3-benzthiazole as pale yellow needles (47 mg, 53%).

Table 2 below summarizes some of the compounds of formula V made according to this example. The yields of the reaction are based on 0.53 mmol of 2-amino-1,3-benzthiazole. These compounds are exemplary of the synthesis compounds of the invention and should not be taken to limit the full scope to which the present inventor is designated.

Table 2 Formula V For the present compounds in Table 2, R1, R2, R3, R4, R5 and R6 are all hydrogen. The remaining substituents are defined later. The performance of each compound is also indicated.

Example 10 Preparation of 2- (cyclohexylamido) -1,3-benzthiazole The present compound was prepared according to procedure B of Example 9. This compound is representative of the compounds of formula III: W-L-Y Formula III wherein Y is a carbocyclic group, more particularly a cyclohexyl group. In this particular example, the target compound was isolated in 66% yield.

The foregoing provides a detailed description of the particular embodiments of the invention. It is recognized that what is left of the disclosed embodiments could be made within the scope of the invention and that obvious modifications will be presented to a person skilled in the art, and are intended to be within the scope of the present invention. The full scope of the invention is set forth in the claims that follow in their equivalents. Therefore, the claims and the specification should not be elaborated to limit exclusively the total scope of protection to which the invention is designated.

Those skilled in the art should, in the clarity of the present disclosure, appreciate that many changes can be made in the specific embodiments where they are set forth herein and still obtain a similar or similar result without departing from the spirit and scope of the invention. All the compositions and methods set forth and claimed herein may be made and executed without undue experimentation in the clarity of the present disclosure. It will be apparent that certain compounds that are physiologically and chemically related could be substituted for the pharmacologically active compounds described herein while achieving the same or similar results.

REFERENCES The following references, to the extent that they provide exemplary procedures or other supplementary details for the provisions herein, are specifically incorporated by reference.

# - Z Benzamid - and 2-anilinobenzothiazoles, Donche, et al. (1970) Ger. Offen 2, 133, 649.

Ghosh-Choudhury, N; Windle, J .; Koop, B.A .; Harris, M.A .; Guerrero, D.L .; Wozney, J.M .; Mundy, G.R .; Harris, S.E .; (1996) Endocrinology, 137: 131-339.

J. Rosen, A. Day, T.K. Jones, E.T. Turner Jones, A.M. Nadzan and R.B. Stein, J. Med. Chem. (1985), £ (25), 4855-4874.

K. Waisser, J. Kunes, Z. Odlerova, Collect. Czech Chem. Comm. 1991, 56, 2978-2985.

K. Kamala, P. J. Rao, K.K. Reddy, Indian J. Chem. 1983, 1194-1196.

M.R. Kirshenbaum, S-F. Chen, C.H. Behrens, L.M. Papp, M.M.

Stafford, J-H. Sun, D.L. Behrens, J.R. Fredericks, S.T. Polkus, P. Sipple, A.D. Patten. D. Dexter, S.P. Seitz, J.L. Gross, Cancer Res. (1994), «ü, 2199-2206.

S.G. Eckhardt, D. Dai, K.K. Davindson, B.J. Forseth, G.M. Wahl, D.D. Von Hoff, Proc. Nat '1. Acad. Sci .. USA (1994), 21, 6674-6679.

Vogel's Textbook of Practical Organic Chemistry, Fifth Ed., B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell, New York: Wiley, 1989.

Comprehensive Organic Transformations, R.C. Larock, New York: VCH, 1989.

Organic Reactions Volumes 1-48, Editorial board, Roger Adams, editor-in-chief, Werner E. Buchmann, Louis F. Fiesser (and others), New York: Wiley, 1942-1996.

Organic Synthesis Volumes 1-73, Editorial board, E. Vedejs, editor-in-chief, New York: Wiley, 1921-1996.

Protective Groups in Organic Synthesis, T. Greene, New York: Wiley, 1991.

Comprehensive Organic Chemistry Vol 1-6, chairman and deputy chairman of the editorial board, Sir Derek Barton and W. David Ollis, New York: Pergamon Press, 1979.

Comprehensive Organic Synthesis: selectivity, strategy and efficiency in modern organic chemistry, Volumes 1-9, Barry M. Trost, Ian Fleming, editor (s), New York: Pergamon Press, 1991.

Comprehensive Organometallic Chemistry: the synthesis, reactions and structures of organometallic compounds, Volumes 1-9, G. Wilkinson, editor, New York: Pergamon Press, 1982.

Comprehensive Hetocyclic Chemistry: the structure, reactions, synthesis and uses of heterocyclic compounds, Volumes 1-8, Alan R. Katritzky, chairman of the editorial board, New York: Pergamon, 1984.

The Chemistry of Heterocyclic Compounds Vol 1-53, New York: Wiley, 1950-1994.

Rodd's Chemistry of Coal Compounds; a modern comprehensive treatise, Volumes 1-4, S. Coffey (ed.), New York, Elsevier Pub. Co., 1964-Compendium of Organic Synthetic Methods, Ian T. Harrison and Shuyen Harrison, New York, Wiley-Interscience ( 1971-Synthetic of Organic Volumes 1-31, New York: S. Karger, 1951-1981.

Annual Reports in Organic Synthesis, New York: Academic Press, 1970-1995.

Advanced Organic Chemistry, 3rd Edition, J. March, Wiley: New York, 1985.

U.S. Patent No. 5,322,847 - Marfat et al. (1994) Marfat et al. (1992), Chemical Abstracts, Vol. 117: 782, Abst. # 90279j.

JP Patent No. 03130216 A2 - Soda et al. (1991) EP # 404440 A2 - Eggler et al. (1990) EP # 395093 Al - Kinoshita et al. (1990) EP # 221211 Al - Ritchey, Thomas R. (1985) It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which It refers to it.

Having described the invention as above, the content of the following is claimed as property.

Claims (36)

RE cjM-JQNgg

1. A method for stimulating osteoblast proliferation, characterized in that it comprises: select substances of general formula I X-L-Z, Formula I where: X is selected from the group consisting of: L is selected from the group consisting of: or a simple link Z is selected from the group consisting of: where: R1 is selected from the group consisting of: H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo and C 1 -C 12 alkylcarbonyloxy; R2 is selected from the group consisting of: H, OH, halo, Cl-6 alkyl, C 1 -C 6 alkenyl, Cl-C 6 alkoxy, and C 1 -C 12 alkylcarbonyloxy; R3 is selected from the group consisting of: H, OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkenyl, and C 1 -C 12 alkylcarbonyloxy; R4 is selected from the group consisting of: H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, and alkyl (Cl-C12) -carbonyloxy; R5 is selected from the group consisting of: H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC (= 0) Me, phthalimide and (C 1 -C 12) alkylcarbonyloxy; R6 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, and C1-C4 alkoxy; R7 is selected from the group consisting of: H, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, and arylalkyl (C 7 -C 10); R8 is selected from the group consisting of: H, OH, halo, -CF3, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, -NHC (= 0) Me and -N (Cl-C4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, -CN, -N02, C 1 -C 4 haloalkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -NHC (= 0) Me and -0C (= 0) Me; R1C is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C4 haloalkyl, -C02H, C1-C12 alkyl, C1-C12 alkoxy, phenyl, C1-C12 alkenyl, (C1-C4) alkoxycarbonyl, -NHC (= 0) Me, (C1-C4) alkylcarbonyl, (C1-C12) alkylcarbonyloxy, and heteroaryl; Ru is selected from the group consisting of: H, OH, halo, C1-C4 haloalkyl, -CF3, C1-C4 alkyl, -NH2, C1-C4 alkoxy, -NHC (= 0) Me, C1-C4 alkenyl, (C1-C4) alkoxycarbonyl, alkylcarbonyl (C1) -C4), and alkylcarbonyloxy (C1-C14; R12 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, and (C1-C4) alkylcarbonyl; Y R13 is selected from the group consisting of: H, OH, halo, -NH2, C1-C4 alkyl, C1-C4 alkoxy, - (C1-C4 alkyl); Y exposing cells containing osteoblast cells for an effective amount of the pharmacologically active compound.

2. The method of claim 1, characterized in that: R10 and R11 could be brought together to form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are bound, wherein the carbocycle and oxacarbocycle are substituted with one or more groups independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, OH, halo, carboxyl, H and aryl, to provide a pharmacologically active compound.

3. The method of claim 2, characterized in that: R10 and Rn are joined to form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are bound, wherein the carbocycle and oxacarbocycle are substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-6 alkoxy C4, OH, halo, carboxyl, H and aryl; with the condition of: 1) L is ?? Z is when X is selected from: 2) when X is then L is selected from the group consisting of: n simple link; when X is: Z is: so L is when X is: Z is: so L is: ando X is: ; then Z is; L is:, R7 J ando X is: ; then Z is: L is: ^^

4. The method of claim 1, characterized in that: R4 is H; Y R9 is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C8 alkyl, C1-C8 alkoxy, NHC (= 0) Me and -0C (= 0) Me;

5. The method of claim 1, characterized in that: X is L is and Z is

6. The method of claim 5, characterized in that: R1, R2, R3, R4, R5 and R6 are all hydrogen; R8 is selected from the group consisting of: H, OH, halo, -CF3, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, -NHC (= 0) Me and -N (Cl-C4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, -CN, -N02, C 1 -C 4 haloalkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -NHC (= 0) Me and -0C (= 0) Me; R1C is selected from the group consisting of: H, OH, halo, -CN, -N02, C1-C4 haloalkyl, -C02H, C1-C12 alkyl, C1-C12 alkoxy, phenyl, C1-C12 alkenyl, (C1-C4) alkoxycarbonyl, -NHC (= 0) Me, (C1-C4) alkylcarbonyl, (C1-C12) alkylcarbonyloxy, and heteroaryl; R11 is selected from the group consisting of: H, OH, halo, C1-C4 haloalkyl, -CF3, C1-C4 alkyl, -NH2, C1-C4 alkoxy, -NHC (= 0) Me, C1-C4 alkenyl, (C1-C4) alkoxycarbonyl, alkylcarbonyl (C1) -C4), and alkylcarbonyloxy (C1-C14; R12 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, and (C1-C4) alkylcarbonyl.

7. The method of claim 6, characterized in that: R8 is selected from the group consisting of: H, methoxy, fluorine and trifluoromethyl; R9 is selected from the group consisting of: H, methyl, methoxy, trifluoromethyl, chloromethyl, nitro, cyano, chloro, and fluoro; R10 is selected from the group consisting of: H, phenyl, n-butyl, t-butyl, chloro, chloromethyl, ethyl, n-propyl, nitro, pentyl, methoxy, cyano and fluoro; R11 is selected from the group consisting of: H, trifluoromethyl, methoxy, and fluoro; Y R12 is H.

8. A method for selecting a pharmacologically active compound or candidate pharmacologically active compound, characterized in that the pharmacological activity is a capacity to stimulate the activity of the BMP-2 promoter, comprising: select candidate compounds having a spatially defined 3-dimensional structure as in formula II W-L-Y Formula II where: W contains an aromatic group having a centroid indicated by the letter "A"; And it contains a carbocyclic group having a centroid indicated by the letter "B"; L is a group that links X and Z; a plane "F" is formed by the aromatic atoms of the aromatic group in W; the centroid "B" falls within about 1, preferably about 0.7 angstroms above or below the "F" plane; the centroid "A" and the centroid "B" are separated approximately 6 to approximately 8 angstroms; to provide the spatially defined molecules; Y select spatially defined molecules capable of stimulating the activity of the BMP-2 promoter.

9. The method of claim 8, characterized in that: the centroid "A" and the centroid "B" are separated approximately 6.6 to approximately 8.5 angstroms.

10. The method of claim 8, characterized in that: the spatially defined molecules are further defined as having at least two groups that accept hydrogen bonds located within or close to the vicinity of L, the hydrogen bond acceptor groups are defined more as follow: 1) the hydrogen bond acceptor groups are in about 2 to about 5 angstroms apart; 2) a hydrogen bond acceptor group is about 4 to about 7 angstroms from centroid "A" and about 2 to about 3 angstroms from centroid "B"; Y 3) a hydrogen bond acceptor group is about 2 to about 3 angstroms, from the centroid "A" and about 4 to about 7 angstroms of the centroid "B".

11. The method of claim 10, characterized in that: hydrogen bond acceptor groups are defined as follows: 1) the hydrogen bond acceptor groups are at about 2.3 about 5.4 angstroms apart; 2) a hydrogen bond acceptor group is about 4.5 to about 7.7 angstroms from centroid "A" and about 2.7 to about 3.8 angstroms from centroid "B"; Y 3) a hydrogen bond acceptor group is about 2.6a about 3.8 angstroms from centroid "A" and about 4.6 to about 6.9 angstroms from centroid "B".

12. The method of claim 8, characterized in that: L is further defined as occupying a space that outside the boundary is less than or equal to about 3 angstroms, as measured by the distance of the heavy atom, above or below and normal to the "P" plane as measured throughout and normal to the "F" plane.

13. The method of claim 12, characterized in that: L is further defined as occupying a space that outside the limit is less than or equal to about 3.1 angstroms, as measured by the distance of the heavy atom, above or below and normal to the "F" plane as measured throughout and normal to the "F" plane.

14. The method of claim 8, characterized in that: L is further defined as occupying a space that outside the boundary is approximately 4 to approximately 6.0 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" and within the flat "F"

15. The method of claim 14, characterized in that: L is further defined as occupying a space that outside the boundary is approximately 4.7 to approximately 6.0 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" and within the flat "F"

16. The method of claim 8, characterized in that: the candidate of formula II is also defined as: 1) no compound of formula X Formula X where R x is H, OH, C 1 -C 17 alkoxy, alkylcarbonyloxy (Cl-C 17), alkylcarbonylamino (C 1 -C 17) or alkylcarbonyl (C 1 -C 17); R2 is (CH2) (1_6) -CH2- heterocycle; and R3 is H, OH, C1-C17 alkoxy, (C1-C17) alkylcarbonyl, (C1-C17) alkylcarbonylamino or (C1-C17) alkylcarbonyl; Y 2) no compound of formula XI Formula XI

17. The method of claim 8, characterized in that: the aromatic ring having the centroid "A" is independently replaced with one or more substituents selected from the group consisting of: H, halo, hydroxy, amino, carboxyl, cyano, Cl-C6 alkyl, C1-C2 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, - 0C (= 0) - (C1-C6 alkyl) and -NHC (= 0) - (C1-C6 alkyl).

18. The method of claim 17, characterized in that: the carbocyclic group having the "B" centroid is independently substituted with one or more of the substituents selected from the group consisting of: H, halo, hydroxy, amino, carboxyl, cyano, Cl-C6 alkyl, C1-C2 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, aryl, heteroaryl, -0C (= 0) - (C1-C6 alkyl) and -NHC (= 0) - (C1-C6 alkyl).

19. A method for treating or preventing the proliferation of malignant tumor cells, characterized in that it comprises: administering to a population of cells, comprising malignant tumor cells, an amount that inhibits the proliferation of malignant tumor cells of a pharmacologically active compound having a spatially defined structure as defined by formula II W-L-Y; Formula II and inhibit malignant tumor cells, wherein the pharmacologically active compound is further defined by a 3-dimensional structure wherein: W contains an aromatic group having a centroid indicated by the letter "A"; And it contains a carbocyclic group having a centroid indicated by the letter "B"; L is a group that links X and Z; a plane "F" is formed by the aromatic atoms of the aromatic group in W; centroid "B" falls within approximately 1 angstrom above or below plane "F"; the centroid "A" and the centroid "B" are separated approximately 6 to approximately 8 angstroms.

20. The method of claim 19, characterized in that: the centroid "B" falls within approximately 0.7 angstroms above or below the "P" plane; Y the centroid "A" and the centroid "B" are separated approximately 6.6 to approximately 8.5 angstroms.

21. The method of claim 19, characterized in that: the pharmacologically active compound is further defined as having a spatially defined structure wherein at least two groups accepting hydrogen bonds are located within or close to the vicinity of L, with the hydrogen bond acceptor groups being defined more as follows : 1) the hydrogen bond acceptor groups are in about 2 to about 5 angstroms apart; 2) a hydrogen bond acceptor group is about 4 to about 7 angstroms from centroid "A" and about 2 to about 3 angstroms from centroid "B"; Y 3) a hydrogen bond acceptor group is about 2 to about 3 angstroms, from the centroid "A" and about 4 to about 7 angstroms of the centroid "B".

22. The method of claim 21, characterized in that: the pharmacologically active compound is further defined as having a spatially defined structure wherein at least two groups accepting hydrogen bonds are located within or close to the vicinity of L, with the hydrogen bond acceptor groups being defined more as follows : 1) the hydrogen bond acceptor groups are at about 2.3 about 5.4 angstroms apart; 2) a hydrogen bond acceptor group is about 4.5 to about 7.7 angstroms from centroid "A" and about 2.7 to about 3.8 angstroms from centroid "B"; Y 3) a hydrogen bond acceptor group is about 2.6a about 3.8 angstroms from centroid "A" and about 4.6 to about 6.9 angstroms from centroid "B".

23. The method of claim 19, characterized in that: L is further defined as occupying a space that outside the boundary is less than or equal to about 2.5 angstroms, as measured by the distance of the heavy atom, up or down and normal to the "F" plane as measured throughout and normal to the "P" plane.

24. The method of claim 23, characterized in that: L is further defined as occupying a space that outside the limit is less than or equal to about 3.1 angstroms, as measured by the distance of the heavy atom, above or below and normal to the "F" plane as measured throughout and normal to the "P" plane.

25. The method of claim 19, characterized in that: L is further defined as occupying a space that outside the boundary is approximately 4 to approximately 5 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" and within the flat "F"

26. The method of claim 25, characterized in that: L is further defined as occupying a space that outside the boundary is approximately 4.7 to approximately 6 angstroms, as measured by the distance of the heavy atom, perpendicular to a line connecting the centroid "A" to the centroid "B" and within the flat "F"

27. A method for stimulating the activity of the BMP-2 promoter or the proliferation of the osteoblast or osteoblast precursor cells, characterized in that it comprises the step of: administering to the osteoblast or osteoblast precursor cell an effective amount of a compound of formula III Formula III where: R1 is selected from the group consisting of: aryl, naphthyl, heteroaryl, cycloalkyl, cycloalkenyl, azacycloalkyl, oxacycloalkyl, azacycloalkenyl, oxacycloalkenyl, substituted cycloalkyl keto, and substituted keto cycloalkenyl, wherein each of the above substituents is substituted by one or more of the groups independently selected from the group consisting of : C1-C7 alkyl, C1-C7 alkoxy, benzyloxy, hydroxy, C1-C2 haloalkyl, halo, cyano, -N02, -CF3, carboxyl, hydrogen, (C1-C4) alkoxycarbonyl, -N (Cl-C4 alkyl) 2, (C 1 -C 4) alkylcarbonyl, aryl, alkylcarbonylamino (C 1 -C 4), alkylcarbonyl (Cl-C 4), alkyl (C 1 -C 4) -aryl, and -NH 2; R2 is selected from the group consisting of: H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy and -NH 2; R3 and R6 are selected from the group consisting of: H, hydroxy, halo, (C1-C5) alkylcarbonyloxy, cyano, C1-C4 alkyl, C1-C4 alkenyl, and C1-C4 alkoxy; R4 and R5 are selected from the group consisting of: H, halo, hydroxy, (C 1 -C 4) alkylcarbonyloxy, cyano, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, benzoyl, alkyl (C 1 -C 4) -aryl, alkylaminocarboni loxy (C 1 -C 6), phenylaminocarbonyloxy, C 1 -C 4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, (C1-C4) alkenyl-aryl, alkynyl (Cl-C4) -aryl, (C1-C4) alkyl-cycloalkyl (C6-C10), (C1-C4) alkenyl-cycloalkyl (C6-C10), alkynyl (Cl-C4) -cycloalkyl (C6-C10), alkyl (C1-C4) -cycloalkenyl (C6-C10), alkenyl (C1-C4) -cycloalkenyl (C6-C10), alkynyl ( C1-C4) -cycloalkenyl (C6-C10), carboxy and alkoxycarbonyl (C1-C4).

28. The method of claim 27, characterized in that: R3 and R4 come together to form a carbocycle or oxacarbocycle of 5-7 members fused to the ring to which they are attached, wherein the carbocycle or oxacarbocycle is independently substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl.

29. The method of claim 27, characterized in that: R4 and R5 together form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, wherein the carbocycle or oxacarbocycle is independently substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl.

30. The method of claim 27, characterized in that: R5 and R6 together form a 5-7 membered carbocycle or oxacarbocycle fused to the ring to which they are attached, wherein the carbocycle or oxacarbocycle is independently substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, alkoxy C1-C4, hydroxy, halo, carboxyl, hydrogen and aryl.

31. The method of claim 27, characterized in that: R1 is selected from the group consisting of: aryl, naphthyl, heteroaryl and cycloalkyl, wherein each of the substituents R1 is independently replaced by one or more of the groups consisting of: C1-C7 alkyl, C1-C7 alkoxy, -N02, -CF3, benzyloxy, hydroxy, C1-C2 haloalkyl, halo, cyano, carboxyl, hydrogen, aryl, alkylcarbonylamino (C1-C4), alkylcarbonyl (C1-C4), alkyl (C1-C4) -aryl, and -NH2; R2 is H, C1-C4 alkoxy, amino, or C1-C4 alkyl; R3 and R6 are independently selected from the group consisting of: H, hydroxy, (C 1 -C 5) alkylcarbonyloxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, and C 1 -C 4 alkoxy; Y R4 and R5 are independently selected from the group consisting of: H, halo, hydroxy, (C 1 -C 4) alkylcarbonyloxy, cyano, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, benzoyl, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkyl - aryl, (C 1 -C 4) alkenyl-aryl, (C 1 -C 4) alkynyl-aryl, (C 1 -C 4) alkyl-cycloalkyl (C 6 -C 10), alkenyl (C 1 -C 4) -cycloalkyl (C 6 -C 10), alkynyl (C1-C4) -cycloalkyl (C6-C10), carboxy and alkoxycarbonyl (C1-C4).

32. The method of claim 27, characterized in that: R4 and R5 are joined to form a 5-6 membered carbocycle or oxacarbocycle fused to the ring to which they are bound, wherein the carbocycle or oxacarbocycle is independently substituted by one or more of the groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, carboxyl, hydrogen and aryl.

33. The method of claim 27, characterized in that: the compound of formula II is 2- (2-methoxybenzamido) -1,3-benzothiazole or a pharmaceutically acceptable salt thereof.

34. A pharmacologically active composition having osteoblast proliferation activity, characterized in that the composition is prepared by means of the process comprising the step of:

35. A pharmacologically active composition, characterized in that it comprises a compound of the formula: Formula IV where: R1, R2, R3, R4, R5 and R6 are all hydrogen; R8 is taken from the group consisting of: H, OH, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -NHC (= 0) Me and -N (Cl-C 4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -NHC (= 0) Me and -0C (= 0) Me; R10 is selected from the group consisting of: H, OH, halo, C1-C4 haloalkyl, -C02H, C1-C12 alkyl, C1-C12 alkoxy, -NHC (= 0) Me, C1-C4 alkenyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl , and (C1-C4) alkylcarbonyloxy; Rn is selected from the group consisting of: H, OH, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, -NH 2, C 1 -C 4 alkoxy, -NHC (= 0) Me, C 1 -C 4 alkenyl, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkylcarbonyl , and (C1-C4) alkylcarbonyloxy; R12 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, -N (Cl-C4 alkyl) 2; with the condition of: 1) when R9, R10, R11, and R12 are all hydrogen, R8 can not be -OH; 2) when R8, R10, Ru, and R12 are all hydrogen, R9 can not be -NH2 or 3) when R8, R9, R11, and R12 are all hydrogen, R10 can not be: hydrogen, chlorine, guanidino, CH2P (= 0) OEt2, CH2P (= 0) OiPr2, CH2P (= 0) (OEt) Ph,

36. A pharmacologically active composition, characterized in that it comprises a compound of the formula: Formula V where: R1, R2, R3, R4, and R6 are all hydrogen; R8 is taken from the group consisting of: H, OH, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -NHC (= 0) Me and -N (Cl-C 4 alkyl) 2; R9 is selected from the group consisting of: H, OH, halo, C1-C8 alkyl, C1-C8 alkoxy, -NHC (= 0) Me and -0C (= 0) Me; R10 is selected from the group consisting of: H, OH, halo, C1-C4 haloalkyl, -C02H, C1-C12 alkyl, C1-C12 alkoxy, -NHC (= 0) Me, C1-C4 alkenyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl , and (C1-C4) alkylcarbonyloxy; Rn is selected from the group consisting of: H, OH, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, -NH 2, C 1 -C 4 alkoxy, -NHC (= 0) Me, C 1 -C 4 alkenyl, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkylcarbonyl , and (C1-C4) alkylcarbonyloxy; R12 is selected from the group consisting of: H, OH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, -N (Cl-C4 alkyl) 2; n the condition that: ) when R9, R10, R11, and R12 are all hydrogen, R8 can not be: azido, nitro, chloro, bromo, fluoro, hydroxy, carboxy, 2-carboxy-5-chlorophenyl, 4 '- (acetyl) benzsulfonyloxy, 41- (cyanoacetyl) benzsulfonyloxy, N- (4'-ethoxyphenyl) amino, di (4) '-hydroxyphenyl) methyl, 4' - (acetoxy) phenylmethyl, or N- (Z-, 3-carboxypropenoyl) amino; ) when R8, R10, Ru, and R12 are all hydrogen, then R9 can not be: bromine, chlorine, or methoxy; ) when R8, R9, Ru, and R12 are all hydrogen, then R10 can not be: chlorine, bromine, fluorine, methyl, nitro, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-pentoxy, benzyloxy, allyloxy, acetoxy, 2 '- (diethylamino) ethoxy, amino, dimethylamino, guanidino, thiomethyl, 4'- (methyl) benzsulfonylamino, di- (ethylphosphono) methyl, di- (i- propylphosphono) methyl, ) when R8 and R10 are all hydrogen, R9 and R11 are bromine then R12 can not be -OH; ) when R8, R10, and R11 are all hydrogen and R12 is hydroxy, then R9 can not be (C6-C15) alkylcarbonyl;