Methods and compositions for stimulating osteoblast proliferation or treating malignant cell proliferation and methods for selecting osteoblast proliferation stimulants

A method for selecting a pharmacologically active compound or candidate pharmacologically active compounds, wherein the pharmacological activity is a capacity for stimulating BMP-2 promoter activity, comprising:

• selecting candidate compounds having a spatially defined 3-dimensional structure as in formula II
• W-L-Y Formula II
• wherein:
• W contains an aromatic group having a centroid indicated by the letter “A”;
• Y contains a carbocyclic group having a centroid indicated by the letter “B”;
• L is a group linking X and Z;
• a plane “P” is formed by the aromatic atoms of the aromatic group in W;
• the centroid “B” lies within about 1, preferably about 0.7 angstroms above or below the plane “P”;
• the centroid “A” and the centroid “B” are spaced apart by about 6 to about 8 angstroms;
• to provide spatially defined molecules;
• and
• selecting spatially defined molecules capable of stimulating BMP-2 promoter activity.

A method for treating or preventing malignant cell proliferation comprising:

• administering to a population of cells, comprising malignant cells, a malignant cell proliferation inhibiting amount of a pharmacologically active compound having a spatially defined structure as defined by formula II
• W-L-Y;
• Formula II and
• inhibiting malignant 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”;
• Y contains a carbocyclic group having a centroid indicated by the letter “B”;
• L is a group linking X and Z;
• a plane “P” is formed by the aromatic atoms of the aromatic group in W;
• the centroid “B” lies within about 1 angstroms above or below the plane “P”;
• and
• the centroid “A” and the centroid “B” are about 6 to about 8 angstroms apart.

A method of stimulating BMP-2 promoter activity or osteoblast proliferation in osteoblast or osteoblast precursor cells comprising the step of:

• administering to the osteoblast or osteoblast precursor cell an effective amount of a compound of the formula III
• 125
• wherein:
• R1 is selected from the group consisting of:
• aryl, naphthyl, heteroaryl, cycloalkyl, cycloalkenyl, azacycloalkyl, oxacycloalkyl, azacycloalkenyl, oxacycloalkenyl, keto substituted cycloalkyl, and keto substituted cycloalkenyl, where 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, —NO2, —CF3, carboxyl, hydrogen, (C1-C4)alkoxycarbonyl, —N(C1-C4 alkyl)2, (C1-C4)alkylcarbonyloxy, aryl, (C1-C4)alkylcarbonylamino, (C1-C4)alkylcarbonyl, (C1-C4)alkyl-aryl, and —NH2;
• R2 is selected from the group consisting of:
• H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C4 alkoxy and —NH2;
• 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)alkyl-carbonyloxy, cyano, C1-C2 haloalkyl, C1-C4 alkoxy, benzoyl, (C1-C4)alkyl-aryl, (C1-C6)alkylaminocarbonyloxy, phenylaminocarbonyloxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, (C1-C4)alkenyl-aryl, (C1-C4)alkynyl-aryl, (C1-C4)alkyl-(C6-C10)cycloalkyl, (C1-C4)alkenyl-(C6-C10)cycloalkyl, (C1-C4)alkynyl-(C6-C10)cycloalkyl, (C1-C4)alkyl-(C6-C10)cycloalkenyl, (C1-C4)alkenyl-(C6-C10)cycloalkenyl, (C1-C4)alkynyl-(C6-C10)cycloalkenyl, carboxy and (C1-C4)alkoxycarbonyl.

A pharmacologically active composition comprising a compound of the formula:

• 126
• wherein.
• R1, R2, R3, R4, R5, and R6 are all hydrogen;
• R8 is taken from the group consisting of:
• H, OH, halo, C1-C4 alkyl, C1-C4 allcoxy, —NHC(═O)Me and —N(C1-C4 alkyl)2;
• R9 is selected from the group consisting of:
• H, OH, halo, C1-C8 alkyl, C1-C8 alkoxy, —NHC(═O)Me and —OC(═O)Me;
• R10 is selected from the set consisting of:
• H, OH, halo, C1-C4 haloalkyl, —CO2H, C1-C12 alkyl, C1-C12 alkoxy, —NHC(═O)Me, C1-C4 alkenyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarbonyl, and (C1-C4)alkylcarbonyloxy;
• R11 is selected from the set consisting of:
• H, OH, halo, C1-C4 haloalkyl, C1-C4 alkyl, —NH2, C1-C4 alkoxy, —NHC(═O)Me, C1-C4 alkenyl, (C1-C4)alkoxycarbonyl, (C1-C4) alkylcarbonyl, and (C1-C4)alkylcarbonyloxy;
• R12 is selected from the set consisting of:
• H, OH, —NH2, C1-C4 alkyl, C1-C4 alkoxy, —N(C1-C4 alkyl)2;
• provided that:
• 1) when R9, R10, R11, and R12 are all hydrogen. R8 cannot be —OH;
• 2) when R9, R10, R11, and R12 are all hydrogen, then R9 cannot be —NH2 or
• 127
• or
• 3) when R8, R9, R11, and R12 are all hydrogen, then R10 cannot be:
• hydrogen, chloro, guanidino, CH2P(═O)OEt2, CH2P(═O)OiPr2, Ch2P(═O)(OEt)Ph,
• 128

A pharmacologically active composition comprising a compound of the formula:

• 129
• wherein:
• R1, R2, R3, R4, and R6 are all hydrogen;
• R8 is taken from the group consisting of:
• H, OH, halo, C1-C4 alkyl, C1-C4 alkoxy, —NHC(═O)Me and —N(C1-C4 alkyl)2;
• R9 is selected from the group consisting of:
• H, OH, halo, C1-C8 alkyl, C1-C8 alkoxy, —NHC(═O)Me and —OC(—O)Me;
• R10 is selected from the set consisting of:
• H, OH, halo, C1-C4 haloalkyl, —CO2H, C1-C12 alkyl, C1-C12 alkoxy, —NHC(═O)Me, C1-C4 alkenyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarbonyl, and (C1-C4)alkylcarbonyloxy;
• R11 is selected from the set consisting of:
• H, OH, halo, C1-C4 haloalkyl, C1-C4 alkyl, —NH2, C1-C4 alkoxy, —NHC(═O)Me, C1-C4 alkenyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarbonyl, and (C1-C4) ukylcarbonylzcy;
• R12 is selected from the set consisting of:
• H, OH, —NH2, C1-C4 alkyl, C1-C4 alkoxy, —N(C1-C4 alkyl)2;
• provided that:
• 1) when R9, R10, R11 and R12 are all hydrogen, R8 cannot be:
• azido, nitro, chloro, bromo, fluoro. hydroxy, carboxy, 2-carboxy-5-chlorophenyl, 41-(acetyl)benzsultonyloxy, 4′-(cyanoacetyl)benzsulfonyloxy, N-(41-ethoxyphenyl)amino, di(4′-hydroxyphenyl)methyl, 4′-(acetoxy)phenylmethyl, or N-(Z-, 3-carbcoxypropenoyl)amino;
• 2) when R8, R10, R11, and R12 are all hydrogen, then R9 cannot b:
• broma, chloro, or methoxy;
• 3) when R8, R9, R11, and R12 are all hydrogen, then R10 cannot be:
• chloro, bromo, fluoro, methyl, nitro, nethoxy, 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-propylposphono)methyl,
• 130
• 4) when R8 and R10 are all hydrogen, R9 and R11 are both bromo then R12 cannot be —OH;
• 5) when R8, R10, and R11 are all hydrogen and R12 is hydrosy, then R9 cannot be (C6-C15)alkylcarbonyl;