METHODS AND COMPOSITIONS OF TARGETED DRUG DEVELOPMENT

• US 20110301193A1
• Filed: 01/06/2011
• Published: 12/08/2011
• Est. Priority Date: 01/06/2010
• Status: Active Grant

• Current Assignee: Joseph P. Errico
• Original Assignee: Joseph P. Errico
• Inventors: Errico, Joseph P., Mugrage, Benjamin, Turchi, Ignatius, Sills, Matthew, Ong, Jane, Allocco, John, Wines, Pam
• Granted Patent: US 8,618,302 B2
• Time in Patent Office: Days
• US Class Current: 514/314
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 335/26 Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
• CPC Class Codes: C07D 207/48 Sulfur atoms
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 215/26 Alcohols; Ethers thereof
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/52 Two oxygen atoms
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/54 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: G16B 15/00 : ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 15/30 : Drug targeting using structural data; Docking or binding prediction

Abstract

Provided herein are compounds having anti-proliferative effect. Also provided are compounds that can modulate the activity of multi-domain proteins comprising a dimerization arm and interdomain tether, such as EGFR, where an untethered, extended conformation is the active state and a tethered conformation is the inactive state, resulting in an autoinhibited configuration. Also provided are methods and pharmacophores for identifying such compounds. Other aspects provide methods or therapeutic treatment for proliferative diseases, disorders, or conditions, such as those associated with EGFR.

Claims

1. A compound having a formula of:

2. The compound of claim 1 wherein R¹ of Formula (2) is selected from the group consisting of:

(i) an 2-(1,3-thiazoyl) of Formula (6), wherein R11 and R12 are independently selected from the group consisting of;

hydrogen;

straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;

C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;

alkoxy —

OR¹⁰ where R¹⁰ is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;

dialkylamino;

trifluoromethyl;

difluoromethyl;

trifluoromethoxy; and

halogen,

3. The compound of claim 1 wherein R¹ is a 2-pyridyl ring of Formula (3) and:

R²⁴ is chloro;

or

R²³ is methyl;

4. The compound of claim 1 wherein R¹ is a 2-pyridyl ring of Formula (3) and:

R⁴ is hydrogen, R²⁴ is fluoro, R³ is hydrogen, and R²³ is fluoro;

R⁴ is methyl, R²⁴ is chloro, R³ is hydrogen, and R²³ is fluoro;

R⁴ is hydrogen, R²⁴ is chloro, R³ is ethyl, and R²³ is fluoro;

R⁴ is hydrogen, R²⁴ is fluoro, R³ is methyl, and R²³ is fluoro;

R⁴ is hydrogen, R²⁴ is chloro, R³ is hydrogen, and R²³ is ethyl;

R⁴ is methyl, R²⁴ is chloro, R³ is hydrogen, and R²³ is chloro;

R⁴ is hydrogen, R²⁴ is chloro, R³ is methyl, and R²³ is fluoro;

R⁴ is hydrogen, R²⁴ is trifluoromethyl, R³ is hydrogen, and R²³ is hydrogen;

R⁴ is hydrogen, R²⁴ is chloro, R³ is hydrogen, and R²³ is methyl;

R⁴ is hydrogen, R²⁴ is chloro, R³ is hydrogen, and R²³ is chloro;

R⁴ is hydrogen, R²⁴ is chloro, R³ is methyl, and R²³ is hydrogen;

or

R⁴ is hydrogen, R²⁴ is chloro, R³ is chloro, and R²³ is hydrogen.

5. The compound of claim 1, wherein R¹ is a 2-pyridyl ring of Formula (3) and:

R²⁴ is chloro and R³ is chloro or methyl or R²³ is chloro or methyl;

R²⁴ is chloro, R³ is hydrogen, and R²³ is methyl;

R²⁴ is chloro, R³ is methyl, and R²³ is fluoro;

R²⁴ is chloro, R³ is chloro, and R²³ is hydrogen;

R²⁴ is chloro, R³ is hydrogen, and R²³ is chloro.

6. The compound of claim 1 wherein R² is selected from the group consisting of:

a phenyl ring substituted at the 2- and 4-positions;

4-trifluoromethylphenyl;

2-fluoro,4-trifluoromethylphenyl; and

2,4-dichlorophenyl.

7. The compound of claim 1 wherein R² is selected from the group consisting of:

4-chlorophenyl;

2-fluoro,4-trifluoromethylphenyl;

3-fluoro,4-chlorophenyl;

2-fluoro,4-chlorophenyl;

2,3-dichlorophenyl;

2,3,5-trichlorophenyl;

2,4-dichlorophenyl;

3,4-dichlorophenyl; and

3,5-dichlorophenyl.

8. The compound of claim 1 wherein R² is selected from the group consisting:

a phenyl ring substituted at the 4 position with chloro and substituted at the 2- or 3-position with chloro or fluoro;

2,4-dichlorophenyl; and

2-chloro,4-fluorophenyl.

9. The compound of claim 1 wherein Formula (2) is not one or more of the following compounds:

12. The compound of claim 1 that inhibits EGFR activity comprising:

six or more of functional groups F(I)1, F(I)2, F(I)3, F(I)4, F(I)5, F(I)6, F(I)7, F(I)8, and F(I)9 of a Scheme I 1505-like pharmacophore;

wherein

functional group F(I)1 donates an H-bond or forms a salt bridge to a carboxylate side chain of receptor Asp553 of SEQ ID NO;

1 and has coordinates of r=56.363, θ

(theta)=94.368, and Φ

(phi)=−

17.752 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)2 donates an H-bond to backbone carbonyl of receptor Thr570 of SEQ ID NO;

1 and has coordinates of r=53.290, θ

(theta)=101.494, and Φ

(phi)=−

23.244 and a spherical radius of about 1.0 {acute over (Å

)};

functional group F(I)3 forms a hydrophobic contact with a side chain of receptor Val568, an imidazole side chain of receptor His566, and an imidazolidine ring of receptor Pro552 of SEQ ID NO;

1 and has coordinates of r=53.726, θ

(theta)=97.830, and Φ

(phi)=−

18.378 and a spherical radius of about 1.7 {acute over (Å

)};

functional group F(I)4 donates an H-bond or forms a salt bridge to the side chain carboxylate of receptor Asp563 of SEQ ID NO;

1 and has coordinates of r=56.103, θ

(theta)=99.536, and Φ

(phi)=−

21.080 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)5 forms a hydrophobic contact with an imidazoline ring of receptor Pro572 and a side chain of Met253 of SEQ ID NO;

1 and has coordinates of r=53.647, θ

(theta)=103.844, and Φ

(phi)=−

20.990 and a spherical radius of about 1.4 {acute over (Å

)};

functional group F(I)6 donates an H-bond to a backbone carbonyl of receptor Cys571 of SEQ ID NO;

1 and has coordinates of r=51.088, θ

(theta)=104.241, and Φ

(phi)=−

25.552 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)7 donates an H-bond to a backbone carbonyl of receptor Cys571 of SEQ ID NO;

1 and has coordinates of r=52.340, θ

(theta)=103.980, and Φ

(phi)=−

27.461 and a spherical radius of about 1.5 {acute over (Å

)};

functional group F(I)8 accepts an H-bond from receptor backbone NH of Ala573 of SEQ ID NO;

1 and has coordinates of r=51.383, θ

(theta)=106.455, and Φ

(phi)=−

24.319 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)9 accepts an H-bond from receptor backbone NH of Ala573 of SEQ ID NO;

1 and has coordinates of r=52.861, θ

(theta)=107.692, and Φ

(phi)=−

25.447 and a spherical radius of about 1.5 {acute over (Å

)}; and

the compound substantially maintains a non-extended tether inactive configuration of EGFR or substantially prevents stabilization of an extended tether active configuration of EGFR.

13. A method of treating a proliferative disease, disorder, or condition comprising:

administering to a subject in need thereof a composition comprising a therapeutically effective amount of;

(i) a compound of any one of claims 1, 10, or 11;

(ii) a compound of Formula (1);

14. The method of claim 13, wherein the proliferative disease, disorder, or condition is associated with EGFR or is selected from the group consisting of:

cancer;

a blood vessel proliferative disorder;

a fibrotic disorder;

a mesangial cell proliferative disorder;

psoriasis;

actinic keratoses;

seborrheic keratoses;

warts;

keloid scars;

eczema; and

hyperproliferative diseases caused by a viral infection.

16. A method for forming a compound of claim 1, comprising:

combining an amino pyridine intermediate compound, an aldehyde intermediate compound, and a hydroxyquinoline intermediate compound in ethanol under conditions sufficient to form a compound of claim 1;

wherein,

the amino pyridine intermediate compound comprises R²—

CHO, where R² is as defined in claim 1;

the aldehyde intermediate compound comprises where R¹ is as defined in claim 1; and

the hydroxyquinoline intermediate compound comprises 8-hydroxyquinoline, optionally substituted with X, where X is as defined in claim 1.

17. The method of claim 16, wherein the aminopyridine intermediate compound is selected from the group consisting of 2-Amino-3-methoxy-5-chloropyridine;

2-Amino-4,5-dichloropyridine;

2-Amino-5-chloro-6-methylpyridine;

2-Amino-5-chloro-3-methylpyridine;

2-Amino-3,5-dichloro-4-methylpyridine;

2-Amino-3,5-dichloro-4,6-dimethylpyridine;

2-Amino-3-fluoro-4-methyl-5-chloropyridine;

2-Amino-3-ethyl-5-chloropyridine;

2-Amino-3-fluoro-4-ethyl-5-chloropyridine; and

2-Amino-4-methyl-3,5-difluoropyridine, or an aminopyridine compound formed according to claim 18.

19. The method of claim 18, wherein

(i) the 2-aminopyridine of reaction (i) comprises Formula (12), wherein R²³, R³, and R⁴ are as defined in claim 1 and R²⁴ is hydrogen;

and the 2-amino-5-chloropyridine derivative comprises Formula (12), wherein R²³, R³, and R⁴ are the same as for the 2-aminopyridine and R²⁴ is chloro;

or

(ii) the substituted 2-aminopyridine comprises Formula (12), wherein R²³ is fluoro, chloro, or bromo;

R³ is hydrogen;

R⁴ is as defined in claim 1; and

R²⁴ is fluoro, chloro, or bromo;

10. A compound having a formula of:

11. A compound having a formula of:

15. A method for identifying an epidermal growth factor receptor (EGFR) inhibitor comprising:

providing a pharmacophore comprising Scheme I as input to a 3-dimensional database;

comparing a three dimensional structure of a candidate compound to the three dimensional structure of the pharmacophore;

selecting a candidate compound with a three dimensional structure that substantially aligns with six or more functional groups of Scheme I (ADS-1505-like);

wherein,

similarity between the three-dimensional structure of the candidate compound and the three-dimensional structure of the pharmacophore is indicative of an ability of the candidate compound to inhibit EGFR by substantially maintaining a tethered inactive configuration of EGFR or substantially preventing stabilization of the untethered active configuration of EGFR; and

Scheme I (ADS-1505-like) comprises functional groups F(I)1, F(I)2, F(I)3, F(I)4, F(I)5, F(I)6, F(I)7, F(I)8, and F(I)9;

wherein

functional group F(I)1 donates an H-bond or forms a salt bridge to a carboxylate side chain of receptor Asp553 of SEQ ID NO;

1 and has coordinates of r=56.363, θ

(theta)=94.368, and Φ

(phi)=−

17.752 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)2 donates an H-bond to backbone carbonyl of receptor Thr570 of SEQ ID NO;

1 and has coordinates of r=53.290, θ

(theta)=101.494, and Φ

(phi)=−

23.244 and a spherical radius of about 1.0 {acute over (Å

)};

functional group F(I)3 forms a hydrophobic contact with a side chain of receptor Val568, an imidazole side chain of receptor His566, and an imidazolidine ring of receptor Pro552 of SEQ ID NO;

1 and has coordinates of r=53.726, θ

(theta)=97.830, and Φ

(phi)=−

18.378 and a spherical radius of about 1.7 {acute over (Å

)};

functional group F(I)4 donates an H-bond or forms a salt bridge to the side chain carboxylate of receptor Asp563 of SEQ ID NO;

1 and has coordinates of r=56.103, θ

(theta)=99.536, and Φ

(phi)=−

21.080 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)5 forms a hydrophobic contact with an imidazoline ring of receptor Pro572 and a side chain of Met253 of SEQ ID NO;

1 and has coordinates of r=53.647, θ

(theta)=103.844, and Φ

(phi)=−

20.990 and a spherical radius of about 1.4 {acute over (Å

)};

functional group F(I)6 donates an H-bond to a backbone carbonyl of receptor Cys571 of SEQ ID NO;

1 and has coordinates of r=51.088, θ

(theta)=104.241, and Φ

(phi)=−

25.552 and a spherical radius of about 1.2 {acute over (Å

)};

functional group F(I)7 donates an H-bond to a backbone carbonyl of receptor Cys571 of SEQ ID NO;

1 and has coordinates of r=52.340, θ

(theta)=103.980, and Φ

(phi)=−

27.461 and a spherical radius of about 1.5 {acute over (Å

)};

functional group F(I)8 accepts an H-bond from receptor backbone NH of Ala573 of SEQ ID NO;

1 and has coordinates of r=51.383, θ

(theta)=106.455, and Φ

(phi)=−

24.319 and a spherical radius of about 1.2 {acute over (Å

)}; and

functional group F(I)9 accepts an H-bond from receptor backbone NH of Ala573 of SEQ ID NO;

1 and has coordinates of r=52.861, θ

(theta)=107.692, and Φ

(phi)=−

25.447 and a spherical radius of about 1.5 {acute over (Å

)}.

18. A method for forming an aminopyridine compound, comprising:

(i) combining a substituted or unsubstituted 2-aminopyridine and N-chlorosuccinimide in a solvent comprising ethylacetate or dimethylformamide under conditions sufficient to form a 2-amino-5-chloropyridine derivative;

or

(ii) combining acetic anhydride in glacial acetic acid and a 2-aminopyridine substituted at 3-position and 5-position with fluoro, chloro, or bromo to form a corresponding acetamide derivative;

combining the acetamide derivative and diisopropyl amine and butyllithium in tetrahydrofuran at about −

70°

C. to deprotonate the acetamide derivative;

combining the deprotonated acetamide derivative and a lower alkyl halide to alkylate the 4-position of the acetamide derivative;

combining the alkylated acetamide derivative and a concentrated hydrochloric acid in a methanol solvent at about 50°

C. to remove the acetamide group and form a 2-amino-3,5-dihalo-4-alkylaminopridine

20. An amino pyridine compound selected from the group consisting of:

2-Amino-3-fluoro-4-methyl-5-chloropyridine;

2-Amino-3-ethyl-5-chloropyridine;

2-Amino-3-fluoro-4-ethyl-5-chloropyridine; and

2-Amino-4-methyl-3,5-difluoropyridine.