Heterocyclic antiestrogens

Patent metadata

Field	Value
Publication number	US-11465990-B2
Application number	US-202017082488-A
Country	US
Kind code	B2
Filing date	Oct 28, 2020
Priority date	Oct 27, 2015
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The present invention provides novel heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/degraders and process for their preparation.

First claim

The invention claimed is:

1. A method of inhibiting the action of endogenous estrogen in estrogen receptor positive breast cancer comprising administering a compound of Formula I to a human:

or salts or stereoisomers thereof wherein,
R 1 is mono or di-substitution on ring A and is selected from a group consisting of, —OR 3 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 3 ) 2 , —NR 3 SO 2 R 3 , —NR 3 CHO, —NR 3 COR 3 , —OC(O)R 3 , —OC(O)N(R 3 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 3 wherein R 3 at each occurrence is selected from hydrogen, C 1-6 linear, branched or cyclic alkyl and C 1-6 linear, branched or cyclic haloalkyl;
R 2 is mono or di-substitution and is a halogen;
R 4 is selected from hydrogen and —C 1-5 alkyl;
L is selected from C 1-7 linear or branched alkyl;
R 7 and R 8 are absent or independently selected from hydrogen and C 1-5 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 to 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 wherein R 6 , at each occurrence is selected from a group comprising hydrogen, C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR 5 —, —S—, —SO—, —S(O) 2 —, —CR 5 ═CR 5 —, —C≡C—, —NR 5 CO—, —CONR 5 —, —NR 5 CONR 5 —, NR 5 C(O)O— and —OC(O)O—;
optionally, R 6 is further substituted with one or more groups selected from a group comprising halogen, —OR 12 , —N(R 12 ) 2 , and —COOR 12 , —CON(R 12 ) 2 or —CON(R 12 )OH; wherein R 12 at each occurrence is selected from hydrogen or C 1-6 linear, branched or cyclic alkyl;
is a double or a triple bond;
R 13 is selected from a group comprising —R 14 , —OR 14 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 14 ) 2 , —NR 14 SO 2 R 14 , —NR 14 CHO, —NR 14 COR 14 , —OC(O)R 14 , —OC(O)N(R 14 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 14 wherein R 14 at each occurrence is selected from hydrogen, and C 1-6 linear, branched or cyclic alkyl; and
X is oxygen.

2. The method of claim 1 wherein the human has breast cancer.

3. The method of claim 1 , wherein R 1 is a mono-substitution and is —OH;
R 2 is di-substitution;
R 7 and R 8 are hydrogen;
R 13 is R 14 , and R 14 is hydrogen;
R 4 is methyl;
L is C 1-3 linear alkyl; and R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4-5 membered ring wherein the ring is substituted with R 6 ; wherein R 6 is selected from C 1-3 linear alkyl and wherein R 6 is further substituted with halogen; and
is a double bond.

4. The method of claim 3 , wherein R 2 is fluoro.

5. A method of treating breast cancer comprising administering a compound of Formula I to a human having the disease:

or salts or stereoisomers thereof wherein,
R 1 is mono or di-substitution on ring A and is selected from a group consisting of, —OR 3 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 3 ) 2 , —NR 3 SO 2 R 3 , —NR 3 CHO, —NR 3 COR 3 , —OC(O)R 3 , —OC(O)N(R 3 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 3 wherein R 3 at each occurrence is selected from hydrogen, C 1-6 linear, branched or cyclic alkyl and C 1-6 linear, branched or cyclic haloalkyl;
R 2 is mono or di-substitution and is a halogen;
R 4 is selected from hydrogen and —C 1-5 alkyl;
L is selected from C 1-7 linear or branched alkyl;
R 7 and R 8 are absent or independently selected from hydrogen and C 1-5 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 to 2 additional heteroatoms selected from oxygen, nitrogen or sulfur; and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 wherein R 6 , at each occurrence is selected from a group comprising hydrogen, C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR 5 —, —S—, —SO—, —S(O) 2 —, —CR 5 ═CR 5 —, —C≡C—, —NR 5 CO—, —CONR 5 —, —NR 5 CONR 5 —, NR 5 C(O)O— and —OC(O)O—;
optionally, R 6 is further substituted with one or more groups selected from a group comprising halogen, —OR 12 , —N(R 12 ) 2 , and —COOR 12 , —CON(R 12 ) 2 or —CON(R 12 )OH; wherein R 12 at each occurrence is selected from hydrogen or C 1-6 linear, branched or cyclic alkyl;
is a double or a triple bond;
R 13 is selected from a group comprising —R 14 , —OR 14 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 14 ) 2 , —NR 14 SO 2 R 14 , —NR 14 CHO, —NR 14 COR 14 , —OC(O)R 14 , —OC(O)N(R 14 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 14 wherein R 14 at each occurrence is selected from hydrogen, and C 1-6 linear, branched or cyclic alkyl; and
X is oxygen.

6. The method of claim 5 ,
wherein R 1 is a mono-substitution and is —OH;
R 2 is di-substitution;
R 7 and R 8 are hydrogen;
R 13 is R 14 , and R 14 is hydrogen;
R 4 is methyl;
L is C 1-3 linear alkyl; and R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4-5 membered ring wherein the ring is substituted with R 6 ; wherein R 6 is selected from C 1-3 linear alkyl and wherein R 6 is further substituted with halogen; and
is a double bond.

7. The method of claim 6 , wherein R 2 is fluoro.

8. A method of inhibiting breast cancer cell growth comprising administering a compound of Formula I to a human:

or salts or stereoisomers thereof wherein,
R 1 is mono or di-substitution on ring A and is selected from a group consisting of, —OR 3 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 3 ) 2 , —NR 3 SO 2 R 3 , —NR 3 CHO, —NR 3 COR 3 , —OC(O)R 3 , —OC(O)N(R 3 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 3 wherein R 3 at each occurrence is selected from hydrogen, C 1-6 linear, branched or cyclic alkyl and C 1-6 linear, branched or cyclic haloalkyl;
R 2 is mono or di-substitution and is a halogen;
R 4 is selected from hydrogen and —C 1-5 alkyl;
L is selected from C 1-7 linear or branched alkyl;
R 7 and R 8 are absent or independently selected from hydrogen and C 1-5 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 to 2 additional heteroatoms selected from oxygen, nitrogen or sulfur; and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 wherein R 6 , at each occurrence is selected from a group comprising hydrogen, C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR 5 —, —S—, —SO—, —S(O) 2 —, —CR 5 ═CR 5 —, —C≡C—, —NR 5 CO—, —CONR 5 —, —NR 5 CONR 5 —, NR 5 C(O)O— and —OC(O)O—;
optionally, R 6 is further substituted with one or more groups selected from a group comprising halogen, —OR 12 , —N(R 12 ) 2 , and —COOR 12 , —CON(R 12 ) 2 or —CON(R 12 )OH; wherein R 12 at each occurrence is selected from hydrogen or C 1-6 linear, branched or cyclic alkyl;
is a double or a triple bond;
R 13 is selected from a

Assignees

• Sun Pharma Advanced Res Co Ltd

Inventors

• Pal Ranjan Kumar
• Sedani Amit Pravinbhai
• Prajapati Kaushikkumar Dhanjibhai
• Rana Dijixa Pinakin
• Pathak Sandeep Pankajbhai
• Desai Japan Nitinkumar
• Aradhye Jayraj Dilipbhai
• Panchal Bhavesh Mohanbhai
• Ghosh Indraneel
• Chitturi Trinadha Rao

Classifications

• A61K31/382

  having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D335/06

  Benzothiopyrans; Hydrogenated benzothiopyrans · CPC title

• C07D311/60 Primary

  with aryl radicals attached in position 2 · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title