Decalin derivatives, a process for the preparation and pharmaceutical composition thereof

Patent metadata

Field	Value
Publication number	US-11724995-B2
Application number	US-201917287404-A
Country	US
Kind code	B2
Filing date	Oct 22, 2019
Priority date	Oct 22, 2018
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

Abstract

Decalin derivative compounds of formula (I) are provided, including processes for preparation thereof, and pharmaceutical compositions including the decalin derivative compounds. Methods are provided for treating blood related disorders, such as sickle cell anemia, in a subject in need thereof using a compound of formula (I).

First claim

The invention claimed is:

1. A process for preparing a decalin derivative compound of formula (A8):

where:
R 1 , R 2 , R 4 , and R 5 , are independently chosen from:
hydrogen; or
unsubstituted C 1 -C 10 alkyl or substituted C 1 -C 10 alkyl; or
unsubstituted C 2 -C 10 alkenyl or C 2 -C 10 alkenyl substituted with hydroxy, alkoxy, ester, or —OTBS; or
amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylate, alkoxy, carbamide, carbamate, or hydrazine,

the process comprising:
(a) protecting and following allylic oxidation of a compound according to formula (A5):

where R 6 is hydrogen, to afford a compound according to formula (A6):

(b) epoxidating and deprotecting the compound according to formula (A6) to afford a compound according to formula (A7):

and
(c) reducing the compound according to formula (A7) to afford the compound according to formula (A8),

wherein:
R 1 , R 2 , R 4 , and R 5 in formulas (A5), (A6), (A7) are as defined in the compound of formula (A8); and
Pg in the compounds of formulas (A6) and (A7) is a protecting group.

2. A process for the preparation of a decalin derivative compound of formula (A13):

where:
R 1 , R 2 , R 4 , R 5 , R 7 , and R 9 are independently chosen from:
hydrogen; or
unsubstituted C1-C 10 alkyl or substituted C 1 -C 10 alkyl; or
unsubstituted C 2 -C 10 alkenyl or C 2 -C 10 alkenyl substituted with hydroxy, alkoxy, ester, or —OTBS; or
amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylate, alkoxy, carbamide, carbamate, or hydrazine,

or wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 9 may be joined to form an unsubstituted or substituted fused cyclic ring, and
represents a single or double bond, the process comprising:
(a) halogenating a compound according to formula (A9):

to afford a compound according to formula (A10):

where X is a halogen;
(b) performing Suzuki Coupling on the compound according to formula (A10) in the presence of a compound according to formula (X):

to afford a compound according to formula (A11):

(c) forming an epoxide on the compound according to formula (A11) to afford a compound according to formula (Al2):

and
(d) reducing the compound according to formula (Al2) to afford the compound according to formula (A13),

wherein:
R 1 , R 2 , R 4 , R 5 , R 7 , and R 9 in of formulas (A9), (A10), (X), (A11), (Al2) are as defined in formula (A13).

3. A process for preparing a decalin derivative compound of formula (A21):

where:
R 1 , R 2 , R 4 , R 5 , R 7 , and R 10 are independently chosen from:
hydrogen; or
unsubstituted C 1 -C 10 alkyl or substituted C 1 -C 10 alkyl; or
unsubstituted C 2 -C 10 alkenyl or C 2 -C 10 alkenyl substituted with hydroxy, alkoxy, ester, or —OTBS; or
amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylate, alkoxy, carbamide, carbamate, or hydrazine, and

wherein any of R 1 , R 2 , R 4 , R 5 , R 7 , or R 10 may be joined to form an unsubstituted or substituted fused cyclic ring,

the process comprising:
(a) undergoing ozonolysis on a compound according to formula (A14):

to afford a compound according to formula (A15):

(b) rearranging the compound according to formula (A15) to afford a compound according to formula (A16):

(c) reducing and protecting the compound according to formula (A16) to afford a compound according to formula (A17):

where R 9 is independently chosen from:
hydrogen; or
unsubstituted C 1 -C 10 alkyl or substituted C 1 -C 10 alkyl; or
unsubstituted C 2 -C 10 alkenyl or C 2 -C 10 alkenyl substituted with hydroxy, alkoxy, ester, or —OTBS, or
amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylate, alkoxy, carbamide, carbamate, or hydrazine;

(d) epoxidating and reducing the compound according to formula (A17) to afford a compound according to formula (A18):

(e) oxidating, deprotecting, and rearranging the compound according to formula (A18), to afford a compound according to formula (A19):

hydrogenating the compound according to formula (A19) to afford a compound according to formula (A20):

and
(g) oxidating the compound according to formula (A20) to afford the compound according to formula (A21),

wherein:
R 1 , R 2 , R 4 , R 5 , R 7 , and R 10 in the compounds of formulas (A14), (A15), (A16), (A17), (A18), (A19), and (A20), are as defined in the compound of formula (A21); and
TBS in formulas (A17) and (A18) is tert-butyldimethylsilyl.

4. A process for preparing a decalin derivative compound of formula (A23) or formula (A25):

where:
R′, R 2 , R 4 , R 5 , R 7 , and R 10 are independently chosen from:
hydrogen; or
unsubstituted C 1 -C 10 alkyl or substituted C 1 -C 10 alkyl; or
unsubstituted C 2 -C 10 alkenyl or C 2 -C 10 alkenyl substituted with hydroxy, alkoxy, ester, or —OTBS; or
amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylate, alkoxy, carbamide, carbamate, or hydrazine,

wherein any of R 1 , R 2 , R 4 , R 5 , R 7 , and R 10 may be joined to form an unsubstituted or substituted fused cyclic ring,

the process comprising:
dihydroxylating a compound according to formula (A22):

wherein R 6 is hydrogen and wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 10 in formula (A22) are as defined in the compound according to formula (A23) to afford the compound according to formula (A23); or
dihydroxylating a compound according to formula (A24):

wherein R

Assignees

• Council Scient Ind Res

Inventors

• Reddy Dumbala Srinivasa
• Kulkarni Kiran Ashok
• Kalmode Hanuman Popat
• Athawale Paresh Ramesh
• Patil Suhag Sanjay
• Rajput Raveena Vijay
• Mankad Yash Jignasu
• Patil Namrata Nandkishor

Classifications

• C07D303/32 Primary

  by aldehydo- or ketonic radicals · CPC title

• C07C43/162

  containing rings other than six-membered aromatic rings · CPC title

• C07C49/573

  containing hydroxy groups · CPC title

• C07C49/577

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C49/733 Primary

  having two rings · CPC title