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Title:
DECALIN DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF
Document Type and Number:
WIPO Patent Application WO/2020/084633
Kind Code:
A1
Abstract:
The present invention relates to decalin derivative compounds of formula (I), a process for preparation and a pharmaceutical composition thereof. The present invention further relates to a method for treating blood related disorders, preferably sickle cell anemia in a subject in need thereof using compound of formula (I).

Inventors:
REDDY DUMBALA SRINIVASA (IN)
KULKARNI KIRAN ASHOK (IN)
KALMODE HANUMAN POPAT (IN)
ATHAWALE PARESH RAMESH (IN)
PATIL SUHAG SANJAY (IN)
RAJPUT RAVEENA VIJAY (IN)
MANKAD YASH JIGNASU (IN)
PATIL NAMRATA NANDKISHOR (IN)
Application Number:
PCT/IN2019/050779
Publication Date:
April 30, 2020
Filing Date:
October 22, 2019
Export Citation:
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Assignee:
COUNCIL SCIENT IND RES (IN)
International Classes:
A61K9/00; C07C35/00
Foreign References:
US5571939A1996-11-05
US3989739A1976-11-02
EP0296564A21988-12-28
EP2067763A22009-06-10
Other References:
HARING HG ET AL.: "Olfactory studies on enantiomeric eremophilane sesquiterpenoids", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 20, no. 5, May 1972 (1972-05-01), pages 1018 - 1021, XP055708827
Attorney, Agent or Firm:
REMFRY & SAGAR (IN)
Download PDF:
Claims:
Claims

1. A decalin derivative compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein,

R1, R2, R4, R5, R7, R8, R9 and R10 represents independently of each other hydrogen, or (un)substituted or substituted Ci-Cio alkyl, Ci-Cio alkenyl (un)substituted or substituted with hydroxy, alkoxy, ester, -OTBS; or amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylic, alkoxy, carbamide, carbamate, hydrazine , or Ri to Rio may form a (un)substituted or substituted fused cyclic ring;

R3 and R6 represent hydrogen or oxygen;

R7 or R8 and R9 or R10 may form epoxide ring;

' . ' represents a single or double bond;

wherein compound of formula (I) is for cell-adhesion inhibition activity.

2. The decalin derivative compound of formula (I) as claimed in claim 1, is selected from the group consisting of 2-((4aS*,8R*,8aS*)-8,8a-Dimethyl-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)allyl acetate (l2a), 2-((4aS,8R,8aS)-8,8a-Dimethyl-3-oxo- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)allyl acetate (13),

( 1 aR* ,3 aS * ,7R* ,7aS * ,7bR* )- 1 a-(3 -Hydroxyprop- 1 -en-2-yl)-7 ,7 a- dimethyloctahydronaphth- o[l,2-b]oxiren-2(laH)-one (14),

( 1 aS * ,2S * ,3 aS * ,7R* ,7aS * ,7bR* )- 1 a-(3 -hydroxyprop- 1 -en-2-yl)-7 ,7 a- dimethyldecahydronaphtho[l,2-b] oxiren-2-ol (15), (4aS*,5R*,8aS*)-3-iodo-4a,5- dimethyl-4a,5,6,7,8,8a-hexahydronaphthalen-2(lH)-one (17), (4aS*,5R*,8aS*)-3-(3- ((tert-butyldimethylsilyl)oxy)prop-l-en-2-yl)-4a,5-dimethyl-4a,5,6,7,8,8a- hexahydronaphthalen-2(lH)-one (18), (4aS*,5R*,8aS*)-3-(3-hydroxyprop-l-en-2-yl)- 4a,5-dimethyl-4a,5,6,7,8,8a-hexahydronapht- halen-2(lH)-one (19), (4R,4aS)-7,8- dihydroxy-4, 4a-dimethyl-4, 4a, 5, 6, 7, 8-hexahydronaphthalen-2(3H)-one (27),

(4R,4aS)-6,7-dihydroxy-4,4a-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one

(28).

3. A process for the preparation of decalin derivative compound of formula (I) as claimed in claim 1, wherein said process comprises the steps of:

a) protecting and following allylic oxidation of A5 to afford A6;

b) epoxidating and deprotecting A6 to afford A7 ; and

c) reducing A7 to afford A8 and its analogues

4. A process for the preparation of decalin derivative compound of formula (I) as claimed in claim 1, wherein said process comprises the steps of:

a) halogenating A9 to afford A 10;

b) carrying Suzuki Coupling on A10 to afford Al l;

c) forming epoxide on Al 1 to afford A12; and

d) reducing A 12 to afford A13.

5. A process for the preparation of decalin derivative compound of formula (I) as claimed in claim 1, wherein said process comprises the steps of:

a) undergoing Ozonolysis A 14 to afford A 15;

b) rearranging A15 to afford A 16;

c) reducing and protecting A16 to afford A 17; d) epoxidating and reducing A 17 to afford A18;

e) oxidating, deprotecting and rearranging A 18 to afford A 19;

f) hydrogenating A 19 to afford A20 and

g) oxidating A20 to afford A21.

6. A process for the preparation of decalin derivative compound of formula (I) as claimed in claim 1, wherein said process comprises the steps of:

a) dihydroxylating compound A22 to afford compound A23 or compound A24 to afford compound A25;

7. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or a stereoisomer, or ester or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

8. The pharmaceutical composition as claimed in claim 7, wherein said composition is for treating blood related disorders, preferably sickle cel] anemia in a subject in need thereof; comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description:
DECALIN DERIVATIVES, A PROCESS FOR THE PREPARATION AND

PHARMACEUTICAL COMPOSITION THEREOF

FIELD OF THE INVENTION:

The present invention relates to decalin derivatives. More particularly, the present invention relates to decalin derivative compounds of formula (I), a process for preparation and a pharmaceutical composition thereof. The present invention further relates to a method for treating blood related disorders, preferably sickle cell anemia in a subject in need thereof using compound of formula (I).

BACKGROUND AND PRIOR ART OF THE INVENTION:

Sickle cell anemia (SCA) is a genetic disorder in which the red blood cells assume a sickle shape instead of a normal disc shape. It occurs due to a mutation in which the amino acid glutamic acid is replaced by valine in the b-globin chain of hemoglobin. The sickle cell patient may suffer from pain, anemia, bacterial infections or stroke at different stages of his life. Treatment of SCA complications often includes antibiotics, pain management, intravenous fluids, blood transfusion and surgery. One of the complications of SCA is a painful condition called vaso-occlusion. The defective RBC’s are more rigid and obstruct blood vessels resulting in restrict blood flow to the organs leading to multiple issues. The tendency of sickle RBC’s to adhere to vascular endothelium is the root cause of vaso- occlusion. The adhesivity of theses defective RBC’s is directly co-related with the severity of the disease. Some drugs targeting cell adhesion are under development for SCA are Rivipansel (Phase III); Propranolol, Sevuparin (Phase II). Along these lines, peribysins were isolated from a strain of Periconia byssoides OUPS-N133 originally separated from the sea hare, Aplysia kurodai by Yamada’s group showed potent cell-adhesion inhibitory activity when they assayed using human leukemia HL60 cells to human umbilical vein endothelial cells (HUVECs). They are useful leads for the control of cancer metastasis and inflammation. Attempts have been made to isolate or synthesize cell-adhesion inhibitors in the literature.

The article titled“Absolute stereo structures of cell-adhesion inhibitors, macrosphelides C, E-G and I, produced by a Periconia species separated from an Aplysia sea hare” by Takeshi Yamada et. al and published in the journal“J. Chem. Soc., Perkin Trans. 1, 2001, 3046 3053” reports isolation of Macrosphelides E-I, along with known macrosphelides A and C, from a strain of Periconia byssoides originally separated from the sea hare Aplysia kurodai, and the elucidation of absolute stereo structures of macrosphelides E-G.

The article titled“Absolute Stereo structures of Cell-adhesion Inhibitors, Peribysins A, E, F and G, Produced by a Sea Hare-derived Periconia sp.” by Takeshi Yamada et al and published in the journal“J Antihiot. 58(3): 185-191, 2005” reports isolation of Peribysins E~G (1-3) from a strain of Periconia byssoides originally separated from the sea hare Aplysia kurodai and elucidation of their absolute stereo structures.

Thus, isolation and elucidation of naturally occurring potent cell adhesion inhibitors Peribysin were reported in the literature.

Therefore, thus there is a need in the art for identifying and developing new cell adhesion inhibitors based on decalin (6,6-fused rings) (6,5-fused rings) scaffolds for treating sickle cell anemia and other blood related disorders.

OBJECTIVES OF THE INVENTION:

The main objective of the present invention is to provide decalin derivative of formula (I), or a pharmaceutically acceptable salt thereof.

Another objective of the present invention is to provide a process for the preparation of decalin derivative of formula (I).

Yet another objective of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

Still another objective of the present invention is to provide a method for treating blood related disorders, preferably sickle cell anemia in a subject in need thereof; comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION:

In accordance with the above objectives, the present invention provides decalin derivatives of formula (I), a process for preparation and pharmaceutical composition thereof.

In an aspect, the present invention provides decalin derivatives of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein,

R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 and R 10 represents independently of each other hydrogen, or (un)substituted or substituted Ci-Cio alkyl, Ci-Cio alkenyl (un)substituted or substituted with hydroxy, alkoxy, ester, -OTBS; or amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylic, alkoxy, carbamide, carbamate, hydrazine, or Ri to Rio may form a (un)substituted or substituted fused cyclic ring;

R 3 and R 6 represent hydrogen or oxygen;

R 7 or R 8 and R 9 or R 10 may form epoxide ring;

' . ' represents a single or double bond;

In another aspect, the present invention provides a process for the preparation of decalin derivatives of formula (I).

In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

In still another aspect, the present invention provides a method for treating blood related disorders, preferably sickle cell anemia in a subject in need thereof; comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In the view of above, the present invention provides decalin derivative of formula (I) or a pharmaceutically acceptable salt thereof, a process for preparation thereof, and use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the treating blood related disorders, preferably sickle cell anemia.

In an embodiment, the present invention provides decalin derivative compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein,

R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 and R 10 represents independently of each other hydrogen, or (un)substituted or substituted Ci-Cio alkyl, Ci-Cio alkenyl (un)substituted or substituted with hydroxy, alkoxy, ester, -OTBS; or amino, halo, hydroxyl, carbonyl, thiocarbonyl, carboxylic, alkoxy, carbamide, carbamate, hydrazine , or Ri to Rio may form a (un) substituted or substituted fused cyclic ring;

R 3 and R 6 represent hydrogen or oxygen;

R 7 or R 8 and R 9 or R 10 may form epoxide ring;

' . ' represents a single or double bond; In a preferred embodiment, the decalin derivatives of formula (I) is selected from the group consisting of l-((4aR*,8R*,8aS*)-8,8a-Dimethyl-3,4,4a,7,8,8a-hexahydronaph thalen-2- yl)ethan-l-one (9), l-((4aS*,8R*,8aS*)-8,8a-Dimethyl-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)ethan-l-one (10), (lR*,4aS*,8aS*)-l,8a-Dimethyl-7-(prop-l-en-2- yl)-l,2,3,4,4a,5,6,8a-octahydronaphthalene (11), 2-((4aS*,8R*,8aS*)-8,8a-Dimethyl-

3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)prop-2-en-l-ol (12), 2-((4aS*,8R*,8aS*)-8,8a- Dimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)allyl acetate (l2a), 2-((4aS,8R,8aS)- 8,8a-Dimethyl-3-oxo-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2- yl)allyl acetate (13), ( 1 aR* ,3 aS * ,7R* ,7aS * ,7bR* )- 1 a-(3 -Hydroxyprop- 1 -en-2-yl)-7 ,7 a-dimethyloctahydronaphth- o[l,2-b]oxiren-2(laH)-one (14), (laS*,2R*,3aS*,7R*,7aS*,7bR*)-la-(3-Hydroxyprop-l-en- 2-yl)-7,7a-dimethyldecahydrona- phtho[l,2-b]oxiren-2-ol (1) and

( 1 aS * ,2S * ,3 aS * ,7R* ,7aS * ,7bR* )- 1 a-(3 -hydroxyprop- 1 -en-2-yl)-7 ,7 a- dimethyldecahydronaphtho[l,2-b] oxiren-2-ol (15), peribysin A, (4aS*,5R*,8aS*)-3-iodo- 4a,5-dimethyl-4a,5,6,7,8,8a-hexahydronaphthalen-2(lH)-one (17), (4aS*,5R*,8aS*)-3-(3-

((tert-butyldimethylsilyl)oxy)prop-l-en-2-yl)-4a,5-dimeth yl-4a,5,6,7,8, 8a- hexahydronaphthalen-2(lH)-one (18), (4aS*,5R*,8aS*)-3-(3-hydroxyprop-l-en-2-yl)-4a,5- dimethyl-4a,5,6,7,8,8a-hexahydronapht- halen-2(lH)-one (19), (4R,4aS)-4,4a-dimethyl- 4,4a,5,6-tetrahydronaphthalen-2(3H)-one (21), tert-butyl(((4R,4aS)-4,4a-dimethyl- 2,3,4,4a,5,6-hexahydronaphthalen-2-yl)oxy)dimethylsil-ane, (4aS,5R)-4a,5-dimethyl-

4,4a,5,6-tetrahydronaphthalen-2(3H)-one (24), (4R,4aS)-7,8-dihydroxy-4,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (27), (4R,4aS)-6,7-dihydroxy-4,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (28), (8R,8aS)-8,8a-dimethyl- 1,7, 8,8a- tetrahydronaphthalene-2,6-dione (29) and (lS,8aS)-l,8a-dimethyl-l,7,8,8a- tetrahydronaphthalene-2 , 6-dione (30).

In another embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Reacting Lewis acid, base with compound of Al and aldehyde to afford compound A2;

b) Hydrogenating A2 to afford A3;

c) Undergoing A3 in Witting reaction to afford A4;

d) Carrying allylic oxidation on A4 to afford A5;

e) Protecting and following allylic oxidation of A5 to afford A6;

f) Epoxidating and deprotecting A6 to afford A7 and

g) Reducing A7 to afford A8 and its analogues.

The process for the preparation of decalin derivatives of formula (I) is as depicted in scheme 1 below:

Wh f ir-E :> -· *J

Scheme 1: General synthetic scheme

In a preferred embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Adding BF 3 OEt 2 dropwise at -78 °C to -80 °C to the reaction mixture of diene (Al) and (£)-2-mcthylbut-2-cnal or (Z)-2-methylbut-2-enal in dry solvent to afford resultant mixture; stirring the resultant mixture at temperature in the range of 30 to 35°C for the time period in the range of 12 to 14 hours to afford compound A2;

b) Hydrogenating A2 with the help of a catalyst selected from (PPh 3 ) 3 RhCl, Pd/C with H 2 or Pd/C with ammonium formate in dry solvent at temperature range of 30°C to 35°C for time period in the range of 12 to 14 hours to afford compound A3;

c) Adding base selected from potassium ieri-butoxide, NaH or n-BuLi to methyl triphenylphosphonium bromide or chloride in dry THF at temperature range in the range of 0 to -5°C to afford canary yellow color solution adding enone A3 in THF to this canary yellow color solution followed by stirring the resultant reaction mixture at temperature range for 0 to -5°C for the time period 1 to 2 hours to afford compound A4;

d) Adding TBHP and Se0 2 or TBHP and Mn0 2 or Pd(OH) 2 and TBHP to a solution of diene A4 in suitable solvent followed by stirring at temperature 30°C to 35°C for the time period in the range of 6 to 7 hours to afford crude product; adding CeCl 3 -7H 2 0 into solution of crude product in alcohol to form resultant reaction mixture; cooling resultant reaction mixture at the temperature ranging from -78°C to 80°C; adding NaBH 4 or LiBH 4 to the cooled reaction mixture and followed by stirring at temperature ranging from -78°C to 80°C for the time period ranging from 30 to 45 minutes to afford compound A5;

e) Adding acetylating agents selected from acetic anhydride, acetyl Chloride in the presence of a base selected from pyridine, tri ethyl amine, or DMAP into solution of A5 in a solvent followed by stirring at temperature in the range of 30 to 35°C for the time period in the range of 1 to 2 hours to afford compound diene acetate; adding PDC and TBHP or Cr0 3 and pyridine or TBHP and (MnOAc) 3 to a solution of diene acetate in solvent followed by stirring at temperature in the range of 30 to 35°C for the time period in the range of 6 to 7 hours to afford dienone acetate compound A6; f) Adding hydrogen peroxide and sodium hydroxide to a solution of A6 in methanol followed by stirring the reaction mixture at temperature in the range of 30 to 35°C for the time period in the range of 6 to 7 hours to afford compound A7 and

g) Adding NaBH 4 in the solution of epoxy alcohol in solvent followed by stirring the reaction mixture at temperature in the range of 0°C to -5°C for the time period in the range of 1 to 2 hours to afford compound A8.

The solvent used in step (a) to (g) is selected from THF, CH 2 Cl 2 , Et 2 0, CH 3 CN, toluene, 1,2- DCE, DMSO, t-butanol or methanol

In still another embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Halogenating A9 to afford A 10;

b) Carrying Suzuki Coupling on A10 to afford Al l;

c) Epoxidating Al 1 to afford A 12 and

d) Reducing A 12 to afford A13.

The process for the preparation of decalin derivatives of formula (I) is as depicted in scheme 2 below:

Scheme 2: Alternate synthetic scheme

In a preferred embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Adding iodine and base in enone A9 in suitable solvent followed by stirring the resultant reaction mixture at temperature in the range of 25 °C to 30°C for the time period in the range of 24 to 30 hours to afford A 10;

b) Adding Pd(PhCN) 2 Cl 2 to a mixture of vinyl iodide A10, alkenyl boronate, Ag 2 0, triphenyl arsine in a solvent followed by stirring the reaction mixture at temperature 30°C to 35°C for the time period in the range of 4 to 5 hours to afford Al l;

c) Adding NaBH 4 or LiBH 4 to compound A12 in methanol at 0 °C and stirring for 30 min to afford A13.

The solvent used for steps (a) to (c) is selected from THF, CH 2 Cl 2 , Et 2 0, CH 3 CN, toluene, l,2-DCE, DMSO, t-butanol or methanol

In still yet another embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Undergoing Ozonolysis A14 to afford A15;

b) Rearranging A15 to afford A 16;

c) Reducing and protecting A16 to afford A 17;

d) Epoxidating and reducing A 17 to afford A18;

e) Oxidating, deprotecting and rearranging A18 to afford A 19;

f) Hydrogenating A19 to afford A20 and

g) Oxidating A20 to afford A21. The process for the preparation of decalin derivatives of formula (I) is as depicted in scheme 3 below:

Scheme 3: Scheme for the enantiopure compounds

In a preferred embodiment, the present invention provides a process for the preparation of decalin derivatives of formula (I) comprising the steps of:

a) Bubbling ozone in the reaction mixture (+)-nootkatone in methanol at temperature ranging from -35°C to -40°C, adding Cu(0Ac) 2 .H 2 0 or Cu(BF 4 ) 2 in water and FeS0 4 .7H 2 0 or Fe(BF 4 ) 2 in water keeping the reaction mixture below -lO°C to -20°C followed by stirring the reaction mixture at temperature in the range of 30°C to 35°C for time period in the range of 1 to 2 hours to afford crude product A 15,

b) Adding base selected from DBU, Et 3 N, diisopropylethyl amine or N-methyl morpholine in solution of crude product A15 in solvent followed by stirring at temperature in the range of 30°C to 35°C for time period in the range of 4 to 5 hours to afford compound A 16;

c) Adding CeCl 3 -7H 2 0 Or without CeCl 3 -7H 2 0 in dienone A16 in alcohol to afford reaction mixture, adding NaBH 4 in reaction mixture to afford allylic alcohol, dissolving allylic alcohol in solvent, adding imidazole followed by adding base selected from Et 3 N or DMAP, and further adding TBSC1 or TBSOTf followed by stirring for time period in the range of 12 to 14 hours to afford TBS diene A 17;

d) Adding m-CPBA or peracetic acid to a solution of TBS diene in solvent followed by stirring at temperature in the range of 0°C to -5°C for time period in the range of 30 min to 45 min to afford crude epoxide product, adding LAH LiBH 4 , NaBH 4 or DIBAL-H in solution of crude epoxide product in solvent followed by stirring the reaction mixture at temperature in the range of 0°C to -5°C for time period in the range of 1 to 2 hours to afford crude alcohol compound A 18;

e) Adding NaHC0 3 and DMP , pyridinium dichromate (PDC) or pyridinium chloro chromate (PCC) to a solution of crude alcohol compound A18 in solvent followed by stirring at temperature in the range of 30°C to 35°C for time period in the range of 2 to 3 hours to afford crude TBS ketone, adding PTSA.H 2 0 or Camphorsulphonic acid to a solution of the ketone in a solvent followed by refluxing at temperature in the range of 40°C to 45°C for time period in the range of 1 to 2 hours to afford (-)- dienone compound A 19;

f) Adding 1% methanolic KOH solution to crude A19 followed by Pd/C and stirring under hydrogen atmosphere for 12 hours at 25 to 30 °C to provide A20. And g) adding IBX to A20 in DMSO and catalytic TFA at 60 °C and stirring for 2 hours to provide A21, and processing A 2l;optionally Dihydroxylating A22 or A24 by OSO4, NMO and t-BuOH , AD-mix alpha or AD-mix beta at temperature in the range of 0°C to -5°C for time period in the range of 2 to 3 hours to afford A23 or A25 respectively;

The solvent used for steps (a) to (h) is selected from THF, CH2CI2, Et 2 0, CH3CN, toluene, l,2-DCE, DMSO, t-butanol or methanol

Preparation of A23, and A25 are as shown in scheme 4.

Scheme 4: Synthesis of enantiopure analogs

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. In still another embodiment, the present invention provides a method for treating blood related disorders preferably sickle cell anemia in a subject in need thereof; comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,

In another embodiment, the present invention relates to administering 'an effective amount' of the 'composition of invention ' to the subject suffering from said disease. Accordingly, compound of formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms. In still yet another embodiment, the present invention provides Sickle cell adhesion inhibition using Sickle cell red blood cells (SS RBCs). Flow adhesion assay are performed with commercial microfluidic-well plate and microfluidic flow adhesion system. Microfluidic channels are coated by perfusion (ldyne/cm 2 , 5 min) and incubated (37 ° C, lh) with lOOng/ml Fibronectin. Channels are then perfused with complete media to remove unbound Fibronectin. Then a uniform monolayer of HUVEC cells is formed by profusing micro channels with the cell suspension at a pressure of 3dyne/cm 2 for 5 sec and kept for 12 hours incubation to form monolayer. The HUVEC monolayer is activated 25ng/ml of TNF-a and incubated (37 ° C, 4h). Meanwhile Sickle cell red blood cell (SS RBCs) are treated with test compound at 100 mM concentration and incubated in hypoxic condition (3% nitrogen, 5% C0 2 , 2h). Flow condition for adhesion assay was pulsatile (1.67 Hz) flow (0.3 dyne/cm 2 ). For adhesion inhibition assay SS RBCs are diluted (2:50) in PBS. SS RBCs are perfused over HUVEC monolayer and incubated for lh. Unbound cells in micro channels are removed by perfusing complete media. Adherent cells are enumerated. Table 1 depicts percentage of inhibition. Table 1 depicts percentage of inhibition when the compounds are tested at 100 mM concentration.

Table 1

EXAMPLES:

Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Example 1: synthesis of l-((4a/?*,8/?*,8aS*)-8,8a-Dimethyl-3,4,4a,7,8,8a- hexahydronaphthalen-2-yl)ethan-l-one (9) :

To a solution of diene (7 g, 0.050 mol) and tiglic aldehyde (12.2 mL, 0.126 mol) in dry CH 2 Cl 2 (300 mL) was added BF 3 OEt 2 (12.5 mL, 0.101 mol) dropwise at -78 °C. The mixture was allowed to stir at 30°C for a period of 12 h. After complete consumption of starting material checked by TLC, the CH2CI2 layer was washed with saturated aqueous NaHC0 3 solution (3 x 50 mL) followed by H2O (50 mL) and brine (50 mL), dried over anhydrous Na 2 S0 4 , concentrated in vacuo. The crude material obtained after the removal of solvent was dissolved in methanol (50 mL), cooled to 0 °C, followed by the dropwise addition of 15% aqueous KOH (30 mL) solution. After stirring for 6 h at room temperature, reaction mass was diluted with petroleum ether (300 mL), washed with water (50 mL), 1N HC1 (50 mL) and brine (50 mL), dried over anhydrous Na 2 S0 4, concentrated in vacuo. Purification by flash column chromatography over silica gel (0.5:9.5; EtOAc-petroleum ether) afforded dienone (9, 4.76 g, 46%). Data for dienone (9): Light yellow oil; IR max(film): 1665, 1637, 1452, 1237 cm 1 ; ¾ NMR (500 MHz, CDCh) d 6.64 (s, 1 H), 5.60-5.56 (m, 1 H), 5.53-5.48 (m, 1 H), 2.28 (s, 3 H), 2.12-2.00 (m, 2 H), 1.93-1.88 (m, 2 H), 1.90-1.63 (m, 3 H), 1.43 (ddd, J = 18.9, 9.15, 5.49 Hz, 1 H), 1.00 (s, 3 H), 0.96 (d, J = 6.4 Hz, 3 H); 13 C NMR (125 MHz, CDCb) d 198.0, 149.3, 137.8, 130.1, 125.5, 40.4, 37.3, 34.2, 31.6, 25.6, 25.5, 22.6, 21.1, 15.1; HRMS (ESI) calc for C I4 H 2I O [M+H] + 205.1587, found 205.1586.

Example 2: synthesis of l-((4aS*,8/?*,8aS*)-8,8a-Dimethyl-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)ethan-l-one (10):

The dienone (9, 4.5 g, 0.022 mol) and Wilkinson’s catalyst [(PPh 3 ) 3 RhCl] (2 g, 2.205 mmol) were placed in an oven-dried round bottom flask. Dry benzene (100 mL) was added via syringe, the flask was then flushed with hydrogen gas to expel the argon. The reaction was allowed to proceed at 30°C under hydrogen balloon pressure for 12 h. Upon completion of reaction (monitored by TLC), the mixture was passed through an alumina column and concentrated. Purification by flash chromatography over silica gel (0.5:9.5; EtOAc- petroleum ether) afforded enone (10, 3.9 g) in 86% yield.

Data for enone (10): Colorless liquid; IRt)max (film): 2926, 2864, 1667, 1634, 1456, 1379, 1266, 1234, 1029, 930, 757 cm 1 ; 3 H NMR (400 MHz, CDCb) d 6.73 (s, 1H), 2.39 (dd, J = 18.0, 3.5 Hz, 1H), 2.26 (s, 3H), 2.10-2.01 (m, 1H), 1.83- 1.65 (m, 3H), 1.45 (dd, / = 9.3, 4.1 Hz, 3H), 1.39-1.36 (m, 2H), 1.29-1.25 (m, 1H), 1.23-1.19 (m, 1H), 1.01 (s, 3H), 0.87 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 200.2, 151.0, 137.3, 39.5, 38.3, 36.5, 31.1, 28.0, 25.5, 23.9, 23.6, 21.2, 20.8, 16.0; HRMS (ESI) calc for C14H23O [M+H] + 207.1743, found 207.1744.

Example 3: synthesis of (l/?*,4aS*,8aS*)-l,8a-Dimethyl-7-(prop-l-en-2-yl)- l,2,3,4,4a,5,6,8a-octahydronaphthalene (11):

To a suspension of methyl triphenylphosphonium bromide (17.8 g, 0.047 mol) in dry THF (60 mL) was added potassium ieri-butoxide (5.3 g, 0.047 mol) at 0 °C. After 5 minutes, the solution became canary yellow color, to that enone (10, 3.9 g, 0.018 mol) in THF (60 mF) was added and allowed to stirred at 0 °C for 1 h. The reaction was quenched with ice cold H 2 0 and extracted with diethyl ether (2 x 60 mF). Combined organic layer was washed with water (40 mF), brine (40 mF) and dried over anhydrous Na 2 S0 4, concentrated in vacuo. Purification by flash chromatography over silica gel (1:9; EtOAc- petroleum ether) afforded diene (11, 3.3 g, 85%).

Data for diene (11): Colorless oil; IRumax (film): 3020, 2927, 1654, 1625, 1215, 1038, 760, 667 cm 1 ; 3 H NMR (400 MHz, CDCb) d 5.77 (s, 1H), 4.98 (s, 1H), 4.86 (s, 1H), 2.32 (dd, J = 16.4, 4.3 Hz, 1H), 2.18 (dd, / = 16.8, 9.8 Hz, 1H), 1.92 (s, 4H), 1.77-1.65 (m, 2H), 1.47- 1.37 (m, 5H), 1.33-1.21 (m, 2H), 0.98 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 144.1, 136.3, 134.1, 110.2, 40.0, 37.4, 36.8, 31.2, 28.3, 26.1, 24.7, 21.6, 21.4, 21.0, 16.1; HRMS (ESI) calc. for Ci 5 H 25 [M+H] + 205.1958, found 205.1960.

Example 4: synthesis of 2-((4aS*,8/?*,8aS*)-8,8a-Dimethyl-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)prop-2-en-l-ol (12):

To a solution of diene (11, 3.3 g, 16.17 mmol) in CH 2 C1 2 (120 mF) at 0 °C was added TBHP (5.0-6.0 M in decane, 5.3 mF, 32.35 mmol) and Se0 2 (0.95 g, 8.085 mmol). Then the reaction was allowed to warm to 30°C and stirred for 6 h, before it was quenched with saturated aqueous Na 2 S 2 0 3 (80 mF) solution at 0 °C. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (4 x 40 mL). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford crude product as mixture.

To a solution of the above crude mixture in CH 2 Cl 2 (60 mL) and MeOH (60 mL) at rt was added CeCl 3 -7H 2 0 (12.1 g, 32.35 mmol). After it was cooled to -78°C, NaBH 4 (1.2 g, 32.35 mmol) was added slowly to the reaction mixture and it was stirred at -78 °C for 30 min. The reaction was quenched with saturated aqueous NH 4 Cl (40 mL) solution at 0 °C and the mixture was concentrated under reduced pressure, filtered through a pad of Celite and washed with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (4 x 60 mL). Then the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (6:1; petroleum ether-EtOAc) to provide allyl alcohol (12, 2.4 g) in 67% yield over 2 steps.

Data for allyl alcohol (12): Colorless oil; IRt)max (film): 3416, 2927, 2866, 1669, 1454, 1376, 1220, 1041, 761, 665 cm 1 ; *H NMR (400 MHz, CDCh) d 5.79 (s, 1H), 5.12 (d, / = 4.9 Hz, 2H), 4.34 (s, 2H), 2.27 (dd, / = 16.5, 4.6 Hz, 1H), 2.20-2.12 (m, 1H), 1.91 (ddd, / = 18.4, 12.7, 5.9 Hz, 1H), 1.78-1.65 (m, 3H), 1.47-1.45 (m, 3H), 1.38 (d, / = 13.7 Hz, 2H), 1.26- 1.16 (m, 2H), 0.96 (s, 3H), 0.84 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 147.5, 136.1, 131.7, 110.1, 64.4, 39.9, 37.4, 36.8, 31.1, 28.2, 26.4, 24.4, 21.5, 21.3, 16.1; HRMS (ESI) calc for Ci 5 H 23 0 [M-H] 219.1743, found 219.1743.

Example 5: synthesis of 2-((4aS*,8/?*,8aS*)-8,8a-Dimethyl-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)allyl acetate: (12a)

To a solution of compound allyl alcohol 12 (2.0 g, 9.09 mmol) in CH 2 Cl 2 (60 mL) at 0 °C was added DMAP (2.2 g, 18.18 mmol) and Ac 2 0 (3.4 mL, 36.3 mmol). Then the reaction was allowed to warm to 30°C and stirred for 1 h, before it was quenched with saturated aqueous NaHC0 3 (20 mL) solution at 0 °C. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 30 mL). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford diene acetate (1.90 g) in 80% yield. Data for diene acetate: Yellowish oily liquid; IRumax (film): 3022, 2928, 2865, 1732, 1605, 1452, 1375, 1220, 1033, 761 cm- 1 ; ¾ NMR (400 MHz, CDCb) d 5.71 (s, 1H), 5.17 (s, 1H), 5.11 (s, 1H), 4.77 (dt, / = 18.5, 12.9 Hz, 2H), 2.29-2.23 (m, 1H), 2.15 (ddd, / = 12.1, 9.6, 6.4 Hz, 1H), 2.07 (s, 3H), 1.93-1.88 (m, 1H), 1.76-1.63 (m, 2H), 1.48-1.43 (m, 3H), 1.36 (dd, / = 10.1, 6.8 Hz, 2H), 1.27-1.18 (m, 2H), 0.94 (s, 3H), 0.82 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 170.9, 142.7, 136.8, 131.3, 112.6, 65.6, 39.9, 37.5, 36.7, 31.1, 28.2, 26.2, 24.4, 21.5, 21.3, 21.1, 16.0; HRMS (ESI) calc for C17H27O2 [M+H] + 263.2013, found 263.2015.

Example 6: synthesis of 2-((4aS,8/?,8aS)-8,8a-Dimethyl-3-oxo-3,4,4a,5,6,7,8,8a- octahydronaphthalen-2-yl)allyl acetate (13):

To a solution of the diene acetate (1.0 g, 3.81 mmol) in benzene 60 mL at 0 °C were added PDC (7.12 g, 19.08 mmol) and TBHP (5.0-6.0 M in decane, 2.45 mL, 19.08 mmol). After the reaction mixture was stirred for 15 min, it was brought to 30 deg C and further stirred for 6 h. The reaction mixture was diluted with ethyl acetate (40 mL), filtered through a pad of celite, and washed with ethyl acetate (2 x 10 mL). The obtained filtrate was concentrated in vacuo and purified by flash column chromatography over silica gel (2:8; EtO Ac -petroleum ether) afforded dienone acetate (13, 0.245 g, 43% brsm) and recovered diene acetate (0.455 g).

Data for dienone acetate (13): Colorless oil; IRt)max (film): 3026, 2930, 2868, 1735, 1668, 1607, 1456, 1377, 1222, 1035, 957, 768 cm 1 ; ¾ NMR (400 MHz, CDCb) d 6.69 (s, 1H), 5.23 (s, 1H), 5.18 (s, 1H), 4.74 (q, / = 13.1 Hz, 2H), 2.67 (dd, / = 17.0, 12.3 Hz, 1H), 2.26 (dd, / = 17.0, 4.3 Hz, 1H), 2.08-2.02 (m, 1H), 1.99 (s, 3H), 1.80 (ddd, / = 13.6, 6.8, 3.4 Hz, 1H), 1.76-1.67 (m, 1H), 1.56-1.51 (m, 1H), 1.48-1.42 (m, 2H), 1.36-1.31 (m, 2H), 1.11 (s, 3H), 0.91 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 198.8, 170.5, 158.8, 141.6, 136.3, 117.0, 66.1, 40.0, 39.6, 39.1, 35.9, 30.2, 27.0, 20.9, 20.7, 20.4, 15.9; HRMS (ESI) calc for C17H25O3 [M+H] + 277.1805, found 277.1804.

Example 7: synthesis of (la/?*,3aS*,7/?*,7aS*,7b/?*)-la-(3-Hydroxyprop-l-en-2-yl)- 7,7a-dimethyloctahydronaphth- o[l,2-Z>]oxiren-2(lai/)-one (14):

To a mixture of dienone acetate (13, 0.110 g, 0.398 mmol) in MeOH (15 mL) was added hydrogen peroxide (30% aqueous solution, 0.30 mL, 3.188 mmol), 10% aq. sodium hydroxide (0.25 mL) solution dropwise at 0 °C. The reaction mixture was allowed to warm gradually to 30°C. After 4 h, more 10% aq. sodium hydroxide (0.750 mL) was added and stirred for additional 2 h. The reaction mixture was filtered, followed by addition of 5 mL saturated aqueous NaHC0 3 solution and extracted with EtOAc (3 x 10 mL). The organic extracts were washed with brine (5 mL), dried over Na 2 S0 4 , and concentrated to afford crude product. Which was purified by flash column chromatography over silica gel (2:8; ethyl acetate-petroleum ether) to obtained epoxy alcohol (14) as inseparable mixture as a yellowish solid (0.083 g, 83%).

Data for epoxy alcohol (14): Yellowish solid; mp 86-88 °C (decomp.); IRt)max (film): 3411, 2926, 2864, 1702, 1453, 1378, 1024, 912, 762 cm 1 ; *H NMR (400 MHz, CDCb) d 5.33 (s, 1H), 5.26 (s, 1H), 5.10 (s, 1H), 5.04 (s, 1H), 4.70 (d, J = 13.3 Hz, 1H), 4.50 (d, J = 13.3 Hz, 1H), 4.28 (d, J = 12.8 Hz, 1H), 4.18 (d, J = 13.0 Hz, 1H), 3.36 (s, 1H), 3.28 (s, 1H), 2.93 (s, 1H), 2.45 (dd, / = 18.8, 11.3 Hz, 1H), 2.31 (dd, / = 18.6, 6.7 Hz, 1H), 2.12 (s, 1H), 2.06 (t, / = 13.7 Hz, 1H), 1.74-1.61 (m, 4H), 1.55 (d, / = 14.2 Hz, 1H), 1.49-1.34 (m, 6H), 1.29-1.25 (m, 3H), 1.20 (s, 2H), 1.11 (s, 3H), 0.95 (d, J = 6.7 Hz, 2H), 0.91 (d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 207.0, 143.3, 143.2, 115.8, 106.5, 99.5, 72.3, 71.4, 68.2, 66.7, 64.2, 64.1, 38.7, 37.2, 37.1, 36.3, 33.4, 32.9, 32.2, 30.9, 30.6, 29.9, 26.6, 25.6, 20.5, 19.9, 17.4, 16.7, 16.4, 16.3; HRMS (ESI) calc for Ci 5 H 22 0 3 Na [M+Na] + 273.1461, found 273.1458.

Example 8: synthesis of (laS*,2/?*,3aS*,7/?*,7aS*,7b/?*)-la-(3-Hydroxyprop-l-en-2-yl )- 7,7a-dimethyldecahydrona- phtho[l,2-Z>]oxiren-2-ol (1) and

(laS*,2S*,3aS*,7/?*,7aS*,7b/?*)-la-(3-hydroxyprop-l-en-2- yl)-7,7a- dimethyldecahydronaphtho[l,2-Z>] oxiren-2-ol (15):

To an inseparable mixture of epoxy alcohol (14, 0.050 g, 0.200 mmol) in MeOH (4 mL) was added NaBH 4 (0.019 g, 0.500 mmol) in small portions at 0 °C. The reaction mixture was stirred for 1 h at same temperature, quenched with saturated NH 4 Cl (5 mL) solution and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na 2 S0 4 , filtered and concentrated. The obtained crude product was purified by flash column chromatography (10:90; ethyl acetate-petroleum ether) to afford peribysin A (1, 0.039 g) and its diastereomer (15, 0.005 g) in 88% of total yield.

Data for peribysin A (1): Colourless crystalline solid; mp 98-100 °C; IRtimax (film): 3357, 2929, 2868, 1647, 1453, 1051, 925, 765 cm 1 ; ¾ NMR (500 MHz, CDCb) d 5.31 (s, 1H), 5.20 (s, 1H), 4.32 (d, = 11.7 Hz, 1H), 4.15 (d, / = 11.7 Hz, 1H), 4.01 (d, / = 6.5 Hz, 1H), 3.34 (br s, 2H), 3.17 (s, 1H), 1.95 (s, 1H), 1.81 (d, / = 11.4 Hz, 1H), 1.68 (m, 1H), 1.52-1.44 (m, 4H), 1.33 (br d, / = 13.3 Hz, 1H), 1.25 (m, 2H), 1.05 (s, 3H), 0.94 (d, J = 6.1 Hz, 3H); 13 C NMR (125 MHz, CDCb) d 145.6, 117.3, 69.8, 68.5, 67.2, 64.2, 35.7, 33.1, 32.5, 31.0, 30.7, 26.9, 20.4, 16.6 (2C); HRMS (ESI) calc for Ci 5 H 24 0 3 Na [M+Na] + 275.1618, found 275.1616.

Data for its diastereomer (15): Colourless crystalline solid; low melting solid; IRumax (film): 3382, 2927, 2864, 1647, 1454, 1388, 1071, 1036, 941, 756 cm 1 ; 3 H NMR (400 MHz, CDCb) d 5.21 (s, 1H), 5.15 (s, 1H), 4.31 (dd, J = 13.2, 12.0 Hz, 1H), 4.22 (d, J = 2.9 Hz, 1H), 4.16 (d, / = 13.3 Hz, 1H), 3.23 (s, 1H), 2.67 (s, 1H), 2.00 (td, / = 14.0, 5.3 Hz, 1H), 1.75-1.60 (m, 4H), 1.43 (d, / = 10.2 Hz, 3H), 1.29 (d, / = 14.2 Hz, 3H), 1.09 (s, 3H), 0.92 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 147.5, 114.0, 71.2, 66.6, 65.4, 64.0, 35.8, 32.5, 31.4, 30.8, 30.0, 26.6, 20.5, 17.4, 16.5; HRMS (ESI) calc for Ci 5 H 24 0 Na [M+Na] + 275.1618, found 275.1617.

Example 9: synthesis of (4aS*,5/?*,8aS*)-3-iodo-4a,5-dimethyl-4a,5,6,7,8,8a- hexahydronaphthalen-2(l//)-one (17) :

To a cold solution of enone (16, 0.250 g, 1.40 mmol) in dry dichloromethane (5 mL) at 0 °C was added I 2 (0.712 g, 2.80 mmol) in dichloromethane (5 mL) and pyridine (2.15 mL, 26.64 mmol). The resultant mixture was gradually warmed to 30°C and stirred for 24 h, quenched with saturated Na 2 S 2 0 3 (40 mL) solution and extracted with ethyl acetate (3 x 30 mL). The obtained organic layer was washed with H 2 0 (25 mL), followed by brine (30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (05:95; ethyl acetate -petroleum ether) to afford vinyl iodide (17, 0.362 g, 85%), as a light yellow oil, which solidified upon standing.

Data for vinyl iodide (17): Yellowish solid; mp 80-82 °C; IRtimax (film): 2927, 1681, 1584, 1461, 1322, 1159, 1004, 937, 898, 712 cm 1 ; 3 H NMR (400 MHz, CDCb) d 7.61 (s, 1H), 2.82 (dd, / = 16.9, 12.6 Hz, 1H), 2.49 (dd, / = 17.0, 4.2 Hz, 1H), 2.12 (ddd, / = 12.3, 8.3, 4.0 Hz, 1H), 1.84 (ddd, / = 17.0, 8.5, 5.0 Hz, 1H), 1.77-1.68 (m, 1H), 1.56-1.52 (m, 1H), 1.48 (dd, / = 12.4, 3.6 Hz, 1H), 1.36 (d, / = 3.7 Hz, 1H), 1.33-1.31 (m, 1H), 1.26 (dd, / = 15.2, 3.6 Hz, 1H), 1.13 (s, 3H), 0.93 (d, / = 6.9 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 193.1, 169.6, 102.2, 44.2, 40.0, 38.5, 35.7, 30.2, 27.0, 20.4, 20.2, 16.1. HRMS (ESI) calc for CnHisOI [M+H] + 305.0397, found 305.0393.

Example 10: synthesis of (4aS*,5/?*,8aS*)-3-(3-((tert-butyldimethylsilyl)oxy)prop-l-e n- 2-yl)-4a,5-dimethyl-4a,5,6,7,8, 8a-hexahydronaphthalen-2(l//)-one (18):

To a mixture of vinyl iodide (17, 1.2 g, 3.94 mmol), alkenyl boronate (1.765 g, 5.92 mmol), Ag 2 0 (1.472 g, 6.35 mmol), triphenyl arsine (0.136 g, 0.45 mmol) in THF (37.5 mL) and H 2 0 (4.7 mL) was added Pd(PhCN) 2 Cl 2 (0.152 g, 0.394 mmol) at 30°C and stirred for 4 h under nitrogen in the dark. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) solution and stirred for 30 minutes. The reaction mixture was filtered through a pad of celite followed by extraction with ethyl acetate (3 x 50 mL). The organic extracts were washed with brine (70 mL), dried over Na 2 S0 4 , and concentrated to afford crude product. Which was purified by column chromatography (04:96; ethyl acetate- petroleum ether) to obtained TBS dienone (18, 1.21 g, 88%), as a light yellow oil.

Data for TBS dienone (18): Light yellow oil; IRnmax (film): 2928, 1677, 1462, 1360, 1251, 1082, 902, 833, 774 cm 1 ; ¾ NMR (400 MHz, CDCb) d 6.73 (s, 1H), 5.23 (s, 1H), 5.06 (s, 1H), 4.33-4.25 (m, 2H), 2.69 (dd, / = 16.8, 12.7 Hz, 1H), 2.24 (dd, / = 17.0, 4.2 Hz, 1H), 2.09-2.03 (m, 1H), 1.82 (ddd, / = 10.1, 6.7, 3.3 Hz, 1H), 1.73-1.69 (m, 1H), 1.57-1.52 (m, 1H), 1.49-1.45 (m, 2H), 1.38-1.34 (m, 1H), 1.30 (dd, / = 14.0, 2.9 Hz, 1H), 1.12 (s, 3H), 0.92 (d, / = 6.8 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13 C NMR (100 MHz, CDCb) d 199.3, 158.6, 146.5, 137.2, 113.8, 65.2, 40.1, 39.8, 39.1, 35.8, 30.3, 27.1, 26.0 (3C), 20.7, 20.6, 18.4, 16.1, -5.22 (2C); HRMS (ESI) calc for C 2i H 36 0 2 NaSi [M+Na] + 371.2377, found 371.2372.

Example 11: synthesis of (4aS*,5/?*,8aS*)-3-(3-hydroxyprop-l-en-2-yl)-4a,5-dimethyl- 4a,5,6,7,8,8a-hexahydronapht- halen-2(l//)-one (19):

To a solution of TBS dienone (18, 1.0 g, 2.90 mmol) in anhydrous THF (45 mL) was added TBAF (2.87 mL, 1M in THF, 2.90 mmol) dropwise at 0 °C under nitrogen atmosphere. The resultant mixture was stirred at same temperature for 1 h and quenched with saturated aqueous ammonium chloride (30 mL) solution and extracted with ethyl acetate (3 x 70 mL). The organic extracts were washed with brine (70 mL), dried over Na 2 S0 4 , and concentrated to afford crude product. The obtained crude product was purified by column chromatography (20:80; ethyl acetate-petroleum ether) to obtained dienone alcohol (19, 0.550 g, 82%), as a yellowish oily liquid. Data for dienone alcohol (19): Yellowish oily liquid; IRumax (film): 3419, 2925, 1668, 1459, 1356, 1229, 1038, 985, 904, 723 cm- 1 ; *H NMR (400 MHz, CDCb) d 6.79 (s, 1H), 5.23 (s, 1H), 5.13 (s, 1H), 4.14 (s, 2H), 3.18 (s, 1H), 2.73 (dd, / = 17.0, 12.8 Hz, 1H), 2.28 (dd, / =

17.2, 4.0 Hz, 1H), 2.09-2.05 (m, 1H), 1.84-1.80 (m, 1H), 1.78-1.69 (m, 1H), 1.55 (ddd, / = 11.7, 8.1, 3.8 Hz, 1H), 1.48 (d, / = 1.7 Hz, 1H), 1.45 (s, 1H), 1.38-1.29 (m, 2H), 1.13 (s, 3H), 0.92 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 200.9, 159.8, 146.7, 138.0, 116.9,

65.3, 40.0, 39.7, 39.2, 35.8, 30.2, 27.0, 20.6, 20.5, 16.0; HRMS (ESI) calc for C15H23O2 [M+H] + 235.1693, found 235.1690.

Example 12: synthesis of (4/f,4aS)-4,4a-dimethyl-4,4a,5,6-tetrahydronaphthalen-2(3H)- one (21):

A stirred solution of (+)-nootkatone (10.0 g, 45.87 mmol) in methanol (70 mL) was cooled to -40 °C using dry ice-acetone bath. Ozone was bubbled through the solution keeping the temperature below -35 °C until the starting material was completely consumed monitored by TLC (approx. 40 min). Then the excess ozone was ceased by bubbling oxygen for two minutes followed by purging the nitrogen for 4 min. Then 30% W/V solution of CU(0AC) 2 .H 2 0 (10.9 g, 55.05 mmol) in water FeS0 4 .7H 2 0 (19.2 g, 68.80 mmol) in water were added sequentially over 4 min keeping the reaction temperature below -10 °C. The reaction mixture was allowed to warm to 30°C gradually and stirred for 1 h. After 1 h reaction mixture was filtered through celite and diluted with ethyl acetate (150 mL), washed with water (50 mL), 1N HC1 (50 mL) and brine (40 mL). The crude reaction mixture was dried over anhydrous sodium sulphate concentrated to give pale yellow oil (7.6 g crude) which was used as such for further reaction. To above crude compound (7.6 g, 43.18 mmol) in acetonitrile (80 mL) at 0 °C was added DBU (7.1 mL, 47.5 mmol) and stirred at 30°C for 4 h. Then the acetonitrile was evaporated under reduced pressure and reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL), 1N HC1 (60 mL) and brine (40 mL). The organic layer was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel) (4% EtOAc:pet ether) to give dienone (21), 4.32 g (53% over two steps) as a pale yellow oil and compound. Data for dienone (21): Pale yellow oil;

+ 203.0 (c = 1.0, CHCb); IR t)max(film): 1653, 1618, 1286 cm 1 ; *H NMR (400 MHz , CDCb) d 6.18-6.16 (m, 1H), 6.08 (d, / = 9.5 Hz, 1H), 5.62 (s, 1H), 2.34-2.21 (m, 4H), 2.01- 1.91 (m, 1H), 1.86-1.82 (m, 1H), 1.33-1.25 (m, 1H), 0.95 (s, 3H), 0.91 (d, / = 6.8 Hz, 3H); 13 C NMR (100 MHz , CDCb) d 200.0, 163.4, 137.9, 128.0, 124.0, 42.5, 39.1, 36.4, 32.6, 23.5, 15.5, 14.9; HRMS (ESI) calc for Ci 2 H 17 0 [M+H] + 177.1274, found 177.1273.

Example 13: synthesis of tert-butyl(((4/?,4aS)-4,4a-dimethyl-2,3,4,4a,5,6- hexahydronaphthalen-2-yl)oxy) dimethylsil-ane (22):

A solution of dienone (21, 3.5 g, 19.88 mmol) in MeOH (40 mL) was cooled to 0 °C and added CeCl 3 -7H 2 0 (11.1 g, 29.83 mmol). After stirring the reaction mixture for 10 min, NaBH 4 (1.5 g, 39.772 mmol) was added portionwise over 10 min and the reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched with saturated aqueous NH 4 Cl solution (30 mL) and diluted with EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). Then the combined organic layers were washed with brine (50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure to obtain allylic alcohol (3.5 g crude) as a colourless oil. The obtained crude compound was dissolved in CH 2 Cl 2 (60 mL) and cooled at 0 °C; then imidazole (2.67 g, 39.32 mmol) was added followed by addition of DMAP (0.240 g, 1.96 mmol). Then TBSC1 (2.12 g, 19.66 mmol) was added portionwise at same temperature. After stirring the reaction mixture for 12 h, the reaction mixture was diluted with water (40 mL), extracted with CH 2 Cl 2 (30 mL). The collective organic layer was washed with brine (35 mL) and concentrated. The crude product was purified by column chromatography (silica gel) to yield TBS diene (22), 3.6 g (63% over two steps) as colourless oil.

Data for TBS diene (22): colourless oil; IR t)max(fihn): 2930, 2856, 1660, 1289 cm 1 ; 3 H NMR (500 MHz, CDCb) d 5.94 (s, 1H), 5.68 (s, 1H), 5.30 (s, 1H), 4.35 (s, 1H), 2.18-2.09 (m, 2H), 1.80-1.42 (m, 4H), 1.26-1.14 (m, 1H), 0.91 (d, J = 6.0 Hz, 15H), 0.09-0.08 (m, 6H); 13 C NMR (125 MHz, CDCb) d 142.7, 128.7, 127.7, 127.6, 69.0, 38.1, 37.4, 35.8, 33.6, 26.1 (3C), 23.4, 18.4, 17.2, 15.5, -4.2, -4.3; HRMS (ESI) calc for Ci 8 H 33 OSi [M+H] + 293.1931, found 293.1928.

Example 14: synthesis of (4aS,5R)-7-((tert-butyldimethylsilyl)oxy)-4a,5-dimethyl- l,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol (23): To a stirred solution of compound 22 (4.0 g, 13.69 mmol) in CH 2 Cl 2 (120 mL) at 0 °C was added m-CPBA (-65%), (3.62 g, 13.69 mmol) and stirred the reaction mixture for 30 min at 0 °C. Then saturated NaHC0 3 solution (40 mL) was added to reaction mixture and stirred for 10 min. Organic layer was separated and aqueous layer was extracted with CH 2 Cl 2 (40 mL). The combined organic layer was dried over sodium sulphate and concentrated to give crude epoxide as a pale yellow oil. To the crude epoxide (4.0 g, 12.987 mmol) in THF (60 mL) at 0 °C was added LAH (1.2 g, 32.47 mmol) and stirred the reaction mixture at 0 °C for 1 h. The reaction mixture was quenched with saturated Na 2 S0 4 solution (10 mL) slowly over 5 min. The mixture was diluted with EtOAc (100 mL) and filtered through celite. The organic layer was washed with brine (30 mL), dried over sodium sulphate and evaporated to give crude alcohol (2.1 g) as colourless oil which was carried forward without characterization.

Example 15: synthesis of (4a5,5/f)-4a,5-dimethyl-4,4a,5,6-tetrahydronaphthalen-2(3TT) - one (24):

To the above crude alcohol (1.9 g, 6.129 mmol) in CH 2 Cl 2 (60 mL) at 0 °C was added solid NaHCCb (0.5 g) followed by DMP (3.9 g, 9.19 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h and stirred for additional 1 h. The reaction mixture was quenched by adding saturated NaHCCb solution (25 mL). The organic layer was separated, washed with brine (30 mL) and evaporated. The crude product was purified by column chromatography (silica gel) to afford ketone, (1.8 g, 50% over three steps) as a sticky colourless oil. To compound TBS ketone (1.9 g, 6.129 mmol) in CH 2 Cl 2 (50 mL) was added catalytic PTSA.H 2 0 (0.040 g) at 30°C and refluxed the reaction mixture for 1 h. After 1 h, solid NaHCCb was added to the reaction mixture and solvent was evaporated. The crude compound was purified by column chromatography (silica gel) to afford (-)-dienone (24, 0.550 g, 51%) as a pale yellow oil.

Data for (-)-dienone (24): pale yellow oil; - 349.1 (c = 0.93, CHCL) IR t)max(film) :

2963, 1646, 1615, 1203 cm 1 ; *H NMR (400 MHz, CDCb) d 6.21-6.17 (m, 1H), 6.10 (d, / = 9.7 Hz, 1H), 5.65 (s, 1H), 2.54-2.49 (m, 1H), 2.40 (dd, / = 17.2, 3.7 Hz, 1H), 2.19 (dd, / = 14.3, 5.2 Hz, 1H), 2.03-1.98 (m, 2H), 1.73-1.66 (m, 2H), 1.00 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCb) d 199.8, 163.7, 138.3, 128.2, 123.6, 38.1, 36.2, 34.1, 33.9, 32.5, 15.0, 14.4; HRMS (ESI) calc for Ci 2 H 17 0 [M+H] + 177.1274, found 177.1272. Example 16: synthesis of (4R,4aS)-7,8-dihydroxy-4,4a-dimethyl-4,4a,5,6,7,8- hexahydronaphthalen-2(3H)-one (27) :

To a stirred solution of enone (21, 100 mg, 0.57 mmol) in i-BuOH (4 mL) was added Os0 4 (0.2 mL, 2.5 M solution in ί-BuOH) followed by addition of NMO (199 mg, 1.70 mmol) at 0°C and stirred the reaction mixture for 2h. After 2h the reaction was quenched with saturated Na 2 S0 3 solution (10 mL) and diluted with EtOAc (20 mL). Organic layer was separated and washed with brine (10 mL), dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography (silica gel) to give diol as a sticky oil (27, 47 mg, 40% yield).

3 H NMR (400 MHz, CDCb) d 5.81 (s, 1 H), 4.19-4.00 (m, 1 H), 3.90-3.67 (m, 1 H), 2.96- 2.78 (m, 2 H), 2.39-2.18 (m, 4 H), 1.97-1.83 (m, 1 H), 1.27 (s, 3 H), 0.97 (d, J = 7.3 Hz, 3 H); 13 C NMR (100 MHz, CDCb) d 199.9, 169.3, 125.7, 71.2, 69.3, 41.7, 41.6, 40.7, 37.8, 35.8, 18.6, 15.1.

Example 17: synthesis of (4R,4aS)-6,7-dihydroxy-4,4a-dimethyl-4,4a,5,6,7,8- hexahydronaphthalen-2(3H)-one (28) :

To a stirred solution of enone (21, 100 mg, 0.57 mmol) in i-BuOH (4 mL) was added Os0 4 (0.2 mL, 2.5 M solution in ί-BuOH) followed by addition of NMO (199 mg, 1.70 mmol) at 0°C and stirred the reaction mixture for 2h. After 2h the reaction was quenched with saturated Na 2 S0 3 solution (10 mL) and diluted with EtOAc (20 mL). Organic layer was separated and washed with brine (10 mL), dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography (silica gel) to give diol 69 mg as a sticky oil (28, 69 mg, 58% yield).

3 H NMR (400 MHz, CDsOD) d 5.79 (s, 1 H), 4.08-4.01 (m, 1 H), 4.01-3.92 (m, 1 H), 2.82- 2.71 (m, 1 H), 2.50 (dd, / = 3.7, 15.9 Hz, 1 H), 2.39-2.28 (m, 1 H), 2.22-2.15 (m, 1 H), 2.14- 2.02 (m, 1 H), 1.88 (dd, 7 = 4.6, 12.5 Hz, 1 H), 1.70-1.57 (m, 1 H), 1.15 (s, 3 H), 1.02 (d, / = 6.7 Hz, 3 H); 13 C NMR (100 MHz, CDsOD) d 201.9, 171.1, 127.8, 71.1, 69.2, 49.8, 49.6, 49.4, 48.9, 48.7, 48.5, 42.4, 41.6, 41.0, 40.9, 40.0, 17.4, 15.3.

Example 18: synthesis of (8R,8aS)-8,8a-dimethyl-l,7,8,8a-tetrahydronaphthalene-2,6- dione (29): A stirred solution of compound 21 (35 mg, 0.199 mmol in acetonitrile (4 mL) at 0 °C was purged with oxygen gas for 10 min then DBU (30 uL, 0.199 mmol) and reaction mixture was heated at 80 °C for 4 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with 1N HC1 (5 mL) followed by brine (5 mL). The combined organic layer was dried over sodium sulphate and evaporated. Purification by column chromatography (silica gel) gave compound 29 as sticky solid 19 mg (50%)

3 H NMR (400 MHz ,CDCb) d = 7.07 (d, J = 9.8 Hz, 1 H), 6.22 (d, J = 10.4 Hz, 1 H), 6.10 (s, 1 H), 2.71 (d, / = 15.9 Hz, 1 H), 2.51 - 2.21 (m, 4 H), 1.17 (s, 3 H), 1.03 (d, / = 6.1 Hz, 3 H); 13 C NMR (100 MHz ,CDC1 3 ) d = 198.7, 197.9, 158.8, 143.7, 131.7, 129.7, 49.0, 41.7, 39.8, 39.0, 18.4, 14.6

Example 19: (lS,8aS)-l,8a-dimethyl-l,7,8,8a-tetrahydronaphthalene-2,6-di one (30)

Compound 30 was synthesized from compound 29 by following the similar procedure used for the synthesis of compound 29. The data for this compound was matching with the literature report

3 H NMR (400 MHz, CDCb) d 7.19 (d, J = 10.0 Hz, 1H), 7.11 (d, J = 10.0 Hz, 1H), 6.41 (s, 1H), 6.37 (dd, / = 10.1, 1.8 Hz, 1H), 6.27 (d, / = 10.0 Hz, 1H), 2.60 (q, / = 6.8 Hz, 1H), 1.32 (d, / = 6.8 Hz, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCb) d 198.5, 185.3, 157.7, 153.5, 142.6, 131.4, 129.1, 128.7, 49.7, 44.4, 22.4, 7.9.

Example 24: Biological assay (Cell adhesion inhibition using RBCs)

Llow adhesion assay were performed with commercial microfluidic-well plate and microfluidic flow adhesion system, Bio flux 200. Microfluidic channels were coated by perfusion (ldyne/cm 2 , 5 min) and incubated (37 ° C, lh) with lOOng/ml Libronectin. Channels were then perfused with complete media to remove unbound Libronectin. Then a uniform monolayer of HUVEC cells was formed by profusing micro channels with the cell suspension at a pressure of 3dyne/cm 2 for 5 sec and kept for 12 hours incubation to form monolayer. The HUVEC monolayer was activated 25ng/ml of TNL-a and incubated (37 ° C, 4h). Meanwhile RBCs were treated with test compound at 100 mM concentration and incubated in hypoxic condition(3% nitrogen, 5% C0 2 , 2h).Llow condition for adhesion assay was pulsatile (1.67 Hz) flow (0.3 dyne/cm 2 ). Lor adhesion inhibition assay RBCs were diluted (2:50) in PBS. RBCs were perfused over HUVEC monolayer and incubated for lh. Unbound cells in micro channels were removed by perfusing complete media. Adherent cells were enumerated. Table 1 depicts percentage of inhibition.

Table 1

Advantages of the invention:

• Compounds are cell adhesion inhibitors, in particular sickled blood cells

• Compounds have potential for treating sickle cell anemia and other blood related disorders

• The developed route can be scalable and useful for synthesis of diverse analogs.