Cyclosporine analogue molecules modified at amino acid 1 and 3

1. A compound of Formula L:

wherein:

a) R′ is H or acetyl;

b) R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;

c) R2 is selected from the group consisting of:

i) an unsubstituted, N-substituted, or N,N-disubstituted amide;

ii) a carboxylic acid;

iii) a nitrile;

iv) an ester;

v) a ketone;

vi) a hydroxy, dihydroxy, trihydroxy, or polyhydroxy alkyl;

vii) a substituted or unsubstituted aryl;

viii) a saturated or unsaturated straight or branched aliphatic carbon chain substituted with a substituent selected from the group consisting of a ketone, a hydroxy, a nitrile, a carboxylic acid, an ester, a 1,3-dioxolane, and an oxo;

ix) an aromatic group substituted with a substituent selected from the group consisting of a halogen, an ester, and a nitro; and

x) a combination of the saturated or unsaturated straight or branched aliphatic carbon chain of viii) and the aromatic group of ix); and

d) R23 is unsubstituted C 1 -C 3 alkyl.

2. The compound of claim 1 , wherein R1-R2 is selected from the group consisting of:

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

wherein:

R5 is a saturated or unsaturated straight or branched aliphatic carbon chain between 1 and 10 carbons in length; and

R6 is a monohydroxylated, dihydroxylated, trihydroxylated, or polyhydroxylated saturated or unsaturated straight or branched aliphatic carbon chain between 1 and 10 carbons in length.

4. The compound of claim 1 , wherein R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 5 to 8 carbon atoms in length.

5. The compound of claim 1 , wherein R′ is H.

6. The compound of claim 1 , wherein R1-R2 is substituted with a substituent selected from the group consisting of a ketone, a hydroxy, a nitrile, an oxo, a carboxylic acid, an ester, and a 1,3-dioxolane.

7. The compound of claim 1 , wherein R23 is selected from the group consisting of:

—CH 3 and —CH 2 CH 3 .

8. The compound of claim 1 , wherein the compound comprises the D-epimer of amino acid 3 which is the amino acid to which R23 is attached.

9. The compound of claim 1 , wherein R23 is methyl.

10. The compound of claim 1 , wherein

in Formula L is selected from the group consisting of:

11. The compound of claim 1 , wherein R1-R2 is at least 6 carbon atoms in length.

12. A compound selected from the group consisting of:

R23

Isomer

a)

—CH 3

L

b)

—CH 3

D

c)

—CH 3

L

d)

—CH 2 CH 3

D

e)

—CH 3

D

f)

—CH 3

L

g)

—CH 2 CH 3

D

h)

—CH 3

D

i)

—CH 2 CH 3

L

j)

—CH 2 CH 3

D

k)

—CH 3

L

l)

—CH 3

D

m)

—CH 3

D

n)

—CH 2 CH 3

D

o)

—CH 3

D

r)

—CH 3

D

s)

—CH 3

L

t)

—CH 3

D

u)

—CH 3

D

v)

—CH 3

L

w)

—CH 2 CH 3

L

x)

—SCH 3

D/L

z)

—(CH 2 ) 3 N + (CH 3 ) 3

D/L

aa)

D

bb)

—CH 3

D

cc)

—CH 3

L

dd)

—CH 3

L

ee)

—CH 3

D

ff)

—CH 2 CH 3

D

gg)

—CH 3

D

hh)

—CH 3

D

ii)

—CH 2 CH 3

D

jj)

—CH 3

D

wherein:

R is

R′ is H or acetyl,

and wherein the isomer is the isomeric form of amino acid 3 which is the amino acid to which R23 is attached.

13. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutical excipients.

14. A method of treating or preventing a cyclophilin mediated disease or injury in a mammal comprising administering the compound of claim 1 to the mammal.

15. The method of claim 14 , wherein the disease or injury is mediated by the over-expression of cyclophilin or the disease is a congenital over-expression of cyclophillin.

16. The method of claim 14 , wherein the cyclophilin mediated disease or injury is selected from the group consisting of a viral infection; inflammatory disease; cancer; muscular disorder; neurological disorder; and injury associated with ischemia, reperfusion, loss of cellular calcium homeostasis, loss of ionic homeostasis, increase in free radical production, or toxins that induce mitochondrial dysfunction;

wherein the viral infection is optionally caused by a virus selected from the group consisting of Human Immunodeficiency Virus, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, SARS-CoV, hCoV-NL63, hCoV-HKU-1, hCoV-OC43, hCOV-229E, coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus;

wherein the inflammatory disease is optionally selected from the group consisting of asthma, autoimmune disease, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivity disease, inflammatory bowel disease, sepsis, vascular smooth muscle cell disease, aneurysms, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis;

wherein the cancer is optionally selected from the group consisting of small and non-small cell lung cancer, bladder cancer, hepatocellular cancer, pancreatic cancer, breast cancer, glioblastoma, colorectal cancer, squamous cell carcinoma, melanoma, and prostate cancer;

wherein the muscular disorder is optionally selected from the group consisting of myocardial reperfusion injury, muscular dystrophy, collagen VI myopathies, Post-cardiac arrest syndrome (PCAS), heart failure, atherosclerosis, and abdominal aortic aneurysm;

wherein the neurological disorder is optionally selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple systems atrophy, multiple sclerosis, cerebral palsy, epilepsy, stroke, diabetic neuropathy, amyotrophic lateral sclerosis (Lou Gehrig's Disease), bipolar disorder, excitotoxic injury, hepatic encephalopathy, hypoglycemia, manganese toxicity, neuronal target deprivation, toxic fatty acids, mechanical nerve injury, spinal cord injury, and cerebral injury; and

wherein the injury associated with loss of cellular calcium homeostasis is optionally selected from the group consisting of myocardial infarct, stroke, acute hepatotoxicity, cholestasis, and storage/reperfusion injury of transplant organs.

17. The method of claim 16 , wherein the toxic fatty acid is arachadonic acid.

18. A process for the preparation of a compound of Formula L:

wherein:

a) R′ is H or acetyl;

b) R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;

c) R2 is selected from the group consisting of:

i) an unsubstituted, N-substituted, or N,N-disubstituted amide;

ii) a carboxylic acid;

iii) a nitrile;

iv) an ester;

v) a ketone;

vi) a hydroxy, dihydroxy, trihydroxy, or polyhydroxy alkyl;

vii) a substituted or unsubstituted aryl;

viii) a saturated or unsaturated straight or branched aliphatic carbon chain substituted with a substituent selected from the group consisting of a ketone, a hydroxy, a nitrile, a carboxylic acid, an ester, a 1,3-dioxolane, and an oxo;

ix) an aromatic group substituted with a substituent selected from the group consisting of a halogen, an ester, and a nitro; and

x) a combination of the saturated or unsaturated straight or branched aliphatic carbon chain of viii) and the aromatic group of ix); and

d) R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain,

comprising the steps of:

1) reacting cyclosporin-A (CsA) with a basic lithium alkylamide, in the presence of a suitable solvent optionally with LiCl, followed by reaction with a suitable electrophile to generate a compound of Formula 1:

2) reacting the compound of Formula 1 with Ac 2 O in the presence of a suitable solvent to form a compound of Formula 2A:

3) reacting the compound of Formula 2A with an oxidant to form a compound of Formula 3A:

4) reacting the compound of Formula 3A with an electrophile to form a compound of Formula 4A:

and

5) optionally deacylating the compound of Formula 4A.

19. The process of claim 18 , wherein the preparation of the compound of Formula L comprises the addition of an excess of LiCl in the suitable solvent in step 1) to form predominantly the L-epimer of the compound of Formula L, or the preparation of the compound of Formula L is carried out in the absence of LiCl in the suitable solvent in step 1) to form predominantly the D-epimer of the compound of Formula L, wherein the chiral center of the L-epimer or the D-epimer of the compound of Formula L is the carbon atom to which R23 is attached.

20. The process of claim 18 , wherein the basic lithium alkylamide is lithium diisopropylamide.

21. The process of claim 18 , wherein the electrophile is selected from the group defined in the following table, to generate the corresponding R23 in the table:

Electrophile

R23

methyl iodide

—CH 3

ethyl iodide

—CH 2 CH 3

allyl bromide

—CH 2 CHCH 2

1,3-diiodopropane

—CH 2 CH 2 CH 2 l

1,4-diiodobutane

—(CH 2 ) 3 CH 2 l

trimethylammonium-3-iodopropane

—(CH 2 ) 3 N + (CH 3 ) 3

hexafluorophosphate

propargyl bromide

—CH 2 CCH

tert-butyl bromoacetate

—CH 2 CO 2 (t-Bu)

benzyl bromide

—CH 2 Ph

Formaldehyde

—CH 2 OH

Acetaldehyde

—CH(OH)CH 3

Pivalaldehyde

—CH(OH)(t-Bu)

Benzaldehyde

—CH(OH)Ph

carbon dioxide

—COOH

dimethyl disulfide

—SCH 3

p-tolyl disulfide

—S(p-Tol)

22. The process of claim 18 , wherein R2 is a carboxylic acid and R23 is —CH 3 .

23. A process for the preparation of the compound of Formula L of claim 1 , comprising the steps of:

reacting a compound of Formula 1A with dimethylaminopyridine in the presence of a suitable solvent, to form a compound of Formula 2:

optionally followed by formation of an aldehyde of Formula 3:

optionally followed by a Wittig reaction to generate the compound of Formula L, wherein R23 is selected from the group consisting of: —CH 3 and —CH 2 CH 3 .

24. A process for the preparation of the compound of Formula L of claim 1 , comprising the steps of:

reacting a compound of Formula 5

wherein R1 and R2 are as defined in claim 1 , with a basic lithium alkylamide, in the presence of a suitable electrophile in an appropriate solvent to form the compound of Formula L, wherein R23 is unsubstituted C 1 -C 3 alkyl.

25. The process of claim 24 , wherein the basic lithium alkylamide is lithium diisopropylamide.

26. The process of claim 24 , wherein R2 is a carboxylic acid and R23 is —CH 3 .

27. A compound of Formula L:

wherein:

a) R′ is H or acetyl;

b) R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;

c) R2 is selected from the group consisting of:

i) an unsubstituted, N-substituted, or N,N-disubstituted amide;

ii) a carboxylic acid;

iii) a nitrile;

iv) an ester;

v) a ketone;

vi) a hydroxy, dihydroxy, trihydroxy, or polyhydroxy alkyl;

vii) a substituted or unsubstituted aryl;

viii) a saturated or unsaturated straight or branched aliphatic carbon chain substituted with a substituent selected from the group consisting of a ketone, a hydroxy, a nitrile, a carboxylic acid, an ester, a 1,3-dioxolane, and an oxo;

ix) an aromatic group substituted with a substituent selected from the group consisting of a halogen, an ester, and a nitro; and

x) a combination of the saturated or unsaturated straight or branched aliphatic carbon chain of viii) and the aromatic group of ix); and

d) R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain,

wherein R1-R2 is at least 6 carbon atoms in length.

28. The compound of claim 27 , wherein R1-R2 is selected from the group consisting of:

29. The compound of claim 27 , wherein R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 5 to 8 carbon atoms in length.

30. The compound of claim 27 , wherein R′ is H.

31. The compound of claim 27 , wherein R1-R2 is substituted with a substituent selected from the group consisting of a ketone, a hydroxy, a nitrile, an oxo, a carboxylic acid, an ester, and a 1,3-dioxolane.

32. The compound of claim 27 , wherein R23 is selected from the group consisting of: —CH 3 , —CH 2 CH 3 , —CH 2 CHCH 2 , —CH 2 CH 2 CH 2 I, —(CH 2 ) 3 CH 2 I, —(CH 2 ) 3 N + (CH 3 ) 3 , —CH 2 CCH, —CH 2 CO 2 (t-Bu), —CH 2 Ph, —CH 2 OH, —CH(OH)CH 3 , —CH(OH)(t-Bu), —CH(OH)Ph, —COOH, —SCH 3 , and —S(p-Tol).

33. The compound of claim 27 , wherein R23 comprises an optionally substituted C 1 -C 3 alkyl.

34. The compound of claim 27 , wherein R23 is substituted with amino.

35. The compound of claim 27 , wherein R23 is C 1 -C 3 alkyl and the compound comprises the D-epimer of amino acid 3 which is the amino acid to which R23 is attached.

36. The compound of claim 27 , wherein R23 is methyl.

37. The compound of claim 27 , wherein

in Formula L is selected from the group consisting of:

38. The compound of claim 27 , wherein R23 is a straight or branched aliphatic carbon chain of 1 to 6 carbons in length.

39. The compound of claim 1 , wherein R1-R2 is

and R23 is methyl, and wherein the compound is a D-epimer, wherein the chiral center of the D-epimer is the carbon to which R23 is attached.