Derivatives of dimethylcurcumin
The invention relates to compounds of Formula I or Ia as disclosed herein: or pharmaceutically acceptable salts thereof or tautomers thereof.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of —OH, —O(C 1 -C 6 alkyl), —NO 2 , —NH 2 , —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl is optionally and independently substituted with one or more deuterium;
R 5 and R 6 are each independently hydrogen, deuterium, halo, or —NO 2 ;
R 7 is hydrogen, deuterium, or —R 13 ;
R 13 is (C 2 -C 6 ) alkenyl optionally substituted with one or more deuterium and substituted with —C(O)R 12 ;
R 12 is —OCH 3 , —OCH 2 CH 3 , —NH(CH 2 CH 3 ), —CN, or —CH 2 OH, wherein each of —OCH 3 , —OCH 2 CH 3 , —NH(CH 2 CH 3 ), and —CH 2 OH is optionally substituted with one or more deuterium;
R 8 and R 11 are each independently hydrogen or deuterium;
R 9 and R 10 are each independently hydrogen or deuterium;
X 1 and X 2 are each independently CH, CD, C(OCH 3 ), C(OCD 3 ) or C(NO 2 );
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 9 , R 10 , X 1 and X 2 comprises deuterium;
and provided that the compound of Formula I is not
2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are independently selected from —OH, —OCH 3 , and —OCD 3 .
3. The compound of claim 1 , wherein R 5 and R 6 are each hydrogen or each deuterium.
4. The compound of claim 1 , wherein R 7 is hydrogen or deuterium.
5. The compound of claim 1 , wherein X 1 is CH or CD.
6. The compound of claim 1 , wherein X 2 is CH or CD.
7. The compound of claim 1 , wherein R 7 is R 13 , wherein R 13 is (C 2 -C 6 ) alkenyl optionally substituted with one or more deuterium and with —C(O)R 12 , and R 12 is —OCD 3 , —OCD 2 CD 3 , —N(H)CD 2 CD 3 , or —CD 2 OH.
8. The compound of claim 1 wherein X 1 ═X 2 ═CH, R 5 ═R 6 ═H and wherein the compound is any one of the compounds of the following table, wherein any atom not designated as deuterium is present at its natural isotopic abundance:
Com-
pound
R 1
R 2
R 3
R 4
R 7
R 8
R 9
R 10
R 11
100
OCD 3
OCD 3
OH
OCD 3
D
D
D
D
D
101
OCD 3
OCD 3
OH
OCD 3
H
D
D
D
D
102
OCD 3
OCD 3
OH
OCD 3
H
H
D
D
D
103
OCD 3
OCD 3
OH
OCD 3
H
D
D
D
H
104
OCD 3
OCD 3
OH
OCD 3
H
H
D
D
H
105
OCD 3
OCD 3
OH
OCD 3
H
H
H
H
H
106
OCD 3
OCD 3
OH
OCD 3
H
D
H
H
D
107
OCD 3
OCD 3
OH
OCD 3
H
D
H
H
H
108
OCD 3
OCD 3
OH
OCD 3
H
H
H
H
D
109
OCH 3
OCD 3
OH
OCD 3
D
D
D
D
D
110
OCH 3
OCD 3
OH
OCD 3
H
D
D
D
D
111
OCH 3
OCD 3
OH
OCD 3
H
H
D
D
D
112
OCH 3
OCD 3
OH
OCD 3
H
D
D
D
H
113
OCH 3
OCD 3
OH
OCD 3
H
H
D
D
H
114
OCH 3
OCD 3
OH
OCD 3
H
H
H
H
H
115
OCH 3
OCD 3
OH
OCD 3
H
D
H
H
D
116
OCH 3
OCD 3
OH
OCD 3
H
D
H
H
H
117
OCH 3
OCD 3
OH
OCD 3
H
H
H
H
D
118
OCD 3
OCH 3
OH
OCH 3
D
D
D
D
D
119
OCD 3
OCH 3
OH
OCH 3
H
D
D
D
D
120
OCD 3
OCH 3
OH
OCH 3
H
H
D
D
D
121
OCD 3
OCH 3
OH
OCH 3
H
D
D
D
H
122
OCD 3
OCH 3
OH
OCH 3
H
H
D
D
H
123
OCD 3
OCH 3
OH
OCH 3
H
H
H
H
H
124
OCD 3
OCH 3
OH
OCH 3
H
D
H
H
D
125
OCD 3
OCH 3
OH
OCH 3
H
D
H
H
H
126
OCD 3
OCH 3
OH
OCH 3
H
H
H
H
D
127
OCH 3
OCH 3
OH
OCH 3
D
D
D
D
D
128
OCH 3
OCH 3
OH
OCH 3
H
D
D
D
D
129
OCH 3
OCH 3
OH
OCH 3
H
H
D
D
D
130
OCH 3
OCH 3
OH
OCH 3
H
D
D
D
H
131
OCH 3
OCH 3
OH
OCH 3
H
H
D
D
H
132
OCH 3
OCH 3
OH
OCH 3
H
D
H
H
D
133
OCH 3
OCH 3
OH
OCH 3
H
D
H
H
H
134
OCH 3
OCH 3
OH
OCH 3
H
H
H
H
D
or a pharmaceutically acceptable salt thereof or a tautomer thereof.
9. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
R 1 and R 2 are the same and are selected from the group consisting of —OH, —O(C 1 -C 6 alkyl), —NO 2 , —NH 2 , —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl is optionally and independently substituted with one or more deuterium;
R 3 and R 4 are the same and are selected from the group consisting of —OH, —O(C 1 -C 6 alkyl), —NO 2 , —NH 2 , —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl is optionally and independently substituted with one or more deuterium;
R 5 and R 6 are the same and are selected from the group consisting of hydrogen and deuterium;
R 7 is selected from hydrogen and deuterium;
R 9 and R 10 are the same and are selected from hydrogen and deuterium;
R 8 and R 11 are the same and are selected from hydrogen and deuterium;
R 14 and R 15 are the same and are selected from hydrogen and deuterium;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 9 , R 10 , R 14 and R 15 comprises deuterium;
and provided that the compound of Formula Ia is not
10. The compound of claim 9 , wherein R 1 and R 2 are the same and are selected from —OH, —OCH 3 and —OCD 3 ; and R 3 and R 4 are the same and are selected from —OH, —OCH 3 and —OCD 3 .
11. The compound of claim 10 , wherein R 1 and R 2 are the same and are selected from —OCH 3 and —OCD 3 ; and R 3 and R 4 are both —OH.
12. The compound of claim 9 , wherein R 7 , R 9 and R 10 are the same and are selected from hydrogen and deuterium.
13. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
14. The compound of claim 9 , wherein R 5 ═R 6 ═H, and R 14 ═R 15 ═H, and wherein the compound is any one of the compounds of the following table, wherein any atom not designated as deuterium is present at its natural isotopic abundance:
Compound
R 1 ═R 2
R 3 ═R 4
R 7
R 8 ═R 11
R 9 ═R 10
200
OCD 3
OCD 3
D
D
D
201
OCD 3
OCH 3
D
D
D
202
OCH 3
OCD 3
D
D
D
203
OCH 3
OCH 3
D
D
D
204
OCD 3
OCD 3
D
H
D
205
OCD 3
OCD 3
H
D
H
206
OCD 3
OCH 3
D
H
D
207
OCD 3
OCH 3
H
D
H
208
OCH 3
OCD 3
D
H
D
209
OCH 3
OCD 3
H
D
H
210
OCH 3
OCH 3
D
H
D
211
OCH 3
OCH 3
H
D
H
212
OCD 3
OCD 3
H
H
H
213
OCD 3
OCH 3
H
H
H
214
OCH 3
OCD 3
H
H
H
215
OCD 3
OCD 3
H
D
D
216
OCD 3
OCH 3
H
D
D
217
OCH 3
OCD 3
H
D
D
218
OCH 3
OCH 3
H
D
D
219
OCD 3
OCD 3
H
H
D
220
OCD 3
OCH 3
H
H
D
221
OCH 3
OCD 3
H
H
D
222
OCH 3
OCH 3
H
H
D
or a pharmaceutically acceptable salt thereof or tautomer thereof.
15. The compound of claim 9 , wherein R 5 ═R 6 ═H, and R 14 ═R 15 ═H, and wherein the compound is any one of the compounds of the following table, wherein any atom not designated as deuterium is present at its natural isotopic abundance:
Compound
R 1 ═R 2
R 3 ═R 4
R 7
R 8 ═R 11
R 9 ═R 10
300
OCD 3
OH
D
D
D
301
OCH 3
OH
D
D
D
302
OCD 3
OH
D
H
D
303
OCD 3
OH
H
D
H
304
OCH 3
OH
D
H
D
306
OCD 3
OH
H
H
H
307
OCD 3
OH
H
D
D
308
OCH 3
OH
H
D
D
309
OCD 3
OH
H
H
D
310
OCH 3
OH
H
H
D
or a pharmaceutically acceptable salt thereof or tautomer thereof.
16. A pyrogen-free pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof or tautomer thereof; and a pharmaceutically acceptable carrier.
17. A method of treating a disease selected from the group consisting of baldness, hirsutism, behavioral disorders, acne, alopecia, skin lesions, Kennedy's disease or spinobulbar muscular atrophy and spermatogenesis where inhibition of spermatogenesis is desired, psoriasis, Alzheimer's disease, mild cognitive impairment, asthma, type 2 diabetes, optic neuropathy, rheumatoid arthritis, osteoarthritis, major depressive disorder, kidney allografts, oral lichen planus, irritable bowel syndrome (IBS), ulcerative colitis, Crohn's disease, chemoradiation side effects, multiple myeloma, pancreatic cancer, myleodysplastic syndromes, colon cancer, colorectal cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer, prostate cancer, familial adenomatous polyposis (FAP), uterine cervical dysplasia, cutaneous T-cell lymphoma, head and neck cancer and osteosarcoma comprising the step of administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof or tautomer thereof.
18. The method of claim 17 wherein the disease is selected from multiple myeloma, pancreatic cancer, myleodysplastic syndromes, colon cancer, colorectal cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer, prostate cancer, familial adenomatous polyposis (FAP), uterine cervical dysplasia, cutaneous T-cell lymphoma, head and neck cancer and osteosarcoma.