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1. (WO2013105997) COMPOSITIONS AND IMPROVED SOFT TISSUE REPLACEMENT METHODS
Примечание: Текст, основанный на автоматизированных процессах оптического распознавания знаков. Для юридических целей просьба использовать вариант в формате PDF

CLAIMS

1. A composition comprising: a) an adipose tissue; b) a silk fibroin material; c) a compound having the structure of formula I,


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or d.6 alkyl; R6 is C02H, C02R7, CON(R7)2, CONHCH2CH2OH, CON(CH2CH2OH)2, CH2OR7, P(0)(OR7)2,


; R7 is independently H, Ci_6 hydrocarbyl; X and Y are each independently selected from H, OH, =0, CI, Br, I, or CF3; Z and Z2 are each independently selected from CH or N; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, 4, 5, or 6; o is 0, 1 , 2, 3, 4; p is 0 or 1 ; and V is Ci-6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

2. The composition according to Claim 1 , wherein the compound has the structure of formula II


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or C-i_6 alkyl; R4 is H or C-i_6 hydrocarbyl; X and Y are each independently selected from H, OH, =0, CI, Br, I, or CF3; Z and Z2 are each independently selected from CH or N; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, aryl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

3. The composition according to Claim 1 or 2, wherein V is


wherein U is N, O, or S; R5 is F, CI, Br, I, Ci_6 hydrocarbyl; and n is 0, 1 , 2, 3, 4, 5,

6, or 7.

4. The composition according to Claim 3, wherein U is S; R5 is F, CI, Br, or I; and n is 1 , 2, or 3.

5. The composition according to Claims 1-4, wherein W2 is thiophene.

6. The composition according to Claims 1-5, wherein the compound has the structure of formula III


III wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or C-i_6 alkyl; R4 is H or C-|-C6 hydrocarbyl; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, optionally substituted aryl or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

7. The composition according to Claims 1-6, wherein the compound has the structure of formula IV


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or Ci_6 linear alkyl; R4 is H, Ci_6 hydrocarbyl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, optionally substituted aryl or optionally substituted

heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

8. The composition according to Claims 1-7, wherein the compound has the structure of formula V


wherein each dashed line represents the presence or absence of a bond; R4 is H, Ci_6 hydrocarbyl; is 0, 1 , 2, 3, or 4; and V is CH3, optionally substituted aryl or optionally substituted heteroaryl, pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

The composition accordin to Claims 1-8, wherein the compound is

a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

. The composition according to Claims 1-9, wherein the compound is


a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

A composition comprising: a) an adipose tissue; b) a silk fibroin material; c) a compound having the structure of formula VI


wherein each dashed line represents the presence or absence of a bond; Z2 and Z3 are independently CH or N; Z Z4, Z5, and Z6 are each independently CR9, CHR9, NH, O, or S; A is - (CH2)6-, or cis -CH2CH=CH-(CH2)3-, wherein 1 or 2 carbons may be substituted with S or O; or A is - (CH2)m-Ar-(CH2)o- wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, the sum of m and o is from 1 , 2, 3, or 4, and wherein one CH2 may be substituted with S or O; R8 is H, hydrocarbyl, or hydrocarbyl-OH; R9 is independently H, Ci_6 alkyl, OH, F, CI, Br, I, or O; J is Ci_6 alkyl, d_6 -O-alkyl, C=0, or CHOH; E is C1-12 alkyl, R 0, or -Y- R 0 wherein Y is CH2, S, or O, and R 0 is optionally substituted aryl or optionally substituted heteroaryl; and n is 0 or 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

12. The composition accordi has the structure of formula VII


wherein each dashed line represents the presence or absence of a bond; Z2 is CH or N; Z5 is CH2, NH, O, or S; Z7 is CH2, O, or S; R8 is H, Ci-6 hydrocarbyl, or Ci_6 hydrocarbyl-OH; R9 and R are independently C1-6 alkyl, OH, F, CI, Br, I, or O; and R 2 is H, OH, O, F, CI, Br, I , C^ -O-alkyl, Ci_4 haloalkyi, or aryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

13. The composition accordi has the structure of formula VIII


wherein each dashed line represents the presence or absence of a bond; Z is CH or N; Z is CH2, NH, O, or S; Z7 and Z8 are independently CH2, O, or S; R8 is H, Ci-6 hydrocarbyl, or Ci-6 alkyl-OH; R9 and R are independently Ci_6 alkyl, OH, F, CI, Br, I, or O; and R 2 is H, OH, O, F, CI, Br, I, C^ -O- alkyl, C-i_4 haloalkyi, or aryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

14. The composition according to Claims 1 1-13, wherein the compound is


a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

15. A composition comprising: a) an adipose tissue; b) a silk fibroin material; and c) a compound having the structure of formula IX,


wherein X1 and X5 are independently CH or N; X7 is NH, O, or S; X8 and X9 are independently CH or N; R 3 is optionally substituted aryl or optionally substituted heteroaryl; and R 4 is Ci_6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

The composition according to Claim 15, wherein the compound has the structure of formula X,


wherein X10, X12, X13, X14, and X15 are each independently CR 9 or N; R 6 is independently H, OH, O, F, CI, Br, I, C-i-6 alkyl, Ci-6 -O-alkyl, CN, or Ci-6 alkyl-CN; and R 9 is independently H, OH, O, F, CI, Br, I, C-i-10 alkyl, Ci_i0 -O-alkyl, or C4.i0 -O-alkyl-heterocyclyl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

17. The composition according to Claim 15 or 16, wherein the compound has the structure of formula XI,

wherein X14 is CR 9 or N; R 6, R 7, and R 8 are each independently H, OH, O, F, CI, Br, I, d_6 alkyl, C-i-6 -O-alkyl, CN, or Ci-6 alkyl-CN; R 9 is H, OH, O, or F, CI, Br, I, C1-10 alkyl, C1-10 -O-alkyl, or

I— O C2 4 alkyl— N O

\ / ' ; and R20 is H, F, CI, Br, or I, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

18. The composition according to Claims 15-17, wherein the compound is

a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

19. A composition comprising: a) an adipose tissue; b) a silk fibroin material; and c) a compound having the structure of compound 24,


Compound 24 a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

20. The composition according to Claims 1-19, wherein the compound is incorporated into

delivery platform comprising a biodegradable polymer matrix.

The composition according to Claims 1-20, wherein the silk fibroin material is in the form of a silk hydrogel, a silk film, a silk scaffold, a silk sheet, a silk porous material, a silk fiber, or any combination thereof.

22. The composition according to Claims 1-21 , wherein the silk fibroin material is substantially sericin free.

23. A use of a composition according to Claims 1-22 in the manufacture of a medicament for the treatment of a soft tissue condition.

24. A use of a composition according to Claims 1-22 for the treatment of a soft tissue condition.

25. A method of treating a soft tissue condition of an individual, the method comprising the step of administering to a site of the soft tissue condition a composition according to Claims 1-22, wherein administration of the composition promotes formation of a blood supply sufficient to support the transplanted tissue, thereby treating the soft tissue site.

26. A method of treating a soft tissue condition of an individual, the method comprising the steps of

a) administering adipose tissue to a site of the soft tissue condition;

b) administering an effective amount of a silk fibroin material to the site of the soft tissue condition; and

c) administering a compound to the site of the soft tissue condition, the compound having the structure of:

formula I,


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or Ci-6 alkyl; R6 is C02H, C02R7, CON(R7)2, CONHCH2CH2OH, CON(CH2CH2OH)2, CH2OR7, P(0)(OR7)2,


; R7 is independently H, Ci_6 alkyl hydrocarbyl; X and Y are each independently selected from H, OH, =0, CI, Br, I, or CF3; Z and Z2 are each independently selected from CH or N; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, 4, 5, or 6; o is 0, 1 , 2, 3, 4; p is 0 or 1 ; and V is Ci_6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof; or

formula VI,


wherein each dashed line represents the presence or absence of a bond; Z2 and Z3 are independently CH or N; Z Z4, Z5, and Z6 are each independently CR9, CHR9, NH, O, or S; A is -(CH2)6-, or cis -CH2CH=CH-(CH2)3-, wherein 1 or 2 carbons may be substituted with S or O; or A is -(CH2)m-Ar-(CH2)0- wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, the sum of m and o is from 1 , 2, 3, or 4, and wherein one CH2 may be substituted with S or O; R8 is H, hydrocarbyl, or hydrocarbyl-OH; R9 is independently H, Ci_6 alkyl, OH, F, CI, Br, I, or O; J is d.6 alkyl, d.6 -O-alkyl, C=0, or CHOH; E is d_12 alkyl, R 0, or -Y- R 0 wherein Y is CH2, S, or O, and R 0 is optionally substituted aryl or optionally substituted heteroaryl; and n is 0 or 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof; or

formula VI,


ix

wherein X1 and X5 are independently CH or N; X7 is NH, O, or S; X8 and X9 are independently CH or N; R 3 is optionally substituted aryl or optionally substituted heteroaryl; and R 4 is Ci_6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof; or

compound 24


Compound 24 a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof;

wherein administration of the compound promotes formation of a blood supply sufficient to support the transplanted tissue, thereby treating the soft tissue site.

The method according to Claim 26, wherein the compound has the structure of formula II


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or Ci_6 alkyl; R4 is H or Ci_6 hydrocarbyl; X and Y are each independently selected from H, OH, =0, CI, Br, I, or CF3; Z and Z2 are each independently selected from CH or N; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, aryl, optionally substituted aryl, or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

28. The method according to Claim 26 or 27, wherein V is


wherein U is N, O, or S; R5 is F, CI, Br, I, Ci-6 hydrocarbyl; and n is 0, 1 , 2, 3, 4, 5, 6, or 7.

29. The method according to Claim 28, wherein U is S; R5 is F, CI, Br, or I; and n is 1 , 2, or 3.

30. The method according to Claims 26-29, wherein W2 is thiophene.

31. The method according to Claims 26-30, wherein the compound has the structure of formula III


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or C-i_6 alkyl; R4 is H or C-|-C6 hydrocarbyl; W and W2 are each independently selected from CH, CH2, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, optionally substituted aryl or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

32. The method according to Claims 26-31 , wherein the compound has the structure of formula IV


wherein each dashed line represents the presence or absence of a bond; R , R2 and R3 are each independently selected from H or Ci_6 linear alkyl; R4 is H, Ci_6 hydrocarbyl; m is 0, 1 , 2, 3, or 4; o is 0, 1 , 2, 3, or 4; p is 0 or 1 ; and V is CH3, optionally substituted aryl or optionally substituted heteroaryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

33. The method according to Claims 26-32, wherein the compound has the structure of formula V


wherein each dashed line represents the presence or absence of a bond; R4 is H, C-i_6 hydrocarbyl; is 0, 1 , 2, 3, or 4; and V is CH3, optionally substituted aryl or optionally substituted heteroaryl, pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

34. The method according to Claims 26-33, wherein the compound is


a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof. 35. wherein the compound is


a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof. 36. The method according to Claim 26, wherein the compound has the structure of formula VII

wherein each dashed line represents the presence or absence of a bond; Z2 is CH or N; Z5 is CH2, NH, O, or S; Z7 is CH2, O, or S; R8 is H, d_6 hydrocarbyl, or C-,.6 hydrocarbyl-OH; R9 and R are independently Ci_6 alkyl, OH, F, CI, Br, I, or O; and R 2 is H, OH, O, F, CI, Br, I , C^ -O-alkyl, Ci_4 haloalkyi, or aryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

37. The method according to Claim 26 or 36, wherein the compound has the structure of formula VIII


wherein each dashed line represents the presence or absence of a bond; Z2 is CH or N; Z5 is CH2, NH, O, or S; Z7 and Z8 are independently CH2, O, or S; R8 is H, C-,.6 hydrocarbyl, or C-,.6 alkyl-OH; R9 and R are independently Ci_6 alkyl, OH, F, CI, Br, I, or O; and R 2 is H, OH, O, F, CI, Br, I, C^ -O- alkyl, Ci_4 haloalkyi, or aryl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

38. The method according to Claim 26, 36, or 37, wherein the compound is

a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

39. The method according to Claim 26, wherein the compound has the structure of formula X,


wherein X10, X12, X13, X14, and X15 are each independently CR 9 or N; R 6 is independently H, OH, O, F, CI, Br, I, d_6 alkyl, C-,.6 -O-alkyl, CN, or C-,.6 alkyl-CN; and R 9 is independently H, OH, O, F, CI, Br, I, C-i-10 alkyl, Ci_i0 -O-alkyl, or C4.i0 -O-alkyl-heterocyclyl, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

40. The method according to Claim 26 or 39, wherein the compound has the structure of formula XI,

wherein X14 is CR 9 or N; R 6, R 7, and R 8 are each independently H, OH, O, F, CI, Br, I, d_6 alkyl, C-i-6 -O-alkyl, CN, or Ci-6 alkyl-CN; R 9 is H, OH, O, or F, CI, Br, I, C1-10 alkyl, C1-10 -O-alkyl, or

I— O C2 4 alkyl— N O

\ / ' ; and R20 is H, F, CI, Br, or I, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

The method according to Claim 26, 39, or 41 , wherein the compound

a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.

42. The method according to Claims 26-41 , wherein the silk fibroin material is substantially sericin free.

43. The method according to Claims 26-42, wherein the silk fibroin material is administered at the same time as, before, or after the compound is administered.

The use according to Claim 23 or 24 or the method according to Claims 25-43, wherein the soft tissue condition is a breast tissue condition, a facial tissue condition, a neck condition, a skin condition, an upper arm condition, a lower arm condition, a hand condition, a shoulder condition, a back condition, a torso including abdominal condition, a buttock condition, an upper leg condition, a lower leg condition including calf condition, a foot condition including plantar fat pad condition, an eye condition, a genital condition, or a condition effecting another body part, region or area.

45. The use or method according to Claim 44, wherein the breast tissue condition is a breast imperfection, a breast defect, a breast augmentation, or a breast reconstruction.

46. The use or method according to Claim 44, wherein the facial tissue condition is a facial imperfection, a facial defect, a facial augmentation, or a facial reconstruction.

47. The use or method according to Claim 44, wherein the facial soft tissue condition is a dermal divot, a sunken cheek, a thin lip, a nasal imperfection or defect, a retro-orbital imperfection or defect, a facial fold, a facial line, a facial wrinkle, or other size, shape or contour imperfection or defect of the face.

48. The use according to Claim 23 or 24 or the method according to Claims 25-43, wherein the soft tissue condition is urinary incontinence, fecal incontinence, or gastroesophageal reflux disease (GERD).