Prostaglandin Analog Compositions And Methods To Treat Epithelial-Related Conditions
The present invention relates to the formulation and delivery of prostaglandin analogs to treat epithelial-related condition. In some embodiments, the compositions of the invention are used to stimulate hair growth. In some embodiments, the compositions of the invention are used to restore hair color to depigmented hair. The present invention further relates to the formulation and delivery of prostaglandin analogs to reduce intraocular pressure.
1 . A topical composition for treating an epithelial-related condition, comprising.
(a) at least one compound of formula I or a salt of Formula I:
wherein
X is
NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate;
a cyclic substituent in which nitrogen is part of the ring, represented as —N(R 4 ) 2 , wherein (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10; or
OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate; and
R 1 , R 2 and R 3 each independently is H, C 1 -C 6 alkyl, a phosphate group, a monosaccharide, a disaccharide or a polysaccharide;
the simple straight line represents a bond lying approximately in the surface plane; the dashed bonds represent a single or double bond which can be in the cis or trans configuration, wherein there is at least one double bond; the wedge shaped bond is directed to the front of surface plane; and the hatched bond is directed in the back of the surface plane;
B is —O—, —S—, —(CH 2 ) a —, where a is 0, 1, or 2, or —NR 6 —, where R 6 is H or C 1 -C 6 alkyl; —SO— or S(O) 2 , such that optically active isomers are included whenever chiral centers are present;
W m wherein m is 0 or greater, is such that any of the carbons on the aryl ring may be replaced by at least two heteroatoms selected from the group consisting of N, S and O;
n is a whole number between 0 and 5; and
Y is one or more C 1 -C 5 alkyl groups, C 1 -C 5 haloalkyl groups, C 1 -C 5 alkoxy groups, C 1 -C 5 haloalkoxy groups, C 1 -C 5 aliphatic acylamino groups, nitro groups, halogen atoms, an aromatic heterocyclic group having 5-6 ring atoms and having at least one heteroatom, the heteroatom being N, O, or S; a C 3 -C 7 cycloalkane or a C 3 -C 7 cycloalkene optionally substituted with C 1 -C 5 alkyl groups.
(b) and a carrier.
wherein the composition stimulates hair growth on an epithelial surface to which the composition has been applied.
2 . The topical composition according to claim 1 , wherein when X is NHR 4 , R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate.
3 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
4 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
5 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
6 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
7 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S(O 2 )—, and m and n are 0.
8 . The topical composition according to claim 2 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
9 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , a is 0, 1, or 2, and m and n are 0.
10 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
11 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
12 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
13 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —S(O) 2 —, and m and n are 0.
14 . The topical composition according to claim 1 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, R 1 , B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
15 . The topical composition according to claim 1 , wherein when X is OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate.
16 . The topical composition according to claim 15 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
17 . The topical composition according to claim 15 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
18 . The topical composition according to claim 15 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
19 . The topical composition according to claim 15 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
20 . The topical composition according to claim 15 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
21 . The topical composition according to claim 15 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
22 . The topical composition according to claim 1 , wherein the composition is an ophthalmic composition.
23 . The topical composition according to claim 1 , wherein the composition restores pigmentation to depigmented hair.
24 . An ophthalmic composition for reducing intraocular pressure, comprising.
(a) at least one compound of formula I or a salt of Formula I:
wherein
X is
NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate;
a cyclic substituent in which nitrogen is part of the ring, represented as —N(R 4 ) 2 , wherein (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10; or
OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate; and
R 1 , R 1 and R 3 each independently is H, C 1 -C 6 alkyl, a phosphate group, a monosaccharide, a disaccharide or a polysaccharide;
the simple straight line represents a bond lying approximately in the surface plane; the dashed bonds represent a single or double bond which can be in the cis or trans configuration, wherein there is at least one double bond; the wedge shaped bond is directed to the front of surface plane; and the hatched bond is directed in the back of the surface plane;
B is —O—, —S—, —(CH 2 ) a —, where a is 0, 1, or 2, or —NR 6 —, where R 6 is H or C 1 -C 6 alkyl; —SO— or S(O) 2 , such that optically active isomers are included whenever chiral centers are present;
W m wherein m is 0 or greater, is such that any of the carbons on the aryl ring may be replaced by at least two heteroatoms selected from the group consisting of N, S and O;
n is a whole number between 0 and 5; and
Y is one or more C 1 -C 5 alkyl groups, C 1 -C 5 haloalkyl groups, C 1 -C 5 alkoxy groups, C 1 -C 5 haloalkoxy groups, C 1 -C 5 aliphatic acylamino groups, nitro groups, halogen atoms, an aromatic heterocyclic group having 5-6 ring atoms and having at least one heteroatom, the heteroatom being N, O, or S; a C 3 -C 7 cycloalkane or a C 3 -C 7 cycloalkene optionally substituted with C 1 -C 5 alkyl groups.
(b) and a carrier.
25 . The ophthalmic composition according to claim 24 , wherein when X is NHR 4 , R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate.
26 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
27 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
28 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
29 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
30 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S(O 2 )—, and m and n are 0.
31 . The ophthalmic composition according to claim 25 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
32 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 , and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , where a is 0, 1, or 2, and m and n are 0.
33 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
34 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
35 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
36 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —S(O) 2 —, and m and n are 0.
37 . The ophthalmic composition according to claim 24 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, R 1 , B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
38 . The ophthalmic composition according to claim 24 , wherein when X is OR 5 , R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate.
39 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
40 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
41 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
42 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
43 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
44 . The ophthalmic composition according to claim 38 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
45 . The ophthalmic composition according to claim 24 , wherein the composition comprises at least one compound selected from the group consisting of 16-phenoxy tetranor PGF 2α cyclopropyl amide, 17 phenyl trinor PGF 2α cyclopropylamide; 16-phenoxy tetranor PGF 2α cyclopropyl methyl amide; 17 phenyl trinor PGF 2α cyclopropyl methyl amide; (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α ) cyclopropyl amide and (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α ) cyclopropyl methyl amide.
46 . The ophthalmic composition according to claim 24 , wherein the at least one compound of formula I is 16-phenoxy tetranor PGF 2α cyclopropyl amide.
47 . The composition according to claim 24 , wherein that least one compound of formula I is 17 phenyl trinor PGF 2α cyclopropylamide.
48 . The composition according to claim 24 , wherein the at least one compound of formula I is 16-phenoxy tetranor PGF 2α cyclopropyl methyl amide.
49 . The composition according to claim 24 , wherein the at least one compound of formula I is 17 phenyl trinor PGF 2α cyclopropyl methyl amide.
50 . The composition according to claim 24 , wherein the at least one compound of formula I is (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α ) cyclopropyl amide.
51 . The composition according to claim 24 , wherein the at least one compound of formula is (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α ) cyclopropyl methyl amide.
52 . A method for treating an epithelial-related condition, the method comprising the steps
(a) preparing at least one compound of Formula I or a salt of Formula I:
wherein
X is
NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate;
a cyclic substituent in which nitrogen is part of the ring, represented as —N(R 4 ) 2 , wherein (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10; or
OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate; and R 1 , R 2 and R 3 each independently is H, C 1 -C 6 alkyl, a phosphate group, a monosaccharide, a disaccharide or a polysaccharide;
the simple straight line represents a bond lying approximately in the surface plane; the dashed bonds represent a single or double bond which can be in the cis or trans configuration, wherein there is at least one double bond; the wedge shaped bond is directed to the front of surface plane; and the hatched bond is directed in the back of the surface plane;
B is —O—, —S—, (CH 2 ) a , where a is 0, 1, or 2, or —NR 6 —, where R 6 is H or C 1 -C 6 alkyl; —SO— or (SO) 2 , such that optically active isomers are included whenever chiral centers are present;
W m wherein m is 0 or greater, is such that any of the carbons on the aryl ring may be replaced by at least two heteroatoms selected from the group consisting of N, S and O;
n is a whole number between 0 and 5; and
Y is one or more C 1 -C 5 alkyl groups, C 1 -C 5 haloalkyl groups, C 1 -C 5 alkoxy groups, C 1 -C 5 haloalkoxy groups, C 1 -C 5 aliphatic acylamino groups, nitro groups, halogen atoms, an aromatic heterocyclic group having 5-6 ring atoms and having at least one heteroatom, the heteroatom being N, O, or S; a C 3 -C 7 cycloalkane or a C 3 -C 7 cycloalkene optionally substituted with C 1 -C 5 alkyl groups;
(b) formulating a composition comprising the at least one compound of step (a) and a carrier; and
(c) topically applying onto an epithelial surface of a subject, including a human, in need thereof, a cosmetically effective amount of the composition.
53 . The method according to claim 52 , wherein when X is NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate.
54 . The method according to 53 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
55 . The method according to claim 53 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
56 . The method according to claim 53 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
57 . The method according to claim 53 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
58 . The method according to claim 53 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(SO 2 )—, and m and n are 0.
59 . The method according to claim 53 , wherein when X is —NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
60 . The method according to claim 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , where a is 0, 1, or 2, and m and n are 0.
61 . The method according to claim 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
62 . The method according to 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
63 . The method according to claim 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
64 . The method according to claim 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
65 . The method according to claim 52 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
66 . The method according to claim 52 , wherein X is OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate.
67 . The method according to 66 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
68 . The method according to claim 66 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
69 . The method according to 66 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
70 . The method according to claim 66 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
71 . The method according to claim 66 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
72 . The method according to claim 66 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
73 . The method according to claim 52 , wherein the epithelial-related condition is alopecia.
74 . The method according to claim 52 , wherein the epithelial surface onto which the composition is applied topically to an eyelid.
75 . The method according to claim 52 , wherein the epithelial-related condition is alopecia of at least one eyelash.
76 . The method according to claim 52 , wherein the epithelial surface onto which the composition is applied topically is a face.
77 . The method according to claim 52 , wherein the condition is alopecia of at least one eyebrow.
78 . The method according to claim 52 , wherein the epithelial surface onto which the composition is applied topically is a scalp.
79 . The method according to claim 52 , wherein the epithelial surface onto which the composition is applied topically is above a lip.
80 . The method according to claim 52 , further comprising the step of restoring hair color to depigmented hair.
81 . The method according to claim 52 , further comprising the step of stimulating hair growth.
82 . A method for reducing intraocular pressure, the method comprising the steps of
(a) preparing at least one compound of Formula I or a salt of Formula I:
X is
NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate;
a cyclic substituent in which nitrogen is part of the ring, represented as —N(R 4 ) 2 , wherein (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10; or
OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate; and R 1 , R 1 and R 3 each independently is H, C 1 -C 6 alkyl, a phosphate group, a monosaccharide, a disaccharide or a polysaccharide;
the simple straight line represents a bond lying approximately in the surface plane; the dashed bonds represent a single or double bond which can be in the cis or trans configuration, wherein there is at least one double bond; the wedge shaped bond is directed to the front of surface plane; and the hatched bond is directed in the back of the surface plane;
B is —O—, —S—, —(CH 2 ) a —, where a is 0, 1, or 2, or —NR 6 —, where R 6 is H or C 1 -C 6 alkyl; —SO— or (SO) 2 , such that optically active isomers are included whenever chiral centers are present;
W m wherein m is 0 or greater, is such that any of the carbons on the aryl ring may be replaced by at least two heteroatoms selected from the group consisting of N, S and O;
n is a whole number between 0 and 5; and
Y is one or more C 1 -C 5 alkyl groups, C 1 -C 5 haloalkyl groups, C 1 -C 5 alkoxy groups, C 1 -C 5 haloalkoxy groups, C 1 -C 5 aliphatic acylamino groups, nitro groups, halogen atoms, an aromatic heterocyclic group having 5-6 ring atoms and having at least one heteroatom, the heteroatom being N, O, or S; a C 3 -C 7 cycloalkane or a C 3 -C 7 cycloalkene optionally substituted with C 1 -C 5 alkyl groups;
(b) formulating an ophthalmic composition comprising the at least one compound of step (a) and a carrier; and
(c) administering an intraocular pressure reducing amount of the ophthalmic composition to an eye of a subject in need thereof.
83 . The method according to claim 82 , wherein when X is NHR 4 , wherein R 4 is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate.
84 . The method according to 83 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
85 . The method according to claim 83 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
86 . The method according to claim 83 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
87 . The method according to claim 83 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
88 . The method according to claim 83 , wherein when X is NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —(SO 2 )—, and m and n are 0.
89 . The method according to claim 83 , wherein when X is —NHR 4 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
90 . The method according to claim 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is (CH 2 ) a , where a is 0, 1, or 2, and m and n are 0.
91 . The method according to claim 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
92 . The method according to 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
93 . The method according to claim 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
94 . The method according to claim 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
95 . The method according to claim 83 , wherein when X is —N(R 4 ) 2 and (R 4 ) 2 is —(CH 2 ) k- where k is 2 to 10, R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
96 . The method according to claim 83 , wherein X is OR 5 , where R 5 is alkenyl, aryl, alkylcycloalkyl, a heterocycle or a carbamate.
97 . The method according to 96 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —(CH 2 ) a —, where a is 0, 1, or 2, and m and n are 0.
98 . The method according to claim 96 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —O—, and m and n are 0.
99 . The method according to 96 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —S—, and m and n are 0.
100 . The method according to claim 96 , wherein when X is —OR 5 2 , R 1 , R 2 and R 3 each independently is H, B is —SO—, and m and n are 0.
101 . The method according to claim 96 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —SO 2 —, and m and n are 0.
102 . The method according to claim 96 , wherein when X is —OR 5 , R 1 , R 2 and R 3 each independently is H, B is —NR 6 — where R 6 is H or C 1 -C 6 alkyl and m and n are 0
103 . The method according to claim 82 , wherein the composition comprises at least one compound selected from the group consisting of 16-phenoxy tetranor PGF 2α cyclopropyl amide, 17 phenyl trinor PGF 2α cyclopropylamide; 16-phenoxy tetranor PGF 2α cyclopropyl methyl amide; 17 phenyl trinor PGF 2α cyclopropyl methyl amide; (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α ) cyclopropyl amide; and (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α )cyclopropyl methyl amide.
104 . The method according to claim 82 , wherein the at least one compound of formula I is 16-phenoxy tetranor PGF 2α cyclopropyl amide.
105 . The method according to claim 82 , wherein the at least one compound of formula I is 17 phenyl trinor PGF 2α cyclopropylamide.
106 . The method according to claim 82 , wherein the at least one compound of formula I 16-phenoxy tetranor PGF 2α cyclopropyl methyl amide.
107 . The method according to claim 82 , wherein the at least one compound of formula I is 17 phenyl trinor PGF 2α cyclopropyl methyl amide.
108 . The method according to claim 82 , wherein the at least one compound of formula I is (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α )cyclopropyl amide.
109 . The method according to claim 82 , wherein the at least one compound of formula is (16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF 2α )cyclopropyl methyl amide.