US2012202773A1PendingUtilityA1
Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising ep4 agonist as active ingredient
Est. expiryJul 23, 2021(expired)· nominal 20-yr term from priority
Inventors:Toru MaruyamaKaoru KobayashiTohru KambeTakayuki MaruyamaHideyuki YoshidaAkio NishiuraNobutaka Abe
A61P 43/00A61P 9/12A61P 37/00A61P 7/08A61P 9/10A61P 37/02A61P 35/04A61P 41/00A61P 7/02A61P 3/14A61P 29/00A61P 25/28A61P 31/04A61P 25/00A61P 25/20A61P 35/00A61P 21/00A61K 9/1647A61K 31/4015A61K 9/19A61P 11/06A61K 31/5575A61P 19/10A61P 17/14A61P 19/02A61P 1/16A61P 19/08A61K 9/0019A61K 9/2054A61K 31/41A61P 11/00A61P 1/02A61P 17/02A61P 1/04A61P 15/08A61P 13/12C07C 405/0033A61K 31/559A61P 19/00
51
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
A pharmaceutical composition for topical administration for prevention and/or treatment of diseases associated with decrease in bone mass comprising an EP 4 agonist as an active ingredient. An EP 4 agonist, in which includes a compound possessing prostaglandin skeleton as a representative, possesses promoting action on bone formation, so it is useful for prevention and/or treatment of diseases associated with decrease in bone mass (bone diseases such as primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss and bone necrosis, postoperative osteogenesis, alternative therapy for bone grafting).
Claims
exact text as granted — not AI-modified1 - 19 . (canceled)
20 . A compound selected from the group of formula (I-3)
wherein is is (1) single bond or (2) double bond,
R 19-3 and R 20-3 are each independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen atom,
T 3 is (1) oxygen atom or (2) sulfur atom,
X 3 is (1) —CH 2 —, (2) —O— or (3) —S—,
A 3 is A 1-3 or A 2-3 ,
A 1-3 is
(1) C2-8 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-8 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-8 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
A 2-3 is -G 1-3 -G 2-3 -G 3-3 -,
G 1-3 is
(1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
G 2-3 is
(1) —Y 3 —,
(2) -(ring1 3 )-,
(3) —Y 3 -(ring1 3 )-,
(4) -(ring1 3 )-Y 3 — or
(5) —Y 3 —(C1-4 alkylene)-(ring1 3 )-,
Y 3 is (1) —S—, (2) —SO—, (3) —SO 2 —, (4) —O— or (5) —NR 1-3 —,
R 1-3 is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl,
G 3-3 is
(1) bond,
(2) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(3) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(4) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
D 3 is D 1-3 or D 2-3 ,
D 1-3 is
(1) —COOH,
(2) —COOR 2-3 ,
(3) tetrazol-5-yl or
(4) CONR 3-3 SO 2 R 4-3 ,
R 2-3 is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl or (4) biphenyl,
R 3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R 4-3 is (1) C1-10 alkyl or (2) phenyl,
D 2-3 is
(1) —CH 2 OH,
(2) —CH 2 OR 5-3 ,
(3) hydroxy,
(4) —OR 5-3 ,
(5) formyl,
(6) —CONR 6-3 R 7-3 ,
(7) —CONR 6-3 SO 2 R 8-3 ,
(8) —CO—(NH-amino acid residue-CO) m-3 —OH,
(9) —O—(CO— amino acid residue —NH) m-3 —H,
(10) —COOR 9-3 ,
(11) —OCO—R 10-3 ,
(12) —COO—Z 1-3 —Z 2-3 —Z 3-3 ,
R 5-3 is C1-10 alkyl,
R 6-3 and R 7-3 are each independently, (1) hydrogen atom or (2) C 1-10 alkyl,
R 8-3 is C 1-10 alkyl substituted by phenyl,
R 9-3 is (1) C 1-10 alkyl substituted by biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
R 10-3 is (1) phenyl or (2) C1-10 alkyl,
m-3 is 1 or 2,
Z 1-3 is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene,
Z 2-3 is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR 11-3 —, (5) —NR 12-3 CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO 2 —, (10) —NR 13-3 —, (11) —NR 14-3 CONR 15-3 —, (12) —NR 16-3 COO—, (13) —OCONR 17-3 — or (14) —OCOO—,
Z 3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 alkynyl, (5) ring2 3 or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR 18-3 — or ring2 3 ,
R 11-3 , R 12-3 , R 13-3 , R 14-3 , R 15-3 , R 16-3 , R 17-3 and R 18-3 are each independently, (1) hydrogen atom or (2) C1-15 alkyl,
R 11-3 and Z 3-3 may be taken together with the nitrogen atom to which they are attached to form 5 to 7 membered saturated monoheterocyclic ring, and the heterocyclic ring may contain other one hetero atom selected from oxygen, nitrogen and sulfur atom,
E 3 is E 1-3 or E 2-3 ,
E 1-3 is
(1) C3-7 cycloalkyl or
(2) ring3 3 ,
E 2-3 is
(1) C3-7 cycloalkyl,
(2) ring4 3 or
(3) ring5 3 ,
ring1 3 and ring5 3 are optionally substituted by 1-3 R 21-3 and/or R 22-3 ,
ring3 3 is optionally substituted by 1-2 R 21-3 ,
C3-7 cycloalkyl represented by E 2-3 is substituted by one of R 21-3 or R 22-3 , and optionally substituted by another 1-2 R 21-3 and/or R 22-3 ,
ring4 3 is substituted by one of R 22-3 , optionally substituted by another 1-2 R 21-3 and/or R 22-3 , and
optionally substituted by heterocyclic ring formed by R 11-3 , Z 3-3 and the nitrogen to which Z 3-3 is attached or ring2 3 may be substituted by R 23-3 ,
R 21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or (6) phenyl,
R 22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10 alkylthio, (4) hydroxy, (5) —NR 24-3 R 25-3 , (6) C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8) C1-10 alkyl substituted by —NR 24-3 R 25-3 , (9) ring6 3 , (10) —O-ring7 3 , (11) C1-10 alkyl substituted by ring7 3 , (12) C2-10 alkenyl substituted by ring7 3 , (13) C2-10 alkynyl substituted by ring7 3 , (14) C1-10 alkoxy substituted by ring7 3 , (15) C1-10 alkyl substituted by —O-ring7 3 , (16) —COOR 26-3 or (17) C1-10 alkoxy substituted by 1-3 halogen atom(s),
R 24-3 , R 25-3 and R 26-3 are each independently, (1) hydrogen atom or (2) C 1-10 alkyl,
R 23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR 27-3 —,
R 27-3 is (1) hydrogen atom or (2) C1-10 alkyl,
ring1 3 , ring2 3 , ring5 3 , ring6 3 and ring7 3 are
(1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or
(2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated,
ring3 3 and ring4 3 are (1) thienyl, (2) phenyl or (3) furyl,
ring6 3 and ring7 3 may be substituted by 1-3 R 28-3 ,
R 28-3 is (1) C1-1 0 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), and
wherein
(1) when T 3 is oxygen atom, X 3 is CH 2 —, A 3 is A 1-3 , and D 3 is D 1-3 , E 3 is E 2-3 ,
(2) ring5 3 is not C3-7 cycloalkyl, phenyl, thienyl nor furyl,
(3) ring6 3 is phenyl, then phenyl have at least one R 28-3 ,
or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
21 . The compound according to claim 20 , wherein —Y 3 — group in A 3 group of a compound of formula (I-3) is —S— group.
22 . The compound according to claim 20 , which is a compound selected from the group consisting of
(1) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid ethyl ester, (2) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (3) (5S,15α,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (4) (15α,13E)-5,5-dimethyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (5) (15α,13E)-5,5-ethano-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (6) (5R,15α,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (7) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (8) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-2,3,4,17,18,19,20-heptanor-1,5-(2,5-interthienylene)-8-azaprost-13-enoic acid, (9) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-hydroxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (10) (15α,13E)-9-oxo-15-hydroxy-16-((E)-1-propenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (11) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (12) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (13) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-methylfuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (14) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (15) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-methoxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (16) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (17) (15α,13E)-9-oxo-15-hydroxy-16-(3-(3-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (18) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (19) (15α,13E)-9-oxo-15-hydroxy-16-(3-cyclopropylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (20) (13E)-9-oxo-15-hydroxy-16,16-difluoro-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (21) (15α,13E)-9-oxo-15-hydroxy-16-(3-benzyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (22) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (23) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (24) (15α,13E)-2,7-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (25) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (26) (15α,13E)-2,7-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (27) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,6-(1,3-interphenylene)-3,4,5,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (28) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (29) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3-ypthiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (30) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interfurylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (31) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (32) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(tetrazol-5-yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (33) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-1-yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (34) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (35) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (36) (15α,13E)-9-oxo-15-hydroxy-16-(3-cyclopropyloxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (37) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (38) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (39) (15α,13E)-9-oxo-15-hydroxy-16-cyclopentyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (40) (15α,13E)-9-oxo-15-hydroxy-16-(thiophen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (41) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (42) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (43) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (44) (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (46) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (47) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (48) (15α,13E)-2,3-methano-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (49) (15α,13E)-9-oxo-15-hydroxy-16-(3-t-butylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (50) (13E)-9-oxo-15-hydroxy-16a-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (51) (13E)-9-oxo-15-hydroxy-16β-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (52) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (53) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (54) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (55) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (56) (15β,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (57) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (58) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-4-(3-hydroxyisoxazol-5-yl)-1,2,3,17,18,19,20-heptanor-5-thia-8-azaprost-13-ene, (59) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-oxadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (60) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-thiadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (61) (15α,13E)-1-methoxy-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene, (62) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (63) (15α,13E)-1-methoxy-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene, (64) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3-yl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (65) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoic acid, (66) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoic acid, (67) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoic acid, (68) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylaminomethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid hydrochloride, (69) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (70) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (71) (15α,13E)-9-oxo-15-hydroxy-16-(2-methyloxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (72) (15α,13E)-9-oxo-15-hydroxy-16-(benzofuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (73) (15α,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (74) (15α,13E)-9-oxo-15-hydroxy-16-(4,5-dimethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (75) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (76) (15α,13E)-9-oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (77) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylisoxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (78) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (79) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (80) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (81) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (82) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (83) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (84) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (85) (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (86) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (87) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (88) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (89) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (90) (15α,13E)-9-oxo-15-hydroxy-16-(3 ,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (91) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (92) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (93) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (94) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (95) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-hydroxymethylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (96) (15 a,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol, (97) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol, (98) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (99) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (100) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (101) (15α,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (102) (15α)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoic acid ethyl ester, (103) (15α)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoic acid, (104) (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoic acid, (105) (15α)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoic acid, (106) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-mesylamide, (107) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-phenylsulfonylamide, (108) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-benzylsulfonylamide, (109) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid N-benzylsulfonylamide, (110) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-benzylsulfonylcarbamoylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (111) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (112) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (113) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (114) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl t-butoxycarbonylglycylglycinate, (115) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl glycylglycinate monohydrochloride, (116) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl glycinate methanesulfonic acid salt, (117) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl tryptophanate bis-trifluoroacetic acid salt, (118) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl tyrosinate trifluoroacetic acid salt, (119) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid isopropyloxycarbonylmethyl ester, (120) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid dimethylaminocarbonylmethyl ester, (121) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (122) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (123) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al, (124) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-al, (125) (15α,13E)-9-oxo-15-hydroxy-16-(3-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (126) (15α,13E)-1-benzoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene, (127) (15α,13E)-1-butanoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene, (128) (15α,13E)-1-(2-aminoacetyloxy)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene trifluoromethanesulfonic acid salt, (129) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester, (130) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic acid 4-phenylbenzyl ester, (131) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic acid 2-dimethylaminoethyl ester hydrochloride, (132) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester, (133) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester, (134) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester, (135) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-heptanoyl-N-methylcarbamoylmethyl ester, (136) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid(4-hexylpiperazin-1-yl)carbonylmethyl ester, (137) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester, (138) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(dipropylamino)acetyloxy)ethyl ester, (139) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl ester, (140) (15a,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester, (141) (15α,13E)-9-oxo-15-hydroxy-16-(4-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (142) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (143) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (144) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (145) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (147) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (148) (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (149) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (150) (15α,13E)-7-(6-carboxyindol-3-yl)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,2,3,4,5,6,17,18,19,20-decanor-8-azaprost-13-ene, (151) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (152) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxyoxazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (153) (15α,13E)-1,7-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,6,17,18,19,20-nonanor-8-azaprost-13-enoic acid, (154) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (155) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (156) (15α,13E)-3,3-Ethano-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (157) (15α,13E)-1,5-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (158) (15α,13E)-1,5-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (159) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-fluoromethylbenzyloxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (160) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-3-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (161) (15α,13E)-9-oxo-15-hydroxy-16-cyclopropyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (162) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (163) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (164) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (165) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-4-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (166) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (167) (15α,13E)-9-oxo-15-hydroxy-16-cyclopentyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (168) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (169) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (170) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (171) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(6-carboxypyridin-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (172) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester, (173) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl ester, (174) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(adamantan-1-ylcarbonyloxy)ethyl ester, (175) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(1-ethyl-1-methylbutanoyloxy)ethyl ester, (176) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-(2-(1-ethyl-1-methylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (177) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-dihydroxyphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (178) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(2-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (179) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (180) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (181) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-trifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (182) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3,5-ditrifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (183) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-t-butylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (184) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (185) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (186) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-chlorophenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (187) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-methoxyphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (188) (15α,13E)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (189) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (190) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (191) (15α,13E)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (192) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (193) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (194) (15α,13E)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (195) (15α,13E)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (196) (15α,13E)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, and (197) (15α,13E)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
23 . The compound according to claim 22 , which is a compound selected from the group consisting of
(2) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (25) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (34) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (35) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (38) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (70) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (86) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (121) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (122) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (129) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester, (132) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester, (133) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester, (134) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester, (135) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-heptanoyl-N-methylcarbamoylmethyl ester, (136) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid(4-hexylpiperazin-1-yl)carbonylmethyl ester, (137) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester, (138) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(dipropylamino)acetyloxy)ethyl ester, (139) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl ester, (140) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester, (172) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester, (173) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl ester, (174) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(adamantan-1-ylcarbonyloxy)ethyl ester, (175) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(1-ethyl-1-methylbutanoyloxy)ethyl ester,
or a non-toxic salt thereof, or cyclodextrin clathrate thereof
24 . The compound according to claim 20 , which is (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
25 . A pharmaceutical composition comprising a compound selected from the group of formula (I-3)
wherein is (1) single bond or (2) double bond,
R 19-3 and R 20-3 are each independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen atom,
T 3 is (1) oxygen atom or (2) sulfur atom,
X 3 is (1) —CH 2 —, (2) —O— or (3) —S—,
A 3 is A 1-3 or A 2-3 ,
A 1-3 is
(1) C2-8 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-8 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-8 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
A 2-3 is -G 1-3 -G 2-3 -G 3-3 -,
G 1-3 is
(1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
G 2-3 is
(1) —Y 3 —,
(2) -(ring1 3 )-,
(3) —Y 3 -(ring1 3 )-,
(4) -(ring1 3 )-Y 3 — or
(5) —Y 3 —(C1-4 alkylene)-(ring1 3 )-,
Y 3 is (1) —S—, (2) —SO—, (3) —SO 2 —, (4) —O— or (5) —NR 1-3 —,
R 1-3 is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl,
G 3-3 is
(1) bond,
(2) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(3) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(4) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
D 3 is D 1-3 or D 2-3 ,
D 1-3 is
(1) —COOH,
(2) —COOR 2-3 ,
(3) tetrazol-5-yl or
(4) CONR 3-3 SO 2 R 4-3 ,
R 2-3 is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl or
(4) biphenyl,
R 3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R 4-3 is (1) C1-10 alkyl or (2) phenyl,
D 2-3 is
(1) —CH 2 OH,
(2) —CH 2 OR 5-3 ,
(3) hydroxy,
(4) —OR 5-3 ,
(5) formyl,
(6) —CONR 6-3 R 7-3 ,
(7) —CONR 6-3 SO 2 R 8-3 ,
(8) —CO—(NH-amino acid residue-CO) m-3 —OH,
(9) —O—(CO— amino acid residue —NH) m-3 —H,
(10) —COOR 9-3 ,
(11) —OCO—R 10-3 ,
(12) —COO—Z 1-3 —Z 2-3 —Z 3-3 ,
R 5-3 is C1-10 alkyl,
R 6-3 and R 7-3 are each independently, (1) hydrogen atom or (2) C1-10 alkyl,
R 8-3 is C1-10 alkyl substituted by phenyl,
R 9-3 is (1) C1-10 alkyl substituted by biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
R 10-3 is (1) phenyl or (2) C1-10 alkyl,
m-3 is 1 or 2,
Z 1-3 is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene,
Z 2-3 is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR 11-3 —, (5) —NR 12-3 CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO 2 —, (10) —NR 13-3 —, (11) —NR 14-3 CONR 15-3 —, (12) —NR 16-3 COO—, (13) —OCONR 17-3 — or (14) —OCOO—,
Z 3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 alkynyl, (5) ring2 3 or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR 18-3 — or ring2 3 ,
R 11-3 , R 12-3 , R 13-3 , R 14-3 , R 15-3 , R 16-3 , R 17-3 and R 18-3 are each independently, (1) hydrogen atom or (2) C1-15 alkyl,
R 11-3 and Z 3-3 may be taken together with the nitrogen atom to which they are attached to form 5 to 7 membered saturated monoheterocyclic ring, and the heterocyclic ring may contain other one hetero atom selected from oxygen, nitrogen and sulfur atom,
E 3 is E 1-3 or E 2-3 ,
E 1-3 is
(1) C3-7 cycloalkyl or
(2) ring3 3 ,
E 2-3 is
(1) C3-7 cycloalkyl,
(2) ring4 3 or
(3) ring5 3 ,
ring1 3 and ring5 3 are optionally substituted by 1-3 R 21-3 and/or R 22-3 ,
ring3 3 is optionally substituted by 1-2 R 21-3 ,
C3-7 cycloalkyl represented by E 2-3 is substituted by one of R 21-3 or R 22-3 , and optionally substituted by another 1-2 R 21-3 and/or R 22-3 ,
ring4 3 is substituted by one of R 22-3 , optionally substituted by another 1-2 R 21-3 and/or R 22-3 , and
optionally substituted by heterocyclic ring formed by R 11-3 , Z 3-3 and the nitrogen to which Z 3-3 is attached or ring2 3 may be substituted by R 23-3 ,
R 21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or (6) phenyl,
R 22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10 alkylthio, (4) hydroxy, (5) —NR 24-3 R 25-3 , (6) C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8) C1-10 alkyl substituted by —NR 24-3 R 25-3 , (9) ring6 3 , (10) —O-ring7 3 , (11) C1-10 alkyl substituted by ring7 3 , (12) C2-10 alkenyl substituted by ring7 3 , (13) C2-10 alkynyl substituted by ring7 3 , (14) C1-10 alkoxy substituted by ring7 3 , (15) C1-10 alkyl substituted by —O-ring7 3 , (16) —COOR 26-3 or (17) C1-10 alkoxy substituted by 1-3 halogen atom(s),
R 24-3 , R 25-3 and R 26-3 are each independently, (1) hydrogen atom or (2) C1-10 alkyl,
R 23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR 27-3 —,
R 27-3 is (1) hydrogen atom or (2) C1-10 alkyl,
ring1 3 , ring2 3 , ring5 3 , ring6 3 and ring7 3 are
(1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or
(2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated,
ring3 3 and ring4 3 are (1) thienyl, (2) phenyl or (3) furyl,
ring6 3 and ring7 3 may be substituted by 1-3 R 28-3 ,
R 28-3 is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), and
wherein
(1) when T 3 is oxygen atom, X 3 is CH 2 —, A 3 is A 1-3 , and D 3 is D 1-3 , E 3 is E 2-3 ,
(2) ring5 3 is not C3-7 cycloalkyl, phenyl, thienyl nor furyl,
(3) ring6 3 is phenyl, then phenyl have at least one R 28-3 ,
or a non-toxic salt thereof, or a cyclodextrin clathrate thereof, as an active ingredient.
26 . A sustained release formulation comprising a compound selected from the group of formula (I-3)
wherein is (1) single bond or (2) double bond,
R 19-3 and R 20-3 are each independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen atom,
T 3 is (1) oxygen atom or (2) sulfur atom,
X 3 is (1) —CH 2 —, (2) —O— or (3) —S—,
A 3 is A 1-3 or A 2-3 ,
A 1-3 is
(1) C2-8 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-8 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-8 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
A 2-3 is -G 1-3 -G 2-3 -G 3-3 -,
G 1-3 is
(1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(3) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
G 2-3 is
(1) —Y 3 —,
(2) -(ring1 3 )-,
(3) —Y 3 -(ring1 3 )-,
(4) -(ring1 3 )-Y 3 — or
(5) —Y 3 —(C1-4 alkylene)-(ring1 3 )-,
Y 3 is (1) —S—, (2) —SO—, (3) —SO 2 —, (4) —O— or (5) —NR 1-3 —,
R 1-3 is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl,
G 3-3 is
(1) bond,
(2) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(3) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or
(4) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl,
D 3 is D 1-3 or D 2-3 ,
D 1-3 is
(1) —COOH,
(2) —COOR 2-3 ,
(3) tetrazol-5-yl or
(4) CONR 3-3 SO 2 R 4-3 ,
R 2-3 is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl or (4) biphenyl,
R 3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R 4-3 is (1) C1-10 alkyl or (2) phenyl,
D 2-3 is
(1) —CH 2 OH,
(2) —CH 2 OR 5-3 ,
(3) hydroxy,
(4) —OR 5-3 ,
(5) formyl,
(6) —CONR 6-3 R 7-3 ,
(7) —CONR 6-3 SO 2 R 8-3 ,
(8) —CO—(NH-amino acid residue-CO) m-3 —OH,
(9) —O—(CO— amino acid residue —NH) m-3 —H,
(10) —COOR 9-3 ,
(11) —OCO—-R 10-3 ,
(12) —COO—Z 1-3 —Z 2-3 —Z 3-3 ,
R 5-3 is C1-10 alkyl,
R 6-3 and R 7-3 are each independently, (1) hydrogen atom or (2) C1-10 alkyl,
R 8-3 is C1-10 alkyl substituted by phenyl,
R 9-3 is (1) C1-10 alkyl substituted by biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
R 10-3 is (1) phenyl or (2) C1-10 alkyl,
m-3 is 1 or 2,
Z 1-3 is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene,
Z 2-3 is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR 11-3 —, (5) —NR 12-3 CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO 2 —, (10) —NR 13-3 —, (11) —NR 14-3 CONR 15-3 —, (12) —NR 16-3 COO—, (13) —OCONR 17-3 — or (14) —OCOO—,
Z 3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 alkynyl, (5) ring2 3 or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR 18-3 — or ring2 3 ,
R 11-3 , R 12-3 , R 13-3 , R 14-3 , R 15-3 , R 16-3 , R 17-3 and R 18-3 are each independently, (1) hydrogen atom or (2) C1-15 alkyl,
R 11-3 and Z 3-3 may be taken together with the nitrogen atom to which they are attached to form 5 to 7 membered saturated monoheterocyclic ring, and the heterocyclic ring may contain other one hetero atom selected from oxygen, nitrogen and sulfur atom,
E 3 is E 1-3 or E 2-3 ,
E 1-3 is
(1) C3-7 cycloalkyl or
(2) ring3 3 ,
E 2-3 is
(1) C3-7 cycloalkyl,
(2) ring4 3 or
(3) ring5 3 ,
ring1 3 and ring5 3 are optionally substituted by 1-3 R 21-3 and/or R 22-3 ,
ring3 3 is optionally substituted by 1-2 R 21-3 ,
C3-7 cycloalkyl represented by E 2-3 is substituted by one of R 21-3 or R 22-3 , and optionally substituted by another 1-2 R 21-3 and/or R 22-3 ,
ring4 3 is substituted by one of R 22-3 , optionally substituted by another 1-2 R 21-3 and/or R 22-3 , and
optionally substituted by heterocyclic ring formed by R 11-3 , Z 3-3 and the nitrogen to which Z 3-3 is attached or ring2 3 may be substituted by R 23-3 ,
R 21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or (6) phenyl,
R 22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10 alkylthio, (4) hydroxy, (5) —NR 24-3 R 25-3 , (6) C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8) C1-10 alkyl substituted by —NR 24-3 R 25-3 , (9) ring6 3 , (10) —O-ring7 3 , (11) C1-10 alkyl substituted by ring7 3 , (12) C2-10 alkenyl substituted by ring7 3 , (13) C2-10 alkynyl substituted by ring7 3 , (14) C1-10 alkoxy substituted by ring7 3 , (15) C1-10 alkyl substituted by —O-ring7 3 , (16) —COOR 26-3 or (17) C1-10 alkoxy substituted by 1-3 halogen atom(s),
R 24-3 , R 25-3 and R 26-3 are each independently, (1) hydrogen atom or (2) C1-10 alkyl,
R 23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR 27-3 —,
R 27-3 is (1) hydrogen atom or (2) C1-10 alkyl,
ring1 3 , ring2 3 , ring5 3 , ring6 3 and ring7 3 are
(1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or
(2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated,
ring3 3 and ring4 3 are (1) thienyl, (2) phenyl or (3) furyl,
ring6 3 and ring7 3 may be substituted by 1-3 R 28-3 ,
R 28-3 is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), and
wherein
(1) when T 3 is oxygen atom, X 3 is CH 2 —, A 3 is A 1-3 , and D 3 is D 1-3 , E 3 is E 2-3 ,
(2) ring5 3 is not C3-7 cycloalkyl, phenyl, thienyl nor furyl,
(3) ring6 3 is phenyl, then phenyl have at least one R 28-3 ,
or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
27 . The formulation according to claim 26 , wherein the sustained release formulation is a microsphere, a microcapsule, a nanosphere or a film.
28 . A method for prevention and/or treatment of diseases associated with decrease in bone mass comprising administrating to a subject an effective amount of a compound of (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
29 . The method according to claim 28 , wherein the disease associated with decrease in bone mass is fracture.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.