ZA200506532B - Methods of treatment using an EP2 selective agonist - Google Patents
Methods of treatment using an EP2 selective agonist Download PDFInfo
- Publication number
- ZA200506532B ZA200506532B ZA200506532A ZA200506532A ZA200506532B ZA 200506532 B ZA200506532 B ZA 200506532B ZA 200506532 A ZA200506532 A ZA 200506532A ZA 200506532 A ZA200506532 A ZA 200506532A ZA 200506532 B ZA200506532 B ZA 200506532B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkylene
- independently
- alkyl
- facilitating
- substituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 9
- 239000000556 agonist Substances 0.000 title 1
- 125000002947 alkylene group Chemical group 0.000 claims description 105
- -1 R'R%-amino Chemical group 0.000 claims description 90
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 125000001153 fluoro group Chemical group F* 0.000 claims description 42
- 229920006395 saturated elastomer Polymers 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 239000000651 prodrug Substances 0.000 claims description 33
- 229940002612 prodrug Drugs 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 239000011593 sulfur Chemical group 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000001589 carboacyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 210000000988 bone and bone Anatomy 0.000 claims description 9
- 230000002496 gastric effect Effects 0.000 claims description 9
- 239000000018 receptor agonist Substances 0.000 claims description 9
- 229940044601 receptor agonist Drugs 0.000 claims description 9
- 208000030016 Avascular necrosis Diseases 0.000 claims description 8
- 208000010392 Bone Fractures Diseases 0.000 claims description 8
- 206010017076 Fracture Diseases 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 208000037848 Metastatic bone disease Diseases 0.000 claims description 8
- 206010030043 Ocular hypertension Diseases 0.000 claims description 8
- 206010031264 Osteonecrosis Diseases 0.000 claims description 8
- 208000025865 Ulcer Diseases 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 210000000845 cartilage Anatomy 0.000 claims description 8
- 210000003298 dental enamel Anatomy 0.000 claims description 8
- 210000004905 finger nail Anatomy 0.000 claims description 8
- 230000004927 fusion Effects 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
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- 210000004185 liver Anatomy 0.000 claims description 8
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 8
- 230000008929 regeneration Effects 0.000 claims description 8
- 238000011069 regeneration method Methods 0.000 claims description 8
- 210000002435 tendon Anatomy 0.000 claims description 8
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- 238000002054 transplantation Methods 0.000 claims description 8
- 230000036269 ulceration Effects 0.000 claims description 8
- 230000029663 wound healing Effects 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 230000035876 healing Effects 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 4
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- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000004419 alkynylene group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- XISKMNBBUQQBBE-ANUZYNSFSA-N bisnordihydrotoxiferine Chemical compound C12C/3=C\N(C4\5)C6=CC=CC=C6C44CCN(C\C6=C\C)C4CC6C/5=C/N1C1=CC=CC=C1C21CCN2C/C(=C/C)C\3CC21 XISKMNBBUQQBBE-ANUZYNSFSA-N 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- WOHRHWDYFNWPNG-UHFFFAOYSA-N evatanepag Chemical compound C1=CC(C(C)(C)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 WOHRHWDYFNWPNG-UHFFFAOYSA-N 0.000 claims description 2
- 235000019000 fluorine Nutrition 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 15
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 description 16
- 125000001544 thienyl group Chemical group 0.000 description 15
- 125000002541 furyl group Chemical group 0.000 description 13
- 125000000335 thiazolyl group Chemical group 0.000 description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- 125000002883 imidazolyl group Chemical group 0.000 description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 6
- 125000000168 pyrrolyl group Chemical group 0.000 description 6
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 5
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 5
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- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 125000002098 pyridazinyl group Chemical group 0.000 description 5
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 4
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 125000002785 azepinyl group Chemical group 0.000 description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000003585 oxepinyl group Chemical group 0.000 description 4
- 125000003777 thiepinyl group Chemical group 0.000 description 4
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 3
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 3
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- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 2
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 2
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 2
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- CYGURBYATNPAOY-UHFFFAOYSA-N 2-[3-[[pyridin-3-ylsulfonyl-[(4-pyrimidin-5-ylphenyl)methyl]amino]methyl]phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(CN(CC=2C=CC(=CC=2)C=2C=NC=NC=2)S(=O)(=O)C=2C=NC=CC=2)=C1 CYGURBYATNPAOY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
USE OF EP2 SELECTIVE RECEPTOR AGONISTS IN MEDICAL TREATMENT . Field of the Invention
The present invention relates to methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease using an EP; selective receptor agonist.
Compounds that are prostaglandin receptor ligands are known to be useful to treat various diseases such as osteoporosis. A variety of natural prostaglandins such as PGE, PGD and PDF are associated with skeletal metabolism. PGEZ2 has been reported to stimulate bone formation, increase bone mass and bone strength in animal models of osteoporosis when administered systemically or locally. However, there are severe side effects associated with PGE2 such as diarrhea, gastrointestinal bieeding, decreased food consumption, dehydration, weight loss and decreased physical activity. Accordingly, PGE2 has not found widespread use in humans because of these side effects. Recently, four different subtypes of PGE2 receptors have been cloned. The four subtypes have been named EP,, EP,, EP; and EP, and research to better understand the pharmacology of the receptor subtypes is presently being conducted.
The present invention provides methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver i regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by ~ metastatic bone disease using an EP, selective receptor agonist. Certain EP,
selective receptor agonists are known in the art. See, for example, U.S. Patent ’ Number 6,498,172.
The present invention provides methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease, the methods comprising administering to a patient in need thereof a therapeutically effective amount of an EP, selective receptor agonist.
The present invention also provides such methods wherein the EP; selective receptor agonist is a compound of Formula
SR
Ky
Formula or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
Ais SO, or CO;
Gis Ar, Ar'-V-Ar%, Ar-(C4-Cg)alkylene, Ar-CONH-(C+-Ce)alkylene, R'R*-amino, : oxy(C;-Cg)alkylene, amino substituted with Ar, or amino substituted with Ar(Cs-
C.)alkylene and R', wherein R'' is H or (C1-Cg)alkyl, R' and R? may be taken separately and are independently selected from H and (C+-Cg)alkyl, or R' and R%are taken together with the nitrogen atom of the amino group to form a five- or six- membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally mono-, di- or tri-substituted independently with up to two oxo, hydroxy, ’ (C+-Ca)alkyl, fluoro or chloro;
Bis Nor CH;
Qis -(Co-Ce)alkylene-W-(C4-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C4-Cs)alkyl,
-(C4-Cg)alkylene-, said alkylene optionally substituted with up to four substituents ‘ independently selected from fluoro or (C;-C,)alkyl, -X-(C4-Cs)alkylene-, said alkylene optionally substituted with up to four a. substituents independently selected from fluoro or (C4-Cu)alkyl, -(C4-Cs)alkylene-X-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C,-Ca)alkyl, -(C+-Cy)alkylene-X-(C4-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C,-Cq)alkyl, ~(C,-C4)alkylene-W-X-(Cy-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C4-C,)alkyl,
-(Co-Cy)alkylene-X-W-(C4-Cz)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Ca)alkyl,
-(C,-Cs)alkylene-W-X-W-(C,-Cs)alkylene-, wherein the two occurrences of W are independent of each other, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Cy)alkyl,
-(C1-Cy)alkylene-ethenylene-(C4-Cs)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Cy)alkyi,
-(C4-Cy4)alkylene-ethenylene-(Co-C;)alkylene-X-(Co-Cs)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Ca)alkyl,
-(C1-Cy4)alkylene-ethenylene-(Co-C;)alkylene-X-W-(C,-Cs)alkylene-, said alkylenes and said ethenylene optionally each substituted with up to four substituents each independently selected from fluoro or (C4-Cs)alkyl,
-(C+-Cs)alkylene-ethynylene-(C,-Cs)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C,4-Cy4)alkyl,or
-(C4-Cs)alkylene-ethynylene-X-(Co-Cs)alkylene-, said alkylenes and said
. ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Cs)alkyl;
: Z is carboxyl, (C+-Cs)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4- oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, (Ci-Ca)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C,-Cg)alkylene, thio(C1-Cy)alkylene, (C+-Ca)alkylenethio(Cs- ‘ C,)alkylene, (C4-C,)alkyleneoxy(C4-C,)alkylene or oxy(C4-Cy)alkylene, said (Cq-
Cg)alkylene optionally mono-unsaturated and wherein, when K is not a bond, K is ' optionally mono-, di- or tri-substituted independently with chloro, fluoro, hydroxy or methyl;
Mis -Ar%, -Ar*-V-Ar®, -Art-S-Ar%, -Ar*-SO-Ar, -Ar'-SO,-Ar® or -Ar*-0-Ar®;
Ar is a partially saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur; or Ar is a fully saturated five to seven membered ring having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen;
Ar! and Ar? are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully . saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur; . said Ar, Ar' and Ar? moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R®, R* and R® wherein R®, R* and R® are ’ independently hydroxy, nitro, halo, carboxy, (C4-Cr)alkoxy, (C4-C4)alkoxy(C4-Cq)alkyl, (C4-Ca)alkoxycarbonyl, (C,-Cr)alkyl, (Co-Cr)alkenyl, (C5-Cy)alkynyl, (C3-Cr)cycloalkyl, (C3s-Cy)eycloalkyl(C4-Ca)alkyl, (Cs-Cr)cycloalkyl(C4-Cas)alkanoyl, formyl, (Cy- Cg)alkanoyl, (C+-Ce)alkanoyl(C+-Ce)alkyl, (C4-Cy4)alkanoylamino, (C+-
C.)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N'- or tri-N,N,N"-(C,-C,)alkyl substituted aminocarbonylamino, sulfonamido, (Cq-
C,)alkylsulfonamido, amino, mono-N- or di-N,N-(C;-C4)alkylamino, carbamoyl, mono-
N- or di-N,N-(C,-C,)alkylcarbamoyl, cyano, thiol, (C+-Ce)alkylthio, (C4-Ce)alkylsulfinyt, (C;-Cy)alkylsulfonyl or mono-N- or di-N,N-(C4-Cy)alkylaminosuifinyl;
AR, Ar and Ar® are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one 10 four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two 0X0 groups substituted on sulfur; said Ar,
Ar® and Ar® moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R*', R*! and R*' wherein R*', R*! and R% are independently hydroxy, nitro, halo, carboxy, (C4-Cr)alkoxy, (C4-Cs)alkoxy(Cq-Ca)alkyl, (C4-Cy)alkoxycarbonyl, (C4-Cr)alkyl, (C~Cy)alkenyl, (Co-Cr)alkynyl, (C;-Cr)cycloalkyl, (C3-Cy)cycloalkyl(C4-Ca)alkyl, (C3-Cr)cycloalkyl(Ci-Ca)alkanoyl, formyl, (Ci- . Cg)alkanoyl, {C4-Cg)alkanoyl(C,-Ce)alkyl, (C4-Cs)alkanoylamino, (C+-
C,)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, : di-N,N'- or tri-N,N,N'-(C;-C4)alky! substituted aminocarbonylamino, sulfonamido, (C4-
C.)alkylsulfonamido, amino, mono-N- or di-N,N-(C;-C,4)alkylamino, carbamoyl, mono-
N- or di-N,N-(C-C,)alkylcarbamoyl, cyano, thiol, (C1-Ce)alkyithio, (C4-Ce)alkylsulfinyl, : (C+-Cys)alkyisulfonyl or mono-N- or di-N,N-(C4-C)alkylaminosulfinyl;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C- ) C,)alkyleneaminosulfonyl-, sulfonylamino, N-(C4-C,)alkylenesulfonylamino, carboxamido, N-(C;-C,)alkylenecarboxamido, carboxamidooxy, N-(C4-
C.)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C;-C,)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C+-C,)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, di- or tri-substituted independently with halo, (C4-Cslalkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C,-C,)alkoxy, or carbamoyl;
R' RZ R® RRS RY, R¥, R* and R®', when containing an alkyl, alkylene, alkenylene or alkynylene moiety, are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V and V' are each independently a bond, thio(C4-Ca)alkylene, (C4-Cq)alkylenethio, (C1-Cs)alkyleneoxy, oxy(Ci-Ca)alkylene or (C4-Cj)alkylene optionally mono- or di- substituted independently with hydroxy or fluoro; with the provisos that: a. when Kis (C.-C4)alkkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex- 1-yl, cyclohept-1-yl or cyclooct-1-yl then said (Cs-Cg)cycloalkyl substituents are not substituted at the one position with hydroxy; and b. when K is a bond; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is (Cs-Cs)alkylene; and Mis Ar® or Ar-Ar®, then Ais sulfonyl.
The present invention also provides methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the . occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver : regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease, the methods comprising administering to a patient in need . thereof a therapeutically effective amount of (3-(((4-tert-butyl-benzyl)-(pyridine-3- sulfonyl)-amino)-methyl)-phenoxy)-acetic acid or a pharmaceutically acceptable salt : thereof.
Examples of EP; selective receptor agonists are set forth in U.S. Patent
Number 6,498,172. A preferred EP, selective receptor agonist that can be used in the present methods is a compound of Formula | as defined above.
A preferred group of compounds designated the A Group, comprises those compounds having the Formula | as shown above, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein B is N; Z is carboxyl, (C-Ce)alkoxycarbonyl or tetrazolyl; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2- pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyt, 1,3,5- triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo(b)thienyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, tetralinyl, decalinyl, 2H-1- benzopyranyl and 1,4-benzodioxan; Ar’, Ar®, Ar®, Ar* and Ar® are each independently cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyi, oxazolyl, thiazolyl, imidazolyl, pyrazolyi, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrofidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, ) 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinylpiperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, cyclopentenyl, . cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indoliziny!, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4- b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl,
indoxazinyl, benzoxazolyi, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4H- ‘ quinolizinyl, quinclinyl, isoquinclinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1- ’ benzopyranyl, 1,4-benzodioxan, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3- benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl; and X is tetrahydrofuranyl, phenyl, thiazolyi, thienyl, pyridyl, pyrrazolyl, furanyl or pyrimidyl, wherein X is optionally mono-, di- or tri-substituted independently with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein each of said Ar, Ar' and Ar? groups are optionally substituted on carbon or nitrogen with up to three substituents independently selected from R®, R* and R®: each of said Ar, Ar'.and Ar? groups are optionally substituted independently on carbon or sulfur with one or two oxo groups; each of said Ar, Ar* and Ar® groups are optionally substituted on carbon or nitrogen independently with up to three R®!, R** and R® groups and each of said Ar’, Ar* and Ar® groups are optionally substituted independently on carbon or sulfur with one or two oxo groups.
A group of compounds within the A Group, designated the B Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is oxy(C:-Cg)alkylene; Q is -(C,-Cg)alkylene-O-(C4-Cj)alkylene-, -(C4-Cg)alkylene-, said -(C,-Cg)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C,-Cy)alkyt, -X-(C,-Cs)alkylene-, -(C4-Cs)alkylene-X-, -(C4-Cs)alkylene-X-(C4-Cs)alkylene-, -(C,-C,)alkylene-O-X-(Cy-Cs)alkylene-, or -(Co-Cs)alkylene-X-O-(Cy-Cs)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, . methoxy, difluoromethoxy, trifluoromethoxy, trifftuoromethyl or methyl.
Another group of compounds which is preferred within the A Group, : designated the C Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; GisAr, Qis
-O- -(C2-Ce)alkylene-O-(C4-Cz)alkylene-, . -(C4-Cg)alkylene-, said -(C,-Cg)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C4-Cg)alkyl, : -X-(C2-Cs)alkylene-, -(C4-Cs)alkylene-X-, -(C4-Cs)alkylene-X-(C,-Cs)alkyiene-, -(C2-C4)alkylene-O-X-(Co-Cs)alkylene-, or -(Co-C4)alkylene-X-0-(C4-Cs)alkylene-; and X is phenyl, thienyl, furany! or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
Another group of compounds which is preferred within the A Group, designated the D Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO: G is R'R?-amino or amino substituted with Ar, or amino substituted with Ar(C-
C,)alkylene and R"", wherein Ris H; Q is -(C2-Cs)alkylene-O-(Cy-Cs)alkylene-, -(C4+-Cg)alkylene-, said -(C4-Cg)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C4-Cs)alkyl, -X-(Co-Cs)alkylene-, -(C4-Cs)alkylene-X-, -(C4-Ca)alkylene-X-(C4-Cs)alkylene-, -(Co-C4)alkylene-O-X-(Co-Ca)alkylene-, or -(Co-Cs)alkylene-X-0-(C4-Cs)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyt;and wherein R' and R? may be taken separately and are independently selected from H and (C4-Cs)alkyl, or R' and R? are taken together to form a five- or six- membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom.
Another group of compounds which is preferred within the G Group, designated the E Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO, G is R'R%amino, or amino substituted with Ar and R""; Q is -(C,-Cs)alkylene-O-(C4-Cs)alkylene-,
-(C4-Cg)alkylene-, said -(C4-Csg)alkylene- optionally substituted with up to four , substituents independently selected from fluoro or (C+-Ca)alkyl, -X-(C,-Cs)alkylene-, ‘ -(C4-Cs)alkylene-X-, -(C,-Cs)alkylene-X-(C4-C3)alkylene-, -(C,-Cs)alkylene-0O-X-(Co-Cs)alkylene-, or ~(Co-Ca)alkylene-X-O-(Cy-Ca)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chioro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R' and R? may be taken separately and are independently selected from H and (C-Cg)alkyl, or R' and R? are taken together to form a five- or six- membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom.
Another group of compounds which is preferred within the A Group, designated the F Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO; G is Ar, Ar(C-Co)alkylene or Ar'-V-Ar%; Q is -(C.-Ce)alkylene-O-(C+-Cs)alkylene-, -(C4-Cg)alkylene-, said -(C4-Cg)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C;-Cy)alkyl, -X-(Co-Cs)alkylene-, -(C4-Cs)alkylene-X-, -(C4-Cj)alkylene-X-(C4-Cs)alkylene-, -(C-C,)alkylene-O-X-(Co-Cs)alkylene-, or -(Co-Ca)alkylene-X-O-(C4-Ca)alkylene-; and X is phenyl,pyrimidyl, pyridyl, thienyl, tetrahydrofuranyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri- substituted with chloro, fluoro, methoxy, difluaromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
A particularly preferred group of compounds within the F Group, designated the FA Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar or Ar-(C4-C,)- alkylene; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl or 1,3,4-thiadiazolyl wherein each of said Ar groups is optionally substituted on carbon or nitrogen with R', R? or R? Ar? is cyclopentyl, cyclohexyl, cycloheptyl, ’ cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyi, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyi, pyrimidinyl, pyrazinyl, pyrrolidiny, 1,2,3- triazolyl, 1,2,4-triazolyl, pyranyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4- triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl wherein each of said Ar* groups is optionally mono- di- or tri-substituted on carbon or nitrogen with R*, R* or R%' ; Ar® is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl! or thiepinyl wherein each of said Ar® groups is optionally mono- di- or tri- substituted on carbon or nitrogen with R?!, R*! or R®"; Q is -(Cs-C;)-alkylene-, -(C+-
C.)-alkylene-X-(C-Co)-alkylene-, -(C4-C;)-X-O-(C4-Co)-alkylene-, -(C,-C,)-alkylene- thienyl-, -(C,-Ca)-alkylene-furanyl- or -(C-C,)-alkylene-thiazolyl-; X is phenyl, pyridyl, pyrimidy! or thienyl; and said X groups are optionally mono-, di- or tri- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; said -(C-Ca)-alkylene-furanyl- and -(C,-C,)-alkylene-thienyl- having a 2,5- substitution pattern, e.g., c.commpene—L oI A
A preferred group of compounds within the FA Group, designated the FB
Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is methylene, Mis
Ar-Ar®, Ar'-O-Ar® or Ar®-S-Ar® and Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or tri-substituted on carbon or nitrogen with R3, R* or R®.
A preferred group of compounds within the FB Group, designated the FC
Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein M is Ar*-Ar’; Aris phenyl, pyridyl or imidazolyi, Art is phenyl, furanyl or pyridyl; and Ar’ is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyraziny!, imidazolyl, pyrazolyl or thiazolyl, wherein Ar, Ar* and Ar® are optionally mono, -di- or tri-substituted on carbon or nitrogen independently with chloro, fluoro, ’ methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.
An especially preferred group of compounds within the FC Group, designated ) the FD Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(Cs-
Cy)alkylene-.
Another especially preferred group of compounds within the FC Group, designated the FE Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is CH,-X-CH,- and X is metaphenylene optionally mono- or di- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
A preferred group of compounds within the FE Group are those compounds, and pharmaceutically acceptable salts and prodrugs thereof, selected from (3- (((pyridine-3-sulfonyl)-(4-pyrimidin-5-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((5-phenyl-furan-2-yimethyl)-(pyridine-3-sulfonyl}-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; and (3-(((4-pyrazin-2-yl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyi)- acetic acid.
An especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yi; Z is carboxy; Mis Ar*-Ar® wherein Ar? is a furanyl ring and Ar° is phenyl wherein said phenyl moiety is substituted at the 5-position of said furanyl ring; and Q is -CH»-X-CH,- wherein X is metaphenylene.
Another especially preferred compound within the FE Group is the compund wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar*-Ar® wherein Ar* is phenyl and Ar is pyrimid-2-yl and said pyrimid-2-yl moiety is substituted at the 4-position of said phenyl ring; and Q is -CH,-X-CHg- wherein X is metaphenylene.
Yet another especially preferred compound within th FE Group is the : compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar‘-Ar® wherein Ar? is phenyl and Ar® is thiazol-2-yl and said thiazol-2-yl moiety is substituted at the 4-position of said phenyl! ring; and Q is -CH,-X-CH,- wherein X is metaphenylene.
Yet another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar*-Ar® wherein Ar* is phenyl k -13- and Ar® is pyrimid-5-y! and said pyrimid-5-yl moiety is substituted at the 4-position of ’ said phenyl ring; and Q is -CH»-X-CH,- wherein X is metaphenylene.
Yet another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar*-Ar® wherein Ar is phenyl and Ar’ is pyrazin-2-yl and said pyrazin-2-yl is substituted at the 4-position of said phenyl ring; and Q is -CHz-X-CH,- wherein X is metaphenylene.
A preferred group of compounds within the FC Group, designated the G
Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C-Ca)- alkylene-thienyl-, -(C>-C4)-alkylene-furanyl- or -(C2-Cq)-alkylene-thiazolyl-.
An especially preferred compound within the G Group is 5-(3-((pyridine-3- sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-propyl)-thiophene-2-carboxylic acid.
An especially preferred compound within the G Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said 16 prodrugs, wherein Q is n-propylenyl; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Artis phenyl; and Ar’ is 2-thiazolyl; said 2-thiazolyl being substituted at the 4-position of said phenyl.
Another especially preferred group of compounds within the FC Group, designated the H Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH»-X-O-CH,-; Ar* is phenyl! or pyridyl; said phenyl and pyridyl are optionally substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl; and X is metaphenylene.
A preferred group of compounds within the H Group are (3-(((4-cyclohexyl- benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3- sulfonyl)-(4-pyridin-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3- sulfonyl)-(4- pyridin-3-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(({pyridine- 3-sulfonyl)-(4-pyridin-4-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; and (3- : (({pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid.
An especially preferred compound within the H Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; Ar? is phenyl; Ar® is cyclohexyl; and said cyclohexyl moiety is substituted at the 4-position of said phenyl ring.
Claims (16)
1. Use of a therapeutically effective amount of an EP, selective receptor agonist, in the manufacture of a medicament for treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension or repairing damage caused by metastatic bone disease.
2. Use of a compound of Formula 1 in the manufacture of a medicament for treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension or repairing damage caused by metastatic bone disease, the compound comprising SN Km Formula } or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Ais SO; or CO; Gis Ar, Ar'-V-Ar%, Ar{C,-Cs)alkylene, Ar-CONH-(C,-Cg)alkylene, R'R%-amino, oxy(Cs-Ce)alkylene, amino substituted with Ar, or amino substituted with Ar(C,- Cd)alkylene and R", wherein R'' is H or (C,-Cs)alkyl, R' and R? may be taken separately and are independently selected from H and (C,-Cs)alkyl, or R' and R? Fon liioZ3 GT are taken together with the nitrogen atom of the amino group to form a five- or six- membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally mono-, di- or tri-substituted independently with up to two oxo, hydroxy, (C4-C4)alkyl, fluoro or chloro; : Bis Nor CH; Qis -(C,-Ce)alkylene-W-(C4-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C+- Cy)alkyl, -(C4-Cg)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C4-Cs)alkyl, -X-(C4-Cs)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C4-Cq)alkyl, -(C4-Cs)alkylene-X-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C4-Cy)alkyl,
-(C+-Cs)alkylene-X-(C4-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C+-Ca)alkyl,
-(C,-Cy)alkylene-W-X~(Co-Cs)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or
(C4-Cy)alkyl,
-(Co-Ca)alkylene-X-W-(C;-Ca)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-Cy)alkyl,
~(C,-Cs)alkylene-W-X-W-(C,-Cs)alkylene-, wherein the two occurrences of W are independent of each other, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Ca)alkyl,
-(C+-C4)alkylene-ethenylene-(C4-Cs)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each
: independently selected from fluoro or (C4-Ca)alkyl, -(C4-Cy)alkylene-ethenylene-(Co-Cz)alkylene-X-(Co-Cs)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (C-C,)alkyl,
~(C1-Cq)alkylene-ethenylene-(Cy-C,)alkylene-X-W-(C,-C3)alkylene-, said : alkylenes and said ethenylene optionally each substituted with up to four substituents each independently selected from fluoro or (C-Cy)alkyl, -(C4-C,)alkylene-ethynylene-(C;-C,4)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C4-C,)alkyl,or -(C4-Cy)alkylene-ethynylene-X-(Co-Cj)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C4-Cy)alkyl; Z is carboxyl, (C4-Ce)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4- oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, (C4-C,)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl, Kis a bond, (C4-Cg)alkylene, thio(C+-Ca)alkylene, (C4-Ca)alkylenethio(C- Cyalkylene, (C1-Cq)alkyleneoxy(C+-Cy)alkylene or oxy(C4-C,)alkylene, said (Cs- Cg)alkylene optionally mono-unsaturated and wherein, when K is not a bond, K is optionally mono-, di- or tri-substituted independently with chloro, fluoro, hydroxy or methyl; Mis -Ar®, -Ar-V-Ar®, -Art-S-Ar®, -Ar*-SO-Ar®, -Ar*-SO,-Ar° or -Ar*-O-Ar®, Ar is a partially saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups
. substituted on carbon or one or two oxo groups substituted on sulfur; or Aris a fully saturated five to seven membered ring having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; Ar! and Ar are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a : bicyclic ring consisting of two fused independently partially saturated, fully . saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur; said Ar, Ar! and Ar® moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R?, R* and R® wherein R?, R* and R® are independently hydroxy, nitro, halo, carboxy, (C4+-C7)atkoxy, (Cs- C,)alkoxy(C4-C)alkyl, (C4-Cg)alkoxycarbonyl, (C4~Cr)alkyl, (C2-Cr)alkenyl, (Co- C;)alkynyl, (Cs-Cr)cycloalkyl, (C3-Cr)cycloalkyl(C1-Ca)alkyl, (Cs-Cr)cycloalkyl(Cs-
C.)alkanoyl, formyl, (C4-Cg)alkanoyl, (C4-Cg)alkanoyl(C4-Ce)alkyl, (C+-
C.)alkanoylamino, (C4-C,)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N'- or tri-N,N,N’-(C,-C,)alkyl substituted aminocarbonylamino, sulfonamido, (C4-C,)alkyisulfonamido, amino, mono-N- or di-N,N-(C4-C,)alkylamino, carbamoyl, mono-N- or di-N,N-(C;-
C.)alkylcarbamoyl, cyano, thiol, (C,-Cs)alkylthio, (C1-Ce)alkylsulfinyl, {C;- Cs)alkylsulfonyl or mono-N- or di-N,N-(C4-C,)alkylaminosulfinyl; Ar®, Ar and Ar® are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen,
. sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen,
sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring : optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur; said Ar’, Ar* and Ar’ moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R*, R* and R*" wherein R*', R*' and R®' are independently hydroxy, nitro, halo, carboxy, (C4-C7)alkoxy, (C4-Ca)alkoxy(C4-C,)alkyl, (C4-Ca)alkoxycarbonyl, (Cy- Cy)alkyl, (Co-Cr)alkenyl, (Co-Cr)alkynyl, (Cs-C;)cycloalkyl, (C3-C;)cycloalky)(Cy- Ca)alkyl, (Cs-Cr)cycloalkyl(C1-Cy)alkanoyl, formyl, (C4+-Cg)alkanoyl, (C;- Ce)alkanoyl(C4-Cg)alkyl, (C4-C,)alkanoylamino, (C-Cy)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N’- or tri-N,N,N'- (C4-Cs)alkyl substituted aminocarbonylamino, sulfonamido, (Cs-
C.)alkylsulfonamido, amino, mono-N- or di-N,N-(C;-C,)alkylamino, carbamoyl, mono-N- or di-N,N-(C,-Cg)alkylcarbamoyl, cyano, thiol, (C1-Cg)alkylthio, (C4- Ce)alkylsulfinyl, (C;-Cs)alkylsulfonyl or mono-N- or di-N,N-(C;- Cy)alkylaminosulfinyl; W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C;- Cs)atkyleneaminosulfonyl-, sulfonylamino, N-(C4-Cy)alkylenesulfonyiamino, carboxamido, N-(C1-Ca)alkylenecarboxamido, carboxamidooxy, N-(C4- C,)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C;-C,)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C;-C,)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines; Xis a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, di- or tri-substituted independently with halo, (C,-Cj)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C+-Cs)alkoxy, or carbamoyl; R', R% R} R‘R% R", R*, R* and R®, when containing an alkyl, alkylene, alkenylene or alkynylene moiety, are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
STEN. V and V' are each independently a bond, thio(C+-Ca)alkylene, (Cy-
C.)alkylenethio, (C4-C.)alkyleneoxy, oxy(C,-C.)alkylene or (C-Csalkylene optionally mono- or di-substituted independently with hydroxy or fluoro; with the provisos that:
a. when K is (CzCy)alkylene and M is Ar’ and Ar® is cyclopent-1-y1, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yi then said (Cs-Cg)cycloalkyl substituents are not substituted at the one position with hydroxy; and b. when K is a bond; G is phenyl, phenylmethyl, substituted phenyl of substituted phenyimethyl; Q is (Cs-Ca)alkylene; and Mis Ar’ or Ar*-Ar, then A is sulfonyl.
3. Use of a therapeutically effective amount of (3-(((4-tert-butyl-benzyl)- (pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension or repairing damage caused by metastatic bone disease.
4. The use of any of claims 1-3 wherein the medicament is for treating hypertension or treating pulmonary hypertension.
5. The use of any of claims 1-3 wherein the medicament is for facilitating joint fusion.
6. The use of any of claims 1-3 wherein the medicament is for facilitating tendon and ligament repair or facilitating cartilage repair.
7. The use of any of claims 1-3 wherein the medicament is for reducing the occurrence of secondary fracture. LLCGLIS SNE
E !
AN . : \ WO 2004/078169 PCT/1B2004/000553 \ N -143-
8. The use of any of claims 1-3 wherein the medicament is for treating avascular necrosis.
9. The use of any of claims 1-3 wherein the medicament is for facilitating bone heating after limb transplantation.
10. The use of any of claims 1-3 wherein the medicament is for facilitating liver regeneration.
11. The use of any of claims 1-3 wherein the medicament is for facilitating wound healing.
12. The use of any of claims 1-3 wherein the medicament is for reducing the occurrence of gastric ulceration.
13. The use of any of claims 1-3 wherein the medicament is for facilitating the growth of tooth enamel, fingernails or toenails.
14. The use of any of claims 1-3 wherein the medicament is for treating glaucoma or treating ocular hypertension.
15. A use of any of claims 1-3 wherein the medicament is for repairing damage caused by metastatic bone disease.
16. Use according to any of the preceding claims, substantially as herein described and exemplified. SIS ID SN
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| US8604055B2 (en) | 2004-12-31 | 2013-12-10 | Dr. Reddy's Laboratories Ltd. | Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors |
| KR101238525B1 (en) | 2004-12-31 | 2013-02-28 | 레디 유에스 테라퓨틱스 인코포레이티드 | Novel benzylamine derivatives as cetp inhibitors |
| US7915316B2 (en) * | 2005-08-22 | 2011-03-29 | Allergan, Inc | Sulfonamides |
| US7696235B2 (en) * | 2005-08-29 | 2010-04-13 | Allergan, Inc. | EP2 receptor agonists for treating glaucoma |
| RU2493252C2 (en) | 2006-03-24 | 2013-09-20 | Чилдрен'З Медикал Сентер Корпорейшн | Method to stimulate expansion of haematopoietic stem cells |
| KR101088942B1 (en) | 2006-07-28 | 2011-12-01 | 화이자 프로덕츠 인코포레이티드 | Ep2 agonists |
| JP5426389B2 (en) | 2006-10-20 | 2014-02-26 | チルドレンズ メディカル センター コーポレーション | Methods for enhancing tissue regeneration |
| US7939671B2 (en) * | 2007-08-21 | 2011-05-10 | Senomyx, Inc. | Compounds that inhibit (block) bitter taste in composition and use thereof |
| AU2009224329B2 (en) * | 2008-03-12 | 2013-11-07 | Ube Corporation | Pyridylaminoacetic acid compound |
| US9056085B2 (en) | 2009-02-03 | 2015-06-16 | Children's Medical Center Corporation | Methods for enhancing hematopoietic stem/progenitor cell engraftment |
| WO2010091052A2 (en) | 2009-02-03 | 2010-08-12 | Children's Medical Center Corporation | Methods for enhancing hematopoietic stem/progenitor cell engraftment |
| CA2757291C (en) | 2009-03-30 | 2017-05-23 | Ube Industries, Ltd. | Medical composition for treatment or prophylaxis of glaucoma |
| WO2010116270A1 (en) | 2009-04-10 | 2010-10-14 | Pfizer Inc. | Ep2/4 agonists |
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| CA2850022C (en) | 2011-09-27 | 2018-05-01 | Dr. Reddy's Laboratories, Ltd. | 5 - benzylaminomethyl - 6 - aminopyrazolo [3,4-b] pyridine derivatives as cholesteryl ester-transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis |
| EP2785350B1 (en) | 2011-12-02 | 2018-05-02 | Fate Therapeutics, Inc. | Improved methods of treating ischemia |
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| EP2804605A4 (en) * | 2012-01-20 | 2015-07-08 | Acucela Inc | Substituted heterocyclic compounds for disease treatment |
| WO2014078434A1 (en) * | 2012-11-16 | 2014-05-22 | Allergan, Inc. | Compounds and methods for skin repair |
| WO2014150602A1 (en) | 2013-03-15 | 2014-09-25 | Fate Therapeutics, Inc. | Cell potency assay for therapeutic potential |
| SG11201507976YA (en) | 2013-03-28 | 2015-10-29 | Ube Industries | Substituted biaryl compound |
| AP2016009502A0 (en) | 2014-05-13 | 2016-10-31 | Novartis Ag | Compounds and compositions for inducing chondrogenesis |
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| UA67754C2 (en) * | 1997-10-10 | 2004-07-15 | Пфайзер, Інк. | Prostaglandin agonists and use thereof for the treatment of bone disorders |
| US6376533B1 (en) * | 2000-10-20 | 2002-04-23 | Allergan Sales, Inc. | Omega-cycloalkyl 17-heteroaryl prostaglandin E2 analogs as EP2-receptor agonists |
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| WO2004078169A8 (en) | 2005-04-21 |
| WO2004078169A1 (en) | 2004-09-16 |
| AU2004216898A1 (en) | 2004-09-16 |
| CL2004000412A1 (en) | 2005-02-04 |
| KR20050105511A (en) | 2005-11-04 |
| CN1859903A (en) | 2006-11-08 |
| TW200424176A (en) | 2004-11-16 |
| BRPI0408061A (en) | 2006-02-14 |
| PL378748A1 (en) | 2006-05-15 |
| JP2006519250A (en) | 2006-08-24 |
| CA2518193A1 (en) | 2004-09-16 |
| EP1601351A1 (en) | 2005-12-07 |
| MXPA05009398A (en) | 2005-12-05 |
| NZ541828A (en) | 2008-06-30 |
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