WO2008152388A1 - Silicon-containing compounds for treatment or prevention of bone loss or restoration of bone mass, or augmentation of bone mass - Google Patents

Silicon-containing compounds for treatment or prevention of bone loss or restoration of bone mass, or augmentation of bone mass Download PDF

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WO2008152388A1
WO2008152388A1 PCT/GB2008/002010 GB2008002010W WO2008152388A1 WO 2008152388 A1 WO2008152388 A1 WO 2008152388A1 GB 2008002010 W GB2008002010 W GB 2008002010W WO 2008152388 A1 WO2008152388 A1 WO 2008152388A1
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prodrug
compound
pharmaceutically acceptable
vertebrate
bone
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PCT/GB2008/002010
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French (fr)
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William Arthur Bains
Tejas Upadhyay
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Opal Drug Discovery Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention describes compounds of the Formula (I) which are selective prostaglandin E2 receptor agonists and their use in treating diseases characterised by bone loss, or prevention of bone loss, or restoration of bone mass, or augmentation of bone mass.

Description

Silicon-Containing Compounds for Treatment or Prevention of Bone Loss or Restoration of Bone Mass, or Augmentation of Bone Mass.
Field of the Invention
This invention relates to silicon-containing compounds useful for treating diseases of bone loss, or prevention of bone loss, or restoration of bone mass, or augmentation of bone mass.
Background to the invention
Compounds that are prostaglandin receptor ligands are known to be useful for treating various diseases such as osteoporosis. PGE2 has been reported to stimulate bone formation, increase bone mass and bone strength in animal models of ostoeporosis when administered systemically or locally. However PGE2 itself has not been used as a drug in humans because of the severe side-effects the agent causes, including gastrointestinal bleeding, dehydration, decreased physical activity and food consumption, and weight loss. In part these effects are believed to be due to activation of different members of the PGE2 receptor family, and consequently that receptor- selective agonists could be developed that bind selectively to specific members of the PGE2 receptor family. Such an agent is disclosed in WO2004/078169. The use of such agents to treat ostoeporosis is disclosed in US6288120;
Sila-substitution (C/Si-exchange) of drugs is a known approach for searching for organo-silicon compounds which have beneficial biological properties. For example, WO 2005/039596 discloses certain dialkyl substituted silyl phenols for promoting vascular health.
A review of silicon-containing durgs is provided by "Silicon Chemistry as a novel source of chemical diversity in drug design" : William Bains; Reinhold Tacke (2003) : Current Opinion in Drug Discovery and Development; 6 (4); 526-543.
Summary of the Invention
This invention provides for compounds that are selective PGE2 receptor agonists which are useful for the treatment of conditions characterised by bone loss, or prevention of bone loss, or restoration of bone mass, or augmentation of bone mass.
Detailed description of the invention
This invention describes compounds according to Formula (I)
Figure imgf000003_0001
FORMULA (I) Where
• G is Ar, AAV-AT2, Ar-(d-C6)alkylene, Ar-CONH-(Ci-C6)alkylene, R1R2 amino, OXy(C1 -C6)alkylene, amino substituted with Ar, or amino substituted with Ar(C1-C4)alkylene and R11, o R1 and R2 may be taken separately and are independently selected from H and (Cι-C%)alkyl, or R1 and R2 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, (C1-C4)alkyl, fluoro or chloro; o wherein R11 is H or (C1-C8)alkyl,
• E is CH orN
Q is selected from
• (C2-C6)alkylene-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substitutes independently selected from fluoro or (C1-C4) alkyl,
• (C4-C8)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (Cl-C4)alkyl,
• X-(C1-C5)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (Ci-C-Oalkyl,
• (C1-C5)alkylene-X-, said alkylene optionally substituted with up to four substituents independently selected fluoro or
Figure imgf000003_0002
• (C1-C3)alkylene-X-(C1-C3)alkylene, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C1- C4)alkyl,
• (C2-C4)alkylene-W-X-(C0-C3)-alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl,
• (Co-C4)alkylene-X-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or
Figure imgf000003_0003
• (C2-C5)alkylene-W-X-W-(C1-C3)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 (C1- C4)alkyl,
• (C1-C4)alkylene-ethenylene-(C1-C4)alkylene-5 said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (CrC4)alkyl,
• (C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-(Co-C5)alkylene-J said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl,
• (C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-W-(C1-C3)alkylene-, said alkylenes and said ethenylene optionally each substituted with up to four substitutes each independently selected from fluoro is (Ci-C4)alkyl,
• (C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl, or
• (C1-C4)alkylene-ethynylene-X-(Co-C3)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (CrC4)alkyl;
Z is carboxyl, (CrC6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo- 1,2,4- oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl5 (Ct-C^alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
J is selected from H, a halogen, J1, NH2, NH(J1), N(J1J2), OH, O- J1, Ar, O-Ar, NH-
Ar5 NH(J!)Ar, where
• J and J are independently selected from C1-C4 alkyl, C2-Cs alkenyl, C2-Cs alkynyl. and where
• 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 bicylic 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;
• Ar1 and Ar2 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 folly unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or folly 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; o where Ar, Ar1 and Ar2 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 one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R , R4 and R5 wherein R , R4 and R5 are independently hydroxy, nitro, halo, carboxy,
Figure imgf000005_0001
C4)alkyl, (C1-C4)allcoxycarbonyl, (CrC7)alkyl, (C2-C7)alkenyl, (C2- C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3- C^cycloalky^d-C^alkanoyl, formyl, (C-[-C8)alkanoyl, (C1- C6)alkanoyl(CrC6)alkyl, (CrC^alkanoylamino, (C1- C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N'- or tri-N5N,N'-(CrC4)alkyl substituted aminocarbonylamino, sulfonamido, (CrC^alkylsulfonamido, amino, mono-N or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di- N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (CrC^alkylthio, (C1- C6)alkylsulfinyl, (Ci-C4)alkylsulfonyl or mono-N or di-N,N-(Ci- C4)alkylaminosulfinyl; Ar3, Ar4 and Ar5 are each independently a partially saturated, folly saturated or folly 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, folly saturated or folly unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfor and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or folly unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or folly 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 sulfor; o where Ar3, Ar4 and Ar5 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 , R41 and R51 wherein R31, R41 and R51 are independently hydroxy, nitro, halo, carboxy, (C1-C7)alkoxy, (Ci- C4)alkoxy(C1-C4)alkyl, (Ci-C4)alkoxycarbonyl, (Q-C^alkyl, (C2- C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)CyClOaIkVl(C1- C4)alkyl, (Cs-C^cycloalkyKCi-C^alkanoyl, formyl, (Ci-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (CrC^alkanoylamino, (C1- C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,N'- or tri-N^NHQ-C^alkyl substituted aminocarbonylamino, sulfonamide, (Q-C^alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di- N5N-(C1 -C4)alkylcarbamoyl, cyano, thiol, (CrC6)alkylthio, (C1- C6)alkylsulfinyl, (Ci-C4)alkylsulfonyl or mono-N- or di-N,N-(Ci- C4)alkylaminosulfinyl;
• W is oxy, thio, sulfϊno, sulfonyl, aminosulfonyl-, HiOnO-N-(C1- C4)alkyleneaminosulfonyl-, sulfonylamino, N-(Ci-C4)alkylenesulfonylamino, craboxamido,
Figure imgf000006_0001
carboxamidooxy, N-(C1- C4)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C1-C4)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, (Ci- C3)alkyl, trifluoromethyl, trifluorornethyloxy, difluoromethyloxy, hydroxyl, (Ci-C4)alkoxy, or carbamoyl;
• R1, R2 , R3 , R4 , R5 , R11 , R31 , R41 and R51, 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 V1 are each independently a bond, thio(C1-C4)alkylene, (C1- C4)alkylenethio, (Ci-C4)alkyleneoxy, oxy(Ci-C4)alkylene or (Ci-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro;
An embodiment of the invention is a compound according to Formula (I) where Q is (Co-C4)alkylene-X-W-(Ci-C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl, and the other terms are as defined above.
An embodiment of the invention is a compound according to Formula (I) where G is Ar and other terms are as defined above.
A further embodiment of the invention is a compound according to Formula(I) where Q is (C0-C4)alkylene-X-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (Ci-C4)alkyl, and G is Ar and other terms are as defined above.
A further embodiment of the invention is a compound according to Formula (II): 2-(3- ((N-(4-(trimethylsilyl)benzyl)pyridine-3-sulfonamido) methyl)phenoxy) acetic acid
Figure imgf000006_0002
FORMULA (II)
This invention can provide methods for treating vertebrates, e.g., a mammal, having a condition which presents with low bone mass comprising administering to said vertebrate, e.g., a mammal, having a condition which presents with low bone mass a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. The phrase "condition(s) which presents will low bone mass" refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843". Included in "condition(s) which presents with low bone mass" are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin- induced osteoporosis and immunosuppressive-induced osteoporosis. Also included is periodontal disease, alveolar bone loss, post-osteotomy and childhood idiopathic bone loss. The phrase "condition(s) which presents with low bone mass" also includes long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery. The phrase "condition(s) which presents with low bone mass" also refers to a vertebrate, e.g., a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60).
Post-menopausal women and men over the age of 80 may be treated. Also included are individuals regardless of age who have significantly reduced bone mass, i.e., greater than or equal to 1.5 standard deviations below young normal levels.
Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis an osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g. a mammal having undergone an osteotomy a bone restoration treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy. In one aspect the Formula I compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to a site of osteotomy. Yet another aspect of this invention is directed to methods for treating alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an alveolar bone or mandibular loss, an alveolar or mandibular bone loss treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., mammal suffering from bone loss associated with periodontitis, a bone loss associated with periodontitis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating childhood idiopathic bone loss is a child comprising administering to a child suffering from childhood idiopathic bone loss a childhood idiopathic bone loss treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating "secondary osteoporosis," which includes gluococorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin- induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal suffering from "secondary osteoporosis," a "secondary osteoporosis" treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating glucocorticoid- induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from gluocorticoid-induced osteoporosis, a glucocorticoid-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating hyperthyrodism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from hyperthyroidism-induced osteoporosis a hyperthyroidism-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immobilization-induced osteoporosis, an immobilization-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating heparin- induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from heparin- induced osteoporosis, a heparin-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immunosuppressive-induced osteoporosis, an immunosuppressive-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating a bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from a bone fracture, a bone fracture treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this invention for treating a bone fracture the Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone fracture. In another aspect of this invention the Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is administered systemically.
Yet another aspect of this invention is directed to methods for enhancing bone healing following focal reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal which has undergone facial reconstruction, maxillary reconstruction or mandibular reconstruction, a bone enhancing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this method a Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone reconstruction.
Yet another aspect of this invention is directed to methods for treating prosthetic ingrowth in a vertebrate, such as promoting bone ingrowth into a bone prothesis in, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from prosthetic ingrowth, a prosthetic ingrowth treating amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal undergoing surgery for vertebral synostosis, a therapeutically effective amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to methods for enhancing long bone extension in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an insufficiently sized long bone, a long bone enhancing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for strengthening a bone graft in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal in receipt of a bone graft, a bone graft strengthening amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Additionally, a compound of Formula 1 a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug can be used as an alternative to bone graft surgery. In one aspect of this method of Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of the bone graft. In another aspect of this method a Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied directly to the bone by injection or direct application to the bone surface.
A preferred dosage is about 0.001 to 100 mg/kg/day of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. An especially preferred dosage is about 0.01 to 10 mg/kg/day of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. The dosage may be administered locally, for example in a topical formulation. The dosage may be administered systemically, for example in oral, parenteral or suppository formulation.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the augmentation of bone mass which comprise a bone mass augmenting amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of a condition which presents with low bone mass in a vertebrate, e.g., a mammal (including a human being), which comprise a low bone mass condition treating amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the local or systemic treatment of osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprises a therapeutically effective amount of a compound of Formula 1 , a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of "secondary osteoporosis", which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin- induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which compositions comprise a "secondary osteoporosis" treating amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise an osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for enhancing bone fracture healing in a vertebrate, e.g., a mammal (including a human being), which comprise a bone fracture treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g. a mammal having undergone an osteotomy a bone restoration treating amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy. In one aspect the Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to an osteotomy site.
This invention is also directed to pharmaceutical compositions for facilitating bone healing after an osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrae, e.g., a mammal having undergone an osteotomy a bone healing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect the Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to an osteotomy site.
This invention is also directed to pharmaceutical compositions for the treatment of alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), which comprise an alveolar or mandibular bone loss treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of childhood idiopathic bone loss in a child which comprise a childhood idiopathic bone loss treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the augmentation of bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrae, e.g., a mammal (including a human being), which comprise a bone healing amount of a compound of the formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), which comprise a bone loss associated with periodontitis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of prosthetic, ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprise a prosthetic ingrowth treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for inducing vertebral synostosis or spinal fusion in a vertebrate, e.g., a mammal (including a human being), which comprise a therapeutically effective amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for enhancing bone union in a long bone extension procedure in a vertebrate, e.g., a mammal (including a human being), which comprise a bone mass augmentation treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise a glucocorticoid-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. This invention is also directed to pharmaceutical compositions for the treatment of hyperthyroidisrn-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise a hyperthyroidism-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise an immobilization-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of heparin-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which comprise a heparin-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt ■ of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which comprise an immunosuppressive-induced osteoporosis treating amount of a compound of the Formula 1 , a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to pharmaceutical compositions comprising a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug and for the use of such compositions for the treatment or prevention of conditions which present with low bone mass, including osteoporosis in a vertebrates, e.g., mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
The combinations of this invention comprise a therapeutically effective amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and a therapeutically effective amount of a second compound, said second compound being an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate.
Another aspect of this invention is directed to methods for treating vertebrates, e.g., mammals which present with low bone mass comprising administering to said vertebrate, e.g., a mammal having a condition which presents with low bone mass. • an amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and • an amount of a second compound, said second compound being an anti- resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate.
Such combination compositions and methods may also be used for other bone mass augmenting uses.
By "pharmaceutically acceptable" it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the Formulation, and not deleterious to the recipient thereof.
The expression "prodrug" refers to compounds that are drug precursors which, following administration, release the drag in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula 1 compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (Ci-C4)alkyl, (C2-C7)alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl) amino)ethyl having from 4 to 10 carbon atoms, 3-ρhthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1- C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(CrC2) alkyl, N,N-di(Ci-C2) alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3) alkyl.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular sterochemical or geometric configuration, giving rise to stereoisomers such as enantiomers and dias'tereomers; and configurational isomers such as cis and trans olefins and cis and trans substitution patterns on saturated alicyclic rings. All such isomers and mixtures thereof are included in this invention. Hydrates and solvates of the compounds of this invention are also included.
Preparation of a Compound according to the Invention
Various methods are available to those of ordinary skill for preparing embodiments of the invention.
By way of example, and without limiting the scope of the invention which is defined in the attached claims, a synthetic scheme is given below for preparing The Compound of Formula II: This synthesis could be modified as necessary in order to prepare other compounds according to the invention having suitable substituent groups (as defined in the claims): Synthetic Scheme:
Figure imgf000015_0001
Intermediate step
Figure imgf000015_0002
LiOH Step:5
Figure imgf000015_0003
Experimental Section:
Synthesis of Ethyl-2-(3-formylphenoxy)acetate (intermediate step)
Figure imgf000016_0001
Intermediate step
Calculations:
Figure imgf000016_0002
Procedure:
In a 250 ml, 4-neck RBF, the aldehyde was dissolved in 50 ml of DMF. K2CO3 was added to the flask. The mixture was stirred for 30 min. The bromo ethyl acetate in DMF (50 ml) was added to this reaction mixture drop-wise and after completion of addition the reaction mixture was stirred overnight. The reaction was monitored by TLC using dichloromethane (DCM) as a mobile phase which indicated that the reaction was complete.
Workup:
After completion of the reaction, the mixture was filtered off and washed with MeOH. The filtrate was evaporated and the residue was diluted with water (250 mL), extracted with ethyl acetate thrice (100 mL X 3). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The resulting 17 g of crude product was subjected to column purification.
Purification:
Column purification was carried out using DCM as an eluent to obtain pure product. Weight of pure product: 13 g; Yield: 76 %
Step 1: Synthesis of 4-Trimethylsilyl benzonitrile
Figure imgf000017_0001
Calculations:
Figure imgf000017_0002
Procedure:
The compound was dissolved in THF and cooled to -78 0C. The addition of n-BuLi was started drop-wise so as to maintain the temperature around -70 0C. After the completion of addition, the mixture was stirred for 1 hr. and the TMSCl was added drop wise to the mixture. The reaction mixture was stirred for another 1 hr. The reaction was monitored by TLC using Ethyl acetate and Hexane (1 :9) as a mobile phase which showed that the reaction was complete.
Workup:
After completion of the reaction, the mixture was treated with saturated ammonium chloride solution (50 niL) and the organic phase was separated. The aqueous layer was extracted with EA twice (50 rnL X 2). The combined organic layer was washed with water and brine, dried over sodium sulphate and concentrated under vacuum. The resulting 3 g of crude product was subjected to column purification.
Purification:
Column purification was carried out using Ethyl acetate: Hexane (2.5:97.5) as an eluent to obtain pure product.
Weight of pure product: 1.1 g; Yield: 38 %
Step 2: Synthesis of 4-Triraethylsilyl benzylamine
Figure imgf000018_0001
Calculations:
Figure imgf000018_0002
Procedure:
In 100 ml of 3 -Neck RBF the cyano compound was dissolved in THF under N2 atmosphere. The LAH was added to the flask and reaction mixture was stirred for 1 hr.
Workup:
After completion of the reaction (EA: Hex 1 :9), the mixture was cooled and treated with ethyl acetate. The reaction mixture was diluted with water (100 mL) and pH was neutralized with concentrated HCl. The aqueous layer was extracted with ethyl acetate thrice (50 mL X 3). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The resulting 1.1 g of crude product was subjected to the next step without column purification. Yield: 97 % (crude)
Step 3: Synthesis of Ethyl 2-(3-((4-(trimethylsilyl)benzylamino)methyl)phenoxy) acetate
Figure imgf000019_0001
Calculations:
Figure imgf000019_0002
Procedure:
The aldehyde compound was dissolved in methanol. The solution of amine in methanol was added to the flask. The mixture was stirred for 30 min. and sodium borohydride was added to the above mixture portion- wise. The mixture was stirred at RT for 1 hr. The reaction was monitored on TLC using Ethyl acetate and Hexane (6:4) as a mobile phase which showed that the reaction was complete.
Workup:
The mixture was poured in cooled water. The aqueous layer was extracted with EA thrice (20 mL X 3). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The resulting 2 g of crude compound was subjected to column purification.
Purification:
Column purification was carried out using Ethyl acetate: Hexane (30:70) as an eluent to obtain pure product.
Weight of pure product: 0.96 g; Yield: 36 %
Step 4: Synthesis of Ethyl 2-(3-((N-(4-(trimethylsilyl)benzyl)pyridine-3-sulfonamido) methyl)phenoxy)acetate
Figure imgf000020_0001
Calculations:
Figure imgf000020_0002
Procedure:
All of above reagents were mixed and stirred for 1-2 hr. The reaction was monitored on TLC using DCM: MeOH (9.5:0.5) as a mobile phase which showed that the reaction was complete.
Workup:
The reaction mixture was poured in to cooled water and treated with cone. HCl to adjust the pH to 3. The aqueous layer was extracted with EA thrice (10 mL X 3). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The resulting 572 mg of crude product was subjected to column purification.
Purification:
Column purification was carried out using DCM: MeOH (99.5:0.5) as an eluent to obtain pure product.
Weight of pure product: 220 mg; Yield: 25 %
Step 5: Synthesis of 2-(3-((N-(4-(trimethylsilyl)benzyl)pyridine-3-sulfonamido) methyl)phβnoxy) acetic acid
Figure imgf000021_0001
Calculations:
Figure imgf000021_0002
Procedure:
All the reagents were mixed and stirred for 3-4 hrs. The reaction was monitored on TLC using DCM: MeOH (9.5:0.5) as a mobile phase which showed that the reaction was complete.
Workup:
After completion of the reaction, the mixture was poured in cooled water and make pH 3-4 using HCl. The aqueous layer extracted with EA thrice (10 mL X 3). The combined organic layer was washed with water and brine, dried over sodium sulphate and concentrated under vacuum. The resulting product was 100 mg. Yield: 49 % (crude)

Claims

I) A compound according to Formula (I)
Figure imgf000022_0001
FORMULA (I) Where
• G is Ar, Ar^V-Ar2, Ar-(C rC6)alkylene, Ar-CONH-(Ci-C6)alkylene5 R1R2 amino, oxy(CrC6)alkylene, amino substituted with Ar, or amino substituted with Ar(Ci-C4)alkylene and R11, o R1 and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1 and R2 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, (d-C4)alkyl, fluoro or chloro; o wherein R1 ! is H or (C1-C8)allcyl, E is CH orN
Q is selected from
• (C2-C6)alkylene-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substitutes independently selected from fluoro or (C1-C4) alkyl,
• (C4-C8)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (Cl-C4)alkyl,
• X-(Ci-C5)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (CrC^alkyl,
• (C1-C5)alkylene-X-5 said alkylene optionally substituted with up to four substituents independently selected fluoro or
Figure imgf000022_0002
• (C1-C3)alkylene-X-(C1-C3)alkylene, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C1- C4)alkyl,
• (C2-C4)alkylene-W-X-(Co-C3)-alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl,
• (C0-C4)alkylene-X-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (Ci-C4)alkyl, • (C2-C5)alkylene-W-X-W-(C1-C3)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 (C1- C4)alkyl,
• (C1-C4)alkylene-ethenylene-(C1-C4)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (Cϊ-C4)alkyl,
• (C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-(Co-C5)alkylene-5 said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl,
• (C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-W-(C1-C3)aU<:ylene-, said alkylenes and said ethenylene optionally each substituted with up to four substitutes each independently selected from fluoro is (Ci-C4)alkyl,
• (C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (Cl-C4)alkyl, or
• (C1-C4)alkylene-ethynylene-X-(Co-C3)ah'cylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo- 1,2,4- oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
J is selected from H, a halogen, J1, NH2, NH(J1), N(J1J2), OH, O-J1, Ar, O-Ar, NH-
A Arr5, NNIH(P)Ar, where
• J and J are independently selected from C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl. and where
• 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 bicylic 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;
• Ar1 and Ar2 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 lieteroatoms 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; o where Ar, Ar1 and Ar2 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 one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R , R4 and R5 wherein R , R4 and R5 are independently hydroxy, nitro, halo, carboxy,
Figure imgf000024_0001
C4)alkyl, (Ci-C4)alkoxycarbonyl, (d-C7)alkyl, (C2-C7)alkenyl, (C2- C7)alkynyl, (C3-C7)cycloalkyl,
Figure imgf000024_0002
(C3- C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1- or , N
Figure imgf000024_0003
,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (Ci-C^alkylthio, (C1- C6)alkylsulfmyl,
Figure imgf000024_0004
or mono-N or (U-N5N-(C1- C4)alkylaminosulfinyl;
Ar3, Ar4 and Ar5 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; . o where Ar3, Ar4 and Ar5 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 , R41 and R51 wherein R31, R41 and R51 are independently hydroxy, nitro, halo, carboxy,
Figure imgf000024_0005
(C1- C4)alkoxy(C1-C4)alkyl, (Ci-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2- C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)CyClOaIlCyI(C1- C4)alkyl, (CrC^cycloalkyKCi-GOalkanoyl, formyl, (C1-C8)alkanoyl,
Figure imgf000024_0006
Figure imgf000025_0001
C4)alkylaminosulfϊnyl;
• W is oxy, thio, sulfmo, sulfonyl, aminosulfonyl-, mono-N-(C1-
Figure imgf000025_0002
C4)alkyleneaminosulfonyl-, sulfonylaminOj N-^i-C^alkylenesulfonylamino, craboxamido, N-(Cj[-C4)alkylenecarboxamido, carboxamidooxy, N-(C1- C4)alkylenecarboxamidooxy, carbamoyl, -mono-N-^i-C^alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C1-C4)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, (C1- C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C^aIkOXy, or carbamoyl;
• R1, R2 , R3 , R4 , R5 , R11 , R31 , R41 and R51, 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 V1 are each independently a bond,
Figure imgf000025_0003
(C1- C4)alkylenethio, (C1-C4)alkyleneoxy, oxy(C1-C4)alkylene or (Ci-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro; or a prodrug or pharmaceutically acceptable salt thereof.
2) A compound according to Claim 1 where Q is (C0-C4)alkylene-X- W-(C1- C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C-OaIkVl, and E is CH.
3) A compound according to Claim 1 where A is SO2 and G is Ar, and E is CH.
4) A compound according to Claim 1 where Q is (C0-C4)alkylene-X- W-(C1- C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4^UCyL A is SO2 and G is Ar and E
Figure imgf000025_0004
5) A compound according to Claim 1 with the structure according to Formula (II)
Figure imgf000025_0005
FORMULA (II)
6) Use of a compound according to Claims 1 to 5 in the treatment of a disease characterised by bone loss, or prevention of bone loss, or restoration of bone mass, or augmentation of bone mass.
7) A pharmaceutical composition comprising as an active ingredient a compound according to claims 1 to 5 for use in treatment of a disease characterised by bone loss, or for prevention of bone loss, or for restoration of bone mass, or for augmentation of bone mass.
8) A pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
9) Use of a compound according to claims 1 to 5, or a prodrug thereof, in the manufacture of a medicament for use in treatment of a disease characterised by bone loss, or for prevention of bone loss, or for restoration of bone mass, or for augmentation of bone mass.
10) A pharmaceutical composition for the augmentation of bone mass which comprises a bone mass augmenting amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
H) A pharmaceutical composition for the treatment of a condition which presents with low bone mass in a vertebrate, e.g., a mammal (including a human being), which comprises a low bone mass condition treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
12). A pharmaceutical composition for the local or systemic treatment of osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprises a therapeutically effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
13) A pharmaceutical composition for the treatment of "secondary osteoporosis", which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprises a "secondary osteoporosis" treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
14) A pharmaceutical composition for the treatment of osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprises an osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. 15) A pharmaceutical composition for enhancing bone fracture healing in a vertebrate, e.g., a mammal (including a human being), which comprises a bone fracture treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
16) A pharmaceutical composition for the treatment of osteotomy in a vertebrate, e.g., a mammal (including a human being), which comprises a bone restoration treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy.
17) A pharmaceutical composition for facilitating bone healing after an osteotomy in a vertebrate, e.g., a mammal (including a human being), which comprises a bone healing amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
18) A pharmaceutical composition for the treatment of alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), which comprises an alveolar or mandibular bone loss treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
19) A pharmaceutical composition for the treatment of childhood idiopathic bone loss in a child which comprises a childhood idiopathic bone loss treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
20) A pharmaceutical composition for the augmentation of bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrae, e.g., a mammal (including a human being), which comprises a bone healing amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
2I) A pharmaceutical composition for the treatment of bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), which comprises a bone loss associated with periodontitis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
22) A pharmaceutical composition for the treatment of prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprises a prosthetic ingrowth treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
23) A pharmaceutical composition for inducing vertebral synostosis or spinal fusion in a vertebrate, e.g., a mammal (including a human being), which comprises a therapeutically effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
24) .A pharmaceutical composition for enhancing bone union in a long bone extension procedure in a vertebrate, e.g., a mammal (including a human being), which comprises a bone mass augmentation treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. .
25) A pharmaceutical composition for the treatment of glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprises a glucocorticoid-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
26) A pharmaceutical composition for the treatment of hyperthyroidism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprises a hyperthyroidism-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
27) A pharmaceutical composition for the treatment of immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprises an immobilization-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
28) A pharmaceutical composition for the treatment of heparin-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which comprises a heparin- induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
29) A pharmaceutical composition for the treatment of immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which . comprises an immunosuppressive-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
30) A pharmaceutical composition which is a combination therapeutic comprising a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 31) A combination according to claim 30 wherein said anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug is an estrogen agonist/antagonist or a bisphosphonate.
32) A method for treating vertebrates, e.g., a mammal (including on human beings), having a condition which presents with low bone mass comprising administering to said vertebrate, e.g., a mammal, having a condition which presents with low bone mass a therapeutically effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
33) A method for treating vertebrates, e.g., mammals which present with low bone mass or for other bone mass augmenting methods comprising administering to said vertebrate, e.g., a mammal (including a human being)
• an amount of a first compound, said first compound being a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and
• an amount of a second compound, said second compound being an anti- resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate.
34) A method for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
35) A method for treating osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis an osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
36) A method for treating osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g. a mammal having undergone an osteotomy, a bone restoration treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy.
37) The method of claim 36 wherein said compound , prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to a site of osteotomy. 38) A method for treating alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an alveolar bone or mandibular loss, an alveolar or mandibular bone loss treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
39) A method for treating bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., mammal suffering from bone loss associated with periodontitis, a bone loss associated with periodontitis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
40) A method for treating childhood idiopathic bone loss is a child comprising administering to a child suffering from childhood idiopathic bone loss a childhood idiopathic bone loss treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
.41) A method for treating "secondary osteoporosis," which includes gluococorticoid- induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal suffering from "secondary osteoporosis," a "secondary osteoporosis" treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
42) A method for treating glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from gluocorticoid-induced osteoporosis, a glucocorticoid- induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
43) A method for treating hyperthyrodism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from hyperthyroidism-induced osteoporosis a hyperthyroidism- induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
44) A method for treating immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immobilization-induced osteoporosis, an immobilization- induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
45) A method for treating heparin-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from heparin-induced osteoporosis, a heparin-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
46) A method for treating immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immunosuppressive-induced osteoporosis, an immunosuppressive-induced osteoporosis treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
47) A method for treating a bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from a bone fracture, a bone fracture treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
48) The method of claim 47 wherein said compound, prodrug thereof of pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone fracture.
49) The method of claim 47 wherein said compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is administered systemically.
50) A method for enhancing bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal which has undergone facial reconstruction, maxillary reconstruction or mandibular reconstruction, a bone enhancing amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
51) The method of claim 50 wherein said compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone reconstruction.
52) A method for treating prosthetic ingrowth in a vertebrate, such as promoting bone ingrowth into a bone prothesis in, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from prosthetic ingrowth, a prosthetic ingrowth treating amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
53) A method for inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal undergoing surgery for vertebral synostosis, a therapeutically effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
54) A method for enhancing long bone extension in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an insufficiently sized long bone, a long bone enhancing amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
55) A method for strengthening a bone graft in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal in receipt of a bone graft, a bone graft strengthening amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
56) A method for treating a condition(s) which presents with low bone mass, including long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery, or for treating a vertebrate, e.g., a mammal known to have a significantly higher than average chance of developing such diseases including osteoporosis, comprising administering to said vertebrate, e.g., a mammal suffering from condition(s) an effective amount of a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
57) A method according to claim 56 wherein said vertebrate is selected from the group consisting of post-menopausal women, men over the age of 60 and men over the age of 80 and individuals regardless of age who have significantly reduced bone mass, i.e., greater than or equal to 1.5 standard deviations below young normal levels.
58) A dosage form comprising a compound according to claims 1 to 5, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug, wherein said dosage form when administered to a vertebrate provides a dosage of said compound or prodrug of 0.001 to 100 mg/kg/day, prefereably 0.01 to 10 mg/kg/day.
59) A kit comprising a dosage form according to claim 58 and instructions for administration of said dosage form in order to obtain said dosage in said vertebrate.
60) A dosage form according to claim 58 for administration orally, parenterally or as a suppository.
PCT/GB2008/002010 2007-06-14 2008-06-12 Silicon-containing compounds for treatment or prevention of bone loss or restoration of bone mass, or augmentation of bone mass WO2008152388A1 (en)

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Citations (3)

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US6288120B1 (en) * 1996-12-20 2001-09-11 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
WO2004026823A1 (en) * 2002-09-20 2004-04-01 Pfizer Products Inc. Amide and sulfonamide ligands for the estrogen receptor
WO2004091518A2 (en) * 2003-04-11 2004-10-28 Anormed Inc. Cxcr4 chemokine receptor binding compounds

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Publication number Priority date Publication date Assignee Title
US6288120B1 (en) * 1996-12-20 2001-09-11 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
WO2004026823A1 (en) * 2002-09-20 2004-04-01 Pfizer Products Inc. Amide and sulfonamide ligands for the estrogen receptor
WO2004091518A2 (en) * 2003-04-11 2004-10-28 Anormed Inc. Cxcr4 chemokine receptor binding compounds

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