WO2008060999A1 - Dérivés pipéridinyl arylsulfonamide comme modulateurs de protéine 1 sécrétée apparentée au récepteur frizzled - Google Patents
Dérivés pipéridinyl arylsulfonamide comme modulateurs de protéine 1 sécrétée apparentée au récepteur frizzled Download PDFInfo
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- WO2008060999A1 WO2008060999A1 PCT/US2007/084248 US2007084248W WO2008060999A1 WO 2008060999 A1 WO2008060999 A1 WO 2008060999A1 US 2007084248 W US2007084248 W US 2007084248W WO 2008060999 A1 WO2008060999 A1 WO 2008060999A1
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- WIPO (PCT)
- Prior art keywords
- compound
- phenyl
- aryl
- methyl
- trifluoromethyl
- Prior art date
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- YGJXBTRLYHCWGD-UHFFFAOYSA-N tert-butyl 4-(bromomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CBr)CC1 YGJXBTRLYHCWGD-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- 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
Definitions
- the present invention relates to novel piperidinyl arylsulfonamide derivatives that act, for example, as modulators of secreted frizzled-related protein- 1.
- the present invention also relates to processes for the preparation of piperidinyl arylsulfonamide derivatives, pharmaceutical compositions containing them and to their use in treating various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- various diseases and disorders including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- Bone remodeling the process by which the adult human skeleton is continuously renewed, is carried out by osteoclasts and osteoblasts, two specialized cell types that originate from hematopoietic and mesenchymal progenitors of the bone marrow, respectively.
- a continuous and orderly supply of these cells is believed to be essential for skeletal homeostasis, as increased or decreased production of osteoclasts or osteoblasts and/or changes in the rate of their apoptosis are largely responsible for the imbalance between bone resorption and formation that underlies several systemic or localized bone diseases.
- enhanced osteoclast activity has been found to play a major role in the pathogenesis of postmenopausal osteoporosis, Paget' s disease, lytic bone metastases, multiple myeloma, hyperparathyroidism, rheumatoid arthritis, periodontitis, and hypercalcemia of malignancy.
- Wnt proteins have been identified as a family of growth factors consisting of more than a dozen structurally related molecules that are involved in the regulation of fundamental biological processes such as apoptosis, adipogenesis, embryogenesis, organogenesis, morphogenesis and tumorigenesis (Nusse and Varmus, Cell 1992, 69:1073-1087).
- Wnt polypeptides are multipotent factors and have biological activities similar to those of other secretory proteins such as transforming growth factor (TGF)- ⁇ , fibroblast growth factors (FGFs), nerve growth factor (NGF), and bone morphogenetic proteins (BMPs).
- TGF transforming growth factor
- FGFs fibroblast growth factors
- NGF nerve growth factor
- BMPs bone morphogenetic proteins
- Frizzled proteins contain an amino terminal signal sequence for secretion, a cysteine-rich domain (CRD) that is thought to bind Wnt, seven putative transmembrane domains that resemble a G-protein coupled receptor, and a cytoplasmic carboxyl terminus.
- CCD cysteine-rich domain
- LDL low-density lipoprotein
- LRP low-density lipoprotein receptor-related proteins
- the first secreted frizzled-related protein was named "Frzb” (for "frizzled motif in bone development") and was purified and cloned from bovine articular cartilage extracts based on its ability to stimulate in vivo chondrogenic activity in rats (Hoang et al., J. Biol. Chem. 1996, 271 :26131-26137; Jones & iom& ⁇ y, Bioessays 2002, 24:811-820). The human homologue of the bovine gene has also been cloned. Unlike the frizzled proteins, however, Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt.
- Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt.
- Frzb cDNA encodes a 325 amino acid/36,000 dalton protein and is predominantly expressed in the appendicular skeleton.
- the highest level of expression is in developing long bones and corresponds to epiphyseal chondroblasts; expression declines and disappears toward the ossification center.
- SFRPs participate in apoptosis. Some SFRPs have thus been identified as "SARPs" for secreted apoptosis related proteins. Additional members of the SFRP family have been identified, and have been shown to be antagonists of Wnt action. There are currently at least five known human SFRP/SARP genes: SFRP-l/FrzA/FRP-l/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP-3/Frzb-l/FrzB/Fritz, SFRP-4 and SFRP-5/SARP-3 (Leimeister et al, Mechanisms of Development 1998, 75:29-42).
- SFRP- 1 Secreted frizzled related protein-1
- SFRP-I Secreted frizzled related protein-1
- the present invention relates to certain piperidinyl arylsulfonamide derivatives and to their use, for example, in medical treatment.
- the invention relates piperidinyl arylsulfonamide derivatives that act as modulators of secreted frizzled related protein- 1.
- the compounds can be used, for example, to treat various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- the present invention is directed to compounds of Formula (1):
- Ri is O, S, SO 2 , or NR 5 ;
- R 2 is Ci -C 3 alkylene
- R 3 is CpC 6 alkyl, C 1 -C 3 perfluoroalkyl, Ci -C 3 perfluoroalkoxy, C 1 -C 3 alkoxy, halogen, or CN;
- R 4 is hydrogen, Ci-C 6 alkyl, -(CH 2 )o- 3 -aryl, -(CH 2 ) 0-3 -substituted aryl, -(CH 2 )o-3- heteroaryl, -(CH 2 ) 0 - 3 -substituted heteroaryl, -SO 2 -Ci-C 6 alkyl, -SO 2 -(CH 2 ) 0 - 3 -aryl, -SO 2 -(CH 2 ) 0 .
- R-5 at each occurrence is selected from H, CpCe alkyl, -(CH 2 )o- 3 -aryl, -(CH 2 )o- 3 - substituted aryl, -(CH 2 )o- 3 -heteroaryl,
- Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
- the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.
- the present invention also provides methods for treating patients suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof, that comprise administering to the patients a therapeutically effective amount of at least one compound of Formula 1.
- alkyl refers to an optionally substituted aliphatic hydrocarbon chain having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 ,1 to 4 or 1-3 carbon atoms.
- alkyl includes straight and branched chains. Straight chain alkyl groups have 1 to 8 carbon atoms and branched chain alkyl groups have 3 to 12 carbon atoms.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl groups.
- perfluoroalkyl refers to an optionally substituted straight or branched aliphatic hydrocarbon chain of 1 to 8 carbon atoms and preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.
- alkoxy refers to the group -O-R' where R' is an alkyl group as previously defined; e.g., of 1-3 carbon atoms.
- perfluoroalkoxy refers to the group -O-R" where R" is a perfluoroalkyl group as previously defined.
- aryl refers to an optionally substituted carbocyclic aromatic ring.
- Aryl groups may be monocyclic or bicyclic and may have 6-14 carbon atoms, e.g., 6-10 carbon atoms.
- Exemplary aryl groups include phenyl and naphthyl.
- heteroaryl refers to an optionally substituted 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur and oxygen.
- Monocyclic rings preferably have 5 to 6 members and bicyclic rings preferably have 8 to 10 membered ring structures.
- heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl.
- halogen or halo, refer to chlorine, bromine, fluorine or iodine.
- substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroalkyl, alkyamino, dialkylamino, alkoxy, alkylcarbonyl, arylcarbonyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, haloalkyl, perfluoroalkylalkyl, alkenyl, alkynyl, arylalkyl and the like.
- Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions.
- the term "optionally substituted aryl” is intended to mean an aryl group that can optionaly have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the aryl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
- impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
- impermissible substitution patterns are well known to the skilled artisan.
- protecting group with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
- Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2- methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
- a reagent such as, but not
- Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.
- Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
- activated or “an activating group” or “G A " as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile.
- activating groups are halogens, such as Cl, Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like.
- An example of an activated group is acetylchloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
- deprotecting refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate. Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T.W., John Wiley & Sons, New York, NY, (1st Edition, 1981).
- terapéuticaally effective amount refers to the amount of a compound of formula 1 that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering or is suspected to suffer. Such conditions include, but are not limited to, osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, and leiomyoma.
- pharmaceutically acceptable salts or “pharmaceutically acceptable salt” includes acid addition salts, namely salts derived from treating a compound of formula 1 with an organic or inorganic acids or bases. Where the compound having formula I has an acidic function, for instance carboxy or phenolic hydroxyl, the term “pharmaceutically acceptable salts” or “pharmaceutically acceptable salt” includes salts derived from bases, for instance, sodium salts.
- patient refers to a mammal.
- administer refers to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
- treat and “treating,” as used herein, refer to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
- shocker and “suffering,” as used herein, refer to one or more conditions with which a patient has been diagnosed, or is suspected to have.
- Ri is O, S, SO 2 , or NR 5 ;
- R 5 is H, Ci-C 6 alkyl, -(CH 2 )o- 3 -aryl, -(CH 2 )o- 3 -substituted aryl, -(CH 2 )o- 3 -heteroaryl, or -(CH 2 )o- 3 -substituted heteroaryl;
- R 2 is C1-C3 alkylene
- R3 is Ci-C 6 alkyl, C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, C 1 -C 3 alkoxy, halogen, or CN;
- R4 is hydrogen, C)-C 6 alkyl, -(CH 2 )o- 3 -aryl, -(CH 2 )o-3 -substituted aryl, -(CH 2 ) 0 -3- heteroaryl, -(CH 2 )o- 3 -substituted heteroaryl, -SO 2 -Ci-C 6 alkyl, -SO 2 -(CH 2 ) 0-3 -aryl, -SO 2 -(CH 2 ) O-3 - substituted aryl, -SO 2 -(CH 2 ) 0 .
- Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
- the aryl and heteroaryl groups found in compounds of Formula 1 are optionally substituted with one or more substituents that include, for example, halogen, CN, OH, NO 2 , amino, -alkylamino, -dialkylamino, alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, Ci to C 3 alkoxy, Ci to C 3 perfluoroalkyl, Ci to C 3 perfluoroalkoxy, -0-(CH 2 )o- 3 -aryl, -S-(CH 2 )o-3-aryl, alkylcarbonyl, including -CO-(Ci to C 6 alkyl) and -CO-(Ci to C 6 substituted alkyl), -CO-(CH 2 )o- 3 -aryl, -SO 2 -(C, to C 6 alkyl), -SO 2 -(Ci to C 6 substituted alkyl), -SO 2 -
- Ar of Formula 1 is aryl or substituted aryl.
- Ar is aryl, and in particularly preferred embodiments, Ar is phenyl.
- Ri is O, S, or SO 2 .
- Ri is S or SO 2 .
- Ri is S.
- R 2 of Formula 1 is methylene or ethylene.
- R 2 is preferably methylene.
- R3 is Ci-C 6 alkyl or C 1 -C 3 perfluoroalkyl.
- R 3 is C 1 -C 3 perfluoroalkyl, and in particularly preferred embodiments, R 3 is perfluoromethyl.
- R 4 is hydrogen, -CO 2 -Ci-C 6 alkyl, -SO 2 -(CH 2 ) 0-3 -substituted aryl, -SO 2 N(R 5 ) 2 , -CO(CH 2 )L 3 -CO 2 -Ci- C 6 -alkyl, -CO(CH 2 )i -3 -CO 2 H, -CO-(CH 2 ) 0 - 3 -substituted aryl, -CO-(CH 2 )o- 3 -substituted heteroaryl, -CON(Rs) 2 , -CONR 5 (CH 2 ) I-3 -CO 2 H, or -CONR 5 (CH 2 )i.3-CO 2 -Ci-C 6 -alkyl.
- Still further embodiments of the invention relate to compounds of Formula 1 in which R 4 is hydrogen, -CO 2 tertbutyl, -SO 2 -substituted phenyl, -SO 2 N(CH 3 ) 2 , -CO(CH 2 ) 2 - CO 2 CH 3 , -CO(CH 2 ) 2 CO 2 H, CO-substituted phenyl, CO-substituted pyridyl, -CON(H)C(CH 3 ) 3 , -CON(CH 3 ) 2 , -CONHCH 2 CO 2 H, or -CONHCH 2 -CO 2 -CH 2 -CH 3 .
- R 4 is -SO 2 -substituted phenyl, CO-substituted phenyl, -CO(CH 2 ) 2 CO 2 H, or -CONHCH 2 CO 2 H. And in particularly preferred embodiments of the invention, R 4 is -SO 2 -substiruted phenyl.
- Additional embodiments of the invention relate to compounds of Formula 1 in which Ar is phenyl; Ri is S or SO 2 ; R 2 is methylene; R 3 is perfluoromethyl; and R 4 is hydrogen, - CO 2 -Ci-C 6 alkyl, -SO 2 -(CH 2 ) 0 -3-substituted aryl, -SO 2 N(R 5 ) 2 , -CO(CH 2 )i.
- representative compounds of Formula 1 include: tert-butyl 4-( ⁇ [5-(phenylsulfonyl)-2-(rrifluoromethyl)phenyl]thio ⁇ methyl)piperidine-l- carboxylate; 4-( ⁇ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl)piperidine hydrochloride; 3- ⁇ [4-( ⁇ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl) ⁇ iperidin-l- yl]sulfonyl ⁇ benzoic acid;
- Particularly preferred compounds of Formula 1 include: 3- ⁇ [4-( ⁇ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl)piperidin-l- yl]sulfonyl ⁇ benzoic acid;
- Compounds of Formula 1 may be used to modulate the activity of secreted frizzled related protein- 1.
- Such compounds are of interest for the treatment of osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, as well as autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.
- the present invention therefore provides methods of treating, preventing, inhibiting, or alleviating each of the maladies listed above in a mammal, preferably in a human, comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a patient suspected to suffer from such a malady.
- the invention relates to compositions comprising at least one compound of Formula 1, or a steroisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
- Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the bone.
- the compositions comprise mixtures of one or more compounds of Formula 1.
- Certain of the compounds of Formula 1 contain stereogenic carbon atoms or other chiral elements and thus give rise to stereoisomers, including enantiomers and diastereomers.
- the invention generally relates to all stereoisomers of the compounds of Formula 1, as well as to mixtures of the stereoisomers.
- the name of a compound without indication as to the absolute configuration of an asymmetric center is intended to embrace the individual stereoisomers as well as mixtures of stereoisomers.
- Reference to optical rotation [(+), (-) and ( ⁇ )] is utilized to distinguish the enantiomers from one another and from the racemate.
- the designations R* and S* are used to indicate relative stereochemistry, employing the Chemical Abstracts convention which automatically assigns R* to the lowest numbered asymmetric center.
- An enantiomer can, in some embodiments of the invention, be provided substantially free of the corresponding enantiomer.
- reference to an enantiomer as being substantially free of the corresponding enantiomer indicates that it is isolated or separated via separation techniques or prepared so as to be substantially free of the corresponding enantiomer.
- substantially free means that a significantly lesser proportion of the corresponding enantiomer is present. In preferred embodiments, less than about 90 % by weight of the corresponding enantiomer is present relative to desired enantiomer, more preferably less than about 1% by weight.
- Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred enantiomers, can be prepared by methods described herein. Methods for the preparation of enantiomers are described, for example, in Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); EHeI, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is hereby incorporated by reference in its entirety.
- HPLC high performance liquid chromatography
- the appropriately substituted sulfonyl chloride 1 can be reacted with an aromatic compound such as benzene, in the presence of a Lewis acid catalyst such as aluminum chloride, with or without heating, to yield the desired aryl sulfone 2.
- a Lewis acid catalyst such as aluminum chloride
- Reaction of 2 with dibromodifluoromethane in a suitable solvent such as N,N-dimethylacetamide in the presence of copper and activated carbon, at an elevated temperature such as 100 0 C, yields the trifluoromethyl aryl sulfone 3.
- the invention relates to compositions comprising at least one compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
- Such compositions are prepared in accordance with general pharmaceutical formulation procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety.
- Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
- the compounds of Formula 1 can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers.
- Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
- the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99 % of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsif ⁇ ers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
- oils e.g. fractionated coconut oil and arachis oil
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
- Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
- Compositions for oral administration can be in either liquid or solid form.
- the compounds of Formula 1 can be administered rectally or vaginally in the form of a conventional suppository.
- the compounds of Formula 1 can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of Formula 1 can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable.
- a variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like.
- compounds of Formula 1 are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
- An amount adequate to accomplish this is defined as a "therapeutically effective amount.”
- the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
- the variables involved include the specific condition and the size, age, and response pattern of the patient.
- the compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa.
- the usual daily dose depends on the specific compound, method of treatment and condition treated.
- the usual daily dose is 0.01 - 1000 mg/kg for oral application, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg for parenteral application, preferably 0.5 - 50 mg/kg.
- the present invention is directed to prodrugs of compounds of Formula 1.
- prodrug means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula 1.
- Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
- Step l l-Chloro-2-nitro-4-(phenylsulfonyl)benzene
- the filtrate was partitioned between 10% ammonium chloride and ethyl acetate.
- the emulsion that formed was separated by the addition of saturated NaCl.
- the organic layer was separated, extracted 5 times with water, dried (anhydrous MgSO 4 ), filtered and the solvent removed under reduced pressure to give 6.61 g of a brown oil.
- N,N-Diisopropylethylamine (190 ⁇ L, 1.09 mmol) was added under nitrogen to a mixture of 4-( ⁇ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl)pi ⁇ eridine hydrochloride (199.8 mg, 0.442 mmol), prepared in Example 2, and 3-chlorosulfonyl-benzoic acid (104.9 mg, 0.476 mmol) in 11 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 3 h. The reaction was extracted 2 times with 2 N HCl, 1 time with water and then concentrated under reduced pressure to a volume of approximately 5 mL.
- N,N-Diisopropylethylamine 180 ⁇ L, 1.03 mmol was added to a mixture of 4- ( ⁇ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl)piperidine hydrochloride (150.0 mg, 0.332 mmol), prepared in Example 2, and 3 -chlorocarbonyl -propionic acid methyl ester (50.5 mg, 0.336 mmol) in 8 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature. The reaction was monitored by thin-layer chromatography (TLC).
- TLC thin-layer chromatography
- Example 16 4- ⁇ [4-( ⁇ [5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]thio ⁇ methyl)piperidin- l-yl]carbonyl ⁇ benzoic acid
- the affinity of test compounds for SFRP-I was determined using a fluorescence polarization binding assay. According to the assay design, a probe compound was bound to SFRP- 1. The fluorescence anisotropy value of the probe compound is increased upon binding to SFRP-I. Upon the addition of a test compound, the fluorescence anisotropy value for the probe compound decreased due to competitive displacement of the probe by the test compound. The decrease in anisotropy as a function of increasing concentration of the test compound provides a direct measure of the test compound's binding affinity for SFRP-I . [0081] To determine IC50 values, fluorescence polarization experiments were conducted in a 384-well format according to the following procedures.
- a 20 mM stock solution of the probe compound was prepared in 100 % DMSO and dispensed in 10 ⁇ L aliquots for long- term storage at -20 0 C.
- the binding assay buffer was prepared by combining stock solutions of Tris-Cl, NacL, glycerol, and NP40 at final concentrations of 25 mM Tris-Cl pH 7.4, 0.5 M NaCl, 5% glycerol and 0.002 % NP40.
- Master stock solutions of the test compounds were prepared in 100 % DMSO at final concentrations of 20 mM.
- the working stock solutions of the test compounds were prepared by serially diluting the 20 mM master stock solution to 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, 0.3125 mM, 0.156 mM, 78 ⁇ M, 39 ⁇ M, 19.5 ⁇ M, 9.8 ⁇ M, 4.9 ⁇ M, 2.44 ⁇ M, 1.22 ⁇ M, 0.31 ⁇ M, 76 nM, and 19 nM in DMSO.
- the working stock solutions of the test compounds were further diluted by combining 6 ⁇ l of the solutions with 24 ⁇ L of Milli-Q purity water, resulting in working stock solutions (10x compound stocks) in 20 % DMSO.
- the assay controls were prepared as follows. A 2 ⁇ L aliquot of the 20 mM fluorescence probe compound was diluted 1000-fold in 100 % DMSO to a final concentration of 20 ⁇ M. 6 ⁇ L of the 20 ⁇ M probe was combined with 5.4 mL of the assay buffer, mixed well, and 18 ⁇ L of the resulting solution was dispensed into 384-well plates.
- SFRP-I /probe complex was prepared by combining 11 ⁇ L of 20 ⁇ M probe compound with 9.9 mL of the assay buffer and SFRP-I stock solution to final concentrations of 22 nM probe compound and 50 nM SFRP-I. 18 ⁇ L of the SFRP-1/probe complex was dispensed into the 384-well plates.
- the plate was incubated in the dark for 15 minutes.
- the fluorescence of the SFRP-1/probe complexs was read in the Tecan Ultra plate reader at excitation and emission maxima of 485 and 535 nm.
- the plate reader settings were as follows:
- Fluorescence anisotropy results from the emission of polarized light in the parallel and perpendicular directions when a fluorophore is excited with vertically polarized light.
- Example 19 Cell-based Assay for in vitro Measurement of SFRP-1/SARP2 Antagonist Activity
- the osteosarcoma cell line U2OS (ATCC, HTB 96), was passaged twice a week with growth medium (McCoy's 5A medium containing 10% (v/v) fetal calf serum, 2mM GlutaMAX-1, and 1% (v/v) Penicillin- Streptomycin).
- the cells were maintained in vented flasks at 37 0 C inside a 5% CO 2 /95% humidified air incubator. One day prior to transfection, the cells were plated with growth medium at 25,000 cells/well into 96-well plates and incubated at 37 0 C overnight.
- the growth medium was removed, and the cells were washed once with OPTIMEM I (Gibco-BRL) medium (100 ⁇ L/well) to remove the serum and antibiotics.
- the wash medium was removed, and the cells were re-fed with OPTI-MEM I medium (100 ⁇ L/well).
- OPTI-MEM I medium 0.1 ⁇ g 16x TCF-tk-Luciferase reporter, 0.02 ⁇ g Wnt 3, Wnt3A, Wnt 1 or empty vector (Upstate Biotechnology), 0.075 ⁇ g hSFRP-1 or empty vector (pcDNA3.1, Invitrogen), and 0.025 ⁇ g CMV- ⁇ gal (Clonetech).
- l ⁇ l of Lipofectamine 2000 reagent Invitrogen was diluted in 25 ⁇ l OPTI-MEM I medium and incubated at room temperature for 5 minutes.
- the diluted DNA's were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. Fifty ⁇ L of the DNA-LF 2000 mixture was added to each well, and the plate(s) were incubated at 37 0 C in a 5% C ⁇ 2 /95% humidified air incubator for 4 hours. The cells were washed once with 150 ⁇ L/well of experimental medium (phenol red-free RPMI Medium 1640 containing 2% fetal bovine serum, 2mM GlutaMAX-1, and 1% Penicillin-Streptomycin). Finally, the cells were treated overnight at 37 0 C with 200 ⁇ L/well of experimental medium containing either vehicle (typically DMSO) or diluted compound in replicates of 8 wells/compound. Dosing
- the cells were washed twice with 150 ⁇ L/well of PBS without calcium or magnesium and were lysed with 50 ⁇ L/well of IX cell culture lysis reagent (Promega Corporation) on a shaker at room temperature for 30 minutes. Thirty ⁇ L aliquots of the cell lysates were transferred to 96-well luminometer plates, and luciferase activity was measured in a MicroLumat PLUS luminometer (EG&G Berthold), or a Victor (PerkinElmer Life Sciences) using 100 ⁇ L/well of luciferase substrate (Promega Corporation). Following the injection of substrate, luciferase activity was measured for 10 seconds after a 1.6 second delay.
- IX cell culture lysis reagent Promega Corporation
- the U2OS cells were transfected in T225 flasks and the transfected cells were frozen.
- the frozen cells were thawed and plated on a 96 well plate and the assay was carried out as detailed above.
- the growth medium was removed from the T225 flasks, and the cells were washed once with OPTI-MEM I medium (approx. 25 ml/flask) to remove the serum and antibiotics.
- the wash medium was removed, and the cells were re-fed with OPTI-MEM I medium (59 ml/flask).
- the diluted DNA's were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. 11.8 mL of the DNA-LF 2000 mixture was added to each flask, and the flask(s) were incubated at 37 0 C in a 5% CO 2 /95% humidified air incubator for 4 hours.
- LF2000 diluted Lipofectamine 2000
- the medium was removed, and the cells were washed once with approximately 25 mL/flask of phenol red-free RPMI Medium 1640, then re-fed with 50 mL/flask of experimental medium (phenol red-free RPMI Medium 1640 containing 2% fetal bovine serum, 2 mM GlutaMAX-1, and 1% Penicillin- Streptomycin) and incubated at 37 0 C overnight.
- the transfected cells were washed twice with 25 mL/flask/wash of PBS without calcium or magnesium. Three ml of Trypsin-EDTA (0.05% Trypsin, 0.53 mM EDTA-4Na) was added to each flask, and the flasks were incubated at room temperature for approximately 5 minutes until the cells were rounded and detached from the surface of the flask(s). The cells were resuspended in 10 mL/flask of phenol red-free RPMI 1640 containing 10% fetal bovine serum and were pipetted up and down several times until a single cell suspension was formed.
- Trypsin-EDTA 0.05% Trypsin, 0.53 mM EDTA-4Na
- the resuspended cells were pooled and a 10 ⁇ L aliquot was removed and diluted at 1 : 10 in PBS.
- the diluted cells were counted using a hemacytometer to determine the total number of cells in the pool.
- the cells were transferred to sterile centrifuge tubes and pelletted at 1500 rpm in a Sorvall RC-3B refrigerated centrifuge at 4 0 C for 5 minutes. The supernatant was aspirated and the cells were resuspended in cold, phenol red-free RPMI 1640 medium containing 50% FBS to a cell density of 2.5E+7 cells/ml.
- Test compounds were then added to the wells (1 well/compound) and the plates were incubated at 37 0 C overnight. After the overnight incubation, luciferase activity was measured using the Luc-Screen Luciferase Assay System (Tropix). Fifty ⁇ L of Luc-Screen buffer 1 , warmed to room temperature, was added directly to the cells in the 96-well plates. Fifty ⁇ L of Luc-Screen buffer 2, warmed to room temperature, was then added, and the plates were incubated in the dark, at room temperature, for 10 minutes. The plates were transferred to a Packard Top Count Microplate Scintillation and Luminescence Counter (Packard), and the light emission was measured for 10 seconds after a 2 minute delay.
- Packard Packard Top Count Microplate Scintillation and Luminescence Counter
- GSK-3 ⁇ a key enzyme involved in the Wnt signaling pathway, served as an internal control for measurement of the cellular response to Wnt signaling.
- the inhibition of GSK-3 results in stabilization of ⁇ -catenin, leading to up-regulation of LEF/TCF regulated reporter genes.
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Abstract
Composés de formule (1), ou leurs sels pharmaceutiquement acceptables, en tant que modulateurs de protéine 1 sécrétée apparentée au récepteur Frizzled. On peut utiliser ces composés et des compositions les renfermant pour traiter une série de troubles, y compris l'ostéoporose.
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WO2006091450A1 (fr) * | 2005-02-18 | 2006-08-31 | Lexicon Genetics Incorporated | Composes 4-piperidin-1-yl-7h-pyrrolo[2,3-d]pyrimidine |
WO2006124875A2 (fr) * | 2005-05-13 | 2006-11-23 | Wyeth | Sulfamides de diarylsulfone et leur utilisation |
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