WO2007003419A1 - Heterocyclic compounds as agonists for the thyroid receptor - Google Patents
Heterocyclic compounds as agonists for the thyroid receptor Download PDFInfo
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- WO2007003419A1 WO2007003419A1 PCT/EP2006/006522 EP2006006522W WO2007003419A1 WO 2007003419 A1 WO2007003419 A1 WO 2007003419A1 EP 2006006522 W EP2006006522 W EP 2006006522W WO 2007003419 A1 WO2007003419 A1 WO 2007003419A1
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- 0 Cc1c(C)c(*)cc(C=C=C)c1 Chemical compound Cc1c(C)c(*)cc(C=C=C)c1 0.000 description 2
- QOJRWPFPYMJNLN-UHFFFAOYSA-N CS(NCc(ccc1c2)nc1ccc2Oc(c(Br)cc(NC(CC(O)=O)=O)c1)c1Br)(=O)=O Chemical compound CS(NCc(ccc1c2)nc1ccc2Oc(c(Br)cc(NC(CC(O)=O)=O)c1)c1Br)(=O)=O QOJRWPFPYMJNLN-UHFFFAOYSA-N 0.000 description 1
- SEZRMOFHXBAJAW-UHFFFAOYSA-N OC(CCc(cc1Br)cc(Br)c1Oc(cc1)cc2c1ncnc2)=O Chemical compound OC(CCc(cc1Br)cc(Br)c1Oc(cc1)cc2c1ncnc2)=O SEZRMOFHXBAJAW-UHFFFAOYSA-N 0.000 description 1
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
Definitions
- the present invention relates to compounds which are agonists or partial agonists of the thyroid receptor and the use of such compounds for therapeutic purposes.
- thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, dyslipidemia, obesity, diabetes, atherosclerosis and cardiac diseases.
- Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence blood levels of serum lipoproteins. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL cholesterol levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
- Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3',5'-tetraiodo-L-thyronine, or T 4 ) and triiodothyronine (3,5,3'-triiodo-L-thyronine, or T 3 ).
- TSH thyroid-stimulating hormone
- thyroxine 3,5,3',5'-tetraiodo-L-thyronine, or T 4
- triiodothyronine 3,5,3'-triiodo-L-thyronine, or T 3
- replacement therapy particularly in older individuals, may be restricted by certain detrimental effects from thyroid hormones.
- thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated.
- these potentially useful influences include for example, lowering of serum LDL levels, weight reduction, amelioration of depression and stimulation of bone formation.
- Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
- useful thyroid agonist drugs should minimize the potential for undesired consequences due to locally induced hypothyroidism, i.e. sub-normal levels of thyroid hormone activity in certain tissues or organs. This can arise because increased circulating thyroid hormone agonist concentrations may cause the pituitary to suppress the secretion of thyroid stimulating hormone (TSH), thereby reducing thyroid hormone synthesis by the thyroid gland (negative feedback control). Since endogenous thyroid hormone levels are reduced, localized hypothyroidism can result wherever the administered thyroid agonist drug fails to compensate for the reduction in endogenous hormone levels in specific tissues.
- TSH thyroid stimulating hormone
- Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Tissue selectivity can also be achieved by selective regulation of thyroid hormone responsive genes in a tissue specific manner.
- the compounds that are thyroid hormone receptor ligands, particularly selective agonists of the thyroid hormone receptor are expected to demonstrate a utility for the treatment or prevention of diseases or disorders associated with thyroid hormone activity, for example: (1) hypercholesterolemia, dyslipidemia or any other lipid disorder manifested by an unbalance of blood or tissue lipid levels ; (2) atherosclerosis; (3) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (4) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (5) obesity; (6) diabetes (7) depression; (8) osteoporosis (especially in combination with a bone resorption inhibitor); (9) goiter; (10) thyroid cancer; (11) cardiovascular disease or congestive heart failure; (12) glaucoma; and (13) skin disorders.
- diseases or disorders associated with thyroid hormone activity for example: (1) hypercholesterolemia, dyslipidemia or any other lipid disorder manifested by an unbalance of blood or tissue lipid levels ; (2) atherosclerosis; (3) replacement therapy in elderly
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt,
- G is a group selected from:
- N is a sp 2 nitrogen with a non-bonded electron pair in an sp 2 orbital
- the ring A is an aromatic or a non-aromatic five- membered or six-membered ring optionally comprising one or more further heteroatoms independently selected from oxygen, sulfur, sp 2 nitrogen, and -N(R 10 )-, the carbon atoms of ring A optionally being substituted with one or more groups R 1 ;
- Each R 10 is independently selected from - ⁇ CH 2 ) P -S-R b , -(CH 2 ) p -SO 2 -R b , -(CH 2 ) p -NH-SO 2 -R b , - (CH 2 ) p -SO 2 -NH-R b , -(CH 2 ) p -NH-CO-R b , -(CH 2 ) p -CO-NH-R b , Ci -12 alkyl, C 2 .
- p 1 or 2;
- each R a is independently selected from a hydrogen atom and a C 1-4 alkyl group optionally substituted with 1, 2 or 3 groups independently selected from halogen, methoxy, halomethoxy, dihalomethoxy and trihalomethoxy;
- each R b is independently selected from hydrogen, C 1 . 4 alkyl, C 2-4 alkenyl, C 2 . 4 alkynyl, fiuoromethyl, difluoromethyl, or trifluoromethyl, benzyl, heterocyclyl and phenyl, said alkyl, alkenyl, alkynyl or phenyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups independently selected from C 1 ⁇ alkyl, halogen, hydroxy, methoxy, halomethoxy, dihalomethoxy and trihalomethoxy;
- Each R is independently selected from hydrogen, hydroxy, halogen, N(R a ) 2 , - ⁇ CH 2 ) m -S-R , - (CH 2 ) m -SO 2 -R b , -(CH 2 ) H1 -NH-SO 2 -R 5 , -(CH 2 ) m -SO 2 -NH-R b , - ⁇ CH 2 ) m -NH-CO-R b , -(CH 2 ) m -CO- NH-R b , C 2-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1 .3 alkyl, phenyl, benzyl and C 3-7 heterocyclyl, said alkyl, alkenyl or alkynyl groups or portions of groups optionally being substituted with 1 , 2 or 3 groups each independently selected from
- n 0, 1 or 2;
- Each R 2 is independently selected from halogen, mercapto, cyano, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and N(R a ) 2 , said alkyl, alkenyl, alkynyl or alkoxy groups optionally being substituted with 1, 2 or 3 groups selected from halogen, hydroxy, v 1-4 alkoxy, C 1-4 alkylthio, haloCi. 4 alkoxy, dihaloC 1-4 alkoxy, and trihaloC 1-4 alkoxy;
- n 0, 1 or 2;
- Y is selected from oxygen, methylene, sulphur, SO, SO 2 and -N(R a )-;
- R 3 and R 4 are independently selected from halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, dihaloC 1-4 alkoxy, trihaloC 1-4 alkoxy, methylthio, halomethylthio, dihalomethylthio and trihalomethylthio;
- W is selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, N(R c )-C 1-3 alkylene, C(O)-C 1-3 alkylene, S-C 1-3 alkylene, O-C].
- alkylene C 1-3 alkylene-O-C 1-3 alkylene, C(O)NH-C 1-3 alkylene, NH(CO)-C 0-3 alkylene and C 1-3 alkyleneC(O)NH-C 1-3 alkylene, said alkylene, alkenylene or alkynylene groups or portions of groups optionally being substituted with 1 or 2 groups selected from hydroxy, mercapto, amino, halogen, C !-3 alkyl, C 1-3 alkoxy, phenyl, Ci_ 3 alkyl substituted with phenyl, haloC 1-3 alkyl, dihaloC 1-3 alkyl, trihaloC 1-3 alkyl, haloC 1-3 alkoxy, dihaloCi_ 3 alkoxy, trihaloC 1-3 alkoxy, and phenyl substituted with 1 , 2 or 3 halogen atoms;
- R c is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkyl, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, haloC 1-4 alkoxy, dihaloCi . 4 alkoxy, and trihaloC 1-4 alkoxy;
- R 5 is selected from -CO 2 R d , -PO(OR d ) 2 , -PO(OR C )NH 2 , -SO 2 OR d , -COCO 2 R", CONR d OR d , - SO 2 NHR d , -NHSO 2 R d , -CONHSO 2 R d , and - SO 2 NHCOR d ; and each R d is independently selected from hydrogen, C 1-4 alkyl, C 2 - 4 alkenyl, C 2 . 4 alkynyl, C 3 . 7 heterocyclyl, C 5 .i 0 aryl and C 5- io aryl substituted with 1, 2 or 3 groups independently selected from amino, hydroxy, halogen or C 1-4 alkyl.
- Compounds of the invention have surprisingly been found to be ligands of the thyroid receptor, in particular agonists or partial agonists of the thyroid receptor.
- the compounds accordingly have use in the treatment or prophylaxis of conditions associated with thyroid receptor activity.
- the compounds of formula (I) may contain chiral (asymmetric) centres or the molecule as a whole may be chiral.
- the individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.
- the present invention provides compounds of formula (I) that are thyroid receptor ligands having a hydrogen bond acceptor in the prime ring while lacking a hydrogen bond donor.
- G is a group selected from:
- G is a group selected from:
- G is a group selected from:
- R 10 is selected from -(CH 2 ) P -S-R b , -(CH 2 ) P -SO 2 -R b , -CCH 2 ) P -NH-SO 2 -R b , -(CH 2 ) P -SO 2 - NH-R b , -(CH 2 ) p -NH-CO-R b , - ⁇ CH 2 ) p -CO-NH-R b , C,. 8 alkyl, C 3-6 cycloalkyl, C 3-6 ycloalkyl-C 1-3 alkyl, phenyl, benzyl and C 3 . 7 heterocyclyl with optional substitution of those groups as described above.
- R 10 is selected from C 1-5 alkyl, phenyl and C 3-7 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, N(R a ) 2 , phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy. Accordingly, examples of preferred R 10 groups include fluoroC 1-12 alkyl, difluoroC 1-12 alkyl, and trifluoroC 1-12 alkyl.
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, N(R a ) 2 , hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- each R 10 is independently selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-3 alkyl, phenyl, and C 3-7 heterocyclyl, said alkyl, alkenyl or alkynyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups each independently selected from halogen, hydroxy, phenyl, C 1-4 alkoxy, halo C 1-4 alkoxy, dihaloC 1-4 alkoxy, and trihaloC 1-4 alkoxy; said cycloalkyl, phenyl or heterocyclyl groups or portions of groups optionally being substituted with 1 , 2 or 3 groups independently selected from halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy;
- R a is independently selected from hydrogen and C 1-4 alkyl with optional substitution of those groups as described above.
- Preferred substituents for said C 1-4 alkyl include halogen groups.
- R a is selected from hydrogen, C 1-4 alkyl and C 1-4 alkyl substituted with 1 to 3 halogen groups.
- R b is selected from hydrogen, C 1-4 alkyl, fluoromethyl, difluoromethyl, or trifluoromethyl, benzyl, C 3-7 heterocyclyl and phenyl with optional substitution of those groups as described above.
- Preferred substituents for said C 1-4 alkyl or phenyl groups include halogen, hydroxy, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- R 1 is selected from hydrogen, hydroxy, halogen, -(CH 2 ) m -S-R b , - ⁇ CH 2 ) m -S ⁇ 2 -R b , -
- R 1 is selected from hydrogen, hydroxy, halogen, Ci -5 alkyl, phenyl, benzyl and C 3-5 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, N(R a ) 2 , phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy. Accordingly, examples of preferred R 1 groups include fluoroCi_i 2 alkyl, difluoroCi -]2 alkyl, and trifluoroCi_i 2 alkyl.
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, hydroxy, N(R a ) 2 , C 1-4 alkyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- each R 1 is independently selected from hydrogen, hydroxy, halogen, Ci. i 2 alkyl, C M2 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-g cycloalkyl-C 1-3 alkyl, phenyl and C 3-7 heterocyclyl, said alkyl, alkenyl or alkynyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups each independently selected from halogen, hydroxy, phenyl, C 1-4 alkoxy, haloC )-4 alkoxy, dihaloC 1-4 alkoxy, and trihaloC 1-4 alkoxy; said cycloalkyl, phenyl, benzyl or heterocyclyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups independently selected from halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2 ⁇ alkynyl, methoxy, halomethoxy,
- each R 2 is independently selected from halogen, mercapto, C 1-4 alkoxy, C 1-4 alkyl and N(R a ) 2 with optional substitution of those groups as described above. More preferably, R 2 is selected from halogen, C 1-4 alkoxy and C 1-4 alkyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl or alkoxy groups or portions of groups include groups independently selected from halogen, hydroxy, C 1-4 alkylthio, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- n is 0 or 1. More preferably n is 0
- R Ia is selected from hydrogen, hydroxy, halogen, , -(CH 2 ) m -NH-SO 2 -R b , -(CH 2 ⁇ -CO-NH- R b , Ci. g alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl and C 3 . 7 heterocyclyl with optional substitution of those groups as described above.
- R la is selected from hydrogen, hydroxy, halogen, -CH 2 -NH-SO 2 -R b , -CH 2 -CO-NH-R b , Ci -5 alkyl, phenyl and C 3 . 7 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- examples of preferred R la groups include fluoroCi. ⁇ alkyl, difiuoroCi_i 2 alkyl, and trifluoroCi. ⁇ 2 alkyl.
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, hydroxy, Q_ 4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- R lb is selected from hydrogen, hydroxy, halogen, Ci. 8 alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, C 3-6 cycloalkyl, C 3 ⁇ cycloalkyl-C 1-3 alkyl, phenyl and C 3 . 7 heterocyclyl with optional substitution of those groups as described above. More preferably, R lb is selected from hydrogen, hydroxy, halogen, C 1-5 alkyl, phenyl and C 3 . 7 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy. Accordingly, examples of preferred R lb groups include fluoroC].i 2 alkyl, difluoroC
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, hydroxy, C 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy. In one embodiment, R lb is hydrogen.
- R lc is selected from hydrogen, hydroxy, halogen, Ci_ g alkyl, C 2-g alkenyl, C 2 . 8 alkynyl, C 3 ⁇ cycloalkyl, C 3 . 6 cycloalkyl-C 1-3 alkyl, phenyl and C 3-7 heterocyclyl with optional substitution of those groups as described above. More preferably, R lc is selected from hydrogen, hydroxy, halogen, C 1- 5 alkyl, phenyl and C 3-7 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy. Accordingly, examples of preferred R lc groups include fluoroC 1- n alkyl, difluoroCi. 12 alkyl, and trifluoroC 1- n alkyl.
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, hydroxy, C 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- R la is selected from hydrogen, hydroxy, halogen, Q-galkyl, C 2- 8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl and C 3-7 heterocyclyl with optional substitution of those groups as described above. More preferably, R la is selected from hydrogen, hydroxy, halogen, Q ⁇ alkyl, phenyl and C 3-7 heterocyclyl with optional substitution of those groups as described above.
- Preferred substituents for said alkyl groups or portions of groups include groups independently selected from halogen, hydroxy, phenyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- examples of preferred R la groups include fluoroC 1-12 alkyl, difluoroC 1-12 alkyl, and trifluoroC 1-12 alkyl.
- Preferred substituents for said cycloalkyl, phenyl or heterocyclyl groups or portions of groups include groups independently selected from halogen, hydroxy, C 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy.
- n 1 and the R 2 group is attached to the phenyl ring at the meta- position to the position of attachment to the Y group.
- R 3 and R 4 are preferably independently selected from halogen, cyano, C 1-4 alkyl, fluoromethyl, difluoromethyl and trifluorom ethyl. More preferably, R 3 and R 4 are independently selected from halogen, methyl, fluoromethyl, difluoromethyl and trifluoromethyl. Amongst the halogens, there are preferred chlorine, bromine, and fluorine, especially chlorine and bromine, in particular bromine.
- Y is selected from oxygen or methylene. Most preferably, Y is oxygen.
- W is preferably selected from C 1-3 alkylene, C 2 . 3 alkenylene, C 2-3 alkynylene, N(R C )-C 1-3 alkylene, C(O)-C 1-3 alkylene, S-C 1-3 alkylene, O-C,. 3 alkylene, C 1-3 alkylene-O-C 1-3 alkylene, C(O)NH-C 1-3 alkylene and NH(CO)-C 0-3 alkylene, said alkylene, alkenylene or alkynylene groups or portions of groups optionally being substituted with 1 or 2 groups selected from hydroxy, mercapto, amino, halogen, C].
- Ci_ 3 alkoxy haloC 1-3 alkyl, dihaloC 1-3 alkyl, trihaloC!.
- W is more preferably selected from C 1-3 alkylene, C 1-3 alkylene-O-C 1-3 alkylene, C 2-3 alkenylene, N(R C )-Ci. 2 alkylene, O-C,. 2 alkylene, C(O)NH-C 1-2 alkylene and NH(C0)-C, -2 alkylene, said alkylene or alkenylene groups or portions of groups optionally being substituted with a group selected from halogen, Ci -2 alkyl, C !-2 alkoxy, haloCi -2 alkyl, dihaloCi -2 alkyl, trihaloC 1-2 alkyl, haloC 1-2 alkoxy, dihaloCi.
- W is selected from C 1-3 alkylene, C 1-3 alkylene-O-C 1-3 alkylene, C(O)NH-Ci -2 alkylene and NH(CO)-C 1-2 alkylene. Most particularly preferably W is ethylene or C(O)NH-CH 2 -.
- the alkylene group (for example the ethylene group) is substituted with one or more halogen groups, for example one or more fluoro groups (for example one fluoro group).
- Monohalo C 1-3 alkylene for example fluoro C 1-3 alkylene
- W thus constitutes a preferred group W.
- W is selected from C 1-3 alkylene, C 2-3 alkenylene, C 1-3 alkylene- O-C 1-3 alkylene, O-C 1-3 alkylene, C(O)NH-C 1-2 alkylene and NH(CO)-C 1-2 alkylene.
- R c is preferably selected from hydrogen, Ci -2 alkyl, fluoromethyl, difiuoromethyl and trifluorom ethyl.
- R 5 is preferably selected from -C0 2 R d , -PO(OR d ) 2 , -SO 2 OR d , -NHSO 2 R d , -COCO 2 R d and CONR d OR d . More preferably, R 5 is -CO 2 R d , -PO(OR d ) 2 or -SO 2 OR d . Most preferably, R 5 is - CO 2 R d , particularly -CO 2 H.
- R d is preferably ethyl, methyl, hydrogen or phenyl and phenyl substituted with 1, 2 or 3 groups independently selected from amino, hydroxy, halogen and methyL
- R d is preferably ethyl, methyl or hydrogen, particularly hydrogen. Most preferably, R d is hydrogen.
- one preferred group of compounds of the invention includes compounds according to formula (Ia) or pharmaceutically acceptable esters, amides, solvates or salts thereof, including salts of such esters or amides, and solvates of such esters, amides or salts
- G is a group selected from:
- Each R 10 is independently selected from -(CH 2 ) P -S-R b , -(CH 2 ) p -SO 2 -R b , -CCH 2 ) p -NH-SO 2 -R b , - (CH 2 ) p -SO 2 -NH-R b , - ⁇ CH 2 ) p -NH-CO-R b , -(CH 2 ) p -CO-NH-R b , C,. 8 alkyl, C 3 . 6 cycloalkyl, C 3-6 CyClOaIlCyI-C 1-3 alkyl, phenyl, benzyl and C 3 .
- alkyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups each independently selected from halogen, hydroxy, N(R a ) 2 , phenyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl, trihaloC 1-4 alkyl, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy;
- p 1 or 2;
- Each R 1 is independently selected from hydrogen, hydroxy, halogen, -(CH 2 ) m -S-R b , -(CH 2 ) m -SO 2 - R b , -(CH 2 ) m -NH-SO 2 -R b , -(CH 2 ) m -SO 2 -NH-R b , - ⁇ CH 2 ) m -NH-CO-R b , -(CH 2 ) m -CO-NH-R b , C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C ⁇ alkyl, phenyl, benzyl and C 3-7 heterocyclyl, said alkyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups each independently selected from halogen, hydroxy, N(R a ) 2 , phenyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl
- n 0, 1 or 2;
- R a is independently selected from a hydrogen atom and a C 1-4 alkyl group optionally substituted with 1 , 2 or 3 groups independently selected from halogen, methoxy, halomethoxy, dihalomethoxy and trihalomethoxy;
- R b is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2 . 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl, benzyl, heterocyclyl and phenyl, said alkyl, alkenyl, alkynyl or phenyl groups or portions of groups optionally being substituted with 1, 2 or 3 groups independently selected from C 1-4 alkyl, halogen, hydroxy, methoxy, halomethoxy, dihalomethoxy and trihalomethoxy;
- Each R 2 is independently selected from halogen, mercapto, C 1-4 alkoxy, C 1-4 alkyl and N(R a ) 2 , said alkyl or alkoxy groups or portions of groups optionally being substituted with 1, 2 or 3 groups selected from halogen, hydroxy, C 1-4 alkylthio, methoxy, halomethoxy, dihalomethoxy, and trihalomethoxy;
- n 0, 1 or 2;
- Y is selected from oxygen, methylene, sulphur, SO, SO 2 and -N(R a )-;
- R 3 and R 4 are independently selected from halogen, C 1-4 alkyl, fluoromethyl, difluoromethyl, and trifluoromethyl;
- W is selected from C 1-3 alkylene, C 2 . 3 alkenylene, C 2 . 3 alkynylene, N(R c )-C 1-3 alkylene, C(O)-C 1-3 alkylene, S-C 1-3 alkylene, O-C]. 3 alkylene, C].
- alkylene-O-C 1-3 alkylene C(O)NH-Ci_ 3 alkylene and NH(CO)-C 0-3 alkylene, said alkylene, alkenylene or alkynylene groups or portions of groups optionally being substituted with 1 or 2 groups selected from hydroxy, mercapto, amino, halogen, C 1-3 alkyl, C 1-3 alkoxy, haloCi_ 3 alkyl, dihaloCi_ 3 alkyl, trihaloC 1-3 alkyl, haloC 1-3 alkoxy, dihaloC 1-3 alkoxy, and trihaloC 1-3 alkoxy;
- R c is selected from hydrogen, Ci. 2 alkyl, fluoromethyl, difluoromethyl, and trifluoromethyl;
- R 5 is selected from -CO 2 R d , -PO(OR d ) 2 , -SO 2 OR d , -NHSO 2 R d , -COCO 2 R d , and CONR d OR d ;
- each R d is independently selected from hydrogen, C 1-4 alkyl, C 2 ⁇ alkenyl, C 2-4 alkynyl, C 3 .7 heterocyclyl, C 5-I0 aryl and C 5 . 10 aryl substituted with 1, 2 or 3 groups independently selected from amino, hydroxy, halogen or C 1-4 alkyl.
- Compounds according to the invention include:
- Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein a counterion or associated solvent is pharmaceutically acceptable.
- salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and physiologically functional derivatives.
- physiologically functional derivative is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto.
- examples of physiologically functional derivatives include esters, amides, and carbamates; preferably esters and amides.
- Suitable salts according to the invention include those formed with organic or inorganic acids or bases.
- Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycollic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, benzenesulfonic, and isethionic acids.
- Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine and N-methyl-D-glucomine.
- esters and amides of the compounds of formula (I) may have an appropriate group, for example an acid group, converted to a Q -6 alkyl, C 5 .i 0 aryl, C 5-I0 aryl-C ⁇ alkyl, or amino acid ester or amide.
- Pharmaceutically acceptable esters of the compounds of formula (I) may have an appropriate group, for example a hydroxy group, converted to a Ci ⁇ alkyl, C 5 . 10 aryl, or C 5-10 aryl-C ⁇ alkyl ester.
- Pharmaceutically acceptable amides and carbamates of the compounds of formula (I) may have an appropriate group, for example an amino group, converted to a Ci- 6 alkyl, C 5-I0 aryl, C 5 . 10 aryl-Ci- 6 alkyl, or amino acid ester or amide, or carbamate.
- a compound which, upon administration to the recipient, is capable of being converted into a compound of formula (I) as described above or an active metabolite or residue thereof, is known as a "prodrug".
- a prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects.
- Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
- alkyl means both straight and branched chain saturated hydrocarbon groups.
- alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i- butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups.
- unbranched alkyl groups there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups.
- alkoxy means the group O-alkyl, where "alkyl” is used as described above.
- alkoxy groups include methoxy and ethoxy groups.
- Other examples include propoxy and butoxy.
- alkenyl means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Up to 5 carbon carbon double bonds may, for example, be present.
- alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and dodecenyl.
- Preferred alkynyl groups include ethenyl, 1- propenyl and 2- propenyl.
- alkynyl means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Up to 5 carbon carbon triple bonds may, for example, be present.
- alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and dodecynyl.
- Preferred alkenyl groups include ethynyl 1- propynyl and 2- propynyl.
- cycloalkyl means a saturated group in a ring system.
- the cycloalkyl group can be monocyclic or bicyclic.
- a bicyclic group may, for example, be fused or bridged.
- monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl.
- Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and cyclooctyl.
- bicyclic cycloalkyl groups include bicyclo [2. 2.1]hept-2-yl.
- the cycloalkyl group is monocyclic.
- aryl means a monocyclic or bicyclic aromatic carbocyclic group.
- aryl groups include phenyl and naphthyl.
- a naphthyl group may be attached through the 1 or the 2 position.
- one of the rings may, for example, be partially saturated.
- examples of such groups include indanyl and tetrahydronaphthyl.
- C 5 ., o aryl is used herein to mean a group comprising from 5 to 10 carbon atoms in a monocyclic or bicyclic aromatic group.
- a particularly preferred C 5-10 aryl group is phenyl.
- halogen means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred. In some embodiments, fluorine is especially preferred. In alternative embodiments, chlorine or bromine are especially preferred.
- heterocyclyl means an aromatic (“heteroaryl”) or a non-aromatic (“heterocycloalkyl”) cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.
- a heterocyclyl group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or only in one of the rings.
- a heteroatom is preferably O or N.
- Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.
- Examples of monocyclic heterocycloalkyl rings include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.
- bicyclic heterocyclic rings in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.
- Examples of monocyclic heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl;
- examples of bicyclic heteroaryl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5- b]pyridiyl, pyridopyrimidinyl, iso
- heterocyclyl groups examples include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrimidyl and indolyl.
- cycloalkylalkyl means a group cycloalkyl-alkyl- attached through the alkyl group, "cycloalkyl” and “alkyl” being understood to have the meanings outlined above.
- the compounds of the invention have activity as thyroid receptor ligands.
- the compounds of the invention are preferably selective agonists or partial agonists of the thyroid receptor.
- compounds of the present invention possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta. They may thus be used in the treatment of diseases or disorders associated with thyroid receptor activity, particularly diseases or disorders for which selective agonists of the thyroid receptor-beta are indicated.
- compounds of the present invention may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T 3 regulated gene.
- Clinical conditions for which an agonist or partial agonist is indicated include, but are not limited to, hypothyroidism; subclinical hyperthyroidism; non-toxic goiter; atherosclerosis; thyroid hormone replacement therapy (e.g., in the elderly); malignant tumor cells containing the thyroid receptor; papillary or follicular cancer; maintenance of muscle strength and function (e.g., in the elderly); reversal or prevention of frailty or age-related functional decline ("ARFD”) in the elderly (e.g., sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and/or treatment of reduced bone mass, density or growth (e.g., osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); accelerating healing of complicated fractures (e.g.
- distraction osteogenesis in joint replacement; eating disorders (e.g., anorexia); treatment of obesity and growth retardation associated with obesity; treatment of depression, nervousness, irritability and stress; treatment of reduced mental energy and low self-esteem (e.g., motivation/assertiveness); improvement of cognitive function (e.g., the treatment of dementia, including Alzheimer's disease and short term memory loss); treatment of catabolism in connection with pulmonary dysfunction and ventilator dependency; treatment of cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); lowering blood pressure; protection against ventricular dysfunction or prevention of reperfusion events; treatment of hyperinsulinemia; stimulation of osteoblasts, bone remodeling and cartilage growth; regulation of food intake; treatment of insulin resistance, including NIDDM, in mammals (e.g., humans); treatment of insulin resistance in the heart; treatment of congestive heart failure; treatment of musculoskeletal impairment (e.g., in the elderly); improvement of the overall pulmonary function; skin disorders
- the compounds of the invention find particular application in the treatment or prophylaxis of the following: (1) hypercholesterolemia, dyslipidemia or any other lipid disorder manifested by an unbalance of blood or tissue lipid levels ; (2) atherosclerosis; (3) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (4) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (5) obesity; (6) diabetes (7) depression; (8) osteoporosis (especially in combination with a bone resorption inhibitor); (9) goiter; (10) thyroid cancer; (1 1) cardiovascular disease or congestive heart failure; (12) glaucoma; and (13) skin disorders.
- the compounds of the invention find especial application in the treatment or prophylaxis of the following: (1) hypercholesterolemia, dyslipidemia or any other lipid disorder manifested by an unbalance of blood or tissue lipid levels; (2) atherosclerosis; (3) obesity; (4) diabetes.
- the invention also provides a method for the treatment or prophylaxis of a condition in a mammal mediated by a thyroid receptor, which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt.
- a thyroid receptor that may be treated by the method of the invention are those described above.
- the invention also provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt, for the manufacture of a medicament for the treatment or prophylaxis of a condition mediated by a thyroid receptor.
- Clinical conditions mediated by a thyroid receptor that may be treated by the method of the invention are those described above.
- active ingredient means a compound of formula (I) as defined above, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt.
- the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
- the compounds of the invention may be administered orally or via injection at a dose of from 0.1 to 1500 mg/kg per day, preferably 0.1 to 500 mg/kg per day.
- the dose range for adult humans is generally from 5 mg to 35 g per day and preferably 5 mg to 2 g per day.
- Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for example units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
- the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, the invention provides a pharmaceutical formulation comprising a compound of formula (I) as defined above or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt, and a pharmaceutically acceptable excipient.
- Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below.
- the pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols), nebulizers or insufflators, rectal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
- parenteral including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular
- inhalation including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols
- nebulizers or insufflators rectal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided'solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
- the present compounds can, for example, be administered in a form suitable for immediate release or extended release.
- Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
- the present compounds can also be administered liposomally.
- compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
- the compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration.
- Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
- Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
- Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
- HPC hydroxy propyl cellulose
- HPMC hydroxy propyl methyl cellulose
- SCMC sodium carboxy methyl cellulose
- maleic anhydride copolymer e.g., Gantrez
- agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
- Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
- Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
- compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
- suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
- compositions for nasal aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
- Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
- Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia.
- exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
- Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
- a compound of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further active agents.
- Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for example an anti-dyslipidemic agent or other pharmaceutically active material.
- the compounds of the present invention may be employed in combination with one or more other modulators and/or ligands of the thyroid receptor or one or more other suitable therapeutic agents selected from the group consisting of cholesterol/lipid lowering agents, hypolipidemic agents, anti- atherosclerotic agents, anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, growth promoting agents, anti-inflammatory agents, anti-anxiety agents, anti-depressants, anti-hypertensive agents, cardiac glycosides, appetite suppressants, bone resorption inhibitors, thyroid mimetics, anabolic agents, anti-tumor agents and retinoids.
- suitable therapeutic agents selected from the group consisting of cholesterol/lipid lowering agents, hypolipidemic agents, anti- atherosclerotic agents, anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, growth promoting agents, anti-inflammatory agents, anti-anxiety agents, anti-depressants, anti-hyp
- hypolipidemic agents for use in combination with the compounds of the present invention also include ezetimibe, simvastatin, atorvastatin, rosuvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, fenofibrate, gemfibrozil and bezafibrate.
- Suitable anti-diabetic agents for use in combination with the compounds of the present invention include biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, glipyride, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones (e.g., troglitazone, rosiglitazone, englitazone, darglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonist
- Suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligand antagonists, calcium sensing receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM) and AP-I inhibitors.
- Suitable anti-obesity agents for use in combination with the compounds of the present invention include aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Patent Nos.
- a lipase inhibitor such as orlistat or ATL-962 (Alizyme)
- a serotonin (and dopamine) reuptake inhibitor such as sibutramine, topiramate (Johnson & Johnson) or axokine
- thyroid receptor beta drugs such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), CB-I (cannabinoid receptor) antagonists (see G. Colombo et al, "Appetite Suppression and Weight Loss After the Cannabinoid Antagonist SR 141716", Life Sciences, VoI 63, PL 113-1 17 (1998)) and/or an anorectic agent, such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
- an anorectic agent such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
- the compounds of the present invention may be combined with growth promoting agents, such as, but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Patent No. 4,411,890.
- growth promoting agents such as, but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Patent No. 4,411,890
- the compounds of the invention may also be used in combination with growth hormone secretogogues such as GHRP-6, GHRP-I (as described in U.S. Patent No. 4,411,890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-I and IGF-2, or with alpha-adrenergic agonists, such as clonidine or serotinin 5-HT D agonists, such as sumatriptan, or agents which inhibit somatostatin or its release, such as physostigmine and pyridostigmine.
- growth hormone secretogogues such as GHRP-6, GHRP-I (as described
- Suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, Enbrel®, cyclooxygenase inhibitors (i.e., COX-I and/or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-I, tumor necrosis factor (TNF) antagonists (e.g., infliximab, OR1384), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g.,
- Suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine pamoate.
- Suitable anti-depressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline, and paroxetine.
- suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g.
- diltiazem verapamil, nifedipine, amlodipine and mybefradil
- diuretics e.g., chlorothiazide, hydrochlorothiazide, fiumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisin
- Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389
- neutral endopeptidase (NEP) inhibitors neutral endopeptidase (NEP) inhibitors
- vasopepsidase inhibitors dual NEP-ACE inhibitors
- omapatrilat and gemopatrilat e.g., omapatrilat and gemopatrilat
- Suitable cholesterol/lipid lowering agents for use in combination with the compounds of the present invention include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, an ileal Na + /bile acid cotransporter inhibitor, cholesterol absorption inhibitors, and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
- HMG-CoA reductase inhibitors e.g., squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, an ileal Na + /bile acid cotransporter inhibitor, cholesterol absorption inhibitors, and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
- MTP inhibitors which may be employed herein in combination with one or more compounds of formula (I) include MTP inhibitors as disclosed in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983 and U.S. Patent No. 5,962,440 all incorporated herein by reference.
- the HMG CoA reductase inhibitors which may be employed in combination with one or more compounds of formula (I) include mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
- Further HMG CoA reductase inhibitors which may be employed herein include fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S. Patent Nos.
- the squalene synthetase inhibitors which may be used in combination with the compounds of the present invention include, but are not limited to, ⁇ -phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates, terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med.
- Bile acid sequestrants which may be used in combination with the compounds of the present invention include cholestyramine, colestipol and DEAE-Sephadex (Secholex®, policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5O5O (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly
- ACAT inhibitors suitable for use in combination with compounds of the invention include ACAT inhibitors as described in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-IOl 1 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev.
- Suitable cholesterol absorption inhibitor for use in combination with the compounds of the invention include SCH48461 (Schering-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
- ileal NaVbile acid cotransporter inhibitors for use in combination with the compounds of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999).
- thyroid mimetics examples include thyrotropin, polythyroid, KB-130015, and dronedarone.
- the compounds of the present invention may be used alone or optionally in combination with a retinoid, such as tretinoin, or a vitamin D analog.
- a retinoid such as tretinoin
- a still further use of the compounds of the invention is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifene, or other androgen receptor modulators, such as those disclosed in Edwards, J. P. et al., Bio. Med. Chem. Lett., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212 (1999).
- a further use of the compounds of this invention is in combination with steroidal or non-steroidal progesterone receptor agonists ("PRA”), such as levonorgestrel, medroxyprogesterone acetate (MPA).
- PRA steroidal or non-steroidal progesterone receptor agonists
- MPA medroxyprogesterone acetate
- the compounds of formula (I) When combined with a hypolipidemic agent, an antidepressant, a bone resorption inhibitor and/or an appetite suppressant, the compounds of formula (I) may be employed in a weight ratio to the additional agent within the range from about 500: 1 to about 0.005: 1, preferably from about 300: 1 to about 0.01 : 1.
- the compounds of formula (I) may be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1.
- the compounds of formula (I) may be employed in a weight ratio to a glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
- the compounds of formula (I) may be employed in a weight ratio to a sulfonylurea in the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.
- the compounds of formula (I) may be employed in a weight ratio to a thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
- the thiazolidinedione may be employed in amounts within the range from about 0.01 to about 2000 mg/day, which may optionally be administered in single or divided doses of one to four times per day.
- these additional agents may be incorporated into a combined single tablet with a therapeutically effective amount of the compounds of formula (I).
- Metformin, or salt thereof may be employed with the compounds of formula (I) in amounts within the range from about 500 to about 2000 mg per day, which may be administered in single or divided doses one to four times daily.
- the compounds of formula (I) may be employed in a weight ratio to a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-alpha/gamma dual agonist, an SGLT2 inhibitor and/or an aP2 inhibitor within the range from about 0.01 :1 to about 100: 1, preferably from about 0.5: 1 to about 5: 1..
- An MTP inhibitor may be administered orally with the compounds of formula (I) in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg, one to four times daily.
- a preferred oral dosage form such as tablets or capsules, may contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, administered on a regimen of one to four times daily.
- the MTP inhibitor may be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, administered on a regimen of one to four times daily.
- a HMG CoA reductase inhibitor may be administered orally with the compounds of formula (I) within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
- a preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
- a squalene synthetase inhibitor may be administered with the compounds of formula (I) within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
- a preferred oral dosage form, such as tablets or capsules, will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
- the compounds of formula (I) as described above also find use, optionally in labelled form, as a diagnostic agent for the diagnosis of conditions associated with malfunction of the thyroid receptor.
- a diagnostic agent for the diagnosis of conditions associated with malfunction of the thyroid receptor.
- such a compound may be radioactively labelled.
- the compounds of formula (I) as described above, optionally in labelled form also find use as a reference compound in methods of discovering other antagonists or partial antagonists of the thyroid receptor.
- the invention provides a method of discovering a ligand of the thyroid receptor which comprises use of a compound of the invention or a compound of the invention in labelled form, as a reference compound.
- such a method may involve a competitive binding experiment in which binding of a compound of formula (I) to the thyroid receptor is reduced by the presence of a further compound which has thyroid receptor-binding characteristics, for example stronger thyroid receptor-binding characteristics than the compound of formula (I) in question.
- Y is S: Harrington, C. R., Biochem. J., 43, 434-437, 1948; Dibbo, A. et al., J. Chem. Soc, 2890-2902, 1961; Yokoyama, N. et al., United States Patent 5, 401, 772, 1995; Y is CH 2 : Homer, L., Medem, H. H. G., Chem. Ber., 85, 520-530, 1952; Chiellini, G. et al., Chemistry & Biology, 5, 299-306, 1998).
- Compounds wherein Y is SO or SO 2 may be synthesised from the corresponding compound in which Y is sulphur by oxidation with a suitable oxidising agent.
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein Y is selected from oxygen, sulphur, SO, SO 2 and -N(R a )-, comprising a step of reacting - a compound of formula (II)
- W, R 3 , R 4 , and R 5 are as defined above and Y is selected from oxygen, sulphur, and -N(R a )-
- R 2 is as defined above and L is a suitable leaving group, optionally in the presence of a suitable base and, optionally, in the presence of copper powder, followed by reduction of the nitro group to an amino group using a suitable reducing agent, followed by interconversion to a compound of formula (I).
- Suitable leaving groups L include triflate, mesilate and halogen, for example a fluoride.
- Suitable bases include carbonates, for example potassium carbonate or cesium carbonate, alkylamines, for example diisopropylamine or triethylamine, and alkali metal hydroxides for example potassium hydroxide or sodium hydroxide. Other combinations of leaving groups and bases may be employed, as is known by the person skilled in the art.
- one or more coupling reagents may be employed. The reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed. The reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Suitable reducing agents include hydrogen and a platinum oxide catalyst, iron in a suitable acid, for example hydrochloric acid, or SnCl 2 in ethanol.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (II) include: 3-(3,5-Dibromo-4-hydroxy-phenyl)-propionic acid methyl ester (E)-3-(3,5-Dibromo-4-hydroxy-phenyl)-acrylic acid methyl ester (3,5-Dibromo-4-hydroxy-phenoxy)-acetic acid methyl ester 3-(3,5-Dibromo-4-hydroxy-phenyl)-2-fluoro-propionic acid methyl ester (3,5-Dibromo-4-hydroxy-benzoylamino)-acetic acid methyl ester N-(3,5-Dibromo-4-hydroxy-phenyl)-malonamic acid methyl ester
- Preferred compounds of formula (HI) include: 1 -Fluoro-4-nitro-benzene 2-Chloro-4-fluoro- 1 -nitro-benzene
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein G is the following group:
- Suitable oxidising agents for use in the reaction include potassium hexacyanoferrate(III) K 3 Fe(CN) 6 .
- Suitable bases for use in the reaction include metal hydroxides, for example sodium hydroxide, lithium hydroxide, or potassium hydroxide. Other bases may be employed, as is known by the person skilled in the art.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (IV) include: 3-[3,5-Dibromo-4-(4-thioacetylamino-phenoxy)-phenyl]-propionic acid methyl ester
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein G is the following group:
- R 1 is as defined above in the presence of a suitable acid, followed optionally by interconversion to another compound of formula (I).
- Suitable acids for use in the reaction include hydrochloric acid.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (V) include: 3-[4-(4-Amino-phenoxy)-3,5-dibromo-phenyl]-propionic acid methyl ester 3-[4-(4-Amino-phenoxy)-3,5-dibromo-phenyl]-2-fluoro-propionic acid methyl ester (E)-3-[4-(4-Amino-phenoxy)-3,5-dibromo-phenyl]-acrylic acid methyl ester [4-(4-Amino-phenoxy)-3,5-dibromo-phenoxy]-acetic acid methyl ester [4-(4-Amino-phenoxy)-3,5-dibrornobenzoylamino]-acetic acid methyl ester N-[4-(4-Amino-phenoxy)-3,5-dibromo-phenyl]-malonamic acid methyl ester
- Preferred compounds of formula (VI) include: (E)-Hept-3-en-2-one (E)-Hex-3 -en-2-one (E)-Hept-4-en-3 -one
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein G is the following group:
- Suitable leaving groups Li and L 2 include halogens, for example a bromide.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein G is the following group:
- R 10 , R 2 , R 3 , R 4 , R 5 , Y and W are as defined above - with a compound of formula (X) wherein R 1 is as defined above and A is H, OH, Cl or OCOR group where R is a C 1-4 alkyl group in the presence of a suitable acid, followed optionally by interconversion to another compound of formula (I).
- Suitable acids for use in the reaction include sodium bisulphite.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (IX) include:
- Preferred compounds of formula (X) include: 2-Methyl-propionaldehyde 4-Methyl-benzaldehyde 4-Bromo-benzaldehyde 3 -Methoxy-benzaldehyde
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein G is the following group:
- R 1 , R 10 , R 2 , R 3 , R 4 , R 5 , Y and W are as defined above in the presence of a suitable acid, followed optionally by interconversion to another compound of formula (I).
- Suitable acids for use in the reaction include acetic acid.
- R 1 is as defined above and A is a suitable leaving group, for example Cl, in the presence of a suitable base, for example an organic amine such as pyridine,
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed. Any step may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (V) include:
- Preferred compounds of formula (XII) include: 3-Methyl-butyryl chloride
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein Y is methylene, comprising a step of reacting - a compound of formula (XIII)
- R and R are as defined above and B is a group suitable for interconversion to the group -
- R 2 is as defined above and X is a suitable leaving group, in the presence of a suitable base, followed by conversion of the group B to the group -W-R 5 , and reduction of the nitro group to an amino group using a suitable reducing agent, followed by interconversion to a compound of formula (I).
- Suitable leaving groups X include halogen, for example a chloride.
- Suitable bases include lithium diisopropylamide or f-butyl lithium. Other combinations of leaving groups and bases may be employed, as is known by the person skilled in the art.
- one or more coupling reagents may be employed.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Suitable groups B include alkyl groups, for example methyl. Conversion of the group B to the group -W-R 5 , may be achieved by the use of one or more suitable functional group interconversion reactions as known to the person skilled in the art.
- Suitable reducing agents include hydrogen and a platinum oxide catalyst, iron in a suitable acid, for example hydrochloric acid, or SnCl 2 in ethanol.
- the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- Preferred compounds of formula (XIII) include: 1 ,3-Dibromo-5-methyl-benzene
- Preferred compounds of formula (XTV) include: /7-Nitro benzylchloride
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein Y is selected from oxygen, sulphur or -N(R a )-, comprising a step of reacting -a compound of formula (II)
- G is a group selected for example from:
- R 1 , R 10 , R 2 and n are as defined above and Z is a suitable leaving group, optionally in the presence of a suitable base and optionally, in the presence of copper powder, followed optionally by removal of the protecting group, if present, and optionally by interconversion to another compound of the invention.
- Suitable leaving groups Z include halogens and boron derivatives, for example a fluoride.
- Suitable bases include carbonates, alkylamines and alkali metal hydroxides, for example potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, diisopropylamine and triethylamine. Other combinations of leaving groups and bases may be employed, as is known by the person skilled in the art.
- one or more coupling reagents may be employed.
- the reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- the groups Y' and Z could be switched, being the leaving group in the (II) fragment (the nucleophilic substituent, Z) and the electrophilic radical Y' in the (XV) fragment.
- Preferred compounds of formula (II) include: Methyl 3 -(3 , 5 -Dibromo-4-hydroxy-pheny l)-propanoate Methyl (E)-3-(3,5-Dibromo-4-hydroxy-phenyl)-acrylate Methyl (3,5-Dibromo-4-hydroxy-phenoxy)-acetate Methyl 3-(3,5-Dibromo-4-hydroxy-phenyl)-2-fluoro-propanoate Methyl (3,5-Dibromo-4-hydroxy-benzoylamino)-acetate
- the invention also provides a method for preparing a compound of formula (I) in accordance with the invention as described above wherein Y is methylene, comprising a step of reacting -a compound of formula (XVI)
- G is a group selected for example from:
- R 1 , R 10 , R 2 and n are as defined above and Z may for example be lithium or a Mg- halide, such as MgBr or MgCl. Alternatively, Z may be a derivative of Sn, Pd, B or Cu.
- nucleophilic attack to an aldehyde may be employed, as is known by the person skilled in the art.
- one or more coupling reagents may be employed.
- the reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed.
- the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3 rd Edition, New York, 1999).
- the groups Y' and Z could be switched, being the leaving group in the (XVI) fragment (the metal substituent, Z) and the aldehyde in the (XVII) fragment.
- MW calculated is an isotopic average and the "found mass” is referring to the most abundant isotope detected in the LC-MS.
- the obtained residue containing 3,5-dibromo-4-(4-nitrophenoxy)phenyl trifluoromethanesulfonate was used without further purification.
- reaction mixture was poured into 500 mL of water/ice, and extracted with diethyl ether (3 x 500 mL). The combined organic phases were washed with aqueous sodium hydroxide (5%, 200 mL) and water (200 mL), dried and concentrated. The residue was purified by flash chromatography to give l,3-Dibromo-5-methyl-2-(4-nitro-phenoxy)- benzene (2.6 g) in 59% of yield. l,3-Dibromo-5-methyl-2-(4-nitro-phenoxy)-benzene (2.60 g, 6.7 mmol) was dissolved in pyridine (30 mL) and water (12 mL), and heated up to refluxing temperature.
- Potassium permanganate (8.5 g, 53.8 mmol) was added in portions to the refluxing solution and the mixture was allowed to cool down and stirred for 6 h at room temperature.
- the reaction solution was diluted with ethyl acetate and filtered with celite.
- the residue obtained after evaporation of the solvent was diluted with hydrochloric acid (2M) and extracted with ethyl acetate.
- the combined organic phases were washed with sodium hydroxide (5%, aqueous).
- the alkaline solution was acidified with hydrochloric acid and extracted with acetate.
- the crude was dissolved in methanol (2 mL) and sodium methoxide (100 mg) was added. The mixture was stirred at room temperature overnight.
- the crude product was purified using semi- preparative-HPLC (Zorbax CombiHT (SB-C8) Mobil Phase: Solvent A. Water with 0.5% formic acid; 5 Solvent B: acetonitrile. Gradient: 80% of A to 5% of A).
- a stirred mixture of potassium carbonate (3 equiv.), the appropriate quinoline (1 equiv.) (e.g. 6- hydroxy-quinoline) (commercially available or prepared from para aminophenol), and the appropriate iodo-benzene (e.g. 3,5-dibromo-4-iodo-nitrobenzene) (1 equiv.) in dimethylformamide (14 mL/mmol) was heated for 18 h at 70 0 C. After dilution with diethyl ether and ammonium chloride (saturated aq. solution), the mixture was extracted with diethyl ether. The combined organic layers were washed with ammonium chloride (saturated aq.
- the biphenylether e.g. 6-(2,6-Dibromo-4-nitro-phenoxy)-quinoline
- tin(II)chloride 5 equiv.
- ethanol 40 mL/mmol
- Ethyl acetate and sodium carbonate sat. aq. solution
- the organic phase was separated and dried (magnesium sulphate).
- the crude was dissolved in tetrahydrofuran (20 mL/mmol) and triethylamine (2.5 equiv.) was added, followed by ethyl malonyl chloride (1.5 equiv.).
- reaction mixture was then cooled to room temperature and transferred to a separatory funnel using ethyl acetate which was washed with sodium carbonate (saturated aqueous solution), dried over magnesium sulphate, filtered and concentrated. The remaining residue was purified by chromatography on silica (gradient diethyl ether/dichloromethane). The desired 6-(4-amino-2,6- dibrornophenoxy)-N-methylquinoline-2-carboxarnide was obtained in 86% yield (29 mg) over two steps.
- 6-(4-Amino-2,6-dibromophenoxy)-N-methylquinoline-2-carboxamide 29 mg, 0.06 mmol was dissolved in dry THF (1.2 mL), and triethylamine (21 ⁇ L, 0.15 mmol) and ethyl malonyl chloride (12 ⁇ L, 0.09 mmol) were added. The reaction was stirred over night at room temperature. The reaction was transferred to a separatory funnel using ethyl acetate which was washed with ammonium chloride (saturated aqueous solution), dried over magnesium sulphate, filtered and concentrated.
- triethylamine 21 ⁇ L, 0.15 mmol
- ethyl malonyl chloride 12 ⁇ L, 0.09 mmol
- 6-(2,6-Dibromo-4-nitrophenoxy)-2-methylquinoline 300 mg, 0.68 mmol was dissolved in carbon tetrachloride (10 mL). Benzoylperoxide (10 mg) and ofN-bromosuccinimide (0.18 g, 1.03 mmol) were added. The reaction was refluxed over night and then concentrated to give a crude product which was purified by flash chromatograpy (ethyl ether/dichloromethane) to give 2-(bromomethyl)- 6-(2,6-dibromo-4-nitrophenoxy)quinoline (142 mg, 40% yield).
- benzothiazole e.g. 3- ⁇ 3,5-dibromo-4-[(2-methyl-l,3- benzothiazol-6-yl)oxy]phenyl ⁇ propanoic acid.
- Dimethylsulfide boran (IM, 6 equiv.) was added to a stirred solution of the appropriate aniline (e.g. methyl (4- ⁇ 3-amino-4-[(3-methylbutanoyl)amino]phenoxy ⁇ -3,5-dibromophenoxy)acetate) (1 equiv.)and acetic acid (2 ml/mmol) in dichloromethane (65 ml/mmol), dry acetone (16 mL/mmol) and tetrahydrofuran (65 ml/mmol)at 0 0 C. The reaction mixture was stirred for 17 h.
- aniline e.g. methyl (4- ⁇ 3-amino-4-[(3-methylbutanoyl)amino]phenoxy ⁇ -3,5-dibromophenoxy
- Example 50 3-( ⁇ 3,5-dibromo-4-[(2-phenyl-2H-indazol-5-yl)oxy]phenyl ⁇ amino)-3-oxopropanoic acid
- dichloromethane 4 mL
- 3,5-dibromo-4-(2-phenyl-2H-indazol-5-yloxy- phenylamine 37 mg, 0.08 mmol
- triethylamine 10 mg, 0.10 mmol
- chlorocarbonyl acetic acid methyl ester 14 mg, 0.10 mmol
- 2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF 4 , 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0 ⁇ 5°C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate.
- HPF 4 tetrafluoroboric acid
- Example 44 (3- ⁇ 3,5-dibromo-4-[(2-isobutyl-l-isopropyl-lH-benzimidazol-6-yl)oxy]phenyl ⁇ -2- fluoropropanoic acid) is a racemic mixture. The single enantiomers were separated by chiral HPLC, providing examples 54 and 55.
- Receptor extracts and tracer are diluted in assay buffer (17 mM K 2 HPO 4 , 3 mM KH 2 PO 4 , 400 mM KCl, 1 mM MgCl 2 , 0.5 mM EDTA and 8.7% glycerol).
- 125 I-T 3 is diluted to a final concentration of 0.2 nM and receptor is diluted to reach a final count in Trilux Microbeta of approximately 10000 ccpm.
- Compounds are typically serially diluted in DMSO from DMSO stock solutions of 10 mM.
- the filters are dried at 60 0 C for 1 hour and then merged with a scintillant wax (MELTILEX, PerkinElmer) on a Wallac Microsealer before measuring in a Trilux Microbeta.
- IC50s the concentration test compound needed to decrease tracer binding by 50 percent, are generated via analysis of data in XLfIt version 2.0 or later with a four parameter logistic model.
- the compounds of the examples were tested in this assay and were found to have an IC 50 at the thyroid receptor-beta receptor in the range of from 0.03 nM to 6 ⁇ M.
- Preferred compounds of the invention were found to have an IC 50 at the thyroid receptor-beta receptor in the range of from 0.03 nM to 700 nM.
- Particularly -preferred compounds of the invention were found to have an IC 50 at the thyroid receptor-beta receptor in the range of from 0.03 nM to 100 nM.
- Vector Constructs, Generation of Reporter Cell Lines (TRAF), and Assay Procedure were found to have an IC 50 at the thyroid receptor-beta receptor in the range of from 0.03 nM to 100 nM.
- the cDNAs encoding the full length human ThR ⁇ l and ThR ⁇ l were cloned in the mammalian expression vector pMT-hGH.
- the pDR4-ALP reporter vector contains one copy of the direct repeat sequence AGGTCA nnnnAGGTCA, fused upstream of the core promoter sequences of the mouse mammary tumor virus long terminal repeat (MMTV), replacing the glucocorticoid response elements.
- the DR4-MMTV promoter fragment was then cloned in the 5' end of the cDNA encoding human placental alkaline phosphatase (ALP), followed in the 3 '-end by the polyA-signal sequence of the human growth hormone gene.
- ALP placental alkaline phosphatase
- Chinese hamster ovary (CHO) Kl cells (ATCC No. CCL 61) were transfected in two steps, first with the receptor expression vectors pMT-hThR ⁇ l and pMT- ThR ⁇ l, respectively, and the drug resistance vector pSV2-Neo, and in the second step, with the reporter vector pDR4-ALP and the drug resistance vector pASV-Hyg. Individual drug resistant clones were isolated and selected based on T 3 inducibility. One stable reporter cell clone each of CHO/hThR ⁇ l and CHO/hThR ⁇ l were chosen for further study in response to various thyroid hormone agonists.
- CHO/hThR ⁇ l and CHO/hThR ⁇ l were seeded in growth medium (Coon ' s/F12, 10% L-3,5,3'- triiodothyronine and L-thyroxine depleted FCS, 2 mM L-glutamine) in 96-well plates at 2O x 10 3 cells per well.
- growth medium Coon ' s/F12, 10% L-3,5,3'- triiodothyronine and L-thyroxine depleted FCS, 2 mM L-glutamine
- conditioned medium was replaced by induction medium (OptiMEM, 2 mM L-glutamine, 50 ⁇ m/ml gentamycin) and cells were exposed to the test compounds at serial dilutions, at final DMSO concentration of 0,5%, or to serial dilution of T 3 (positive control), to assess agonist activity of test compounds.
- induction medium OptiMEM, 2 mM L-glutamine, 50 ⁇ m/ml gentamycin
- T 3 positive control
- CHO/hThR ⁇ l and CHO/hThR ⁇ l cells were exposed to serial dilution of the compounds in the presence of 1 nM T 3 (CHO/hThR ⁇ l) or 3 nM T 3 (CHO/hThR ⁇ l).
- the level of alkaline phosphatase expressed and secreted into the cell culture medium was analyzed by chemiluminescence on MicroBeta Trilux.
- the compounds were found to exhibit agonism of at least 12% at the thyroid receptor-beta.
- Preferred compounds of the invention were found to exhibit agonism of over 40% at the thyroid receptor-beta.
- Further preferred compounds of the invention were found to exhibit agonism of over 60% at the thyroid receptor-beta.
Abstract
Description
Claims
Priority Applications (7)
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US11/922,554 US20100004271A1 (en) | 2005-07-04 | 2006-07-04 | Heterocyclic compounds as aganist for the thyroid receptor |
CA002612591A CA2612591A1 (en) | 2005-07-04 | 2006-07-04 | Heterocyclic compounds as agonists for the thyroid receptor |
AU2006265274A AU2006265274A1 (en) | 2005-07-04 | 2006-07-04 | Heterocyclic compounds as agonists for the thyroid receptor |
EP06754670A EP1899309A1 (en) | 2005-07-04 | 2006-07-04 | Heterocyclic compounds as agonists for the thyroid receptor |
JP2008518760A JP2009500305A (en) | 2005-07-04 | 2006-07-04 | Heterocyclic compounds as agonists for thyroid receptors |
NO20076418A NO20076418L (en) | 2005-07-04 | 2007-12-12 | Heterocyclic compounds as agonists for the thyroid receptor |
IL188550A IL188550A0 (en) | 2005-07-04 | 2008-01-02 | Heterocyclic compounds as agonists for the thyroid receptor |
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GBGB0513692.4A GB0513692D0 (en) | 2005-07-04 | 2005-07-04 | Novel pharmaceutical compositions |
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EP (1) | EP1899309A1 (en) |
JP (1) | JP2009500305A (en) |
CN (1) | CN101238110A (en) |
AU (1) | AU2006265274A1 (en) |
CA (1) | CA2612591A1 (en) |
GB (1) | GB0513692D0 (en) |
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US11542247B2 (en) | 2015-09-23 | 2023-01-03 | Janssen Pharmaceutica Nv | Bi-heteroaryl substitute 1,4-benzodiazepines and uses thereof for the treatment of cancer |
WO2020169069A1 (en) | 2019-02-21 | 2020-08-27 | Nanjing Ruijie Pharma Co., Ltd. | Novel compounds and their uses as thyroid hormone receptor agonists |
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EP1899309A1 (en) | 2008-03-19 |
JP2009500305A (en) | 2009-01-08 |
AU2006265274A1 (en) | 2007-01-11 |
IL188550A0 (en) | 2008-04-13 |
GB0513692D0 (en) | 2005-08-10 |
NO20076418L (en) | 2008-03-25 |
CA2612591A1 (en) | 2007-01-11 |
CN101238110A (en) | 2008-08-06 |
US20100004271A1 (en) | 2010-01-07 |
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