EP1100485A1 - Substituted anilide compounds and methods - Google Patents
Substituted anilide compounds and methodsInfo
- Publication number
- EP1100485A1 EP1100485A1 EP99937589A EP99937589A EP1100485A1 EP 1100485 A1 EP1100485 A1 EP 1100485A1 EP 99937589 A EP99937589 A EP 99937589A EP 99937589 A EP99937589 A EP 99937589A EP 1100485 A1 EP1100485 A1 EP 1100485A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methoxyphenyl
- ethoxy
- amino
- methylethyl
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61K31/425—Thiazoles
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- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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Definitions
- This invention relates to substituted anilide compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.
- T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases.
- Increased numbers or enhanced activation state of T cells, especially CD4+ T cells have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506. 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin.
- T cells as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors.
- chemokines a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues.
- R ANTES which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors.
- the CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).
- RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells.
- RANTES was originally identified as gene product induced late after antigen activation of T-cells (TJ. Schall, J. Jongstra, B.J. Dyer, J. Jorgensen, et al., J. Immunol. 141: 1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D. Proud, et _ al., J. Immunol.
- RANTES rriRNA is rapidly upregulated in response to LL-1 or TNF*.
- RANTES rnRNA is not usually detected in normal tissues (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate.
- RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. T presenteda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med.
- CCR5 when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
- T cells and macrophages express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, . atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans.
- CCR5 since CD8+ T cells and macrophages have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD.
- selective receptor modulators may be useful in the treatment of HIV infection.
- this class of non-peptide compounds function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
- the present invention is to novel compounds of formula (I), or pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCR5 -mediated disease states:
- the basic nitrogen in moiety E may be optionally quaternized with Ci .galkyl or is optionally present as the N-oxide;
- pl and P ⁇ are independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11 -members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
- V is oxygen or sulfur
- D is nitrogen, carbon, or a CH group
- NR 27 CO(CH 2 ) d 'NR 27 R 28 ', NR 27 'CONR 27 R 28' , NRlO'c ⁇ 2 R 13 ', NR 10 'SO R 14' , N CNR 27 'NR 27 R 28 ', nitro, hydroxy, C ⁇ _ 6 alkoxy, hydroxyCi.
- R ' is hydrogen, C galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyCj. 6 alkyl, .ealkylOC ⁇ galkyl, CONR 36 R 37' , CO 2 R 38 ', cyano, aryl, trifluoromethyl, NR 39 R 4 0 ' , nitro, hydroxy, C ⁇ alkoxy, C ⁇ .galkanoyl, acyloxy, or halogen;
- R 35' , R 36 ', R 37' , R 38 ', R 39' , and R 40' are independently hydrogen or C ⁇ galkyl
- R 8 ' is hydrogen or Ci.galkyl, providing that D is nitrogen or a CH group;
- R 9 ' is hydrogen or C ⁇ alkyl, providing that D is nitrogen or a CH group;
- RIO' and R ⁇ ' are independently hydrogen or C ⁇ alkyl, or RlO' and R ⁇ l' together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom;
- R 2 ' is hydrogen, Ci. ⁇ alkyl, or C _4alkoxyalkyl;
- R13' S R25' ) an R32' are independently C 1 . galkyl
- R* ' is C ⁇ galkyl or phenyl
- R 15 ' and R 6 ' are independently hydrogen or C ⁇ .galkyl, or R x ⁇ ' and R 16 ' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom;
- R* 7 ' is Cl ⁇ 4 alkyl, optionally substituted by Cj.galkoxy;
- R ° is hydrogen or Ci .galkyl optionally substituted with one or two substituents selected from C ⁇ alkyl, Cj.galkoxy, hydroxy, or NRIO'RI I ';
- R 29 ' and R 3 ⁇ ' are independently hydrogen or Ci .galkyl, or R 29 ' and R 3 ⁇ ' together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom;
- R 33' and R 34' are independently hydrogen or Ci .galkyl, or R 33' and R 34 ' - together with the nitrogen to which they are attached form 5- to 6-membered . .
- heterocyclic ring which, when there are six ring members, may optionally contain iri the ring one oxygen or one sulfur atom; a' and b' are independently 1 , 2, or 3 ; c' is O, l, or 2; d'is 1, 2, 3, or 4; e'is O, 1, 2, or 3; f is 1, 2, or 3; E represents (a):
- R! and R 2 are independently hydrogen or Ci.galkyl; alternatively B(CR!R 2 ) a is OCR ⁇ CR ⁇ OH ⁇ R ⁇ R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 ;
- R 3 and R 4 are independently hydrogen, C ⁇ _5alkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C galkyl, aryl, CONR ⁇ R 1 1 , NR 10 R! 1, hydroxy, OCOR 12 , NHCOCQ. galkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 R 13 , and NHCO 2 R 14 ;
- R 5 is hydrogen, C ⁇ galkyl, aryl, CN, CONR 15 Rl 6 , CO 2 R 17 , trifluoromethyl, NHCO 2 R 18 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH CO 2 C ⁇ _ 6 alkyl, OCF3, S(O) R 19 , SO 2 NR 20 R 21 or halogen;
- R 9 is hydrogen, Ci.galkyl, or phenylCi . ⁇ alkyl;
- R 13 , R 14 , R 18 , and R 19 are independently Ci.galkyl;
- a is 1, 2, 3, or 4;
- b is 1 or 2;
- c and d are independently 0, 1 or 2;
- e is 2, 3 or 4;
- f is O, 1, 2 or 3; alternatively, E represents
- R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are independently hydrogen or C ⁇ _6alkyl
- R 3 ⁇ is hydrogen, Cj.galkyl, or C3_7cycloalkyl
- J is oxygen, CR 36 R 37 , or NR 38 , or J is a group S(O)k;
- R 34 , R 35 , R 36 , R 37 , and R 38 are independently hydrogen or C galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is O, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents (c):
- Q is oxygen, S(O) n , CR ⁇ CR 45 , CR 44 R 45 , or Q is NR 46 ;
- R 39 and R 4 ⁇ are independently hydrogen or C ⁇ .galkyl;
- R 1 is a group of formula (d):
- R 4 ⁇ is a group of formula (e):
- R 42 is hydrogen, C ⁇ alkyl, aryl, CN, CONR 48 R 49 , CO 2 R 50 , trifluoromethyl, NHCO R 51 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH 2 CO 2 Cj.
- R 43 is hydrogen or R 43 together with R 8' forms a group R where R is
- R 47 is hydrogen, C ⁇ .galkyl, or C3.7 cycloalkyl;
- R ⁇ l and R ⁇ 2 are independently C galkyl;
- l is O, 1, 2, or 3;
- m is 1 or 2;
- n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3;
- r is 0,1, 2, or 3;
- s is O, l, or 2;
- t is 2 or 3; alternatively, E represents (f):
- R ⁇ 7 and R ⁇ 8 are independently hydrogen or C ⁇ alkyl
- R59 and R ⁇ O are independently hydrogen, Cj.galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C i ⁇ alkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO R 64 and NHCO2R 65 ;
- T is -(CR 66 R 67 ) V - or -O(CR66R67) W _ ;
- R 61 , R 62 , R6 , R66 R 67 R68 ( R69 ; an d R are independently hydrogen or
- R" 4 and R ⁇ 5 are independently C galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
- R 7 1 is an optionally substituted 5 to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur or R 7 * is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur;
- R 72 is hydrogen, C galkyl, aryl, CN, CONR 74 R 7 5, CO 2 R 76 , trifluoromethyl, NHCO2R 77 , hydroxy, Cj ⁇ alkoxy, benzyloxy, OCH2CO2C1. galkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 8 0, or halogen;
- R 74 , R 75 , R 76 , R 79 , R 80 , R 81 , and R 82 are independently hydrogen or C ⁇ . 6alkyl;
- R 77 and R 7 are independently C galkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents group (h):
- R 83 and R 84 are independently hydrogen or C ⁇ alkyl;
- R 8 5 an d R 8 ⁇ are independently hydrogen, C ⁇ galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ alkyl, aryl, CONR 88 R 89 , NR 90 R 91 , hydroxy, OCOR 92 , NHCOC ⁇ -6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 R 93 , and NHCO 2 R 94 ;
- R 87 is hydrogen or C ⁇ .galkyl, C ⁇ alkoxy, or halogen, or R 87 together with- R 8 ' forms a group -AA- where AA is (CR 95 R 9 6) ad or AA is (CR
- Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
- R 88 , R 89 , R 90 , R 91 , R 92 , R 95 , and R 96 are independently hydrogen or C . galkyl;
- R 93 and R 94 are independently C galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents group (i):
- R 97 and R 98 are independently hydrogen, C ⁇ .galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ alkyl, aryl, CONR 102 R 103 , NR 104 R 105 , hydroxy, OCOR 106 , NHCOC ⁇ -6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO 2 Rl° 7 , and NHCO 2 R 108 ;
- R 99 and R!°0 are independently hydrogen or C ⁇ .galkyl;
- RlOl is hydrogen or C galkyl or
- AC is oxygen, GR! 11R1 l2 or NRl I 3 or AC is a group S(O)a ;
- R!° and Rl° are independently C galkyl; af is O, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is O, 1, 2, or 3; and ak is 0, 1 or 2.
- the present invention is to a method of treating CCR5 mediated disease states, including, but not limited to, COPD, asthma and atopic disorders ⁇ fqr example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarco dosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease and HIV infection, all in mammals, preferably humans, comprising administering to such mammal in need thereof, a anilide of formula (I), or pharmaceutically active salts thereof.
- the present invention is to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
- the pharmaceutical compositions of the present invention are used for treating CCR5-mediated disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, COPD and HIV all in mammals, preferably humans.
- substituted anilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans ("CCR5-mediated diseases"). Also, since CCR5 is a co- receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
- alkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
- cycloalkyl and cyclic alkyl are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
- halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
- heterocyclic ring is used herein at all occurrences to mean a saturated or partially saturated 5-, 6-, or 7-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with C[_ 6 lkyl or C3_7cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine.
- heterocyclic ring When the heterocyclic ring is fused to a phenyl group, the term "heterocyclic ring", together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro-l,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by Cj.galkyl or oxo.
- 6,6 or 6,5 bicyclic ring means a 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C ⁇ alkyl.
- CCR5 mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
- monocyclic heterocyclic ring is used herein at all occurrences to mean a single aromatic ring of 5 to 7 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur represented by pi and/or P 2 including thienyl, furyl, pyrrolyl, and pyridyl.
- fused bicyclic heterocyclic ring is used herein at all occurrences to mean a fused bicyclic ring system of 8 to 11 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur including indole, benzofuran, benzothiophene, quinoline, and isoquinoline rings.
- pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate, and stearate.
- the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
- the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms.
- the stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention.
- various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with C ⁇ _ galkyl or is optionally present as the N-oxide.
- p and P 2 are suitably independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11 -members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur.
- pl is phenyl and P 2 is phenl or quinoxalinyl. More preferably pl and P 2 are phenyl.
- ' is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur
- suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl.
- Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams.
- the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom.
- Suitable substituents for these rings include one to two of R 3 .
- A is attached to pl meta or para to L, more preferably, A is attached to pl para to L.
- V is suitably oxygen or sulfur. V is preferably oxygen.
- D is suitably nitrogen, carbon or a CH group. D is preferably nitrogen.
- Rl' and R 2 ' are suitably independently hydrogen, C ⁇ .galkyl, C 2 _galkenyl, C 2 .galkynyl, C3_7cycloalkyl, C3_7cycloalkenyl, aryl, (CH2)d'NRl° ' RH ' , (CH 2 )d'NRl°'CORl 2 ', (CH 2 ) d 'NRlO ' CO 2 Rl 3 ', (CH 2 ) d .NR 10 'SO 2 R 14 ',
- NR 2 ' CO(CH 2 ) d 'NR 27 'R 28' , NR 27' CONR 27 'R 28' , NR 10' C O 2 R1 3 ', NR 1 0 , SO 2 R 14' , N CNR 27 'NR 27' R 28' , nitro, hydroxy, Cj.galkoxy, hydroxyCj. 6alkoxy, C 1 . 6 alkoxyC 1 .
- R 1 ' is an optionally _ substituted 5 to 7 : membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.
- R 1 ' and R 2 ' are preferably hydrogen, C j .galkyl, - hydroxy, or halogen.
- R 3' is suitably hydrogen, C ⁇ alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, hydroxyC ⁇ alkyl, Ci.galkylOCi.galkyl, CONR 3 6'R 37 ', CO 2 R 38 ', cyano, aryl, trifluoromethyl, NR 3 R 40 ', nitro, hydroxy, C galkoxy, Cj.galkanoyl, acyloxy, or halogen.
- R 3 ' is preferably hydrogen, nitro, sulfamoyl or C ⁇ ⁇ alkylamino.
- R 4 ', R5', R6', R 7 ', Rl8', R19', R20' R 21 ', R 22', R 23', R 24', R 27', R 28', R 31', R 35' , R 36' , R 37 ', R 38 ', R 39 ', and R 40 ' are suitably independently hydrogen or C galkyl;
- R 8' is suitably hydrogen or Cj.galkyl, providing that D is nitrogen or a CH group.
- R 8' is preferably hydrogen.
- R 9 ' is suitably hydrogen or C ⁇ _galkyl, providing that D is nitrogen or a CH group.
- RIO ' and R 1 1 ' are suitably independently hydrogen or C ⁇ alkyl, or RlO' and R 11 ' together with the nitrogen to which they are attached, forms a 5- to 6- membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom.
- R 12 ' is suitably hydrogen, C ⁇ galkyl, or Cj ⁇ alkoxyalkyl.
- R13' 5 R25' ; and R 32 ' are suitably independently C ⁇ .galkyl.
- R! 4 is suitably C galkyl or phenyl.
- Rl5' and R 16' are suitably independently hydrogen or C galkyl, or R ⁇ ' and Rl6 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
- R! 7 ' is suitably Cl" alkyl, optionally substituted by C ⁇ _galkoxy.
- R 26 is suitably hydrogen or Cj ⁇ alkyl optionally substituted with one or two substituents selected from Cj.gaikyl, .galkoxy, hydroxy, or NRIO R 1 ' .
- R 29 and R 30 ' re suitably independently hydrogen or C ⁇ .galkyl, or R 29 and R30 together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.
- R 33 and R 34' are suitably independently hydrogen or Ci. ⁇ alkyl, or R 33 and
- R 34 together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.
- a' and b' are independently 1, 2, or 3.
- c' is suitably 0, 1, or 2.
- d' is suitably 1, 2, 3, or 4.
- e' is suitably 0, 1, 2, or 3.
- f is suitably 1, 2, or 3.
- E suitably represents (a):
- B is preferably CR R 8 , or oxygen. More preferably, B is CH 2 or oxygen.
- R 1 and R 2 are suitably independently hydrogen or Cj.galkyl; alternatively B(CR R 2 ) a is or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 .
- R 1 and R 2 are hydrogen.
- R 3 and R 4 are suitably independently hydrogen, C galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C galkyl, aryl, CONR ⁇ R 1 l , NR 10 R! 1, hydroxy, OCOR 12 , NHCOCo-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R 13 , and NHCO 2 R 14 .
- R 3 and R 4 are both C galkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7- membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. More preferably, R 3 and R 4 are C3_6alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, optionally substituted with one or more of Cj.galkyl, N-acetamido, or hydroxy.
- R 3 and R 4 are isopropyl or R 3 is isopropyl and R 4 is tert-butyl, or together with the nitrogen to which they are attached are 1 -(2,2,6,6- tetramethylpiperidinyl), l-(4-acetamido-2,2,6,6-tetramethylpiperidinyl), l-(4- hydroxy-2,2,6,6-tetramethylpiperidinyl), or 1 -(4-hydroxy-2,2,4,6,6- pentamethylpiperidinyl).
- B-(CR 1 R 2 ) a -NR R 4 is ortho to R 5 , meta to L, and para to R 6 , and R-> is para to L.
- R 5 is suitably hydrogen, C ⁇ galkyl, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl, NHCO2R 18 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH2CO2C1. 6 alkyl, OCF3, S(O) d R 19 , SO 2 NR 20 R 21 , or halogen.
- R5 is preferably C ⁇ alkoxy, SC ⁇ galkyl, or halogen; more preferably methoxy, methylthio, or iodo, most preferably methoxy. When R ⁇ is methoxy, it is preferably para to L.
- R 6 is hydrogen.
- R 7 , R 8 , RiO, Rl 1, Rl5, R 6 , R 17, R20 ( R 21 , R 22 an d R 23 are independently hydrogen or C ⁇ .galkyl.
- R 9 is hydrogen, Cj.galkyl, or phenylC galkyl.
- R 12 , R 13 , R 14 , R 18 , and R 19 are independently C galkyl.
- a is suitably 1, 2, 3, or 4.
- a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH , most preferably, a is 2 when B is oxygen.
- b is suitably 1 or 2.
- b is 1.
- c and d are suitably independently 0, 1, or 2.
- e is suitably 2, 3, or 4.
- f is suitably 0, 1, 2, or 3. alternatively, E suitably re
- R 24 , R 2 5, R26 5 R27, R 28 ( R29, R31 f and R 32 are suitably independently hydrogen or .galkyl.
- R 24 R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are preferably hydrogen.
- R 30 is suitably hydrogen, C galkyl, or C3_7cycloalkyl.
- R 30 is C ⁇ galkyl, more preferably, R 30 is C3_6alkyl, most preferably, R 30 is isopropyl.
- R 33 is hydrogen.
- J is suitably oxygen, CR 36 R 37 , or NR 38 , or J is a group 8(0) ⁇ , Preferably, J is oxygen. Preferably, J is para to L.
- R 34 , R 3 ⁇ , R 3 6 ( R37 ; R38 a re suitably independently hydrogen or C ⁇ alkyl.
- g is suitably 1, 2, or 3.
- g is 2 or 3, more preferably 2.
- h is suitably 1, 2, or 3.
- h is 1.
- i is suitably 2, 3, or 4.
- j is suitably 0, 1, 2, or 3.
- k is. suitably 0, 1 or 2.
- E may be optionally quaternized with C galkyl or is optionally present as the N-oxide;
- E is (b); J is CH 2 ; g is 1, 2, or 3; h is 1, 2, or 3; R 24 , R 5, R 26 , R27 ; R 28, R29 ; R 31 t a d R 32 are hydrogen;
- R 30 is hydrogen or C galkyl;
- R 33 is hydrogen, C galkyl, trifluoromethyl, or halogen;
- L is CONR 8' or NR CO;
- R 8' and R 9' are independently hydrogen or C ⁇ alkyl;
- P and P 2 are phenyl;
- A is CO, O or S(O) ⁇ -2;
- R ' is hydrogen;
- R 2 ' is hydrogen or 1, 2, or 3 of hydroxy, C ⁇ alkyl, cyano, halogen, or trifluoromethyl;
- R 3' is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluor
- the basic nitrogen in moiety E may be optionally quaternized with Cj.galkyl or is optionally present as the N- oxide;
- E is (b); J is CH 2; g is 1, 2, or 3; h is 1, 2, or 3; R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are hydrogen;
- R 30 is hydrogen or C galkyl;
- R 33 is hydrogen, C ⁇ alkyl, trifluoromethyl, or halogen;
- L is CH2NH;
- P 1 is heteroaryl, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyr
- R 1 * is an optionally substituted heterocyclic ring selected from furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl;
- R 2 * is hydrogen or 1, or 2 of hydroxy, cyano, halogen, trifluoromethyl, NR 10 *COR 12 *, NR 1 0*CO 2 R 13 *, NR 27 *CONHR 28 *, NHS(O)
- R 38 * are independently hydrogen or C ⁇ alkyl
- R 13 * and R 32 * are independently Cj.galkyl
- R 14 * is Cj.galkyl or phenyl
- R 26 * is hydrogen or C j.gal yl optionally substituted with one or two of hydroxy, has been described in WO 98/25604, published 18 June 1998, as chemokine receptor modulators.
- a preferred subgenus of the compounds of formula (I) are compounds of formula (la) in which R 1 ' , R 2 ', R 3' , P 1 , P 2 , A, a', b', L, R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R31, R 32 , R 33 , J, g, and h are defined as above:
- the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of this invention ("active ingredient") in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, ("CCR5-mediated disease states”) with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
- the pharmaceutical carrier employed may be, for example, either a solid or liquid.
- solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- liquid carriers are syrup, peanut oil, olive oil, water and the like.
- the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
- the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg.
- the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
- the active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states.
- the amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
- a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
- topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
- systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
- an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
- the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
- topical formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
- the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
- Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
- the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
- bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
- Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
- Lotions according to the present invention include those suitable for application to the skin or eye.
- An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
- Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
- Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
- the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol.
- the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
- suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
- Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
- the active ingredient may also be administered by inhalation.
- inhalation is meant intranasal and oral inhalation administration.
- Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
- the daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
- this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and H1N infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound of this invention.
- atopic disorders for example, atopic dermatitis and allergies
- sarcoidosis and other fibrotic diseases for example, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and H1N infection
- a CCR5 receptor modulator for example, atopic dermatitis and allergies
- rheumatoid arthritis for example, atopic dermatitis and allergies
- treating is meant either prophylactic or therapeutic therapy.
- Such compound can be administered to such mammal in a conventional dosage form prepared by combining the compound of this invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
- the compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic diseases, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIN infection, in an amount sufficient to decrease symptoms associated with these disease states.
- atopic disorders for example, atopic dermatitis and allergies
- rheumatoid arthritis for example, atopic dermatitis and allergies
- rheumatoid arthritis for example, atopic dermatitis and allergies
- atherosclerosis for example, atopic dermatitis and allergies
- sarcoidosis and other fibrotic diseases for example, atopic dermatitis and allergies
- psoriasis autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIN infection
- the route of administration may be oral
- parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
- the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
- the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient.
- the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient.
- the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
- suitably substituted aryl or heteroarylcarboxylic acids are treated with a suitable reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I).
- a suitable base such as diisopropylethylamine
- a suitable solvent such as dichloromethane
- 1-4 is treated with a ten-fold excess of an equimolar mixture of a 3- aryl- or heteroaryl carboxylic acid, triphenylphosphine and N-bromosuccinimide, in a suitable solvent, such as dichloromethane, after which a ten-fold excess of a suitable base, such as pyridine, is added, and the mixture is gently agitated for a suitable time, for example, forty-eight hours, to afford the resin-bound amide 1-6.
- dimethylformamide may be added to the resulting mixture to increase the solubility of the 3-aryl- or heteroaryl carboxylic acid.
- Example 1(a) The resin of Example 1(a) was placed in an Irori Micro Kan and treated with a ten-fold molar excess of an equimolar mixture of 4-chlorocinnamic acid, N- bromosuccinimide, and triphenylphosphine in dichloromethane, followed by addition of a ten-fold excess of pyridine. The mixture was gently agitated for 48 h after which the resin was washed three-times, sequentially with dimethylformamide, dichloromethane, and methanol to afford the title adduct.
- Example 2-30 Following the procedure of Example l(a)-(c), except using 4-[(2- diisopropylamino)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (J. Med. Chem. 1995, 38, 1657-65), 3-[(2-diisopropylamino)ethoxy]aniline (WO 99/01127), 4-[2-(diethylamino)ethoxy]aniline (J. Med. Chem. 1995, 38, 1657-65), 3-[(2-diisopropylamino)ethoxy]aniline (WO
- Example 44 Preparation of N-r3-r3-rBis(l-methylethyl)amino1propyl1-4-methoxyphenyll-4- phenoxybenzamide Following the procedure of Example 36, except substituting 4-phenoxybenzoic acid for 4-(3-hydroxyphenoxy)benzoic acid and 3-[(3- diisopro ⁇ ylamino)propyl]-4-methoxyaniline for 3-[(2-diisopropylamino)ethoxy]-4- methoxyaniline, afforded the title compound. MS (ES) m/e 461.3 (M+H) + .
- Example 45 Preparation of N-f3-r2-rBis( l-methylethyl)aminolethoxy1-4-methoxyphenyll-4- [(hydroxyimino)phenylmethyllbenzamide
- a solution of the compound of Example 39 (0.24 g, 0.5 mmol), hydroxylamine hydrochloride (0.17 g), and triethylamine (0.24 mL) in ethanol (10 mL) was heated to reflux for 20 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water to give the title compound.
- MS (ES) m/e 490.0 (M+H) + .
- Example 46 Preparation of N-f3-r2-rBis( l-methylethyl)amino1ethoxy1-4-methoxyphenyll-4- (hydroxyphenylmethyl)benzamide
- a mixture of the compound of Example 39 (0.24 g, 0.5 mmol), ethanol (21 mL), water (7 mL), methanol (5 mL), and dichloromethane (5 mL) was treated with sodium borohydride (0.13 g, 3.5 mmol) and stirred at RT for 2 h.
- the mixture was diluted with water, reduced in volume in vacuo, and extracted three times with dichloromethane.
- the combined organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound (40 mg).
- MS (ES) m/e 477.2 (M+H)+.
- Example 50 Preparation of N-f 1 -[2-rBis( l-methylethyl)aminolethvn- 1 ,2.3,4-tetrahydroquinol-7- ⁇ y 1] -4-phenoxybenzamide Following the procedure of Example 31 , except substituting 4-phenoxybenzoic acid for 3-phenoxybenzoic acid and substituting the compound of Preparation 3(b) for 3-[(2-diisopropylamino)ethoxy]-4- methoxyaniline, gave the title compound. MS (ES) m/e 472.2 (M+H) + .
- Example 51 Preparation of N-[3-r2-fBis( l-methylethyl)amino1ethoxyl-4-methoxyphenyll-4- phenoxybenzamide Methiodide
- the compound of Example 32 (93 mg, 0.2 mmol) in methanol (3 mL) was treated with iodomethane (8 mL), maintained at RT for 4 d, concentrated in vacuo, and the residue was triturated with ethyl acetate and then withl:l ethyl acetate:ether. The residue was stirred with 1:1 ethyl acetate:ether for several hours and filtered to afford the title compound.
- MS (ES) m/e 477 (M+H) + .
- CCR5 Receptor Binding Assay CHO cell membranes (0.25 xlO 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125 I-RANTES in a 96 well plate for 45 min at room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF/C) were washed twelve times with a solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % NaN 3 . The radioactivity bound to filters was measured by liquid scintillation spectrometry. Non-specific binding was determined in the presence of unlabelled RANTES (10 or 30 nM) and averages 30-50% of total binding.
- the cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca + mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5).
- Agonist activity is determined by Ca 2+ mobilization in the same cells which is inhibitable by a selective CCR5 antagonist.
- Cells were grown to 80- 100% confluency in T-150 flasks and washed with phosphate-buffered saline.
- Cells were resuspended at 2 X 10 ⁇ cells/mL in the same buffer with 2 ⁇ -M Fura- 2AM, and incubated for 35 min at 37° C. Cells were centrifuged at 200 x g for 3 min and resuspended in the same buffer without Fura-2AM, then incubated for 15 min at 37° C to complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells (10 6 cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM CaCl 2 , 1 mM MgCl 2 and 0.1% gelatin and maintained on ice until assayed.
- the percent of maximal RANTES -induced Ca 2+ was determined for each concentration of antagonist and the IC50 defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists).
- the compounds of this invention show CCR5 receptor modulator activity having IC50 values in the range of 0.0001 to 100 ⁇ M.
- the full structure/activity relationship has not yet been established for the compounds of this invention.
- one of ordinary skill in the art can utilize the present assays in order to determine which compounds of this invention are modulators of the CCR5 receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 ⁇ M.
- All publications, including, but not limited to, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
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Abstract
Description
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US134157P | 1999-05-14 | ||
PCT/US1999/017121 WO2000006146A1 (en) | 1998-07-28 | 1999-07-28 | Substituted anilide compounds and methods |
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IL (1) | IL141028A0 (en) |
NO (1) | NO20010446L (en) |
PL (1) | PL345713A1 (en) |
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WO (1) | WO2000006146A1 (en) |
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BR0112856A (en) * | 2000-07-31 | 2003-07-01 | Smithkline Beecham Plc | Method for treating the disorder, compound or a salt or solvate thereof, process for preparing the disorder, pharmaceutical composition, method of treatment and / or prophylaxis of one or more of the disorders, use of a compound, and method for treatment of diabetes, major depression, manic depression, anxiety, schizophrenia, and sleep disorders in human and non-human mammals |
EP1343796A4 (en) * | 2000-10-23 | 2005-01-12 | Smithkline Beecham Corp | Compounds and methods |
US7507767B2 (en) | 2001-02-08 | 2009-03-24 | Schering Corporation | Cannabinoid receptor ligands |
US7067539B2 (en) | 2001-02-08 | 2006-06-27 | Schering Corporation | Cannabinoid receptor ligands |
MXPA04004674A (en) | 2001-11-14 | 2004-08-12 | Schering Corp | Cannabinoid receptor ligands. |
JP2005533809A (en) | 2002-06-19 | 2005-11-10 | シェーリング コーポレイション | Cannabinoid receptor agonist |
EP2385040A1 (en) | 2003-03-14 | 2011-11-09 | ONO Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient |
AR043633A1 (en) | 2003-03-20 | 2005-08-03 | Schering Corp | CANABINOID RECEIVERS LINKS |
US7498323B2 (en) | 2003-04-18 | 2009-03-03 | Ono Pharmaceuticals Co., Ltd. | Spiro-piperidine compounds and medicinal use thereof |
US7407976B2 (en) * | 2003-11-14 | 2008-08-05 | Vertex Pharmaceuticals Incorporated | Thiazoles and oxazoles useful as modulators of ATP-Binding Cassette transporters |
US7544803B2 (en) * | 2004-01-23 | 2009-06-09 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
JP2008510728A (en) | 2004-08-19 | 2008-04-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | Muscarinic receptor modulators |
US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
KR101231466B1 (en) | 2004-09-13 | 2013-02-07 | 오노 야꾸힝 고교 가부시키가이샤 | Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient |
US7863449B2 (en) | 2004-11-29 | 2011-01-04 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
EP1889622A4 (en) | 2005-05-31 | 2009-12-23 | Ono Pharmaceutical Co | Spiropiperidine compound and medicinal use thereof |
AP2008004459A0 (en) * | 2005-10-06 | 2008-06-30 | Univ Massachusetts | Composition and sythesis of new reagents for inhibition of HIV replication |
DK1942108T3 (en) | 2005-10-28 | 2013-12-09 | Ono Pharmaceutical Co | Compound containing basic group and use thereof |
EP1961744B1 (en) | 2005-11-18 | 2013-04-17 | Ono Pharmaceutical Co., Ltd. | Basic group-containing compound and use thereof |
KR20080087841A (en) | 2005-12-22 | 2008-10-01 | 버텍스 파마슈티칼스 인코포레이티드 | Modulators of muscarinic receptors |
JP2009527569A (en) | 2006-02-22 | 2009-07-30 | バーテックス ファーマシューティカルズ インコーポレイテッド | Modulator of muscarinic receptor |
CA2643320A1 (en) | 2006-02-22 | 2007-09-07 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
CN101443322A (en) | 2006-03-10 | 2009-05-27 | 小野药品工业株式会社 | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
WO2007132846A1 (en) | 2006-05-16 | 2007-11-22 | Ono Pharmaceutical Co., Ltd. | Compound having acidic group which may be protected, and use thereof |
EP2040706A2 (en) | 2006-06-29 | 2009-04-01 | Vertex Pharmceuticals Incorporated | Modulators of muscarinic receptors |
JP5245827B2 (en) | 2006-07-31 | 2013-07-24 | 小野薬品工業株式会社 | Compound containing spiro-bonded cyclic group and use thereof |
WO2008021375A2 (en) | 2006-08-15 | 2008-02-21 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7786107B2 (en) | 2006-08-18 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
GB0625523D0 (en) * | 2006-12-21 | 2007-01-31 | Ge Healthcare Ltd | In vivo imaging agents |
US7973162B2 (en) | 2007-10-03 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
WO2010129351A1 (en) | 2009-04-28 | 2010-11-11 | Schepens Eye Research Institute | Method to identify and treat age-related macular degeneration |
EP2741777B1 (en) | 2011-08-12 | 2017-01-18 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for treatment of pulmonary hypertension |
FR2984318B1 (en) | 2011-12-16 | 2014-06-27 | Oreal | CATIONIC AMINO-1,2,3,4-TETRAHYDROQUINOLINE 7 STRUCTURE COUPLER, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES |
FR2984323B1 (en) | 2011-12-16 | 2019-08-30 | L'oreal | STRUCTURE COUPLER 7 AMINO-1,2,3,4-TETRAHYDROQUINOLINES, TINCTORIAL COMPOSITION COMPRISING THE SAME, METHODS AND USES |
FR3072286B1 (en) | 2017-10-13 | 2022-08-12 | Oreal | PARTICULAR 7-AMINO-1,2,3,4-TETRAHYDROQUINOLEINS, METHOD AND COMPOSITION |
US11629196B2 (en) | 2020-04-27 | 2023-04-18 | Incelldx, Inc. | Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions |
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BR9912406A (en) | 2001-04-24 |
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TR200100267T2 (en) | 2001-09-21 |
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