WO2007135350A1 - Dérivés de la benzotriazépinone - Google Patents

Dérivés de la benzotriazépinone Download PDF

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Publication number
WO2007135350A1
WO2007135350A1 PCT/GB2006/004512 GB2006004512W WO2007135350A1 WO 2007135350 A1 WO2007135350 A1 WO 2007135350A1 GB 2006004512 W GB2006004512 W GB 2006004512W WO 2007135350 A1 WO2007135350 A1 WO 2007135350A1
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Prior art keywords
alkyl
aryl
aralkyl
alkaryl
groups
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PCT/GB2006/004512
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English (en)
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Iain Mair Mcdonald
John Spencer
Ildiko Maria Buck
David John Dunstone
Ian Duncan Linney
Patrizia Tisselli
Robert Anthony David Hull
Carol Austin
Elaine Anne Harper
David Sykes
Eric Griffin
Mark Shaxted
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James Black Foundation
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Publication of WO2007135350A1 publication Critical patent/WO2007135350A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH

Definitions

  • the present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production.
  • the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-I or PTH/PTHrp receptor ligands).
  • PTH parathyroid hormone
  • PTHrp parathyroid hormone related protein
  • the invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
  • PTH is an 84 amino acid peptide circulating hormone produced by the parathyroid glands.
  • the primary function of PTH is to maintain a constant concentration of calcium in the extracellular fluid. It does so by acting directly or indirectly on various peripheral target tissues to mobilise calcium entry into the blood. Ia turn, PTH synthesis and release are controlled principally by the level of serum calcium. When the concentration of calcium is low, PTH secretion increases but is decreased when the calcium concentration is high. PTH enhances the distal tubular reabsorption of calcium in the kidney (Marcus, R. in The Pharmacological Basis of Therapeutics, 9 th Ed. (1996), ppl525-1529, Hardman, J. G.; Goodman Gilman, A. and Limbard, L. E. Ed.
  • osteoblasts Once located at the bone surface these cells are transformed into multinucleated osteoblasts that cause bone lysis by secretion of acid and enzymes thereby generating resorption pits in the bone. Bone remodeling is completed by ingress of preosteoblasts into theses cavities which on progression into osteoblasts deposit bone matrix constituents such as collagen and osteocalcin, amongst other proteins.
  • PTHrp Parathyroid hormone related peptide
  • PTHrp shares some of the actions of PTH (Clemens, T. L. et al, Br. J. Pharmacol, (2001), 134, 1113-1116).
  • PTHrp is found in three forms of 173, 141 and 139 amino acids and shares significant N-terminal amino acid sequence homology with PTH, particularly within the first 13 residues.
  • PTHrp is not normally present in the circulation but is thought to act as a paracrine or autocrine factor.
  • PTHrp regulates chondrocyte growth, differentiation in the growth plates of developing long bones, and branching morphogenesis of the mammary gland.
  • tumour cell types including those responsible for prostate, breast, lung, ovarian, bladder and squamous carcinomas and in Leydig tumour cells and other cancers of the kidney.
  • PTH-I receptors PTH-I or PTH/PTHrp receptors, hereinafter termed PTH-I receptors, are located predominantly in the kidney and on bone osteoblasts and are responsible for the effects of PTH on calcium homeostasis (Gardella, T. J. and Juppner, H. Trends in Endocrinology and Metabolism, (2001), 12(5), 210-217).
  • PTHrp is a selective stimulant of PTH-I receptors.
  • PTH-2 receptors are predominantly located in the brain suggesting a distinct physiological role to PTH-I receptors.
  • TIP39 tuberoinfundibular peptide
  • ligands Compounds which interact with PTH-I receptors are important because of their potential pharmaceutical use as antagonists, partial inverse agonists, inverse agonists, agonists or partial agonists of the endogenous peptides PTH or PTHrp. Such compounds are described herein as ligands. Thus, the term ligand, as used herein, can mean that the compound is an antagonist, partial inverse agonist, inverse agonist, agonist or partial agonist.
  • Disruption of calcium homeostasis may produce clinical impairment of bone such as osteoporosis, as well as other clinical disorders including, anaemia, renal impairment, ulcers, myopathy and neuropathy.
  • Hypercalcemia is a condition characterised by elevation of serum calcium and is often associated with primary hyperparathyroidism in which an excess of PTH production occurs.
  • PTHrp-producing squamous, renal, breast, ovarian or bladder carcinomas Both forms of hypercalcemia may be expected to benefit from a PTH-I receptor antagonist.
  • Cell lines originating from tumours in kidney, breast, prostate, lung and from osteosarcomas have been shown to be capable of growing in response to either PTH or PTHrp.
  • a PTH-I antagonist may have a role in the treatment or prevention of primary tumours, most especially osteosarcoma, clear cell renal carcinoma, and prostate, breast, gastric, ovarian, and bladder cancers, tissue from each of which has been shown to contain both PTH-I receptors and to secrete PTHrp.
  • cancers of the lung, prostate and breast have a propensity for metastasis to bone, a process underpinned by PTH and PTHrp (Guise, T. A. et al, J. Clin. Invest, (1996), 98(7), 1544-1549).
  • PTH-I receptors are present on bone osteoblasts and control the activation of osteoclasts. Osteoclasts act on bone, providing sites for bone metastases to form and resulting in number of factors to b,e released, including PTHrp, which act to stimulate growth of both the primary tumour and of the bone metastases. These actions release more PTHrp leading to a vicious cycle of tumour growth.
  • PTH-I antagonists may be expected to help treat or prevent bone metastases resulting from these primary cancers.
  • these compounds might be expected to alleviate the clinical sequelae, such as fracture, severe bone pain, spinal cord compression and hypercalcaemia often associated with bone metastases.
  • PTHrp is also considered to contribute to cachexia, the condition of malnutrition, muscle wasting and net protein loss often associated with cancer patients.
  • PTH-I receptor antagonists may be expected to help prevent this condition, hi addition elevated PTH and/or
  • PTHrp levels have been associated with lack of hair eruption in transgenic mice, in congestive heart failure and in a number of inflammatory and auotoknmune diseases such as rheumatoid arthritis. These findings suggest a possible role may exist for PTH-I receptor antagonists in helping to treat or prevent these and other conditions either associated with elevated levels of
  • PTH or PTHrp or with over-activation of PTH-I receptors.
  • PTH has an anabolic action on osteoblasts therefore indicating a potential benefit for a PTH-I receptor ligand (such as an agonist or partial agonist) in helping to prevent or treat osteoporosis.
  • a PTH-I receptor ligand such as an agonist or partial agonist
  • Other conditions where such compounds may be considered to have a potential role are, for example, in the treatment of diabetes, in wound healing and other conditions either associated with lowered levels of PTH or PTHrp, or with under-activation of PTH-I receptors.
  • PTH-I receptor antagonists have been described based on the bovine sequence of PTH (([NIe 8 ' 18 , D-Trp 12 , Tyr 34 ]bPTH(7-34)NH 2 , (BIM-44002)), (Rosen, H. N. et al, Calcif. Tissue Int.
  • WO-A-03/041714 discloses a number of benzotriazepinone derivatives for use in the treatment of gastrin related disorders.
  • EP-A-0645378 describes a class of bicyclic compounds which are said to inhibit squalene synthetase.
  • R 1 , R 4 and R 5 are independently selected from H, COOH, COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH 5 S(C 1-6 alkyl), S(C 6-20 aryl), S(C 7-20 alkaryl), S(C 7-20 aralkyl), SO 2 H, SO 3 H 5 SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(Ci -6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaiyl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0
  • R la and R 5a are independently selected from H, COOH, COOCH 3 , COOCH 2 CH 3 , halo, OH, OCH 3 , OCH 2 CH 3 , OCF 3 , CF 3 , CH 3 , OCCl 3 , CCl 3 , OCF 2 CF 31 CF 2 CF 31 NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHC(O)(CH 3 ), NO 2 , CN, OC(O)CH 3 and C(O)H; or R 1 is joined to R 5 , R 5a or R la to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R 5 is joined to R 1 , R 5a or R la to form a 5, 6, 7, 8, 9 or
  • R 3 is selected from H, COOH, COO(Cj -20 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), CN, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl), SO 2 N(Cj -6 alkyl) 2 , SO 2 NH(C 6-20 aryl), SO 2 N(C 6-20 aryl) 2 , SO 2 NH(C 7-20 aralkyl), SO 2 NH(C 7-20 alkaryl), SO 2 N(Cj -6 alkyl)(C 6-20 aryl), SO 2 N(Cj -6 alkyl)(C 7-20 aralkyl), SO 2 N(Cj -6 alkyl)(C 7-20 alkaryl), SO 2 N(
  • R 2 is a group
  • Z, Z 1 and Z 2 are selected from the group consisting of C and N, wherein Z and Z 1 are not the same; n is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1, 2, 3, 4 or 5; n 1 is an integer of 0 or 1; m 1 is an integer of 0 or 1 ; m 2 is an integer of 0, 1, 2, 3, 4 or 5; wherein the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are optionally independently substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group; wherein the -(O) 1n 1 - and -(O) n 1 - groups are not directly linked to one another;
  • R 7 and R 8 are independently selected from the group consisting of H, COOH, COO(Ci -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH, S(C 1-6 alkyl), SO 2 H, SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(C 1-6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaryl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(O)(C 1-6 alkyl), NO 2 , CN, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl),
  • R 9 is selected from the group consisting of H and Ci -6 alkyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 6-20 aryl, C 7-20 aralkyl, C 7-20 alkaryl, C 1-20 heteroaryl and C 2-20 heterocyclyl;
  • R 10 is selected from the group consisting of, H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, Cg -30 heterocyclylalkaryl, C 4-30 heterocyclylalkoxyalkyl,
  • R 9 and R 10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R 10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C 1-I0 alkyl, C 1-20 haloalkyl, C 1-20 perhaloalkyl, C 1-20 hydroxyalkyl, C 3-10 cycloalkyl, halo, OH, OC 1-6 alkyl, NH 2 , OC(C 1-6 alkyl), OC(C 6-20 aryl), OC(C 7-20 aralkyl), OC(C 7-20 alkaryl), OCO(C 1-6 alkyl), OCO(C 6-20 aryl), OCO
  • each R 14 is joined to one another to form a 5, 6, 7, 8, 9 or
  • R 15 is selected from the group consisting of H, CN, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl,
  • the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are substituted by 1 -OH groups on the CH 2 backbone.
  • each compound of formula (I) only one of the groups -(CH 2 ) m - and -(CH 2 ) m 2 - is substituted .
  • neither of the -(CH 2 ) m - and -(CH 2 ) m 2 - groups are substituted by -OH groups.
  • the groups -(O) n , 1 - and -(O) n 1 - groups are not directly bonded to one another, i.e., there is no O-O bond.
  • n 1 is O
  • m 2 is O
  • n, n 1 , m, m 1 and m 2 are all O.
  • Z is N and Z 1 is C.
  • Z 2 is C.
  • Z is N, Z 1 is C and Z 2 is N. In another embodiment, Z is N, Z 1 is C and Z 2 is C.
  • R 2 is selected from the group consisting of the structures (i), (ii) and (iii) shown below: wherein, n, n 1 , m, m 1 , m 2 , R 6 , R 7 and R 8 have the same meaning as above; and the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are optionally independently substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group.
  • R 2 comprises the structure (ii).
  • R 2 is selected from the group consisting of the structures (ia), (iia) and (iiia) shown below: wherein R 7 and R 8 are independently selected from the group consisting of H, C 1-6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(C 1-6 alkyl) and C(O)(Ci -6 alkyl), R 6 is as defined above, wherein n is O or 1, m 1 is O or 1, m is 1, 2 or 3, and the group -(CH 2 ) m - is optionally substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group.
  • R 7 and R 8 are independently selected from the group consisting of H, C 1-6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH,
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the -(CH 2 ) n - group, most preferably the meta position.
  • n is O
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • R 7 and R 8 are both H.
  • n is O.
  • m is O.
  • R 2 is represented by the structure (iia).
  • R 2 is a group having the structure (ib) or (iib) shown below:
  • R 7 and R 8 are independently selected from the group consisting of H, Ci -6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(C 1-6 alkyl) and C(O)(Ci -6 alkyl), R 6 is as defined above and n is O or 1.
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the -(CH 2 ) n - group, most preferably the meta position.
  • n is O
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • R 7 and R 8 are both H.
  • n is O.
  • R 2 comprises the structure (iib).
  • R 2 is a group having the structure (ic) or (iic) shown below: wherein R 7 and R 8 are independently selected from the group consisting of H, Ci -6 alkyl, halo, OH, NH 2 and CN.
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • -NR 9 R 10 is located in the meta or para position relative to the N 1 atom (the N 1 atom being shown in the representative structure of compound of formula (I) above).
  • R 7 is H and R 8 is H, Cl, Br, or F, preferably H or Br.
  • R 7 and R 8 are both H.
  • R 2 comprises the structure (iic).
  • R 2 is a group having the structure (id) or (iid) shown below:
  • R 2 comprises the structure (iid).
  • n, m, m 1 , n 1 and m 2 are all 0, and -R 6 is located in the meta or para position relative to the notional (CH 2 ) n group, most preferably the para position.
  • R 2 is selected from the group consisting of ((I H-imidazol-2-yl)methylamino)-pyridinyl, ((I H-imidazol-2-yl)ethylamino)-pyridinyl,
  • the pyridyl moiety of the R 2 group is substituted with the named substituents in the para position relative to the point of attachment of the R 2 group to the rest of the compound of formula (I).
  • the pyridinyl moiety is a pyridin-2-yl moiety.
  • R 6 comprises a guanidinyl moiety.
  • R 9 is selected from H, methyl, ethyl, propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
  • R 10 is selected from the group consisting of Ci -I5 heteroaryl, C 2- i 5 heterocyclyl, C 2-I5 heteroaralkyl, C 3-I5 heterocyclylalkyl, Ci -I5 alkyl, C 6-20 aryl, C 7-20 aralkyl, C 3-I5 cycloalkyl and C 4-I5 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1 , 2, 3 or 4 groups, independently selected from NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , NH(C 6-16 aryl), N(C 6-16 aryl) 2 , NH(C 7-J6 aralkyl), N(C 7-I6 aralkyl) 2 , NH(C 7-I6 alkaryl), N(C 7-J6 alkaryl) 2 , N(Q -4 alkyl)(C
  • R 10 is selected from the group consisting Of C 6-20 aryl, C 7-20 aralkyl, C 3-15 cycloalkyl, C 4-I5 cycloalkylalkyl, C 1-I5 heteroaryl, C 2-15 heterocyclyl, C 2-15 heteroaralkyl, C 3-15 heterocyclylalkyl and C 1-I0 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH 2 , NH(Ci -4 alkyl) OrN(Ci -4 3 UCyI) 2 .
  • R 10 is selected from the group consisting of Ci -10 heteroaryl, C 2-I0 heterocyclyl, C 3-I0 heteroaralkyl, C 4-I5 cycloalkylalkyl, C 3-I0 heterocyclylalkyl and Ci -6 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from NH 2 , NH(Ci -4 alkyl) or N(Cj -4 alkyl) 2 .
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, furanyl(C 1-3 alkyl), pyridyl, pyridyl(Ci -3 alkyl), phthalimido, phthalimido(C 1-3 alkyl),
  • imidazolemethyl dihydroimidazolyl, dihydroimidazolyl(Ci. 3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci. 3 alkyl), benzimidazolyl, benzimidazoly ⁇ Q ⁇ alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci. 3 alkyl), pyrazolidinyl, pyrazolidinyl(C 1-3 alkyl), tetrahydrofuranyl, tetrahyrdofuranyl(Ci.
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, pyridyl, pyridyl(Ci -3 alkyl), phthalimido, phthalimido(C 1-3 alkyl), pyrrolyl, pyrrolyl(Ci
  • imidazolidinyl imidazolidinyl(Ci -3 alkyl), imidazolinyl, imidazolinyl(Ci. 3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(Ci -3 alkyl), dihydroimidazolyhnethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci.
  • R 10 is selected from the group consisting of cyclopentylmethyl, piperidylmethyl, methylaminoethyl, aminocyclopentyhnethyl, methylaminocyclopentylmethyl, methylaminoethyl, tetrahydro-pyranylaminoethyl, tetrahydro- pyranylaminopropyl, propylaminoethyl, propylaminopropyl, dimethylaminoethyl, furanylmethylaminoethyl, piperidinylmethyl and l-meth.yl-piperidin-4-ylmeth.yl, any of which may be substituted with 1 or more groups independently selected from C 1-6 alkyl, halo, haloCi -6 alkyl, hydroxyC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)
  • R 9 and R 10 are joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, preferably a 5 or 6-membered, saturated, unsaturated or aromatic heterocyclic ring is formed.
  • Preferred ring systems are selected from the group consisting of 5 or 6-membered heterocyclyl and heteroaryl rings containing 1 or 2 nitrogen atoms. Such rings may additionally comprise 1 or more oxygen and/or sulphur atoms.
  • Preferred ring systems are selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • R 10 is not H.
  • each R 14 is independently selected from the group consisting of H, C 1-10 alkyl, C 2-10 alkenyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 4-20
  • (cycloalkyl)alkyl Cs -20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-2O alkaryl, C 6-20 aryl, C 1-20 heteroaryl, C 2-2O heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, Cj -10 aminoalkyl,
  • R 15 is selected from the group consisting of H, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkoxyalkyl, C 7-2O alkoxyaryl, C 2- io alkynyl, C 3-2O cycloalkyl, C 4-20 (cycloalkyl)alkyl, Cs -20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl and C 2-20 heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, C 1-10 aminoalkyl, C 6-I0 aminoaryl, guanidinyl C 1-6 alkyl, C 2-12 alkylguanidinylalkyl, ureayl C 1-6 alkyl and C 2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on
  • R 15 and one of R 14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 14 not joined to R 15 is H or C 1-6 alkyl.
  • each R 14 is independently selected from the group consisting of H and Ci -4 alkyl, or R 15 and one of R 14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 14 not joined to R 15 is selected from the group consisting of H and C 1-4 alkyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
  • each R 14 is independently selected from the group consisting of H and methyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl.
  • R 6 is a group
  • R 3 is independently selected from the group consisting of H, COOH, COO(Ci -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 alkaryl), COO(C 7-20 aralkyl), C(O)H, C(O)(Ci -6 alkyl), C(O)NH 2 , C(O)NH(Ci -6 alkyl), C(O)N(Ci -6 alkyl) 2 , C(O)NH(C 6-15 aryl), C(O)N(C 6-I5 aryl) 2 , C(O)NH(C 7-I5 aralkyl), C(O)N(C 7-J5 aralkyl) 2 , C(O)NH(C 7-I5 alkaryl), C(O)N(C 7-15 alkaryl) 2 and hydrocarbyl or heterocarbyl groups selected from C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 2- 20
  • R 3 is not H.
  • R 3 is -(CR 16 R 1 V-X-R 18 ; wherein: m 3 is 0, 1, 2, 3 or 4;
  • R 16 and R 17 are independently selected from the group consisting of H, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, C 1-10 aminoalkyl and C 6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C 1-6 alkyl), SH, S(Ci -6 alkyl), SO 2 H, SO 2 (C 1-6 alkyl), SO 2
  • R 18 is selected from the group consisting of H, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, Ci 2-30 aryloxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, Ci -I0 aminoalkyl, C 6-20 aminoaryl, guanidine Ci -I0 alkyl, C 2-20 alkylguanidinylalkyl, urea Ci -I0 alkyl and C 2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on
  • X is a bond, C(O)NH, C(O)N(Cj -6 alkyl), C(O)N(C 6-20 aryl), NH, N(Cj -6 alkyl) or O.
  • R 16 and R 17 are independently selected from the group consisting of H, C 1-J0 alkyl, C 2-20 alkoxyalkyl, C 7-20 alkoxyaryl, Cj 2-20 aryloxyaryl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl and C 3-20 heterocyclylalkyl.
  • R 16 and R 17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, saturated, unsaturated or aromatic ring.
  • the ring may be a heterocyclic or heteroaromatic ring.
  • the ring formed by R 16 and R 17 is a cycloalkyl, heterocyclyl or heteroaromatic group.
  • the ring is a C 6-10 cycloalkyl, C 4-10 heterocyclyl or C 1-10 heteroaryl group.
  • m 3 is O
  • X is a bond and R 18 is a Cs -12 cycloalkyl group.
  • X is a bond, C(O)NH or C(O)N(C 1-6 alkyl).
  • X is a bond
  • R 16 and R 17 are both H
  • m 3 is O or 1
  • X is C(O)NH
  • R 16 and R 17 are both H
  • m 3 is O or 1
  • X is a bond
  • R 18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tetrahydropyranyl, tolyl, ethylbenz
  • X is a bond
  • m 3 is O
  • R 18 is C 2-2O heterocyclyl
  • R 3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), halo, trihalomethyl, OH, NH 2 , 0(Ci -6 alkyl), 0(C 6-20 aryl), 0(C 7-20 aralkyl), 0(C 7-20 alkaryl), Ci -6 alkyl, C 6-I2 aryl, C 7-I2 aralkyl, C 7-I2 alkaryl, C 8-I2 aralkynyl, C 6-I2 aryloxy, C 1-I2 heteroaryl, C 5-12 cycloalkyl and C(O)(Ci -6 alkyl) on the backbone.
  • 1, 2 or 3 groups independently selected from COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C
  • R 3 comprises a methyl, ethyl, propyl, butyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, tetrahydropyranyl, naphthyl, benzocycloheptyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci -6 alkyl), halo, trihalomethyl, OH, NH 2 , 0(C 1-6 alkyl), C 1-6 alkyl, C 6 - I2 aryl, C 7-12 aralkyl, C 7-12 alkaryl, C 6-I2 aryloxy, C 1-12 heteroaryl, C 5-I2 cycloalkyl and C(O)(Ci -6 alkyl) on the backbone.
  • R 3 is preferably a tetrahydropyranyl group or a propyl group.
  • R 19 is not H.
  • R 19 is selected from the group consisting of dihydroimidazolyl and imidazolyl, particularly lH-imidazol-2-yl and 4,5-dihydro-lH-imidazol-2-yl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups.
  • Such preferred groups may be optionally substituted with 1, 2 or 3 groups selected from halo, CH 3 , OH, OCH 3 , OCH 2 CH 3 and NH 2 .
  • R 19 is not substituted in the backbone.
  • R 19 is not substituted on the backbone.
  • R 1 , R 4 and R 5 are independently selected from the group consisting of H, COOH, COO(C 1-6 alkyl), CN, SH, S(C 1-6 alkyl), S(C 6-20 aryl), S(C 7-20 alkaryl), S(C 7-20 aralkyl), SO 2 H, SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(Cj -6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaryl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0(Ci -6 alkyl), NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , NHC(O)(C 1-6 alkyl), NO 2 , CN, SO 2 NH 2 , C(C 1-6
  • R 1 is joined to R 5 , R 5a or R la to form a ring, or when R 5 is joined to R 5a or R la to form a ring, preferably it is a 5, 6 or 7-membered ring which is optionally substituted with 1, 2 or 3 of the groups independently selected from the groups defined in (b) and (c) above.
  • none of R 1 , R la , R 5 or R 5a are joined to one another to form a ring.
  • R 5a , R 5 , R 1 and R la are in the 6, 7, 8 and 9 positions respectively of the compound of formula (I).
  • R 5a , R 5 , R 1 and R la are linked with one another to form a ring, adjacently positioned groups are linked, rather than remotely positioned groups.
  • R 5a and R 5 are preferably joined to one another when they are in the 6 and 7 position respectively.
  • R 1 and R 5 are independently selected from the group consisting of H, COOH, SH 3 SO 2 H, P(OH)(O) 2 , F, Cl, Br, I, OH, NH 2 , NO 2 , CN, SO 2 NH 2 , C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci -6 alkyl, Ci -6 alkoxy, C 2-6 alkoxyalkyl, C 7-20 alkoxyaryl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl and C 2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c):
  • R 1 and R 5 are independently selected from the group consisting of C 1-4 alkyl, C 5-8 cycloalkyl, C 1-4 alkoxy, C 1-4 alkylcarbonylamino, Ci -4 alkylaminocarbonyl, C 3-10 cycloalkylcarbonylamino, C 3-10 cycloaUcylaminocarbonyl, C 2- I 0 heterocyclylcarbonylamino, C 2-10 heterocyclylaminocarbonyl, C 6- io arylcarbonylamino, C 6- I 0 arylaminocarbonyl, C 1-1O heteroarylcarbonylamino, C 1-I0 heteroarylaminocarbonyl, C 1-6 alkylamino, di (C 1-4 alkyl)amino, C 7-1O aralkyl, C 7-1O alkaryl, C 6-1 O aryl, C 1-10 heteroaryl and C 2- io heterocyclyl, any of which are optionally substituted with one
  • R 1 and R 5 are independently selected from the group consisting of H, F, Cl, Br, Ci -4 alkyl, C(O)Ci -6 alkyl, C 5-8 cycloalkyl, C 1-4 alkoxy, dimethylamino, tolyl, xylyl, pyridyl, pyridinyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 and N(CH 3 ) 2 .
  • R 5 is H and R 1 is selected from the group consisting of H, F, Cl, Br, methoxy, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 andN(CH 3 ) 2 .
  • R 5 and R 1 are both H.
  • R 5 is H and R 1 is selected from methyl, Cl and methoxy.
  • R 1 and R 5 are located in the 8 and 7 positions respectively of the compound of formula (I).
  • R 1 is a methyl group located in the 8-position of the compound of formula (I) as indicated herein.
  • R 4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci -I0 alkyl, C 2-1O alkoxyalkyl, C 12-20 aryloxyaryl, C 7-20 aryloxyalkyl, C 1-I o alkoxy, C 7-2O alkoxyaryl, C 4-20 alkoxycycloalkyl, C 3-2O cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-2O aralkyl, C 7-2O alkaryl, C 6-2O aryl, Ci -2O heteroaryl, C 2-2O heteroaralkyl and C 2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 2-6 alkoxyalkyl, C 12-20 aryloxyaryl, C 7-12 aryloxyalkyl, Ci -I0 alkoxy, C 7-12 alkoxyaryl, C 5-I2 alkoxycycloalkyl, C 3-I2 cycloalkyl, C 4-I2 (cycloalkyl)alkyl, C 7-12 aralkyl, C 7-I2 alkaryl, C 6-I2 aryl, Ci -I2 heteroaryl, C 2-12 heteroaralkyl and C 2-I2 heterocyclyl, any of which is optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c): (a) S, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O,
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 3-I2 cycloalkyl, C 6-12 aryl, Q- I2 heteroaryl, C 2-12 heterocyclyl, C 2-6 alkoxyalkyl, Cs -I2 alkoxycycloalkyl, C 2-I0 alkylthioalkyl, C 4-12 alkylthiocycloalkyl, C 2-I0 alkylsulfonylalkyl, C 6-12 alkylsulfonylcycloalkyl and C 6-12 alkylarninocycloalkyl.
  • R 4 is selected from the group consisting of methyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, tetrahydropyranyl, piperidinyhnethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
  • R 4 is a cyclohexyl group.
  • R 4 is not H.
  • R la and R 5a are independently selected from H, CH 3 , F, Cl, Br and OH. Most preferably, both R la and R 5a are H.
  • R la and R 5a are located in the 9 and 6 positions respectively of the compound of formula (I).
  • the substitution may be in any of the positions designated 6, 7, 8 or 9 in formula (I).
  • the nitrogen atom is unsubstituted.
  • the benzo moiety of the benzotriazepinone ring system is unsubstituted in the benzo ring.
  • Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures.
  • 1,3,4-benzotriazepinones are prepared by treatment of a suitable 2-amino phenyl ketone (III), with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3 ' thereof).
  • a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3 ' thereof).
  • thiophosgene may be used in place of a suitable bifunctional carbonyl reagent to afford a l,3,4-benzotriazpin-2-thione (IV), followed by basic peroxide-mediated oxidation to obtain the 1,3,4-benzotriazepinone (V) (Reaction Scheme 2).
  • Reaction Scheme 2 Reaction Scheme 2
  • 1,3,4-benzotriazepinones (V) may also be obtained by initial activation of a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as /> ⁇ ra-nitrobenzyl chloroformate, bis(trichloromethyl) carbonate or l,l'-carbonyldiimidazole, followed by treatment with a suitable urethane-protected hydrazine, P 1 NHNHR 3 (wherein P 1 represents a urethane protecting group and R 3 represents R 3 or a suitable precursor thereof) to form a substituted semicarbazide derivative (VI) as an intermediate (Reaction Scheme 3). Removal of the urethane protecting group P', results in concomitant ring closure to form the 1,3,4-benzotriazepinones (V).
  • a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as />
  • the 1,3,4-benzotriazepine (V) may also be obtained by starting from a suitable 2-iodo aniline (VII) (Reaction scheme 4). Sonogashira reaction (Tykwinski, R. R. Angew. Int. Ed. (2003), 42, 1566) affords the corresponding acetylide derivative (VIII) which, on reaction with a suitable bifunctional carbonyl reagent and a suitable urethane-protected hydrazine, PTSfHNHR 3 ', affords the semicarbazide intermediate (EX).
  • Mercuric oxide-mediated oxidation yields the required ketone precursor (VI), suitable for conversion to the 1,3,4-benzotriazepine (V) according to the method outlined in reaction scheme 3.
  • N-I substituted benzodiazepines (X) are obtained from (V) by base catalysed alkylation using sodium hydride and a suitable alkyl halide, R 2 Br or R 2 F, (wherein R 2' represents a suitable precursor of R 2 ) (Reaction scheme 5).
  • arylation may be achieved by copper-mediated arylation reaction with a suitable aryl iodide R 2 1.
  • R 2 groups which are suitable precursors of R 2 will depend on the particular nature of R 2 .
  • a suitable precursor of R 2 is:
  • a suitable precursor of R 2 is:
  • R 6 is a suitable precursor of R 6 .
  • R 6 groups which are suitable precursors of R 6 will depend on the particular nature of R 6 .
  • Suitable R 6 substituents include NO 2 , which can be reduced by tin (II) chloride or catalytic hydrogenation to the corresponding aniline.
  • the aniline substituent can be further modified to the required R 6 group by, amongst others, acylation with amino acid derivatives, reductive amination with an appropriate aldehyde, or guanylation with a suitable guanylating agent.
  • Other suitable R 6 substituents include esters that can be converted to amide derivatives via the corresponding carboxylic acid.
  • R 6 represents a dihydroimidazolyl group
  • suitable R 6 ' substituents include CHO, which can be converted to a dihydroimidazolyl group by the method of Huh (D.H. Huh, J. S. Jeong, H.B. Lee et al. Tetrahedron, 2002, 58, 9925).
  • Other suitable R 6' substituents include CN, from which a dihydroimidazolyl group can be obtained by formation of the corresponding imidate, using methanolic-HCl, followed by treatment with a 1,2-ethylenediamine (G. Marciniak, D. Decolin, et al., J. Med. Chem., 1988, 31, 2289).
  • R 6 represents an imidazolyl group
  • suitable R 6 substituents include alkyl halides or activated alcohols, from which the desired imidazolyl group can be obtained by displacement of the halide or activated alcohol with a suitable imidazolecarbanion.
  • R 3 substituents which are suitable precursors of R 3 will depend on the particular nature of R 3 .
  • P represents R 3
  • these can obtained directly by treatment of (III) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as
  • the present invention also provides a method of making compounds according to formula (I).
  • Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), substantially as described hereinbefore, with a pharmaceutically acceptable diluent or carrier.
  • Yet another aspect of the present invention is a method of making a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) substantially as described hereinbefore, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, for use in therapy.
  • Some diseases that may be treated according to the present invention include, cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal.
  • the present invention provides a method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of cancer, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of osteoporosis, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of an inflammatory disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of an autoimmune disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of metastases, particularly bone metastases, by administration to a subject of- a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the treatment of lack of hair eruption, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • Specific diseases that may be treated or prevented according to the present invention include osteoporosis, anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing.
  • the present invention also provides the use of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described hereinbefore.
  • the compounds of the present invention may also be present in the form of pharmaceutical acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • FDA approved pharmaceutical acceptable salt forms International J. Pharm. 1986, 33,201-217; J. Pharm. Sci., 1977, Jan, 66 (1), pi
  • salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
  • Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine. Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids.
  • Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.
  • Hydrochloride salts of compound (I) are particularly preferred.
  • the invention also comprehends derivative compounds ("pro-drugs") which are degraded in vivo to yield the species of formula (T).
  • Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded.
  • Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drags may be found in Stella, V. J. et al, "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, Drugs, 1985, 29, pp. 455-473 and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Pro-drag forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (T) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COOR a , wherein R a is Ci -6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:
  • Amidated acid groups include groups of the formula -CONR b R°, wherein R b is H, C 1-5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R c is -OH or one of the groups just recited for R b .
  • compositions of formula (T) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.
  • administering shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly pro-drug esters that may be convertible by solvolysis under physiological conditions to the compounds of the present invention having tree hydroxy groups.
  • the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose.
  • Corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • Effective doses of the compounds of the present invention may be ascertained be conventional methods.
  • the specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 ⁇ g/kg and 50 mg/kg, especially between 10 ⁇ g/kg and 10 mg/kg, between 100 ⁇ g/kg and 2 mg/kg. Where reference is made to dialkyl groups [e.g. N(C 1-6 alkyl) 2 ], it is understood that the two alkyl groups may be the same or different.
  • Formulaic representation of apparent orientation of a group within the backbone is not necessarily intended to represent actual orientation.
  • a divalent amide group represented as C(O)NH is also intended to cover NHC(O).
  • linking bonds may be on any suitable ring atom, subject to the normal rules of valency.
  • pyrrolyl substituted on the backbone contemplates all possible isomeric forms.
  • pyrrolyl substituted on the backbone includes all of the following permutations:
  • halogen or "halo” is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents. Groups such as 1IaIo(C 1-6 alkyl) includes mono-, di- or tri-halo substituted Ci -6 alkyl groups. Moreover, the halo substitution may be at any position in the alkyl chain. "Perhalo” means completely halogenated, e.g., trihalomethyl and pentachloroethyl.
  • the terms “comprising” and “comprises” means “including” as well as “consisting” e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.
  • May means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • solvate means a compound of as defined herein, or a pharmaceutically acceptable salt of a compound of structure (I), wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the groups R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 10 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are unsubstituted, in or on the backbone.
  • the group R 1 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 3 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 3 or 4, more preferably by 1 substituent, as defined herein.
  • the group R 4 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 5 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 7 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 8 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 10 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 14 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 15 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 16 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 17 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 18 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 19 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • backbone preferably means the carbon backbone of the group being referred to.
  • backbone includes the possibility for substitution on a heteroatom, such as nitrogen, which is located in the carbon backbone.
  • the term "in the backbone" when referring to a substitution means that the backbone is interrupted by one or more of the groups indicated. Where more than one substitution occurs, they may be adjacent to one another or remote, i.e., separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms.
  • both “ethylaminocarbonyl” and “methylaminocarbonylbutyl” fall under the scope of the definition "C 1-6 alkyl group substituted with an NHC(O) group".
  • the NHC(O) group links the ethyl group to the rest of the molecule
  • the NHC(O) group interrupts the carbon chain
  • the butyl moiety links the methylaminocarbonyl moiety to the rest of the molecule.
  • the term "on the backbone" when referring to a substitution means that one or more hydrogen atoms on the backbone is replaced by one or more of the groups indicated. Where more than one substitution occurs, they may be on the same, adjacent or remote carbon atoms, i.e., located on carbon atoms that are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms apart.
  • a group comprises two or more moieties defined by a single carbon atom number, for example, C 2-20 alkoxyalkyl
  • the carbon atom number indicates the total number of carbon atoms in the group.
  • heteroatom includes N, O, S, P, Si and halogen (including F, Cl, Br and I).
  • hydrocarbyl group refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more hydrogen atoms.
  • hydrocarbyl group is intended to cover alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, cycloalkynyl, aralkyl, alkaryl, aryl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term “hydrocarbyl group”.
  • heterocarbyl group refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more heteroatoms in or on the carbon backbone, and optionally containing one or more hydrogen atoms.
  • heterocarbyl group is intended to cover alkoxyalkyl, alkoxyaryl, heteroaryl, heterocyclyl, heteroaralkyl, heterocyclylalkyl, aryloxyalkyl, alkoxy, cycloalkyloxy, aryloxy, alkylamino, cycloalkylamino, arylamino, alkylaminoalkyl, aralkylamino, alkarylamino, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkaryl, guanidinyl, guanidinylalkyl, alkylguanidinyl, alkylguanidinylalkyl, ureayl, ureaylalkyl, alkylureayl and alkylureaylalkyl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope
  • alkyl refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated.
  • suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, dodecyl and eicosyl.
  • alkenyl refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl, penentyl, hexenyl, octenyl, nonenyl, dodecenyl and eicosenyl, wherein the double bond may be located any where in the carbon backbone.
  • alkynyl refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon triple bond.
  • suitable alkynyl groups include ethynyl, propynyl, butynyl, penynyl, hexynyl, octynyl, nonynyl, dodycenyl and eicosynyl, wherein the triple bond may be located any where in the carbon backbone.
  • the te ⁇ n "cycloalkyl” refers to a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, spiroundecyl, bicyclooctyl and adamantyl.
  • (cycloalkyl)alkyl refers to an alkyl group with a cycloalkyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • suitable (cycloalkyl)alkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyhnethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexyhnethyl, cycloheptyhnethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl, methylcyclohexylmethyl, di
  • cycloalkenyl and “cycloalkynyl” refer to cyclic unsaturated monovalent hydrocarbon radicals.
  • a “cycloalkenyl” is characterized by a carbon-carbon double bond and a “cycloalkynyl” is characterized by a carbon-carbon triple bond.
  • Such groups have the number of carbon atoms as indicated.
  • suitable cycloalkenyl groups include cyclohexene and cyclohexadiene.
  • Alkoxy refers to the group "alkyl-O-", where alkyl is as defined above.
  • suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • Aryloxy refers to the group "aryl-O", where aryl is as defined herein.
  • suitable aryloxy groups include phenoxy, tolyloxy and xylyloxy.
  • alkoxyalkyl refers to an alkyl group having an alkoxy substituent. Binding is through the alkyl group.
  • the alkyl group and/or the alkoxy group has the number of carbon atoms as indicated.
  • the alkyl moiety may be straight or branched.
  • the alk and alkyl moieties of such a group may be substituted as defined above, with regard to the definition of alkyl.
  • suitable alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl.
  • alkoxyaryl refers to an aryl group having an alkoxy substituent. Binding is through the aryl group.
  • the aryl group and/or the alkoxy group have the number of carbon atoms as indicated.
  • the alkoxy and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkoxy and aryl.
  • the alkyl moiety may be straight or branched.
  • suitable alkoxyaryl groups include methoxyphenyl, ethoxyphenyl, dimethoxyphenyl and trimethoxyphenyl.
  • aryl refers to monovalent unsaturated aromatic carbocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic.
  • aryl refers to an aromatic monocyclic ring containing 6 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4 or 5 substituents as defined herein; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents as defined herein; or an aromatic tricyclic ring system containing 10, 11, 12, 13 or 14 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 substituents as defined herein.
  • suitable aryl groups include phenyl, biphenyl, binaphthyl, indanyl, phenanthryl, fluoryl, flourenyl, stilbyl, benzphenanthryl, acenaphthyl, azulenyl, phenylnaphthyl, benzfluoryl, tetrahydronaphthyl, perylenyl, picenyl, chrysyl, pyrenyl, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, aminophenyl, diaminophenyl, triaminophenyl, cyanophenyl,
  • heteroaryl refers to a monovalent unsaturated aromatic heterocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic.
  • heteroaryl refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic or fused ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom.
  • suitable heteroaryl groups include furanyl, pyranyl, pyridyl, phthalimido, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyronyl, pyrazinyl, tetrazolyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl,
  • heterocyclyl refers to a saturated or partially unsaturated ring having three members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or additional N atom; a saturated or partially unsaturated ring having four members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one or two additional N atoms; a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having seven members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atom
  • heterocycles comprising peroxide groups are excluded from the definition of hetercyclyl.
  • suitable heterocyclyl groups include pyrrolinyl, pyrrolidinyl, dioxolanyl, tetrahydrofuranyl, morpholinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl and piperazinyl.
  • heterocyclylalkyl refers to an alkyl group with a heterocyclyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the heterocyclyl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heterocyclyl and alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable heterocyclylalkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the heterocyclyl groups indicated immediately above.
  • alkaryl refers to an aryl group with an alkyl substituent. Binding is through the aryl group. Such groups have the number of carbon atoms as indicated.
  • the alkyl and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkyl and aryl.
  • the alkyl moiety may be straight or branched.
  • alkaryl include tolyl, xylyl, butylphenyl, mesityl, ethyltolyl, methylindanyl, methylnaphthyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, propylnaphthyl, butylnaphthyl, methylfluoryl and methylchrysyl.
  • aralkyl refers to an alkyl group with an aryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the aryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of aryl and alkyl.
  • the alkyl moiety may be straight or branched.
  • aralkyl include benzyl, methylbenzyl, ethylbenzyl, dimethylbenzyl, diethylbenzyl, methylethylbenzyl, methoxybenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, biphenylmethyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, phenyltolylmethyl, trifluoromethylbenzyl, bis(trifluoromethyl)benzyl, propylbenzyl, tolyhnethyl, fluorophenethyl, fluorenyhnethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenyl
  • heteroarylkyl refers to an alkyl group with a heteroaryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the heteroaryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heteroaryl and alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable heteroaralkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the specific heteroaryl groups indicated above.
  • alkylamino refers to an amine group with an alkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated.
  • the alkyl moiety of such a group may be substituted as defined herein, with regard to the definition of alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable alkylamino groups include methylamino, ethylamino, propylamino, butylamino, pentylamino and hexylamino.
  • cycloalkylamino refers to an amine group with a cycloalkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated.
  • the cycloalkyl moiety of such a group may be substituted as defined herein, with regard to the definition of cycloalkyl.
  • the alkyl moiety may be straight or branched.
  • suitable cycloalkylamino groups include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, cyclononylamino and cyclododecylamino.
  • aminoalkyl refers to an alkyl group with an amine substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group maybe substituted as defined herein, with regard to the definition of alkyl.
  • suitable aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl and aminohexyl.
  • arylamino refers to an amine group with an aryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The aryl moiety of such a group may be substituted as defined herein, with regard to the definition of aryl.
  • suitable arylamino groups include phenylamino, biphenylamino, methylphenylamino, methoxyphenylamino, tolylamino and chlorophenylamino.
  • alkarylamino refers to an amine group with an alkaryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched.
  • aminooaralkyl refers to an aralkyl group with an amine substituent. Binding is through the aralkyl group. Such groups have the number of carbon atoms as indicated. The aralkyl moiety of such a group may be substituted as defined herein, with regard to the definition of aralkyl. The alkyl moiety may be straight or branched.
  • aminoalkaryl refers to an alkaryl group with an amine substituent. Binding is through the alkaryl group. Such groups have the number of carbon atoms as indicated.
  • the alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl.
  • the alkyl moiety may be straight or branched.
  • guanidinyl refers to a guanidine group that has had one or more hydrogen atoms removed to form a radical.
  • ureayl refers to a urea group that has had one or more hydrogen atoms removed to form a radical.
  • substituents which are referred to as being on the carbon backbone of a group with a compound definition for example, "alkaryl”
  • the substituent may be on either or both of the component moieties, e.g., on the alkyl and/or aryl moieties.
  • substituents which are referred to as being in the carbon backbone of a group with a compound definition for example, “heteroaralkyl”
  • the substituent may interrupt either or both of the component moieties, e.g., in the alkyl and/or aryl moieties.
  • cyclic systems e.g., cycloalkyl, aryl, heteroaryl, etc.
  • Such systems comprise fused, non-fused and spiro conformations, such as bicyclooctyl, adamantyl, biphenyl and benzofuran.
  • Step a Subcloning and engineering of IMAGE clones encoding the human PTHlR into a mammalian expression vector
  • NCBI database http://www.ncbi.nlm.nih.gov
  • the NCBI database contained 4 mRNA sequences for the human PTHl receptor, having the accession numbers L04308 (Schipani et al. Endocrinology 132, 2157-2165 (1993)), U17418 (Adams et al. Biochemistry, 34, 10553-10559 (1995)), X68596 (Schneider et al. Eur. J. Pharmacol. 246, 149-155 (1993)) and NM_000316 (Hoey et al. Br J Cancer 2003, 88, 567-573). Alignment of these sequences revealed that all four sequences had 100% amino acid identity.
  • the consensus sequence was taken as the wild type (WT) sequence.
  • IMAGE clones Integrated Molecular Analysis of Genomes and their Expression
  • HGMP Human Genome Mapping Project, Cambridge, U.K.
  • Plasmid DNA was prepared using EndoFreeTM plasmid Maxi-prep columns (Qiagen). The DNA was then sequenced using primers 1-5 (see Table 1).
  • the Maxi-prep plasmid DNAs for clones 5183607 and 5186838 were amplified by PCR (polymerase chain reaction) from the start codon to the stop codon using primers 6 and 7, containing Eco Rl (Promega) and Xba I (Promega) restriction sites, respectively.
  • the PCR was performed in 2OmM Tris-HCl (pH 8.8), 1OmM KCl, 1OmM (NHO 2 SO 4 , 2mM MgCl 2 , 0.2mM dNTP containing 0.1 ⁇ M of each primer and Ing of the template DNA.
  • a hot start PCR was used: the reactions were denatured for 2min at 95 0 C, cooled to 75 0 C, then IU of Taq Polymerase (hivitrogen) was added and the reactions were cycled 30 times at 95 0 C for lmin, 55 0 C for 30sec and 72 0 C for 3min. After a final extension at 72 0 C for 5min, the samples were cooled to 4 0 C and analysed by electrophoresis.
  • PCR products from IMAGE clones 5183607 and 5186838 were purified separately using the MinEluteTM PCR purification kit.
  • 5 ⁇ g of the 1.8kb PCR product generated from IMAGE clone 5183607 (N138S mutation) was restriction-digested with Eco Rl and Kpn I in buffer E (Promega, 6mM Tris-HCl, 6mM MgCl 2 , 10OmM NaCl, pH 7.5, ImM DTT) containing O.l ⁇ g/ ⁇ l BSA at 37 0 C for Ih 40min.
  • Both PCR fragments i.e. 60ng of the 337bp fragment and 280ng of the 1.4kb fragment
  • PCR fragments were ligated together in a single ligation reaction in the presence of lOOng of Eco Rl I Xba I digested and shrimp alkaline phosphatase (Promega) treated mammalian expression vector using the QuickStickTM DNA Ligation kit (Bioline). After 15 min at room temperature, 2.5 ⁇ l of the ligation mix was transformed into lOO ⁇ l XLl -Blue competent cells (Stratagene).
  • DNA from eleven of the resulting transformed colonies was prepared using plasmid Mini prep columns (Qiagen) according to the manufacturer's instructions. Of the ten clones that were positive (as determined by restriction digestion of the miniprep DNA), DNA was prepared from one positive clone using the plasmid Maxi-prep columns. The resulting DNA was then fully sequenced by MWG-Biotech AG (Ebersberg, Germany) on both strands using primers 2 and 8-12 (see Table 1). Sequence analysis revealed 100% amino acid identity within the coding region compared to sequence L04308 (WT human PTHlR).
  • HEK293 cells from the European Collection of Cultures were cultured in Minimal Essential Media (with Earle's Salts) (hivitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (hivitrogen).
  • Cells (2.1 x 10 6 ) were seeded into 100mm x 20mm dishes (Corning) and transfected the following day using the TransfastTM reagent (Promega), using either 13, 26 or 31 ⁇ g of the plasmid DNA containing the engineered hPTHlR per dish, at a ratio of 1:1 (TransfastTM reagentDNA).
  • the cells were trypsinised (Culture of Animal Cells, a Manual of Basic Techniques; 4th ed.; Freshney, R. Wiley Press) and seeded in duplicate 35mm x 10mm dishes at low densities (10,000, 2,500 or 500 cells/dish) in media containing 800 ⁇ g/ml G-418. The remainder of the cells were kept for whole cell radioligand binding analyses.
  • the plated cells were selected for 20 days, with media changes every 3-4 days, using 10% conditioned media from untransfected HEK293 cells, until individual colonies appeared visible to the naked eye. Cloning rings were used to isolate individual, well-separated colonies and trypsinisation was used to transfer the cells in each colony to a suitable vessel for expansion.
  • the cells were expanded and analysed by RT-PCR and radioligand binding analysis.
  • Media containing 400 ⁇ g/ml G-418, was used for routine culture of the HEK293/hPTHlR cell lines.
  • Cells were trypsinised and used straight away for whole cell radioligand binding assays or frozen as a pellet on dry ice then stored at -8O 0 C for membrane-based radioligand binding assays.
  • Step c Clonal selection Stable clones, with the greatest expression of the human PTHj receptor, were selected by establishing the specific binding of [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) at a range of cell concentrations (2.5 x 10 4 - 7.5 x 10 5 cell ml "1 ) using assay conditions previously described (ORLOFF, J.G., WU, T.L., HEATH, H. W., BRADY, T.G., BRINES, M.L. & STEWART, A.F. J. Biol. Chem., (1989), 264, 6097-6103).
  • clone 9B3 was selected because it gave the highest amount of specific binding (74% and 4911cpm) at an added cell concentration of 1 x 10 5 cell niTW [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) concentration of 2OpM. hi addition, there was a linear relationship between cell concentration and specific binding.
  • Step e Incubation conditions
  • membranes were prepared as described in step d and used at a concentration of 3 x 10 4 cells ml "1 .
  • Non-specific binding was defined with PTH( J-34) (50 ⁇ l; lO ⁇ M).
  • competition 200pM
  • saturation 2pM-300nM
  • Step g Competition studies A number of reference compounds and compounds of the invention were tested for their ability to compete for human PTH 1 receptors labelled with [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34). Compounds were diluted and added to 96 well plates together with radioligand and membranes using a Beckman Biomek. The ability of compounds to inhibit specific binding was determined in at least two experiments, in triplicate and over a range of concentrations at half-log unit intervals. Compound affinity values (pICso; mid-point curve location) and mid-point slope parameter (nu) were derived through fitting competition data to the Hill equation (Graph-Pad Prism).
  • Dissociation constants were determined using the Cheng & Prusoff equation (1973) to correct for the receptor occupancy of the ligand. In practice pIC 5 o values are equivalent to pKj values due to the low occupancy of the radioligand.
  • the PK 1 values for reference compounds are shown in the table below.
  • Step a Cell culture and harvesting
  • Human SaOS2 cells obtained from the ATCC were seeded into Tl 75 cm 2 dishes and grown in McCoys 5 A medium containing 2mM glutamax and 10% foetal bovine serum (FBS) (1.7 million cells). Cells were maintained at 37 0 C in 5% C ⁇ 2 /humidified air the media being changed every 3-4days. On the 13 th day of culture the media was changed to OptiMEM medium. The following day the cell culture medium was removed and the monolayer briefly washed in 1OmL Hank's buffered salt solution (HBSS). Hanks based cell dissociation medium (1OmL) was added and left for 5min at 37 0 C and cell detachment was aided by gently tapping the culture flask.
  • HBSS Hank's buffered salt solution
  • Step b Preparation of drug solutions hHPTH(l-34), hPTHrP(l-34), [Nle 30 ]-hTIP(7-39) and hTIP(l-39) were dissolved in 20% ultra high purity (UHP) water and 80% ethanol to provide a stock concentration of ImM.
  • CFM cell freezing medium
  • Step d Opimisation of cell concentration for PTH induced accumulation of cAMP
  • hHPTH(l-34) was diluted in RPMI containing 25mM HEPES (20pM-20 ⁇ M) and aliquoted in triplicate (5 ⁇ l) into 384-well OptiPlates prior to the addition of SaOS-2 whole cells (5 ⁇ l, 3x10 5 , 6XlO 5 HiL '1 ).
  • the assay was terminated by addition of detection buffer after 120min at 21 ⁇ 3°C.
  • TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min. Following a 16h incubation the plates were counted on an EnVision (PerkinElmer) counter. A cell concentration of 6x10 5 cells mL "1 was chosen for the experiments.
  • Step e Establishing optimal assay stimulation times Basal and hPTH(l-34)-stimulated cAMP accumulation was determined by incubating whole cells at 21+3 0 C (5 ⁇ l, 6xlO 5 cells mL "1 ) for increasing time intervals with RPMI containing 25mM HEPES (5 ⁇ l) and hPTH(l-34) (5 ⁇ l, 20pM-20mM) respectively.
  • the assay was terminated by addition of detection buffer, Alexa Fluor ® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further productin of cAMP.
  • TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min.
  • cAMP formation in response to PTH-R ligands was measured in whole cells seeded in 384-well Optiplates plates using FRET-based LANCE technology (PerkinElmer). Briefly, cells, 3xlO 3 per well were incubated in stimulation buffer consisting of RPMI containing 25mM HEPES (pH7.4), bacitracin O.SmgmL "1 , IBMX 2.5mM and rolipram ImM and actiated by 120 min exposure to the PTH-R ligands.
  • stimulation buffer consisting of RPMI containing 25mM HEPES (pH7.4), bacitracin O.SmgmL "1 , IBMX 2.5mM and rolipram ImM and actiated by 120 min exposure to the PTH-R ligands.
  • Antagonist potency was determined by pre- incubating the cells with antagonist for 30min before addition to 384-well Optiplates plates containing PTH-R agonists. Finally, detection mix containing the Alexa Fluor ® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further production of cAMP.
  • Step f Assay characterisation with PTH-R ligands
  • Ligands (hPTH(l-34), hTIP(l-39), hPTHrP(l-34) and [Nle 30 ]-hTIP(7-39)) were serially diluted into RPMI containing 25mM HEPES and aliquoted (5 ⁇ l) in triplicate into Optiplates (2XlO "11 ⁇ XIO -5 M) prior to the addition of whole cells resuspended in RPMI containing 25mM HEPES, 5mM IBMX and 2mM rolipram (5 ⁇ l; 5x10 6 cells/ mL).
  • a cAMP standard curve, defined in triplicate was included in each assay.
  • PTHi receptor peptide antagonists namely hPTHrP(7-34) and [Nle 30 ]-hTIP(7-39) to inhibit hPTH(l- 34)- and hPTHrP(l-34)-stimulated cAMP production.
  • Antagonists were preincubated with cells for a standard 30min.
  • a cAMP standard curve defined in triplicate was included in each assay.All data was analysed using GraphPad Prism software to determine P[A] 5O , upper asymptote ( ⁇ ) and mid-point slope parameter (n ⁇ - equivalent to the Hill slope). The values below are estimated by logistic fitting of the mean data (triplicates) obtained from n experiments where p[A] 5 o is the midpoint location of the agonist concentration-effect curve and n H is the midpoint slope parameter of the curve.
  • Affinity estimates (pA 2 and pK ⁇ values) were mathematically derived from either single (JpA 2 ) or multiple concentrations (pK ⁇ ) of antagonist.
  • DCM dichloromethane
  • DCE 1,2-dichloroethane
  • EtOAc ethyl acetate
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • the reaction mixture was allowed to warm to ambient temperature and was washed with H 2 O
  • step f 120mg, 0.12mmol was dissolved in 4N HCl in dioxan (1OmL) and stirred at ambient temperature for Ih. The solvent was removed at reduced pressure and the residue was diluted with DCM (2OmL) and reconcentrated. Et 2 O was added and the solvent was evaporated to afford the title compound as the HCl salt (75mg, 34%).
  • HCl salt of the title compound was obtained using steps f and g of example 1 except that methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester was used in step f in place of ⁇ -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Example 4 ⁇ -Chloro- ⁇ -cyclohexyl-l- ⁇ - ⁇ -methylamino-ethylaminoJ-pyridin ⁇ -ylJ-S- (tetrahydro-pyran-4-y I)-IH-1 , 3, 4-benzot ⁇ azepin-2(3H)-one
  • Step a l-(5-Amino-pyridin-2-yl)-8-chloro-5-cycloheocyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was obtained using steps a, and steps c-e of example 1 except that 3- chloro aniline was used in step a in place of m-toluidine.
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that 1 -(5-amino-pyridin-2-yl)-8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 5 5-Cyclohexyl-8-methoxyA-(5-(2-methylamino-ethylamino)-pyridin-2-yl)-S- (tetrahydro-pyran-4-yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
  • Step a 5-Cyclohexyl-8-methoxy-l-(5-nitro--py ⁇ din-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained using steps a, c and d of example 1 except that 3- methoxy aniline was used in step a in place of m-toluidine.
  • step a The product from step a (1.39g, 2.91mmol) was dissolved in MeOH-THF (1:1 / 12mL) with 10% Pd/C (150mg) and stirred under a hydrogen atmosphere for 16h. After filtration through a pad of Celite, the solvents were removed at reduced pressure. The residue was purified by chromatography (EtOAc-hexane (1:2)) to afford the product (1.23g, 94%).
  • Step c l-(5-(2-(N-tert-Butoxycarbonyl)methylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin ⁇ 2(3H)-one was obtained using step f of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)- carbamic acid tert-butyl ester were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran
  • the HCl salt of the title compound was obtained using step g of example 1 except that l-(5-(2- (N-tert-butoxycarbonyl)memylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 1-(5-((1-N- te ⁇ butoxycarbonylammo-cyclopen1yhiiethyl)-arnmo)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step a l-(5-(2-Amino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4- yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using step f of example 1 except that tert- butyl N-(2-oxoethyl)carbamate was used in step f in place of 1-TV-ter ⁇ -butoxycarbonylamino cyclopentanecarboxaldehyde.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and tetrahydro-4H-pyran-4 ⁇ one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l ⁇ -l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one (Example 6, step a) and acetone were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 8 8-Chloro-5-cyclohexyl-l-(5-(2-dimethylamino-ethylamino)-pyridin-2-yl)-3- (tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • Example 9 S-Cyclohexyl-S-methoxy-l ⁇ S-fmethyl ⁇ -methylarnino-ethyiyaminoypyridin ⁇ -yl)- 3-(tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-(2-(N-te ⁇ butoxycarbonyl)methylammo-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one (example 5, step c) and formaldehyde were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8
  • Step a N'-Isopropyl-hydrazinecarboxylic acid tert-butyl ester was obtained using step b of example 1 except that acetone was used in place of tetrahydro-4H-pyran-4-one.
  • 1 H NMR (CDCl 3 ) 6.12 (IH, br s), 3.85 (IH, br s), 3.12 (IH, m), 1.46 (9H, s), 1.02 (6H, d).
  • Step b 5-Cycloheocyl-3'isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3Hyone was obtained using step c of example 1 except that N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester was used in place of N'-(tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester.
  • Step c l-(5-Amino-pyHdin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one was obtained using steps d and e of example 1 except that 5-cyclohexyl-3- isopropyl-8-methyl-l,2-dihydro-lH-l,3,4-benzotriazepin-2(3H)-one was used in step d in place of 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-amino-pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyllH-l,3,4-benzotriazepin-2(3H)-one and 1-methyl- piperidine-4-carbaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 12 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(2-methylamino-ethylamino)-pyndin-2- yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and methyl-(2-oxo-ethyl)-carbamic acid tert-bvtiyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH
  • Step b 6-(5-Cyclohexyl-2, 3-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-nicotinic acid methyl ester was obtained using step d of example 1 except that 6-fluoro-nicotinic acid methyl ester was used in place of 2-fluoro-5-nitro-pyridine.
  • Step d 6-(5-Cyclohexyl-l, 2-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-pyridine-3-carbaldehyde DMSO (113 ⁇ L, 1.5mniol) in DCM (5mL) was added dropwise to a solution of oxalyl chloride (108mg, 0.86mmol) in DCM (5mL) at -78°C.
  • Example 14 l-(5-((J-Amino-cyclopentylmethyl)-amino)-py ⁇ din-2-yl)-5-cyclohexyl-8-methyl- 3-isopropyl-lH-l, 3, 4-benzot ⁇ azepin-2(3H)-one
  • Step a l-fS-ffl-N-tert-Butoxycarbonylamino-cyclopentylmethylJ-aminoJ-pyridin ⁇ -yfy-S- cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) was used in
  • Step a l-(5-((l-(N-tert-Butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotTiazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) and l-(N-tert- butoxycarbonyl-N-methylamino) cyclopentanecarboxaldehyde were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran
  • the title compound was obtained using the method of example 14 step b, except that l-(5-((l- (N-tert-butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2-yl)-5-cyclohexyl- 3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l-N-tert- butoxycarbonylamino-cyclopentyknethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 3-(l,3-dioxoisoindolin-2-yl)propanal (J. Joossens et al, J. Med. Chem. 2004, 47, 2411) was used in place of 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Step b l-(5-(3- ⁇ An ⁇ inopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H' pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • the title compound was obtained by the method of example 1 step f, except that l-(5-(3- ammopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH- l,3,4-benzotriazepin-2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-
  • the title compound was obtained by the method of example 1 step f, except that l-(5-(3- aminopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)- IH- l,3,4-benzotriazepin-2(3H)-one (example 16, step b) and acetone were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and 1-iV-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Step a 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained by the method of example 1 step f, except that 1- (5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde (R. Thayumanavan, F.
  • Step b l-(5-(2-Amifioethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained by the method of example 16 step b, except that 5- cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one.
  • Step c The title compound was obtained by the method of example 1 step f, except that l-(5-(2- amdnoethylainino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one and 3-furaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3 -(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)ethylammo)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde was used in place of ⁇ -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Step b l-fS ⁇ -AminoethylaminoJpyridin ⁇ -ylJS-cyclohexyl-S-methyl-S-ftetrahydro ⁇ H-pyran-
  • Step c l-(5-(2-(4-tert-Butyloxycarbonyl-piperazin-l-yl)ethylamino)pyridin-2-yl)-5-cyclohexyl- 8-methyl ⁇ 3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzot ⁇ azepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-(2-aminoethylamino)pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-2H-pyi-an-4-yl)-lH-l ,3,4-benzotriazepin-2(3H)-one and N- (tert-butyloxycarbonyl)-4-piperidone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl
  • the title compound was obtained using the method of example 14 step b, except that l-(5-(2- (4-tert-butyloxycarbonyl-piperazin-l-yl)emylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l- N-tert-butoxycarbonylamino-cyclopentylmethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one.
  • the title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopro ⁇ yl-8-methyl-lH-l,3,4-benzotriazephi- 2(3H)-one (example 18 step b) and acetone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-7V- ter ⁇ -butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 23 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(2-(tetrahydro-2H-pyran-4- ylamino)ethylammo)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
  • Step a (2 ⁇ Amino-4-chlorophenyl)(cyclohexyl)methanone was obtained using the method of example 1 step a, except that 3-chloroaniline was used in place of r ⁇ -toluidine.
  • Step b 8-Chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step c, except that (2-amino-4- chlorophenyl)(cyclohexyl)methanone and N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)-cyclohexyl-methanone and N'- (tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester respectively.
  • Step c 8 ⁇ Chloro-5-cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step d, except that 8-chloro-5- cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl- 8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step d l-(5-Aminopyridin ⁇ 2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step e, except that 8-chloro-5- cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-nitro-pyridin-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one.
  • Step e 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-aminopyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)- one and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde were used in place of l-(5-amino-pyridin-2- yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV
  • Step f l ⁇ S ⁇ -Aminoethylaminojpyridin ⁇ -yiyS-chloroS-cyclohexylS-isopropyl-lH-l.
  • SA- benzotriazepin-2(3H)-one was obtained using the method of example 16 step b, except that 8- cMoro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one.
  • the title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin- 2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino-pyridm-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- IH-1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N- tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • HCl salt of the title compound was obtained using steps f and g of the method of example 1, except that except that l-(5-aminopyrimidin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH- l,3,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-bntyl ester were used in place of l-(5-arnino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively in step f.

Abstract

La présente invention concerne des dérivés de la benzotriazépinone, leurs intermédiaires, leurs utilisations et leurs procédés de production. En particulier, la présente invention se rapporte à la parathormone (PTH) et aux ligands de récepteurs protéiques apparentés à la parathormone (PTHrp), (ligands de récepteurs PTH-1 ou PTH/PTHrp). L'invention porte, de surcroît, sur des procédés de préparation de tels ligands et des composés utiles comme intermédiaires dans de tels procédés.
PCT/GB2006/004512 2006-05-19 2006-12-04 Dérivés de la benzotriazépinone WO2007135350A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3607866A (en) * 1968-08-15 1971-09-21 Sterling Drug Inc 3,4-dihydro-1h-1,3,4-benzotria-zepine-2,5-diones and their preparation
FR2191893A1 (en) * 1972-07-17 1974-02-08 Ferlux N'-Substd dihydro benzotriazepine diones - analgesics, antiinflammatories, anticonvulsants, hypnosedatives and tranquillisers
US5091381A (en) * 1991-04-12 1992-02-25 Biomeasure, Inc. 2H-1,3,4-benzotriazepin-2-ones
WO2002102782A2 (fr) * 2001-06-15 2002-12-27 Novartis Ag Derives de la quinazoline
WO2003041714A1 (fr) * 2001-11-13 2003-05-22 James Black Foundation Limited Benzotriazepines utilisees comme ligands de recepteurs de cholecystoquinine et de gastrine
WO2004101533A1 (fr) * 2003-05-12 2004-11-25 Janssen Pharmaceutica, N.V. Sels de 1,3,4-benzotriazepine et leur utilisation comme ligands du recepteur de cck

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3607866A (en) * 1968-08-15 1971-09-21 Sterling Drug Inc 3,4-dihydro-1h-1,3,4-benzotria-zepine-2,5-diones and their preparation
FR2191893A1 (en) * 1972-07-17 1974-02-08 Ferlux N'-Substd dihydro benzotriazepine diones - analgesics, antiinflammatories, anticonvulsants, hypnosedatives and tranquillisers
US5091381A (en) * 1991-04-12 1992-02-25 Biomeasure, Inc. 2H-1,3,4-benzotriazepin-2-ones
WO2002102782A2 (fr) * 2001-06-15 2002-12-27 Novartis Ag Derives de la quinazoline
WO2003041714A1 (fr) * 2001-11-13 2003-05-22 James Black Foundation Limited Benzotriazepines utilisees comme ligands de recepteurs de cholecystoquinine et de gastrine
WO2004101533A1 (fr) * 2003-05-12 2004-11-25 Janssen Pharmaceutica, N.V. Sels de 1,3,4-benzotriazepine et leur utilisation comme ligands du recepteur de cck

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