Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to therapeutically active hydroxamic and carboxylic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine.
• the compounds are inhibitors of matrix metalloproteinases involved in tissue degradation, especially collagenases such as human fibroblast collagenase (MMP- 1 ), human neutrophil collagenase (MMP-8) and collagenase-3 (MMP-13).
• MMPs matrix metalloproteinases
• rheumatoid arthritis osteoarthritis
• osteopenias such as osteoporosis
• periodontitis gingivitis
• corneal epidermal or gastric ulceration corneal epidermal or gastric ulceration
• tumour metastasis invasion and growth.
• MMP inhibitors are also of potential value in the treatment of neuroinfiammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascuiar glaucoma, ocular tumours, angiofibromas and hemangiomas.
• angiogenesis dependent diseases which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascuiar glaucoma, ocular tumours, angiofibromas and hemangiomas.
• angiogenesis dependent diseases which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascuiar glaucoma, ocular tumours, angiofibromas and hemangiomas
• Metalloproteinases are characterised by the presence in the structure of a zinc(ll) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes human fibroblast collagenase (MMP-1 ), human neutrophil collagenase (MMP-8) and collagenase-3 (MMP-13), 72 kDa-gelatinase, 92 kDa-geiatinase, - stromelysin-1 , stromelysin-2 and PUMP-1 (J.F. Woessner, FASEB J, 1991 , 5, 2145- 2154).
• MMP-1 human neutrophil collagenase
• MMP-13 collagenase-3
• 72 kDa-gelatinase 72 kDa-gelatinase
• 92 kDa-geiatinase 92 kDa-geiatinase
• stromelysin-1 stromelysin-2
• the present compounds conform to general formula (IA), but differ in structure from prior art compounds of that general formula principally in the identity of the group X.
• the group X is a sulfonamidoalkyl group, not contemplated by any of EP-A-0574758, EP-A-0684240, or WO 95/33731.
• V is HO- or HONH-
• n 1 , 2, 3 or 4;
• R is a C ⁇ C ⁇ alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, perfluoroalkyl, phenyl(C r C 6 alkyl)-, heteroaryl ⁇ -Ce alkyl)-, non-aryl heterocyclyl(C r C 6 alkyl)-, cycloalkyl(C C 6 alkyl)-, cycioalkenyl(C r C 6 alkyl)-, phenoxy(C C 6 alkyl)-, heteroaryloxy(C C 6 alkyl)-, phenyl(C r C ⁇ alkyl)O(C r C 6 alkyl)-, heteroaryl(C r C 6 alkyl)O(C r C 6 alkyl)-, phenyl(C r C 6 alkyl)S(C C ⁇ alkyl)- or heteroaryl(C C 6 alkyl)S(C r C
• R 2 is a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, (i) optionally contains as a ring member O, S, SO, SO 2 , or NR 5 wherein R 5 is hydrogen, hydroxy, C r C 6 alkyl, (C r C 6 alkoxy)C r C 6 alkyl, benzyl, acyl, an amino protecting group, or a group -SO 2 R 6 wherein R 6 is C r C 6 alkyl or a substituted or unsubstituted phenyl or heteroaryl group, and/or (ii) is optionally substituted on one or more C atoms by hydroxy, C r C 6 alkyl, C C 6 alkoxy, cyano, oxo, ketalised oxo, amino, mono(C r C 6 alkyl)amino, di(C 1 -C 6 alky
• R 3 is hydrogen, C ⁇ Cg alkyl, benzyl, acyl, an amino protecting group, or a group -(CH 2 ) m COZ where m is an integer from 1 to 6, and Z represents OH, C r C 6 alkoxy or -NR x R y where R x , R y each independently represent hydrogen or C r C 6 alkyl; and
• R 4 is optionally substituted C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ Cg perfluoroalkyl, cycloalkyl, cycloalkyl(C r C 6 alkyl)-, cycloalkenyl, cycloalkenyl ⁇ -Cg alkyl)-, di-(C r C 6 alkyl)amino, 5 phenyl, phenyl(C r C ⁇ alkyl)-, biphenyl, phenyl-heteroaryl, naphthyl, non-aryl heterocyclyl, non-aryl heterocyclyl(C r C 6 alkyl)-, heteroaryl or heteroaryl(C r C 6 alkyl)-; heteroaryl-phenyl; heteroaryl-heteroaryl; aryloxyaryl or
• R 3 and R 4 taken together represent a divalent C 3 -C 6 alkylene or alkenylene group which may optionally be (i) substituted by an oxo group, and/or (ii) substituted by (C r C 6 )alkoxy, hydroxy, mercapto, (C r C 6 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro, - COOH, -CONH 2 , -CONHR A or -CONR A R B wherein R A and R B are independently a (C r C 6 )alkyl group, and/or (iii) fused to a phenyl or heteroaryl group which itself may be substituted;
• the present compounds are useful in human or veterinary medicine since they are active as inhibitors of MMPs.
• Enzyme inhibition assays useful for determining the activity of a particular compound of the invention against MMPs are known, see for example the assays described in Biological Example A below, and the MMP inhibition assays described in patent publications listed above- in the section "Background to the Invention”. 9
• this invention concerns:
• a method of management by which is meant treatment or prophylaxis of diseases or conditions mediated by MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound which is a member of the group defined above, or a pharmaceutically acceptable salt thereof;
• Diseases or conditions mediated by MMPs include those involving tissue breakdown such as bone resorption, inflammatory diseases, dermatological conditions and tumour invasion by secondary metastases, in particular rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion by secondary metastases as well as neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis.
• a pharmaceutical or veterinary composition comprising a compound which is a member of the group defined above together with a pharmaceutically or veterinarily acceptable excipient or carrier.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, . the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular 10 disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.
• the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
• the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• non-aqueous vehicles which may include edible oils
• almond oil fractionated coconut oil
• oily esters such as glycerine, propylene
• the drug may be made up into a cream, lotion or ointment.
• Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia. 11
• the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
• Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
• the active ingredient may also be administered parenterally in a sterile medium.
• the drug can either be suspended or dissolved in the vehicle.
• adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• Preparative Examples A, B and C describe the synthetic procedures used for the preparation of the compounds of the invention.
• the products of Preparative Examples A, B and C are disclosed in PCT/GB97/02891.
• Examples 1- 29 relate to compounds of the present invention.
• Reagents and conditions (A) Bzl-Br, K 2 C0 3 in acetone; (B) 9-BBN, H 2 0 2 in THF; (C) MsCI, Et 3 N in THF, 0°C; (D) NaN 3 , n Bu 4 l, in toluene/water, reflux; (E) H 2 ,10% Pd/C in ethanol; (F) Z-ONSu, Et 3 N, THF; (G) piperidine EDC, HOBt, THF; (H) H 2 , 10% Pd/C in ethanol; (I) 4-Me0(C 6 H 4 )S0 2 CI, Et 3 N in THF; (J) TFA in CH 2 CI 2 .4°C; (K) HOBt, EDC in D F, then H 2 NOH.HCI, N M. 14
• Step A 2S-Allyl-3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl ester
• Step B 2S-(3-Hydroxypropyl)-3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl ester
• Step C 3R-lsobutyl-2S-(3-methanesulfonyloxy-propyl)-succinic acid 4-benzyl ester 1 -tert-butyl ester
• Step D 2S-(3-Azido-propyl)-3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl ester
• the reaction mixture was diluted with ethyl acetate (100 ml) and the organic layer was separated, washed with water (3 x 80 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.
• the product thus obtained (5.5 g, 95%) was used without further purification.
• Step E 2S-(3-Amino-propyl)-3R-isobutyl-succinic acid 1-tert-butyl ester 16
• Step F 2S-(3-Benzyloxycarbonylamino-propyl)-3R-isobutyl-succinic acid 1-tert-butyl ester
• Step G 2S-(3-Benzyloxycarbonylamino-propyl)-5-methyl-3R-(piperidine-1 -carbonyl)- 17 hexanoic acid tert-butyl ester
• Step H 2S-(3-Amino-propyl)-5-methyl-3R-(piperidine-1-carbonyl)-hexanoic acid tert- butyl ester
• Step I 2S-[3-(4-Methoxybenzenesulfonyl-amino)-propyl]-5-methyl-3R-(piperidine-1 - carbonyl)-hexanoic acid tert-butyl ester
• Step J 2S-[3-(4-Methoxybenzenesulfonyl-amino)-propyl]-5-methyl-3R-(piperidine-1- carbonyl)-hexanoic acid 18
• Step K 2S-[3-(4-Methoxybenzenesulfonyl-amino)-propyl]-5-methyl-3R-(piperidine-1 - carbonyl)-hexanoic acid hydroxyamide
• Reagents and conditions (A) H 2 , 10% Pd/C in EtOAc; (B) piperidine aq. HCHO in ethanol; (C) Bzl-Br, K 2 C0 3 in acetone; (D) TFA, CH 2 CI 2 , 4°C; (E) piperidine, EDC, HOBt in EtOAc; (F) MeNH 2 in methanol; (G) H 2 , 10% Pd/C in ethanol, (H) 4-Me0(C 6 H 4 )S0 2 CI, Et 3 N in THF, (I) HOBt, EDC in DMF, then H 2 NOH.HCI, N M 20
• Step A 2-Carboxy-3R-isobutyl-succinic acid 4-tert-butyl ester
• Step B 3R-lsobutyl-2-methylene-succinic acid 4-tert-butyl ester
• Step C 3R-lsobutyl-2-methylene-succinic acid 1 -benzyl ester 4-tert-butyl ester
• Step D 3R-lsobutyl-2-methylene-succinic acid 1 -benzyl ester
• Step E 2-[3-Methyl-1 R-(piperidine-1-carbonyl)-butyl]-acrylic acid benzyl ester
• Step F 5-Methyl-2S-methylaminomethyl-3R-(piperidine-1-carbonyl)-hexanoic acid benzyl ester
• Step G 5-Methyl-2S-methylaminomethyl-3R-(piperidine-1-carbonyl)-hexanoic acid
• the title compound was prepared by hydrogenolysis of the benzyl ester (550 mg, 1.52 mmol) by the method described earlier (Preparative Example A, Step E). The product was isolated as a white amorphous solid (410 mg, 99%).
• Step H 2S- ⁇ [(4-Methoxybenzenesulfonyl)-methyl-amino]-methyl ⁇ -5-methyl-3R- (piperidine-1 -carbonyl)-hexanoic acid
• Step I 2S- ⁇ [(4-Methoxybenzenesulfonyl)-methyl-amino]-methyl ⁇ -5-methyl-3R- (piperidine-l-carbonyl)-hexanoic acid hydroxyamide
• StepC StepD StepE
• Step A 3-lsobutyl-2-methylaminomethyl-succinic acid 1 -benzyl ester 4-tert-butyl ester
• Step B 3R-lsobutyl-2-[(Methanesulfonyl)-methyl-amino)-methyl]-succinic acid 1- benzyl ester 4-tert-butyl ester
• Step C 3R-lsobutyl-2-[(Methanesulfonyl)-methyl-amino)-methyl]-succinic acid 1- benzyl ester
• Step D 2S-[(Methanesulfonyl)-methyl-amino)-methyl]-5-methyl-3R-(piperidine-1 - carbonyl)-hexanoic acid benzyl ester
• Step E 2S-[(Methanesulfonyl)-methyl-amino)-methyl]-5-methyl-3R-(piperidine-1 - carbonyl)-hexanoic acid
• Step F 2S-[(Methanesulfonyl)-methyl-amino)-methyl]-5-methyl-3R-(piperidine-1 - carbonyl)-hexanoic acid hydroxyamide
• the potency of compounds of the present invention as inhibitors of human fibroblast collagenase may be determined by the procedure of Cawston and Barrett, (Anal. Biochem.. 99, 340-345, 1979), hereby incorporated by reference, whereby a 1 mM solution of the compound being tested, or a dilution thereof, was incubated at 37°C for 16 hours with collagen and human fibroblast collagenase (buffered with 25mM Hepes, pH 7.5 containing 5mM CaCI 2 , 0.05% Brij 35 and 0.02% NaN 3 ).
• the collagen was acetylated 14 C collagen prepared by the method of Cawston and Murphy, (Methods in Enzymology, 80, 711 , 1981 ), hereby incorporated by reference.
• the samples were centrifuged to sediment undigested collagen, and an aliquot of the radioactive supernatant removed for assay on a scintillation counter as a measure of hydrolysis.
• the collagenase activity in the presence of 1mM of the test compound, or a dilution thereof, was compared to activity in a control devoid of inhibitor and the result reported below as that of inhibitor concentration effecting 50% inhibition of the collagenase activity (IC 50 ).
• Compounds of the invention tested in this assay were shown to be active as inhibitors of human fibroblast collagenase.

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• 1998
  • 1998-03-25 AU AU68435/98A patent/AU6843598A/en not_active Abandoned
  • 1998-03-25 WO PCT/GB1998/000914 patent/WO1999048881A1/en not_active Application Discontinuation
  • 1998-03-25 EP EP98913910A patent/EP1066273A1/en not_active Withdrawn
  • 1998-03-25 JP JP2000537864A patent/JP2003522723A/ja active Pending

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