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WO1992016507A1 - Composes heterocycliques, leur preparation et utilisation pharmaceutique - Google Patents

Composes heterocycliques, leur preparation et utilisation pharmaceutique Download PDF

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Publication number
WO1992016507A1
WO1992016507A1 PCT/GB1992/000509 GB9200509W WO9216507A1 WO 1992016507 A1 WO1992016507 A1 WO 1992016507A1 GB 9200509 W GB9200509 W GB 9200509W WO 9216507 A1 WO9216507 A1 WO 9216507A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
compounds according
alkyl
methyl
Prior art date
Application number
PCT/GB1992/000509
Other languages
English (en)
Inventor
Susan Elaine Barrie
Michael Jarman
Raymond Mccague
Gerard Andrew Potter
Martin George Rowlands
Original Assignee
British Technology Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB919106031A external-priority patent/GB9106031D0/en
Priority claimed from GB919125308A external-priority patent/GB9125308D0/en
Application filed by British Technology Group Limited filed Critical British Technology Group Limited
Priority to EP92907133A priority Critical patent/EP0594629A1/fr
Publication of WO1992016507A1 publication Critical patent/WO1992016507A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Definitions

  • This invention relates to derivatives containing the 3-pyridylacetyl function, namely esters and amides of 3-pyridylacetic add as well as 3-pyridylmethyl ketones, together with certain derivatives thereof, their preparation and use in treating prostatlc cancer.
  • R a represents a specified alicyclic group (e.g. cyclohexyl or a terpene residue) or
  • R b represents a hydrogen atom or a methyl group
  • R b represents a hydrogen atom or a methyl group
  • inhibit the 17 ⁇ -hydroxylase/C 17-20 lyase enzyme complex which is essential for biosynthesis of androgens.
  • the inhibition of androgen biosynthesis by virtue of the hydroxylase/lyase inhibition indicates that the compounds of McCague et al., supra, could be useful for the treatment of prostate cancer since many such tumours depend on androgens for growth.
  • the compounds of McCague et al. are also inhibitors of aromatase.
  • Aromatase is an enzyme required in the biosynthesis of estrogens. The ability to inhibit aromatase is considered a desirable property in compounds which are to be used to treat breast cancer.
  • a compound should be a strong inhibitor of both aromatase and hydroylase/lyase since the inhibition of aromatase would prevent the removal, by further conversion into oestrogens, of any products of the hydroxylase/lyase enzyme complex which escaped the blockade of hydroxylase/lyase.
  • a patient could lose some of the benefits of hydroxylase/lyase inhibition.
  • the paper envisages similar dimethyl substitution of compound of formula (1) wherein R a is an alicyclic group of the terpene residue type, notwithstanding that in such compounds the IC 50 lyase/aromatase ratio in unmethylated compounds is bigger than for the cyclohexyl compounds (1).
  • 3-pyridylacetyl compounds of formula (3) below have useful hydroxylase/lyase inhibitory activity with low IC 50 lyase/aromatase ratios, and are therefore of potential value in treating androgen-induced cancers such as prostatic cancer.
  • These compounds have the general formula:
  • each of R 1 and R 2 independently represents hydrogen or lower alkyl or together represent the residue of a cycloalkyl group of 3 to 6 carbon atoms;
  • A represents 0, NR 4 where R 4 is defined as for R 1 and R 2 , or CR 5 R 6 where R 5 and R 6 are defined as for R 1 or R 2 as separate substituents;
  • R 3 represents a bridged all cyclic group
  • the invention includes each of the optical Isomers and mixtures thereof, especially racemic mixtures.
  • R 3 group in the preferred compounds of the invention can be defined in various ways, all reflecting the fact that R 3 is hydrocarbyl, cyclic and non-aromatic and has at least one bridge across a ring. Because R 3 is defined as bridged, it contains at least two alicyclic rings. It can contain more than two alicyclic rings, either by having more than one bridge or by having one or more other fused rings (not resulting from a bridge). In this invention, a bridge is regarded as joining two non-adjacent carbon atoms of the ring by means of at least one intermediate carbon atom. A fused ring is produced when two non-adjacent carbon atoms are joined directly by a bond.
  • R 3 group as a substituted cyclohexyl group in which the substituents comprise bridging members.
  • substituents comprise bridging members. Examples of preferred R 3 groups fitting this definition are shown below, along with the adjacent oxygen atom:- isopinocampheyl (cyclohexyl substituted by a 3,5-1 sopropylidene bridge and additionally having a 2-methyl substituent)
  • adamantyl (cyclohexyl substituted by a first 1,3-(1,3-propylene), bridge and further substituted by a second bridge between its 5-carbon atom and the middle carbon atom of the first bridge)
  • methyladamantyl (cyclohexyl substituted by a first 2,4-(1,3- propylene) bridge, further substituted by a second bridge between its 6-carbon atom and the middle carbon of the first bridge, and additionally having a 1-methyl substituent on the cyclohexane ring)
  • cedryl cyclohexyl substituted by a 2,4-isobutylene bridge, having a methyl-substituted cyclopentane ring fused to the 4 carbon atom of the cyclohexane ring and the 1-carbon atom of the bridge and additionally having a 1-methyl substituent on the cyclohexane ring).
  • R 3 groups can be defined by reference to the largest carbocyclic ring which is bridged, which in cedryl is a cycloheptane ring and in adamantyl is a cyclooctane ring.
  • R 3 represents a bridged alicyclic group having from 6 to 8 ring atoms (excluding any bridge atoms) and optionally having one or more alicyclic groups fused to the bridged ring, e.g. a substituted cyclopentane or cyclohexane ring.
  • the bridges are normally of 1 or 2 carbon atoms in linear length (counting only those carbon atoms lying within the bridge, between the ring atoms, not counting as within the bridge the ring atoms with which the bridge starts or finishes and not counting as within the linear length any carbon atoms pendant from a bridge atom, e.g. in the two methyls of an isopropyl1dene bridging group).
  • the all cyclic groups of R 3 which are bridged are cycloalkane rings, which can contain unsaturation, but are not aromatic, and can be substituted by one or more simple hydrocarbyl substituents such as alkyl of 1-4 carbon atoms, especially methyl.
  • the bridges need not be wholly linear and thus may have pendant C 1-4 alkyl, especially methyl groups, for example.
  • the said cycloalkane rings or bridges or both can have cycloalkane, especially cyclopentane or cyclohexane, rings fused thereto.
  • the fused rings may themselves be simply substituted, as mentioned above for the bridged rings, especially by alkyl of 1 to 4 carbon atoms.
  • the invention includes optically active forms of the compounds of formula (3), particularly with reference to borneyl, isoborneyl, cedryl and isopinocampheyl.
  • the A group in formula (3) is preferably -O-, but when It Is -CH 2 - potentially hydrolysable ester and amide bonds are not present, which is also advantageous.
  • R 1 and R 2 are preferably both methyl except when R 3 is an extremely bulky group, such as cedryl, in which substituents pendant from a bridge extend into the vicinity of the ester oxygen atom. In such an event preferably no more than one of R 1 and R 2 is a lower alkyl group and most preferably they are both hydrogen. Alternatively R 1 and R 2 together with the carbon atom to which they are attached can complete a ring of 3, 4, 5 or 6 carbon atoms, cyclopentane being preferred.
  • R 4 is preferably hydrogen, but can have any of the other meanings for the individual R 1 and R 2 substituents, of which lower alkyl, especially methyl, is preferred.
  • R 5 and R 6 are preferably hydrogen, one is methyl and the other hydrogen or both are methyl. R 5 and R 6 do not together represent a cycloalkyl or alkylene group.
  • the compounds of the invention can be prepared in various ways, conveniently starting from 3-pyrldylacetic add or an ester thereof.
  • the starting ester Is the methyl or ethyl ester.
  • the reactive substituent X is any reactive for the purpose of forming an ester or amide of formula (3).
  • the compounds of formula (4) can be reacted with primary amines in the usual way.
  • a suitable procedure would involve the reaction between an alkali metal salt of 3-picoline, e.g. 3-picolyllithium (C. G. Screttas, T. F. Estham, C. W. Kamienskl, Chimia, 24, 109-111 , 1970) and an appropriate methyl ester R 3 ACO 2 Me where A is another CR 5 R 6 group, according to the method used by 3. L. Bond, D. L. Krottlnger, R. M. Schumacher, E. H. Sund and T. 3. Weaver, Journal of Chemical and Engineering Data, 18, 349-350, (1973) to make alkyl 4-pyridylmethylketones from 4-picolyl sodium and RCO 2 Me.
  • 3-picolyllithium C. G. Screttas, T. F. Estham, C. W. Kamienskl, Chimia, 24, 109-111 , 1970
  • R 3 ACO 2 Me where A is another CR 5 R 6 group
  • the compounds of formula (3) being prepared are those in which R 1 or R 2 is other than hydrogen, it may be convenient to use as the starting compound of formula (4) an unsubstituted pyridyl acetic add compound wherein R 1 and R 2 are hydrogen, prepare the corresponding compound of formula (3) and subsequently introduce the desired R 1 or R 2 substituent by the action of an alkali metal hydride followed by a lower alkyl or cycloalkyl bromide or Iodide.
  • the compounds may be prepared as salts, e.g. the hydrochloride and converted to the free base form and thereafter to such other conventional pharmaceutically acceptable salts as acetates, citrates and lactates, as may seem appropriate.
  • the present invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of the invention, in association with a therapeutically acceptable carrier or diluent.
  • the composition of the invention can, for example, be in a form suitable for parenteral (e.g. intravenous, intramuscular or intracavital), oral, topical or rectal administration.
  • Particular forms of the composition may be, for example, solutions, suspensions, emulsions, creams, tablets, capsules, Upsomes or micro-reservoirs, especially compositions in orally ingest1ble or sterile injectable form.
  • the preferred form of composition contemplated is the dry solid form, which includes capsules, granules, tablets, pills, boluses and powders.
  • the solid carrier may comprise one or more excipients, e.g. lactose, fillers, disintegrating agents, binders, e.g. cellulose, carboxymethyl cellulose or starch or anti-stick agents, e.g. magnesium stearate, to prevent tablets from adhering to tabletting equipment. Tablets, pills and boluses may be formed so as to disintegrate rapidly or to provide slow release of the active ingredient.
  • excipients e.g. lactose
  • binders e.g. cellulose, carboxymethyl cellulose or starch or anti-stick agents, e.g. magnesium stearate
  • Tablets, pills and boluses may be formed so as to disintegrate rapidly or to provide slow release of the active ingredient.
  • the present invention also includes a method of treating androgen-dependent tumours in the mammalian body, which comprises administering a compound of the invention to a mammalian patient in a therapeutically effective dose, e.g.
  • the invention includes the compounds of the invention for use in said treatment and their use in the manufacture of medicaments for that purpose.
  • the assay was carried out as described by S. E. Barrle et al., J. Steroid Blochem. 6, 1191-5, (1989) except that recently the radioactivity in the peaks of interest has been monitored on-line by mixing the HPLC effluent with Ecosdnt A (National Diagnostics) scintillation fluid, 1:1, and passing the mixture through a Bertold LB506C radiochemical monitor.
  • Ecosdnt A National Diagnostics
  • testes were obtained from previously untreated patients undergoing orchldectomy for prostatic cancer. The testes were decapsulated and stored in liquid nitrogen until use.
  • a microsomal preparation was prepared essentially as described by S. E. Barrle et al., supra. The material was then thawed, finely chopped, and homogenised in 0.25M sucrose (5ml/gm wet weight) using a Potter homogeniser. The homogenate was centrifuged at 12000g for 30 min, and then the microsomes were pelleted by spinning the supernatant at 100,000g for 1hr. The pellet was washed by being resuspended in 0.25M sucrose and repel leted. The microsomal pellet was then resuspended in 50mM sodium phosphate pH 7.4/glycerol (3/1 v/v) and stored in aliquots in liquid nitrogen.
  • the enzyme activities were measured separately.
  • the basic assay mixture was similar to that used for the rat enzyme except that the EDTA concentration was 0.2mM, and the substrate, 3 H-progesterone, concentration was 3 ⁇ M.
  • the human enzyme was more sensitive to ethanol than the rat one, and so the compound under test were dissolved in 50% DMSO and the final concentrations of ethanol and DMSO were 1% each.
  • reaction was carried out for 15min. For all other compounds, the reaction time was extended to 1 hour. It was terminated by the addition of 2 vols. of methanol/ acetonitrile (2/1 v/v) containing approx.
  • Example 2 For the compound of Example 2 and Its 4-pyrldyl analogue, the separation of the steroids by HPLC was by the same method as described for the rat assay in S.E. Barrle et al., supra. For all other compounds, the separation was carried out on a 10cm. "Nucleosil” 5 ⁇ C18 column with a “Nucleosil” pre-column. Elutlon was with 60% methanol at 1ml /min. The effluent was mixed on-line 1:1 with Ecoscint A containing 25% acetonitrile and then passed through a Berthold LB506C radlochemical detector. In all cases, the hydroxylase activity was measured as the production of 17 ⁇ -hydroxyprogesterone, androstenedione and testosterone.
  • the HPLC separation used for the lyase involved a 10cm 5 ⁇ Apex C18 column with a 5cm PELL ODS C18 precolumn.
  • the eluant was 38:12:50 methanol:acetonitrile:water flowing at 1ml /min.
  • the effluent was mixed 1:1 with Ecosdnt A containing 10% methanol and the radioactivity was measured directly by a Berthold LB506C radlochemical detector.
  • the lyase activity was measured as the production of androstenedione and testosterone. Calculation of IC 50 .
  • the enzyme activity was measured in the presence of at least 4 concentrations of each compound, and the data were fitted by linear regression to the Dixon equation (Dixon, M., Webb, E. C. Enzymes, 2nd ed., Academic Press, New York, 1964).
  • the IC 50 0nd its 95% confidence limits were calculated from the slope and Its 95% confidence limits. Where the full determination of the IC 50 has not been carried out the values given are approximate and no confidence limits are shown.
  • Aromatase activity was determined by the method of A. B. Foster et al., J. Med. Chem. 22, 50-54 (1983), using human placenta! mlcrosomes.
  • the Michael is constant K m for [1 ⁇ - 3 H] androstenedione was 0.039 ⁇ M.
  • K i values were obtained from Dixon plots of reciprocal velocity of reaction versus concentration of inhibitor at two concentrations of the androstenedione substrate. K i values are given in parenthesis after IC 50 values. The comparative results are shown in Table 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

On décrit des composés de formule générale (3), dans laquelle R1 et R2 représentent indépendamment hydrogène ou C1-4 alkyle ou ensemble représentent le reste d'un groupe cycloalkyle de 3 à 6 atomes de carbone; A représente O, NR4 où R4 a la même définition que R1 ou R2 ou CR5R6, où R5 et R6 ont la même définition que R1 ou R2 en tant que substituants séparés; et R3 représente un groupe alicyclic ponté; comme bases libres ou leurs sels pharmaceutiquement acceptables. Lesdits composés sont utiles pour traiter les cancers liés à l'androgène et surtout celui du prostate.
PCT/GB1992/000509 1991-03-22 1992-03-20 Composes heterocycliques, leur preparation et utilisation pharmaceutique WO1992016507A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP92907133A EP0594629A1 (fr) 1991-03-22 1992-03-20 Composes heterocycliques, leur preparation et utilisation pharmaceutique

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9106031.9 1991-03-22
GB919106031A GB9106031D0 (en) 1991-03-22 1991-03-22 Heterocyclic compounds,their preparation and pharmaceutical use
GB9125308.8 1991-11-28
GB919125308A GB9125308D0 (en) 1991-11-28 1991-11-28 Heterocyclic compounds,their preparation and pharmaceutical use

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WO1992016507A1 true WO1992016507A1 (fr) 1992-10-01

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EP (1) EP0594629A1 (fr)
AU (1) AU1417592A (fr)
GB (1) GB2253851B (fr)
IE (1) IE920900A1 (fr)
NZ (1) NZ242054A (fr)
PT (1) PT100275A (fr)
WO (1) WO1992016507A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041037A1 (fr) * 2004-10-08 2006-04-20 Nippon Kayaku Kabushiki Kaisha Nouveau dérivé de pyridine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU668692B2 (en) * 1991-08-22 1996-05-16 Chiroscience Limited Chiral glutarate esters, their resolution and derived glutarimide compounds
ATE448204T1 (de) * 2000-05-31 2009-11-15 Santen Pharmaceutical Co Ltd 1-ä(adamantyl)alkylü-3- ä(pyridinyl)alkylüharnstoff-verbindungen als tnf- .alpha hemmer zur behandlung von autoimmunerkrankungen

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169062A1 (fr) * 1984-07-19 1986-01-22 National Research Development Corporation Dérivés de l'imide de l'acide glutarique, leur préparation et préparations pharmaceutiques les contenant
EP0194901A2 (fr) * 1985-03-15 1986-09-17 Shionogi & Co., Ltd. Dérivés d'isoprénoidamine, compositions contenant ceux-ci, leur préparation et utilisation
EP0253681A2 (fr) * 1986-07-18 1988-01-20 FARMITALIA CARLO ERBA S.r.l. Dérivés cycloalkyles des pyridines 4-substituées et procédé pour leur synthèse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169062A1 (fr) * 1984-07-19 1986-01-22 National Research Development Corporation Dérivés de l'imide de l'acide glutarique, leur préparation et préparations pharmaceutiques les contenant
EP0194901A2 (fr) * 1985-03-15 1986-09-17 Shionogi & Co., Ltd. Dérivés d'isoprénoidamine, compositions contenant ceux-ci, leur préparation et utilisation
EP0253681A2 (fr) * 1986-07-18 1988-01-20 FARMITALIA CARLO ERBA S.r.l. Dérivés cycloalkyles des pyridines 4-substituées et procédé pour leur synthèse

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
J. STEROID BIOCHEMISTRY vol. 25, no. 5B, 1988, pages 867 - 876; HENDERSON D. ET AL.: 'Aromatase Inhibitors and benign prostatic hyperplasia.' *
J. STEROID BIOCHEMISTRY vol. 31, no. 4B, 1988, pages 677 - 683; ZOPPI S. ET. AL.: 'Antihormonal activities of 5-alpha-reductase and aromatase inhibitors' *
J. STEROID BIOCHEMISTRY vol. 37, no. 6, 20 December 1990, pages 1043 - 1048; BRODIE A. M. ET. AL.: 'Aromatase and other inhibitors in breast and prostatic cancer.' *
JOURNAL OF MEDICINAL CHEMISTRY. vol. 33, no. 11, 1990, WASHINGTON US pages 3050 - 3055; R. MCCAGUE ET. AL.: 'INHIBITION OF ENZYMES OF ESTROGEN AND ANDROGEN BIOSYNTHESIS BY ESTERS OF 4-PYRIDYLACETIC ACID' *
STEROIDS vol. 50, no. 1-3, 1988, pages 219 - 233; HENDERSON D. ET. AL.: 'Estrogens and Benign Prostatic Hyperplasma' *
STEROIDS vol. 50, no. 4-6, 1988, pages 449 - 457; KARR J. P. ET. AL.: 'The potential significance of aromatase in the etiology and treatment of prostatic disease.' *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041037A1 (fr) * 2004-10-08 2006-04-20 Nippon Kayaku Kabushiki Kaisha Nouveau dérivé de pyridine

Also Published As

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GB2253851A (en) 1992-09-23
PT100275A (pt) 1993-06-30
AU1417592A (en) 1992-10-21
GB2253851B (en) 1993-10-06
GB9206062D0 (en) 1992-05-06
IE920900A1 (en) 1992-09-23
EP0594629A1 (fr) 1994-05-04
NZ242054A (en) 1993-11-25

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