PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 95/19978
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6 :
`C07D 471/14, A61K 311395, C07D
`471/04, 209/14 II (C07D 471/14, 241:00,
`221:00, 209:00)
`
`A1
`
`( 43) International Publication Date:
`
`27 July 1995 (27.07.95)
`
`(21) International Application Number:
`
`PCT/EP95/00183
`
`i '
`
`(22) International Filing Date:
`
`19 January 1995 (19.01.95)
`
`(30) Priority Data:
`9401090.7
`
`21 January 1994 (21.01.94)
`
`GB
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, PI, GB, GE, HU, JP, KE, KG,
`KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW,
`MX, NL, NO, NZ, PL, PT, RO, RU, SD, SE, Sl, SK, TJ,
`TT, UA, US, UZ, VN, European patent (AT, BE, CH, DE,
`DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, CF, CG, Cl, CM, GA, GN, ML, MR, NE,
`SN, TD, TG), ARIPO patent (KE, MW, SD, SZ).
`
`(71) Applicant (for all designated States except US): LABORA-
`TOIRES GLAXO S.A. [FR/FR]; 42, rue Vineuse, F-75016 Published
`With international search report.
`Paris (FR).
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): DAUGAN, Alain, Claude(cid:173)
`Marie [FR/FR]; Laboratoires Glaxo S.A., Centre de
`Recherches, Z.A. de Courtabreuf, 25, avenue de Quebec,
`F-91940 Les Ulis (FR).
`
`(74) Agents: GALLAFENT, Alison et al.; Glaxo plc, Glaxo House,
`Berkeley Avenue, Greenford, Middlesex UB6 ONN (GB).
`
`(54) Title: TETRA CYCLIC DERIVATIVES, PROCESS OF PREPARATION AND USE
`
`Ro
`
`(/ I
`~.... ........
`
`0
`
`•
`
`N-R1
`
`3
`NY-R
`0
`
`•
`R2
`
`I
`
`~
`
`(I)
`
`(57) Abstract
`
`~
`
`(a)
`
`A compound of formula (I) and salts and solvates thereof, in which: Ro represents hydrogen, halogen or Ci-6 alkyl; Ri represents
`hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, haloCJ-6alkyl, C3-scycloalkyl, C3-scycloalkylCJ-3alkyl, arylCJ-3alkyl or heteroarylC1-3alkyl;
`R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally
`substituted bicyclic ring (a) attached to "the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring (A)
`is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or
`two heteroatoms selected from oxygen, sulphur and nitrogen; and R3 represents hydrogen or Ci-3 alkyl, or Ri and R3 together represent
`a 3- or 4-membered alkyl or alkenyl chain. A compound of formula (I) is a potent and selective inhibitor of cyclic guanosine 3',5'(cid:173)
`monophosphate specific phosphodiesterase (cGMP specific PDE) having a utility in a variety of therapeutic areas where such inhibition is
`beneficial, including the treatment of cardiovascular disorders.
`
`INTELGENX 1015
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`Ll
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`Sl
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`VietNam
`
`INTELGENX 1015
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`TETRACYCLIC DERIVATIVES, PROCESS OF PREPARATION AND USE
`
`This invention relates to a series of tetracyclic derivatives, to processes for
`their preparation, pharmaceutical compositions containing them, and their use
`as therapeutic agents.
`In particular, the invention relates to tetracyclic
`derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'(cid:173)
`monophosphate specific phosphodiesterase (cGMP specific POE) having utility
`in a variety of therapeutic areas where such inhibition is thought to be
`beneficial, including the treatment of cardiovascular disorders.
`Thus, according to a first aspect, the present invention provides compounds
`of formula (I)
`
`0
`
`(I)
`
`and salts and solvates (e.g. hydrates) thereof, in which:
`RO represents hydrogen, halogen or C1-6 alkyl;
`R1 represents hydrogen, C1-6alkyl, C2-s alkenyl, C2-s alkynyl, haloC1-6alkyl,
`C3-Bcycloalkyl, C3-acycloalkyiC1-3alkyl, aryiC1-3alkyl or heteroaryiC1-3alkyl;
`R2 represents an optionally substituted monocyclic aromatic ring selected
`from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic
`
`ring ~ attached to the rest of the molecule via one of the benzene
`
`ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring
`which may be saturated or partially or fully unsaturated and comprises carbon
`atoms and optionally one or two heteroatoms selected from oxygen, sulphur and
`nitrogen; and
`R3 represents hydrogen or C1•3 alkyl, or R1 and R3 together represent a 3- or
`4- membered alkyl or alkenyl chain.
`There is further provided by the present invention a subgroup of compounds
`of formula (I), the subgroup comprising compounds of formula (Ia)
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`and salts and solvates (e.g. hydrates) thereof, in which:
`RO represents hydrogen, halogen or c1-6 alkyl;
`R1
`represents hydrogen, C1-6alkyl,
`haloC1-6alkyl, C3-acycloalkyl,
`C3-acycloalkyiC1-3alkyl, aryiC1-3alkyl or heteroaryiC1-3alkyl; and
`R2 represents an optionally substituted monocyclic aromatic ring selected
`from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic
`
`ring ~ attached to the rest of the molecule via one of the benzene
`
`ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring
`which may be saturated or partially or fully unsaturated and comprises carbon
`atoms and optionally one or two heteroatoms selected from oxygen, sulphur and
`nitrogen.
`Within R1 above, the term "aryl" as part of an aryiC1-3alkyl group means
`phenyl or phenyl substituted by one or more (e.g. 1, 2 or 3) substituents
`selected from halogen, C1-6alkyl, C1-5alkoxy and methylenedioxy. The term
`"heteroaryl" as part of a heteroaryiC1-3alkyl group means thienyl, furyl or pyridyl
`each optionally substituted by one or more (e.g. 1, 2 or 3) substituents selected
`from halogen, C1-6 alkyl and C1-5alkoxy. The term "C3-acycloalkyl" as a group
`or part of a C3-acycloalkyiC1-3alkyl group means a monocyclic ring comprising
`three to eight carbon atoms. Examples of suitable cycloalkyl rings include the
`C3-6cycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
`Within R2 above, optional benzene ring substituents are selected from one or
`more (e.g. 1, 2 or 3) atoms or groups comprising halogen, hydroxy, C1-6alkyl,
`C1-5alkoxy, -C02Rb, haloC1-6alkyl, haloC1-6alkoxy, cyano, nitro and NRaRb,
`where Ra and Rb are each hydrogen or C1-6alkyl, or Ra may also represent
`C2-7alkanoyl or C1-6alkylsulphonyl. Optional substituents for the remaining
`ring systems are selected from one or more (e.g. 1, 2 or 3) atoms or groups
`comprising halogen, C1-6alkyl, C1-5alkoxy and aryiC1-3alkyl as defined above.
`
`INTELGENX 1015
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`3
`
`as
`such
`heterocycle
`benzimidazole, quinoline,
`
`benzisoxazole,
`benzothiazole,
`benzoxazole,
`indole, benzothiophene or benzofuran or
`
`The bicyclic ring ~ may, for example, represent naphthalene, a
`o:x,
`
`(C~)n
`/
`(where n is an integer 1 or 2 and X and Y may each represent
`Y
`CH2, 0, S or NH).
`In the above definitions, the term "alkyl" as a group or part of a group means
`a straight chain or, where available, a branched chain alkyl moiety. For
`example, it may represent a C1-4alkyl function as represented by methyl, ethyl,
`n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term 'alkenyl' as used herein
`includes straight-chained ar:'d branched alkenyl groups, such as vinyl and allyl
`groups. The term 'alkynyl' as used herein includes straight-chained and
`branched alkynyl groups, suitably acetylene. The term "halogen" herein means
`a fluorine, chlorine, bromine or iodine atom. The term "haloC1-ealkyl" means an
`alkyl group as defined above comprising one to six carbon atoms substituted at
`one or more carbon atoms by one or more (e.g. 1, 2 or 3) halogen atoms.
`Similarly, a haloC1-ealkoxy group is a haloC1-ealkyl group as defined above
`linked to the R2 benzene ring via an oxygen atom. Examples of haloC1-ealkyl
`groups include trifluoromethyl and 2,2,2-trifluoroethyl. An example of a
`haloC1-ealkoxy group is trifluoromethoxy. The term "C2-7alkanoyl" means a
`C1-ealkylcarbonyl group where the C1-ealkyl portion is as defined above. An
`example of a suitable C2-7alkanoyl group is the C2alkanoyl group acetyl.
`It will be appreciated that when RO is a halogen atom or a C1-ealkyl group
`this substituent may be sited at any available position on the phenyl portion of
`the tetracyclic ring. However, a particular site of attachment is the ring 10-
`position.
`The compounds of formula (I) may contain two or more asymmetric centres
`and thus can exist as enantiomers or diastereoisomers. In particular, in formula
`(I) above two ring chiral centres are denoted with asterisks.
`It is to be
`understood that the invention includes both mixtures and separate individual
`isomers of the compounds of formula (I).
`The compounds of formula (I) may also exist in tautomeric forms and the
`invention includes both mixtures and separate individual tautomers thereof.
`
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`The pharmaceutically acceptable salts of the compounds of formula (I) which
`contain a basic centre are acid addition salts formed with pharmaceutically
`acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate
`or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate,
`fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, ·
`benzenesulphonate and p-toluenesulphonate salts. Compounds of the formula
`(I) can also provide pharmaceutically acceptable metal salts, in particular alkali
`metal salts, with bases. Examples include the sodium and potassium salts.
`A particular group of compounds of the invention are those compounds of
`formula (I) in which RO
`is hydrogen or: halogen (e.g. fluorine}, especially
`hydrogen.
`Another particular group of compounds of the invention are those compounds
`of formula (I) in which R1 represents hydrogen, C1-4alkyl, haloC1-4alkyl,
`C3-acycloalkyl, C3-acycloalkylmethyl, pyridyiC1-3alkyl,
`furyiC1-3alkyl or
`optionally substituted benzyl. Within this particular group of compounds,
`·examples of C1-4alkyl groups are methyl, ethyl, n-propyl, i-propyl and n-butyl.
`Examples of C3-acycloalkylmethyl groups are cyclopropylmethyl and
`cyclohexylmethyl. Examples of optionally substituted, benzyl groups include
`benzyl and halobenzyl (e.g. fluorobenzyl).
`invention are
`A further particular group of compounds of the
`those
`compounds of formula (I) in which R2 represents an optionally substituted
`benzene, thiophene, furan, pyridine or naphthalene ring or an optionally
`
`(Xx,
`
`(C~)n
`/
`(where n is 1 or 2 and X and Y are
`substituted bicyclic ring
`Y
`each CH2 or 0). Within this particular group of compounds, examples of
`substituted benzene groups are benzene substituted by one of halogen (e.g.
`chlorine), hydroxy, c1-3alkyl (e.g. methyl, ethyl or i-propyl), c1-3alkoxy (e.g.
`methoxy or ethoxy), -C02Rb, halomethyl (e.g. trifluoromethyl}, halomethoxy (e.g.
`trifluoromethoxy), cyano, nitro or NRaRb where Ra and Rb are each hydrogen
`or methyl or Ra is acetyl; or benzene substituted by dihalo (e.g. dichloro) or by
`C1-3alkoxy (e.g. methoxy) and one of halogen (e.g. chlorine) and hydroxy. An·
`example of a substituted thiophene ring is a halo (e.g. bromo) substituent
`thiophene ring.
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`A still further particular group of compounds of formula I are those wherein R3
`represents hydrogen or R 1 and R3 together represent a 3-membered alkyl chain.
`A preferred group of compounds of the invention are the cis isomers of
`formula (I) represented by formula (lb)
`
`(lb)
`
`0
`,,)l__N-R1
`
`NfR3
`
`0
`
`-R
`
`2
`
`Ro
`
`and mixtures thereof with their cis optical enantiomers, including racemic
`mixtures, and salts and solvates (e.g. hydrates) of these compounds in which
`2
`RO is hydrogen or halogen (e.g. fluorine), especially hydrogen and R1
`and R3
`, R
`are as defined previously.
`The single isomers represented by formula (lb), i.e. the 6R, 12aR isomers,
`are particularly preferred.
`Within the above definitions R1 may preferably represent C1-4alkyl {e.g.
`i-propyl and n-butyl), C3-ecycloalkyl (e.g. cyclopentyl) or
`methyl, ethyl,
`C3-ecycloalkylmethyl {e.g. cyclopropylmethyl).
`R2 may preferably represent a substituted benzene ring such as benzene
`substituted by C1-3alkoxy (e.g. methoxy) or by C1-3alkoxy (e.g. methoxy) and
`halogen
`(e.g.
`chlorine),
`particularly 4-methoxyphenyl
`or 3-chloro-4-
`methoxyphenyl, or R2 may preferably represent 3,4-methylenedioxyphenyl.
`It is to be understood that the present invention covers all appropriate
`combinations of particular and preferred groupings hereinabove.
`Particular individual compounds of the invention include:
`Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-( 4-pyridylmethyl)-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2', 1' : 6,1 ]pyrido[3,4-b]indole-1 ,4-dione;
`Cis-2,3,6,7, 12, 12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-
`pyrazino[2', 1':6, 1]pyrido[3,4-b]indole -1 ,4-dione;
`Cis-2,3,6, 7, 12, 12a-hexahydro-6-( 5-bromo-2-thienyl)-2-methyl(cid:173)
`pyrazino[2', 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;
`Cis-2,3,6, 7, 12, 12a-hexahydro-2-butyl-6-( 4-methylphenyl)(cid:173)
`pyrazino[2', 1 ':6, 1 ]pyrido[3,4-b ]indole -1 ,4-dione;
`(6R, 12aR)-2,3,6, 7, 12, 12a-Hexahydro-2-isopropyl-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2', 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;
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`
`(6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-2-cyclopentyl-6-(3,4-
`methylenedioxyphenyl )-pyrazino[2', 1' :6, 1 ]pyrido[3,4-b ]indole -1 ,4-dione;
`(6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)(cid:173)
`pyrazino[2', 1':6, 1 ]pyrido[3,4-b ]indole -1 ,4-dione;
`(6R,12aR)-2,3,6, 7, 12, 12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl(cid:173)
`pyrazino[2', 1' :6, 1 ]pyrido[3,4-b ]indole -1 , 4-dione;
`(6R, 12aR)-2, 3,6, 7, 12, 12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)(cid:173)
`pyrazino[2', 1':6, 1 ]pyrido[3,4-b]indole-1 ,4-dione;
`(6R, 12aR)-2,3,6, 7, 12, 12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-
`pyrazino[2', 1' : 6,1] pyrido [3,4-b] indole-1 ,4-dione;
`(5aR, 12R, 14aS)-1 ,2,3,5,6,11, 12, 14a-Octahydro-12-(3,4-
`methylenedioxyphenyl)-pyrrolo[1" ,2" : 4' ,5']pyrazino[2', 1' : 6,1 ]pyrido[3,4-
`b]indole-5-1 ,4-dione;
`and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
`A specific compound of the invention is:
`(6R, 12aR)-2,3,6,7, 12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)(cid:173)
`pyrazino[2', 1':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;
`and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
`It has been shown that compounds of the present invention are potent and
`selective inhibitors of cGMP specific POE. Thus, compounds of formula (I) are
`of interest for use in therapy, specifically for the treatment of a variety of
`conditions where inhibition of cGMP specific POE is thought to be beneficial.
`As a consequence of the selective POE V inhibition exhibited by compounds
`of the present invention, cGMP levels are elevated, which in turn can give rise
`to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory,
`natriuretic and diuretic activities as well as potentiation of the effects of
`endothelium-derived relaxing factor (EORF), nitrovasodilators, atrial natriuretic
`factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)
`and endothelium-dependent relaxing agents such as bradykinin, acetylcholine
`and 5-HT 1. The compounds of formula (I) therefore have utility in the treatment
`of a number of disorders, including stable, unstable and variant (Prinzmetal)
`angina, hypertension, pulmonary hypertension, congestive heart failure, renal
`failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post(cid:173)
`percutaneous transluminal coronary angioplasty), peripheral vascular disease,
`vascular disorders such as Raynaud's disease, inflammatory diseases, stroke,
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`treatment extend
`
`bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and
`diseases characterised by disorders of gut motility (e.g.
`irritable bowel
`syndrome).
`It will be appreciated that references herein to
`prophylaxis as well as treatment of established conditions.
`It will also be appreciated that 'a compound of formula (I),' or a physiologically
`acceptable salt or solvate thereof can be administered as the raw compound, or
`as a pharmaceutical composition containing either entity.
`There is thus provided as a further aspect of the invention a compound of
`formula (I) for use in the treatment of stable, unstable and variant (Prinzmetal)
`angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary
`disease, congestive heart failure, renal failure, atherosclerosis, conditions of
`reduced blood vessel patency, (e.g. post-PTCA), peripheral vascular disease,
`vascular disorders such as Raynaud's disease, inflammatory diseases, stroke,
`bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or
`diseases characterised by disorders of gut motility (e.g. IBS).
`According to another aspect of the invention, there is provided the use of a
`compound of formula (I) for the manufacture of a medicament for the treatment
`of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary
`hypertension, chronic obstructive pulmonary disease, congestive heart failure,
`renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g.
`post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's
`disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic
`asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut
`motility (e.g. IBS).
`In a further aspect, the invention provides a method of treating stable,
`unstable and
`variant
`(Prinzmetal) angina, hypertension,
`pulmonary
`hypertension, chronic obstructive pulmonary disease, congestive heart failure,
`renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g.
`post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's
`disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic
`asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut
`motility (e.g.
`IBS) in a human or non-human animal body which comprises
`administering to said body a therapeutically effective amount of a compound
`with formula (I).
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`Compounds of the invention may be administered by any suitable route, for
`example by oral, buccal, sub-lingual, rectal, vaginal, nasal, topical or parenteral
`(including
`intravenous,
`intramuscular, subcutaneous and
`intracoronary)
`administration. Oral administration is generally preferred.
`For administration to man in the curative or prophylactic treatment of the
`disorders identified above, oral dosages of a compound of formula (I) will
`generally be in the range of from 0.5-800mg daily for an average adult patient
`(70kg). Thus for a typical adult patient, individual tablets or capsules contain
`from 0.2-400mg of active compound, in a suitable pharmaceutically acceptable
`vehicle or carrier, for administration in single or multiple doses, once or several
`times per day. Dosages for intravenous, buccal or sublingual administration will
`typically be within the range of from 0.1-400 mg per single dose as required. In
`practice the physician will determine the actual dosing regimen which will be
`most suitable for an individual patient and it will vary with the age, weight and
`response of the particular patient. The above dosages are exemplary of the
`average case but there can be individual instances in which higher or lower
`dosage ranges may be merited, and such are within the scope of this invention.
`For human use, a compound of the formula (I) can be administered alone, but
`will generally be administered in admixture with a pharmaceutical carrier
`selected with regard to the intended route of administration and standard
`pharmaceutical practice. For example, the compound may be administered
`orally, buccally or sublingually, in the form of tablets containing excipients such
`as starch or lactose, or in capsules or ovules either alone or in admixture with
`excipients, or in the form of elixirs or suspensions containing flavouring or
`colouring agents.
`Such
`liquid preparations may be prepared with
`pharmaceutically acceptable additives such as suspending agents (e.g.
`methylcellulose, a semi-synthetic glyceride such as witepsol or mixtures of
`glycerides such as a mixture of apricot kernel oil and PEG-6 esters or mixtures
`of PEG-8 and caprylic/capric glycerides). A compound may also be injected
`parenterally, for example intravenously, intramuscularly, subcutaneously or
`intracoronarily. For parenteral administration, the compound is best used in the
`form of a sterile aqueous solution which may contain other substances, for
`example salts, or monosaccharides such as mannitol or glucose, to make the
`solution isotonic with blood.
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`Thus, the invention provides in a further aspect a pharmaceutical composition
`comprising a compound of the formula (I) together with a pharmaceutically
`acceptable diluent or carrier therefor.
`There is further provided by the present invention a process of preparing a
`pharmaceutical composition comprising a compound of formula (1), which
`process comprises mixing a compound of formula (I)
`together with a
`pharmaceutically acceptable diluent or carrier therefor.
`A compound of formula (I) may also be used in combination with other
`therapeutic agents which may be useful in the treatment of the above-mentioned
`disease states. The invention thus provides, in another aspect, a combination
`of a compound of formula (I) together with another therapeutically active agent.
`The combination referred to above may conveniently be presented for use in
`the form of a pharmaceutical formulation and thus pharmaceutical compositions
`comprising a combination as defined above together with a pharmaceutically
`acceptable diluent or carrier comprise a further aspect of the invention.
`The individual components of such a combination may also be administered
`either sequentially or simultaneously in separate pharmaceutical formulations.
`Appropriate doses of known therapeutic agents for use in combination with a
`compound of formula (I) will be readily appreciated by those skilled in the art.
`Compounds of formula (I) may be prepared by any suitable method known in
`the art or by the following processes which form part of the present invention. In
`the methods below R0, R1 and R2 are as defined in formula (I) above unless
`otherwise indicated.
`Thus, a process (A) for preparing a compound of formula (I) wherein R3
`represents hydrogen comprises treating a compound of formula (II)
`0
`
`OAlk
`
`NYC~Hal
`
`R2
`
`0
`
`(ll)
`
`(in which Alk represents C1-salkyl, e.g. methyl or ethyl and Hal is a halogen
`atom, e.g. chlorine) with a primary amine R1 NH2 in a suitable solvent such as
`an alcohol (e.g. methanol or ethanol) or a mixture of solvents, conveniently at a
`temperature of from 2ooc to reflux (e.g. at about 500C).
`A compound of formula (II) may conveniently be prepared by treating a
`compound of formula (Ill)
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`0
`
`OAlk
`
`(ill)
`
`with a haloacetyl halide (e.g. chloroacetyl chloride) in a suitable solvent such as
`a halogenated hydrocarbon (e.g. trichloromethane or dichloromethane), or an
`ether (e.g. tetrahydrofuran), preferably in the presence of a base such as an
`organic amine (e.g. a trialkylamine such as triethylamine) or an alkali metal
`carbonate or bicarbonate (e.g. NaHC03). The reaction may conveniently be
`effected at a temperature of from -20°C to +200C (e.g. at about QOC).
`A compound of formula (I) may also be prepared from a compound of formula
`(Ill) in a two-step procedure via a compound of formula (II) isolated without
`purification.
`Compounds of formula (I) may be prepared as individual enantiomers in two
`steps from the appropriate enantiomer of formula (Ill) or as mixtures (e.g.
`racemates) of either pairs of cis or trans isomers from the correspondong
`mixtures of either pairs of cis or trans isomers of formula (Ill).
`Individual enantiomers of the compounds of the invention may be prepared
`from racemates by resolution using methods known in the art for the separation
`of racemic mixtures into their constituent enantiomers, for example using HPLC
`(high performance liquid chromatography) on a chiral column such as Hypersil
`naphthyl urea.
`A compound of formula (Ill) may conveniently be prepared from a tryptophan
`alkyl ester of formula (IV)
`
`0
`
`OAlk
`
`(IV)
`
`N
`H
`(where Alk is as previously defined) or a salt thereof (e.g. the hydrochloride salt)
`according to either of the following procedures (a) and (b). Procedure (b) is only
`suitable for preparing cis isomers of formula (Ill) and may be particularly
`suitable for preparing individual cis enantiomers of formula (Ill) from 0- or L(cid:173)
`tryptophan alkyl esters as appropriate.
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`Procedure (a)
`This comprises a Pictet-Spengler cyclisation between a compound of formula
`(IV) and an aldehyde R2CHO. The reaction may conveniently be effected in a
`suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or
`an aromatic hydrocarbon (e.g. toluene) in the presence of an acid such as
`trifluoroacetic acid. The reaction may conveniently be carried out at a
`temperature of from -2ooc to reflux to provide a compound of formula (Ill) in one
`step. The reaction may also be carried out in a solvent such as an aromatic
`hydrocarbon (e.g. benzene or toluene) under reflux, optionally using a Dean-
`Stark apparatus to trap the water produced.
`The reaction provides a mixture of cis and trans isomers which may be either
`individual enantiomers or racemates of pairs of cis or trans isomers depending
`upon whether racemic or enantiomerically pure tryptophan alkyl ester was used
`as the starting material. Individual cis or trans enantiomers may conveniently be
`separated
`from mixtures
`thereof by
`fractional crystallisation or by
`chromatography (e.g. flash column chromatography) using appropriate solvents
`and eluents. Similarly, pairs of cis and trans isomers may be separated by
`chromatography (e.g. flash column chromatography) using appropriate eluents.
`An optically pure trans isomer rnay also be converted to an optically pure cis
`isomer using suitable epimerisation procedures.
`One such procedure
`comprises treating the trans isomer or a mixture (e.g. 1 : 1 mixture) of cis and
`trans isomers with methanolic or aqueous hydrogen chloride at a temperature of
`from ooc to the refluxing temperature of the solution. The mixture may then be
`subjected to chromatography (e.g. flash column chromatography) to separate
`the resulting diastereoisomers, or in the procedure utilising aqueous hydrogen
`chloride the desired cis isomer precipitates out as the hydrochloride salt which
`may then be isolated by filtration.
`
`Procedure (b)
`This comprises a four-step procedure from a compound of formula (IV) or a
`salt thereof (e.g. the hydrochloride salt). The procedure is particularly suitable
`for preparing a 1 R, 3R isomer of formula (Ill) from a 0-tryptophan alkyl ester of
`formula (IV) or a salt thereof (e.g. the hydrochloride salt). Thus, a first step (i)
`comprises treating a compound of formula (IV) with an acid halide R2COHal
`(where Hal is as previously defined) in the presence of a base, e.g. an organic
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`base such as a trialkylamine (for example triethylamine), to provide a compound
`of formula (V)
`
`0
`
`(V)
`
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`10
`
`The reaction may be conveniently carried out in a suitable solvent such as a
`(e.g.
`(e.g. dichloromethane) or an ether
`halogenated hydrocarbon
`tetrahydrofuran) and at a temperature of from
`-2ooc to +400C.
`Step (ii) comprises treating a compound of formula (V) with an agent to
`convert the amide group to a thioamide group. Suitable sulfurating agents are
`well-known in the art. Thus, for example, the reaction may conveniently be
`This reaction may
`treating (V) with Lawesson's reagent.
`effected by
`conveniently be carried out in a suitable solvent such as an ether (e.g.
`dimethoxyethane) or an aromatic hydrocarbon (e.g. toluene) at an elevated
`temperature such as from 400C to sooc to provide a compound of formula (VI)
`0
`
`OAlk
`
`(VI)
`
`15
`
`Step (iii) comprises treating a compound of formula (VI) with a suitable agent
`to provide a compound of formula (VII)
`
`0
`
`OAlk
`
`Hal-
`
`(VII)
`
`(where Hal is a halogen atom, e.g. iodine). The reaction may conveniently be
`effected by treating (VI) with an alkylating agent such as a methyl halide (e.g.
`methyl iodide) or an acylating agent such as an acetyl halide (e.g. acetyl
`chloride) in a suitable solvent such as a halogenated hydrocarbon (e.g.
`dichloromethane) at an elevated temperature (e.g. under reflux).
`In step (iv) the resulting iminium halide of formula (VII) may be treated with a
`reducing agent such as boron hydride, e.g. sodium borohydride, to provide the
`desired compound of formula (Ill). The reduction may conveniently be effected
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`at a low temperature, e.g. within the range of -1oooc to ooc, in a suitable
`solvent such as an alcohol (e.g. methanol).
`There is further provided by the present invention a process (B) for preparing
`a compound of formula (1), wherein R1 and R3 together represent a 3- or 4-
`membered alkyl or alkenyl chain, which process (B) comprises cyclisation of a
`compound of formula (VIII)
`
`0
`
`Ro
`
`Alk
`
`N-R1
`NI('R3
`
`0
`
`(Vill)
`
`wherein Alk represents C1-salkyl and R1 and R3 together represent a 3- or 4-
`membered chain both as hereinbefore described. The cyclisation is suitably
`carried out in an organic solvent or solvents, such as an alcoholic solvent (e.g.
`methanol) and optionally an ether solvent such as tetrahydrofuran, and in the
`presence of a reducing agent, aptly a palladium catalyst, such as palladium on
`carbon.
`Conveniently a compound of formula (VIII) is prepared by reaction of a
`compound of formula (Ill) as hereinbefore described with a compound of formula
`(IX)
`
`(IX)
`
`wherein Hal represents a halogen atom as hereinbefore described, R 1 and R3
`together represent a 3- or 4-membered chain as hereinbefore described and R4
`represents a protecting group, suitably a benzyloxycarbonyl group or the like.
`Typically the reaction is carried out in a chlorinated organic solvent, such as
`dichloromethane, and a