United States Patent [19]
`Daugan
`
`US005859006A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,859,006
`Jan. 12, 1999
`
`[54] TETRACYCLIC DERIVATIVES; PROCESS
`OF PREPARATION AND USE
`
`[75] Inventor: Alain Claude-Marie Daugan, Les Ulis,
`France
`
`Primary Examiner—Mukund J. Shah
`Assistant Examiner—Tamthom T. Ngo
`Attorney, Agent, or Firm—Marshall, O’Toole, Gerstein,
`Murray & Borun
`[57]
`
`ABSTRACT
`
`[73] Assignee: ICOS Corporation, Bothell, Wash.
`[21] Appl. No.:
`669,389
`[22] PCT Filed:
`Jan. 19, 1995
`
`[86] PCT No.:
`
`PCT/EP95/00183
`
`§ 371 Date:
`
`Jul. 17, 1996
`
`§ 102(e) Date: Jul. 17, 1996
`
`[87] PCT Pub. No.: WO95/19978
`
`PCT Pub. Date: Jul. 27, 1995
`Foreign Application Priority Data
`
`[30]
`
`Jan. 21, 1994 [GB]
`
`United Kingdom ................. .. 9401090
`
`[51]
`
`Int. Cl.6 ........................ .. A01N 43/58; A01N 43/42;
`C07D 241/36; C07D 471/00
`[52] US. Cl. ........................ .. 514/249; 514/250; 514/292;
`544/343; 546/81; 546/85
`[58] Field of Search ........................... .. 544/343; 514/249,
`514/250, 292; 546/81, 85
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2/1972 Schulenberg .......................... .. 260/295
`3,644,384
`2/1973 Schulenberg
`260/268
`3,717,638
`3,917,599 11/1975 Saxena et al. ........................ .. 260/268
`
`FOREIGN PATENT DOCUMENTS
`
`0 357 122A 3/1990 European Pat. Off. .
`0 362 555A 4/1990 European Pat. Off. .
`1454171 10/1976 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Dellouve—Courillon et al., Tetrahedron, 46(9), 3245—66
`(1990).
`Brana et al., Synth Comm., 20(12), 1793—1810 (1990).
`SaXena et al., Journal ofMedicinal Chemistry, 16(5), 1973,
`560—564.
`Ishida et al., Chem. Pharm. BulL, 33(8), 1985, 3237—3249.
`
`A compound of formula (I)
`
`and salts and solvates thereof, in Which:
`R0 represents hydrogen, halogen or Cli?alkyl;
`R1 represents hydrogen, Cli?alkyl, Czi?alkenyl,
`Czi?alkynyl, haloCli?alkyl, C3i8cycloalkyl,
`C3i8cycloalkylC1i3alkyl, arylC1i3alkyl or
`heteroarylC1i3alkyl; R2 represents an optionally sub
`stituted 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 C1i3alkyl, or R1 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‘-monophosphate spe
`ci?c phosphodiesterase (cGMP speci?c PDE) having a
`utility in a variety of therapeutic areas Where such
`inhibition is bene?cial, including the treatment of car
`diovascular disorders.
`
`15 Claims, No Drawings
`
`ICOS Exhibit 2002
`IntelGenX v. ICOS
`IPR2016-00678
`
`Page 1 of 33
`
`

`
`1
`TETRACYCLIC DERIVATIVES; PROCESS
`OF PREPARATION AND USE
`
`2
`R2 represents an optionally substituted monocyclic aro
`matic ring selected from benZene, thiophene, furan and
`pyridine or an optionally substituted bicyclic ring
`
`5,859,006
`
`This is a 371 application of Pct/EP ?led on Jan. 19, 1995.
`This invention relates to a series of tetracyclic
`derivatives, to processes for their preparation, pharmaceu
`tical compositions containing them, and their use as thera
`peutic agents. In particular, the invention relates to tetracy
`clic derivatives Which are potent and selective inhibitors of
`cyclic guanosine 3‘,5‘-monophosphate speci?c phosphodi
`esterase (cGMP speci?c PDE) having utility in a variety of
`therapeutic areas Where such inhibition is thought to be
`bene?cial, including the treatment of cardiovascular disor
`ders.
`Thus, according to a ?rst aspect, the present invention
`provides compounds of formula (I)
`
`(I)
`
`R2
`
`O
`
`and salts and solvates (e.g. hydrates) thereof, in which:
`R0 represents hydrogen, halogen or C1i6alkyl;
`R1 represents hydrogen, C1i6alkyl, C2i6alkenyl,
`CZiGalkynyl, halocli?alkyl, C3i8cycloalkyl,
`C3i8cycloalkylC1i3alkyl, arylC1i3alkyl or
`heteroarylC1i3alkyl;
`R2 represents an optionally substituted monocyclic aro
`matic 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
`arylC1i3alkyl group means phenyl or phenyl substituted by
`one or more (eg 1, 2 or 3) substituents. selected from
`halogen, C1i6alkyl, C1i6alkoxy and methylenedioxy. The
`term “heteroaryl” as part of a heteroarylC1i3alkyl group
`means thienyl, furyl or pyridyl each optionally substituted
`by one or more (eg 1, 2 or 3) substituents selected from
`halogen, C1i6alkyl and C1i6alkoxy. The term
`“C3i8cycloalkyl” as a group or part of a
`C3i8cycloalkylC1i3alkyl group means a monocyclic ring
`comprising three to eight carbon atoms. Examples of suit
`able cycloalkyl rings include the C3i6cycloalkyl rings
`cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
`Within R2 above, optional benZene ring substituents are
`selected from one or more (eg 1; 2 or 3) atoms or groups
`comprising halogen, hydroxy, C1i6alkyl, C1i6alkoxy,
`—CO2Rb, halocli?alkyl, halocli?alkoxy, cyano, nitro and
`NRaRb, Where R“ and Rb are each hydrogen or C1i6alkyl, or
`R“ may also represent C2i7alkanoyl or C1i6alkylsulphonyl.
`Optional substituents for the remaining ring systems are
`selected from one or more (eg 1, 2 or 3) atoms or groups
`comprising halogen, C1i6alkyl, C1i6alkoxy and
`arylC1i3alkyl as de?ned above. The bicyclic ring
`
`15
`
`25
`
`0
`
`35
`
`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 C1i3alkyl, 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 com
`prising compounds of formula (la)
`
`(la)
`
`55
`
`and salts and solvates (e.g. hydrates) thereof, in Which:
`R0 represents hydrogen, halogen or C116 alkyl;
`R1 represents hydrogen, C1i6alkyl, halocli?alkyl,
`C3i8cycloalkyl, C3i8cycloalkylC1i3alkyl,
`arylC1i3alkyl or heteroarylC1i3alkyl; and
`
`65
`
`may, for example, represent naphthalene, a heterocycle such
`as benZoxaZole, benZothiaZole, benZisoxaZole,
`benZimidaZole, quinoline, indole, benZothiophene or benZo
`furan or
`
`Y
`
`(Where n is an integer 1 or 2 and X and Y may each represent
`CH2, 0, S or NH).
`In the above de?nitions, 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 C1i4alkyl 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 and
`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 ?uorine, chlorine, bromine or
`iodine atom. The term “halocli?alkyl” means an alkyl group
`
`Page 2 of 33
`
`

`
`5,859,006
`
`4
`are each hydrogen or methyl or R“ is acetyl; or benZene
`substituted by dihalo (e.g. dichloro) or by C1i3alkoxy (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.
`A still further particular group of compounds of formula
`I are those Wherein R3 represents hydrogen or R1 and R3
`together represent a 3-membered alkyl chain.
`Apreferred group of compounds of the invention are the
`cis isomers of formula (I) represented by formula (lb)
`
`3
`as de?ned above comprising one to six carbon atoms sub
`stituted at one or more carbon atoms by one or more (e.g. 1,
`2 or 3) halogen atoms. Similarly, a halocli?alkoxy group is
`a halocli?alkyl group as de?ned above linked to the R2
`benZene ring via an oxygen atom. Examples of
`halocli?alkyl groups include tri?uoromethyl and 2,2,2
`tri?uoroethyl. An example of a halocli?alkoxy group is
`tri?uoromethoxy. The term “C2i7alkanoyl” means a
`C1i6alkylcarbonyl group Where the C1i6alkyl portion is as
`de?ned above. An example of a suitable C2i7alkanoyl group
`is the C2alkanoyl group acetyl.
`It Will be appreciated that When R0 is a halogen atom or
`a C1i6alkyl 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 under
`stood that the invention includes both mixtures and separate
`individual isomers of the compounds of formula
`The compounds of formula (I) may also exist in tauto
`meric forms and the invention includes both mixtures and
`separate individual tautomers thereof.
`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, sul
`phate or bisulphate, phosphate or hydrogen phosphate,
`acetate, benZoate, succinate, fumarate, maleate, lactate,
`citrate, tartrate, gluconate, methanesulphonate, benZene
`sulphonate 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 R0 is hydrogen or
`halogen (e.g. ?uorine), especially hydrogen.
`Another particular group of compounds of the invention
`are those compounds of formula (I) in Which R1 represents
`hydrogen, C1i4alkyl, haloC1i4alkyl, C3i6cycloalkyl,
`C3i6cycloalkylmethyl, pyridylC1i3alkyl, furylC1i3alkyl or
`optionally substituted benZyl. Within this particular group of
`compounds, examples of C14alkyl groups are methyl, ethyl,
`n-propyl, i-propyl and n-butyl. Examples of
`C3i6cycloalkylmethyl groups are cyclopropylmethyl and
`cyclohexylmethyl. Examples of optionally substituted, ben
`Zyl groups include benZyl and halobenZyl (e.g.
`?uorobenZyl).
`A further particular group of compounds of the invention
`are those compounds of formula (I) in Which R2 represents
`an optionally substituted benZene, thiophene, furan, pyridine
`or naphthalene ring or an optionally substituted bicyclic ring
`
`(CH2),
`/
`Y
`
`(Where n is 1 or 2 and X and Y are each CH2 or O). Within
`this particular group of compounds, examples of substituted
`benZene groups are benZene substituted by one of halogen
`(e.g. chlorine), hydroxy, C1i3alkyl (e.g. methyl, ethyl or
`i-propyl), C1i3alkoxy (e.g. methoxy or ethoxy), —CO2Rb,
`halomethyl (e.g. tri?uoromethyl), halomethoxy (e.g.
`tri?uoromethoxy), cyano, nitro or NRaRb Where R“ and Rb
`
`15
`
`25
`
`35
`
`45
`
`a O
`
`and mixtures thereof With their cis optical enantiomers,
`including racemic mixtures, and salts and solvates (e.g.
`hydrates) of these compounds in Which R0 is hydrogen or
`halogen (e.g. ?uorine), especially hydrogen and R1, R2 and
`R3 are as de?ned previously.
`The single isomers represented by formula (Ib), ie the
`6R, 12aR isomers, are particularly preferred.
`Within the above de?nitions R1 may preferably represent
`C1i4alkyl (e.g. methyl, ethyl, i-propyl and n-butyl),
`C3i6cycloalkyl (e.g. cyclopentyl) or C3i6cycloalkylmethyl
`(e.g. cyclopropylmethyl).
`R2 may preferably represent a substituted benZene ring
`such as benZene substituted by C1i3alkoxy (e.g. methoxy) or
`by C1i3alkoxy (e.g. methoxy) and halogen (e.g. chlorine),
`particularly 4-methoxyphenyl or 3-chloro4-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 group
`ings 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-hexahydro6-(2,3-dihydrobenZo[b]furan
`5-yl)-2-methyl-pyraZino[2‘,1‘z6,1]pyrido[3,4b]indole-1,4
`dione;
`Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2
`methyl-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)
`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;
`(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)-pyraZino[2‘,
`1‘16,1]pyrido[3,4-b]indole-1,4-dione;
`(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro4
`methoxyphenyl)-2-methyl-pyraZino[2‘,1‘16,1]pyrido[3,4
`b]indole-1,4-dione;
`(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-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-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)-pyraZino[1“,2“:4‘,5‘]pyraZino[2‘,
`1‘:6,1]pyrido[3,4-b]indole-5-1,4-dione;
`
`Page 3 of 33
`
`

`
`5,859,006
`
`5
`and physiologically acceptable salts and solvates (e.g.
`hydrates) thereof.
`A speci?c compound of the invention is:
`(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4
`methylenedioxyphenyl)-pyraZino[2‘,1‘16,1]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 inven
`tion are potent and selective inhibitors of cGMP speci?c
`PDE. Thus, compounds of formula (I) are of interest for use
`in therapy, speci?cally for the treatment of a variety of
`conditions Where inhibition of cGMP speci?c PDE is
`thought to be bene?cial.
`As a consequence of the selective PDE V inhibition
`exhibited by compounds of the present invention, cGMP
`levels are elevated, Which in turn can give rise to bene?cial
`anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory,
`natriuretic and diuretic activities as Well as potentiation of
`the effects of endothelium-derived relaxing factor (EDRF),
`nitrovasodilators, atrial natriuretic factor (AN F), brain natri
`uretic peptide (BNP), C-type natriuretic peptide (CNP) and
`endothelium-dependent relaxing agents such as bradykinin,
`acetylcholine and 5-HT1. 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, con
`ditions of reduced blood vessel patency (e.g. post
`percutaneous transluminal coronary angioplasty), peripheral
`vascular disease, vascular disorders such as Raynaud’s
`disease, in?ammatory diseases, stroke, 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 treatment
`extend 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 pharma
`ceutical 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, pul
`monary 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 dis
`orders such as Raynaud’s disease, in?ammatory 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, pul
`monary 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 dis
`orders such as Raynaud’s disease, in?ammatory 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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
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`55
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`60
`
`65
`
`6
`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 dis
`orders such as Raynaud’s disease, in?ammatory 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 thera
`peutically effective amount of a compound With formula
`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 identi?ed above, oral dosages of
`a compound of formula (I) Will generally be in the range of
`from 0.5800 mg daily for an average adult patient (70 kg).
`Thus for a typical adult patient, individual tablets or capsules
`contain from 0.2—400 mg of active compound, in a suitable
`pharmaceutically acceptable vehicle or carrier, for adminis
`tration in single or multiple doses, once or several times per
`day. Dosages for intravenous, buccal or sublingual admin
`istration 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 phar
`maceutical 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 contain
`ing ?avouring 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 glycer
`ides such as a mixture of apricot kernel oil and PEG-6 esters
`or mixtures of PEG-8 and caprylictcapric glycerides). A
`compound may also be injected parenterally, for example
`intravenously, intramuscularly, subcutaneously or intracoro
`narily. 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 monosaccha
`rides such as mannitol or glucose, to make the solution
`isotonic With blood.
`Thus, the invention provides in a further aspect a phar
`maceutical 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 compris
`ing a compound of formula (I), Which process comprises
`mixing a compound of formula (I) together With a pharma
`ceutically acceptable diluent or carrier therefor.
`A compound of formula (I) may also be used in combi
`nation With other therapeutic agents Which may be useful in
`the treatment of the above-mentioned disease states. The
`
`Page 4 of 33
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`5,859,006
`
`7
`invention thus provides, in another aspect, a combination of
`a compound of formula (I) together With another therapeu
`tically active agent.
`The combination referred to above may conveniently be
`presented for use in the form of a pharmaceutical formula
`tion and thus pharmaceutical compositions comprising a
`combination as de?ned above together With a pharmaceuti
`cally 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 de?ned 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)
`
`15
`
`(II)
`
`25
`
`(in Which Alk represents Cli?alkyl, e.g. methyl or ethyl and
`Hal is a halogen atom, e.g. chlorine) With a primary amine
`RlNH2 in a suitable solvent such as an alcohol (e.g. metha
`nol or ethanol) or a mixture of solvents, conveniently at a
`temperature of from 20° C. to re?ux (e.g. at about 50° C.).
`A compound of formula (II) may conveniently be pre
`pared by treating a compound of formula (III)
`
`35
`
`(III)
`
`R2
`
`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. NaHCO3).
`The reaction may conveniently be effected at a temperature
`of from —20° C. to +20° C. (e.g. at about 0° C.).
`A compound of formula (I) may also be prepared from a
`compound of formula (III) in a tWo-step procedure via a
`compound of formula (II) isolated Without puri?cation.
`Compounds of formula (I) may be prepared as individual
`enantiomers in tWo steps from the appropriate enantiomer of
`formula (III) or as mixtures (e.g. racemates) of either pairs
`of cis or trans isomers from the corresponding mixtures of
`either pairs of cis or trans isomers of formula (III).
`Individual enantiomers of the compounds of the invention
`may be prepared from racemates by resolution using meth
`ods 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 col
`umn such as Hypersil naphthylurea.
`
`45
`
`55
`
`65
`
`8
`A compound of formula (III) may conveniently be pre
`pared from a tryptophan alkyl ester of formula (IV)
`
`0
`
`(IV)
`
`OAlk
`
`R0
`
`I
`
`NHZ
`
`N
`H
`
`(Where Alk is as previously de?ned) or a salt thereof (e. g. the
`hydrochloride salt) according to either of the folloWing
`procedures (a) and
`Procedure (b) is only suitable for
`preparing cis isomers of formula (III) and may be particu
`larly suitable for preparing individual cis enantiomers of
`formula (III) from D- or L-tryptophan alkyl esters as appro
`priate.
`Procedure (a)
`This comprises a Pictet-Spengler cyclisation betWeen a
`compound of formula (IV) and an aldehyde RZCHO. 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 tri?uoroacetic acid. The reaction may
`conveniently be carried out at a temperature of from —20° C.
`to re?ux to provide a compound of formula (III) in one step.
`The reaction may also be carried out in a solvent such as an
`aromatic hydrocarbon (e. g. benZene or toluene) under re?ux,
`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 race
`mic or enantiomerically pure tryptophan alkyl ester Was
`used as the starting material. Individual cis or trans enanti
`omers may conveniently be separated from mixtures thereof
`by fractional crystallisation or by chromatography (e.g. ?ash
`column chromatography) using appropriate solvents and
`eluents. Similarly, pairs of cis and trans isomers may be
`separated by chromatography (e.g. ?ash column
`chromatography) using appropriate eluents. An optically
`pure trans isomer may 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 0° C. to the re?uxing temperature of the solution. The
`mixture may then be subjected to chromatography (e.g. ?ash
`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 ?ltra
`tion.
`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 1R, 3R
`isomer of formula (III) from a D-tryptophan alkyl ester of
`formula (IV) or a salt thereof (e.g. the hydrochloride salt).
`Thus, a ?rst step
`comprises treating a compound of
`formula (IV) With an acid halide R2COHal (Where Hal is as
`previously de?ned) in the presence of a base, eg an organic
`base such as a trialkylamine (for example triethylamine), to
`provide a compound of formula (V)
`
`Page 5 of 33
`
`

`
`5,859,006
`
`(V)
`
`OAlk
`
`NHCOR2
`
`N
`H
`
`The reaction may be conveniently carried out in a suitable
`solvent such as a halogenated hydrocarbon (e.g.
`dichloromethane) or an ether (e.g. tetrahydrofuran) and at a
`temperature of from —20° C. to +40° C.
`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
`effected by treating (V) With LaWesson’s reagent. This
`reaction may 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 tempera
`ture such as from 40° C. to 80° C. to provide a compound
`of formula (VI)
`
`R0
`
`0
`
`(v1)
`
`OAlk
`
`NHCSRZ
`
`N
`H
`Step (iii) comprises treating a compound of formula (VI)
`With a suitable agent to provide a compound of formula
`(VII)
`
`10
`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 (III) as hereinbefore
`described With a compound of formula (IX)
`
`(IX)
`
`15
`
`25
`
`0
`
`Wherein Hal represents a halogen atom as hereinbefore
`described, R1 and R3 together represent a 3- or 4-membered
`chain as hereinbefore described and R4 represents a protect
`ing group, suitably a benZyloxycarbonyl group or the like.
`Typically the reaction is carried out in a chlorinated organic
`solvent, such as dichloromethane, and a tertiary amine, such
`as triethylamine or the like.
`According to a further aspect of the present invention,
`there is provided a process (C) for preparing a compound of
`formula (I) Wherein R3 represents C1i3alkyl, Which process
`comprises cyclisation of a compound of formula
`
`(X)
`
`(v11)
`
`35
`
`(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 (eg under
`re?ux).
`In step (iv) the resulting iminium halide of formula (VII)
`may be treated With a reducing agent such as boron hydride,
`eg sodium borohydride, to provide the desired compound
`of formula (III). The reduction may conveniently be effected
`at a loW temperature, eg Within the range of —100° C. to 0°
`C., 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 (I),
`Wherein R1 and R3 together represent a 3- or 4-membered
`alkyl or alkenyl chain, Which process (B) comprises cycli
`sation of a compound of formula (VIII)
`
`45
`
`55
`
`(VIII)
`
`Wherein Alk represents Cli?alkyl and R1 and R3 together
`represent a 3- or 4-membered chain both as hereinbefore
`
`65
`
`Wherein Alk represents Cli?alkyl as hereinbefore described
`and R5 represents Czisalkyl, substituted at C1 by a halogen
`atom, the halogen atom being as hereinbefore described.
`Suitably the cyclisation is achieved by re?ux for many
`hours, such as 22 to 26 hours, in the presence of an ether
`solvent, such as tetrahydrofuran, and a suitable amine as
`hereinafter described in the accompanying examples.
`Aptly a compound of formula
`can be prepared from
`a compound of formula (III) by suitable acylation
`techniques, such as reaction With a C1i3carboxylic acid,
`substituted at C2 by a halogen atom in a halogenated organic
`solvent, such as dichloromethane.
`Compounds of formula (I) may be converted to other
`compounds of formula
`Thus, for example, When R2 is a
`substituted benZene ring it may be necessary or desirable to
`prepare the suitably substituted compound of formula (I)
`subsequent to process (A), (B) or (C) as above. Examples of
`appropriate interconversions include nitro to amino or
`aralkyloxy to hydroxy by suitable reducing means (eg
`using a reducing agent such as SnCl2 or a palladium catalyst,
`such as palladium-on-carbon), or amino to substituted amino
`such as acylamino or sulphonylamino using standard acy
`lating or sulfonylating conditions. In the case Where R2
`represents a substituted bicyclic system, suitable intercon
`version can involve removal of a substituent, such as by
`treatment With a palladium catalyst (e.g. palladium-on
`carbon) Whereby, for example, a benZyl substituent may be
`removed from a suitable bicyclic system.
`The pharmaceutically acceptable acid addition salts of the
`compounds of formula (I) Which contain a basic centre may
`be prepared in a conventional manner. For example, a
`solution of the free base may be treated With a suitable acid,
`either neat or in a suitable solution, and the resulting salt
`
`Page 6 of 33
`
`

`
`5,859,006
`
`12
`INTERMEDIATES