`
`[19]
`
`[11] Patent Number:
`
`6,140,329
`
`Daugan
`
`[45] Date of Patent:
`
`Oct. 31, 2000
`
`US006140329A
`
`M. Wilkins et al., Prac. Natl. Acad. Sci, USA, Aug. 1990),
`87, 6465-6469.
`M. Wilkins et al., J. Clin.
`1274-1279.
`
`(Apr. 1990), 85,
`
`Invest,
`
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`
`(Jul. 1988),
`
`A. Zorgniotti, J. Ural., (Apr. 1992), 147(4), 308A.
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`et al., Eds., W.B. Saunders Co., 709-728 (1991).
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`
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`
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`(1987), 21(6),
`
`D. Green et al., Geriatrics, (Jan. 1993), 48(1), 46-58.
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`1990), 4(1), 265-289.
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`
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`(May 1993), 87 Supp. V,
`V-30-V-32.
`
`R. Pickard et al., J. Ural., (May 1993) 149 (4 Supp.), 245A.
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`536P—537P.
`
`F. Trigo—Rocha et al., J. Ural., (Apr. 1993), 149, 872-877.
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`(Supp. 2), s11—s19.
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`1344, 1941-1943.
`R. Morales et al., Warld J. Ural., (1990), 8, 80-83.
`J. Cortijo, Br. J. Pharmacal., (Feb. 1993), 108(2), 562-568.
`
`(List continued on next page.)
`
`Primary Examiner—Minna Moezie
`Attorney, Agent, ar Firm—Marsha1l, O’Toole, Gerstein,
`Murray & Borun
`
`[57]
`
`ABSTRACT
`
`The use of (6R,12aR)-2,3,6,7,12,12a-heXahydro-2-methyl-
`6-(3,4-rnethylenedioxyphenyl)-pyrazino[2‘,1‘:6,1]pyrido[3,
`4-b]indo1e-1,4-dione,
`(3S 6R,12aR)-2,3,6,7,12,12a-
`hexahydro-2,3-dimethyl-6-(3,4-methy1enedioXyheny1)-
`pyrazino[2',1‘:6,1]pyrido[3,4-b]indole-1,4-dione, and
`physiologically acceptable salts and solvates thereof,
`in
`methods and compositions for the treatment of impotence.
`
`21 Claims, No Drawings
`
`Monosol V. ICOS
`
`IPR2017-00412
`
`[54] USE OF CGMP-PHOSPHODIESTERASE
`INHIBITORS IN METHODS AND
`COMPOSITIONS TO TREAT IMPOTENCE
`
`[75]
`
`Inventor: Alain Claude-Marie Daugan, Les Ulis,
`France
`
`[73] Assignee:
`
`ICOS Corporation, Bothell, Wash.
`
`[21] Appl. No.:
`
`08/981,989
`
`[22]
`
`PCT Filed:
`
`Jul. 11, 1996
`
`[86]
`
`PCT No.:
`
`PCT/EP96/03024
`
`§ 371 Date:
`
`Mar. 10, 1998
`
`§ 102(e) Date: Mar. 10, 1998
`
`[87]
`
`PCT Pub. No.: WO97/03675
`
`PCT Pub. Date: Feb. 6, 1997
`
`[30]
`
`Foreign Application Priority Data
`
`Jul. 14, 1995
`
`[GB]
`
`United Kingdom ................. .. 9514464
`
`Int. Cl.7 ....................... .. A61K 31/50; A61K 31/495
`[51]
`[52] U.S. Cl.
`............................................................ .. 514/250
`[58] Field of Search ............................................. .. 514/250
`
`[56]
`
`References Cited
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`
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`..
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`.... .. C07D 471/04
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`.... .. C07D 487/04
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`European Pat. Off.
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`10/1976 United Kingdom
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`1 454 171
`11/1989 WIPO . . . . . . . . . . . . . . . .
`. . . .. A61K 31/35
`WO 89/10123
`WO 94/28902 12/1994 WIPO
`A61K 31/505
`WO 95/19978
`7/1995 WIPO ........................ .. C07D 471/14
`
`
`
`OTHER PUBLICATIONS
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`
`MonoSol 1003-0001
`
`MonoSol 1003-0001
`
`Monosol v. ICOS
`IPR2017-00412
`
`
`
`Earl et al., Life Sciences, (1984), 35, 525-534.
`Saxena et al., Journal ofMedicinal Chemistry, Vol. 16, No.
`5, 560-564 (1973).
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`(1985).
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`(1990).
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`Page 2
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`(Sep. 14-17, 1992).
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`No. 4, 236-238.
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`
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`
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`Agent,” D. Cotton ed., American Elsevier, NY, (1974), 3-15.
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`Burke et al., Med. J. Aust., (1980), 382-383.
`
`MonoSol 1003-0002
`
`MonoSol 1003-0002
`
`
`
`1
`USE OF CGMP-PHOSPHODIESTERASE
`INHIBITORS IN METHODS AND
`COMPOSITIONS TO TREAT IMPOTENCE
`
`6,140,329
`
`2
`
`C3_8cycloalkylC1_3alkyl,
`heteroarylC1_3alkyl;
`R2 represents an optionally substituted monocyclic aro-
`matic ring selected from benzene,
`thiophene, furan and
`5 pyridine or an optionally substituted bicyclic ring
`
`arylC1,3alkyl or
`
`This application is a 371 of PCT/EP96/03024, filed Jul.
`11, 1996.
`This invention relates to the use of tetracyclic derivatives
`which are potent and selective inhibitors of cyclic guanosine
`3',5‘-monophosphate specific phosphodiesterase (CGMP
`specific PDE) in the treatment of impotence.
`Impotence can be defined as a lack of power, in the male,
`to copulate and may involve an inability to achieve penile
`erection or ejaculation, or both. More specifically, erectile
`impotence or dysfunction may be defined as an inability to
`obtain or sustain an erection adequate for intercourse. Its
`prevalence is claimed to be between 2 and 7% of the human
`male population, increasing with age, up to 50 years, and
`between 18 and 75% between 55 and 80 years of age.
`Reports of well-controlled clinical trials in man are few
`and the efficacy of orally administered drugs is low.
`Although many different drugs have been shown to induce
`penile erection, they are only effective after direct injection
`into the penis, e.g. intraurethrally or intracavernosally (i.c.),
`and are not approved for erectile dysfunction. Current medi-
`cal treatment is based on the i.c.
`injection of vasoactive
`substances and good results have been claimed with
`phenoxybenzamine, phentolamine, papaverine and prostag-
`landin E1, either alone or in combination; however, pain,
`priapism and fibrosis of the penis are associated with the i.c.
`administration of some of these agents. Potassium channel
`openers (KCO) and vasoactive intestinal polypeptide (VIP)
`have also been shown to be active i.c., but cost and stability
`issues could limit development of the latter. An alternative
`to the i.c. route is the use of glyceryl trinitrate (GTN) patches
`applied to the penis, which has been shown to be effective
`but produces side-effects in both patient and partner.
`As a general alternative to pharmacological intervention,
`a variety of penile prostheses has been used to assist
`achievement of an erection. The short term success rate is
`
`good, but problems with infection and ischaemia, especially
`in diabetic men, make this type of treatment a final option
`rather than first-line therapy.
`The compounds of the invention are potent inhibitors of
`cyclic guanosine 3',5'-monophosphate phosphodiesterases
`(CGMP PDEs). GB 9514464.8, which is the priority docu-
`ment for the present application describes the syntheses of
`the compounds of the invention and their utility in impo-
`tence. WO95/19978, which was unpublished at the priority
`date of the present application, also describes the syntheses
`of the compounds of the invention and their utility in other
`diseases associated with inhibition of cGMP PDEs. The
`
`compounds may be represented by the following general
`formula (I):
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`(1)
`
`55
`
`
`
`and salts and solvates (e.g. hydrates) thereof, in which:
`R0 represents hydrogen, halogen or C1,6 alkyl;
`R1 represents hydrogen, C1,5alkyl, C2,6all<enyl,
`C2_6alkynyl, haloC1_6all<yl, C3,8cycloalkyl,
`
`MonoSol 1003-0003
`
`60
`
`65
`
`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_3alkyl, or R1 and R3
`together represent a 3- or 4-membered alkyl or alkenyl
`chain.
`Suitable individual compounds of the invention for use in
`the treatment of erectile dysfunction 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-2,3,6,7,12,12--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-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':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-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)-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;
`Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2‘,1‘:6,1]pyrido[3,4-b]
`indole-1,4-dione;
`(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro -3-methyl-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2‘,1‘:6,1]pyrido[3,4-b]
`indole-1,4-dione;
`and physiologically acceptable salts and solvates (e.g.
`hydrates) thereof.
`The specific compounds of the invention are:
`(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(Compound A); and
`(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,
`4-methylenedioxyphenyl)-pyrazino[2‘,1‘:6,1]pyrido[3,4-
`b]indole-1,4-dione (Compound B);
`
`MonoSol 1003-0003
`
`
`
`3
`
`4
`
`6,140,329
`
`and physiologically acceptable salts and solvates (e.g.
`hydrates) thereof.
`Unexpectedly, it has now been found that compounds of
`formula (I), and in particular compounds A and B, are useful
`in the treatment of erectile dysfunction. Furthermore the
`compounds may be administered orally, thereby obviating
`the disadvantages associated with i.c. administration. Thus
`the present invention concerns the use of compounds of
`formula (I), and in particular compounds A and B, or a
`pharmaceutically acceptable salt thereof, or a pharmaceuti-
`cal composition containing either entity, for the manufacture
`of a medicament for the curative or prophylactic treatment
`of erectile dysfunction in a male animal, including man.
`The pharmaceutically acceptable salts of the compounds
`of formula (I), and in particular compounds A and B which
`contain a basic centre are acid addition salts formed with
`
`pharmaceutically acceptable acids. Examples include the
`hydrochloride, hydrobromide, sulphate or bisulphate, phos-
`phate or hydrogen phosphate, acetate, benzoate, succinate,
`fumarate, maleate,
`lactate, citrate,
`tartrate, gluconate,
`methanesulphonate, benzenesulphonate and
`p-toluenesulphonate salts. Compounds of formula (I), and in
`particular compounds A and B can also provide pharmaceu-
`tically acceptable metal salts, in particular alkali metal salts,
`with bases. Examples include the sodium and potassium
`salts.
`
`It has been shown that compounds of the present inven-
`tion are potent and selective inhibitors of cGMP specific
`PDE. It has now been surprisingly found that human corpus
`cavernosum contains three distinct PDE enzymes. The pre-
`dominant PDE has further surprisingly been found to be
`cGMP PDE. As a consequence of the selective PDE V
`inhibition exhibited by compounds of the present invention,
`the subject compounds can elevate cGMP levels, which in
`turn can mediate relaxation of the corpus cavernosum tissue
`and consequent penile erection.
`Although the compounds of the invention are envisaged
`primarily for the treatment of erectile dysfunction or male
`sexual dysfunction, they may also be useful for the treatment
`of female sexual dysfunction including orgasmic dysfunc-
`tion related to clitoral disturbances.
`
`Generally, in man, oral administration of the compounds
`of the invention is the preferred route, being the most
`convenient and avoiding the disadvantages associated with
`i.c. administration.
`In circumstances where the recipient
`suffers from a swallowing disorder or from impairment of
`drug absorption after oral administration, the drug may be
`administered parenterally, e.g. sublingually or buccally.
`For administration to man in the curative or prophylactic
`treatment of the disorders identified above, oral dosages of
`a compound of formula (I), and in particular compounds A
`and B will generally be in the range of from 0.5—800 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 pharmaceu-
`tically acceptable vehicle or carrier, for administration in
`single or multiple doses, once or several times per day.
`Dosages for buccal or sublingual administration will typi-
`cally be within the range of from 0.1—400 mg per single dose
`as required. In practice the physical will determine the actual
`dosing regiment which will be most suitable for an indi-
`vidual 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, compounds of formula (I), and in par-
`ticular compounds A and B can be administered alone, but
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`will generally be administered in admixture with a pharma-
`ceutical carrier selected with regard to the intended route of
`administration and standard pharmaceutical practice. For
`example, the compound may be administered orally, buc-
`cally 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).
`For veterinary use, a compound of formula (I), and in
`particular compound A or B or a non-toxic salt thereof is
`administered as a suitably acceptable formulation in accor-
`dance with normal Veterinary practice and the veterinary
`surgeon will determine the dosing regiment and route of
`administration which will be most appropriate for a particu-
`lar male animal.
`
`Thus the invention includes a pharmaceutical composi-
`tion for the curative or prophylactic treatment of erectile
`dysfunction in a male animal, including man, comprising a
`compound of formula (I), and in particular compound A or
`B, or a pharmaceutically acceptable salt thereof, together
`with a pharmaceutically acceptable diluent or carrier.
`There is further provided a process for the preparation of
`a pharmaceutical composition for the curative or prophy-
`lactic treatment of erectile dysfunction in a male animal,
`including man, comprising formulating a compound of
`formula (I), and in particular compound A or B, or a
`pharmaceutically acceptable salt thereof, with a pharmaceu-
`tically acceptable diluent or carrier.
`The invention also provides a method of treating a male
`animal, including man, to cure or prevent erectile dysfunc-
`tion which comprises treating said male animal with an
`effective amount of a compound of formula (I), and in
`particular compound A or B, or a pharmaceutically accept-
`able salt thereof, or a pharmaceutical composition contain-
`ing either entity.
`Moreover, the invention includes the use of a compound
`of formula (I), and in particular compound A or B, or a
`pharmaceutically acceptable salt thereof, or a pharmaceuti-
`cal composition containing either entity, for the manufacture
`of a medicament for the curative or prophylactic treatment
`of erectile dysfunction in a male animal, including man.
`A compound of formula (I), and in particular compound
`A or B, may also be used in combination with other
`therapeutical agents which may be useful in the treatment of
`erectile dysfunction substantially as hereinbefore described.
`The invention thus provides, in another aspect, a combina-
`tion of a compound of formula (I), and in particular com-
`pound A or B together with another therapeutically 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 defined 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 the invention will be
`readily appreciated by those skilled in the art.
`
`MonoSol 1003-0004
`
`MonoSol 1003-0004
`
`
`
`5
`
`6,140,329
`
`The compounds of the invention may be prepared by any
`suitable method known in the art or by the following process
`which forms part of the present invention. The process has
`been previously substantially described in the priority docu-
`ment of the present invention GB9514464.8, and in WO95/
`19978. Thus, a process for preparing a compound of formula
`(I) comprises treating a compound of formula (I)
`
`(H)
`
`
`
`(in which Alk represents C1,6alkyl, e.g. methyl or ethyl and
`Hal is a halogen atom, e.g. chlorine) with a primary amine
`R1NH2 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 reflux (e.g. at about 50° C.).
`A compound of formula (II) may conveniently be pre-
`pared by treating a compound of formula (III) with a
`compound of formula (IV)
`
`(III)
`
`(IV)
`
`OAlk
`
`Hal
`
`Hal
`
`R3
`
`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 purification.
`Compounds of formula (I) may be prepared as individual
`enantiometers in two steps for the appropriate enantiomer of
`formula (III) 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 (III).
`Individual enantiomers of the compounds of the invention
`may be prepared form 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.
`A compound of formula (III) may conveniently be pre-
`pared form a tryptophan alkyl ester of formula (V)
`
`MonoSol 1003-0005
`
`OAlk
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(where Alk is as previously defined) or a salt thereof (e. g. the
`hydrochloride salt) with an aldehyde RZCHO. The reaction
`may conveniently be effected in a suitable solvent such as a
`halogenated hydrocarbon (e.g. dichloromethane) or an aro-
`matic 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 —20° C. to reflux 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 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 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 pictures 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 eluants. 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 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 filtra-
`tion.
`
`The pharmaceutically acceptable acid addition salts of a
`compound of formula (I), and in particular compound A or
`B 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 isolated either by
`filtration or by evaporation under vacuum of the reaction
`solvent. Pharmaceutically acceptable base addition salts
`may be obtained in an analogous manner by treating a
`solution of compoundAor B with a suitable base. Both types
`of salt may be formed or interconverted using ion-exchange
`resin techniques.
`Compounds of the invention may be isolate din associated
`with solvent molecules by crystallisation from or evapora-
`tion of an appropriate solvent.
`The syntheses of compounds A and B and of the inter-
`mediates for use therein are illustrated by the following
`examples. The examples have been previously described in
`the priority document of the instant invention GB9514464.8,
`and the corresponding Intermediate or Example numbers
`therein are shown in parentheses next to the current Inter-
`mediate or Example number.
`In the Examples section hereinafter the following abbre-
`viations are used:
`
`MonoSol 1003-0005
`
`
`
`7
`
`8
`
`6,140,329
`
`MeOH (methanol) and EtOH (ethanol),
`Intermediate 1 (54)
`(1R,3R)-Methyl 1,2,3,4-tetrahydro-1-(3,4-
`methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-
`carboxylate, cis isomer
`To a stirred solution of D-tryptophan methyl ester (11 g)
`and piperonal (7.9 g) in anhydrous CH2Cl2 (400 mL) cooled
`at 0° C. was added dropwise trifluoroacetic acid (7.7 mL)
`and the solution was allowed to react at ambient tempera-
`ture. After 4 days,
`the yellow solution was diluted with
`CH2Cl2 (200 mL) and washed with a saturated aqueous
`solution of NaHCO3, then with water (3><200 mL) and dried
`over Na2SO4. The organic layer was evaporated under
`reduced pressure and the residue containing the two geo-
`metric isomers was purified by flash chromatography eluting
`with dichloromethane/ethyl acetate (97/3) to give as the first
`eluting product the title compound (6.5 g)
`m.p.: 154° C.
`Intermediate 2 (83)
`(1R,3R)-Methyl 1,2,3,4-tetrahydro-2-(2-chloropropionyl)-
`1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-
`carboxylate
`To a solution of (R)-(+)-2-chloropropionic acid (191 yl,
`2.2 mmol) in anhydrous dichloromethane (30 mL), was
`added dicyclohexylcarbodiimide (0.45 g, 2.2 mol). Interme-
`diate 1 (0,7 g, 2 mmol) was then added and the mixture was
`stirred at room temperature for 20 hours. The formed
`precipitate of dicyclohexylurea was removed by filtration,
`the filtrate was evaporated in Vacuo and the crude product
`was purified by flash chromatography eluting with toluene/
`ethyl acetate: 95/5. The oily compound obtained was then
`crystallised from either/hexane to give the title compound as
`pale yellow crystals (0.74 g)
`m.p.: 126—128° C.
`
`EXAMPLE 1 (78) (Compound A)
`(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
`a) To a stirred solution of intermediate 1 (0.5 g) and
`NaHCO3 (0.14 g) in anhydrous CHCI3 (20 mL) was added
`dropwise chloroacetyl chloride (0.27 mL) at 0° C. The
`resulting mixture was stirred for 1 hour at the same tem-
`perature and diluted with CHCI3 (20 mL). Water (10 mL)
`was then added dropwise with stirring to the mixture,
`followed by a saturated solution of NaHCO3. The organic
`layer was washed with water until neutrality and dried over
`Na2SO4. After evaporation of the solvent under reduced
`pressure,
`(6R,12aR)-methyl 1,2,3,4-tetrahydro-2-
`chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-
`b]indole-3-carboxylate was obtained as an oil which was
`crystallised from ether to give a solid (0.38 g, m.p.: 233° C.)
`which was used without further purification in the next step.
`b) To a stirred suspension of the chloroacetyl intermediate
`(0.37 g) in MeOH (20 mL) was added at room temperature
`a solution of methylamine (33% in EtOH) (0.4 mL) and the
`resulting mixture was heated at 50° C. under N2 for 16
`hours. The solvent was removed under reduced pressure and
`the residue was dissolved in CH2Cl2 (50 mL). After washing
`with water (3><20 mL), drying over Na2SO4 and evaporating
`to dryness, the residue was purified by flash chromatography
`eluting with CH2Cl2/MeOH (99/1) and recrystallised from
`2-propanol to give the title compound as white crystals (0.22
`g)
`
`m.p.: 302—303° C. Analysis for C22H19N3O4: Calculated:
`C,67.86; H,4.92; N,10.79; Found: C,67.77; H,4.92;
`N,10.74%. [a]2°°D=+71.0° (C=1.00; CHC13).
`EXAMPLE 2 (117) (Compound B)
`(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,
`4-methylenedioxyphenyl)-pyrazino[2‘,1‘;6,1]pyrido[3,4-b]
`indole-1,4-dione
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`To a stirred solution of intermediate 2 (0.3 g, 0.68 mmol)
`in THF (30 mL) was added at room temperature a solution
`of methylamine (33% in EtOH) (0.68 mL) and the resulting
`solution was treated at reflux under N2 for 6 days. The
`solvent was removed under reduced pressure and the residue
`was dissolved in CH2Cl2 (50 mL). After washing with water
`(2,25 mL), drying over Na2SO4 and evaporating to dryness,
`the crude product was purified by flash chromatography
`eluting with dichloromethane/methanol: 99/1. The oily resi-
`due obtained was crystallised from methanol to give the title
`compound as white crystals (40 mg) m.p.: 307—309° C.
`Analysis for C23H21N3O4: Calculated: C,68.47; H,5.25;
`N,10.42; Found: C,68.35; H,5.33; N,10.42%.
`[ot]2°°D=+
`65.2° (C=1.15; CHCI3).
`The following compound was similarly prepared:
`EXAMPLE 3
`
`(3S,6R,12aR)-2,3,6,7,12,12a-Hexahydro-3-methyl-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2‘,1';6,1]pyrido[3,4-b]
`indole-1,4-dione as white crystals using ammonia as the
`base.
`
`m.p.: 319—321° C. Analysis for C22H19N3O4: Calculated:
`C,67.86; H,4.92; N, 10.79; Found: C,67.86; H,5.17;
`N,10.72%. [a]2°°D=+107° (c=1; pyridine).
`Compounds A and B have been included in pharmacy
`formulations and details of such formulations are given
`below.
`TABLETS FOR ORAL ADMINISTRATION
`
`A. Direct Compression
`
`1.
`
`Active ingredient
`Crospovidone USNF
`Magnesium Stearate Ph Eur
`Anhydrous Lactose
`
`mg/tablet
`
`50.0
`8.0
`1.0
`141.0
`
`The active ingredient was sieved and blended with the
`excipients. The resultant mix was compressed into tablets.
`
`2.
`
`Active ingredient
`Colloidal Silicon Dioxide
`Crospovidone
`Sodium Iauryl Sulphate
`Magnesium Stearate Ph Eur
`Microcrystalline Cellulose USNF
`
`mg/tablet
`
`50.0
`0.5
`8.0
`1.0
`1.0
`139.5
`
`The active ingredient was sieved and blended with the
`excipients. The resultant mix was compressed into tablets.
`