51)
`United States Patent
`6,140,329
`[45] Date of Patent:
`Oct. 31, 2000
`Daugan
`
`[11] Patent Number:
`
`US006140329A
`
`Invest.,
`
`(Apr. 1990), 85,
`
`(Jul. 1988),
`
`M. Wilkins et al., Proc. Natl. Acad. Sci., USA, Aug. 1990),
`87, 6465-6469.
`M. Wilkins et al, J. Clin.
`1274-1279.
`J. Raifer, N. Eng. J. Med., (Jan. 1992), 326(2), 90-94.
`H. Knispel, Urol. Res., (1992), 20, 253-257.
`G. Gwinup, Annals. of Internal Medicine,
`162-163.
`A. Zorgniotti, J. Urol., (Apr. 1992), 147(4), 308A.
`K. Azadzoi et al., J. Urol., (Nov. 1992), 148, 1587-1591.
`K. Azadzoi et al., J. Urol., (Jan. 1992), 147, 220-225.
`C. Sparwasseret al., J. Urol., (Dec. 1994), 152, 2159-2163.
`T. Lue, “Campbell’s Urology,” 6th Ed., Chap. 16, P. Walsh
`et al., Eds., W.B. Saunders Co., 709-728 (1991).
`N. Kim et al., J. Clin. Invest., (1991), 88, 112-118.
`S. Francis et al., in J. Beavo et al. eds. “Cyclic Nucleotide
`PDEs,” Ch. 5 (1990) 117-140.
`R. Weishaaret al., J. Med. Chemn., (1985), 28:5, 537-542.
`H. Ahn et al. Biochem. Pharmacol.,
`(1989), 39:19,
`331-3339.
`C. Lugnier et al., Biochem. Pharmacol., (1986), 35:10,
`1743-1751.
`J. Doremieux et al. Ann. Urol. Paris,
`429-434,
`
`(1987), 21(6),
`
`[54] USE OF CGMP-PHOSPHODIESTERASE
`INHIBITORS IN METHODS AND
`COMPOSITIONS TO TREAT IMPOTENCE
`
`[75]
`
`Inventor: Alain Claude-Marie Daugan, Les Ulis,
`France
`
`[73] Assignee:
`
`[COS 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 ........ ee 9514464
`
`Int. Ch? oe A61K 31/50; A61K 31/495
`[51]
`[52] US. C1 ences sseeseessesseseesteneceneaeesseseaseneees 514/250
`[58] Field of Search oo... eeeeeeseeeeeeeeeees 514/250
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,644,384
`3,717,638
`3,917,599
`4,188,390
`4,686,228
`$5,145,852
`§,270,323
`
`2/1972 Schulenberg 0.0... 260/295 C
`... 260/268 PC
`2/1973 Schulenberg....
`
`. 260/268 PC
`11/1975 Saxenaetal. ..
`
`2/1980 Campbell oo.
`eee 424/251
`8/1987 Campbell et al. ow. 514/307
`
`9/1992 Virago... eeecceeseecsescseeesenees $14/253
`12/1993 Milne, Jy. et al. wee 514/309
`
`FOREIGN PATENT DOCUMENTS
`
`D. Green et al., Geriatrics, (Jan. 1993), 48(1), 46-58.
`M. Webster et al., Hematol. Oncol. CL of N. Am., (Feb.
`1990), 4(1), 265-289.
`F. Holmquist et al., Acta. Physiol. Scand., (1991), 141,
`441-442.
`
`J. Taher et al., J. Urol., (Apr. 1993), 149, 285A.
`S. Uckert et al., , 495A.
`W.Aronsonetal., J. Urol., (1991), 145 (4 Supp.), 341A.
`P. Bushet al., Fed. Am. Soc. Exp. Biol., (1991), 5(4), 175.
`P. Bush et al., Fed. Am. Soc. Exp. Biol., (1992), 6(4), 2092.
`W.Aronsonet al., J. Urol., (1992), 147 (4 Supp.), 454A.
`P. Bush et al., Circulation,
`(May 1993), 87 Supp. V,
`V-30-V-32.
`R. Pickardet al., J. Urol., (May 1993) 149 (4 Supp.), 245A.
`R. Pickard et al., Clin. Pharmacoi., (Jan. 1993), 35(5),
`536P-537P.
`
`...... CO7D 471/04
`3/1990 European Pat. Off.
`0357122
`...... CO7D 241/08
`4/1990 European Pat. Off.
`0 362555
`..... A61K 31/505
`12/1991
`European Pat. Off.
`459 666
`F. Trigo-Rochaet al., J. Urol., (Apr. 1993), 149, 872-877.
`...... CO7D 487/04
`1/1992 European Pat. Off.
`463 756
`M. Krupp et al., J. Cardiovas. Pharmacol., (1989), 13
`...... CO7D 487/04
`2/1993
`European Pat. Off.
`526 004
`=2/1991)
`Japan oe eects A61K 31/52
`03044324
`(Supp. 2), $11-S19.
`10/1976 United Kingdom
`.. CO7D 471/14
`1454 171
`“Physicians’ Desk Reference,” (1992), 683,1099-1100,
`
`11/1989 WIPO oe eeeeeceeeee A61K 31/35
`WO 89/10123
`
`1344, 1941-1943.
`.. AGLK 31/505
`WO 94/28902 12/1994 WIPO ....
`
`R. Morales et al., World J. Urol., (1990), 8, 80-83.
`WO 95/19978=7/1995 WIPO we eececceseseeeeeeees COo7D 471/14
`J. Cortijo, Br J. Pharmacol., (Feb. 1993), 108(2), 562-568.
`
`OTHER PUBLICATIONS
`
`A. Bowmanet al., Br J. Pharmac., (1984), 81, 665-674.
`F. Trigo-Rocha et al., Am. J. Physiol., (Feb. 1993), 264,
`H419-H422.
`J. Reiser et al., Br J. Dis. Chest, (1986), 80, 157-163.
`P. Bushet al., J. Urol., (Jun. 1992), 147, 1650-1655.
`F. Holmquistet al., J. Urol. (Oct. 1993), 150, 1310-1315.
`R. Rudd et al., Br J. Dis. Chest, (1983), 77, 78-86.
`E. McMahonetal., J. Pharmacol. Exp. Thera., (1989), 251,
`1000-1005.
`F. Holmquist et al., Acta Physiol. Scand., (1991), 143,
`299-304.
`G. Barbanti, Urol. Res., (1988), 16, 299-302.
`L. Ignarro et al., Biochem. and Biophys. Res. Commun.,
`(1990), 170(2), 843-850.
`J. Krall et al., Bio. Reprod., (1988), 39, 913-922.
`
`(List continued on next page.)
`
`Primary Examiner—Minna Moezie
`Attorney, Agent, or Firm—Marshall, O’Toole, Gerstein,
`Murray & Borun
`
`[57]
`
`ABSTRACT
`
`The use of (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,
`(3S 6R,12aR)-2,3,6,7,12,12a-
`hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyhenyl)-
`pyrazino[2’,1':6,1 |pyrido[3,4-b Jindole-1,4-dione, and
`physiologically acceptable salts and solvates thereof,
`in
`methods and compositions for the treatment of impotence.
`
`21 Claims, No Drawings
`
`ATI 1003-0001
`
`ATI v. ICOS
`
`IPR2018-01183
`
`ATI 1003-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`6,140,329
`Page 2
`
`Segasouthy et al., Med. J. Malaysia, (1982), 37(4), 384.
`Yiitalo et al., Acta Med. Scand., (1983), 213, 319-320.
`Robbinset al., J. Urol., (1983), 130, 975.
`Adamset al., J. Urol., (1984), 132, 1208.
`Russell et al., Med. J. Aust., (1985), 143, 321.
`Taheret al., Int. J. Impotence Res., Abstracts, Milan,Italy
`(Sep. 14-17, 1992).
`Trigo—Rocha et al., Neurourology and Urodynamics, 13,
`(1994), 71-80.
`Beyer et al., Phys. and Behav., (1981), 27, 731-733.
`Pickard et al., Br. J. Pharmacol., (1991), 104 755-759.
`Martinez—Pineiro et al., Eur. Urol., (1993), 24, 492-499.
`Mironeet al., Br J. Urol., (Mar., 1993), 71(3), 365.
`Murrayet al., Biochemical Soc. Trans., (1992), 20, 460-464.
`Raeburn et al., Prog. Drug Res., (1993), 12-32.
`Merkel, Cardio. Drug. Rev., (193), 11(4), 501-515.
`“Physicians’ Desk Reference,” (1992) 2207-2208.
`Cimino et al., Biochem. Pharmacology, (1988), 37(14),
`2739-2745.
`Watanabe et al., Federation Proceedings, (1982), 41(7),
`2292-2399.
`Earl et al., Life Sciences, (1984), 35, 525-534.
`Saxenaet al., Journal of Medicinal Chemistry, vol. 16, No.
`5, 560-564 (1973).
`Ishida et al., Chem. Pharm. Bull., vol. 33, No. 8, 3237-3249
`(1985).
`Gillespie et al., Molecular Pharmacology, 36:773-781
`(1989).
`Branaet al., Synthetic Communications, 20(12), 1793-1820
`(1990).
`Dellouve—Courillon et
`3245-3266 (1990).
`Murray, DN&P 6(3), 150-156 (1993).
`Zorgniotti et al. Int. J. Impotence Res., 6, 33-36 (1994).
`
`9,
`
`al., Tetrahedron,
`
`46, No.
`
`OTHER PUBLICATIONS
`
`E. Kim et al., J. Urol., (1995), 153, 361-365.
`S. Korenmanet al., JAGS, (Apr. 1993), 41(4), 363-366.
`K. Allenby et al., Angiology, (1991), 42, 418-420.
`H. Hamilton et al., J. Med. Chem., (1987), 30, 91-96.
`H. Padma—Nathanet al., Sem. in Urol., (Nov. 1986), vol. IV,
`No. 4, 236-238.
`J. Beavo et al., TiPS, (Apr. 1990), 11, 150-155.
`S. Korenman et al., Clin, Res., (1988), 36, 123A.
`D. Halsted et al., J. Urol, (Jul. 1986), 136, 109-110.
`W. Thompson, Pharmac. Ther., (1991), 51, 13-33.
`M. Giembyczet al., Clin. and Exper. Allergy, (1992), 22,
`337-344.
`C. Nicholson et al., TIPS, (Jan. 1991), 12, 19-27.
`J. LeBlanc et al, Eur. J. Cardiothorac Surg., (1993), 7,
`211-215.
`C. Stief et al., J. Urol., (Nov. 1992), 148, 1437-1440.
`C, Stief et al., World J. Urol., (1991), 9, 237-239,
`C. Clyne et al., Br J. Surg., (Apr. 1987), 74, 246-248.
`V. Mironeet al., Acta. Urol. Ltd., (1992), Suppl. 4, 11-12.
`P. Bush, Ph.D. Thesis (1992), pp. 159-160.
`T. Lincoln, Pharmac. Ther., (1989), 41, 479-502.
`J. Heaton et al., Urology, (Feb. 1995), 45(2), 200-206.
`Brindley, Brit. J. Phychiat., (1983), 143, 332-337.
`Keogh, Aust. NZ. J. Med., (1989), 19, 108-112.
`Funderbunk, New Engl. J. Med., (1974), 290, 630-631.
`Beretta, Acta European Fertilitatis, (1986), 17, 43-45.
`“Physicians’ Desk Reference,” (1992), 1778-1779.
`Hess in “Prazosin: Evaluation of a New Antihypertensive
`Agent,” D. Cotton ed., American Elsevier, NY, (1974), 3-15.
`Dadkaret al., Ind. J. Exp. Biol., (1982), 20, 484-487.
`D’Armientoet al., Eur. J. Pharmacol., (1980), 65, 234-247.
`Bhalla et al., Brit. Med. J., (1979), 2, 1059.
`Burkeet al., Med. J. Aust., (1980), 382-383.
`
`ATI 1003-0002
`
`ATI 1003-0002
`
`

`

`6,140,329
`
`1
`USE OF CGMP-PHOSPHODIESTERASE
`INHIBITORS IN METHODS AND
`COMPOSITIONS TO TREAT IMPOTENCE
`
`This application is a 371 of PCT/EP96/03024, filed Jul.
`11, 1996.
`This invention relates to the use of tetracyclic derivatives
`whichare 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, ¢.g. intraurethrally or intracavernosally(i.c.),
`and are not approvedfor 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 E,, either alone or in combination; however, pain,
`priapism andfibrosis of the penis are associated with thei.c.
`administration of some of these agents. Potassium channel
`openers (KCO)and vasoactive intestinal polypeptide (VIP)
`have also been shownto 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 shownto beeffective
`but produces side-effects in both patient and partner.
`As a generalalternative 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 treatmenta 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 (1):
`
`®
`
`and salts and solvates (e.g. hydrates) thereof, in which:
`R° represents hydrogen, halogen or C,_, alkyl;
`R’
`represents hydrogen, C,_,alkyl, C,_,alkenyl,
`C, ,alkynyl, haloC, ,alkyl, C3 _,cycloalkyl,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`60
`
`65
`
`ATI 1003-0003
`
`2
`C,_scycloalkylC,_,alkyl,
`heteroarylC,,alkyl;
`R* represents an optionally substituted monocyclic aro-
`matic ring selected from benzene,
`thiophene, furan and
`pyridine or an optionally substituted bicyclic ring
`
`arylC,_,alkyl or
`
`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 atomsand optionally
`one or two heteroatoms selected from oxygen, sulphur and
`nitrogen; and
`R® represents hydrogen or C,_3alkyl, or R’ and R*
`together represent a 3- or 4-membered alkyl or alkenyl
`chain.
`Suitable individual compoundsof the invention for use in
`the treatment of erectile dysfunction include:
`Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethy])-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 Jindole-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 Jindole-1,4-dione;
`Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylpheny])-
`pyrazino[2',1':6,1 ]pyrido[3,4-b Jindole-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 Jpyrido[3,4-b Jindole-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 Jpyrido[3,4-b Jindole-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-methy]-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);
`
`ATI 1003-0003
`
`

`

`6,140,329
`
`10
`
`15
`
`25
`
`30
`
`35
`
`20
`
`3
`4
`and physiologically acceptable salts and solvates (e.g.
`will generally be administered in admixture with a pharma-
`hydrates) thereof.
`ceutical carrier selected with regard to the intended route of
`Unexpectedly, it has now been found that compoundsof
`administration and standard pharmaceutical practice. For
`formula (1), and in particular compounds A andB,are useful
`example, the compound may be administered orally, buc-
`in the treatment of erectile dysfunction. Furthermore the
`cally or sublingually,
`in the form of tablets containing
`compounds may be administered orally, thereby obviating
`excipients such as starch or lactose, or in capsules or ovules
`the disadvantages associated with i.c. administration. Thus
`either alone or in admixture with excipients, or in the form
`the present invention concerns the use of compounds of
`of elixirs or suspensions containing flavouring or colouring
`formula (I), and in particular compounds A and B, or a
`agents. Such liquid preparations may be prepared with
`pharmaceutically acceptable salt thereof, or a pharmaceuti-
`pharmaceutically acceptable additives such as suspending
`cal composition containing either entity, for the manufacture
`agents (e.g. methylcellulose, a semi-synthetic glyceride such
`of a medicamentfor the curative or prophylactic treatment
`as witepsol or mixtures of glycerides such as a mixture of
`of erectile dysfunction in a male animal, including man.
`apricot kernel oil and PEG-6 esters or mixtures of PEG-8
`The pharmaceutically acceptable salts of the compounds
`and caprylic/capric glycerides).
`of formula (1), and in particular compounds A and B which
`contain a basic centre are acid addition salts formed with
`For veterinary use, a compound of formula (1), and in
`particular compound A or B or a non-toxic salt thereof is
`pharmaceutically acceptable acids. Examples include the
`administered as a suitably acceptable formulation in accor-
`hydrochloride, hydrobromide, sulphate or bisulphate, phos-
`dance with normal veterinary practice and the veterinary
`phate or hydrogen phosphate, acetate, benzoate, succinate,
`surgeon will determine the dosing regiment and route of
`fumarate, maleate,
`lactate, citrate,
`tartrate, gluconate,
`administration which will be most appropriate for a particu-
`methanesulphonate, benzenesulphonate and
`lar male animal.
`p-toluenesulphonate salts. Compoundsof formula(1),and in
`Thus the invention includes a pharmaceutical composi-
`particular compoundsA and B canalso provide pharmaceu-
`tion for the curative or prophylactic treatment of erectile
`tically acceptable metalsalts, in particular alkali metal salts,
`dysfunction in a male animal, including man, comprising a
`with bases. Examples include the sodium and potassium
`salts.
`compound of formula (I), and in particular compound A or
`B, or a pharmaceutically acceptable salt thereof, together
`It has been shown that compoundsof the present inven-
`with a pharmaceutically acceptable diluent or carrier.
`tion are potent and selective inhibitors of cGMPspecific
`There is further provided a process for the preparation of
`PDE. It has now been surprisingly found that human corpus
`a pharmaceutical composition for the curative or prophy-
`cavernosum contains three distinct PDE enzymes. The pre-
`lactic treatment of erectile dysfunction in a male animal,
`dominant PDE has further surprisingly been found to be
`including man, comprising formulating a compound of
`cGMP PDE. As a consequence of the selective PDE V
`formula (I), and in particular compound A or B, or a
`inhibition exhibited by compoundsof the present invention,
`pharmaceutically acceptable salt thereof, with a pharmaceu-
`the subject compounds can elevate cGMPlevels, which in
`tically acceptable diluent or carrier.
`turn can mediate relaxation of the corpus cavernosum tissue
`The invention also provides a method oftreating a male
`and consequent penile erection.
`animal, including man, to cure or prevent erectile dysfunc-
`Although the compounds of the invention are envisaged
`tion which comprises treating said male animal with an
`primarily for the treatment of erectile dysfunction or male
`effective amount of a compound of formula (1), and in
`sexual dysfunction, they mayalso be useful for the treatment
`
`of female sexual dysfunction including orgasmic dysfunc- particular compoundAor B, or a pharmaceutically accept-
`40
`tion related to clitoral disturbances.
`able salt thereof, or a pharmaceutical composition contain-
`Generally, in man, oral administration of the compounds
`ing either entity.
`of the invention is the preferred route, being the most
`Moreover, the invention includes the use of a compound
`of formula (I), and in particular compound A or B, or a
`convenient and avoiding the disadvantages associated with
`ic. administration.
`In circumstances where the recipient
`pharmaceutically acceptable salt thereof, or a pharmaceuti-
`suffers from a swallowing disorder or from impairment of
`cal composition containing either entity, for the manufacture
`drug absorption after oral administration, the drug may be
`of a medicamentfor the curative or prophylactic treatment
`administered parenterally, e.g. sublingually or buccally.
`of erectile dysfunction in a male animal, including man.
`A compound of formula (1), and in particular compound.
`For administration to man in the curative or prophylactic
`treatment of the disorders identified above, oral dosages of
`A or B, may also be used in combination with other
`a compound of formula (1), and in particular compounds A
`therapeutical agents which maybe useful in the treatment of
`and B will generally be in the range of from 0.5-800 mg
`erectile dysfunction substantially as hereinbefore described.
`daily for an average adult patient (70 kg). Thusfor a typical
`The invention thus provides, in another aspect, a combina-
`tion of a compound of formula (I), and in particular com-
`adult patient, individual tablets or capsules contain from
`0.2-400 mg of active compound, in a suitable pharmaceu-
`pound A or B together with another therapeutically active
`agent.
`tically acceptable vehicle or carrier, for administration in
`single or multiple doses, once or several times per day.
`The combination referred to above may conveniently be
`Dosages for buccal or sublingual administration will typi-
`presented for use in the form of a pharmaceutical formula-
`cally be within the range of from 0.1-400 mg per single dose
`tion and thus pharmaceutical compositions comprising a
`as required. In practice the physical will determine the actual
`combination as defined above together with a pharmaceuti-
`dosing regiment which will be most suitable for an indi-
`cally acceptable diluent or carrier comprise a further aspect
`of the invention.
`vidual patient and it will vary with the age, weight and
`response of the particular patient. The above dosages are
`The individual components of such a combination may
`exemplary of the average case but there can be individual
`also be administered either sequentially or simultaneously in
`instances in which higher or lower dosage ranges may be
`separate pharmaceutical formulations.
`merited, and such are within the scope of this invention.
`Appropriate doses of known therapeutic agents for use in
`For human use, compounds of formula (I), and in par-
`combination with a compound of the invention will be
`ticular compounds A and B can be administered alone, but
`readily appreciated by those skilled in theart.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`ATI 1003-0004
`
`ATI 1003-0004
`
`

`

`6,140,329
`
`5
`The compoundsof the invention may be prepared by any
`suitable method knownin theart or by the following process
`which forms part of the present invention. The process has
`been previously substantially described in the priority docu-
`mentof the present invention GB9514464.8, and in WO95/
`19978. Thus, a process for preparing a compound of formula
`(1) comprises treating a compound of formula (1)
`
`a)
`
`(in which Alk represents C,_,alkyl, e.g. methyl or ethyl and
`Halis a halogen atom, e.g. chlorine) with a primary amine
`R‘NH,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)
`
`
`
`(In)
`
`(Vv)
`
`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 suchas triethylamine)
`or an alkali metal carbonate or bicarbonate (e.g. NaHCO,).
`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 enantiomerof
`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(II).
`Individual enantiomers of the compoundsofthe invention
`may be prepared form racemates by resolution using meth-
`ods knownin 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)
`
`ATI 1003-0005
`
`(Vv)
`
`
`
`(where Alk is as previously defined) ora salt thereof(e.g. the
`hydrochloride salt) with an aldehyde R*CHO. Thereaction
`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 (IID in one step. The
`reaction may also be carried out in a solvent such as an
`aromatic hydrocarbon(e.g. benzeneor 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 maybeeither 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. Individualcis or trans enanti-
`omers may conveniently be separated from pictures thereof
`byfractional 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 mayalso 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 beisolated byfiltra-
`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 ina
`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 mannerby treating a
`solution of compound AorB with a suitable base. Both types
`of salt may be formed or interconverted using ion-exchange
`resin techniques.
`Compoundsofthe invention may beisolate din associated
`with solvent molecules by crystallisation from or evapora-
`tion of an appropriate solvent.
`The syntheses of compounds A and B and ofthe inter-
`mediates for use therein are illustrated by the following
`examples. The examples have been previously described in
`the priority documentof 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:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`ATI 1003-0005
`
`

`

`6,140,329
`
`8
`7
`
`MeOH (methanol) and EtOH (ethanol), Toastirred solution of intermediate 2 (0.3 g, 0.68 mmol)
`Intermediate 1 (54)
`in THF (30 mL) was added at room temperature a solution
`(1R,3R)-Methyl 1,2,3,4-tetrahydro-1-(3,4-
`of methylamine (33% in EtOH) (0.68 mL) andtheresulting
`methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-
`solution was treated at reflux under N, for 6 days. The
`carboxylate, cis isomer
`solvent was removed under reduced pressure and the residue
`To a stirred solution of D-tryptophan methylester (11 g)
`wasdissolved in CHCl, (50 mL). After washing with water
`and piperonal(7.9 g) in anhydrous CHCl, (400 mL) cooled
`(2,25 mL), drying over Na,SO, and evaporating to dryness,
`at 0° C. was added dropwise trifluoroacetic acid (7.7 mL)
`the crude product was purified by flash chromatography
`and the solution was allowed to react at ambient tempera-
`eluting with dichloromethane/methanol: 99/1. The oily resi-
`ture. After 4 days,
`the yellow solution was diluted with
`due obtained wascrystallised from methanolto give the title
`CH,CL, (200 mL) and washed with a saturated aqueous
`compound as white crystals (40 mg) m.p.: 307-309° C.
`solution of NaHCO, then with water (3x200 mL) and dried
`Analysis for C,,H,,N,0,: Calculated: C,68.47; H,5.25;
`over Na,SO,. The organic layer was evaporated under
`N,10.42; Found: C,68.35; H,5.33; N,10.42%. [af,=+
`reduced pressure and the residue containing the two geo-
`65.2° (C=1.15; CHCL).
`metric isomers was purified by flash chromatographyeluting
`The following compound was similarly prepared:
`with dichloromethane/ethyl acetate (97/3) to giveasthefirst
`eluting product the title compound (6.5 g)
`EXAMPLE3
`m.p.: 154° C.
`(3S,6R,12aR)-2,3,6,7,12,12a-Hexahydro-3-methyl-6-(3,4-
`Intermediate 2 (83)
`methylenedioxyphenyl)-pyrazino[2',1';6,1 ]pyrido[3,4-b]
`(1R,3R)-Methyl 1,2,3,4-tetrahydro-2-(2-chloropropionyl)-
`indole-1,4-dione as white crystals using ammonia as the
`1-(3,4-methylenedioxyp henyl)-9H-pyrido[3 ,4-b Jindole-3-
`base.
`carboxylate
`m.p.: 319-321° C. Analysis for C,,H,.N;0,: Calculated:
`To a solution of (R)-(+)-2-chloropropionic acid (191 yd,
`C,67.86; H,4.92; N, 10.79; Found: C,67.86; H,5.17;
`2.2 mmol) in anhydrous dichloromethane (30 mL), was
`N,10.72%. [a}°,=+107° (C=1; pyridine).
`added dicyclohexylearbodiimide (0.45 g, 2.2 mol). Interme-
`Compounds A and B have been included in pharmacy
`diate 1 (0,7 g, 2 mmol) was then added and the mixture was
`formulations and details of such formulations are given
`stirred at room temperature for 20 hours. The formed
`below.
`precipitate of dicyclohexylurea was removedbyfiltration,
`TABLETS FOR ORAL ADMINISTRATION
`the filtrate was evaporated in vacuo and the crude product
`was purified by flash chromatography eluting with toluene/
`A. Direct Compression
`ethyl acetate: 95/5. The oily compound obtained was then
`crystallised from either/hexaneto give the title compound as
`pale yellow crystals (0.74 g)
`m.p.: 126-128° C.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1.
`
`me/tablet
`
`EXAMPLE1 (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
`NaHCO, (0.14 g) in anhydrous CHCL, (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 CHC1, (20 mL). Water (10 mL)
`was then added dropwise with stirring to the mixture,
`followed by a saturated solution of NaHCO. The organic
`layer was washed with water until neutrality and dried over
`Na,SO,. 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 suspensionof 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 N, for 16
`hours. The solvent was removed under reduced pressure and
`the residue was dissolved in CHCl, (50 mL). After washing
`with water (3x20 mL), drying over Na,SO, and evaporating
`to dryness, the residue waspurified by flash chromatography
`eluting with CH,Cl./MeOH (99/1) and recrystallised from
`2-propanolto give the title compound as white crystals (0.22
`g
`
`m.p.: 302—303° C. Analysis for C,,H,.N,0,: Calculated:
`C,67.86; H,4.92; N,10.79; Found: C,67.77; H,4.92;
`N,10.74%. [af° ,=+71.0° (C=1.00; CHCL).
`EXAMPLE2 (117) (Compound B)
`(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,
`4-methylenedioxypheny])-pyrazino[2',1';6,1 ]pyrido[3,4-b]
`indole-1,4-dione
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Active ingredient
`Crospovidone USNF
`Magnesium Stearate Ph Eur
`Anhydrous Lactose
`
`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 Lauryl Sulphate
`Magnesium Stearate Ph Eur
`Microcrystalline Cellulose USNF
`
`me/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.
`B. WET GRANULATION
`
`1.
`
`Active ingredient
`Polyvinyl pyrollidone
`Polyethylene glycol
`Polysorbate 80
`Magnesium Stearate Ph Eur
`Croscarmellose Sodium
`Colloidal Silicon Dioxide
`Microcrystalline Cellulose USNF
`
`me/tablet
`
`50.0
`150.0
`50.0
`10.0
`2.5
`25.0
`2.5
`210.0
`
`The polyvinyl pyrollidone, polyethylene glycol and
`polysorbate 80 were dissolved in water. The resultant