[19]
`United States Patent
`6,140,329
`[11] Patent Number:
`[45] Date of Patent: Oct. 31, 2000
`Daugan
`
`
`
`USOO6140329A
`
`[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] US. Cl.
`.............................................................. 514/250
`[58] Field of Search ............................................... 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
`5,270,323
`
`2/1972 Schulenberg ........................ 260/295 C
`2/1973 Schulenberg
`260/268 PC
`
`..
`11/1975 Saxena et a1.
`260/268 PC
`2/1980 Campbell ..................... 424/251
`
`..... 514/307
`8/1987 Campbell et a1.
`..
`
`9/1992 Virag ........................ 514/253
`...................... 514/309
`12/1993 Milne, Jr. et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`...... C07D 471/04
`3/1990 European Pat. Off.
`0 357 122
`...... C07D 241/08
`4/1990 European Pat. Off.
`0 362 555
`..... A61K 31/505
`12/1991
`European Pat. Off.
`459 666
`...... C07D 487/04
`1/1992 European Pat. Off.
`463 756
`...... C07D 487/04
`2/1993
`European Pat. Off.
`526 004
`2/1991
`Japan ............................. A61K 31/52
`03044324
`10/1976 United Kingdom
`C07D 471/14
`1 454 171
`
`11/1989 WIPO ..................... A61K 31/35
`WO 89/10123
`
`WO 94/28902 12/1994 WIPO
`A61K 31/505
`
`7/1995 WIPO .......................... C07D 471/14
`WO 95/19978
`
`OTHER PUBLICATIONS
`
`A. Bowman et a1., Br. J. Pharmac., (1984), 81, 665—674.
`F. Trigo—Rocha et a1., Am. J. Physiol, (Feb. 1993), 264,
`H419—H422.
`
`J. Reiser et a1., Br. J. Dis. Chest, (1986), 80, 157—163.
`P. Bush et a1., J. Urol, (Jun. 1992), 147, 1650—1655.
`F. Holmquist et al., J. Ural. (Oct. 1993), 150, 1310—1315.
`R. Rudd et a1., Br: J. Dis. Chest, (1983), 77, 78—86.
`E. McMahon et a1.,J. Pharmacol. Exp. Thera., (1989), 251,
`1000—1005.
`
`F. Holmquist et a1., Acta Physiol. Scand, (1991), 143,
`299—304.
`
`G. Barbanti, Ural. Res., (1988), 16, 299—302.
`L. Ignarro et a1., Biachem. and Biophys. Res. Commun,
`(1990), 170(2), 843—850.
`J. Krall et a1., Bio. Reprod., (1988), 39, 913—922.
`
`ATI 1003-0001
`
`M. Wilkins et a1., Prac. Natl. Acad. Sci, USA, Aug. 1990),
`87, 6465—6469.
`M. Wilkins et
`1274—1279.
`
`(Apr. 1990), 85,
`
`a1., J. Clin.
`
`Invest,
`
`J. Raifer, N. Eng. J. Med, (Jan. 1992), 326(2), 90—94.
`H. Knispel, Ural. Res, (1992), 20, 253—257.
`G. Gwinup, Annals. of Internal Medicine,
`162—163.
`
`(Jul. 1988),
`
`A. Zorgniotti, J. Ural, (Apr. 1992), 147(4), 308A.
`K. Azadzoi et a1.,J. Ural, (NOV. 1992), 148, 1587—1591.
`K. Azadzoi et a1., J. Urol, (Jan. 1992), 147, 220—225.
`C. Sparwasser et a1.,J. Ural, (Dec. 1994), 152, 2159—2163.
`T. Lue, “Campbell’s Urology,” 6th Ed., Chap. 16, P. Walsh
`et a1., Eds., W.B. Saunders Co., 709—728 (1991).
`N. Kim et a1., 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. Weishaar et a1., J. Med. Chem, (1985), 28:5, 537—542.
`H. Ahn et
`a1., Biachem. Pharmacol,
`(1989), 39:19,
`331—3339.
`
`C. Lugnier et a1., Biochem. Pharmacol, (1986), 35:10,
`1743—1751.
`
`J. Doremieux et a1., Ann. Ural. Paris,
`429—434.
`
`(1987), 21(6),
`
`D. Green et a1., Geriatrics, (Jan. 1993), 48(1), 46—58.
`M. Webster et a1., Hematol. Oncol. Cl. of N. Am, (Feb.
`1990), 4(1), 265—289.
`F. Holmquist et a1., Acta. Physiol. Scand, (1991), 141,
`441—442.
`
`J. Taher et a1., J. Ural, (Apr. 1993), 149, 285A.
`S. Uckert et a1.,
`, 495A.
`W. Aronson et a1., J. Urol, (1991), 145 (4 Supp), 341A.
`P. Bush et a1., Fed. Am. Soc. Exp. Biol, (1991), 5(4), 175.
`P. Bush et a1., Fed. Am. Soc. Exp. Biol, (1992), 6(4), 2092.
`W. Aronson et a1., J. Ural, (1992), 147 (4 Supp), 454A.
`P. Bush et
`a1., Circulation,
`(May 1993), 87 Supp. V,
`V—30—V—32.
`
`R. Pickard et a1., J. Urol, (May 1993) 149 (4 Supp), 245A.
`R. Pickard et a1., Clin. Pharmacol, (Jan. 1993), 35(5),
`536P—537P.
`
`F. Trigo—Rocha et a1., J. Ural, (Apr. 1993), 149, 872—877.
`M. Krupp et al., J. Cardiavas. Pharmacol, (1989), 13
`(Supp. 2), $11—$19.
`“Physicians” Desk Reference,” (1992), 683,1099—1100,
`1344, 1941—1943.
`R. Morales et a1., World J. Ural, (1990), 8, 80—83.
`J. Cortijo, Br. J. Pharmacol, (Feb. 1993), 108(2), 562—568.
`
`(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-hexahydr0-2-methy1-
`6-(3,4-methy1enedi0xypheny1)-pyrazino[2',1‘:6,1]pyrido[3,
`4-b]ind01e-1,4-di0ne,
`(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]ind01e-1,4-di0ne, and
`physiologically acceptable salts and solvates thereof,
`in
`methods and compositions for the treatment of impotence.
`
`21 Claims, No Drawings
`
`ATI V. ICOS
`
`IPR2018-01183
`
`ATI 1003-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`Earl et al., Life Sciences, (1984), 35, 525—534.
`Saxena et al., Journal ofMedicinal 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).
`Brana et 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).
`
`al., Tetrahedron,
`
`46, No.
`
`9,
`
`6,140,329
`
`Page 2
`
`Segasouthy et al., Med. J. Malaysia, (1982), 37(4), 384.
`Ylitalo et al., Acta Med. Scand., (1983), 213, 319—320.
`Robbins et al., J. Urol, (1983), 130, 975.
`Adams et al., J. Urol, (1984), 132, 1208.
`Russell et al., Med. J. Aust., (1985), 143, 321.
`Taher et 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 Behau, (1981), 27, 731—733.
`Pickard et al., Br. J. Pharmacol, (1991), 104 755—759.
`Martinez—Pineiro et al., Eur. Urol, (1993), 24, 492—499.
`Mirone et al., Br. J. Urol, (Mar, 1993), 71(3), 365.
`Murray et 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.
`
`OTHER PUBLICATIONS
`
`E. Kim et al.,J. Urol, (1995), 153, 361—365.
`S. Korenman et 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—Nathan et 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. Giembycz et 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. Mirone et 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.
`Dadkar et al., Ind. J. Exp. Biol, (1982), 20, 484—487.
`D’Armiento et al.,Eur. J. Pharmacol, (1980), 65, 234—247.
`Bhalla et al., Brit. Med. J., (1979), 2, 1059.
`Burke et al., Med. J. Aust., (1980), 382—383.
`
`ATI 1003-0002
`
`ATI 1003-0002
`
`

`

`1
`USE OF CGMP-PHOSPHODIESTERASE
`INHIBITORS IN METHODS AND
`COMPOSITIONS TO TREAT IMPOTENCE
`
`6,140,329
`
`2
`
`C378cycloa1ky1C173alkyl,
`heteroarlelisalkyl;
`R2 represents an optionally substituted monocyclic aro-
`matic ring selected from benzene,
`thiophene, furan and
`5 pyridine or an optionally substituted bicyclic ring
`
`ary1C173a1ky1 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
`
`(I)
`
`55
`
`
`
`and salts and solvates (e.g. hydrates) thereof, in which:
`R0 represents hydrogen, halogen or C1,6 alkyl;
`R1 represents hydrogen, Clifialkyl, Czifialkenyl,
`C276a1kynyl, haloClisalkyl, C378cycloalky1,
`
`ATI 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 C173alkyl, 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-y1)-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‘,1'26,1]pyrido[3,4-b]indole-1,4-dione;
`Cis-2,3,6,7,12,12a-hexahydro-2-buty1—6-(4-methy1pheny1)—
`pyrazino[2‘,1‘:6,1]pyrido[3,4-b]indole-1,4-dione;
`(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropy1-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2',1‘26,1]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‘26,1]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‘26,1]pyrido[3,4-b]
`indole-1,4-dione;
`(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2',1'26,1]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‘26,1]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',1'26,1]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‘26,1]pyrido[3,4-b]
`indole-1,4-dione(Compound A); and
`(35,6R,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
`
`

`

`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 05—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.
`
`ATI 1003-0004
`
`ATI 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 Clisalkyl, 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 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)
`
`(111)
`
`(1V)
`
`
`
`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)
`
`ATI 1003-0005
`
`
`
`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:
`
`ATI 1003-0005
`
`

`

`7
`
`8
`
`6,140,329
`
`MeOH (methanol) and EtOH (ethanol),
`Intermediate 1 (54)
`1 ,2,3,4-tetrahydro-1 -(3,4-
`(1R,3R)-Methyl
`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 CHZCl2 (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 (3x200 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 MI,
`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 CHCl3 (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 CHCl3 (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 (3x20 mL), drying over Na2SO4 and evaporating
`to dryness, the residue was purified by flash chromatography
`eluting with CH2C12/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 NazSO4 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) mp: 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=+
`652° (C=1.15; CHC13).
`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.
`B. WET GRANULATION
`
`1.
`
`Active ingredient
`Polyvinyl pyrollidone
`Polyethylene glycol
`Polysorbate 80
`Magnesium Stearate Ph Eur
`Croscarmellose Sodium
`Col