CA2340636C - Combinations of tetracyclic cyclic gmp-specific phosphodiesterase inhibitors with further therapeutic agents - Google Patents

Combinations of tetracyclic cyclic gmp-specific phosphodiesterase inhibitors with further therapeutic agents Download PDF

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CA2340636C
CA2340636C CA002340636A CA2340636A CA2340636C CA 2340636 C CA2340636 C CA 2340636C CA 002340636 A CA002340636 A CA 002340636A CA 2340636 A CA2340636 A CA 2340636A CA 2340636 C CA2340636 C CA 2340636C
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indole
pyrido
dione
methyl
hexahydro
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CA2340636A1 (en
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Alain Claude-Marie Daugan
Francoise Gellibert
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Icos Corp
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    • C07D471/14—Ortho-condensed systems

Abstract

A compound of formula (I) and salts and solvates thereof, in which: R0 represents hydrogen, halogen, or C1-6alkyl; R1 represents hydrogen, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, C3-8cycloalkyl, C3-8cyloalkylC1-3alkyl, arylC1-3alkyl, or heteroarylC1-3alkyl; R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring (a) attached to the rest of the molecule via one of the benzene ring carbon atoms, and wherein the fused ring (A) is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen;
and R3 represents hydrogen or C1-3alkyl, or R1 and R3 together represent a 3- or 4-membered alkyl or alkenyl chain. A compound of formula (I) is a potent and selective inhibitor of cyclic guanosine 3', 5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having a utility in a variety of therapeutic areas where such inhibition is beneficial, including the treatment of cardiovascular disorders and erectile dysfunction.

Description

COMBINATIONS OF TETRACYCLIC CYCLIC GMP-SPECIFIC PHOSPHODIESTERASE
INHIBITORS WITH FURTHER THIERAPEUTIC AGENTS

FIELD AND SACKGROUND OF THE INVENTION
This invention relates to a series of tetracyclic derivatives, to processes for their preparation, pharmaceutical con-positions containing them, and to their use as therapeutic agents. In particular, the invention relates to tetracyclic derivatives that are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP-specific PDE) having utility in a variety of therapeutic areas where such inhibi-tion is thought to be beneficial, including the treatment of cardiovascular disorders and erectile dysfunction.

SUMMARY OF THE INVENTION

Thus, according to a first aspect, the present invention provides compounds of formula (I) 3 0 N, R3 <)~ RO I
N

(I}
and salts and solvates (e.g., hydrates) thereof, in which:
R represents hydrogen, halogen, or C1-6alkyl;
Rl represents hydrogen, C1-6alkyl, C2_6_ -alkenyl, C2_6alkynyl, haloC1_6alkyl, C3-acycloalkyl, C3-gcycloalkylC1-3alkyl, ary1C1_3alkyl, or hetero-arylCI_3alkyl;
R 2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring / I A

attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen; and R3 represents hydrogen of C1_3alkyl, or Rl and R3 together represent a 3- or 4-membered alkyl or alkenyl chain.
There is further provided by the present invention a subgroup of compounds for formula (I), the subgroup comprising compounds of formula (Ia) / I I N-Rl R~
\ N~
H

( Ia) and salts and solvates (e.g., hydrates) thereof, in which:
R represents hydrogen, halogen, or C.
6alkyl;
Rl represents hydrogen, C1_6alkyl, haloCl_6-alkyl, C3_scycloalkylC1_3alkyl, arylC1-3alkyl, or heteroarylCl_3alkyl; and R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring ce 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 can be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen.
There is yet further provided by the present invention a further subgroup of compounds of formula (I), the-compounds comprising compounds of formula (Ib) -RO
\. N= *

H

(Ib) and solvates (e.g., hydrates) thereof, in which:
R represents hydrogen, halogen, or C1_6-alkyl;
R1 represents hydrogen or C1-6alkyl;
R2 represents the bicyclic ring o r o o--1 which can be optionally substituted by one or more groups selected from halogen and C1-3alkyl; and R3 represents hydroger.i or Cl_3alkyl.
Within R1 above, the term "aryl" as part of an arylC1=3alkyl group means phenyl or phenyl substi-tuted by one or more (e.g., 1, 2, or 3) substituents selected from halogen, Cl_6alkyl, C1_6alkoxy, and methylenedioxy. The term "heteroaryl" as part of a heteroarylCl_3alkyl group means thienyl, furyl, or pyridyl, each optionally substituted by one or more (e.g., 1, 2, or 3) substituents selected from halo-gen, Cl_salkyl, and C1_6alkoxy. The term "C3_8cyclo-alkyl" as a group or part of a C3_BCycloalkylCl-3alkyl group means a monocyclic ring comprising three to eight carbon atoms. Examples of suitable cycloalkyl rings include the C3_6cycloalkyl rings cyclopropyl, -cyclobutyl, cyclopentyl, and cyclohexyl.
Within R2 above, optional benzene ring substituents are selected from one or more (e.g., 1, 2, or 3) atoms or groups comprising halogen, hy-droxy, C1_6alkyl, C1-6alkoxy, C02Rb, haloC,_6alkyl, halo-C,_6alkoxy, cyano, nitro, and NR3Rb, where Ra and Rb are each hydrogen or C,..6alkyl, or R' also can repre-sent C2-7alkanoyl or C,_6alkylsulphonyl. Optional substituents for the remaining ring systems are selected from one or more (e.g., 1, 2, or 3) atoms or groups comprising halogen, C,-6alkyl, C1_6alkoxy, and arylCl-?alkyl as defined above. The bicyclic ring CA
can, for example, represent naphthalene, a hetero-cycle such as benzoxazole, benzothiazole, benzisox-azole, benzimidazole, quinoline, indole, benzothio-phene, benzofuran, or ( CH2) n cry wherein n is an integer 1 or 2 and X and Y each can represent CH2, 0, S, or NH.
In the above definitions, the term "alkyl," as a group or part of a group, means a straight chain or, where available, a branched chain -moiety containing the indicated number of carbon atoms. For example, it can represent a C1_4alkyl function as represented by methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. The term "alkenyl" as used herein includes straight chained and branched alkenyl groups containing the indicated number of carbon atoms, such as vinyl and allyl groups. The term "alkynyl" as izsed herein includes straight chained and branched alkynyl groups con-taining the indicated number of carbon atoms, suit-ably acetylene.
The term "halogen" herein means a fluor-ine, chlorine, bromine, or iodine atom.
The term "haloC,_6alky]." means an alkyl group as defined above comprising one to six carbon atoms substituted at one or more carbon atoms by one or more (e.g., 1, 2, or 3) halogen atoms. Similar-ly, a haloCl_6alkoxy group is a haloCl_6alkyl group as defined above linked to the R2 benzene ring via an oxygen atom. Examples of haloC7_6alkyl groups include trifluoromethyl and 2,2,,2-trifluoroethyl.
An example of a haloC1_6alkoxy group is trifluoro-methoxy. The term "C2-,alkanoyl" means a C1_6alkanoyl group where the C1_6alkyl portiori is as defined above. An example of a suitable C2-7alkanoyl group is the C2alkanoyl group acetyl.
When R is a halogen atom or a C1_6alkyl group, this substituent can be sited at any avail-able position on the phenyl portion of the tetra-cyclic ring. However, a particular site of attach-ment is the ring 10-position.
The compounds of formula (I) can contain two or more asymmetric centers, and, thus, can exist -as enantiomers or diastereoisom.ers. In particular, in formula (I) above, two ring chiral centers are denoted with asterisks. It is to be understood that the invention includes both mixture and separate individual isomers of the compounds of formula (I).
The compounds of formula (I) also can exist in tautomeric forms, and the invention includes both mixtures and separate individual tautomers thereof.
The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic center are acid addition salts formed with pharma-ceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, and p-toluenesulphonate salts. Compounds of formula (I) also can provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases.
Examples include the sodium and potassium salts.
A particular group of compounds of the invention are those compounds of formula (I) in which R is hydrogen or halogen (e.g., fluorine), especially hydrogen.
Another particular group of compounds of the invention are those compounds of formula (I) in which Rl represents hydrogen, C7_9alkyl, haloCl_qalkyl, C3_6cycloalkyl, C3_6cycloalkylmethyl, pyridylC1_3alkyl, furylCl_3alkyl, or optionally su;bstituted benzyl.
Within this particular group of compounds, examples of C1_9alkyl groups are methyl, ethyl, n-propyl, i-propyl, and n-butyl. Examples of C3_6cycloalkyl- -methyl groups are cyclopropylmethyl and cyclohexyl-methyl. Examples of optionally substituted, benzyl groups include benzyl and halobenzyl (e.g., fluoro-benzyl ) .
A further group of compounds of the inven-tion are those compounds of formula (I) in which R2 represents an optionally substituted benzene, thio-phene, furan, pyridine, or naphthalene ring, or an optionally substituted bicyclic ring (CHZ' n cry wherein n is 1 or 2, and X and Y are each CH2 or 0.
Within this particular group of compounds, examples of substituted benzene groups are benzene substi-tuted by one of halogen (e.g.,.chlorine), hydroxy, C1-3al kyl ( e. g., methyl, ethyl, or i-propyl ), C1_3-alkoxy (e.g., methoxy or ethoxy), C02Rb, halomethyl (e.g., trifluoromethyl), halomethoxy (e.g., tri-fluoromethoxy), cyano, nitro, or NRaRb wherein Ra and Rb are each hydrogen or methyl, or Ra is acetyl, or benzene substituted by dihalo (e.g., dichloro) or by C1_3alkoxy (e.g., methoxy) and one of halogen (e.g., chlorine) and hydroxy. An example of a substituted _ g -thiophene ring is a halo (e.g., bromo) substituted thiophene ring.
A still further particular group of com-pounds of formula (I) are those where R3 represents hydrogen or R' and R3 together represent a 3-membered -alkyl chain.
A preferred group of compounds of the invention are the cis isomers of formula (I) repre-sented by formula (Ic) O
R9 N-Rl H =

(Ic) and mixtures thereof with their cis optical enantiomers, including racemic mixtures, and salts and solvates (e.g., hydrates) of these compounds in which R is hydrogen or halogen (e.g., fluorine), especially hydrogen, and R', R2, and R3 are as defined previously.
The single isomers represented by formula (Ic), i.e., the 6R, l2aR isomers, are particularly preferred.
Within the above definitions, R1 preferably can represent C1-4alkyl (e.g., methyl, ethyl, i-propyl, and n-butyl), C3_6cycloalkyl (e.g., cyclo-pentyl) or C3_6cycloalkylmethyl (e.g., cyclopropyl-methyl ) .
R2 preferably can represent a substituted benzene ring such as benzene su:bstituted by C1_3-WO 00l15228 PCT/US99/19466 alkoxy (e.g., methoxy) or by C1_3alkoxy (e.g., meth-oxy) and halogen (e.g., chloririe), particularly 4-methoxyphenyl or 3-chloro-4-methoxyphenyl, or R2 preferably can represent 3,4-methylenedioxyphenyl.
A particularly preferred subgroup of --compounds according to the present invention are compounds wherein R represents hydrogen.
A further preferred subgroup includes compounds wherein R' is selected from hydrogen, methyl, and isopropyl.
Preferably, R2 represents the unsubstituted bicyclic ring 90) ~~ 20 A still further subgroup of compounds of formula (I), are compounds wherein R3 represents hydrogen or methyl.
It is to be understood that the present 25 invention covers all appropriate combinations of particular and preferred groupings hereinabove.
Particular individual compounds of the invention include:
cis-2, 3, 6, 7, 12, 12a-he:xahydro-2- (4-pyridyl-30 methyl)-6-(3,4-methylenedioxyphenyl)-pyrazino-[2',l':6,1]pyrido[3,4-b]indole-l,4-dione;

cis-2, 3, 6, 7, 12, 12a-hexahydro-6- (2, 3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methylpyrazino[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-l,4-dione;
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2' , 1' : 6, 1] pyri.do [3, 4-b] indole-1, 4-dione;
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2',l':6,1]pyrido[3,4-b]indole-1,4-dione;
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyp:henyl)-pyrazino-[2',l':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-methylenedioxyphe:nyl)-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;

(6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuranyl)-2-methyl-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione;
(6R,l2aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl) -pyrazino [2' , 1' : 6, 1]pyrido [3, 4-b] - -indole-1,4-dione;
(3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6-(5-benzofuranyl)-3-methyl-pyra2:ino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione;
(3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6-(5-benzofuranyl)-2,3-dimethyl-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione;
(6R, 12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-2-isopropyl-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione; and physiologically accep-table solvates (e.g., hydrates) thereof.
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-bjindole-1,4-dione; and (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-2-methyl-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione; and physiologically accep-table solvates (e.g., hydrates) thereof.
DETAILED DESCRIPTION OF THE P:REFERRED EMBODIMENTS
It has been shown that compounds of the present invention are potent and selective inhibi-tors of cGMP-specific PDEs 1, 5, and 6, and par-ticularly PDE5. Thus, compounds of formula (I) are of interest for use in therapy, specifically for the treatment of a variety of conditions where selective inhibition of PDES is considered to be beneficial.
In summary, the biochemical, physiologi-cal, and clinical effects of PDE5 inhibitors suggest their utility in a variety of disease states in --which modulation of smooth muscle, renal, hemo-static, inflammatory, and/or endocrine function is desirable. The compounds of formula (I), therefore, have utility in the treatment of a number of dis-orders, including stable, unstable, and variant (Prinzmetal) angina, hypertension, pulmonary hyper-tension, congestive heart failure, acute respiratory distress syndrome, acute and chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g., postpercutaneous transluminal coro-nary or carotid angioplasty, or post-bypass surgery graft stenosis), peripheral vascular disease, vascu-lar disorders, such as Raynaud's disease, thrombo-cythemia, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, osteoporosis, preterm labor, benign pros-tatic hypertrophy, male and female erectile dys-function, and diseases characterized by disorders of gut motility (e.g., irritable bowel syndrome).
An especially important use.is the treat-ment of male erectile dysfunction, which is one form of impotence and is a common medical problem. Impo-tence can be defined as a lack of power, in the male, to copulate and can involve an inability to achieve penile erection or ejaculation, or both.
The incidence of erectile dysfunction increases with age, with about 50% of men over the age of 40 suf-fering from some degree of erectile dysfunction.

Many compounds have been investigated for their therapeutic potential in the treatment of MED, including phenoxybenzamine, papaverine, prostaglan-din El (PGE1), and phentolamine. These compounds, either alone or in combination, are typically self- --administered by intracavernosal (i.c.) injection.
While such treatments are effective, a treatment that is less invasive than injection therapy is preferred because pain, priapism, and fibrosis of the penis are associated with the i.c. administra-tion of these agents.
For example, alprostadil (i.e., prosta-glandin El) delivered by intraurethral deposition has been approved for the treat:ment of MED. How-ever, clinical studies showed that this route of administration is not effective in all patients. In addition, phentolamine and apomorphine are being evaluated as oral and sublingual therapies for MED, but neither compound has demonstrated efficacy across a broad range of subjects. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) also have 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 an alternative to pharmacological treatment, a variety of penile prostheses have been used to assist achievement of an erection. The short-term success rate is good, but problems with infection and ischemia, especially in diabetic men, make this type of treatment a f'inal option rather than a first-line therapy.
Because of the disadvantages of prior treatments for MED, new stratecries to improve erectile response that exploit different physiologi-cal mechanisms are being investigated. One area of investigation is increasing the intracellular con-centration of cGMP by providing a new type of oral therapy for the treatment of MED.
Increasing cGMP concentration is an important step in the physiology of penile erec-tions. A penile erection is caused by neural stimuli that ultimately cause vasodilation of the arteries and sinusoidal spaces of the corpus cavernosum. Research indicates that nitric oxide plays a central role in this vasodilation.
In particular, atrial natriuretic peptides (ANP) and nitric oxide (NO, sometimes referred to as endothelium-derived relaxing factor or EDRF) relax smooth muscle by increasing guanylyl cyclase activity, which raises intracellular cGMP concen-tration. Intracellular cGMP is hydrolyzed by phos-phodiesterases (PDEs), thereby terminating the action of the cyclic nucleotide. PDES is the major cGMP hydrolyzing enzyme in vascular smooth muscle.
Accordingly, PDE5 inhibition potentiates the relaxant effects of ANP and nitric oxide by increas-ing the cGMP levels. Therefore, a compound that inhibits the PDE5 enzyme (and thereby indirectly inhibits the hydrolysis of cGMP) should potentiate the vascular response to nitric oxide, thereby facilitating the achievement and maintenance of erection.

PDE5 inhibitors have potential for use in treating male erectile dysfunction (MED), hyper-tension, heart failure, and other disease states because of their ability to facilitate the action of ANP and NO. For example, sildenafil, a PDE inhibi-tor showing little selectivity with respect to PDE6, has the structure:

CH
CH3CH2~ 3 N
N

S02", N

N

and has shown efficacy in oral administration clin-ical trials for MED, which supports the hypothesis that augmenting normal or subnormal guanylyl cyclase stimuli has therapeutic benefits.
It is envisioned, the:refore, that com-pounds of formula (I) are useful in the treatment of erectile dysfunction. Furthermore, the compounds can be administered orally, the:reby obviating the disadvantages associated with intracavernosal admin-istration. Thus, the present invention concerns the use of compounds of formula (I), or a pharmaceut-ically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manu-ii facture of a medicament for the, curative or prophyl-actic treatment of erectile dysfunction in a male animal, including man.
It also has been observed that human corpus cavernosum contains three distinct PDE --enzymes (see A. Taher et al., U7. Urol., 149, p. 285A
(1993)), one of which is the cGMP-specific PDE5. As a consequence of the selective PDES inhibition exhibited by compounds of the present invention, the present compounds sustain cGMP levels, which in turn mediate relaxation of the corpus cavernosum tissue and consequent penile erection.
Although the compounds of the invention are envisioned primarily for the treatment of erectile dysfunction in humans, such as male erectile dysfunction and female sexual dysfunction, including orgasmic dysfunction related to clitoral disturbances, they also can be used for the treat-ment of premature labor and dysmenorrhea.
It is understood that references herein to treatment extend to prophylaxis, as well as treat-ment of established conditions.
It also is understood that "a compound of formula (I)," or a physiologically acceptable salt or solvate thereof, can be administered as the neat compound, or as a pharmaceutical composition con-taining either entity.
A further aspect of the present invention is providing a compound of formula (I) for use in the treatment of stable, unstable, and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, acute respiratory distress syndrome, acute and chronic renal failure, athero-sclerosis, conditions of reduced blood vessel patency (e.g., post-PTCA or post-bypass graft stenosis), peripheral vascular disease, vascular disorders such as Raynaud's disease, thrombo- -cythemia, inflammatory diseases, prophylaxis of myocardial infarction, prophylaxis of stroke, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, osteoporosis, preterm labor, benign prostatic hypertrophy, male and female erectile dysfunction, or diseases characterized by disorders of gut motility (e.g.,, IBS).
According to another aspect of the present invention, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of the above-noted conditioris and disorders.
In a further aspect, the present invention provides a method of treating the above-noted con-ditions and disorders in a human or nonhuman animal body which comprises administering to said body a therapeutically effective amount of a compound of formula (I) .
Compounds of the invention can be admin-istered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, transurethral, nasal, topical, percutaneous, i.e., transdermal, or parenteral (incJ!uding intravenous, intramuscular, subcutaneous, and intracoronary) administration. Parenteral administration can be accomplished using a needle and syringe, or using a high pressure technique, like POWDERJECT-. Oral administration generally is pref'erred.

With respect to treating sexual dysfunc-tion and particularly erectile dysfunction in humans, oral administration of the compounds of the invention is the preferred rout.e. Oral administra-tion is the most convenient and avoids the disad-vantages associated with intracavernosal administra-tion. For patients suffering f'rom a swallowing dis-order or from impairment of drug absorption after oral administration, the drug can be administered parenterally, e.g., sublingually or buccally.
For administration to man in the curative or prophylactic treatment of the conditions and disorders identified above, oral dosages of a com-pound of formula (I) generally are about 0.5 to about 1000 mg daily for an average adult patient (70 kg). Thus, for a typical adult patient, individual tablets or capsules contain 0.2 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day.
Dosages for intravenous, buccal, or sublingual ad-ministration typically are 0.1 to 500 mg per single dose as required. In practice, the physician determines the actual dosing regimen which is most suitable for an individual patient, and the dosage varies 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 dosages are merited, and such are within the scope of this invention.

For human use, a compound of the formula (I) can be administered alone, :but generally is administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical prac-tice. For example, the compour.Ld can be administered orally, buccally, or sublingually in the form of -tablets containing excipients such as starch or lactose, or in capsules or ovul.es, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents (e.g., methylcellulose, a semisynthetic glyceride such as witepsol, or mixtures of glycerides such as a mixture of apricot kernel oil and PEG-6 esters, or mixtures of PEG-8 and caprylic/capric glycerides). A compound also can be injected parenterally, for example, intra-venously, intramuscularly, subcutaneously, or intra-coronarily. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which can contain other substances, for example, salts, or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
For veterinary use, a compound of formula (I? or a nontoxic salt thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.
Thus, the invention provides in a further aspect a pharmaceutical composition comprisirig a il.

compound of the formula (I), together with a pharm-aceutically acceptable diluent or carrier therefor.
There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a compound of formula (I), -which process comprises mixing a compound of formula (I), together with a pharmaceutically acceptable diluent or carrier therefor.
In a particular embodiment, the invention includes a pharmaceutical composition for the cura-tive or prophylactic treatment of erectile dysfunc-tion in a male animal, including man, comprising a compound of formula (I) or a pharmaceutically accep-table salt thereof, together with a pharmaceutically acceptable diluent or carrier.
A compound of formula (I) also can be used in combination with other therapeutic agents which can be useful in the treatment of the above-mentioned and other disease states. The invention thus provides, in another aspect, a combination of a compound of formula (I), together with a second therapeutically active agent.
A compound of formula (I) can be used in the preparation of a medicament for co-administra-tion with the second therapeutically active agent in treatment of conditions where inhibition of a cGMP-specific PDE is beneficial. Ir.t addition, a compound of formula (I) can be used in the preparation of a medicament for use as adjunctive therapy with a second therapeutically active compound to treat such conditions. Appropriate doses of known second therapeutic agents for use in combination with a compound of formula (I) are readily appreciated by those skilled in the art.
In particular, because compounds of the present invention maintain cGMP levels, the com-pounds of formula (I) can provide beneficial anti- -platelet, antineutrophil, antivasospastic, vasodila-tory, natriuretic, and diuretic activities, as well as potentiate the effects of endothelium-derived relaxing factor (EDRF), gastric NO administration, nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and endothelium-dependent relaxing agents such as bradykinin, acetyicholine,. and 5-HT1.
The present selective PDE5 inhibitors in combination with vasodilators, including nitric oxide and nitric oxide donators and precursors, such as the organic nitrate vasodilators which act by releasing nitric oxide in vivo, are especially use-ful in treatment of angina, congestive heart fail-ure, and malignant hypertension (e.g., pheochromo-cytoma). Related to the capacity of the present PDE5 inhibitors to potentiate nitric oxide donors and precursors is their ability, in spontaneously hypertensive rats, to reverse the desensitization to these agents.that occurs with chronic use.
Examples of vasodilators that can be used in conjunction with the compounds of formula (I) include, but are not limited to, (a) organic nitrates, such as nitroglycerin, isosorbide di-nitrate, pentaerythrityl tetranitrate, isosorbide-5-mononitrate, propatyl nitrate, trolnitrate, nicro-andil, mannitol hexanitrate, incisitol hexanitrate, N-[3-nitratopivaloyl]-L-cysteine: ethyl ester, (b) organic nitrites, like isoamyl nitrite, (c) thionitrites, (d) thionitrates, (e) S-nitrosothiols, like S-nitroso-N-acetyl-D,L-penicillamine, (f) nitrosoproteins, (g) substituted furoxanes, such as 1,2,5-oxadiazole-2-oxide and furazan-N-oxide, (h) substituted sydnonimines, such as molsidomine and mesocarb, (i) nitrosyl complex compounds, like iron nitrosyl compounds, especially sodium nitroprusside, and Q) nitric oxide (NO) itself.

Other classes of therapeutic agents that can be used in conjunction with the compounds of formula (I), in addition to vasodilators, include, but are not limited to, a-adrenergic blockers, mixed a,p-blockers, prostagiandin El (PGEI) and prostacyclin (PGI2), angiotensin converting enzyme inhibitors (ACE

inhibitors), neutral endopeptidase (NEP) inhibitors, centrally acting dopaminergic agents (such as apomorphine), vasoactive intestinal peptides (VIP), calcium channel blockers, and compounds like thiazides or a mixture thereof.

Alpha-adrenergic blockers inhibit vasoconstriction in the corpus cavernosum. Because PDE5 inhibitors enhance vasodilation of the same smooth muscle tissue, a PDE5 inhibitor of formula (I) and an a-adrenergic blocker, like phentolamine or prazocin, or a centrally acting.dopaminergic agent, like apomorphine, can be expected to potentiate one another in a treatment for MED or other disorders. Potentiation of mixed a,(3-blockers, like carvedilol, which is employed in treatment of hypertension, also is expected. Similarly, a2 -adrenergic blockers, like yohimbine, can be potentiated.

WO 00/15228 PCT/[JS99/19466 Prostaglandin El enhances relaxation of the corpus cavernosum by increasing the formation of cyclic AMP. Cyclic.AMP can be degraded in the corpus cavernosum by PDE3, which is inhibited by cyclic GMP. By maintaining cyclic GMP levels, a PDE5 inhibitor can indirectly inhibit PDE3 activity, and hence block degradation of cyclic AMP. There-fore, a PDE5 inhibitor of formula (I) can be expected to potentiate the activity of PGE1 in the treatment of MED or compounds having similar activities, such as PGI2, in trte treatment of pulmonary hypertension, for exaLmple.
Angiotensin convertir.Lg enzyme (ACE) inhibitors block the conversion of angiotensin I
into angiotensin II, which causes systemic vasocon-striction and the retention of sodium and water.
PDE5 inhibitors cause vasodilation in hypertensive animals, and stimulate the excretion of sodium and water in normotensive animals. Therefore, a PDE5 inhibitor of formula (I) can be combined with an ACE
inhibitor to achieve more powerful vasodilatory and natriuretic effects in, for example, treatment of congestive heart failure or hypertensive states.
Neutral endopeptidase (NEP) inhibitors inhibit the degradation of atrial natriuretic pep-tide (ANP) by NEP. PDE5 inhibitors can be expected to potentiate the action of ANP by inhibiting degra-dation of its second messenger, cyclic GMP, and, therefore, a compound of formula (I) can potentiate the effects of agents, like NEP inhibitors, that increase blood levels of ANP.
The combination referred to above can be presented for use in the form of a single pharma-ceutical formulation, and, thus, pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier comprise a f'urther aspect of the invention. -The individual comporients of such a combination, therefore, can be administered either sequentially or simultaneously from the same or separate pharmaceutical formulations. As is the case for the PDE5 inhibitors of: formula (I), a second therapeutic agent can be administered by any suitable route, for example, by oral, buccal, inhalation, sublingual, rectal, vaginal, trans-urethral, nasal, topical, percutaneous (i.e., trans-dermal), or parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary) administration.
In some embodiments, the compound of formula (I) and the second therapeutic agent are administered by the same route, either from the same or from different pharmaceutical compositions.
However, in other embodiments, using the same route of administration for the compound of formula (I) and the second therapeutic agent either is impossible or is not preferred. For example, if the second therapeutic agent is nitric oxide, which typically is administered by inhalation, the com-pound of formula (I) must be administered by a different route. Furthermore, if a compound of formula (I) is used in combination with a nitrate vasodilator, for example, in treatment of an erectile dysfunction, it is preferred that the compound of formula (I) is administered orally and the vasodilator is administereci topically, and preferably in a manner which avoids substantial systemic delivery of the nitrate.
The combination of a compound of formula (I) and a second therapeutic aclent is envisioned in -the treatment of several disease states. Examples of such treatments are the systemic and topical treatment of male and female sexual dysfunction, wherein a compound of formula (I) is used in combi-nation with phentolamine, prazocin, apomorphine, PDE1, or a vasoactive intestinal peptide. The compound of formula (I) can be administered orally or transuretherally, and the second therapeutic agent can be administered orally, topically, or intracavernosally, for example. Persons skilled in the art are aware of the best modes of administra-tion for each therapeutic agent, either alone or in a combination.
Other disease states that can be treated by a combination of a compound of formula (I) and a second therapeutic agent include, but are not limited to:
(a) treatment of hypertension using a compound of formula (I) in combi-nation with an a-adrenergic blocker, a mixed a,R-blocker, like carvedilol, a thiazide, sodium nitroprusside, an ACE inhibitor, or a calcium channel blocker;
(b) treatment of pulinonary hypertension using a compound of formula (I) in combination with inhaled NO on other inhaled vasodilators, or with PGI2 administered via, an IV pump; and (c) treatment of chronic obstructive pulmonary disease using a compound of formula (I) in combination with --inhaled NO.
Examples of individual compounds of the invention for use in the treatment of erectile dysfunction include:
cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridyl-methyl)-6-(3,4-methylenedioxyphenyl)-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
cis-2,3,6,7,12,12a-hexahydro-2-butyl-(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-methylenedioxy,phenyl)-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-:L,4-dione;
( 6R, 12aR) -2, 3, 6, 7, 12, :L2a-hexahydro-6- (3-chloro-4-methoxyphenyl)-2-methy:L-pyrazino-[2',1':6,ltpyrido[3,4-b]indole-'1,4-dione;

( 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphE:nyl)-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-l,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-methylenediox:yphenyl)-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-he:xahydro-2-cyclo-propyl-6-(3,4-methylenedioxyphe!nyl)-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.
Especially useful 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; 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; and physiologically acceptable salts and solvates (e.g., hydrates) thereof.
Compounds of formula (I) can be prepared by any suitable method known in the art or by the following processes which form part of the present invention. In the methods below, R , R', and R 2 are as defined in formula (I) above unless otherwise indicated.
Thus, a process (A) for preparing a com-pound of formula (I) wherein R3 represents hydrogen comprises treating a compound caf formula (II) -Ro k OAl k N NN ir CH2Ha1 H

(II) , 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., methanol 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) can be conven-iently prepared by treating a compound of formula (III) oAlk Rfl NH
N

(III) with a haloacetyl halide (e.g., chloroacetyl chloride) in a suitable solvent, such as a halo-genated hydrocarbon (e.g., trichloromethane or dichloromethane) or an ether (e.g., tetrahydro-furan), 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 bi-carbonate (e.g., NaHCO3). The reaction conveniently can be effected at a temperature of from -20 C to +20 C (e.g., at about 0 C).
A compound of formula (I) also can 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) can be prepared as individual enantiomers in two steps from the appropriate enantiomer of formula (III) or as mixtures (e.g., racemates) of either pairs of cis or trans isomers from the corresponding mixtures of either pairs of cis or trans isomers of formula (III).

Individual enantiomers of the compounds of the invention can be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constit-uent enantiomers, for examples, using HPLC (high performance liquid chromatography) on a chiral column such as Hypersil naphthylurea.
A compound of formula (III) conveniently can be prepared from a tryptophan alkyl ester of formula (IV) Ro ~OAlk H (IV) (where Alk is as previously defined) or a salt thereof (e.g., the hydrochloride salt) according to either of the following procedures (a) and (b).
Procedure (b) is only suitable for preparing cis isomers of formula (III) and can be particularly suitable for preparing individual cis enantiomers of formula (III) from D- or L- tryptophan alkyl esters as appropriate.

Procedure (a) This comprises a Pictet-Spengler cycliza-tion between a compound of formiula (IV) and an aldehyde R2CHO. The reaction can be conveniently effected in a suitable solvent such as a halogenated hydrocarbon (e.g., dichloromethane) or an aromatic hydrocarbon (e.g., toluene) in the presence of an acid, such as trifluoroacetic acid. The reaction conveniently can be carried out at a temperature of from -20 C to reflux to provide a compound of formula (III) in one step. The reaction also can be carried out in a solvent such as an aromatic hydro-carbon (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 can be either individual enantiomers or racemates of pairs of cis or trans isomers, depending upori whether racemic or enantio-merically pure tryptophan alkyl ester was used as the starting material. Individual cis or trans enantiomers conveniently can be separated from mixtures thereof by fractional crystallization or by chromatography (e.g., flash column chromatography) using appropriate solvents and eluents. Similarly, pairs of cis and trans isomers can be separated by chromatography (e.g., flash col_umn chromatography) using appropriate eluents. An optically pure trans isomer also can be converted to an optically pure cis isomer using suitable epimerization 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 reflux-ing temperature of the solutior.i. The mixture then can be subjected to chromatography (e.g., flash column chromatography) to separate the resulting diastereoisomers, or in the procedure utilizing aqueous hydrogen chloride, the desired cis isomer precipitates out as the hydrocY;Lloride salt which then can be isolated by filtration.

Procedure (b) This comprises a four-step procedure from a compound of formula (IV) or a salt thereof (e.g., the hydrochloride salt). The procedure is particu-larly suitable for preparing a 1R, 3R isomer of formula (III) from a D-tryptoprian alkyl ester of formula (IV) or a salt thereof (e.g., the hydro-chloride salt). Thus, a first step (i) comprises treating a compound of formula (IV) with an acid halide R2COHa1 (where Hal is as previously defined) -in the presence of a base, e.g., an organic base such as a trialkylamine (for example, triethyl-amine), to provide a compound of formula (V).

Ro <)C, ~OAlk N
H

(V) The reaction can be c:onveniently carried out in a suitable solvent, such. as a halogenated hydrocarbon (e.g., dichlorometh.ane) or an ether (e.g., tetrahydrofuran), and at a temperature of from -20 C to +40 C.
Step (ii) comprises treating a compound of formula (V) with an agent to convert the amide group to a thioamide group. Suitable sulfurating agents are well known in the art. Thus, for example, the reaction can be conveniently effected by treating (V) with Lawesson's reagent. This reaction can be conveniently carried out in a suitable solvent, such as ether (e.g., dimethoxyethane) or an aromatic hydrocarbon (e.g., toluene), at an elevated temper-ature, such as from 40 C to 80 C to provide a com-pound of formula (VI) RO OAlk I l N;HCSR2 _ H

(VI) Step (iii) comprises treating a compound of formula (VI) with a suitable agent to provide a compound of formula (VII) Ro ~OAlk NH+
N Hal-H

(VII) wherein Hal is a halogen atom, e.g., iodine. The reaction can be conveniently effected by treating (VI) with an alkylating agent, such as a methyl halide (e.g., methyl iodide), or an acylating agent, such as an acetyl halide (e.g., acetyl chloride), in a suitable solvent, such as a halogenated hydro-carbon (e.g., dichloromethane) at an elevated temperature (e.g., under reflux).
In step (iv), the resialting iminium halide of formula (VII) can be treated with a reducing agent, such as a boron hydride, e.g., sodium boro-hydride, to provide the desired compound of formula (III). The reduction can be conveniently effected at a low temperature, e.g., within the range of -100 C to 0 C, in a suitable solvent, such as an alcohol (e.g., methanol).
There is further provided by the present invention a process (B) for preparing a compound of --formula (I), wherein R' and R3 together represent a 3- or 4-membered alkyl or alkenyl chain, which .process (B) comprises cyclizat.:Lon of a compound of formula (VIII) >_Alk Rp ~ I I N-R1 \ N.

(VIII) wherein Alk represents C1_6alkyl and Rl and R3 together represent a 3- or 4-mE:mbered chain, both as hereinbefore described. The cyclization is suitably carried out in an organic solvent or solvents, such as an alcoholic solvent (e.g., methanol), and optionally an ether solvent such as tetrahydrofuran, and in the presence of a reducing agent, aptly a palladium catalyst, such as palladium on carbon.
Conveniently, a compound of formula (VIII) is prepared by reaction of a compound of formula (III) as hereinbefore described with a compound of formula (IX) Rq~
N-R'-Hal -<~ R

(IX) wherein Hal represents a halogen atom as herein-before described, R' and R3 together represent a 3-or 4-membered chain as hereinbefore described, and R' represents a protecting group, suitably a benzyloxy-carbonyl group or the like. Typically, the reaction is carried out in a chlorinated. organic solvent, such as dichloromethane, and a tertiary amine, such as triethylamine or the like.
According to a further aspect of the present invention, there is provided a process (C) for preparing a compound of formula (I) wherein R3 represents C1-3alkyl, which process comprises cycli-zation of a compound of formula (X) .25 Ro <:XN ~oAlk H

(X) wherein Alk represents C1-6alkyl as hereinbefore described and R5 represents C2_5alkyl, substituted at C1 by a halogen atom, the halogen atom being as hereinbefore described. Suitably, the cyclization is achieved by reflux for many hours, such as 22 to 26 hours, in the presence of an ether solvent, such as tetrahydrofuran, and a suitable amine as here-inafter described in the accompanying examples.
Aptly, a compound of formula (X) can be prepared from a compound of formula (III) by suit-able acylation techniques, such as reaction with a C3_6carboxylic acid, substituted at C-2 by a halogen atom in a halogenated organic solvent, such as dichloromethane.
Compounds of formula (I) can be converted to other compounds of formula (I). Thus, for example, when R2 is a substituted benzene ring, it may be necessary or desirable to prepare the suit-ably substituted compound of formula (I) subsequent to process (A), (B), or (C), as above. Examples of appropriate interconversions include nitro to amino or aralkyloxy to hydroxy by suitable reducing means (e.g., using a reducing agent such as SnC12 or a palladium catalyst, such as pal:ladium-on-carbon), or amino to substituted amino, such as acylamino or sulphonylamino using standard acylating or sulphonylating conditions. In the case where R2 represents a substituted bicyclic system, suitable interconversion can involve renloval of a substit-uent, such as by treatment with a palladium catalyst (e.g., palladium-on-carbon) whereby, for example, a benzyl substituent can be removed from a suitable bicyclic system.
The pharmaceutically acceptable acid addition salts of the compounds, of formula (I), which contain a basic center, c:an be treated with a suitable acid, either neat or in a suitable solu-tion, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous --manner by treating a solution of a compound of formula (I) with a suitable base. Both types of salt can be formed or interconverted using ion-exchange resin techniques.
Compounds of the invention can be isolated in association with solvent molecules by crystal-lization from or evaporation of an appropriate solvent.
Thus, according to a further aspect of the invention, we provide a process for preparing a compound of formula (I) or a salt or solvate (e.g., hydrate) thereof which comprises process (A), (B), or (C) as hereinbefore described followed by (i) an interconversion step, and/or either (ii) salt formation, or (iii) solvate (e.g., hydrate) formation.
There is further provided by the present invention compounds of formulae (II), (VIII), (X), and further compounds of formulae (III), (V), (VI), and (VII), with the exception f'or compounds (III), (V), (VI), and (VII), wherein R is hydrogen, R2 is phenyl, and Alk is methyl.
The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic center can be prepared in a conven-tional manner. For example, a solution of the free base can 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 can be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base. Both types of salt can be formed or interconverted using ion-exchange resin techniques.
Thus, according to a further aspect of the invention, a method for preparing a compound of formula (I) or a salt or solvate (e.g., hydrate) is provided, wherein the method comprises process (A), (B), or (C) as hereinbefore described, followed by (i) salt formation, or (ii) solvate (e.g., hydrate) formation. The method of preparing the following Intermediates 1 through 92 and Examples 1 through 125, and characterization of the compounds, can be found in published PCT applications WO 95/19978, WO
97/03985, and WO 97/03675.

Intermediates 1 and 2 Methyl 1,2,3,4-tetrahydro-l-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 3 and 4 Methyl 1,2,3,4-tetrahydro-l-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 5 Methyl 1,2,3,4-tetrahydro-l-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer Intermediates 6 and 7 -Methyl 1,2,3,4-tetrahydro-l-(4--ethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 8 and 9 Methyl 1,2,3,4-tetrahydro-l-(2,3-dihydrobenzo[b]-furan-5-yl)-9H-pyrido[3,4-b]indcle-3-carboxylate, cis and trans isomers Intermediates 10 and 11 Methyl 1,2,3,4-tetrahydro-1-(3,4-ethylenedioxy-phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 12 Methyl 1,2,3,4-tetrahydro-l-(2-chlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, mixture of cis and trans isomers Intermediates 13 and 14 Methyl 1,2,3,4-tetrahydro-l-(4-chlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxyla'te, cis and trans isomers Intermediates 15 and 16 Methyl 1,2,3,4-tetrahydro-l-(3,.4-dichlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 17 Methyl 1,2,3,4-tetrahydro-1-(1.,2,3,4-tetrahydro-6-naphthyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer _ Intermediates 18 and 19 Methyl 1,2,3,4-tetrahydro-l-(2-naphthyl)-9H-pyrido-[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 20 and 21 Methyl 1,2,3,4-tetrahydro-l-(2-thienyl)-9H-pyrido-[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 22 and 23 Ethyl 1,2,3,4-tetrahydro-l-(3-thienyl)-9H-pyrido-[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 24 and 25 Methyl 1,2,3,4-tetrahydro-l-(5-bromo-2-thienyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 26 and 27 Methyl 1,2,3,4-tetrahydro-l-(4-bromo-2-thienyl))-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 28 Methyl 1,2,3,4-tetrahydro-l-(3-furyl)-9H-pyrido[3,4-b]indole-3-carboxylate, mixture of cis and trans isomers Intermediates 29 and 30 Ethyl 1,2,3,4-tetrahydro-l-(5-methyl-2-furyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 31 and 32 Ethyl 1,2,3,4-tetrahydro-l-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 33 and 34 Methyl 1,2,3,4-tetrahydro-l-(3-:methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 35 and 36 Methyl 1,2,3,4-tetrahydro-l-(4-trifluoromethyl-phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 37 and 38 Ethyl 1,2,3,4-tetrahydro-l-(4-cyanophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 39 Methyl 1,2,3,4-tetrahydro-l-(4-hydroxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer Intermediate 40 Methyl 1,2,3,4-tetrahydro-l-(3-hydroxy-4-methoxy-phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer Intermediate 41 Methyl 1,2,3,4-tetrahydro-l-(4-hydroxy-3-methoxy-phenyl) -9H-pyrido [3, 4-b] indole--3-carboxylate, cis isomer , Intermediate 42 Methyl 1,2,3,4-tetrahydro-l-(4--ethylphenyl)-9H-pyrido[3,4-b]indole-3-carboxyla.te, cis and trans isomers Intermediates 43 and 44 Methyl 1,2,3,4-tetrahydro-l-(4-isopropylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 45 and 46 Ethyl 1,2,3,4-tetrahydro-l-(4-nitrophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 47 Ethyl 1,2,3,4-tetrahydro-l-(4-dimethylaminophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, mixture of cis and trans isomers Intermediates 48 and 49 Ethyl 1,2,3,4-tetrahydro-l-(3-p:yridyl)-9H-pyrido-[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 50 and 51 Methyl 1,2,3,4 tetrahydro-6-fluoro-l-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 52 and 53 Methyl 1,2,3,4-tetrahydro-6-fluoro-l-(4-methoxy-phenyl)-9H-pyrido[3,4-b]indole-:3-carboxylate, cis and trans isomers -Intermediates 54 and 55 (1R, 3R) -Methyl 1, 2, 3, 4-tetrahyd:ro-1- ( 3, 4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer and (iS,3R)-methyl 1,2,3,4-tetrahyd:ro-1-(3,4-methylene-dioxy-phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate trans isomer Intermediate 56 (1S, 3S) Methyl-1,2,3,4-tetrahydro-l-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, .cis isomer and (1R, 3S) methyl-1,2,3,4-tetrahydro-l-(3,4-methylene-dioxy-phenyl)-9H-pyrido[3,4-b]indole-3,-carboxylate, trans isomer Intermediates 57 and 58 (1R,3R)-Methyl 1,2,3,4-tetrahyd:ro-1-(4-methoxy-phenyl)-9H-pyrido[3,4-b]indole-:3-carboxylate, cis isomer and (1S,3R)-methyl 1,2,3,4-tetrahyd:ro-1-(4-methoxy-phenyl)-9H-pyrido[3,4-b]indole-:3-carboxylate, trans isomer Intermediates 59 and 60 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-l-(3-chloro-4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer and (iS, 3R)-methyl 1,2,3,4-tetrahydro-l-(3-chloro-4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, trans isomer Intermediates 61 and 62 (1R,3R)-Methyl 1,2,3,4-tetrahyd.ro-1-(2,3-dihydro-benzo[b]furan-5-yl)-9H-pyrido[3,4-b]indole-3-car-boxylate, cis isomer and (1S,3R)-methyl 1,2,3,4-tetrahydro-l-(5-(2,3-dihydro-benzo[blfuran))-9H-pyrido[3,4-b]indole-3-carboxyl-ate, trans isomer Intermediates 63 and 64 (1R,3R)-Methyl 1,2,3,4-tetrahydro-l-(5-indanyl)-9H-pyrido[3,4-b]indole-3-carboxylate cis isomer and (1S,3R)-methyl 1,2,3,4-tetrahydro-l-(5-indanyl)-9H-pyrido[3,4-b]indole-3-carboxylate trans isomer Intermediate 65 Ethyl 1,2,3,4-tetrahydro-l-(4-trifluoromethoxy-phenyl)-9H--pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediate 66 Methyl 1,2,3,4-tetrahydro-l-(5-:methyl-2-thienyl)-9H-pyrido [3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 67 and 68 (iS,3R)-Methyl 1,2,3,4-tetrahyd:ro-1-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate and (1R,3R)-methyl 1,2,3,4-tetrahyd:ro-1-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate Intermediate 69 (1R, 3R) -Methyl 1, 2, 3, 4-tetrahyd:ro-1- (3, 4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate Intermediate 70 (R) -N"- (3, 4-Methylenedioxyphenyl.carbonyl ) -tryptophan methyl ester Intermediate 71 (R)-N"-(3,4-Methylenedioxyphenyl.thiocarbonyl)-trypto-phan methyl ester Intermediate 72 (1R,3R)-Methyl 1,2,3,4-tetrahyd:ro-1-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]inidole-3-carboxylate Intermediate 73 (1R,3R)-Methyl 1,2,3,4-tetrahyd:ro-2-chloroacetyl-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate Intermediate 74 Methyl 1,2,3,4-tetrahydro-6-methyl-i-(3,4-methylene-dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis and trans isomers Intermediates 75 and 76 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-l-(7-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazir.Lyl))-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer and (iS, 3R)-Methyl 1,2,3,4-tetrahydro-l-(7-=(4-methyl-3,4-dihydro-2H-benzo[1,4]-oxazinyl))-9H-pyrido[3,4-b]indole-3-carboxylate, trans isomer Intermediate 77 Methyl 1,2,3,4-tetrahydro-l-(5-=(N-benzylindolinyl))-9H-pyrido[3,4-b]indole-3-carboN:ylate, mixture of (1R, 3R) and (1S, 3R) isomers Intermediates 78 and 79 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-l-(4-carbo-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer and (1S, 3R)-methyl 1,2,3,4-tetrahydro-l-(4-carbomethoxy-phenyl)-9H-pyri.do[3,4-b]indole-3-carboxylate, trans isomer Intermediate 80 (1R, 3R) -Methyl 1, 2, 3, 4-tetrahydro-2- [2- (benzyloxy-carbonyl)-R-prolylj-l-(3,4-metriylenedioxyphenyl)-9H-pyrido [3, 4-b] indole-3-carboxylate Intermediate 81 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-2-[2-(benzyloxy-carbonyl)-S-prolyl]-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate Intermediate 82 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-2-(2-chloro-propionyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido-[3,4-b]indole-3-carboxylate -Intermediate 83 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-2-(2-chloro-propionyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido-[3,4-b]indoie-3-carboxylate Intermediates 84 and 85 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-l-(3,4-dibenzyl-oxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate cis isomer and (iS, 3R)-methyl 1,2,3,4-tetrahydro-l-(3,4-dibenzyloxyphenyl)-9H-pyrido [3,4-b]indole-3-carboxylate trans isomer Intermediate 86 (6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- (3, 4-dibenzyl-oxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione Intermediate 87 Methyl 1,2,3,4-tetrahydro-l-(5-(2-methylisoindol-inyl))-9H-pyrido[3,4-b]indole-3-carboxylate, mixture of (1R,3R) and (1S,3R) isomers Intermediates 88 and 89 (1R,3R)-Methyl 1,2,3,4-tetrahydro-l-(5-benzo-furanyl)-9H-pyrido[3,4-b]indole-3-carboxylate, cis isomer and (1S,3R)-methyl 1,2,3,4-tetrahyd.ro-1-(5-benzo- --furanyl)-9H-pyrido[3,4-b]indole-3-carboxylate trans isomer Intermediate 90 (1R,3R)-Methyl 1,2,3,4-tetrahyd.ro-1-(5-benzo-furanyl)-2-chloroacetyl-9H-pyrido[3,4-b]indo,le-3-carboxylate Intermediate 91 (1R, 3R) -Methyl 1, 2, 3, 4-tetrahyd.ro-1- (5-benzo-furanyl)-2-(2-(S)-benzyloxycarbonylaminopropionyl)-9H-pyrido[3,4-b]indole-3-carbox:ylate Intermediate 92 (1R,3R)-Methyl 1,2,3,4-tetrahyclro-1-(5-benzo-furanyl) -2- [2- (S) -benzyloxycarbonylmethylamino)propionyl]-9H-pyrido-[3,4-b[indole-3-carboxylate Example 1 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2--methyl-6- ( 3, 4-methylene-di.oxyphenyl)-pyrazino[2',l':6,1]pyrido-[3,4-b]indole-1,4-dione--from Intermediate 1 and methylamine.
The following compour.Lds were obtained in a similar manner:

Example 2 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-10-fluoro-6-(4-methoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from but.ylamiine and Intermediate 52. -Example 3 Trans-2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-6- ( 3, 4-methyl-enedioxyphenyl)-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione--from methylamine and Intermediate 2.

Example 4 Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl) -pyrazino [2' , 1' : 6, 1] pyrido [3, 4-b] indole-]., 4-dione--from ammonia and Intermediate 1.
Example 5 Cis-2,3,6,7,12,12a-hexahydro-10-fluoro-6-(4-methoxy-phenyl)-2-(2,2,2-trifluoroethyl)-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from 2,2,2-trifluoroethylamine and I:ntermediate 52.
Example 6 Cis-2,3,6,7,12,12a-hexahydro-10-fiuoro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,1]-pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 50.

Example 7 (6R, 12aS)-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--from methylamine and the trans isomer of Intermediate 56. -Example 8 (6S, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino [2',1':6.1]pyrido-[3,4-b]indole-l,4-dione--from methylamine and Intermediate 55.

Example 9 Cis-2, 3, 6, 7, 12, 12a-hexahyciro-2- [2- (2-pyridyl) -ethyl]-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1'-6,1]pyrido[3,4-b]indole-l,4-dione--from 2-(2-pyridyl)ethylamine and Intermediate 1.

Example 10 Cis-2,3,6,7,12,12a-hexahydro-2--(2-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from 2-pyridylmethyl-amine and Intermediate 1.

Example 11 Cis-2,3,6,7,12,12a-hexahydro-2--(3-pyridylmethyl)-6-(3,4-meth,ylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from 3-pyridylmethyl-amine and Intermediate 1.

_ 52 -Example 12 Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyra.zino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from 4-pyridylmethyl-amine and Intermediate 1. -Example 13 Cis-2,3,6,7,12,12a-hexahydro-2-ethyl-6-(3,4-methyl-enedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indo le -1,4-dione--from ethylamine and Intermediate 1.
Example 14 Cis-2,3,6,7,12,12a-hexahydro-2-(2,2,2-trifluoro-ethyl)-6-(3,4-methylenedioxyphe.nyl)-pyrazino-[2',l':6,1]pyrido[3,4-b]indole-1,4-dione--from 2,2,2-trifluoroethylamine and Intermediate 1.
Example 15 Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl)-2-propyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from propylamine and Interme-diate 1.

Example 16 Cis-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--from isopropylamine and Inter-mediate 1.

Example 17 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--from cyclopropylamine and Inter-mediate 1. -Example 18 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-butyl-6- (3, 4-methyl-enedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from butylamine and Intermediate 1.

Example 19 Trans-2,3,6,7,12,12a-hexahydro-2-butyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 2.

Example 20 Cis-2, 3, 6,'7, 12, 12a-hexahydro-2-cyclopropylmethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from cyclopropyl-methylamine and Intermediate 1.

Example 21 Cis-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from cyclopentylamine and Intermediate 1.

Example 22 Cis-2,3,6,7,12,12a-hexahydro-2-cyclohexyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]pyrido[3,4-b]indole-1,4-dione--from cyclohexylamine and Intermediate 1.
Example 23 Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from benzylamine and Interme-diate 1.

Example 24 Cis-2,3,6,7,12,12a-hexahydro-2-(4-fluorobenzyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from 4-fluorobenzyl-amine and Intermediate 1.

Example 25 Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from methylamine and Intermediate 3.

Example 26 Trans-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from methylamine and Intermediate 4.

Example 27 Cis-2,3,6,7,12,12a-hexahydro-2-ethyl-6-(4-methoxy-phenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from ethylamine and Intermediate 3.

Example 28 Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethyl)-pyrazino~[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione--from 2,2,2-trifluoro-ethylamine and Intermediate 3. --Example 29 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methoxy-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 3.

Example 30 Trans-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methoxy-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 4.
Example 31 Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-cyclopropylmethylpyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from cyclopropylmethylamine and Intermediate 3.

Example 32 Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-(4-methoxy-phenyl)-pyrazino[21,11:6,1]pyri.do[3,4-b]indole-1,4-dione--from benzylamine and Intermediate 3.
Example 33 Cis-2,3,6,7,12,12a-hexahydro-6-(3-methoxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyridLo[3,4-b]indole-l,4-dione--from methylamine and Intermediate 5.

Example 34 Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethoxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 6.
-Example 35 Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethoxyphenyl)-2-cyclopropylmethyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopropylmethylamine and Intermediate 6.

Example 36 Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]-furan-5-yl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-di.one--from methylamine and Interme-diate 8.

Example 37 Cis-2, 3, 6, 7, 12, 12a-hexahydro-6- (2, 3-dihydrobenzo [b] -furan-5-yl)-2-cyclopropylmethyl-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--frorn cyclopropyl-methylamine and Intermediate 8.

Example 38 Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-ethylenedioxy-phenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from methylamine and Interme-diate 10.

Example 39 Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-ethylenedi-oxyphenyl)-2-cyclopropylmethyl-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from cyclopropyl-methylamine and Intermediate 10. -Example 40 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-butyl-6- (2-chloro-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 12.

Example 41 Cis-2, 3, 6, 7, 12, 12a-hexahydro-6- (4-chlorophenyl) -2-methyl-pyrazino[2',1':6,1]pyrid.o[3,4-b]indole-1,4-dione--from methylamine and Intermediate 13.
Example 42 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-chloro-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 13.

Example 43 Cis-2,3,6,7,12,12a-hexahydro-6--(3,4-dichiorophenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 15.

Example 44 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-phenyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and cis-methyl 1,2,3,4-tetra-hydro-l-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate.

Example 45 Cis-2,3,6,7,12,12a-hexahydro-2-:benzyl-6-phenyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from benzylamine and cis-methyl-1,2,3,4-tetrahydro-l-phenyl-9H-pyrido[3,4-b]indole-3- -carboxylate.

Example 46 Trans-2,3,6,7,12,12a-hexahydro-2-benzyl-6-phenyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from benzylamine and cis-methyl-1,2,3,4-tetrahydro-l-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate.

Example 47 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(1,2,3,4-tetrahydro-6-naphthyl)-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione--from methylamine and Intermediate 17.
Example 48 Cis-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(1,2,3,4-tetrahydro-6-naphthyl)-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione--from isopropylamine and Intermediate 17.
Example 49 Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(1,2,3,4-tetrahydro-6-naphthyl))-pyrazino[2',1':-6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopropyl-methylamine and Intermediate 17.

Example 50 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-rnethyl-6- (2-naphthyl)-pyrazino[2',l':6,1]py.rido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 18.
-Example 51 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-:butyl-6- (2-thienyl) -pyrazino [2' , 1' : 6, 1] pyrido [3, 4-b] indole-1, 4-dione--from butylamine and Intermediate 20.
Example 52 Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',l':6,l]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 24.
Example 53 Cis-2,3,6,7,12,12a-hexahydro-6-(4-bromo-2-thienyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 26.
Example 54 Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-cyclopropylmethyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopropylmethylamine and Intermediate 24.

Example 55 Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-cyclopentyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopentylamine and Intermediate 24.

Example 56 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(5-methyl-2-thienyl)-pyrazino[2',1':6,1]pyr:ido[3,4-b]indole-1,4-dione--from methylamine and the cis isomer of Intermediate 66. -Example 57 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-thienyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 22.

Example 58 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(3-thienyl)-pyrazino [2' , 1' : 6, 1] pyrido [ 3, 4-b] indole-1, 4-dione--from butylamine and Intermediate 22.
Example 59 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-furyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and the cis isomer of Intermediate 28.

Example 60 Cis-2,3,6,7,12,12a-hexahydro-2-:methyl-6-(5-methyl-2-furyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 29.
Example 61 Cis-2,3,6,7,12,12a-hexahydro-2-:methyl-6-(4-methyl-phenyl)-pyrazino[21,1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 31.

Example 62 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-:Lsopropyl-6- (4-methylphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from isopropylamine and Intermediate 31.
Example 63 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methyl-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 31.
Example 64 Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methylphenyl)-pyrazino[2',1'::6,1]pyrido[3,4-b]-indole-1,4-dione--from cyclopropylmethylamine and Intermediate 31.

Example 65 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-6- (3-methyl-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 33.
Example 66 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-trifluoro-methylphenyl)-pyrazino[2',1':6,:1]pyrido[3,4-b]-indole-1,4-dione--from butylamine and Intermediate 35.

Example 67 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-tri-fluoromethoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and the cis isomer of Intermediate 65.

Example 68 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-hydroxy-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 39.
--Example 69 Cis-2,3,6,7,12,12a-hexahydro-6-(3-hydroxy-4-meth-oxyphenyl)-2-methyl-pyrazino[2',l':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Interme-diate 40.

Example 70 Cis-2,3,6,7,12,12a-hexahydro-6-(4-hydroxy-3-meth-oxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Interme-diate 41.

Example 71 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-cyano-phenyl)-pyrazino[2',11:6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 37.
Example 72 Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethylphenyl)-2-isopropyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from isopropylamine and the cis isomer of Intermediate 42.

Example 73 Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethylphenyl)-2-cyclopropylmethyl-pyrazino[2',l~:6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopropylmethylamine and the cis isomer of Intermediate 42.

Example 74 Cis-2,3.,6,7,12,12a-hexahydro-6-(4-isopropylphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 43.
-Example 75 Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-nitro-phenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from butylamine and Intermediate 45.
Example 76 Cis-2, 3, 6, 7, 12, 12a-hexahydro-6- ( 4-dimethylamino-phenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from methylamine and the cis isomer of Intermediate 47.

Example 77 Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-pyridyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 48.
Example 78 (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--Intermediate 54 and methylamine.

The following compounds were obtained in a similar manner:

Example 79 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-( 3, 4-methylenedioxyphenyl ) -pyriazino [ 2' , 1' : 6, 1 ] -pyrido [3, 4-b] indole-1, 4-dione-=-from isopropylamine and Intermediate 54. --Example 80 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-2-butyl-6- (3, 4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-l,4-dione--from butylamine and Interme-diate 54.

Example 81 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isobutyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from isobutylamine and Intermediate 54.

Example 82 (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---from cyclopentylamine and Intermediate 54.

Example 83 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylene-dioxyphenyl)-2-cyclohexylmethyl-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from cyclohexyl-methylamine and the cis isomer of Intermediate 56.

Example 84 (6R,12aR)-2,3;6,7,12,12a-Hexahydro-2-cyclopropyl-methyl-6-(4-methoxyphenyl)=pyra.zino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from cyclopropyl-methylamine and Intermediate 57. --Example 85 (6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-2-butyl-6- (4 -methoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from butylamine and Intermediate 57.

Example 86 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-( 4-methoxyphenyl )-pyrazino [ 2' , 1.' : 6, 1] pyrido [ 3, 4-b]indole-1,4-dione--rom cyclopentylamine and Intermediate 57.

Example 87 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-cyclopropylmet:hyl-pyrazino-[2' , 1' : 6, 1] pyrido [ 3, 4-b] indole--l, 4-dione--from cyclopropylmethylamine and Intermediate 59.

Example 88 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3-chloro-4-methoxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from cyclopentylamine and Intermediate 59.

Example 89 ( 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--from methylamine and Intermediate 59. --Example 90 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3-chloro-4-methoxyphenyl)-pyrazino[2',1':6,1]pyrido-[3,4-b]indole-1,4-dione--from isopropylamine and Intermediate 59.

Example 91 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(2,3-dihydro-benzo[b]furan-5-yl)-2-methyl-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from methylamine and Intermediate 61.

Example 92 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- (2, 3-dihydro-benzo[b]furan-5-yl)-2-methylcyc.lopropyl-pyrazino-[2',1':6,1]pyrido[3,4-b]indole-:1,4-dione--from methylcyclopropylamine and Intermediate 61.

Example 93 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- (5-indanyl) -2-methyl-pyrazino[2',l':6,1]pyrid:)[3,4-b]indole-1,4-dione--from methylamine and Intermediate 63.

Example 94 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-indanyl)-2-cyclopropylmethyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from cyclopropylmethylamine and Intermediate 63. Example 95 ( 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--from Intermediate 73 and methyl-amine.

Example 96 Cis-2,3,6,7,12,12a-hexahydro-2,10-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure used to prepare Example 1, but startincl from methylamine and the cis isomer of Intermediate 74.

Example 97 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-(3,4-dimethoxy-benzyl)-6-(3,4-methylenedioxyphenyl)-pyrazino-[2',1':6,1]pyrido[3,4-b]indole--1,4-dione--from the same procedure as used to prepare Example 78, but starting from veratrylamine and Intermediate 54.
Example 98 Cis-2, 3, 6, 7, 12,12a-hexahydro-6-= ( 4-aminophenyl) -2-butyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from Example 75.

Example 99 Cis-2,3,6,7,12,12,a-hexahydro-6--(4-acetamidophenyl)-2-butyl-pyrazino[2',1':6,1]pyr:Ldo[3,4-b]indole-1,4-dione--from Example 98.
-Example 100 Cis-2, 3, 6, 7, 12, 12a-hexahydro-2--butyl-6- (4-methyl-sulfonamidophenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from Example 98.
Example 101 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methyl-enedioxyphenyl)-pyrazino[2',1';;6,1]pyrido[3,4-b]-indole-1,4-dione--from the same procedure as Example 100 starting from ammonia and Intermediate 54.
Example 102 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylene-dioxyphenyl)-2-(2-propynyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione---from the same pro-cedure as Example 100 starting from propargylamine and Intermediate 54.

Example 103 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-2- ( 3, 4-methylene-dioxybenzyl)-6-(3,4-methylenedioxyphenyl)-pyrazino-[2',l':6,1]pyrido[3,4-b]indole--1,4-dione--from the same procedure as Example 100 starting from piper-onylamine and Intermediate 54.

Example 104 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-(3,4-dimethoxy-phenethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 3,4-dimethoxyphen- -ethylamine and Intermediate 54.

Example 105 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-furfuryl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from the same pro-cedure as Example 100 starting from furfurylamine and Intermediate 54.

Example 106 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylene-dioxyphenyl)-2-(2-thienylmethyl)-pyrazino[2',1':-6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 starting from 2-thiophene-methylamine and Intermediate 54.
Example 107 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(4-methoxy-phenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 starting from methylamine and Interme-diate 57.

Example 108 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-ethyl-6-(4-methoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-l,4-dione--from the same procedure as Example 10,0 starting from ethylamine and Intermediate 57.

Example 109 (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (7- (4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl))-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 starting from --Intermediate 75.

Example 110 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- ( 5- (N-benzyl-indolinyl))-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 starting from Intermediate 77.

Example 111 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-indolinyl)-2-methyl-pyrazino[2',l':6,1]pyrido[3,4-b]indole-1,4-dione--from Example 110.

Example 112 Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethylphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 start-ing from methylamine and the cis isomer of Interme-diate 42.
Example 113 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- ( 4-carbometh-oxyphenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from the same procedure as Example 100 starting from Intermediate 78 (cis isomer) and methylamine.

Example 114 (SaR, 12R, 14aR) -1, 2, 3, 5a, 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--from Intermediate 80. --Example 115 (5aR, 12R, 14aS) -1, 2, 3, 5, 6, 11, 12, :L4a-Octahydro-12-( 3, 4-methylenedioxyphenyl ) -pyrrolo [ 1 " , 2 " : 4' , 5' ] -pyrazino[2',11:6,1]pyrido[3,4-b]indole-5-1,4-dione--from Intermediate 81.

Example 116 (3R, 6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-2, 3-dimethyl-6-(3,4-methylenedioxyphenyl)-py:razino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--:from Intermediate 82 and methylamine.

Example 117 (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-py.razino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione--from Intermediate 83 and methylamine.

Example 118 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-dihydroxy-phenyl)-2-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione--from Intermediate 86.

Example 119 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(5-(2-methylisoindolinyl))pyrazino[2',1':6,1]pyrido[3,4b]i ndole-1,4-dione--from Intermediate 87 and methyl-amine.
Example 120 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzo-furanyl)-2-methyl-pyrazino[2'1':6,1]pyrido[3,4-b]-indole-1,4-dione--and Intermediate 91 and methyl-amine.

Example 121 ( 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- ( 5-benzo-furanyl)-pyrazino[2',1':6,l]pyrido[3,4-b]indole-1,4-dione--from ammonia and Intermediate 91.

Example 122 (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzo-furanyl)-2-isopropyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from Intermediate 91.
Example 123 (3S,6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzo-furanyl)-3-methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from Intermediate 92.

Example 124 (3S, 6R, 12aR) -2, 3, 6, 7, 12, 12a-Hexahydro-6- (t-benzo-furanyl)-2,3-dimethyl-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione--from Intermediate 93.

II

Example 125 (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--from Intermediate 43 and ammonia. --TABLETS FOR ORAL ADMINISTRATION

A. Direct Compression 1. mg/tablet Active Ingredient 50.0 Crospovidone USNF 8.0 Magnesium Stearate Ph Eur 1.0 Anhydrous Lactose 141.0 The active ingredient was sieved and blended with the excipients. The resultant mix was compressed into tablets.

2. mg/tablet Active Ingredient 50.0 Colloidal Silicon Dioxide 0.5 Crospovidone 8.0 Sodium Lauryl Sulfate 1.0 Magnesium Stearate Ph Eur 1.0 Microcrystalline Cellulose USNF 139.5 The active ingredient was sieved and blended with the excipients. The resultant mix was compressed into tablets.

B. Wet Granulation --l, mg/tablet Active ingredient 50.0 Polyvinylpyrrolidone 150.0 Polyethylene glycol 50.0 Polysorbate 80 10.0 Magnesium Stearate Ph Eur 2.5 Croscarmellose Sodium 25.0 Colloidal Silicon Dioxide 2.5 Microcrystalline Cellulose USNF 210.0 The polyvinylpyrrolidone, polyethylene glycol, and polysorbate 80 were dissolved in water.
The resultant solution was used to granulate the active ingredient. After drying, the granules were screened then extruded at elevated temperatures and pressures. The extrudate was milled and/or screened, then was blended with the microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The resultant mix was compressed into tablets.

II', 2. mg/tablet Active Ingredient 50.0 Polysorbate 80 3.0 Lactose Ph Eur 178.0 Starch BP 45.0 Pregelatinized Maize Starch BP 22.5 Magnesium Stearate BP 1.5 The active ingredient was sieved and blended with the lactose, starch, and pregelatinized maize starch. The polysorbate 80 was dissolved in purified water. Suitable volumes of the polysorbate 80 solution were added and the powders were gran-ulated. After drying, the granules were screened and blended with the magnesium stearate. The gran-ules were then compressed into tablets.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to the other excipients.

FILM COATED TABLETS

The aforementioned tablet formulations were film coated.

Coating Suspension % w/w Opadry white t 13.2 Purified water Ph Eur to 100.0*

* The water did not appear in the final product.
The maximum theoretical weight of solids applied during coating was 20 mg/tablet.

t Opadry white is a proprietary material obtainable from Colorcon Limited, UK, which contains hydroxypropyl methylcellulose, titanium dioxide, and triacetin.

The tablets were film. coated using the coating suspension in conventional film coating equipment.

CAPSULES

1. mg/capsule Active Ingredient 50.0 Lactose 148.5 Polyvinylpyrrolidone 100.0 Magnesium Stearate 1.5 The active ingredient: was sieved and blended with the excipients. The mix was filled into size No. 1 hard gelatin capsules using suitable equipment.

2. mg/capsule Active Ingredient 50.0 Microcrystalline Cellulose 233.5 Sodium Lauryl Sulfate 3.0 Crospovidone 12.0 Magnesium Stearate 1.5 The active ingredient:, was sieved and blended with the excipients. The mix was filled into size No. 1 hard gelatin ca.psules using suitable equipment.
Other doses can be prepared by altering the ratio of active ingredient to excipient, the fill weight, and, if necessary, changing the capsule size.
3. mg/capsule Active Ingredient 50.0 Labrafil M1944CS to 1.0 ml The active ingredient was sieved and blended with the Labrafil. The suspension was filled into soft gelatin capsules using appropriate equipment.
Inhibitory Effect on cGMP-PDE
cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells et al., Biochim. Biophys.

Acta, 384, 430 (1975). The reaction medium con-tained 50 mM Tris-HCl, pH 7.5, 5 mM magnesium ace-tate, 250 ug/ml 5'-Nucleotidase,, 1 mM EGTA, and 0.15 pM 8- [H3] -cGMP. The enzyme usedl was a human recombi-nant PDE5 (ICOS Corp., Bothell, Washington). ' Compounds of the invention were dissolved in DMSO finally present at 2% in the assay. The incubation time was 30 minutes during which the total substrate conversion did not exceed 30%.
The IC50 values for the compounds examined were determined from concentration-response curves typically using concentrations ranging from 10 nM to 10 pM. Tests against other PDE enzymes using standard methodology also showed that compounds of the invention are highly selective for the cGMP-specific PDE enzyme.

cGMP Level Measurements Rat aortic smooth muscle cells (RSMC), prepared according to Chamley et al., Cell Tissue Res., 177, 503-522 (1977), were used between the 10th and 25th passage at confluence in 24-well culture dishes. Culture media was aspirated and replaced with PBS (0.5 ml) containing the compound tested at the appropriate concentration. After 30 minutes at 37 C, particulates guanylate cyclase was stimulated by addition of ANF (100 nM) for 10 minutes. At the end of incubation, the medium was withdrawn, and two extractions were performed by addition of 65% ethanol (0.25 ml). The two ethanol-ic extracts were pooled and eva:porated until dry-ness, using a Speed-vac system. cGMP was measured after acetylation by scintillation proximity immuno-assay (AMERSHAM). The EC50 values are expressed as the dose-giving half of the stiinulation at saturat-ing concentrations.
Biological Data The compounds according to the present invention were typically found to exhibit an IC50 value of less than 500 nM and an EC50 value of less than 5 pM. In vitro test data for representative compounds of the invention is given in the following table:

Table 1: In vitro Results Example No. IC50 (nM) ECso (pM) 12 10 0.15 36 <10 0.5 52 20 0.8 63 30 0.35 78 2 0.2 79 <10 0.15 82 20 0.5 84 10 0.4 89 10 <0.1 95 2 0.2 101 10 0.3 115 <10 0.4 117 2 0.2 120 15 0.6 121 20 <1 122 30 <1 123 8 <1 124 8 <1 The hypotensive effects of compounds according to the invention as identified in Table 2 were studied in conscious spontaineously hypertensive rats (SHRs). The compounds were administered orally at a dose of 5 mg/kg in a mixture of 5% DMF and 95%
olive oil. Blood pressure was measured from a catheter inserted in the carotid. artery and recorded for five hours after administration. The results are expressed as Area Under the Curve (AUC) from 0 to 5 hours, mm Hg=hours of the fall in blood pressure over time.

Table 2. In vivo results Example No. SHR AUC PO (mm Hg.h) 82 ill Obviously, many modifications and varia-tions of the invention as hereiribefore set forth can be made without departing from t:he spirit and scope thereof, and, therefore, only such limitations should be imposed as are indicated by the appended claims.

Claims (12)

CLAIMS:
1. A combination comprising:

(a) a compound represented by a formula (I) and salts and solvates thereof, in which:

R0 represents hydrogen, halogen or C1-6-alkyl;

R1 represents hydrogen, C1-6alkyl, C2-6-alkenyl, C2-6alkynyl, haloC1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylC1-3alkyl, arylC1-3alkyl, or heteroarylC1-3alkyl;

R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine or an optionally substituted bicyclic ring 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; and (b) a second therapeutically active agent, comprising a prostaglandin E1, prostacyclin, an .alpha.-adrenergic blocker, a mixed .alpha.,.beta.-blocker, an .alpha.2-adrenergic blocker, an ACE inhibitor, an NEP inhibitor, a centrally acting dopaminergic agent, a vasoactive intestinal peptide, a calcium channel blocker, a thiazide, or a mixture thereof for simultaneous, separate, or sequential use in the treatment of condition where inhibition of a cGMP-specific PDE is of a therapeutic benefit.
2. A pharmaceutical formulation comprising a combination according to claim 1, together with a pharmaceutically acceptable diluent or carrier.
3. The combination of claim 1 wherein the condition is stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, malignant hypertension, pheochromocytoma, congestive heart failure, acute respiratory distress syndrome, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, carotid angioplasty, myocardial infarction, post-bypass surgery graft stenosis, a peripheral vascular disease, a vascular disorder, Raynaud's disease, thrombocythemia, an inflammatory disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, osteoporosis, preterm labor, benign prostatic hypertrophy, a gut motility disorder, or irritable bowel syndrome.
4. The combination of claim 1 wherein the condition is erectile dysfunction in a male or female animal.
5. The combination of claim 1 wherein the second therapeutially active compound is selected from the group consisting of prostaglandin E1, prostocyclin, apomorphine, yohimbine, phentolamine, prazocin, carvedilol, and mixtures thereof.
6. Use of a combination of claim 1 for treating a condition where inhibition of a cGMP-specific PDE is of therapeutic benefit, in a human or a nonhuman animal body.
7. The use of claim 6, wherein the cGMP-specific PDE is PDE5.
8. The use of claim 6, comprising a prophylactic or curative treatment of erectile dysfunction in a male or female animal.
9. The use of claim 6, wherein the male or female animal is a human male or female animal.
10. The use of claim 6, wherein the treatment is an oral treatment.
11. Use of a combination of claim 1 for treating stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, thrombocythemia, an inflammatory disease, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, or irritable bowel syndrome, in a human or nonhuman animal body.
12. The use of claim 11, wherein the combination is a formulation suitable for oral administration.
CA002340636A 1998-09-16 1999-08-26 Combinations of tetracyclic cyclic gmp-specific phosphodiesterase inhibitors with further therapeutic agents Expired - Fee Related CA2340636C (en)

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