LV11690B

LV11690B - Tetracyclic derivatives, process of preparation and use

Info

Publication number: LV11690B
Application number: LVP-96-228A
Authority: LV
Inventors: Alain Claude-Marie Daugan
Original assignee: Glaxo Lab Sa
Priority date: 1994-01-21
Filing date: 1996-07-10
Publication date: 1997-06-20
Also published as: US6369059B1; DK0740668T3; ZA95424B; CA2181377C; PE49495A1; LU91017I2; EP0740668B1; AP556A; ES2122543T3; JP2004217674A; FI962927A0; PL179744B1; US20020119976A1; DE69503753D1; JPH09508113A; MY114663A; DE69503753T2; IL112384A0; HRP950023A2; CA2181377A1

Description

TETRACYCL1C DERIVATIVES, PROCESS OF PREPARATION AND USE

This invention relates to a series of tetracyciic derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic aģents. In particular, the invention relates to tetracyclic derivatives vvhich are potent and selective inhibitors of cyclic guanosine 3',5'monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas vvhere such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.

Thus, according to a first aspect, the present invention provides compounds of formula (I)

and salts and solvates (e.g. hydrates) thereof, in vvhich:

R° represents hydrogen, halogen or C-j_e alkyl;

R¹ represents hydrogen, Ci_galkyl, C₂^alkenyl, C₂^ alkynyl, haloC-ļ _galkyl, C3_Qcycloalkyl, C3_gcycloalkylCi_3alkyl, arylCi_3alkyl or heteroarylC-ļ_3alkyl;

R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic

CE>

ring attached to the rest of the molecule via one of the benzene ring carbon atoms and vvherein the fused ring A is a 5- or 6-membered ring vvhich may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or tvvo heteroatoms selected from oxygen, sulphur and nitrogen; and

R³ represents hydrogen or Ckj alkyl, or R¹ and R³ together represent a 3- or

4- membered alkyl or alkenyl chain.

There is further provided by the present invention a subgroup of compounds of formula (I), the subgroup comprising compounds of formula (la)

and salts and solvates (e.g. hydrates) thereof, in vvhich:

R° represents hydrogen, halogen or C-ļ_5 alkyl;

R¹ represents hydrogen, C^alkyl, haloC-ļ_6alkyl, C3_8cycloalkyl, C3_8cycloalkylC-|_3alkyl, arylC-|_3alkyl or heteroarylC-|_3alkyl; and

R2 represents an optionaliy 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 vvherein the fused ring A is a 5- or 6-membered ring vvhich may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or tvvo heteroatoms selected from oxygen, sulphur and nitrogen.

Within Rl above, the term aryl as part of an arylC-ļ_3alkyl group means phenyl or phenyl substituted by one or more (e.g. 1, 2 or 3) substituents selected from halogen, C^alkyl, C^alkoxy and methylenedioxy. The term heteroaryl as part of a heteroary!C-|_3alkyl group means thienyl, furyl or pyridyl each optionally substituted by one or more (e.g. 1, 2 or 3) substituents selected from halogen, C-ļalkyl and C-,_galkoxy. The term C3_gcycloalkyl as a group or part of a C3_gcycloalkylC-|.3alkyl group means a monocyclic ring comprising three to eight carbon atoms. Examples of suitable cycloalkyl rings include the C3_gcycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

VVithin R^ above, optional benzene ring substituents are selected from one or more (e.g. 1, 2 or 3) atoms or groups comprising halogen, hydroxy, C-ļ_galkyl, C-ļ_galkoxy, -C0₂R^b, haloCj^alkyl, haloC-ļ_5alkoxy, cyano, nitro and NR^aR^b, vvhere R^a and R& are each hydrogen or C-|_5alkyl, or R^a may also represent C₂-7alkanoyl or C-ļ_galkylsulphonyl. 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-ļ_galkyl, C-ļ_galkoxy and arylC₁.₃alkyl as defined above.

The bicyclīc ring

may, for example, represent naphthalene, a heterocycle such as benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline, indole, benzothiophene or benzofuran or (where n is an integer 1 or 2 and X and Y may each represent

CH₂, O, S or NH).

In the above definitions, the term alkyl as a group or part of a group means a straight chain or, vvhere available, a branched chain alkyl moiety. For example, it may represent a C-j_4alkyl function as represented by methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term ‘alkenyl’ as used herein indudes straight-chained and branched alkenyl groups, such as vinyl and allyl groups. The term ‘alkynyl· as used herein indudes straight-chained and branched alkynyl groups, suitably acetylene. The term halogen herein means a fluorine, chlorine, bromine or iodine atom. The term haloC-ļ^alkyl 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. Similarly, a haloC-|_ealkoxy group is a haloC<]_galkyl group as defined above linked to the R² benzene ring via an oxygen atom. Examples of haloC-|_galkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. An example of a haloC-|_galkoxy group is trifluoromethoxy. The term C2-7alkanoyl means a C-ļ_5alkylcarbonyl group vvhere the C-j_^aIkyl portion is as defined above. An example of a suitable C2-7alkanoyl group is the C₂alkanoyl group acetyl.

It vvill be appredated that vvhen R° is a halogen atom or a C-ļ _galkyl group this substituent may be sited at any available position on the phenyl portion of the tetracydic ring. Hovvever, a particular site of attachment is the ring 10position.

The compounds of formula (I) may contain tvvo or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. In particular, in formula (I) above tvvo ring chiral centres are denoted with asterisks. It is to be understood that the invention indudes both mixtures and separate individual isomers of the compounds of formula (I).

The compounds of formula (I) may also exist in tautomeric forms and the invention indudes both mixtures and separate individual tautomers thereof.

The pharmaceutical ly acceptable salts of the compounds of formula (I) which contain a basie centre are acid addition salts formed with pharmaceutically acceptable acids. Examples inelude the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. Compounds of the formula (I) can also provide pharmaceutically acceptable mētai salts, in particular alkali mētai salts, vvith bases. Examples inelude 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 R^ represents hydrogen, C-ļ_4alkyl, haloC-ļ _4alkyl,, C3_5cycloalkyl, C3_gcycloalkylmethyl, pyridylC-| _3alkyl, furylCj _3alkyl or optionally substituted benzyl. Wīthin this particular group of compounds, examples of C-|_4alkyl groups are methyl, ethyl, n-propyl, i-propyl and n-butyl. Examples of C3_gcycloalkylmethyl groups are cyclopropylmethyl and cyclohexylmethyl. Exampies of optionally substituted, benzyl groups inelude benzyl and halobenzyl (e.g. fluorobenzyl).

A further particular group of compounds of the invention are those compounds of formula (I) in vvhich R² represents an optionally substituted benzene, thiophene, furan, pyridine or naphthalene ring or an optionally substituted bicyclic ring (vvhere n is 1 or 2 and X and Ύ are each CHg or 0). VVithin this particular group of compounds, examples of substituted benzene groups are benzene substituted by one of halogen (e.g. chlorine), hydroxy, C-ļ_3alkyl (e.g. methyl, ethyl or i-propyl), C-|_3alkoxy (e.g. methoxy or ethoxy), -CO₂R^b, halomethyl (e.g. trifluoromethyl), halomethoxy (e.g. trifluoromethoxy), cyano, nitro or NR^aRb vvhere R^a and Rb are each hydrogen or methyl or R^a is acetyl; or benzene substituted by dihalo (e.g. dichloro) or by Cj_3alkoxy (e.g. methoxy) and one of halogen (e.g. chlorine) and hydroxy. An example of a substituted thiophene ring is a halo (e.g. bromo) substituent thiophene ring.

A stili further particular group of compounds of formula I are those vvherein R³represents hydrogen or R¹ and R³ together represent a 3-membered alkyl chain.

A preferred group of compounds of the invention are the cis isomers of formula (I) represented by formula (lb)

and mixtures thereof vvith their cis optical enantiomers, including racemic mixtures, and salts and solvates (e.g. hydrates) of these compounds in vvhich R° is hydrogen or halogen (e.g. fluorine), especially hydrogen and R¹, R and R³are as defined previously.

The single isomers represented by formula (lb), i.e. the 6R, 12aR isomers, are particularly preferred.

Within the above defīnitions R¹ may preferably represent C^alkyl (e.g. methyl, ethyl, i-propyl and n-butyl), C3_5cycloalkyl (e.g. cyclopentyl) or C3^^cycloalkylmethyl (e.g. cyclopropylmethyl).

R² may preferably represent a substituted benzene ring such as benzene substituted by C-ļ_3alkoxy (e.g. methoxy) or by Cļ_3alkoxy (e.g. methoxy) and halogen (e.g. chlorine), particularly 4-methoxyphenyl or 3-chloro-4methoxyphenyl, or R² may preferably represent 3,4-methylenedioxyphenyl.

It is to be understood that the present invention covers ali appropriate combinations of particular and preferred groupings hereinabove.

Particular individual compounds of the invention include:

Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4methylenedioxyphenyl)-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-methylpyrazino[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 -1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4methylenedioxyphenyl)-pyrazino[2',r:6,1]pyrido[3,4-b]indole -1,4-dione;

(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4methylenedioxyphenyl)-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-bjindole -1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methylpyrazino[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-methyienedioxyphenyl)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-(3,4methylenedioxyphenyl)-pyrrolo[1,2 : 4',5']pyrazino[2',1': 6,1]pyrido[3,4b]indole-5-1,4-dione;

and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

A specific compound of the invention is:

(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 physiologically acceptable salts and solvates (e.g. hydrates) thereof.

It has been shovvn that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE. Thus, compounds of formula (I) are of interest for use in therapy, specifically for the treatment of a variety of conditions vvhere inhibition of cGMP specific PDE is thought to be beneficial.

As a conseque'nce of the selective PDE V inhibition exhibited by compounds of the present invention, cGMP Ievels are elevated, vvhich in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic and diuretic activities as vvell as potentiation of the effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing aģents such as bradykinin, acetylcholine and 5-HTļ. The compounds of formula (I) therefore have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, rēnai failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. postpercutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, ailergic rhinitis, glaucoma and diseases characterised by disorders of gut motility (e.g. irritable bovvel syndrome).

It will be appreciated that references herein to treatment extend to prophylaxis as well as treatment of established conditions.

It vvill also be appreciated that 'a compound of formula (I),' or a physiologically acceptable salt or solvate thereof can be administered as the raw compound, or as a pharmaceutical composition containing either entity.

There is thus provided as a further aspect of the invention a compound of formula (I) for use in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, rēnai failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, infiammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility (e.g. IBS).

According to another aspect of the invention, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, rēnai failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility (e.g. IBS).

In a further aspect, the invention provides a method of treating stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, rēnai failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility (e.g. IBS) in a human or non-human animal body vvhich comprises administering to said body a therapeutically effective amount of a compound vvith formula (I).

Compounds of the invention may be administered by any suitable route, for example by oral, buccal, sub-lingual, rectal, vaginai, nasal, topical or parenterāl (including intravenous, intramuscular, subcutaneous and intracoronary) administration. Oral administration is generally preferred.

For administration to man in the curative or prophylactic treatment of the disorders identified above, oral dosages of a compound of formula (I) vvill generally be in the range of from 0.5-800mg daily for an average adult patient (70kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.2-400mg 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 administration will typically be vvithin the range of from 0.1-400 mg per single dose as required. In practice the physician vvill determine the actual dosing regimen vvhich vvill be most suitable for an individual patient and it vvill vary vvith the age, vveight and response of the particular patient. The above dosages are exemplary of the average case but there can be individual instances in vvhich higher or lovver dosage ranges may be merited, and such are vvithin the scope of this invention.

For human use, a compound of the formula (I) can be administered alone, but vvill generally be administered in admixture vvith a pharmaceutical carrier selected vvith regard to the intended route of administration and Standard pharmaceutical practice. For example, the compound may be administered orally, buccally or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture vvith excipients, or in the form of elixirs or suspensions containing flavouring or colouring aģents. Such liquid preparations may be prepared vvith pharmaceutically acceptable additives such as suspending aģents (e.g. methylcellulose, a semi-synthetic glyceride such as vvitepsol or mixtures of glycerides such as a mixture of apricot kemel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glycerides). A compound may also be injected parenterally, for exampie intravenously, intramuscularly, subcutaneously or intracoronarily. For parenterāl administration, the compound is best used in the form of a sterile aqueous solution vvhich may contain other substances, for example salts, or monosaccharides such as mannitol or glucose, to make the solution isotonic vvith blood.

Thus, the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (I) together with a pharmaceutically acceptable diiuent 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 pharmaceutica!ly acceptable diiuent or carrier therefor.

A compound of formula (I) may also be used in combination vvith other therapeutic aģents which may be useful in the treatment of the above-mentioned disease States. The invention thus provides, in another aspect, a combination of a compound of formula (I) together vvith another therapeutically active aģent.

The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diiuent or carrier comprise a further aspect of the invention.

The individual components of such a combination may also be administered either sequentially or simultaneously in separate pharmaceutical formulations.

Appropriate doses of knovvn therapeutic aģents for use in combination vvith a compound of formula (I) vvill be readiiy appreciated by those skilled in the art.

Compounds of formula (I) may be prepared by any suitable method knovvn in the art or by the following processes vvhich form part of the present invention. In the methods belovv R°, R^ and R^ are as defined in formula (I) above unless othervvise indicated.

Thus, a process (A) for preparing a compound of formula (I) wherein R³represents hydrogen comprises treating a compound of formula (II)

(in vvhich Alk represents C-ļ_ealkyl, e.g. methyl or ethyl and Hal is a halogen atom, e.g. chlorine) vvith 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) may conveniently be prepared by treating a compound of formula (III)

(ΠΓ) vvith a haloacetyl halide (e.g. chloroacetyl chloride) in a suitable solvent such as a halogenated hydrocarbon (e.g. trichloromethane or dichloromethane), or an ether (e.g. tetrahydrofuran), preferably in the presence of a base such as an organic amine (e.g. a trialkylamine such as triethylamine) or an alkali metal carbonate or bicarbonate (e.g. NaHCOg). The reaction may conveniently be effected at a temperature of from -20°C to +20°C (e.g. at about O°C).

A compound of formula (I) may also be prepared from a compound of formula (III) in a two-step procedure via a compound of formula (II) isolated vvithout purification.

Compounds of formula (I) may be prepared as individual enantiomers in two steps from the appropriate enantiomer of formula (III) or as mixtures (e.g. racemates) of either pairs of cis or trans isomers from the correspondong mixtures of either pairs of cis or trans isomers of formula (III).

Individual enantiomers of the compounds of the invention may be prepared from racemates by resolution using methods knovvn in the art for the separation of racemic mixtures jnto their constituent enantiomers, for example using HPLC (high performance liquid chromatography) on a chiral column such as Hypersil naphthylurea.

A compound of formula (III) may conveniently be prepared from a tryptophan alkyl ester of formula (IV)

(vvhere Alk is as previously defined) or a salt thereof (e.g. the hydrochloride salt) according to either of the follovving procedures (a) and (b). Procedure (b) is only suitable for preparing cis isomers of formula (III) and may be particularly suitable for preparing individual cis enantiomers of formula (III) from D- or Ltryptophan alkyl esters as appropriate.

Procedure (a)

This eomprises a Pictet-Spengler cyclisation betvveen a compound of formula (IV) and an aldehyde R²CHO. The reaction may conveniently be effected in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in the presence of an acid such as trifluoroacetic acid. The reaction may conveniently be carried out at a temperature of from -20°C to reflux to provide a compound of formula (III) in one step. The reaction may also be carried out in a solvent such as an aromatic hydrocarbon (6.g. benzene or toluene) under reflux, optionally using a DeanStark apparatus to trap the vvater produced.

The reaction provides a mixture of cis and trans isomers vvhich may be either individual enantiomers or racemates of pairs of cis or trans isomers depending upon vvhether racemic or enantiomerically pure tryptophan alkyl ester vvas used as the starting material. Individual cis or trans enantiomers may conveniently be separated from mixtures thereof by fractional crystallisation or by chromatography (e.g. flash column chromatography) using appropriate solvents and eluents. Similarly, pairs of cis and trans isomers may be separated by chromatography (e.g. flash column chromatography) using appropriate eluents. An optically pure trans isomer may also be converted to an optically pure cis isomer using suitable epimerisation procedures. One such procedure eomprises treating the trans isomer or a mixture (e.g. 1 : 1 mixture) of cis and trans isomers vvith methanolic or aqueous hydrogen chloride at a temperature of from 0°C to the refluxing temperature of the solution. The mixture may then be subjected to chromatography (e.g. flash column chromatography) to separate the resulting diastereoisomers, or in the procedure utilising aqueous hydrogen chloride the desired cis isomer precipitates out as the hydrochloride salt v/hieh may then be isolated by filtration.

Procedure (b)

This eomprises a four-step procedure from a compound of formula (IV) or a salt thereof (e.g. the hydrochloride salt). The procedure is particularly suitable for preparing a 1R, 3R isomer of formula (III) from a D-tryptophan alkyl ester of formula (IV) or a salt thereof (e.g. the hydrochloride salt). Thus, a first step (i) eomprises treating a compound of formula (IV) vvith an acid halide R²C0Hal (vvhere Hal is as previously defined) in the presence of a base, e.g. an organic base such as a trialkylamine (for example triethylamine), to provide a compound of formula (V)

The reaction may be conveniently carried out in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) and at a temperature of from -20°C to +40°C.

Step (ii) comprises treating a compound of formula (V) vvith an aģent to convert the amide group to a thioamide group. Suitable sulfurating aģents are well-known in the art. Thus, for example, the reaction may conveniently be effected by treating (V) vvith Lavvesson’s reaģent. This reaction may conveniently be carried out in a suitable solvent such as an ether (e.g. dimethoxyethane) or an aromatic hydrocarbon (e'g. toluene) at an elevated temperature such as from 40°C to 80°C to provide a compound of formula (VI)

Step (iii) comprises treating a compound of formula (VI) with a suitable aģent to provide a compound of formula (VII)

OAlk

Hal(VID (vvhere Hal is a halogen atom, e.g. iodine). The reaction may conveniently be effected by treating (VI) vvith an alkylating aģent such as a methyl halide (e.g. methyl iodide) or an acyiating aģent such as an acetyl halide (e.g. acetyl chloride) in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) at an elevated temperature (e.cļ. under reflux).

ln step (iv) the resulting iminium halide of formula (Vil) may be treated with a reducing aģent such as boron hydride, e.g. sodium borohydride, to provide the desired compound of formula (III). The reduction may conveniently be effected at a lovv temperature, e.g. within the range of -100°C to O°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), vvherein R’ and R³ together represent a 3- or 4membered alkyl or alkenyl chain, vvhich process (B) comprises cyclisation of a compound of formula (VIII)

(Vm) vvherein Alk represents Ci-6alkyl and R¹ and R³ together represent a 3- or 4membered chain both as hereinbetore described. The cyclisation is suitably carried out in an organic solvent or solvents, such as an aleoholie solvent (e.g. methanol) and optionally an ether solvent such as tetrahydrofuran, and in the presence of a reducing aģent, aptly a palladium catalyst, such as palladium on carbon.

Conveniently a compound of formula (VIII) is prepared by reaction of a compound of formuia (III) as hereinbetore described vvith a compound of formula (IX)

vvherein Hal represents a halogen atom as hereinbetore described, R¹ and R³together represent a 3- or 4-membered chain as hereinbetore described and R⁴represents a protecting group, suitably a benzyloxycarbonyl group or the like. Typically the reaction is carried out in a chlorinated organic solvent, such as dichloromethane, and a tertiary amine, such as triethylamine or the like.

According to a further aspect of the present invention, there is provided a process (C) tor preparing a compound of formula (I) wherein R³ represents Cļ.

₃alkyl, vvhich process comprises cyclisation of a compound of formula (X)

vvherein Alk represents Ci-6alkyl as hereinbefore described and R⁵ represents 5 C₂.₅alkyl, substituted at C, by a halogen atom, the halogen atom being as hereinbefore described. Suitably the cyclisation 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 hereinafter described in the accompanying examples.

Aptly a compound of formula (X) can be prepared from a compound of formula (III) by suitable acylation techniques, such as reaction vvith a C3-6carboxylic acid, substituted at C₂ by a halogen atom in a halogenated organic solvent, such as dichloromethane.

Compounds of formula (I) may be converted to other compounds of formula (I). Thus, for example, vvhen R² is a substituted benzene ring it may be necessary or desirable to prepare the suitably substituted compound of formula (I) subsequent to process (Α), (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 aģent such as SnCl2 or a palladium catalyst, such as palladium-on-carbon), or amino to substituted amino such as acylamino or sulphonylamino using Standard acylating or sulphonylating conditions. In the case vvhere R² represents a substituted bicyclic system, suitable interconversion can involve removal of a substituent, such as by treatment vvith a palladium catalyst (e.g. palladium-on-carbon) whereby, for example, a benzyl substituent may be removed from a suitable bicyclic system.

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) vvhich contain a basie centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.

Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of a compound of formula (I) vvith a suitable base. Both types of salt may be formed or interconverted using ionexchange resin techniques.

Compounds of the invention may be isolated in association vvith solvent molecules by crystallisation from or evaporation of an appropriate solvent.

Thus, according to a further aspect of the invention, vve provide a process for preparing a compound of formula (I) or a salt or solvate (e.g. hydrate) thereof vvhich comprises process (Α), (B) or (C) as hereinbefore described follovved 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 (lll), (V), (VI) and (VII), vvith the exception for compounds (lll), (V), (VI) and (VII) vvherein R° is hydrogen, R² is phenyl and Alk is methyl.

The synthesis of the compounds of the invention and of the intermediates for use therein are illustrated by the follovving, non-limiting Examples. In the Examples section hereinafter the foilowing abbreviations are used:

DMSO (dimethylsulphoxide), MeOH (methanol), EtOH (ethanol), DMF (dimethylformamide), EtOAc (ethyl acetate) and THF (tetrahydrofuran).

Intermediates 1 and 2

Methvl 1,2.3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyridof3,4bīmdole-3-carboxylate, cis and trans isomers

To a stirred solution of racemic tryptophan methyl ester (13 g) and piperonal (9.7 g) in anhydrous CH2CI2 (300 mL) cooled at 0°C vvas added dropvvise trifluoroacetic acid (9 mL) and the solution vvas allovved to react at ambient temperature. After 4 days, the yellow solution vvas diluted vvith CH2CI2 (100 mL), vvashed with a saturated aqueous solution of NaHCO3, then with vvater and dried over Na2SO4. The organic layer vvas evaporated to dryness under reduced pressure and the residue vvas purified by flash chromatography eluting vvith CH2Cl2/MeOH (99/1) to give first Intermediate 1. the cis isomer (6.5 g) m.p.

: 90-93°C followed by Intermediate 2, the trans isomer (6.4 g) m.p. : 170°C.

The following compounds vvere obtained in a similar manner:

Intermediates 3 and 4

Methvl 1,2,3,4-tetrahydro-1 -(4-methoxvphenvn-9H-pyridof3,4-bļindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4methoxybenzaldehyde gavē Intermediate 3, the cis isomer as white crystals m.p.: 142°C and Intermediate 4. the trans isomer as vvhite crystals m.p.: 209210°C.

Intermediate 5

Methvl 1,2,3.4-tetrahydro-1-(3-methoxyphenvl)-9H-pyridoi3,4-b1indole-3carboxylate, cis isomer

The same method but starting from racemic tryptophan methyl ester and 3methoxybenzaldehyde gavē the title compound as vvhite crystals m.p.: 146°C.

Intermediates 6 and 7

Methvl 1,2,3,4-tetrahydro-1 -(4-ethoxyphenvl)-9H-pyridor3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4ethoxybenzaldehyde gavē Intermediate 6. the cis isomer as vvhite crystals m.p. : 180°C and Intermediate 7, the trans isomer as vvhite crystals m.p. : 196-198°C.

Intermediates 8 and 9

Methvl 1,2,3,4-tetrahydro-1-(2.3-dihvdrobenzofbTfuran-5-yl)-9l-l-pvridof3,4b1indole-3-carboxylate₁ cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 2,3dihydrobenzo[b]furan-5- carboxaldehyde gavē Intermediate 8, the cis isomer as vvhite crystals m.p. : 106-109°C and Intermediate 9. the trans isomer as vvhite crystals m.p. : 219-222°C.

Intermediates 10 and 11

Methvl 1,2,3,4-tetrahydro-1 -(3.4-ethvlenedioxyphenyl)-9H-pyridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 1,4benzodioxan-6-carboxaldehyde gavē Intermediate 10, the cis isomer as vvhite crystals m.p. : 104-106^eC and Intermediate 11, the trans isomer as vvhite crystals m.p.: 207-209°C.

Intermediate 12

Methvl 1.2,3,4-tetrahvdro-1 -(2-chlorophenvO-9H-pyridof3,4-b1indole-3carboxylate, mixture of cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 2chlorobenzaldehyde gavē the title compound as vvhite crystais m.p.: 154°C.

Intermediates 13 and 14

Methvl 1,2,3,4-tetrahydro-1 -(4-chlorophenyl)-9H-pyridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4chlorobenzaldehyde gavē Intermediate 13, the cis isomer as vvhite crystais m.p. : 208-209°C and Intermediate 14. the trans isomer as vvhite crystals m.p. : 108109°C.

Intermediates 15 and 16

Methvl 1,2,3,4-tetrahydro-1 -(3,4-dichlorophenvl)-9H-pvridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 3,4dichlorobenzaldehyde gavē Intermediate 15, the cis isomer as a vvhite solid NMR (CDCI3) δ (ppm): 7.8-7 (m, 8H, H aromatic); 5.15 (brs, 1H, H-1) ; 3.9 - 3.8 (dd, 1H, H-3) 3.7 (s, 3H, CO₂CH₃) ; 3.2 - 3.1 (ddd, 1H, H-1) 2.9 (m, 1H, H-4) ; 2.4 (brs, 1H, NH) and Intermediate 16, the trans isomer as a white solid m.p. : 204°C.

Intermediate 17

Methvl 1,2.3,4-tetrahydro-1-(1,2,3,4-tetrahydro-6-naphthvl)-9H-pyridof3,4b1indole-3-carboxylate, cis isomer

The same method but starting from racemic tryptophan methyl ester and 1,2,3,4tetrahydronaphthyl-6- carboxaldehyde gavē the title compound as a vvhite solid ¹H NMR (CDCI3) δ (ppm) : 7.7-7(m, 8H, H aromatic) ; 5.2 (s, 1H, H-1) ; 4.0 (dd,

Η, H-3); 3.8 (s, 3H, CO₂CH₃); 3.2 (m, 1H. H-4); 3.0 (m, 1H, H-4); 2.7 (m, 4H,

CH^Ar); 1.7 (s, 4H, Cļ^C^Ar).

Intermediates 18 and 19

Methvl 1,2.3,4-tetrahydro-1 -(2-naphthvl)-9H-pvridoi3,4-b1indole-3-carboxvlate.

cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 2naphthaldehyde gavē Intermediate 18, the cis isomer as a vvhite solid H NMR (CDCI₃) δ (ppm): 8-6.9 (m, 12H, H aromatic); 5.4 (s, 1H, H-1) ; 3.95 (dd, 1H, H3) ; 3.7 (s, 3H, CO₂CH₃) 3.2 (ddd, 1H, H^t); 3 (m, 1H, H^t); 2.5 (brs, 1H, NH) and Intermediate 19, the trans isomer as a vvhite solid (0.6 g) m.p. : 119°C.

Intermediates 20 and 21

Methvl 1,2,3,4-tetrahvdro-1-(2-thienyl)-9H-pvridoi3,4-b1indole-3-carboxvlate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 2thiophenecarboxaldehyde gavē Intermediate 20, the cis isomer as a pale yellow solid m.p. : 134-137°C and Intermediate 21. the trans isomer as vvhite crystals m.p. :169°C.

Intermediates 22 and 23

Ethvl 1,2,3,4-tetrahydro-1 -(3-thienyl)-9H-pvridof3,4-b1indole-3-carboxYlate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 3thiophenecarboxaldehyde gavē Intermediate 22, the cis isomer as vvhite crystals m.p. : 130°C and Intermediate 23, the trans isomer as white crystals m.p. :182184°C.

Intermediates 24 and 25

Methvl 1,2,3,4-tetrahydro-1-(5-bromo-2-thienvl)-9H-pyridor3,4-blindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 5bromo-2-thiophenecarboxaldehyde gavē Intermediate 24. the cis isomer as a cream solid m.p.: 130°C and Intermediate 25. the trans isomer as a cream solid m.p. : 205°C.

Intermediates 26 and 27

Methvl 1.2.3,4-tetrahydro-1 -(4-bromo-2-thienyl))-9H-pvridor3,4-bļindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4bromo-2-thiophenecarboxaldehyde gavē Intermediate 26. the cis isomer as a cream solid m.p.: 200°C and Intermediate 27. the trans isomer as a cream solid m.p.: 120°C.

intermediate 28

Methvl 1,2,3,4-tetrahydro-1 -(3-furvl)-9H-pyridoi3,4-b1indole-3-carboxvlate, mixture of cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 3furaldehyde gavē the title compound as a yellow solid m.p. : 130°C.

Intermediates 29 and 30

Ethvi 1,2,3.4-tetrahvdro-1-(5-methyl-2-furyl)-9H-pyridor3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 520 methylfurfural gavē Intermediate 29. the cis isomer as a oily compound ¹H NMR (CDCI3) δ (ppm): 7.7 (brs, 1H, NH indole); 7.5 (d, 1H, H aromatic); 7.25-6.9 (m, 3H, H aromatic); 6.15 (d, 1H, H aromatic); 5.85 (m, 1H, H aromatic); 5.25 (brs, 1H, H-1); 4.2 (q, 2H, CO₂CH₂CH₃); 3.8 (dd, 1H, H-3); 3.2 - 2.8 (m, 2H, H-4); 2.2 (s, 3H, CH3); 1.25 (t, 3H, CO₂CH₂CH3) and Intermediate 30, the trans isomer as a cream solid m.p. : 152°C.

Intermediates 31 and 32

Ethvi 1,2,3,4-tetrahydro-1-(4-methvlphenvl)-9H-pyridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and ptolualdehyde gavē Intermediate 31, the cis isomer as white crystals m.p. : 148°C and Intermediate 32. the trans isomer as vvhite crystals m.p. : 180°C.

Intermediates 33 and 34

Methvl 1,2,3,4-tetrahvdro-ļ -(3-methylphenyl)-9H-pyridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and mtolualdehyde gavē Intermediate 33, the cis isomer as vvhite crystals 1H NMR (CDCI3) 5(ppm): 7.6-7 (m, 9H, H aromatic); 5.2 (brs, 1H, H-1); 4-3.9 (dd, 1H, H3) 3.8 (s, 3H, CO₂CH₃) ; 3.2 - 3.1 (ddd, 1H, H-4) 3 (m, 1H, H-4) ; 2.35 (s, 3H, CH3); 1.7 (brs, 1H, NH) and Intermediate 34, the trans isomer as a white solid m.p. : 175°C.

Intermediates 35 and 36

Methvl 1,2,3,4-tetrahydro-1 -(4-trifluoromethylphenvl)-9H-pyrido[3,4-blindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4trifluoromethylbenzaldehyde gavē Intermediate 35. the cis isomer as pale yellow crystals m.p. : 190°C and Intermediate 36, the trans isomer as pale yellow crystals m.p. ; 203°C.

Intermediates 37 and 38

Ethvl 1,2.3,4-tetrahydro-1-(4-cvanophenyl)-9H-pyridof3.4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 4cyanobenzaldehyde gavē Intermediate 37. the cis isomer as vvhite crystals m.p.

; 200°C and Intermediate 38, the trans isomer as vvhite crystals m.p. : 156°C.

Intermediate 39

Methvl 1,2.3,4-tetrahydro-1 -(4-hvdroxvphenvl)-9H-pyridof3,4-b1indole-3carboxylate, cis isomer

The same method but starting from racemic tryptophan ethyl ester and 4hydroxybenzaldehyde gavē the title compound as pale yellow crystals ¹H NMR (DMSO) 5(ppm) : 10.3 (s, 1H, NH-indole) 9.4 (s, 1H, OH) ; 7.8 - 7.5 (m, 8H, H aromatic) ; 5.1 (brs, 1H, H-1) ; 3.9 (m, 1H, H-3) ; 3.75 (s, 3H, CO₂CH₃) 3.1 (m, 1H, H-4) ; 2.8 (m, 1H, H-4).

Intermediate 40

Methvl 1,2,3,4-tetrahydro-1 -(3-hvdroxv-4-methoxvphenvl)-9H-pyrido[3,4bļindole-3-carboxylate, cis isomer

The same method but starting from racemic tryptophan methyl ester and 3hydroxy-4-methoxybenzaldehyde gavē the title compound as a yellow solid m.p. : 140-148°C.

Intermediate 41

Methvl 1,2,3,4-tetrahydro-1 -(4-hvdroxv-3-methoxyphenvl)-9H-pyrido[3,4blindole-3-carboxylate, cis isomer

The same method but starting from racemic tryptophan methyl ester and 4hydroxy-3-methoxybenzaldehyde gavē the title compound as a cream solid m.p.

: 195°C.

Intermediate 42

Methvl 1.2,3,4-tetrahvdro-1 -(4-ethylphenyl)-9H-pyrido[3,4-blindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 4ethylbenzaldehyde gavē the cis and trans isomer of the title compound.

Cis isomer: vvhite solid ¹H NMR (CDCI3) 5(ppm): 7.65-7.1 (m, 9H, H aromatic);

5.25 (brs, 1H, H-1) ; 4(dd, 1H, H-3); 3.9 (s, 3H, CO₂CH₃) ; 3.4 (ddd, 1H, H-1) ;

3.1 (m, 1H, H-4); 2.7 (q, 2H, CH2CH3) 1.4 (t, 3H, CH2CH3).

Trans isomer: vvhite solid m.p. : 187°C.

Intermediates 43 and 44

Methvl 1,2,3,4-tetrahvdro-1 -(4-isopropylphenvl)-9H-pyridor3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 4isopropylbenzaldehyde gavē Intermediate 43. the cis isomer as a vvhite solid 1H NMR (DMSO) 6(ppm): 10.15 (s, 1H, NH indole); 7.3-6.7 (m, 8H, H aromatic); 5 (brs, 1H, H-1); 3.6 (m, 1H, H-3); 3.5 (s, 3H, CO₂CH₃); 2.95-2.5 (m, 3H, H-4 + CH-(Me)₂) 2.4 (brs, 1H, NH) ; 1 (d, 6H, 2xCH₃) and Intermediate 44, the trans isomer as a vvhite solid m.p. : 189°C.

Intermediates 45 and 46

Ethvl 1,2.3,4-tetrahydro-1 -(4-nitrophenvl)-9H-pyridoi3,4-b1indol&-3-carboxvlate.

cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 4nitrobenzaldehyde gavē Intermediate 45, the cis isomer as yellow crystals m.p. : 168°C and Intermediate 46. the trans isomer as yellowcrystals m.p. : 195°C.

Intermediate 47

Ethvl 1,2,3,4-tetrahvdro-1-(4-dimethvlar n'nophenvl)-9H-pyridof3,4-b1indole-3carboxylate, mixture of cis and trans iscmers

The same method but starting from racemic tryptophan ethyl ester and 4dimethylaminobenzaldehyde gavē the title compound as vvhite crystals m.p. : 170°C.

Intermediates 48 and 49

Ethvl 1,2,3,4-tetrahydro-1 -(3-pyridvl)-9H-pyridor3.4-b1indole-3-carboxvlate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 3pyridinecarboxaldehyde gavē Intermeciate 48, the cis isomer as pale yellow crystals m.p. : 230-232°C and Intermediate 49. the trans isomer as vvhite crystals m.p. : 210-214’C.

Intermediates 50 and 51

Methvl 1,2,3,4 tetrahydro-6-fluoro-1 -(3,4-methvlenedioxvphenvl)-9H-pyrido[3,4b1indole-3-carboxvlate. cis and trans isomers

The same method but starting from racemic 5-fluoro-tryptophan methyl ester and piperonal gavē Intermediate 50. the cis isomer as a cream solid m.p. :60°C and Intermediate 51. the trans isomer as a cream solid m.p. : 213°C.

Intermediates 52 and 53

Methvl 1,2,3,4-tetrahydro-6-fluoro-1 -(4-methoxyphenvl)-9H-pyrido(3,4-bļindole3-carboxylate, cis and trans isomers

The same method but starting from racemic 5-fluoro-tryptophan methy! ester and 4-methoxybenzaldehyde gavē Intermediate 52, the cis isomer as a solid 1H

NMR (CDCI3) δ (ppm) : 7.4-6.8 (m, 8H, H aromatic) ; 5.15 (brs, 1H, H-1) ; 3.9 (dd, 1H, H-3) 3.8 (s, 3H, CO2CH3) ; 3.2-2.9 (m, 2H, H-4) and Intermediate 53, the trans isomer as a solid m.p. : 197°C.

Intermediates 54 and 55 (1 R,3R)-Methyl 1,2,3,4-tetrahydro-1 -(3,4-methylenedioxyphenvl)-9H-pyrido|3,4b1indole-3-carboxylate, cis isomer and (1 S,3R)-methyl 1,2,3,4-tetrahydro-1 -(3,4-methylenedioxvphenvl)-9H-pvrido|3,4blindole-3-carboxylate trans isomer

To a stirred solution of D-tryptophan methyl ester (11 g) and piperonal (7.9 g) in anhydrous CH2CI2 (400 mL) cooled at 0°C vvas added dropwise trifluoroacetic acid (7.7 mL) and the solution vvas allovved to react at ambient temperature. After 4 days, the yellow solution vvas diluted vvith CH2CI2 (200 mL) and vvashed vvith a saturated aqueous solution of NaHCO3, then vvith vvater (3x200 mL) and dried over Na2SO4- The organic layer vvas evaporated under reduced pressure and the residue vvas purified by flash chromatography eluting vvith dichloromethane/ethyl acetate (97/3) to give first Intermediate 54. the cis isomer (6.5 g) m.p. : 154°C follovved by Intermediate 55, the trans isomer (8.4 g) m.p. : 188°C.

The follovving compounds vvere obtained in a similar manner:

Intermediate 56 (1S, 3S) Methyl-ī.2,3,4-tetrahydro-1 -(3,4-methvlenedioxyphenvl)-9H-pyrido|3,4b1indole-3-carboxylate, cis isomer and (1R, 3S) methyl-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido|3,4bļindole-3-carboxylate, trans isomer

The same method but starting from L-tryptophan methyl ester and piperonal gavē the cis and trans isomers of the title compound.

Cis isomer: vvhite crystals m.p.: 154°C.

Trans isomer: vvhite crystals m.p. : 187-189’C.

Intermediates 57 and 58 (1 R,3R)-Methyl 1,2,3,4-tetrahydro-1 -(4-methoxyphenvl)-9H-pyridof3,4-b1indole3-carboxylate, cis isomer and (1 S,3R)-methyl 1,2,3,4-tetrahydro-1 -(4-methoxvphenyl)-9H-pyrido[3,4-b1indole3-carboxylate' trans isomer

The same method but starting from D-tryptophan methyl ester and 4methoxybenzaldehyde gavē Intermediate 57. the cis isomer as vvhite crystals m.p.: 124-125°C and Intermediate 58, trans isomer as vvhite crystals m.p. : 219222°C.

Intermediates 59 and 60 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-1 -(3-chloro-4-methoxyphenyl)-9H-pvridof3,4bIindole-3-carboxyiate, cis isomer and (1S, 3R)-methyl 1.2,3,4-tetrahvdro-1-(3-chloro-4-methoxyphenvl) 9H-pyridof3,4b1indoie-3-carboxylate. trans isomer

The same method. but starting from D-tryptophan methyl ester and 3-chloro-4methoxybenzaldehyde gavē Intermediate 59. the cis isomer isolated as the hydrochloride salt as white crystals m.p. : 200°C and Intermediate 60, the trans isomer as vvhite crystals m.p. ; 164°C.

Intermediates 61 and 62 (1 R,3R)-Methyl 1,2.3,4-tetrahydro-1 -(2,3-dihydrobenzofb1furan-5-yl)-9HPvridof3,4-b1indole-3-carboxylate, cis isomer and (1 S,3R)-methyl 1,2,3,4-tetrahydro-1 -(5-(2,3-dihydrobenzorbļfuran))-9Hpyridoi3,4-b1indole-3-carboxylate, trans isomer

The same method but starting from D-tryptophan methyl ester and 2,3dihydrobenzo[b]furan-5-carboxaldehyde gavē Intermediate 61, the cis isomer as vvhite crystals m.p. : 282°C and Intermediate 62, the trans isomer as vvhite crystais m.p. : 204°C.

Intermediates 63 and 64 (1 R,3R)-Methyl 1,2,3,4-tetrahydro-1 -(5-indanyl)-9H-pyridof3,4-b1indole-3carboxyiate cis isomer and (1 S,3R)-methyl 1,2,3,4-tetrahydro-1 -(5-indanyl)-9H-pyridof3,4-b1indole-3carboxylate trans isomer

The same method but starting from D-tryptophan methyl ester and indan-5carboxaldehyde gavē Intermediate 63, the cis isomer as vvhite crystais m.p. :

130-131 °C and Intermediate 64, the trans isomer as vvhite crystals m.p. : 196°C.

Intermediate 65

Ethvl 1,2,3,4-tetrahydro-1 -(4-trifluoromethoxvphenvl)-9H-pyridof3,4-b1indole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan ethyl ester and 4trifluoromethoxybenzaldehyde gavē cis and trans isomers of the title compound. Cis isomer: vvhite crystals m.p. : 88°C.

Trans isomer: vvhite crystals m.p. : 152°C.

Intermediate 66

Methvl 1,2,3,4-tetrahydro-1-(5-methvl-2-thienvl)-9H-pyrido [3,4-bļindole-3carboxylate, cis and trans isomers

The same method but starting from racemic tryptophan methyl ester and 5methyl-2-thiophenecarboxaldehyde gavē the cis and trans isomers of the title compound.

Cis isomer: oily compound ¹H NMR (CDCI3) δ (ppm): 8.4 (brs, 1H, NH-indole); 7.7 - 6.6 (m, 6H, H aromatic); 5.5 (brs, 1H, H-1); 3.9 (dd, 1H, H-3); 3.85 (s, 3H, CO₂CH₃); 3.3 - 2.9 (m, 2H, H-4); 2.5 (s, 3H, CH3).

Trans isomer: vvhite crystals m.p. : 194°C.

Intermediates 67 and 68 (1S,3R)-Methyl 1,2,3,4-tetrahydro-1-(3,4-methvlenedioxvphenvl)-9H-pyridoi3_l4bļindole-3-carboxylate and (1 R,3R)-methyl 1,2,3,4-tetrahvdro-1-(3,4-methvlenedioxyphenvl)-9H-pyridof3.4bļindole-3-carbQxvlate

To a stirred solution of D-tryptophan methyl ester (obtained by treating the corresponding hydrochloride salt in vvater vvith saturated aqueous NaHCO3 solution and extraction vvith CH2CI2) (25.7g) and piperonal (19.4g) in anhydrous dichloromethane (700ml) cooled to O’C vvas added dropvvise trifluoroacetic acid (18.1 ml) and the solution vvas allowed to react at 4°C. After 5 days, the yellow solution vvas diluted vvith dichloromethane (500ml). The organic layer was vvashed vvith a saturated aqueous solution of NaHCC>3, then vvith vvater (3 x 500ml) until the pH vvas neutral and dried over Na2SC>4. The organic layer vvas evaporated under reduced pressure to a volume of about 500ml. The transisomer, vvhich crystal!ised, vvas filtered and the filtrate vvas reduced to 200ml.

Another fraction of the trans-isomer crystallised. The fractions of trans-isomer were combined to give the (1S,3R) isomer, Intermediate 67, as vvhite crystals (11.4g).

mp: 188°C

20° [α]β = +32.4° (c = 1.03, CHCIg).

The filtrate containing mainly the cis-isomer vvas reduced to 100ml and isopropyl ether (200ml) vvas added. Upon cooling, the (1R,3R) isomer, Intermediate 68, crystallised as a vvhite solid (17.4g).

mp: 154-155°C [a]g°= + 24.4° (c = 1.03, CHCI₃).

Intermediate 69 (1R,3R)-Methyl 1,2.3,4-tetrahvdro-1-(3.4-methvlenedioxvphenvl)-9H-pyridoi3,4b1indole-3-carboxylate

Method A

Intermediate 67 (5.0g) vvas dissolved in methanol (150ml). Hydrogen chloride vvas bubbled into the solution for several minūtes at 0°C and the resulting yellow solution vvas refluxed for 24 hours. The solvent vvas removed under reduced pressure and the residue was basified vvith a saturated aqueous solution of NaHCO3 and extracted vvith dichloromethane. The organic layer vvas vvashed with vvater, dried over Na₂SC>4 and purified by flash chromatography eluting vvith dichloromethane/methanol (99/1) to give the title compound (2.3g) corresponding to an authentic sample of Intermediate 68.

Method B

Intermediate 67 (25g) vvas heated in 1N hydrochloric acid (78.5ml) and vvater (400ml) at 60°C for 36 hours. From the initial pale yellovv solution, a white solid precipitated. The mixture vvas then allovved to cool to 0°C and the solid fīltered. The solid vvas then vvashed vvith diisopropyl ether (3 x 200ml) and dried to give the hvdrochloride salt ofthe title compound (20g) as a vvhite solid.

mp (dec.): 209-212°C

Method C

Α 1 : 1 mixture of the cis and trans isomers of Intermediates 54 and 55 (2g) was heated in 1N hydrochloric acid (6.8ml) and vvater (15ml) at 50°C for 72 hours. A similar vvork-up as described in Method B above gavē the hvdrochloride salt of the title compound (1.7g) as a vvhite solid.

Intermediate 70 (R)-N^CL-(^,3,4-Methvlenedioxvphenvlcarbonvl)-tryptophan methvl ester To a suspension of D-tryptophan methyl ester hydrochloride (10.2g) in anhydrous CH2CI2 (150ml) cooled at 0°C vvas added dropvvise triethylamine (12.3ml). To the resulting solution solid piperonyloyl chloride (8.16g) vvas added portionvvise at the same temperature, and the mixture was stirred at room temperature for 2 h. The mixture vvas vvashed successively vvith vvater, 0.5N hydrochloric acid, vvater, a saturated aqueous solution of NaHCC>3 and again with vvater. After drying over Na2SC>4 and evaporation of the solvent under reduced presure, the resulting oil on trituration from hot cyclohexane afforded the title compound as a vvhite sofid (14.7g).

mp: 123-124’C [α] 2° = - 84.4° (c = 1.04, CHCķ).

Intermediate 71 (R)-N^a-(3,4-MethvlenedioxvphenvlthiocarbonvD-tryptophan methvl ester

A mixture of Intermediate 70 (14g) and Lavvesson's reaģent (9.28g) in dimethoxyethane' (280ml) vvas heated at 60°C under N2 for 16 hours vvith stirring. The reaction mixture vvas evaporated to dryness and the resulting oil was dissolved in ethyl acetate, then vvashed successively vvith an aqueous saturated solution of NaHCO3 and vvater and dried over Na2SO4. The oily residue obtained after evaporation under reduced pressure gavē, on trituration from cyclohexane, a yellow povvder vvhich vvas filtered and vvashed vvith cooled methanol to afford the title compound (9.74g).

mp: 129-130’C 90° [α]θ =-186.8’ (c = 1.14, CHCI₃).

Intermediate 72 (1R,3R)-Methyl 1,2,3,4-tetrahvdro-1-(3,4-methvlenedioxvphenvl)-9H-pyridoF3,4b1indole-3-carboxylate

A solution of Intermediate 71 (9g) and methyl iodide (10ml) in anhydrous dichloromethane (200ml) vvas heated at reflux under an argon atmosphere vvith protection from light. After 24 hours, the solvent vvas removed under reduced pressure to give an orange oil vvhich on trituration from hexane gavē a solid which vvas vvashed vvith ether and used vvithout further purification in the next step. This compound (13.11g) vvas dissolved in methanol (250ml) and the solution vvas cooled to -78°C. NaBH4 (0.99g) vvas then added by portions and the mixture vvas stirred at the same temperature for 1 hour. The reaction vvas quenched by addition of acetone (10ml) and the solvent vvas removed under reduced pressure. The residue vvas dissolved in CH2CI2, vvashed vvith vvater and then vvith brine and dried over Na2SC>4. After evaporation of the solvent, the orange oil gavē on trituration from a hot mixture of diethyl ether/cyclohexane an orange povvder vvhich vvas recrystallised from diethyl ether/pentane to afford the title compound as a pale yellow solid (5.15g) corresponding to an authentic sample of Intermediate 68.

Intermediate 73 (1R,3R)-Methyl 1,2,3,4-tetrahvdro-2-chloroacetvl-(3,4-methvlenedioxyphenyl)9H-pyridoi3.4-b1indole-3-carboxylate

Method A

To a stirred solution of Intermediate 72 (9.7g) and NaHCC>3 (2.79g) in anhydrous CHCI3 (200ml) was added dropvvise chloroacetyl chloride (5.3ml) at 0°C under N2. The resulting mixture vvas stirred for 1 hour at the same temperature and diluted vvith CHCI3 (100ml). Water (100ml) vvas then added dropvvise vvith stirring to the mixture, follovved by a saturated aqueous solution of NaHCO3- The organic layer vvas vvashed vvith vvater until neutrality and dried over Na2SO4. After evaporation ofthe solvent under reduced pressure, the oily compound obtained vvas crystallised from ether to give the title compound as a pale yellow solid (9.95g).

mp: 233°C [a]2°°=-125.4° (c= 1.17, CHCIg).

Method B

Chloroacetyl chloride (4ml) was added dropvvide to a solution of Intermediate 72 (16.1g) and triethylamine (7ml) in anhydrous CH2CI2 (200ml) at 0°C under N2. The solution was stirred at 0°C for 30 minūtes, then diluted vvith CH2CI2 (300ml). The solution vvas vvashed vvith vvater (200ml), a saturated aqueous solution of NaHCO3 (300ml) and brine (400ml). After drying over Na2SO4 and evaporation under reduced pressure, the resulting solid vvas vvashed with ether (300ml) to give the title compound as a pale yellow solid (18.3g).

Intermediate 74

Methvl 1,2,3,4-tetrahvdro-6-methvl-1-(3,4-methvlenedioxvphenvl)-9H-pyridoi3,4bļindole-3-carboxylate, cis and trans isomers

The cis and trans isomers of the title compound were prepared using the method described in Intermediate 1 but starting from racemic 5-methyitryptophan methyl ester and piperonal.

Cis isomer: yellow solid m.p.: 85°C.

Trans isomer: yellow solid m.p.: 185°C.

Intermediates 75 and 76 (1R, 3R)-Methyl 1,2,3.4-tetrahvdro-1-(7-(4-methvl-3.4-dihydro-2Hbenzof1,4ioxaziriyl))-9H-pyridof3,4-b1indole-3-carboxylate, cis isomer and (1S,

3R)-Methyl 1,2,3,4-tetrahydro-1-(7-(4-methvl-3,4-dihydro-2Hbenzofļ ,41oxazinvl))-9H-pyridof3,4-b1indole-3-carboxvlate, trans isomer The same method, as described for intermediates 54 and 55, but starting from D-tryptophan methyl ester and 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7carboxaldehyde gavē Intermediate 75 the cis isomer as an oily compound ¹H NMR (CDCI3) δ (ppm): 7.6-7.1 (m, 5H); 6.9-6.6 (m, 3H); 5.15 (brs, 1H); 4.3 (t, 2H); 4 (dd, 1H); 3.8 (s, 3H); 3.3 (t, 2H); 3.3-2.95 (m, 2H); 2.9 (s, 3H); 1.6 (br s) and intermediate 76, the trans isomer as vvhite crystals m.p. : 119-121’C.

Intermediate 77

Methvl 1,2,3,4-tetrahydro-1 -(5-(N-benzylindolinvl))-9H-pyridof3,4-b1indole-3carboxylate, mixture of (1R, 3R) and (1S, 3R) isomers

The same method, as described for intermediates 54 and 55, but starting from

D-tryptophan methyl ester and N-benzylindoline-5-carboxaldehyde gavē intermediate 77 as an oily compound.

Intermediates 78 and 79 (1R, 3R)-Methyl 1,2,3,4-tetrahvdro-1-(4-carbomethoxvphenvl)-9H-pyridof3,4b1indole-3-carboxylate, cis isomer and (1S, 3R)-methyl 1,2,3,4-tetrahydro-1-(4carbomethoxyphenvl)-9H-pvridof3,4-bļindole-3-carboxvlate, trans isomer

The same method, as described for intermediates 54 and 55, but starting from D-tryptophan methyl ester and methyl 4-formy!benzoate gavē Intermediate 78, the cis isomer as vvhite crystals m.p. : 157-160°C and Intermediate 79, the trans isomer as pale yellow crystals m.p.; 124-126^OC.

Intermediate 80 (1R, 3R)-Methyl 1,2,3.4-tetrahydro-2-[2-(benzvloxvcarbonvl)-R-prolyll-1 -(3,4methvlenedioxvphenyl)-9H-pvrido[3.4-b1indole-3-carboxvlate

A solution of N-(benzyloxycarbonyl)-D-proline acid chloride (0.64 g, 2.4 mmol) in anhydrous dichloromethane (10 mL) vvas added dropvvise to a stirred solution of intermediate 54 (0.7 g, 2 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (15 mL) at - 10°C. The mixture vvas stirred for 2 h at - 10°C after vvhich it vvas diluted vvith dichloromethane (50 mL), vvashed vvith hydrochloric acid (1N), vvater, a saturated solution of NaHCO₃, a saturated NaCI solution and dried over Na₂SO4. Evaporation of the solvent and recrystallisation of the crude product from methanol gavē the title compound as pale yellow crystals (0.75 g) m.p. : 268-270°C.

Intermediate 81 (1R, 3R)-Methyl 1,2,3,4-tetrahydro-2-f2-(benzvloxvcarbonvl)-S-prolvH-1-(3,4methvlenedioxyphenyl)-9H-pvridof3,4-b1indole-3-carboxvlate

A solution of N-(benzyloxycarbonyl)-L-proline acid chloride (0.86 g, 3.2 mmol) in anhydrous dichloromethane (10 mL) vvas added dropvvise to a stirred solution of intermediate 54 (0.91 g, 2.6 mmol) and triethylamine (0.44 mL, 3.2 mmol) in dichloromethane (20 mL) at - 10°C. The mixture vvas stirred for 2 hours at - 10°C after vvhich it vvas diluted vvith dichloromethane (60 mL), vvashed vvith hydrochloric acid (1N), vvater , a saturated solution of NaHCO₃, a saturated NaCI solution and dried over Na₂SO₄. Evaporation of the solvent and recrystallisation of the crude product from methanol/vvater gavē the title compound as pale yellow crystals (0.8 g) m.p.: 115-120°C.

Intermediate 82 (1R, 3R)-Methyl 1,2.3,4-tetrahydro-2-(2-chloropropionyl)-1-(3.4methylenedioxvphenvl)-9H-pyridoF3,4-bļindole-3-carboxYlate

To a solution of (S)-(-)-2-chloropropionic acid (87 μΙ, 1 mmol) in anhydrous dichloromethane (15 mL), vvas added dicyclohexylcarbodiimide (0.23 g,

l. 1 mmol). Intermediate 54 (0,35 g, 1 mmol) vvas then added and the mixture vvas stirred at room temperature for 20 hours. The formed precipitate of dicyclohexylurea vvas removed by filtration, the filtrate vvas evaporated in vacuo and the crude product vvas purified by flash chromatography eluting vvith toluene/ethyl acetate : 95/5. The oily compound obtained vvas then crystallised from ether/hexane to give the title compound as pale yeilow crystals (0.31 g)

m. p. ; 125-127°C.

Intermediate 83 (1R, 3R)-Methyl 1,2.3,4-tetrahvdro-2-(2-chloropropionyi)-1-(3,4methylenedioxvphenvl)-9H-pyridoF3.4-bļindole-3-carboxvlate

To a solution of (R)-(+)-2-chloropropionic acid (191 pl, 2.2 mmol) in anhydrous dichloromethane ’ (30 mL), vvas added dicyclohexylcarbodiimide (0.45 g,

2.2. mol). Intermediate 54 (0,7 g, 2 mmol) was then added and the mixture was stirred at room temperature for 20 hours. The formed precipitate of dicyclohexylurea was removed by filtration, the filtrate vvas evaporated in vacuo and the crude product was purified by flash chromatography eluting with toluene/ethyl acetate ; 95/5. The oily compound obtained vvas then crystallised from ether/hexane to give the title compound as pale yellow crystals (0.74 g) m.p. : 126-128°C.

Intermediates 84 and 85 (1R, 3R)-Methyl 1,2.3,4-tetrahydro-1-(3,4-dibenzvloxyphenyl)-9H-pyridoF3,4b1indole-3-carboxylate cis isomer and (1S, 3R)-methyl 1,2,3,4-tetrahydro-143.4dibenzyloxvphenvD-9H-pyrido F3,4-b1indole-3-carboxylate trans isomer

The same method as described for intermediates 54 and 55 but starting from Dtryptophan methyl ester and 3,4-dibenzyloxybenzaldehyde gavē intermediate 84, the cis isomer as an oily compound 1H NMR (CDCI3) 6(ppm): 7.5 - 6.95 (m, 15H) ; 6.85 (s, 1H) ; 6.75 (s, 2H) ; 5.1 (s, 2H) ; 5 (br s, 1H) ; 4.95 (d, 2H) 3.85 (dd, 1H) ; 3.7 (s, 3H) ; 3.2-2.8 (m, 2H) ; 2.3 (br s, 1H) and intermediate 85, the trans isomer as an oily compound ¹HNMR (CDCI3) δ (ppm) 7.6-7 (m, 15H); 6.96.7 (m, 3H) ; 5.2 (br s, 1H) ; 5.1 (s, 2H) ; 5 (s, 2H) ; 3.8 (t, 1H) ; 3.65 (s, 3H) ;

3.3-3 (m, 2H); 2.25 (brs, 1H).

Intermediate 86 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-dibenzyloxyphenvl)-2-methylpyrazino[2', 1': 6,npyrido[3,4-blindole-1,4-dione

The same two step procedure but starting from intermediate 84 and methylamine gavē, after recrystallisation from dichloromethane/ether, the title compound as vvhite crystals m.p. : 158-160°C, [a]²⁰’_D = + 11.7° (c = 1.23 ; CHCI3).

Intermediate 87

Methvl 1,2,3,4-tetrahydro-1-(5-(2-methvlisoindolinvl))-9H-pvridof3,4-b1indole-3carboxylate, mixture of (1R.3R) and (1S.3R) isomers

The same method, as described for intermediates 54 and 55, but starting from D-tryptophan methyl ester and N-methylisoindoline-5-carboxaldehyde gavē intermediate 87 as an oily compound.

Example 1

Cis-2,3,6.7,12,12a-hexahydro-2-methvl-6-(3.4-methvlenedioxyphenvl)pyrazinof2^,.T:6.npyridof3.4-b1indole -1,4-dione

a) To a stirred solution of intermediate 1 (2 g) and NaHCC>3 (0.6 g) in anhydrous CHCI3 (40 mL) was added dropwise chloroacetyl chloride (1.1 mL) at 0°C, The resulting mixture was stirred for 1 hour at the same temperature and diluted vvith CHCI3. Water (20 mL) vvas then added dropwise vvith stirring to the mixture, followed by a saturated solution of NaHCO3. The organic layer vvas vvashed vvith water until neutrality and dried over Na2SC>4. After evaporation of the solvent under reduced pressure, cis-methvl 1,2,3,4LV 11690 tetrahydro-2-chloroacetyl-1-(3.4-methylenedioxyphenyl)-9H-pyrido[3,4bļindole-3-carboxylate was obtained as an oil vvhich vvas crystallised from ether (2 g, m.p. ; 215-218^eC) and vvas used without further purification in the next step.

b)To a stirred suspension of the chloroacetyl intermediate (0.34 g) in MeOH (20 mL) vvas added at ambient temperature a solution of methylamine (33% in EtOH) (0.37 mL) and the resulting mixture vvas heated at 50^eC under N2 for 14 hours. The solvent vvas removed under reduced pressure and the residue vvas dissolved in CH2CI2 (50 mL). After vvashing vvith vvater (3x30 mL), drying over Na2SO4 and evaporating to dryness, the residue vvas purified by flash chromatography eluting vvith CH2Cl2/MeOH (99/1) and recrystallised from MeOH to give the title compound as vvhite crvstals (0.19 g) m.p. : 253-255°C.

Analysis for C22HigN3O4_;

Calculated:C,67.86;H,4.92;N,10.79;

Found:C,67.53;H,4.99;N, 10.62%.

The follovving compounds vvere obtained in a similar manner:

Example 2

Cis-2, 3, 6, 7, 12, 12a-hexahydro-2-butyl-10-fluoro-6-(4-methoxyphenyl)pyrazinof2', Γ : 6,11pyrido f3,4-b1indole-1.4-dione

The same tvvo step procedure but starting from butylamine and intermediate 52 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p.: 182°C.

Analysis for C25H26FN3O3 (0.1 H2O):

Calculated : C, 68.67 ; H, 6.04 ; N, 9.61;

Found ; C, 68.38 ; H, 6.11 ; N, 9.53%.

Example 3

Trans-2.3.6,7,12.12a-hexahvdro-2-methyl-6-(3,4-methylenedioxyphenyl)Pvrazino^'.l'^.npvridoOA-blindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 2 gavē, after recrystallisation from toluene, the title compound as vvhite crystals

m.p. : 301-303°C.

Analysis for C22H19N3O4·

Calculated: C,67.86;H,4.92;N,10.79;

Found:C,67.98;H,4.98;N,10.73%.

Example 4

Cis-2,3,6,7,12,12a-hexahvdro-6-(3.4-methvlenedioxyphenyl)pyrazinoi2', 1 ':6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from ammonia and intermediate 1 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 283-285°C.

Analysis for C₂1H -ļ 7^04;

Calculated: C,67.19;H,4.56;N, 11.19;

Found:C,67.04;H,4.49;N, 11.10%.

Example 5

Cis-2,3,6,7,12,12a-hexahydro-10-fluoro-6-(4-methoxyphenvD-2-(2,2,2trifluoroethyl)-pvrazinoi2^,,T : 6,npyrido f3.4-bļindole-1,4-dione

The same two step procedure but starting from 2,2,2-trifluoroethylamine and intermediate 52 gavē, after recrystallisation from ethanol/diisopropyl ether, the title compound as'vvhite crystals m.p. : 190°C.

Analysis for C₂3H-ļgF4N3O3:

Calculated : C, 59.87 ; H, 4.15 ; N, 9.11;

Found : C, 59.81 ; H, 4.18 ; N, 9.21%.

Example 6

Cis-2,3,6,7.12,12a-hexahydro-10-fluoro-2-methyl-8-(3,4-methylenedioxvphenvl)pyrazino[2',T : 6,npyridof3,4-bļindole-1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 50 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p. : 292°C.

Analysis for C^H-jgFNgC^·

Calculated : C, 64.86 ; H, 4.45 ; N, 10.31;

Found : C, 64.66 ; H, 4.60 ; N, 10.21%.

Example 7 (6R, 12aS)-2.3,6,7.12,12a-hexahvdro-2-methvl-6-(3,4-methvlenedioxvphenvOpvrazinoi2’.T : 6, npyridof3,4-b1indole-1,4-dione

The same tvvo step procedure but starting from methylamine and the trans isomer of intermediate 56 gavē, after recrystallisation from toluene, the title compound as vvhite crystals m.p. :287-289°C.

Analysis for C22H19N3O4 (0.25 toluene):

Calculated : C, 69.16 ; H, 5.13 ; N, 10.19;

Found : C,69.09 ; H, 5.14 ; N, 10.19%.

20’ [ct]_D = -293.4° (C=1.28; CHCIg).

Example 8 (6S, 12aR)-2,3.6,7,12.12a-hexahydro-2-methvl-6-(3,4-methvlenedioxvphenvl)pvrazino 12'. T : 6, npyridof3,4-b1indole-1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 55 gavē, after recrystailisation from toluene, the title compound as vvhite crystals m.p. : 287’C.

Analysis for C22H19N3O4 (0.3 toluene):

Calculated : C, 69.41 ; H, 5.17 ; N, 10.08;

Found : C, 69.56 ; H,5.24 ; N, 10.08%.

20’ [a]_D = +297.9’(C=1.21; CHCI₃).

Example 9

Cis-2, 3, 6, 7, 12, 12a-hexahvdro-2-f2-(2-pyridvl)-ethvn-6-(3,4methvlenedioxyphenvl)-pvΓazinoΓ2^,, 1 '-6,1 ļpyridof3.4-b1indole-1,4-dione The same two step procedure but starting from 2-(2-pyridyl)ethylamine and intermediate 1 gavē, after recrystallisation from 2-propanol, the title compound as white crystals m.p.: 218-222’C.

Analysis for C28H24N4O4;

Calculated : C, 69.99 ; H, 5.03 ; N, 11.66;

Found : C, 69.92 ; H, 5.16 ; N, 11.48%.

Example 10

Cis-2.3,6.7,12,12a-hexahvdro-2-(2-pyridvlmethyl)-6-(3,4Γη6ΐΚν1βΓ^ΐοχνρήΘηνΙ)-ρνΓ3ζίηο12', 1': 6, npyridof3,4-b1indole-1,4-dione

The same two step procedure but starting from 2-pyridylmethylamine and intermediate 1 gavē, after recrystallisation from DMF/water, the title compound as cream crystals m.p : 285-286’C.

Analysis for C27H22N4O4 (0.4 H₂O):

Calculated : C, 68.46 ; H.4.85 ; N, 11.83;

Found : C, 68.58 ; H, 4.88 ; N, 11.90%.

Example 11

Cis-2,3,6,7,12,12a-hexahydro-2-(3-pvridylmethyl')-6-(3,4methvlenedioxvphenyl)-pvrazinoί2^,. 1': 6, npyridor3,4-b1indole-1,4-dione

The same two step procedure but starting from 3-pyridylmethylamine and intermediate 1 gavē, after recrystallisation from ΟΗ₂ΟΙ₂/ΜβΟΗ, the title compound as cream crystals m.p. : 292-293°C.

Analysis ; C97H99N4O4:

Calculated : C, 69.52 ; H, 4.75 ; N, 12.01;

Found : C, 69.27 ; H, 4.74 ; N, 11.37%.

Example 12

Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4methvlenedioxyphenvl)-pyrazinof2', 1' : 6, npyridof3,4-bļindole-1,4-dione

The same tv/o step procedure but starting from 4-pyridylmethylamine and intermediate 1 gavē, after recrystallisation from MeOH, the title compound as pale yellow crystals m.p. : 273-274°C.

Analysis for C27H22N4O4 (1.8 H₂O):

Calculated : C, 65.00 ; H, 5.17 ; N, 11.23;

Found : C, 65.11 ; H, 4.85 ; N, 11.07%.

Example 13

Cis-2.3,6,7.12,12a-hexahvdro-2-ethvl-6-(3,4-methylenedioxyphenvl)pvrazinof2'.T:6,npyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from ethylamine and intermediate 1 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 272-274^eC.

Analysis for C23H21N3O4·

Calculated: C,68.47;H,5.25;N,10.42;

Found:C,68.52;H,5.35;N,10.53%.

Example 14

Cis-2,3,6,7,12,12a-hexahydro-2-(2,2,2-trifluoroethyl)-6-(3,4methvlenedioxyphenyl)-pvrazino|^,2^,, T:6,11pyridor3,4-b1indole -1,4-dione The same tvvo step procedure but starting from 2,2,2-trifluoroethylamine and intermediate 1 gavē, after recrystallisation from EtOH, the title compound as white crystals m.p. : 303°C.

Analysis for C23H18F3N3O4:

Calculated: C,60.40;H,3.97;N,9.19;

Found:C,60.43;H,4.15;N,9,16%.

Example 15

Cis-2,3,6,7.12,12a-hexahvdro-6-(3,4-methvlenedioxyphenvl)-2-propylpvrazino[2',1':6,npvrido|3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from propylamine and intermediate 1 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 270-271 °C:

Analysis for C24H23N3O4:

Calculated: C,69.05;H,5.55;N,10.07;

Found:C,69.22;H,5.50;N,9.80%.

Example 16

Cis-2,3,6,7,12,12a-hexahvdro-2-isopropvl-6-(3.4-methylenedioxyphenyl)Pvrazinoi2^,,T:6.npyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from isopropylamine and intermediate gavē, after recrystallisation from methanol, the title compound as white crystals m.p. : 248-250°C.

Analysis for C24H23N3O4:

Calculated: C,69.05;H,5.55;N,10.07;

Found:C,68.86;Η,5.66;Ν,10.21%.

Exampte 17

Cis-2,3,6,7,12,12a-hexahydro-2-cvciopropyl-6-(3,4-methvlenedioxvphenv05 pvrazir^', 1 ’:6,11pyridof3,4-bHndole -1,4-dione

The same tvvo step procedure but starting from cyclopropylamine and intermediate 1 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 290-292°C.

Analysis for C24H21N3O4:

Calculated: C,69.39;H,5.10;N,10.11;

Found:C,69.11;H,5.20;N,9.94%.

Example 18

Cis-2,3,6,7,12,12a-hexahydro-2-butvl-6-(3,4-methvlenedioxvphenyl)15 pvrazinof2',T:6.npyridoi3.4-b]indole-1,4-dione

The same tvvo step procedure but starting from butyiamine and intermediate 1 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p.: 241-243’C.

Analysis for C25H25N3O4:

Calculated: C,69.59,H,5.84;N,9.74;

Found:C,69.77;H,5.82;N,9.81%.

Example 19

T rans-2,3,6,7,12,12a-hexahydro-2-butvl-6-(3,4-methvlenedioxyphenyl)25 pvrazinor2^,,T:6.npvrido[3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 2 gavē, after recrystallisation from toluene, the title compound as vvhite crystals m.p. : 243°C.

Analysis for C25H25N3O4:

Calculated: C,69.59;H,5.84;N,9.74;

Found:C,69.80;H,5.78;N,9.52%.

Example 20

Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethvl-6-(3,435 methylenedioxyphenvl)-pvrazinof2^,l 1 *:6,1 |pyrido[3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 1 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 217-218°C.

Analysis for C25H23N3O4:

Calculated: C,69.92;H,5.40;N,9.78;

Found:C,70.02;H,5.47;N,9.84%.

Example 21

Cis-2,3.6,7.12.12a-hexahydro-2-cyclopentyl-6-(3,4-methvlenedioxvphenvl)pyrazinof2^,,T:6,1ļpyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopentyfamine and intermediate 1 gavē, after recrystallisation from acetone, the title compound as vvhite crystals m.p.: 270°C.

Analysis for C26H25N3O4:

Calculated: C,70.41 ;H,5.68;N,9.47;

Found:C,70.58;H,5.63;N,9.38%.

Example 22

Cis-2.3,6,7.12,12a-hexahydro-2-cvclohexvl-6-(3,4-methvlenedioxyphenvDρνΓ3ζΐηοί2',T:6,11ovridof3.4-blindole -1,4-dione

The same tvvo step procedure but starting from cyclohexylamine and intermediate 1 gavē, after recrystallisation from methanol/water, the title compound as white crystals m.p. : 268-269°C.

Analysis for C27H27N3O4:

Calculated: C,70.88;H,5.95;N,9.18;

Found:C,70.82;H,5.89;N,9.21%.

Example 23

Cis-2,3,6.7.12.12a-hexahvdro-2-benzvl-6-(3,4-methylenedioxyphenyl)pyrazino[2^,.1':6,11ovridof3.4-b]indole -1,4-dione

The same two step procedure but starting from benzylamine and intermediate 1 gavē, after recrystallisation from dichloromethane/hexane, the title compound as vvhite crystals m.p. : 285-287°C.

Analysis for 028^23^304(1 H2O):

Calculated: C,69.55;H,5.21 ;N,8.69;

Found:C,69.30;H,5.06;N,8.48%.

Example 24

Cis-2,3,6,7,12,12a-hexahvdro-2-(4-fluorobenzvl)-6-(3,4-methvlenedioxvphenvl)pvrazinote', 1 ’:6,11pyridof3,4-b1indole -1,4-<Jione

The same tvvo step procedure but starting from 4-fluorobenzylamine and intermediate 1 gavē, after recrystallisation from acetone, the title compound as vvhite crystals m.p.: 281-283°C.

Analysis for C28H22FN3O4:

Calculated: C,69.56;H,4.59;F,3.93;N,8.69;

Found:C69.54;H,4.58;F,3.82;N,8.63%.

Example 25

Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenvl)-2-methylpyrazinof2', 1' :6,11ovridor3.4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 3 gavē, after recrystallisation from 2-propanol, the title compound as vvhite crystals m.p.: 257-263’C.

Analysis for C22H21N3O3:

Calculated: C,70.38;H,5.64;N,11.19;

Found:C,70.11;H,5.55;N,11.15%.

Example 26

Trans-2,3,6,7,12,12a-hexahydro-6-(4-methoxvphenyl)-2-methvipyrazinof2', 1': 6,1 ļpyridoi3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 4 gavē, after recrystallisation from diisopropyl ether, the title compound as vvhite crystals m.p. : 225-228’C,

Analysis for C22H21N3O3:

Calculated: C,70.38;H,5.64;N,11.19;

Found:C,70.34;H,5.77;N, 11.19%.

Example 27

Cis-2,3,6,7,12,12a-hexahydro-2-ethyl-6-(4-methoxyphenvl)pvrazinof2', 1 ':6,1 ļpvridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from ethylamine and intermediate 3 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.; 245-255’C.

Analysis for C23H23N3O3:

Calculated: C,70.93;H,5.95;N,10.79;

Found:C,70.74;H,6.06;N,10.87%.

Example 28

Cis-2,3.6,7,12.12a-hexahydro-6-(4-methoxyphenvl)-2-(2.2,2trifluoroethyl)pyrazinoi2', 1 ’:6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from 2,2,2-trifluoroethylamine and intermediate 3 gavē, after recrystallisation from ethanol , the title compound as vvhite crystals m.p. : 232°C.

Analysis for C23H20F3N3O3:

Calculated: C,62.30;H,4.55;N,9.48;

Found:C,62.08;H,4.66;N,9.54%.

Example 29

Cis-2,3.6.7.12,12a-hexahvdro-2-butyl-6-(4-methoxyphenyl)pyrazinof2', 1 ’:6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 3 gavē, after recrystallisation from methanol,the title compound as vvhite crystals m.p. : 157°C.

Analysis for C₂5H₂7N303(0.5H₂0);

Calculated: C,70.40;H,6.62;N,9.85;

Found.C,70.25,H,6.60;N,9.83%.

Example 30

T rans-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methoxyphenvl)pvrazino^¹,1 ':6,1 ļpyridof3.4-b1indole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 4 gavē, after recrystallisation from methanol, the title compound as white crystals m.p. : 212-214’C.

Analysis for C25H27N3O3:

Calculated: C,71.92;H,6.52;N,10.06;

Found:C,71.81 ;H,6.55;N,10.03%.

Example 31

Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxypheny0-2-cvclopropylmethyl5 pyrazinof2', T:6,1Ipyridof3,4-b1indole -1,4-dione

The same two step procedure but starting from cyclopropylmethylamine and intermediate 3 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 180-185°C.

Analysis for C25H25N3O3 (O.5H2O):

Calculated: C,70.74;H,6.17;N,9.90;

Found:C, 70.91 ; H, 6.16 ; N, 9.80%.

Example 32

Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-(4-methoxyphenyl)15 pyrazinof2'.T:6.npvridof3.4-blindole -1,4-dione

The same tvvo step procedure but starting from benzylamine and intermediate 3 gavē, after recrystallisation from acetone, the title compound as white crystals m.p.: 275-279°C.

Analysis for 028^Η25^Ν3θ3^:

Calculated: C,74.48;H,5.58;N,9.31;

Found:C,74.53;H,5.60;N,9.20%.

Example 33

Cis-2,3,6,7,12,12a-hexahydro-6-(3-methoxvphenvn-2-methyl25 pyrazinor2', 1 ’:6,11pvridof3,4-bļindole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 5 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 267-269°C.

Analysis for C22H21N3O3:

Calculated: C,70.38;H,5.64;N,11,19;

Found;C,70.32;H,5.59;N, 11.25%.

Example 34

Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethoxyphenvl)-2-methyl35 pvrazinof2^,,T:6.1lpyridoi3.4-bļindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 6 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 247-248’C.

Analysis for C23H23N3O3:

Calculated: C,70.93.H,5.95;N,10.79;

FoundīC,71.23;H,5.95;N,10.63%.

Example 35

Cis-2,3,6,7.12.12a-hexahydro-6-(4-ethoxyphenyl)-2-cvclopropvlmethvlpyrazinoi2', 1 ’:6,11pyridof3,4-blindole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 6 gavē, after recrystallisation from 2-propanol, the title compound as vvhite crystals m.p. : 160-162°C.

Analysis for C26H27N3O3:

Calculated: C,72.71,Ή,6.34;Ν,9.78;

Found:C,72.28;H,6.39;N,9.71 %.

Example 36

Cis-2,3,6,7,12,12a-hexahvdro-6-(2.3-dihydrobenzofbTfuran-5-vl)-2-methylpyrazinoi2^,.T:6,npvridoi3,4-b1indole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 8 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 292-294°C.

Analysis for C23H21N3O3:

Calculated: C,71.30;H,5.46;N,10.85;

Found:C,71.15;H,5.56;N,10.84%.

Example 37

Cis-2,3,6,7,12,12a-hexahydro-6-(2.3-dihvdrobenzofbTfuran-5-vl)-2cyclopropylmethvl-pvrazino[2', 1 ',6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 8 gavē, after recrystallisation from methanol, the title compound as white crystals m.p. : 165-166’C.

Analysis for C26H25N3O3:

Calculated: C,73.05;H,5.89;N,9.83;

Found:C,73.08;H,5.97;N,9.87%.

Example 38

Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-ethylenedioxvphenyl)-2-methyl5 pvrazinof2^l,T:6,npyridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 10 gavē, after recrystallisation from acetone, the title compound as vvhite crystals m.p. : 303-305°C.

Analysis for C23H21N3O4;

Calculated: C,68.47;H,5.25;N,10.42;

Found.C,68.35;H,5.31;N,10.27%.

Example 39

Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-ethylenedioxvphenvl)-2-cvclopropylmethvl15 pyrazinof2', 1 ':6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 10 gavē, after recrystallisation from dichloromethane/ether, the title compound as vvhite crystals m.p. : 288-290°C.

Analysis for C26H25N3O4:

Calculated; C,70.41 ;H,5.68;N,9.47;

Found:C,70.15;H,5.62;N,9.30%.

Example 40

Cis-2,3,6,7,12,12a-hexahydro-2-butvl-6-(2-chlorophenyl)25 pvrazinore', 1':6,11pyridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from butyiamine and intermediate 12 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p. : 146°C.

Analysis for C24H24CIN3O2(0.75 H2O):

Calculated: C,66.20;H,5.90;N,9.65;

Found.C,66.15;H,5,95;N,9.69%.

Example 41

Cis-2,3,6,7,12,12a-hexahydro-6-f4-chlorophenyl)-2-methyl35 pyrazinof2', 1 ':6,1 |pvridoi3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 13 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 274’C.

Analysis for C21 H-ļgCIN3O2 (0.25 H2O):

Calculated: C,65.63;H,4.85;N, 10.93;

Found:C,65.39;H,4.84;N,10.85%.

Example 42

Cis-2,3,6,7.12,12a-hexahydro-2-butvl-6-(4-chlorophenyl)pyrazinor2', 1 ':6,11pyrido[3,4-b1indole -1,4-dione

The same two step procedure but starting from butylamine and intermediate 13 gavē, after recrystallisation from ethanol/vvater, the title compound as vvhite crystals m.p. : 164-166’C.

Analysis for C24H24CIN3O2:

Calculated: C,68.32;H,5.73;CI,8.40;N,9.96;

Found:C,68.48;H,5.64;CI,8.37;N,9.99%.

Example 43

Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-dichlorophenvl)-2-methylpyrazinoF2',T:6,npyridof3,4-bļindole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 15 gavē, after recrystallisation from ethanoi/DMF, the title compound as vvhite crystals m.p. : >260°C.

Analysis for C21H-17CI2N3O2 (0.5 H2O):

Calculated: C,59.39;H,4.29;N,9.93;

Found:C,59.32;H,4.16;N,9.99%.

Example 44

Cis-2,3,6,7,12,12a-hexahvdro-2-butyl-6-phenyl-pyrazino[2^,, T:6,1 ļpyridof3,4blindole -1,4-dione

The same tvvo step procedure but starting from butylamine and cis-methyl

1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-cart>oxylate1 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p. : 243-245’C.

Analysis for C24H25N3O2:

Calculated: C,74.39;H,6.50;N, 10.84;

Found:C,74.54;H, 6.51 ;N, 10.86%.

1. D. Soerens et al.. J. Org. Chem. 44, 535 - 545 (1979).

Example 45

0ί5_Ξ2_±3_ι6₁7υ_2Κ2^4τθ2<3)τγ0ΓΌ_;2-6βηζγ1_Ξ6_Σ2ΗβπγΙ_;ργΓ3ζίηο[2ΐυ26χ1]βϊ£1^οί34_Ξ blindole -1,4-dione

The same tvvo step procedure but starting from benzylamine and cis-methyl1,2,3,4-tetrahydro-1-phenyI-9H-pyndo[3,4-b]indole-3-carboxylate gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. ; 193195°C.

Analysis for C27H23N3O2:

Calculated: C,76.94;H,5.50;N,9.97;

Found:C,77.23;H,5.54;N,9.97%.

Example 46

Trans-2,3,6,7.12,12a-hexahydro-2-benzyl-6-phenvl-pvrazino[2',1':6,npyridof34bļindole -1,4-dione

The same tvvo step procedure but starting from benzylamine and cis-methyl1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate gavē, after... recrystallisation from methanol, the title compound as vvhite crystals m.p. : 284°C.

Analysis for C27H23N3O2:

Calculated: C,76.94;H,5.50;N,9.97;

Found:C,76.88;H,5.45;N,9.89%.

Example 47

Cis^.S.ej.^^a-heĶahvdro^-methvl-e-d^.SA-tetrahvdro-e-naphthvl)pyrazino[2'.T:6.npyridof3,4-b1indole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 17 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : >260°C.

Analysis for C25H25N3O2:

Calculated: C,75.16;H,6.31;N, 10.52;

Found:C,74.93;H,6.43;N, 10.63%.

Example 48

Cis-2.3,6,7,12.12a-hexahvdro-2-isopropyl-6-(1,2,3,4-tetrahvdro-6-naphthvl)pyrazinor2', 1 ':6,1 lpyridor3,4-bļindole -1,4-dione 5 The same two step procedure but starting from isopropylamine and intermediate gavē, after recrystallisation from the title compound as off-vvhite crystals m.p. : 244-246°C.

Analysis for C27H29N3O2 (O.25H2O):

Calculated: C,75.06;H,6.88;N,9.73;

Found:C,75.00;H,6.83;N,9.69%.

Example 49

Cis-2,3,6,7,12,12a-hexahydro-2-cvclopropylmethvl-6-(1,2,3,4-tetrahydro-6naphthvl))-pvrazinof2\T:6.npvridof3,4-blindole -1,4-dione 15 The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 17 gavē, after recrystallisation from ethanol/pentane, the title compound as vvhite crystals m.p.: 125°C.

Analysis for C28H29N3O2 (0.25 H2O):

Calculated: C,75.73;H,6.70;N,9.46;

Found:C,75.45;H,6.86;N,9.14%.

Example 50

Cis-2,3,6,7.12,12a-hexahydro-2-methyi-6-(2-naphthyl)pyrazinof2',T:6,npYridof3,4-b1indole -1,4-dione 25 The same tvvo step procedure but starting from methylamine and intermediate 18 gavē, after recrystallisation from dichloromethane/methanol, the title compound as white crystals m.p.: >260°C.

Analysis for C25H21N3O2 (O.25H2O):

Calculated: C,75.08;H,5.42;N,10.51;

Found:C,75.35;H,5.42;N, 10.49%.

Example 51

Cis-2,3,6,7,12,12a-hexahydro-2-butvl-6-(2-thienvl)-pvrazino[2^,l 1 ’.β, 1 ļpyridof3,4bļindole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 20 gavē, after recrystallisation from ethanol, the title compound as white crystals

m.p. : 226°C.

Analysis for C97H93N3O9S:

Calculated: C,67.15;H,5.89;N,10.68;

Found:C,67.39;H,5.88;N, 10.77%.

Example 52

Cis-2,3,6,7.12,12a-hexahydro-6-(5-bromo-2-thienvl)-2-methyipyrazinoF2', T:6,1 lpyridoF3,4-blindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 24 gavē, after recrystallisation from ethanol, the title compound as a cream povvder m.p. : 258°C.

Analysis for C-igH-ļ5BrN3O2S:

Calculated: C,53.03;H,3.75;N,9.76;

Found:C,53.01 ;H,3.78;N,9.69%.

Example 53

Cis-2,3,6,7,12,12a-hexahydro-6-(4-bromo-2-thienyl)-2-methylpyrazinoF2^,,T:6,1lpvridof3.4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 26 gavē, after recrystallisation from ethanol, the titie compound as vvhite crystals mp.: 292°C.

Analysis for CjgH-|gBrN3O2S (0.25H2O):

Calculated: C,52.48;H,3.82;N,9.66;

Found.C,52.46;H,3.81 ;N,9.60%.

Example 54

Cis-2,3,6,7,12,12a-hexahvdro-6-(5-bromo-2-thienyl)-2-cvclopropylmethvlρνΓ3Ζΐηοί2', T:6,1 lpyridoF3,4-b1indole-1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 24 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p. : 190°C.

Analysis for ¢22^20^^3028:

Calculated: C,56.18;H,4.29;N,8.93;

Found:C,55.92;H,4.28;N,8.74%.

Example 55

Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-cyclopentvlpvrazino^'.rze.npvridofS.A-blindole -1,4-dione

The same tvvo step procedure but starting from cyclopentylamine and intermediate 24 gavē, after -recrystallisation from ethanol, the title compound as vvhite crystals m.p. : 252^eC.

Analysis for C23H22BfN3O2S;

Calculated; C,57.03,H,4.58;N,8.67;

Found:C,56.87;H,4.66;N,8.68%.

Example 56

Cis-2,3,6,7,12,12a-hexahvdro-2-methyl-6-(5-methyl-2-thienyl)pyrazinof2', 1 ':6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and the cis isomer of intermediate 66 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p.: 282°C.

Analysis for C20H19N3O2S (O.25H2O):

Calculated: C,64.93;H,5.31;N,11.36;

Found;C,64.84;H,5.28;N,10.81%.

Example 57

Cis-2,3,6,7,12,12a-hexahydro-2-methvl-6-(3-thienyl)pyrazinof2',T:6,npyrido[3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 22 gavē, after recrystaliisation from acetone, the title compound as vvhite crystals m.p. : 290-295°C.

Analysis for C-ļgH-|7N3O2S;

Calculated: C,64.94;H,4.88;N,11.96;

Found: C, 64.81 ; H,4.95 ; N.11.68%.

Example 58

Cis-2,3,6,7,12,12a-hexahvdro-2-butyl-6-(3-thienvl)-pyrazinof2^,, 1 ':6,1 ļpyridof3,4bļindole -1,4-dione

The same two step procedure but starting from butylamine and intermediate 22 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 236-239^eC.

Analysis for C22H23N3O2S:

Calculated: C,67.15;H,5.89;N,10.68;S,8.15;

Found:C,67.42;H,5.76;N,10.57;S,8.01%.

Example 59

Cis-2,3,6,7,12,12a-hexahvdro-2-methvl-6-(3-furvl)-pyrazinoi2',1':6,npvridoi3,410 bļindole -1,4-dione

The same tvvo step procedure but starting from methylamine and the cis isomer of intermediate 28 gavē, after recrystallisation from ether, the title compound as a vvhite solid m.p.: 250°C.

Analysis for G-] gH-j 7N3O3 (O.5H2O):

Calculated: C,66.27;H,5.27;N,12.20;

Found:C,66.33;H,5.48;N,12.02%.

Example 60

Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-( 5-methyl-2-furyl)20 pyrazinor2^,,T:6,npyrido[3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 29 gavē, after recrystallisation from ethanol, the title compound as a cream powder m.p. : 303°C.

Analysis for C20H19N3O3 (O.25H2O):

Calculated: C,67.88;H,5.55;N,11.87;

Found:C,67.90;H,5.50;N,11.98%.

Example 61

Cis-2,3,6,7,12,12a-hexahydro-2-methvl-6-(4-methylphenvl)30 pvrazinof2',T:6,npvridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 31 gavē, after recrystallisation from ethanol, the title compound as white crystals m.p. :>260°C.

Analysis for 022^Η21^3θ2 (θ-25 H2O):

Calculated: C,72.61 ;H,5.95;N,11.55;

Found:C,72.73;H,5.96;N,11.59%.

Example 62

Cis-2,3,6,7.12,12a-hexahydro-2-isopropyl-6-(4-methylphenyl)5 pyrazinof2', 1 ’:6,11pyridor3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from isopropylamine and intermediate 31 gavē, after recrystallisation from the title compound as vvhite crystals m.p. : 170°C.

Analysis for C24H25N3O2 (O.5H2O):

Calculated: C,72.70;H,6.61 ;N,10.60;

Found:C,73.06;H,6.43;N,9.66%.

Example 63

Cis-2,3,6,7,12,12a-bexahydro-2-butvl-6-(4-methylphenvl)15 pyrazinof2', 1':6,1 lpyridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from butvlamine and intermediate 31 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 194°C.

Analysis for C25H27N3O2 (O.5H2O):

Calculated: C,73.15;H,6.87;N,10.24;

Found:C,73.01 ;H,6.84.N, 10.26%.

Example 64

Cis-2.3,6,7.t2,12a-riexahvdro-2-cvclopropvlmethvl-6-(4-methylphenyl)pyrazino|2', 1':6,1 lpyridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 31 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p.: 194°C.

Analysis for C25H25N3O2 (1.1H2O);

Calculated: C,71.61 ;H,6.54;N, 10.02;

Found:C,71.42.H,6.07;N,9.95%.

Example 65

Cis-2.3.6,7,12,12a-hexahydro-2-methyl-6-f3-methylphenyl)pyrazinoi2^,.T:6,npyridof3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 33 gavē, after recrystallisation from ethanol , the title compound as vvhite crystals m.p. : >260°C.

Analysis for C22H2IN3O2Calculated: C,73.52;H,5.89;N, 11.69;

Found:C,73.60;H,5.97;N, 11.66%.

Example 66

Cis-2,3,6,7,12,12a-hexahydro-2-butvl-6-(4-trifluoromethylphenyl)pyrazino[2', 1 ':6,11pyridof3,4-blindole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 35 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p.: 155°C.

Analysis for C25H24F3N3O2 (O.5H2O):

Calculated: C,64.65;H,5.43;N,9.05;

Found:C,64.78;H,5.40;N,9.01 %.

Example 67

Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-trifluoromethoxvphenvl)pvrazinof2'.T:6,1 |pyrido[3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and the cis isomer of intermediate 65 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 174-180°C.

Analysis for C99H1SF3N3O3 (O.5H2O):

Calculated: C,60.27;H,4.37;N,9.58;

Found:C,60.24;H,4.28;N,9.50%.

Example 68

Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-hydroxvphenyl)pvrazinof2^,,1':6,npyridof3.4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 39 gavē, after recrystallisation from methanol, the title compound as yellow crystals m.p. :179-180°C.

Analysis for C₂ļH-|gN3O3(1,25H₂O):

Calculated: C,65.70;H,5.64;N, 10.94;

Found:C,65.46;H,5.45;N,10.92%.

Example 69

Cis-2,3,6,7,12.12a-hexahvdro-6-(3-hvdroxv-4-methoxvphenvl)-2-methvlpyrazinoi2^l, Γ:6,11pyridof3,4-b1indole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 40 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p. :320°C.

Analysis for C₂₂H₂i N3O4(0.25H₂O):

Calculated: C,66.74;H,5.47;N,10.61;

Found:C,66.72;H,5.46;N,10.53%.

Example 70

Cis-2,3,6,7,12,12a-hexahydro-6-(4-hvdroxv-3-methoxvphenvl)-2-methvlpyrazinof2', T:6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 41 gavē, after recrystallisation from dichloromethane/ethanol, the title compound as yellow crystals m.p. :264-265°C.

Analysis for C₂₂H₂i N3O4:

Calculated: C,67.51;H,5.41;N, 10.74;

Found:C,67.05;H,5.41;N, 10.62%.

Example 71

Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-cvanophenyl)pyrazinof2^,,T:6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from butylamine and intermediate 37 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p. : 246^eC.

Analysis for C₂5H₂4N4O₂ (1H₂O):

Calculated: C,69.75;H,6.09;N,13.01;

Found:C,69.50;H,5.96;N,12.86%.

Example 72

Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethylphenvl)-2-isopropvlpyrazinof2', 1 ':6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from isopropylamine and the cis isomer of intermediate 42 gavē, after recrystallisation from n-pentane, the title compound as vvhite crystals m.p. : 130°C.

Analysis for C25H27N3O2 (0.5Η₂Ο):

Calculated: C,73.15;H,6.87; N, 10.24;

Found:C,73.39,H,7.08;N,9.81 %.

Example 73

Cis-2,3,6.7,12,12a-hexahvdro-6-(4-ethvlphenvl)-2-cvclopropylmethvlpyrazinof2^,,T:6.npyridoi3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethyiamine and the cis isomer of intermediate 42 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p.: 160°C.

Analysis for C26H27N3O2:

Calculated: C,75.52;H,6.58;N, 10.16;

Found:C,75.54;H,6.62;N,10.08%.

Example 74

Cis-2,3,6,7,12,12a-hexahydro-6-(4-isopropylphenyl)-2-methylPvrazinoIZ', T:6,11pyrido[3,4-b1indole -1,4-dione

The same tvvo^- step procedure but starting from methylamine and intermediate 43 gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p.: 244°C.

Analysis for C24H25N3O2:

Calculated: C,74.39;H,6.50;N,10.84;

Found:C,74.27;H,6.53;N,11.05%.

Example 75

Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-nitrophenvl)pyrazino[2', 1 ’:6,1 lpyridor3,4-bBndole -1,4-dione

The same two step procedure but starting from butylamine and intermediate 45 gavē, after recrystallisation from methanol, the title compound as vvhite crystals

m.p. : 182°C.

Analysis for C24H24N4O4 (0.25H2O):

Calculated: C,65.97;H,5.65;N,12.82;

Found:C,65.92;H,5.62;N, 12.96%.

Example 76

Cis-2.3,6,7,12,12a-hexahvdro-6-(4-dimethvlaminophenyl)-2-methvlpvrazinoi2^,,1^l:6,npyrido[3.4-blindole -1,4-dione

The same tvvo step procedure but starting from methylamine and the cis isomer of intermediate 47 gavē after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 266^eC.

Analysis for C23H24N4O2:

Calculated: C,71.11 ;H,6.23;N, 14.42;

Found:C, 71.19 ; H, 6.24 ; N, 14.34%.

Example 77

Cis-2,3,6,7.12,12a-hexahvdro-2-methyl-6-(3-pyridyl)pyrazinoF2', T:6,11pyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 48 gavē after recrystallisation from chloroform, the title compound as vvhite crystals m.p. : 312^eC.

Analysis for θ2θΗΐ8^4θ2^;

Calculated: C,69.35;H,5.24;N,16.17;

Found:C,69.08;H,5.20;N,16.19%.

Example 78 (6R, 12aR)-2,3,6,7.12.12a-Hexahvdro-2-methvl-6-(3,4-methvlenedioxvphenyl)pyrazinof2^l.1':6.1lpyridoi3,4-b1indole -1,4-dione

a) To a stirred solution of intermediate 54 (0.5 g) and NaHCC>3 (0.14 g) in anhydrous CHCI3 (20 mL) was added dropvvise chloroacetyl chloride (0.27 mL) at 0^eC. The resulting mixture vvas stirred for 1 hour at the same temperature and diluted vvith CHCI3 (20 mL). Water (10 mL) vvas then added dropwise vvith stirring to the mixture, follovved by a saturated solution of NaHCO3- The organic layer vvas vvashed vvith vvater until neutrality and dried over Na2SO4- After evaporation of the solvent under reduced pressure, (6R,12aR)-methyl 1,2.3,4-tetrahydro-2-chloroacetyl-1-(3,456 methylenedioxvphenyD-9H-pvridor3.4-b1indole-3-carboxylate was obtained as an oil vvhich vvas crystallised from ether to give a solid (0.38 g, m.p.; 233^eC) vvhich vvas used vvithout further purification in the next step.

b) To a stirred suspension of the chloroacetyl intermediate (0.37 g) in MeOH (20 mL) vvas added at room temperature a solution of methylamine (33% in EtOH) (0.4 mL) and the resulting mixture vvas heated at 50°C under N₂ for 16 hours. The solvent was removed under reduced pressure and the residue vvas dissolved in CH₂Cl2 (50 mL). After washing vvith water (3x20 mL), drying over Na₂SO4 and evaporating to dryness, the residue vvas purified by flash chromatography eluting vvith CH₂CI₂/MeOH (99/1) and recrystallised from 2propanol to give the title compound as vvhite crystals (0.22 g) m.p. : 302303°C.

Analysis for C22H19N3O4:

Calculated:C,67.86;H,4.92;N,10.79;

Found:C,67.77;H,4.92;N, 10.74%.

20° [a]_D =+71.0°(C=1.00;CHCI₃).

20.

The follovving compounds vvere obtained in a similar manner:

Example 79 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,425 methvlenedioxvphenvl)-pvrazinof2^,. 1 ':6.11oyridof3,4-blindole -1,4-dione

The same tvvo step procedure but starting from isopropylamine and intermediate 54 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 290-293°C.

Analysis for C24H23N3O4:

Calculated: C,69.05;H,5.55;N,10.07;

Found:C,69.06;H,5.49;N,10.12%.

20° [<x]_D =+52.6° (C=1.14; CHCI₃).

Example 80 (6R, 12aR)-2,3,6,7,12,12a-Hexahvdro-2-butvl-6-(3,4-methylenedioxyphenvl)pyrazinof2', 1 ’:6,11pyridoF3,4-blindole -1,4-dione

The same two step procedure but starting from butylamine and intermediate 54 gavē, after recrystallisation from toluene/hexane, the title compound as white crystals m.p.: 209-210^eC.

Analysis for C25H25N3O4:

Calculated: C,69.59;H,5.84;N,9.74;

Found:C,69.70;H,5.93;N,9.74%.

20° [ct]_D = +50.2° (C=0.53; CHCI₃).

Example 81 (6R, 12aR)-2,3,6,7,12,12a-Hexahvdro-2-isobutvl-6-(3,4-methvlenedioxvphenyl)pyrazino[2',T:6,npyridof3,4-b1indole -1,4-dione

The same two step procedure but starting from isobutylamine and intermediate 54 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 227-228’C.

Analysis for C25H25N3O4:

Calculated: C,69.59;H,5.84;N,9.74;

Found:C,69.52;H,5.87;N,9.74%.

20° [<x]_D =+45° (C=1.04; CHCI₃).

Example 82 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cvclopentvl-6-(3,4methvlenedioxvphenvl)-pvrazinof2^,, 1 ':6,11pyridof3,4-bļindole -1,4-dione The same two step procedure but starting from cyclopentylamine and intermediate 54 gavē, after recrystallisation from ether, the title compound as vvhite crystals m.p.: 237-239°C.

Analysis for C26H25N3O4:

Calculated: C,70.41 ;H,5.68;N,9.47;

Found:C,70.13.H,5.67.N,9.42%.

20° [a]_D = +36.6° (C=0.98; CHCI₃).

Example 83 (6R,12aR)-2,3,6,7,12,12a-Hexahvdro-6-(3,4-methvlenedioxvphenvl)-2cyclohexylmethvl-pyrazinof2', 1 ':6,11pyridof3,4-blindole -1,4-dione

The same tvvo step procedure but starting from cyclohexylmethylamine and the cis isomer of intermediate 56 gavē, after recrystallisation from 2-propanol the title compound as white crystals m.p.: 209°C.

Analysis for C28H29N3O4:

Calculated: C,71.32;H,6.20;N,8.91;

Found:C,71.30;H,6.29;N,8.74%.

20° [<x]_D = +40.0° (C=0.99; CHCI₃).

Example 84 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cvclopropylmethvl-6-(4-methoxyphenvl)pyrazinof2'.T:6,1lpyridoF3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 57 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 204-205°C.

Analysis for ¢35^5^03(0.5H2O):

Calculated: C,70.74;H,6.17;N,9.90;

Found:C,70.98;H,6.09;N,9.92%.

20° [a]_D =+54.1°(C=1.03; CHCI₃).

Example 85 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-butvl-6-(4-methoxyphenvl)pyrazinof2',r:6,11pyrido[3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from buyiamine and intermediate 57 gavē, after recrystallisation from 2-propanol, the title compound as vvhite crystals m.p. : 183-184°C.

Analysis for C25H27N3O3(0.5H2O):

Calculated: C,70.40;H,6.62;N,9.85;

Found:C,70.55;H,6.64;N,9.92%.

20° [<x]_D = +45.4° (C=1.04; CHCI₃).

Example 86 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(4-methoxyphenyl)pyrazinof2^,,r:6,1lpyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from cyclopentylamine and intermediate 57 gavē, after recrystallisation from ether, the title compound as vvhite crystals m.p.; 210-211°C.

Analysis for C26H27N3O3·

Calculated: C,72.71 ;H,6.34;N,9.78;

Found:C,72.53;H.6.39;N,9.53%.

20° [ct]_D =+29.8’(C=1.07;CHCI₃).

Example 87 (6R, 12aR)-2,3,6,7,12,12a-Hexahvdro-6-(3-chloro-4-methoxvphenyl)-2cyclopropylmethvl-pvrazinof2', 1 *:6,11pyridof3,4-blindole -1,4-dione

The same tvvo step procedure but starting from cyclopropylmethylamine and intermediate 59 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 218-219°C.

Analysis for C25H24CIN3O3 (0.25 H2O):

Calculated: C,66.08;H,5.43;N,9.25 ; Cl, 7.80;

Found; C, 66.11 ; H, 5.33 ; N, 9.03 ; Cl, 7.74%.

20° [cc]_D = +49.4° (C=1.03; CHCķ).

Example 88 (6R.12aR)-2,3,6,7,12,12a-Hexahydro-2-cvclopentvl-6-(3-chloro-4methoxyphenvl)-pyrazinoi2'.r:6,npvrido[3,4-bļindole -1,4-dione

The same tvvo step procedure but starting from cyclopentylamine and intermediate 59 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.; 260-262°C.

Analysis for C26H26CIN3O3:

Calculated: C,67.31 ;H,5.65;CI,7.64;N,9.06;

Found:C,66.98;H,5.67;CI,8.06;N,9.04%.

20° [a]_D = +27.6° (C=1.05; CHCI₃).

Example 89 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxvphenvl)-2-methylpyrazinof2', 1 ’:6,11pyridoi3,4-b1indole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 59 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 283-284’C.

Analysis for C22H20CIN3O3:

Calculated: C,64.47;H,4.92;CI,8.65;N, 10.25;

Found:C,64.49;H,4.92.CI8.33.N, 10.02%.

20° [<x]_D = +61.3° (C=1.00; CHCI₃).

Example 90 (6R, 12aR)-2,3,6,7,12.12a-Hexahvdro-2-isopropyl-6-(3-chloro-4-methoxvphenyl)pyrazino[2^,,T:6,1lpyridof3,4-b1indole -1,4-dione

The same tvvo step procedure but starting from isopropylamine and intermediate 59 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 302-304°C.

Analysis for C24H24CIN3O3:

Calculated: C,65.83;H,5.52;N,9.60;

Found:C,65.83;H,5.57.N,9.73%.

20° [<x]_D = +39.8° (C=0.95; CHCIg).

Example 91 (6R,12aR)-2,3,6,7.12.12a-Hexahvdro-6-(2,3-clihydrobenzofblfuran-5-yl)-2methvl-pyrazino[2',r:6,npyrido[3,4-b|indole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 61 gavē, after recrystallisation from dichloromethane/methanol, the title compound as vvhite crystals m.p.: 288-291 °C.

Analysis for C23H21N3O3:

Calculated: C,71.30;H,5.46;N,10.85;

Found:C,71.27;H,5.49;N,10.96%.

20° [aJ_D = +65.6° (C=0.4; CHCI₃).

Example 92 (6R,12aR)-2.3,6,7.12,12a-Hexahvdro-6-(2,3-dihydrobenzofb1furan-5-yl)-2methvlcvcIopropvI-pvrazinoiZ', 1 ':6,11pyridor3.4-b1indole -1,4-dione

The same tvvo step procedure but starting from methylcyclopropylamine and intermediate 61 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 242-244°C.

Analysis for C26H25N3O3:

Calculated: C,73.05;H,5.89;N,9.83;

Found:C,72.90;H,5.93;N,9.98%.

20° [a]_D = +55.4° (C=0.99; CHCIg).

Example 93 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-indanvl)-2-methylpyrazinoF2', 1 ':6,11pyridof3,4-bļindole -1,4-dione

The same two step procedure but starting from methylamine and intermediate 63 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 262^eC.

Analysis for C24H23N3O2:

Calculated: C,74.78;H,6.01 ;N, 10.90;

Found:C,74.65;H,5.90;N, 10.67%.

20° [a]_D = +68.6° (C=0.98; CHCI₃).

Example 94 (6R, 12aR)-2,3,6,7.12,12a-Hexahvdro-6-(5-indanvl)-2-cvclopropylmethvlPvrazinoi2'.T:6,npvridoF3,4-b1indole -1,4-dione

The same two step procedure but starting from cyclopropylmethylamine and intermediate 63 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 176°C.

Analysis for C27H27N3O2 (O.25H2O):

Calculated: C,75.41 ; H, 6.45 ; N, 9.77;

Found:C, 75.25 ; H, 6.51 ; N, 9.75%.

20° [ct]_D = +57.9° (C=1.00; CHCI₃).

Example 95 (6R, 12aR)-2,3,6,7,12,12a-Hexahvdro-2-methyl-6-(3,4-methylenedioxyphenyl)Pvrazino|2',T:6,npyrido[3.4-b1indole-1,4-dione

To a stirred suspension of Intermediate 73 (12.5g) in MeOH (400ml) vvas added at room temperature a solution of methylamine (33% in EtOH) (13.7ml) and the resulting mixture vvas heated at 50°C under N2 for 14 hours. The solvent vvas removed under reduced pressure and the residue vvas dissolved in CH2CI2 (11). After vvashing with water (3 x 500ml), drying over Na2SC>4 and evaporating to dryness, the vvhite solid obtained vvas recrystallised from 2-propanol to give the title compound as vvhite needles (7.5g).

mp : 298-300°C.

20° [a]_D = +71.3° (c = 0.55, CHCI₃).

Elemental analysis (C22H19N3O4) calculated: C, 67.86; H, 4.92; N, 10.79;

found: C, 67.79; H, 4.95; N, 10.61%.

Example 96

Cis-2,3,6,7,12,12a-hexahydro-2,10-dimethyl-6-(3,4-methylenedioxyphenyl)pvrazinofZ.ļ': 6,npyridof3,4-bltndole-1,4-dione

The same tvvo step procedure as used to prepare Example 1, but starting from methylamine and the cis isomer of Intermediate 74, gavē after recrystallisation from ethanol, the title compound as white crystals m.p. : 275°C.

Analysis for C23H21N3O4 ( O.4H2O):

Calculated : C, 67.27 ; H, 5.35 ; N, 10.23;

Found : C, 67.36 ; H, 5.21 ; N, 10.31%.

Example 97 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-(3,4-dimethoxybenzyl)-6-(3,4methvlenedioxyphenvl)-pyrazinoi2',T ; 6, npyridof3,4-b1indole-1,4-dione The same two step procedure as used to prepare Example 78, but starting from veratrylamine and intermediate 54 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p,: 224-226’C.

Analysis for C30H27N3O6:

Calculated : C,68.56 ; H.5.18 ; Ν,δ.ΟΟ;

Found : C,68.80 ; H.5.11 ; N.8.06%.

20° [a]_D = + 43.9° (C = 1.02; CHCI₃₎.

Example 98

Cis-2,3,6,7,12,12a-hexahvdro-6-(4-aminophenvl)-2-butylPvrazino[2',T:6.npyridof3,4-bļindole-1,4-dione

To a solution of Example 75 (1.5 g) in methanol (100 mL) vvas added SnCl2-H2O (3.06) and the resulting mixture vvas heated at reflux for 8 hours. The mixture vvas cooled to ambient temperature, poured into ice and vvas adjusted to pH5 vvith 1N NaOH. The methanol vvas evaporated off and the_ residue was basified to pH11 vvith 1N NaOH and extracted vvith EtOAc (2 x 150 mL). After drying over Na2SO4 and evaporation of EtOAc, the resulting yellow povvder vvas purified by radial chromatography eluting vvith CH2CI2 to give the title compound as a vvhite povvder (550 mg) m.p. : 192°C.

Analysis for C24H26N4O2 (1.3 H2O):

Calculated : C,67.68 ; H,6.77 ; N, 13.15;

Found : C,67.74 ; H, 6.68 ; N, 13.02%.

Example 99

Cis-2.3.6,7,12,12a-hexahydro-6-(4-acetamidophenvl)-2-butvlpyrazino[2', 1 ':6,1 lpyridof3,4-blindole-1,4-dione

To a solution of Example 98 (0.2 g) in THF (15 mL) vvas added triethylamine (76 pL) and acetyl chloride (39 pL) and the resulting solution vvas stirred at room temperature for 2 hours. After evaporation of THF, the resulting residue vvas taken up in CH2CI2 (100 mL), vvashed vvith vvater (2 x 50 mL) and dried over

Na2SO4- After evaporation of CH2CI2, the resulting solid vvas recrystallised from MeOH/H2O to give the title compound as a cream povvder (120 mg) m.p. :

246°C.

Analysis for C26H28N4O3:

Calculated : C,70.25 ; H,6.35 ; N,12.60;

Found : C,69.85 ; H, 6.38 ; N, 12.56%.

Example 100

Cis-2,3,6,7.12,12a-hexahydro-2-butvl-6-(4-methylsulfonamidophenvl)pvrazinoi2^,,r:6,npyridof3,4-b1indole-1,4-dione

To a solution of Example 98 (0.2 g) in THF (5 mL) was added triethylamine (228 pL) and methanesulfonyl chloride (126 pL) and the solution vvas heated at reflux for 6 hours. After evaporation of THF, the residue vvas taken up in CH2CI2, vvashed vvith vvater and dried over Na2SC>4. After evaporation of CH2CI2, the residue vvas purified by radial chromatography eluting vvith CH2Cl2/MeOH (95/5) to give the title compound as a brovvn powder (30 mg) m.p.: 188°C. Analysis for C25H28N4O4S (0.75 H2O):

Calculated ; C,60.77 ; H,6.02 ; N, 11.34;

Found : C,60.61 ; H, 6.02 ; N, 10.82%.

Example 101 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methvlenedioxyphenyl)pyrazinof2', 1'; 6,11 pvrido [3,4-bļ indole-1,4-dione

The same tvvo step procedure but starting from ammonia and intermediate 54 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 285-290’C.

Analysis for C21H-17N3O4:

Calculated : C, 67.19 ; H, 4.56 ; N, 11.19 ;

Found : C, 67.30 ; H, 4.66 ; N, 11.11 %.

[a]²⁰‘_D = + 88° (c = 0.48 ; pyridine).

Example 102 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methvlenedioxyphenyl)-2-(2propvnvD-pvrazino [2', 1' : 6,11 pvrido [3,4-bļ indole-1,4-dione

The same two step procedure but starting from propargylamine and intermediate 54 gavē, after recrystallisation from acetone, the title compound as vvhite crystals m.p.: 271 ^eC.

Analysis for C₂₄HigN₃O4:

Calculated : C, 69.72 ; H, 4.63 ; N, 10.16 ;

Found: C, 69.95 ; H, 4.66 ; N, 10.06 %.

[a]²⁰’p = + 51.7° (c = 0.49 ; CHCI₃).

Example 103 (6R, 12aR)-2,3,6,7,12.12a-Hexahydro-2-(3,4-methvlendioxvbenzyl)-6-(3,4methvlenedioxvphenvl)-pyrazinoi2', T: 6,11 pvrido f3,4-bl indole-1,4-dione

The same tvvo step procedure but starting from piperonylamine and intermediate 54 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p.: 204-206°C.

Analysis for C₂₉H₂3N₃O₆:

Calculated : C, 68.36 ; H, 4.55 ; N, 8.25 ;

Found : C, 68.25 ; H, 4.49 ; N, 8.41.

[cc]²⁰’_d = + 43° (c= 1.01 ; CHCI₃).

Example 104 (6R, 12aR)-2,3,6.7,12,12a-Hexahvdro-2-(3.4-dimethoxvphenethvl)-6-(3,4methvlenedioxyphenvl)-pyrazino f2‘, 1': 6,11 pvrido f3,4-bļ indole-1,4-dione

The same two step procedure but starting from 3,4-dimethoxyphenethylamine and intermediate 54 gavē, after recrystallisation from dichloromethane/ether, the title compound as vvhite crystals m.p.: 265-266°C.

Analysis for C₃-ļH₂gN₃O6:

Calculated : C, 69.00 ; H, 5,42 ; N, 7.79 ;

Found : C, 68.68 ; H, 5.35 ; N, 7.78 %.

[_α]20·_ο = + 38.3° (c = 1.12 ; CHCI₃).

Example 105 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-furfurvl-6-(3,4-methvlenedioxyphenvl)pvrazino f2', T : 6,11 pvrido [3,4-bļ indole-1,4-dione

The same tvvo step procedure but starting from furfuryfamine and intermediate gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 219°C.

Analysis for C₂6H2iN₃O5:

Calculated : C, 68.56 ; H, 4.65 ; N, 9.23 ;

Found: C, 68.16 ; H, 4.63 ; N, 9.15 %.

W²⁰’d = + 58.1° (c= 1.2 ; CHCI₃)

Example 106 (6R, 12aR)-2.3,6,7.12,12a-Hexahydro-6-(3,4-methylenedioxyphenvl)-2-(2thienvlmethvh-pvrazino f2', 1': 6,11 pvrido i3,4-bļ indole-1,4-dione

The same tvvo step procedure but starting from 2-thiophenemethylamine and intermediate 54 gavē, after recrystallisation from methanol/vvater, the title compound as vvhite crystals m.p.: 155-157°C.

Analysis for C26H2iN₃O₄S:

Calculated : C, 66.23 ; H, 4.49 ; N, 8.91 ; S, 6.8 ;

Found : C, 66.13 ; H, 4.54 ; N, 9.12 ; S, 6.78 %.

[<x]²⁰’_D = + 70.4° (c = 1.03 ; CHCI₃).

Example 107 (6R, 12aR)-2,3,6,7,12.12a-Hexahydro-€-(4-methoxyphenvl)-2-methvl-pvrazino f2\ T : 6,11 ovrido f3,4-b] indole-1,4-dione

The same tvvo step procedure but starting from methylamine and intermediate 57 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 285-288°C.

Analysis for C22H21N3O3:

Calculated : C, 70.38 ; H, 5.64 ; N, 11.19 ;

Found : C, 70.31 ; H, 5.69 ; N, 11.29 %.

[a]²⁰'o = + 59° (c=1.19;CHCI₃).

Example 108 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-ethyl-6-(4-methoxyphenvl)-pvrazino [2',

T : 6,11 pvrido [3,4-bļ indole-1,4-dione

The same tvvo step procedure but starting from ethylamine and intermediate 57 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 277’C.

Analysis for C₂₃H₂₃N₃O₃:

Calculated ; C, 70.93 ; H, 5.95 ; N, 10.79 ;

Found: C, 70.90 ; H, 5.96 ; N, 10.54 %.

[_α]20·_ο = + 52» (_C = 1.28 ; CHCI₃).

Example 109 (6R, 12aR)-2,3.6,7,12,12a-hexahydro-6-(7-(4-methyl-3,4-dihydro-2Hbenzo(1,41oxazinvl))-2-methvl-pvrazinof2^,,T : 6,npyridof3,4-b1 indole-1,4-dione

The same tvvo step procedure but starting from intermediate 75 and methylamine gavē, after recrystallisation from ethanol, the title compound as vvhite crystals m.p.: 285-288’C.

Analysis for C₂4H₂₄N4O₃ (0.5 H₂O):

Calculated : C, 67.75 ; H, 5.92 ; N, 13.17 ;

Found: C, 68.02 ; H, 6.00 ; N, 13.18 %.

[ct]²⁰’_D = + 71.7’ (c = 1, pyridine).

Example 110 (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-(N-benzvlindolinyl))-2-methylpyrazino[2’, T : 6,npyridof3,4-b1indole-1,4-dione

The same tvvo step procedure but starting from intermediate 77 and methylamine gavē, after recrystallisation from dichloromethane/methanol, the title compound as vvhite crystals m.p.: 223-225°C.

Analysis for C₃₀H₂₈N4O₂:

Calculated : C, 75.61 ; H, 5.92 ; N, 11.76 ;

Found : C, 75.2 ; H, 5.78 ; N, 11.67 %.

[ct]²⁰’_D = + 20.4° (c = 0.5, CHCI₃).

Example 111 (6R, 12aR)-2,3,6.7,12.12a-Hexahvdro-6-(5-indolinyl)-2-methyl-pyrazinoF2'.T :

6,11pyrido[3,4-b1indole-1,4-dione

A solution of Example 110 (1.05 g , 2.2 mmol) in methanol (100 mL) vvas hydrogenated in the presence of 10 % Pd-C (100 mg) for 48 hours at room temperature. After removal of the catalyst, the solvent was evaporated in vacuo to leave a residue which vvas purified by flash chromatography eluting vvith dichloromethane/methanol : 96/4. The solid obtained vvas recrystallised from dichloromethane/methanol to give the title compound (300 mg) as vvhite crystals

m.p.: 240°C.

Analysis for C23H22N4O2 (0.5 H₂O) :

Calculated : C, 69.86 ; H, 5.86 ; N, 14.17 ;

Found : C, 70.13 ; H, 5.77 ; N, 14.06 %.

[a]²⁰’_D = + 55.9° (c = 1.18 ; pyridine).

Example 112

Cis-2,3,6,7,12,12a-hexahvdro-6-(4-ethvlphenvl)-2-methvl-pvrazino[2', 1¹ :

6,11pyrido[3,4-b1indole-1,4-dione

The same two step procedure but starting from methylamine and the cis isomer of intermediate 42 gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 254°C.

Analysis for C23H23N3O2 (0.25 H₂O):

Calculated : C, 73.09 ; H, 6.27 ; N, 11.12 ;

Found: C, 73.03 ; H, 6.18 ; N, 11.36 %.

Example 113 (6R, 12aR)-2,3,6,7,12.12a-Hexahydro-6-(4-carbomethoxvphenvl)-2-methylPvrazinof2’,T: 6, npyridof3,4-b1indole-1,4-dione

The same tvvo step procedure but starting from intermediate 78 (cis isomer) and methylamine gavē, after recrystallisation from methanol, the title compound as vvhite crystals m.p. : 308-312°C.

Analysis for C23H21N3O4:

Calculated : C, 68.47 ; H, 5.25 ; N, 10.42 ;

Found: C, 68.76 ; H, 5.18 ; N, 10.35 %.

[ct]²⁰*_D = + 97.7° (c = 1, pyridine).

Example 114 (5aR, 12R, 14aR)-1,2,3,5a,6,11.12,14a-Octahydro-12-(3,4methvlenedioxvphenvl)-pvrrolof1^,,,2’^, : ^.S’ļpvrazinofZ.T : 6,npyridof3,4bļindole-5-1,4-dione

A solution of intermediate 80 (0.7 g, 1.2 mmol) in a mixture of methanol/THF (80/40 mL) vvas hydrogenated in the presence of 10 % Pd-C (75 mg) for 48 hours at 40°C. After removal of the catalyst, the solvent was evaporated in vacuo to leave a residue, vvhich vvas purified by flash chromatography eluting vvith dichloromethane/methanol : 98/2. The vvhite solid obtained vvas recrystallised from methanol to give the title compound (180 mg) as vvhite crystals m.p. : 284-287^eC.

Analysis for C24H₂iN₃O₄ :

Calculated : C, 69.39 ; H, 5.10 ; N, 10.11 ;

Found : C, 69.47 ; H, 5.11 ; N, 9.97 %.

[a]²⁰*_D = + 21.7° (c = 0.64, CHCI₃).

Example 115 (5aR, 12R, 14aS)-1.2,3,5.6,11.12,14a-Octahydro-12-(3,4methylenedioxyphenyl)-pyrroloU,2: 4’.5'lpvrazinor2'.T : 6,npvridof3,4bļindole-5-1,4-dione

A solution of intermediate 81 (0.8 g, 1.37 mmol) in methanol (40 mL) vvas hydrogenated in the presence of 10 % Pd-C (100 mg) for 5 h at 45°C. After removol of the catalyst the solvent was evaporated in vacuo to leave a residue, vvhich vvas purified by flash chromatography eluting vvith dichloromethane/rhethanol : 98/2. The solid obtained vvas recrystallised from methanol to give the title compound (300 mg) as vvhite crystals m.p. : 302304°C.

Analysis for C24N21N3O4:

Calculated : C, 69.39 ; H, 5.10 ; N, 10.11 ;

Found: C, 69.35 ; H, 5.11 ; N, 10.10 %.

[_α]20·_ο = + 106.8° (c = 1.08, CHCI₃).

Example 116 (3R, 6R, 12aR)-2,3.6,7,12.12a-hexahydro-2,3-dimethyl-6-(3,4methvlenedioxvphenyl)-pyrazinof2', 1': 6,11pyridof3,4-b1indole-1,4-dione

To a stirred solution of intermediate 82 (0.15 g, 0.34 mmol) in THF (15 mL) vvas added at room temperature a solution of methylamine (33 % in EtOH) (0.32 mL) and the resulting solution was heated at reflux under N₂ for 24 hours. The solvent was removed under reduced pressure and the residue vvas dissolved in

CH2CI2 (25 mL). After washing vvith water (2 x 20 mL), drying over Na₂SO₄ and evaporating to dryness, the crude product was purified by flash chromatography eluting vvith dichloromethane/methanol : 99/1. The vvhite solid obtained vvas recrystallised from methanol to give the title compound as vvhite crystals (80 mg) m.p. : 219-220^eC.

Analysis for C23H21N3O4:

Calculated : C, 68.47 ; H, 5.25 ; N, 10.42 ;

Found: C, 68.39; H, 5.21; N, 10.42%.

[α]^2θ°ο = + 89.6° (c = 1 ; CHCI₃).

Example 117 (3S, 6R, 12aR)-2,3,6,7,12,12a-hexahvdro-2,3-dimethyl-6-(3,415 methvlenedioxvphenvl)-pyrazinof2^, 1'; 6,11ovridor3,4-blindole-1,4-dione

To a stirred solution of intermediate 83 (0.3 g, 0.68 mmol) in THF (30 mL) vvas added at room temperature a solution of methylamine (33 % in EtOH) (0.68 mL) and the resulting solution was treated at reflux under N₂ for 6 days. The solvent vvas removed under reduced pressure and the residue vvas dissolved in 0Η₂Ο₂ (50 mL). After washing vvith vvater (2,25 mL), drying over Na₂SO₄ and evaporating to dryness, the crude product vvas purified by flash chromatography eluting vvith dichloromethane/methanol : 99/1. The oily residue obtained vvas crystallised from methanol to give the title compound as vvhite crystals (40 mg) m.p. : 307-309°C.

Analysis for C23H₂iN₃O₄ :

Calculated : C, 68.47 ; H, 5.25 ; N, 10.42 ;

Found : C, 68.35; H, 5.33; N, 10.42%.

[α]²% = + 65.2° (c = 1.15 ; CHCI3).

Example 118 (6R, 12aR)-2,3,6,7,12,12a-Hexahvdro-6-(3,4-dihvdroxvphenvl)-2-methvlονΓ3ζίηοί2', 1': 6, noyridof3,4-b1indole-1,4-dione

A solution of intermediate 86 (0,75 g ; 1,34 mmol) in a mixture of ethanol/THF (70/30 mL) vvas hydrogenated in the presence of 10 % Pd-C (75 mg) for 24 h at room temperature. After removal of the catalyst, the solvent vvas evaporated in vacuo to leave a vvhite solid vvhich was recrystallisated from methanol to give the title compound (0.35 g) as white crystals m.p.: 224-226’C.

Analysis for C2iH₁₉N₃O4:

Calculated : C, 66.83 ; H, 5.07 ; N, 11.13 ;

Found: C, 66.58 ; H, 5.01 ; N, 11.04 %.

[a]²⁰°_D = + 58.4° (c = 1.04 ; pyridine).

Example 119 (6R, 12aR)-2.3,6,7,12,12a-Hexahydro-2-methyl-6-(5-(2methvlisoindolinvIHpvrazinore’· 1': 6.1 lpyridof3,4-blindole-1,4-dione The same tvvo steps procedure but starting from intermediate 87 and methylamine gavē a crude oil vvhich vvas purified by flash chromatography eluting vvith dichloromethane/methanol/triethylamine : 92/8/0.1 %. The solid obtained vvas recrystallized from isopropanol/propyl ether/vvater to give the title compound (20 mg) as off-white crystals m.p.: 236°C.

Analysis for C24H24N4O2 (2.68 H₂O)

Calculated: C, 64.23 ; H, 6.59 ; N, 12.48 ;

Found : C, 64.21 ; H, 6.43 ; N, 12.02 %.

[a]²⁰‘_D = +61.1° (c = 0.5 ; CH3OH).

Example 120

Compounds of formula (I) have been included in pharmacy formulations and details of such formulations are given belovv.

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 vvith the excipients. The resultant mix vvas compressed into tablets.

2.	mg/tablet
Active ingredient	50.0
Colloidal Silicon Dioxide	0.5
Crospovidone	8.0
Sodium Lauryl Sulphate	1.0
Magnesium Stearate Ph Eur	1.0
Microcrystalline Cellulose USNF	139.5

The active ingredient vvas sieved and blended vvith the excipients. The resultant mix vvas compressed into tablets.

B. WET GRANULATION

1.	mg/tablet
Active ingredient	50.0
Polyvinyl pyrollidone	150.0
Polyethylene glycol	50.0
Polysorbate 80	10.0
Magnesium Stearate Ph Eur	2.5
Croscamriellose Sodium	25.0
Colloidal Silicon Dioxide	2.5
Microcrystalline Cellulose USNF	210.0

The polyvinyl pyrollidone, polyethylene glycol and polysorbate 80 were dissolved in water. The resultant solution was used to granulate the active ingredient. After drying the granules vvere screened, then extruded at elevated temperatures and pressures. The extrudate was milled and/or screened then was blended vvith the microcrystalline cellulose, croscarmellose sodium, colloidal Silicon dioxide and magnesium stearate. The resultant mix was compressed into tablets.

2.	mg/tablet
Active ingredient	50.0
Polysorbate 80	3.0
Lactose Ph Eur	178.0
Starch BP	45.0
Pregelatinised Maize Starch BP	22.5
Magnesium Stearate BP	1.5

The active ingredient vvas sieved and blended vvith the lactose, starch and pregelatinised maize starch, The polysorbate 80 vvas dissolved in purified vvater. Suitable volumes of the polysorbate 80 solution vvere added and the povvders were granulated, After drying, the granules vvere screened and blended vvith the magnesium stearate. The granules vvere 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 vvere film coated.

Coating Suspension	% w/w
Opadry vvhitef	13.2
Purified vvater Ph Eur	to 100.0*

* The vvater did not appear in the final product. The maximum theoretical vveight of solids applied during coating vvas 20mg/tabIet.

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

The tablets vvere film coated using the coating suspension in conventional film coating eguipment.

CAPSULES

1.	mg/capsule
Active ingredient	50.0
Lactose	148.5
Polyvinyl pyrollidone	100.0
Magnesium Stearate	1.5
The active ingredient vvas sieved and blended vvith the excipients. The mix was
filled into size No. 1 hard gelatin capsules using suitable eguipment.
2.	mg/capsule
Active ingredient	50.0
Microcrystalline Cellulose	233.5
Sodium Lauryl Sulphate	3.0
Crospovidone	12.0
Magnesium Stearate	1.5

The active ingredient vvas sieved and blended vvith the excipients. The mix vvas filled into size No. 1 hard gelatin capsules using suitable equipment.

Other doses may be prepared by altering the ratio of active ingredient to excipient, the fill vveight and if necessary changing the capsule size.

3.	mg/capsule
Active ingredient	50.0
Labrafil M1944CS	to 1.0 ml

The active ingredient vvas sieved and blended vvith the Labrafil. The suspension vvas filled into soft gelatin capsules using appropriate equipment.

Example 121

Inhibitorv effect on cGMP-PDE cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells at al. (Wells, J. N., Baird, C. E., Wu, Y. J.

and Hardman, J. G., Biochim. Biophys. Acta 384, 430 (1975)). The reaction medium contained 50mM Tris-HCI.pH 7.5, 5mM Mg-acetate, 250pg/ml 5’Nucleotidase, 1mM EGTA and 0.15μΜ e-fH^-cGMP. The enzyme used vvas a human recombinant PDE V (ICOS, Seattle USA).

Compounds of the invention vvere dissolved in DMSO finally present at 2% in the assay. The incubation time was 30 minūtes during vvhich the total substrate conversion did not exceed 30%.

The ICso values for the compounds examined vvere determined from concentration-response curves using typically concentrations ranging from 10nM to 10μΜ. Tests against other PDE enzymes using Standard methodology also shovved that compounds of the invention are highly selective for the cGMP specific PDE enzyme.

-cGMP Ievel measurements

Rat aortic smooth muscle celis (RSMC) prepared according to Chamley et al. in Celi Tissue Res. 177. 503 - 522 (1977) vvere used betvveen the 10th and 25th passage at confluence in 24-weil culture dishes. Culture media vvas aspirated and replaced vvith PBS (Q.5ml) containing the compound tested at the appropriate concentration. After 30 minūtes at 37°C, particulates guanylate cyclase vvas stimulated by addition of ANF (100nM) for 10 minūtes. At the end of incubation, the medium vvas vvithdravvn and tvvo extractions vvere performed by addition of 65% ethanol (0.25ml). The tvvo ethanolic extracts vvere pooled and evaporated until dryness, using a Speed-vac system. c-GMP vvas measured after acetylation by scintillation proximity immunoassay (AMERSHAM).

The compounds according to the present invention were typically found to exhibit an ICso value of less than 500nM, and an ECso value of less than 5. In vitro tēst data for representative compounds of the invention is given in follovving Table 1:

Table 1

Example No.	IC50 nM	ECso μΜ
12	10	0.15
36	<10	0.5
52	20	0.8
63	30	0.35
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

Example 122

-Antihvpertensive activitv in rats

The hypotensive effects of compounds according to the invention as identified in table 2 vvere studied in conscious spontaneousiy hypertensive rats (SHR). The compounds vvere administered orally at a dose of 5mg/kg in a mixture of 5% DMF and 95% olive oil. Blood pressure vvas measured from a catheter inserted in the carotid artery and recorded for 5 hours after administration. The results are expressed as Area Under the Curve (AUC from 0 to 5 hours, mmHg.hour) of the fall in blood pressure over time.

Claims

IZGUDROJUMA FORMULA

1. Savienojums ar vispārējo formulu (I) un tā sāļi un solvāti, kurā:

RO ir ūdeņraža atoms, halogēns vai Ο-μθ alkilgrupa;

R1 ir ūdeņraža atoms, C-ļ.g alkil-, C2-6 alkenil-, C2-6 alkinil-, haloC-ļ .galkil-, Cg.gcikioalkil-, Cg.gcikloalkilC-ļ. galkil-, arilC-| .galkil- vai heteroarilC-| .galkilgrupa;

R² ir neobligāti aizvietots monociklisks aromātiskais gredzens, kuru izvēlas no grupas benzēns, tiofēns, furāns vai neobligāti aizvietots divciklisks gredzens piesaistīts molekulas atlikumam ar vienu no benzēna gredzena oglekļa atomiem un kurā kondensētais gredzens A ir 5- vai 6-locekļu gredzens, kurš var būt piesātināts vai daļēji vai pilnīgi nepiesātināts un satur oglekļa atomus un neobligāti vienu vai divus heteroatomus, kurus izvēlas no grupas skābeklis, sērs un slāpeklis; un

R³ ir ūdeņraža atoms vai C-ļ .galkilgrupa, vai R¹ un R³ kopā ir 3- vai 4-locekļu alkil- vai alkenilvirkne.
2. Savienojums ar vispārējo formulu (la) un ta sali un solvati, kurā:

R° ir ūdeņraža atoms, halogēns vai C-|_6 alkilgrupa;

R1 ir ūdeņraža atoms, C-|_galkil-, haloC-ļ .galkil-, C3_QCīkloalkil-, C3_gcikloalkilC-|_3alkil-, arilC-ļ _3alkil- vai heteroarilC-j _3alkilgrupa; un r2 ir neobligāti aizvietots monociklisks aromātiskais gredzens, kuru izvēlas no grupas benzēns, tiofēns, furāns un piridīns vai neobligāti aizvietots biciklisks gredzens piesaistīts pie molekulas atlikuma ar vienu no benzēna gredzena oglekļa atomiem un kurā kondensētais gredzens A ir 5- vai 6-locekļu gredzens, kurš var būt piesātināts vai daļēji vai pilnīgi nepiesātināts un satur oglekļa atomus un neobligāti vienu vai divus heteroatomus, kurus izvēlas no grupas skābeklis, sērs un slāpeklis.
3. Savienojums saskaņā ar 1. vai 2. punktu, kur R° ir ūdeņraža atoms.
4. Savienojums saskaņā ar jebkuru no 1. līdz 3. punktam, kurā R^ ir ūdeņraža atoms, Cgalkil-, haloCj ^alkil-, C3_gcikloalkil-, Cs-gcikloalkilmetil-, piridiiC-| _3alkil-, furilCj _3alkilgrupa vai neobligāti aizvietota benzilgrupa.
5. Savienojums saskaņā ar jebkuru no 1. līdz 3. punktam, kur R1 un R^ kopā ir 3-locekļu alkilvirkne.
6. Savienojums saskaņā ar jebkuru no 1. līdz 4. punktam, kur R^ ir ūdeņraža atoms.
7. Savienojums saskaņā ar jebkuru no 1. līdz 6. punktam, kur R^ ir neobligāti aizvietots benzēna, tiofēna, furāna, piridīna vai naftalīna gredzens vai neobligāti aizvietots biciklisks gredzens kur n ir 1 vai 2 un X un Y katrs ir CH2 vai O.
8. Formulas (I) cis izomers pārstāvēts ar formulu (Ib) un to maisījumi ar tā cis optisko enantiomēru, ietverot racēmiskos maisījumus, un šo savienojumu sāļi un solvāti, kuros R° ir ūdeņraža atoms vai halogēns un R¹, R² un R³ ir tādi kā uzrādīti jebkurā iepriekšminētajā punktā.
9. Cis-2,3,6,7,12,12a-heksahidro-2-(4-piridilmetil)-6-(3,4-metilēndioksifenil)pirazino[2‘, 1': 6, 1 ]pirido[3,4-b]indol-1,4-dions;

Cis-2,3,6,7,12,12a-heksahidro-6-(2,3-dihidrobenzo[b]furan-5-il)-2-metilpirazino[2', 1': 6, 1 ]pirido[3,4-b]indol-1,4-dions;

Cis-2,3,6,7,12,12a-heksahidro-6-(5-bromo-2-tienil)-2-metil-pirazino[2', 1 6, 1 ]pi rido[3,4-b]indol-1,4-dions;

Cis-2,3,6,7,12,12a-heksahidro-2-butil-6-(4-metilfenil)-pirazino [2',1': 6, 1 ]pirido[3,4-b]indol-1,4-dions;

(6R,12aR)-2,3,6,7,12,12a-Heksahidro-2-izopropil-6-(3,4-metilēndioksifenil)pirazino[2', Γ: 6, 1]pirido[3,4-b]indol-1,4-dions;

(6R, 12aR)-2,3,6,7,12,12a-Heksahidro-2-ciklopentil-6-(3,4-metilēndioksifenil)pirazino[2', Γ: 6, 1 ]pirido[3,4-b]indol-1,4-dions (6R,12aR)-2,3,6,7,12,12a-Heksahidro-2-ciklopropilmetil-6-(4-metoksifenil)pirazino[2', 1': 6, 1]pirido[3,4-b]indol-1,4-dions;

(6R, 12aR)-2,3,6,7,12,12a-Heksahidro-6-(3-hloro-4-metoksifenil)-2-metilpirazino[2', 1': 6, 1]pirido[3,4-b]indol-1,4-dions;

(6R,12aR)-2,3,6,7,12,12a-Heksahidro-2-metil-6-(3,4-metilēndioksifenil)pirazino[2‘, 1': 6, 1]pirido[3,4-b]indol-1,4-dions;

(6R, 12aR)-2,3,6,7,12,12a-Heksahidro-6-(3,4-metilēndioksifenil)-pirazino[2', 1': 6, 1 ]pi rido[3,4-b]indol-1,4-dions;

(5aR, 12R, 14aS)-1,2,3,5,6,11,12,14a-Oktahidro-12-(3,4-metilēndioksifenil)pirolo[1, 2 : 4',5']pirazino[2', 1': 6, 1]pirido[3,4-b]indol-5-1,4-dions; un to fizioloģiski pieņemamie sāļi un solvāti.
10.(6R, 12aR)-2,3,6,7,12,12a-heksahidro-2-metil-6-(3,4metilēndioksifenil)-pirazino[2', 1': 6, 1 ]pirido[3,4-b]indol-1,4-dions; un tā fizioloģiski pieņemamie sāļi un solvāti.
11. Savienoums saskaņā ar jebkuru no 1. līdz 10. punkta, tādu slimību ārstēšanai kā noturīgā, nenoturīgā un citāda stenokardija, hipertenzija, plaušu hipertenzija, hroniskas plaušu nosprostojuma slimības, hroniskā sirds nepietiekamība, nieru mazspēja, ateroskleroze, asinsvadu nepietiekamība, perifēriālais vaskulīts, vaskulārie iekaisumi, insults, bronhīti, hroniskā astma, alerģiskā astma, alerģiskais rinīts, glaukoma vai slimības, kas raksturojas ar zarnu motorikas traucējumiem.
12. Savienojuma saskaņā ar jebkuru no 1. līdz 10. punktam izmantošana medikamentu ražošanā tādu slimību ārstēšanai kānoturīgā, nenoturīgā un citāda stenokardija, hipertenzija, plaušu hipertenzija, hroniskas plaušu nosprostojuma slimības, hroniskā sirds nepietiekamība, nieru mazspēja, ateroskleroze, asinsvadu nepietiekamība, perifēriālais vaskulīts, vaskulārie iekaisumi, insults, bronhīti, hroniskā astma, alerģiskā astma, alerģiskais rinīts, glaukoma vai slimības, kas raksturojas ar zarnu motorikas traucējumiem.
13. Farmaceitiskā kompozīcija, kas ietver savienojumu saskaņā ar jebkuru no 1. līdz 10. punktam kopā ar tā farmaceitiski pieņemamu šķīdinātāju vai nesēju.
14. Farmaceitiskās kompozīcijas, kura satur savienojumu saskaņā ar jebkuru no 1. līdz 10. punktam, izgatavošanas paņēmiens, kur paņēmiens ietver minētā savienojuma samaisīšanu kopā ar tā farmaceitiski pieņemamu šķīdinātāju vai nesēju.
15. Savienojuma ar formulu (I) izgatavošanas paņēmiens, kas ietver:

paņēmienu (A) savienojuma ar formulu (I), kur R3 ir ūdeņraža atoms, kurā Alk ir C-ļ .galkilgrupa un Hal ir halogēna atoms, apstrādi ar pirmējo amīnu NHg; vai paņēmienu (B) savienojuma ar formulu (I), kurā R* un R⁸ kopa ir 3- vai 4locekļu alkil- vai alkenilvirkne, izgatavošanai, kur paņēmiens (B) ietver kur Alk ir C-ļ-6^alkil9^ruP^{a un} R^{1 un} R^ kopā ^{ir 8} vai 4-locekļu virkne, abi tādi kā noteikts iepriekš, cīklizāciju; vai paņēmienu (C) savienojuma ar formulu (I) , kurā R⁸ ir C-ļ .galkilgrupa, izgatavošanai, kur paņēmiens (C) ietver savienojuma ar formulu (X)

O kurā Alk ir C-|.galkilgrupa un R⁵ ir Cg-galkilgrupa, kura pie C-ļ aizvietota ar halogēna atomu, ciklizāciju; vai paņēmienam (Α), (B) vai (C) kā tie aprakstīti iepriekš sekojošu

i) savstarpējas pārvēršanas stadiju; un/vai vai nu ii) sāls veidošanu; vai iii) solvāta veidošanu.
16. Savienojumi ar formulu (II) (III) (V) (VI) (VII) (VIII) izņemot savienojumus (III) (V) (VI) (VII) kur R° ir ūdeņraža atoms, R² ir fenilgrupa