HRP980216A2 - Therapeutic 1,2,3,4-tetrahydroisoquinolines - Google Patents

Description

This invention relates to new compounds that prevent hepatic production of apoprotein B-100 (apoB-100), and to processes for their preparation, pharmaceutical preparations containing them and their medical use. More specifically, this invention relates to new 1,2,3,4-tetrahydroisoquinolines and their use in therapy. Some tetrahydroisoquinolines with therapeutic use are described in WO9800403.

ApoB-100 is a major component of low-density lipoprotein-cholesterol (LDL-C) protein. High plasma levels of LDL-C are a major risk factor for atherosclerosis and coronary artery disease. ApoB-100 plasma levels are correlated with LDL-C plasma levels and also form a cardiovascular risk factor in them. ApoB-100 is exclusively produced by hepatocytes and reduced hepatic production of ApoB-100 should cause a decrease in LDL-C plasma levels. Compounds that act as ApoB-100 inhibitors are described in PCT.EP97.05636.

This invention describes compounds of formula (I)

[image]

where

R 0 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or a methylenedioxy group, and n is an integer from 1-4;

R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy or methylenedioxy group, and p is an integer from 1-4;

R 2 is one or more groups selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy group, NR 4 R 5 , -(C 1-4 alkylene)-NR 6 R 7 , -NR 4 - or -O-(C 1-4 alkylene)-NR 8 R 9 , 4-morpholino,

or

[image] , and m is an integer from 1-4;

R 3 is hydrogen or C 1-4 alkyl;

R4-R10 are independently hydrogen or C1-4 alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable inorganic acids such as, for example, hydrochlorides, hydrobromides or sulfates.

Solvates can be, for example, hydrates.

Further references to compounds according to the invention include compounds of formula (I) and their pharmaceutically acceptable salts together with pharmaceutically acceptable solvates.

Those skilled in the art should note that compounds of formula (I) contain at least 2 chiral centers (shown as * and ** in formula (I)). Compounds of formula (I) are preferred in their (R) center * form. In the center **, the compounds of formula (I) are preferred in the form obtained from the use of the intermediate (+)-1,2,3,4-tetrahydro-1-naphthaleneamine.

References to the general formula (I), alkyl and alkylene include both normal and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, isopropyl and tert-butyl groups, and examples of alkylene groups include methylene, ethylene, isopropylene and tert-butylene groups.

Referring to the general formula (I), the halogen atom can be a fluorine, chlorine, bromine or iodine atom.

Referring to the general formula (I), the methylenedioxy group denotes the -O-CH2-O- group attached to the adjacent carbons of the aromatic ring.

R 0 is suitably a hydrogen, methoxy or methylenedioxy group and n is suitably 1.

R0 is suitably substituted at the 6- or 7-position of the bicyclic ring, or where R0 is a methylenedioxy group, at the 6- and 7-positions of the ring. R 0 is suitably hydrogen.

R 1 is suitably hydrogen, C 1-4 alkyl, ie methyl or isopropyl, halogen, ie fluorine or chlorine, methoxy or trifluoromethoxy, and p is suitably 1,2 or 3. Suitably R 1 is substituted on any, one, two or three of the 3-, 4-, 5-, 6-, 7-, and 8-positions of the bicyclic ring, including gem substitution where appropriate. R 1 is suitably methyl, methoxy or isopropyl substituted at the 7-position of the bicyclic ring. R 1 is most conveniently isopropyl substituted at the 7-position of the bicyclic ring.

R2 is suitably hydrogen, C1-4alkyl, ie methyl, halogen, ie chlorine, methoxy, methylenedioxy, NMe2, -O-(C1-4alkylene)-NR6R7, ie 2-dimethylamino-ethoxy, 2-dimethylamino-propoxy, 2-dimethylamino-1-methyl-ethoxy, 2-dimethylamino-2-methyl-propoxy or 2-dimethylamino-1,1-dimethyl-ethoxy, 4-morpholino

or

[image] , and m is 1, 2 or 3 as appropriate.

Suitably, R 2 is mono-, di- or tri-substituted at the 2-, 3- or 4-positions of the phenyl ring, or where R 2 is methylenedioxy, at the 3- and 4-positions of the phenyl ring. Preferably, R 2 is mono-substituted at the 3-position of the phenyl ring.

Preferably, R 2 is methyl, dimethylamino or 4-morpholino.

Most preferably, R 2 is 2-dimethylamino-ethoxy substituted in the 3-position of the phenyl ring.

R 3 is suitably hydrogen.

Suitable compounds according to the invention include:

2-(4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-dimethylamino-4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ;

2-(3-dimethylamino benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-(morpholin-4-yl)benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide;

2-(3-(morpholin-4-yl)benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide;

2-(3-dimethylamino benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-(4-methyl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3,4-methylenedioxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholino-4-yl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-[3-(2-diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-[3-(3-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(4-methyl-benzoyl)-N-(6,7-methylenedioxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(6,7-methylenedioxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(4-methyl-benzoyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(4-methyl-benzoyl)-N-(6-fluoro-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-(3-Methoxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-[3-(4-methyl-piperazin-1-yl)-benzoyl]-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide;

2-(3-dimethylamino-4-methoxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-(4-chloro-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(2-dimethylamino-benzoyl)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(4,4,6-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 1;

2-(3-dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-trifluoromethoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-[3-(2-dimethylamino-2-methyl-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide;

2-[3-(2-dimethylamino-1,1-dimethyl-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2, 3,4-tetrahydroisoquinoline-3-carboxamide;

or a pharmaceutically acceptable salt or solvate thereof.

Preferred compounds of the invention include:

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-(4-methyl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3,4-methylenedioxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide;

2-[3-(2-diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-(3-morpholin-4-yl-benzoyl)-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide;

2-[3-(3-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide;

2-[3-(2-dimethylamino-1-methyl-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide;

or a pharmaceutically acceptable salt or solvate thereof.

Particularly preferred compounds of the invention include 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2, 3,4-tetrahydroisoquinoline-3-carboxamide;

or a pharmaceutically acceptable salt or solvate thereof.

The compounds of the invention are inhibitors of hepatic production of apoB-100 and as such are useful in the treatment of conditions arising from elevated circulating levels of apoB-100.

The ability of the compounds of the invention to inhibit apoB-100 production by human hepatocytes in vitro was determined using the human hepatocarcinoma cell line, Hep G2, as a model system. The specificity of the compounds from the invention was determined by comparing the effects of the production of apoB-100, apoprotein A-1, and fibrinogen. A specificity of at least 100 is desirable.

The in vivo profile of the compounds was determined with acute oral administration of the compounds of the invention to DBA/2 mice and Wistar rats with measurement of apoB-100 plasma levels as a percentage of control values. Active compounds were further evaluated in Wistar rats with repeated oral administration (once daily) with measurement of total cholesterol, low-density lipoprotein-cholesterol, triglycerides, 1poB-100 and apoA-I plasma levels as a percentage of control values.

The compounds of the invention are strong and specific inhibitors of hepatic production of apoB-100, which furthermore show good oral bioavailability and duration of action.

The compounds of the invention are useful in the treatment of atherosclerosis, pancreatitis, non-insulin-dependent diabetes mellitus (NIDDM) and chronic heart diseases.

The compounds of the invention are also useful in lowering serum levels of lipids, cholesterol and/or triglycerides, and are useful in the treatment of hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, and/or hypertriglyceridemia.

The invention therefore provides compounds of formula (I) or its pharmaceutically acceptable salts or solvates for use in therapy, especially in human medicine.

Also, as a further aspect of the invention, the use of compounds of formula (I) or its pharmaceutically acceptable salts or solvates in the preparation of a drug for use in the treatment of conditions resulting from elevated circulating levels of apoB-100 is ensured.

In an alternative or further aspect, there is described a method for the treatment of mammals, including humans, particularly in the treatment of conditions resulting from elevated circulating levels of apoB-100, comprising the introduction of an effective amount of compounds of formula (I) or a pharmaceutically acceptable salt thereof.

It should be noted that the treatment reference is intended to include prophylaxis as well as relief of established symptoms. The compounds of formula (I) can be introduced as a chemically crude but active ingredient which is preferably presented as a pharmaceutical formulation.

Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such preparations are preferably adapted in form for use in medicine, especially human medicine, and can be conventionally formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.

Such compound formulas (I) may be formulated for oral, oral, parenteral, transdermal, topical (including ocular and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (through the mouth or nose).

For oral administration, the pharmaceutical preparations may take the form of, for example, tablets or capsules obtained by conventional means with pharmaceutically acceptable excipients, such as binding agents (ie, pregelatinized grain starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (ie lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (ie magnesium stearate, talc or silicon dioxide); disintegrators (ie potato starch or sodium starch glycolate); or wetting agents (ie sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid formulations for oral administration may take the form of, for example, solutions or suspensions, or may be presented as a dry product to be combined with water or other suitable vehicle prior to use. Such liquid formulations can be obtained by conventional means with pharmaceutically acceptable additives such as suspending agents (ie sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (ie lecithin or acacia); non-aqueous carriers (ie almond oil, oil esters, ethyl alcohol or fractionated vegetable oils); and preservatives (ie methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain salt buffers, flavoring, coloring and sweetening agents as needed.

Preparations for oral administration can be suitably formulated to provide controlled release of the active compound.

For oral administration, the preparation can take the form of tablets or pastilles formulated in a suitable way.

For transdermal introduction of the compounds according to the invention, they can be formulated as creams, gels, ointments or lotions or as a transdermal salve. Such compositions may for example be formulated with an aqueous or oil base with the addition of suitable curing, gelling, emulsifying, stabilizing, dispersing, suspending, and/or coloring agents.

The compounds of the invention may be formulated for parenteral administration by injection of a large tablet or by continuous infusion. Formulations for injection can be presented in unit dosage form, ie in ampoules or multi-dose containers, with an added preservative.

preparations may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, with a suitable carrier, i.e. pyrogen-free sterile water, prior to use.

The compounds of the invention may be formulated for topical application as ointments, creams, jellies, lotions, pessaries, aerosols, or drops (ie, eye, ear, or nose drops). Ointments and creams can be formulated, for example, with a water or oil base with the addition of suitable hardening and/or gelling agents. Ointments for application to the eye can be obtained in a sterile manner using sterilized components.

Lotions can be formulated with an aqueous or oil base and will generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, hardening agents, or coloring agents. Drops can be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.

The compounds of the invention may also be formulated in rectal preparations such as suppositories or retained enemas, i.e. containing conventional base suppositories such as coconut butter or other glycerides.

The compounds of the invention can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in a suitable oil) or ion-exchange resins, or as moderately soluble derivatives, for example as a moderately soluble salt.

For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitably metered or unit dose device or alternatively as a powder mixture with a suitable carrier for administration using a suitable delivery device.

Preparations can contain from 0.1% to, i.e. 0.1-99% of active material, depending on the introduction procedure. The suggested dose of the compounds of the invention is 0.25 mg/kg to about 125 mg/kg of body weight per day, i.e. 20 mg/kg to 100 mg/kg per day. It should be noted that it may be necessary to make routine variations, depending on the age and condition of the patient, and the precise dosage will be the sole responsibility of the doctor or veterinarian on duty. The dosage will also depend on the route of administration and the specific compound chosen.

The compounds of formula (I) may, if desired, be administered with one or more therapeutic agents, and are formulated for administration by any convenient route in a conventional manner. Appropriate doses will be easily determined by experts. For example, compounds of formula (I) can be administered in combination with an HMG CoA reductase inhibitor or a bile acid transport inhibitor.

The compounds of formula (I), and their salts and solvates, can be prepared by the general procedures described below. In the following description, the groups R0, R1, R2 and R3 are, as previously defined, for compounds of formula (I).

According to the general procedure, compounds of formula (I) can be obtained by reacting a compound of formula (II) with a compound of formula (III)

[image]

where X is a suitable halide leaving group, ie chloride, or X is a hydroxy group. The reaction is conventionally carried out under standard coupling conditions for acid or for coupling acid halides with amines.

Compounds of formula (II) can be obtained by reacting compounds of formula (IV) with compound (V)

[image]

where Y is a suitable amine protecting group, ie tert-butoxycarbonyl (Boc), under standard coupling conditions for acid/amine coupling, followed by deprotection under suitable conditions.

The various general procedures described above may be useful for introducing the desired groups at any stage of formation in the phases of the claimed compound, and it should be noted that these general procedures may be combined in various ways in such multi-stage procedures. The reaction sequence of multi-phase processes should of course be chosen so that the reaction conditions used do not affect the groups in the molecules that are desired for the final product.

Thus, according to another method, compounds of formula (I) can be obtained by reacting compounds of formula (VI) and compounds of formula (V)

[image]

under standard conditions for amine-acid coupling.

Compounds of formula (VI) can be obtained by reacting a compound of formula (VII) with a compound of formula (III)

[image]

where Z is a suitable C1-4 alkyl protecting group, ie methyl, and X is OH, under standard conditions for acid-amine couplings, followed by removal of the protecting acid group.

It should be noted that some intermediates, i.e. compounds of formula (II) and (V), are novel and therefore may provide the following aspect of the present invention. Compounds of formula (III), (IV), (V) and (VII) are known or can be obtained by standard procedures.

Pharmaceutically acceptable salts may also be obtained from other salts, including other pharmaceutically acceptable salts, of compounds of formula (I) using conventional methods.

Compounds of formula (I) can be readily isolated together with the solution molecules by crystallization or evaporation of the appropriate solution to obtain the appropriate solvates.

When a specific enantiomer of a compound of general formula (I) is required, this can be obtained for example by resolution of the corresponding enantiomeric mixture of a compound of formula (I) using conventional procedures.

Thus, in one example, a suitable optically active acid can be used to form a salt with an enantiomeric mixture of a compound of general formula (I). The resulting mixture of isomeric salts can be separated, for example, with fractional crystallization into diastereoisomeric salts from which the required enantiomer of compounds of general formula (I) can be isolated by conversion to the required free base.

Alternatively, enantiomers of general formula (I) can be synthesized from suitable optically active intermediates using the general procedures described herein.

The invention is further illustrated with the following intermediates and examples. All temperatures are in degrees Celsius.

Intermediary 1

(+)-7-methyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine

A solution of (L)-(+)-tartaric acid (11, 2 g) in methanol (70 ml) and the resulting solution was kept overnight at room temperature. The crystalline salt was filtered and dried to give the tartrate salt (9.7 g) as white crystals (MP: 189-191 °C). The salt was treated with 1N aqueous NaOH, extracted with diethyl ether and the resulting organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound as a yellow liquid (4.7 g).

(�)D= +46.8° (c=0.5; CHCl3).

Intermediary 2

(+)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamine

To a stirred suspension of racemic 7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamine (20 g) in water (80 ml) was added (L)-(+)-tartaric acid (16.9 ) and the resulting suspension was heated for complete dissolution. After 3 hours at room temperature, the crystalline salt was filtered and then recrystallized twice from methanol to give the tartrate salt (8 g) as white crystals (M.P.: 211-212 °C) The salt (1 g) was treated with 1N aqueous NaOH , extracted with diethyl ether, and the resulting organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound as a pale yellow liquid (0.5 g).

(�)D= +45.9° (c=1.12; MeOH).

Intermediary 3

3-dimethylamino-4-methyl benzoic acid methyl ester

37% aqueous formaldehyde solution (8 ml) and 10% palladium on carbon (0.66 g) were added to a mixed suspension of 3-amino-4-methyl benzoic acid methyl ester (6.6 g) in methanol (60 ml) and the mixture was stirred under a hydrogen atmosphere for 16 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated under reduced pressure and the residue was then purified by chromatography eluting with dichloromethane/ethyl acetate (90/10) to afford the title compound as a colorless liquid (6.7 g).

GC/MS (EI, 70 eV): m/z=193

Intermediary 4

3-dimethylamino-4-methyl bezoic acid

1N NaOH solution (48.9 ml) was added to a solution of 3-dimethylamino-4-methyl benzoic acid methyl ester (6.3 g) in methanol (60 ml) and the solution was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure and 1N HCl (48.9 ml) was added. The aqueous layer was extracted with dichloromethane and the organic phase was washed with brine, dried over sodium sulfate and evaporated. The resulting white solid was recrystallized from hexane to afford the title compound as white crystals (5 g).

M.p.: 131-133 °C.

Intermediary 5

2-tert-butoxycarbonyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

Boc-D-1,2,3,4 was added to a solution of (+)-7-methyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine (4.8 g) in dichloromethane (100 ml) -tetrahydroisoquinoline-3-carboxylic acid (8.24 g), 1-hydroxybenzotriazole (5.21 g) and triethylamine (3.86 g). The mixture was cooled to 0 °C and treated with 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (7.37 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed sequentially with water, 1N HCl, aqueous NaHCO 3 , and brine, and then dried over sodium sulfate and evaporated. The oily residue was crystallized from diisopropyl ether to give the title compound as white crystals (9.7 g).

T.p.: 140-142 °C.

Similarly, it was obtained:

Intermediary 6

2-(tert-butoxycarbonyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

as white crystals (16 g), mp: 149-151 °C,

from (+)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamine (8.5 g), and Boc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (13.3 g).

Intermediary 7

N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

In a mixed solution of 2-(tert-butoxycarbonyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4 tetrahydro isoquinoline-3-carboxamide (intermediate 5) (9.7 g) trifluoroacetic acid (32 ml) was added to anhydrous dichloromethane (70 ml) cooled to 0 °C and the solution was allowed to react at room temperature. After 4 hours, the reaction mixture was evaporated to dryness under reduced pressure and the residue taken up in water, basified with saturated aqueous NaHCO3 and extracted with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The resulting white solid was recrystallized from diisopropyl ether to give the title compound as white crystals (6.7 g).

T.p.: 132-134 °C.

Similarly, it was obtained:

Intermediary 8

N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

as white crystals (11.8 g), M.p.: 131-133 °C,

from 2-(tert-butoxycarbonyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (16 g) (intermediate 6).

Intermediary 9

4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one oxime

A solution of hydroxylamine hydrochloride (1 g) in water (20 ml) was added to a solution of 4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (1.7 g) in ethanol (30 ml) and sodium acetate (2.2 g). After 48 hours at room temperature, the solutions were removed under reduced pressure and the residue taken in water was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness to give the title compound as an oil (2 g).

GC/MS (EI, 70 eV): m/z=203 (M + ).

The following were obtained similarly:

[image]

Intermediary 13

7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine hydrochloride

A solution of 7-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime (3.5 g) in methanol (60 ml) was hydrogenated in the presence of 10% Pd/C (0.3 g) for 16 hours at room temperature. After removal of the catalyst, the solution was evaporated in vacuo, and the residue was dissolved in diethyl ether and treated with a solution of hydrochloric acid in diethyl ether. The resulting precipitate was filtered and washed with diethyl ether to give the title compound as white crystals (3.7 g).

M.p.: 234-236 °C.

The following were obtained similarly:

[image]

Intermediary 19

7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylamine

A solution of 7-fluoro-3,4-dihydro-2H-naphthalen-1-one oxime (0.56 g) in acetic acid (15 ml) was hydrogenated in the presence of 10% Pd/C (0.06 g) for 16 h at 40 °C. After removing the catalyst, the solution was evaporated in vacuo and the residue was made basic with sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane/methanol (90/10) to give the title compound as white crystals (0.07 g).

T.p.: 62-64 °C.

Intermediary 20

(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)-amine

A solution of 7-isopropyl-3,4-dihydro-2H-naphthalen-1-one (14.5 g), (S)-(-)-�-methyl benzylamine (27.9 g) and a catalytic amount of p-toluenesulfonic acid in toluene (150 ml) was refluxed under a Dean-Stark separator until the conversion was complete (48 hours). The solution was then evaporated under reduced pressure and the oily residue (22.5 g) was dissolved in methanol (300 ml). The solution was cooled to 0 °C and treated in portions with sodium borohydride (1.8 g), and then stirred for 0.5 h at the same temperature. Water was then added and the mixture was evaporated to dryness and filtered on silica gel eluting with dichloromethane/methanol (95/5) to give the title compound (20.4 g) as an oil.

GC/MS (EI, 70 eV): m/z=293 (M + ).

Similarly, it was obtained:

Intermediary 21

(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)-amine

as an oil (15.2 g), GC/MS (EI, 70 eV): m/z=307 (M+),

of 7-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (10.1 g) and (S)-(-)-�-methyl benzylamine (18.5 g).

Intermediary 22

(+)-7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine hydrochloride

A mixture of (7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)-amine (20.2 g; 69 mmol), ammonium formate (13 g; 306 mmol) ) and 10% Pd/C (1 g) in methanol (300 ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with 1N sodium hydroxide, extracted with diethyl ether, and the organic phase was dried over sodium sulfate and filtered. The organic solution was then treated with hydrochloric acid and the precipitate was filtered and dried to give the title compound (10.5 g) as a white solid.

T.p.: > 250 °C.

(�)D=+29.4° (C=0.52; MeOH).

Similarly, it was obtained:

Intermediary 23

(+)-7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine hydrochloride

as a white solid (10.2 g), M.p.: > 250 °C, (�)D= +28 ° (C=0.58; MeOH),

from (7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)-amine (15.2 g).

They were similarly obtained as intermediate 5:

[image]

Intermediary 27

2-(tert-butoxycarbonyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide as

mixture of diastereomers.

Boc-D-1,2,3,4 was added to a solution of racemic 5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine hydrochloride (1.1 g) in dichloromethane (20 ml) -tetrahydroisoquinoline-3-carboxylic acid (1.4 g), 1-hydroxybenzotriazole (0.9 g) and triethylamine (1.1 g). The mixture was cooled to 0 °C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed successively with 1N HCl, aqueous NaHCO3 solution and brine, and then dried over sodium sulfate and evaporated. The residue was crystallized from diisopropyl ether to give the title compound (2 g) as white crystals.

M.p.: 152-154 °C.

The following were obtained similarly:

[image]

They were similarly obtained as intermediate 7:

[image]

Intermediary 39

3-(4-Methyl-piperazin-1-yl)benzoic acid ethyl ester

A mixture of 3-amino-benzoic acid ethyl ester (19.7 g), bis-(2-chloro-ethyl)-methylamine (23 g) and sodium carbonate (63 g) in butanol (450 ml) was stirred and heated under reflux. during 16 hours. The mixture was evaporated under reduced pressure and the residue was taken up in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give the title compound as a pale yellow oil (3.8 g).

GC/MS (EI, 70 eV): m/z=248 (M+).

Intermediary 40

3-(3-Dimethylamino-propoxy)-benzoic acid ethyl ester

A mixture of 3-hydroxy-benzoic acid ethyl ester (3.32 g), (3-chloro-propyl)-dimethylamine hydrochloride (3.79 g) and anhydrous potassium carbonate (6.62 g) in acetone (150 ml) was mixed under reflux for 24 hours. It was then cooled, and the solid material was filtered and washed with acetone. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give the title compound (4 g) as a pale yellow oil.

GC/MS (EI, 70 eV): m/z=251 (M + ).

The following were obtained similarly:

[image]

Intermediary 43

3-(2-dimethylamino-1-methyl-ethoxy)-benzoic acid ethyl ester and 3-(2-dimethylamino-propoxy)-benzoic acid ethyl ester

A mixture of 3-hydroxy-benzoic acid ethyl ester (16.6 g), (2-chloro-propyl)-dimethylamine hydrochloride (21.6 g) and anhydrous potassium carbonate (41.1 g) in acetone (400 ml) was mixed under reflux for 16 hours. It was then cooled, and the solid material was filtered and washed with acetone. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give: first 3-(2-dimethylamino-1-methyl-ethoxy)-benzoic acid ethyl ester (7 g) as pale yellow oil with

GC/MS (EI, 70 eV): m/z=251 (M+);

followed by 3-(2-dimethylamino-propoxy)-benzoic acid ethyl ester (10 g) as a pale yellow oil with

GC/MS (EI, 70 eV): m/z=251 (M+).

Intermediary 44

3-(2-dimethylamino-1,1-dimethyl-ethoxy)-benzoic acid ethyl ester and 3-(2-dimethylamino-2-methyl-propoxy)-benzoic acid ethyl ester

A solution of 3-hydroxybenzoic acid ethyl ester (1.6 g) in tetrahydrofuran (50 ml) containing triphenyl phosphine (2.9 g) was stirred at room temperature while diethyl azodicarboxylate (1.9 g) was added dropwise. To this solution was added 2-dimethylamino-2-methyl-propan-1-ol (1.2 g) and the mixture was stirred at room temperature for 16 hours. Evaporation of the solution in vacuo gave an oil which was dissolved in diethyl ether and the organic layer was washed with water, dried over sodium sulfate, evaporated and purified by flash chromatography eluting with dichloromethane/methanol (90/10) to give: first 3-(2 -dimethylamino-1,1-dimethyl-ethoxy)-benzoic acid ethyl ester (1.2 g) as a pale yellow oil with

GC/MS (EI, 70 eV): m/z=265 (M+);

followed by 3-(2-dimethylamino-2-methyl-propoxy)-benzoic acid ethyl ester (0.3 g) as a pale yellow oil with

GC/MS (EI, 70 eV): m/z=265 (M + ).

Intermediary 45

3-morpholin-4-yl-benzoic acid

1N sodium hydroxide solution (55 ml) was added to a solution of 3-morpholin-4-yl-benzoic acid ethyl ester (6.1 g) in ethanol (40 ml) and the mixture was heated under reflux for 1 hour. Ethanol was then evaporated under reduced pressure, and the aqueous solution was extracted with diethyl ether and neutralized with 1N hydrochloric acid solution (55 ml). The aqueous layer was then extracted with dichloromethane, and the organic layer was dried over sodium sulfate and evaporated to dryness. The resulting solid was recrystallized from acetonitrile to give the title compound (3.6 g) as white crystals.

T.p.: 168-170 °C.

The following were obtained similarly:

[image]

Intermediary 48

3-(3-Dimethylamino-propoxy)-benzoic acid hydrochloride

A solution of sodium hydroxide (1.3 g) in water (50 ml) was added to a solution of 3-(3-dimethylamino-propoxy)-benzoic acid ethyl ester (4 g) in ethanol (50 ml) and the mixture was heated to 60 ° C for 1.5 hours. The ethanol was then evaporated under reduced pressure and the solution was acidified with concentrated hydrochloric acid. The aqueous solution was evaporated to dryness, and the resulting solid residue was extracted with hot ethanol, and the solution was filtered and evaporated. The resulting solid was recrystallized from propanol-2 to give the title compound (3.5 g) as white crystals.

T.p.: 180-182 °C.

The following were obtained similarly:

[image]

Intermediary 52

3-(2-dimethylamino-propoxy)-benzoic acid hydrochloride

To a solution of 3-(2-dimethylamino-propoxy)-bezoic acid ethyl ester (10 g) in ethanol (100 ml) was added normal sodium hydroxide solution (80 ml) and the mixture was heated under reflux for 0.5 hours. The ethanol was then evaporated under reduced pressure and the solution was acidified with concentrated hydrochloric acid. The aqueous solution was evaporated to dryness and the resulting solid residue was extracted with hot ethanol, and the solution was filtered and evaporated. The resulting solid was washed with diisopropyl ether to give the title compound (9.5 g) as white crystals.

M.p.: 177-179 °C.

The following were obtained similarly:

[image]

Intermediary 56

(R)-2-(3-dimethylamino-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester

3-Dimethylamino-benzoic acid (4 g), 1- hydroxy benzotriazole (4.2 g) and triethylamine (5.4 g). The mixture was cooled to 0 °C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.9 g) followed by stirring for 4 hours at room temperature. The reaction mixture was washed successively with water, aqueous NaHCO 3 and brine, and then dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate (90/10) to give the title compound as a yellow oil (6.5 g).

GC/MS (EI, 70 eV): m/z=352 (M+).

Similarly, it was obtained:

Intermediary 57

(R)-2-(3-morpholin-4-yl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester

as a yellow oil (2.2 g), GC/MS (EI, 70 eV): m/z=394 (M+),

of (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride (1.8 g) and 3-morpholin-4-yl-benzoic acid (1.6 g).

Intermediary 58

(R)-2-(3-dimethylamino-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

A mixed solution of (R)-2-(3-dimethylamino-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (6.5 g) in a mixture of THF, MeOH, H2O (30/10/ 10 ml) cooled to 5 °C, was treated with LiOH.H2O (1.2 g) and the mixture was stirred at the same temperature for 8 hours. The solutions were removed under reduced pressure, and the residue was neutralized with 1N HCl, and extracted with dichloromethane. The organic phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting solid was recrystallized from ethyl acetate to give the title compound as white crystals (5 g).

M.p.: 202-204 °C.

Similarly, it was obtained:

Intermediary 59

(R)-2-(3-morpholin-4-yl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

as white crystals (1.7 g), M.p.: 106-108 °C,

of (R)-2-(3-morpholin-4-yl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (2.2 g).

Example 1

2-(4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

Procedure A:

In a solution of N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 7) (160 mg) in dichloromethane ( 8 ml) 4-methyl benzoic acid (68 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (61 mg) were added. The mixture was cooled to 0 °C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg) followed by stirring for 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and washed successively with 1N HCl, aqueous NaHCO3 and brine, and then dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate (90/10) and crystallized from dichloromethane/hexane to give the title compound as white crystals (150 mg).

M.p.: 161-162 °C, (�)D= +47.1 ° (C=1.1; CHCl3).

Analysis for C29H30N2O2: Calculated: C 79.42; H 6.89; N 6.39.

Found: C 79.01; H 7.10; N 6.43%.

Procedure B

A solution of 4-methyl benzoyl chloride (913 mg) in dry dichloromethane (10 ml) was added dropwise to a solution of N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2, of 3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 7) (1.8 g) and triethylamine (597 mg), with stirring under nitrogen in an ice bath for cooling. After 0.5 hours, the solution was evaporated with 1N HCl, aqueous NaHCO3 and brine, then dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate (90/10) and crystallized from dichloromethane/hexane to give the title compound as white crystals (2 g).

M.p.: 157-159 °C,

(�)D= +46 ° (C=1.2; CHCl3).

Analysis for C29H30N2O2: Calculated: C 79.42; H 6.89; N 6.39.

Found: C 78.99; H 7.01; N 6.31 %.

The following were obtained similarly:

Example 2

2-(3-dimethylamino-4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

like white crystals,

T.t.: 140-141 °C,

(�)D= +43.6 ° (C=1.2; CHCl3).

Analysis for C31H35N3O2: Calculated: C 77.31; H 7.32; N 8.72.

Found: C 77.04; H 7.54; N 8.66 %.

from N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 7) and 3-dimethylamino-4-methyl benzoic acid.

Example 3

2-(3-dimethylamino benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

like white crystals,

T.p.: 186-187 °C,

(�)D= +41 ° (C=0.4; CHCl3).

Analysis for C30H33N3O2: Calculated: C 77.06; H 7,11; N 8.99.

Found: C 77.22; H 7.04; N 9.03%.

of N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 7) and 3-dimethyl amino benzoic acid.

Example 4

2-(3-(morpholin-4-yl)benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide

as a white solid,

T.p.: 96-101 °C,

(�)D= +33.6 ° (C=1; CHCl3).

Analysis for C32H35N3O3: Calculated: C 75.41; H 6.92; N 8,24.

Found: C 75.69; H 7.19; N 7.99%.

from N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 7) and 3-(morpholin-4- il) benzoic acid.

Example 5

2-(3-(morpholin-4-yl)benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide

like white crystals,

T.p.: 124-126 °C,

(�)D= +23.9 ° (C=0.4; CHCl3).

Analysis for C32H35N3O4: Calculated: C 73.12; H 6.71; N 7.99.

Found: C 73.32; H 7.13; N 8.05 %.

from N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 8) and 3-(morpholin-4- il) benzoic acid.

Example 6

2-(3-(dimethylamino benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

like white crystals,

T.p.: 164-166 °C,

(�)D= +25.6 ° (C=0.5; CHCl3).

Analysis for C30H33N3O3: Calculated: C 75.51; H 6.88; N 8.69.

Found: C 74.42; H 7.26; N 8.72 %.

of N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 8) and 3-dimethylamino benzoic acid.

Example 7

2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide

In a solution of N-(7-isopropyl-1,2,3,4-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 30) (2.84 g) in dichloromethane ( 100 ml) 3-(2-dimethylamino-ethoxy)-benzoic acid hydrochloride (2 g), 1-hydroxybenzotriazole (1.43 g) and triethylamine (1.89 g) were added. The mixture was cooled to 0 °C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2 g) followed by stirring for 16 hours at room temperature.

The reaction mixture was diluted with dichloromethane and washed successively with water, aqueous NaHCO3 solution and brine, then dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/methanol (96/4) and crystallized from diisopropyl ether to give the title compound as a white solid (3.2 g).

T.p.: 88-90 °C.

(�)D= +27.2 ° (C=1; CHCl3).

Analysis for C34H41N3O3: Calculated: C 75.66; H 7.66; N 7.79.

Found: C 75.21; H 7.85; N 7.71 %.

The following were obtained similarly:

[image]

[image] [image]

Example 32

2-(3-morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide isomer 1 and isomer 2

To a solution of (R)-2-(3-morpholin-4-yl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (0.33 g) in dichloromethane (10 ml) was added racemic 4 ,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamine hydrochloride (0.22 g), 1-hydroxy benzotriazole (0.17 g) and triethylamine (0.23 g). The mixture was cooled to 0°C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed successively with water, 1N HCl, aqueous NaHCO3 solution and brine, then dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/methanol (99/1) to afford the title compound, isomer 1 as a white solid (0.12 g).

M.p.: 113-115 °C.

(�)D= +20 ° (C=0.4; CHCl3).

Analysis for C34H39N3O3: Calculated: C 75.95; H 7.31; N 7.81;

Found: C 75.80; H 7.59; N 7.61%;

followed by:

Example 33

Isomer 2

as a white solid (0.08 g),

T.p.: 117-119 °C,

(�)D= +25.4 ° (C=0.4; CHCl3).

Analysis for C34H39N3O3: Calculated: C 75.95; H 7.31; N 7.81.

Found: C 75.47; H 7.23; N 7.87%.

The following were obtained similarly:

[image]

[image]

Biological experiment

HepG2 cells were seeded at 30,000 cells/well in 96-well dishes. After 4 days, confluent cells were incubated with compounds for 24 hours in RPMI medium containing 1% FCS and 50 µCi/ml 35S-methionine. Compounds were dissolved in DMSO and tested in cells from 5 µM to 0.32 nM. The production of radiolabeled apoB-100 and apoA-1 (used as a selectivity control) was quantified by analyzing the supernatants using SDS PAGE and exposing the gels to a PhosphorImager screen. Inhibition of apoB-100 and apoA-1 secretion by compounds was calculated using untreated cells as controls, and the IC50 of each compound was determined on both apoproteins.

Biological results

The following table shows the activity of the compound of the invention in the experiment described above.

[image]

Tablet preparations

The following preparations A and B can be obtained by wet granulation of ingredients (a) to (c) and (a) to (d) with povidone solution, followed by addition of magnesium stearate and compression.

Preparation A

[image]

Preparation B

[image]

Preparation C

[image]

The following preparations D and E can be obtained by direct compression of the mixed ingredients. The lactose used in preparation E is of the direct compression type.

Preparation D

[image]

Preparation E

[image] Preparation F (controlled release preparation)

[image]

The preparation can be obtained by wet granulation of ingredients (a) to (c) with povidone solution, followed by addition of magnesium stearate and compression.

Preparation G (enteric-coated tablet)

Enteric-coated tablets of formulation C can be obtained by coating the tablets with 25 mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also contain 10% by mass (the amount of polymer used) of plasticizers to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

Preparation H (enteric-coated controlled-release tablet)

Enteric-coated tablets of formulation F can be obtained by coating the tablets with 50 mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also contain 10% by mass (the amount of polymer used) of plasticizers to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

(ii) Capsule preparations

Preparation A

Capsules can be obtained by mixing the ingredients of preparation D above and filling two-part hard gelatin capsules with the resulting mixture. Preparation B (infra) can be obtained in a similar way.

Preparation B

[image]

Preparation C

[image]

Capsules can be obtained by melting Macrogol 4000 BP, dispersing the active ingredient into a solution and filling two-part hard gelatin capsules with it.

Preparation D

[image]

Capsules can be obtained by dispersing the active ingredient in lecithin and arachis oil and filling elastic gelatin capsules with the dispersion.

Preparation E (controlled release capsule)

[image]

A controlled release capsule preparation can be obtained by ejecting the mixed ingredients (a) to (c) using an ejector, then forming a sphere and drying the ejected material. The dried pills are coated with a controlled-release membrane (d) and filled into two-part, hard gelatin capsules.

Preparation F (intestinal capsule)

[image]

The intestinal capsule preparation can be obtained by ejecting the mixed ingredients (a) to (c) using an ejector, then forming a sphere and drying the ejected material. The dried pills are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part, hard gelatin capsules.

Preparation G (enteric-coated controlled-release capsule)

Enteric-coated capsules of preparation E can be obtained by coating controlled-release tablets with 50 mg/capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also contain 10% by mass (the amount of polymer used) of plasticizers to prevent membrane cracking during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

(iii) Intravenous injection of preparations

[image]

The active ingredient is mostly dissolved in phosphate buffer at 35-40 °C, then filled to full volume, and filtered through a filter with sterile micropores into sterile glass vials of 10 ml (type 1) that are sealed with a sterile cap and lid.

(iv) Intramuscular injection preparation

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The active ingredient is dissolved in glycofurol. Benzyl alcohol was then added and dissolved, and water was added to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).

(v) Syrup preparation

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Sodium benzoate was dissolved in a portion of purified water and sorbitol solution was added. The active ingredient is added and dissolved. The resulting solution was mixed with glycerol and then made up to the required volume with purified water.

(vi) Suppository preparation

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One fifth of Witepsol H15 is melted in a vessel with an outer steam liner at 45 °C maximum. The active ingredient was passed through a 200 lm screen and added to the molten base with stirring, using a Silverson fitted with a cutting head, until a uniform dispersion was achieved. Keeping the mixture at 45 °C, the remaining Witpsol H15 was added to the suspension which was stirred to ensure a homogeneous mixture. The entire suspension was then passed through a 250 lm stainless steel screen and, with continuous stirring, allowed to cool to 40 °C. At a temperature of 38-40 °C, a 2.02 g aliquot of the mixture was filled into suitable plastic molds and the suppositories were allowed to cool to room temperature.

(vii) Pessary preparation

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The above ingredients were mixed directly and pessaries were obtained by compressing the resulting mixture.

(viii) Transdermal preparation

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The active ingredient and alcohol USP are made into jelly with hydroxyethyl cellulose and packaged in a transdermal device with a surface area of 10 cm2.

Claims (16)

1. Compound of formula (I) [image] characterized by: R 0 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or a methylenedioxy group, and n is an integer from 1-4; R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy or methylenedioxy group, and p is an integer from 1-4; R 2 is one or more groups selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy group, NR 4 R 5 , -(C1-4alkylene)-NR6R7, -NR4- or -O-(C1-4alkylene)-NR8R9, 4-morpholino, or [image] , and m is an integer from 1-4; R 3 is hydrogen or C 1-4 alkyl; R4-R10 are independently hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound as claimed in claim 1, characterized in that R 0 is hydrogen. 3. A compound according to claim 1 or claim 2, characterized in that R1 is hydrogen, C1-4 alkyl, halogen, methoxy, or trifluoromethoxy, p is 1, 2 or 3, and R1 is substituted on any one, two or three of 3-, 4-, 5-, 6-, 7- and 8-positions of the bicyclic ring, including gem substitution. 4. A compound as claimed in any one of claims 1 to 3, characterized in that R1 is isopropyl substituted in the 7-position of the bicyclic ring. 5. A compound as claimed in any one of claims 1 to 4, characterized in that R2 is hydrogen, C1-4 alkyl, halogen, methoxy, methylenedioxy, NMe2, -O-(C1-4 alkylene)-NMe2, 4-morpholino or [image] , and m is suitably 1, 2 or 3. 6. A compound as claimed in any one of claims 1 to 5, characterized in that R 2 is 2-dimethylamino-ethoxy substituted in the 3-position of the phenyl ring. 7. A compound as claimed in any one of claims 1 to 6, wherein R 3 is hydrogen. 8. Compound according to claim 1, characterized in that it is selected from: 2-(4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamia; 2-(3-dimethylamino-4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ; 2-(3-dimethylamino benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-(morpholin-4-yl)benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide; 2-(3-(morpholin-4-yl)benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxamide; 2-(3-dimethylamino benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide; 2-(4-methyl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3,4-methylenedioxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide; 2-[3-(2-diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide; 2-[3-(3-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-[3-(2-diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-(4-methyl-benzoyl)-N-(6,7-methylenedioxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(6,7-methylenedioxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-(4-methyl-benzoyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(4-methyl-benzoyl)-N-(6-fluoro-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide; 2-(3-Methoxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(4-methyl-piperazin-1-yl)-benzoyl]-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide; 2-(3-dimethylamino-4-methoxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide; 2-(4-chloro-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(2-dimethylamino-benzoyl)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide isomer 1; 2-(3-morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-morpholin-4-yl-benzoyl)-N-(4,4,6-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide isomer 1; 2-(3-morpholin-4-yl-benzoyl)-N-(4,4,6-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4- tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide isomer 1; 2-(3-morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 1; 2-(3-morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 2; 2-(3-dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 1; 2-(3-dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 2; 2-(3-morpholin-4-yl-benzoyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 1; 2-(3-morpholin-4-yl-benzoyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide isomer 2; 2-(3-morpholin-4-yl-benzoyl)-N-(7-trifluoromethoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide; 2-(3-morpholin-4-yl-benzoyl)-N-(7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamide; 2-[3-(2-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide; 2-[3-(2-dimethylamino-1-methyl-ethoxy))-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3 ,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-2-methyl-propoxy))-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2,3 ,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-1,1-dimethyl-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,2, 3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 9. A compound according to claim 1, characterized in that it is a compound 2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalene-1- yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 10. A compound according to any one of claims 1 to 9, characterized in that it is used in therapy. 11. A method for treating mammals, including humans, for conditions resulting in elevated circulating levels of apoB-100, characterized in that it comprises the administration of an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof. 12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is used in the production of a drug used for the treatment of conditions resulting in elevated circulating levels of apoB-100. 13. Pharmaceutical preparation, characterized in that it contains a compound according to any one of claims 1 to 9 or its pharmaceutically acceptable derivative, together with one or more pharmaceutically acceptable carriers. 14. Process for obtaining the compound of formula (I) as required in claim 1, characterized in that it comprises: (a) reacting a compound of formula (II) with a compound of formula (III) [image] wherein X is a suitable halide leaving group or X is a hydroxy group, or (b) with the reaction of the compound of formula (VI) and the compound of formula (V) [image] under standard conditions for amine-acid coupling. 15. Intermediate represented by formula (II) [image] characterized by: R 0 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or a methylenedioxy group, and n is an integer from 1-4; R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy or methylenedioxy group, and p is an integer from 1-4; R 3 is hydrogen or C 1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof. 16. Intermediate represented by formula (VI) [image] characterized by: R 0 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or a methylenedioxy group, and n is an integer from 1-4; R 2 is one or more groups selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy group, NR 4 R 5 , -(C 1-4 alkylene)-NR 6 R 7 , N or -O-(C 1-4 alkylene)-NR 8 R 9 , 4-morpholino , or [image] , and m is an integer from 1-4; R 3 is hydrogen or C 1-4 alkyl; R4-R10 are independently hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.