WO2007009682A1

WO2007009682A1 - Oral pharmaceutical formulations comprising substituted pyrazoline compounds

Info

Publication number: WO2007009682A1
Application number: PCT/EP2006/006956
Authority: WO
Inventors: Helmut H. Buschmann
Original assignee: Laboratorios Del Dr. Esteve, S.A.
Priority date: 2005-07-15
Filing date: 2006-07-15
Publication date: 2007-01-25

Abstract

The present invention relates to oral pharmaceutical formulations comprising substituted pyrazoline compounds, as well as their use for the preparation of a medicament for the treatment of humans and animals.

Description

Oral pharmaceutical formulations comprising substituted pyrazoline compounds

Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana. The most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly Δ⁹-THC.

These naturally occuring cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.

At present, two distinct types of receptors that bind both the naturally occurring and synthetic cannabinoids have been identified and cloned. These receptors, which are designated CBi and CB₂ are involved in a variety of physiological or pathophysiological processes in humans and animals, e.g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.

Therefore, compounds, which have a high binding affinity for these cannabinoid receptors and which are suitable for modulating these receptors are useful in the prevention and/or treatment of cannabinoid-receptor related disorders.

In particular, the CBrReceptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type Il diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.

Thus, it was an object of the present invention to provide suitable pharmaceutical formaulations for novel compounds for use as active substances in medicaments. In particular, these active substances should be suitable for the modulation of

Cannabinoid receptors, more particularly for the modulation of Cannabinoid 1 (CBi) receptors.

Said object was achieved by providing the substituted pyrazoline compounds of general formula I given below, their stereoisomers, corresponding salts and corresponding solvates thereof.

It has been found that these compounds have a high affinity for cannabinoid receptors, particularly for the CBi-receptor, and that they act as modulators e.g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or food disorders or reproduction in humans and/or animals, preferably humans including infants, children and grown-ups.

Thus a very preferred aspect of the invention relates to a pharmaceutical composition for the oral administration comprising at least one compound of formula (I) :

(I) wherein, R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

R³ represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R³ represents an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or R³ represents an -NR⁴R⁵-moiety,

R⁴ and R⁵, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, an -SO2-R⁶- moiety, or an -NR⁷R⁸-moiety,

R⁶ represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring- system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,

R⁷ and R⁸, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,

with the proviso that R⁴ and R⁵ do not both represent a hydrogen atom, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or an alkyl group, which is optionally at least mono-substituted with an alkoxy group, an alkoxyalkoxy group, a halogen atom or a phenyl group, the other one of these residues R⁴ and R⁵ does not represent a pyrid-2-yl group, which is optionally mono-substituted in the 5- position, a pyrid-5-yl group, which is optionally mono-substituted in the 2-position, a pyrimid-5-yl group, which is optionally mono-substituted in the 2-position, a pyridaz-3- yl group, which is optionally mono-substituted in the 6-position, a pyrazin-5-yl group, which is optionally mono-substituted in the 2-position, a thien-2-yl group, which is optionally mono-substituted in the 5 position, a thien-2-yl group, which is optionally at least mono-substituted in the 4-position, a benzyl group, which is optionally mono- substituted in the 4-position of the ring, a phenethyl group, which is optionally mono- substituted in the 4-position of the ring, an optionally mono-, di- or tri-substituted phenyl group, a di-substituted phenyl group, wherein the two substituents together form an -OCH₂O-, -OCH₂CH₂O- or -CH₂CH₂O- chain, which is optionally substituted with one or more halogen atoms or one or two methyl groups, an -NH-phenyl-moiety, wherein the phenyl group may be mono-substituted in the 4-position, and

that if one of the residues R⁴ and R⁵ represents an alkynyl group, the other one of these residues R⁴ and R⁵ does not represent a phenyl group, which is optionally substituted in the 4-position, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or a linear or branched, saturated or unsaturated, unsubstituted or substituted aliphatic radical, the other one of these residues R⁴ and R⁵ does not represent an unsubstituted or substituted thiazole group or an unsubstituted or substituted [1 ,3,4]thiadiazole group. optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof;

and/or

at least one compound of formula (II),

wherein

R¹ represents hydrogen or a linear or branched d-₄-alkyl group,

R² , R³ and R⁴ independently of each other represent hydrogen, a linear or branched Ci-β-alkyl group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^8', SH, SR^8', SOR^8', SO₂R^8', NH₂, NHR^8', NR⁸ R^9', -(C=O)-NH₂, -(C=O)-NHR^8' or -(C=O)-NR⁸R^9' whereby R^8' and R⁹ for each substituent independently represent linear or branched Ci_-6 alkyl,

R⁵ and R⁶ independently of each other represent a linear or branched d-β-alkyl group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH2F, CHF2,

CF₃, CN, OH, NO₂, -(C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰R^11', - (C=O)-NH₂, -(C=O)-NHR^10' and -(C=O)-NR¹⁰ R^11>, whereby R^10' and optionally R¹¹ for each substituent independently represent linear or branched Ci_-6 alkyl;

R⁷ represents hydrogen, a linear or branched C^-alky! group, a linear or branched Ci-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, - (C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰ R^11', -(C=O)-NH₂, -(C=O)- NHR^10' and -(C=O)-NR¹⁰R^11', whereby R^10' and optionally R^11' for each substituent independently represent linear or branched Ci-6 alkyl;

with the proviso that if R¹ and R⁷ are H and R⁵ and R⁶ both represent Cl in the 3- and 4-position of the phenyl ring neither of R² , R³ and R⁴ may represent F in the 4-position of the phenyl ring if the other two of R², R³ and R⁴ both represent H;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof;

and/or

at least one compound of formula (III)

III

wherein

R¹ represents hydrogen or a linear or branched Ci-₄-alkyl group,

R¹², R¹³, R¹⁴ or R¹⁵ independently of each other represent a linear or branched d-₆-alkyl group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, SH, NH₂, hydrogen, methyl, ethyl, F, Cl₁ Br and CF₃, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,

characterized in that the pharmaceutial composition is in any of the following pharmaceutical forms (a), (b), (c), (d), or (e) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients; or b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer; or c) at least one additive which insures a penetration of water into the core of the preparation and at least one hydrogel forming polymer; or d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients; or e) an inert core, with

(aa) a first layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients;

(bb) a second layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients.

It has been found that the substituted pyrazoline compounds of general formula I, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors. Thus, this applies also to the inventive formulations comprising these compounds. In particular, these pyrazoline compounds show little or no development of tolerance during treatment, particularly with respect to food intake, i.e. if the treatment is interrupted for a given period of time and then continued afterwards, the inventively used pyrazoline compounds will again show the desired effect. After ending the treatment with the pyrazoline compounds, the positive influence on the body weight is found to continue.

Compounds according to formulas Il or III (namely example 18) are inhibitors of high blood levels of triglicerides. Again, this clearly applies also to the inventive formulations comprising these compounds.

Furthermore, all these pyrazoline compounds seem to show relatively weak Herg channel affinity, thus a low risk of prolongation of the QT-interval is to be expected for these compounds.

In summary, the inventively used pyrazoline compounds are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient. So generally speaking this effect can be seen with the pharmaceutical formulations according to the invention as well.

A very highly preferred aspect of this present invention further relates to a pharmaceutical composition for the oral administration comprising at least one

substituted pyrazoline compounds of general formula I,

I

wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Compounds according to formula I have a high affinity for cannabinoid receptors, particularly for the CBi-receptor, and show a marked and prolonged effect on body weight. Particularly preferably the following provisos (disclaimers) apply for the pyrazoline compounds of general formula I given above:

that R⁴ and R⁵ do not both represent a hydrogen atom, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or a linear or branched, saturated or unsaturated, unsubstituted or substituted aliphatic radical, the other one of these residues R⁴ and R⁵ does not represent an unsubstituted or substituted thiazole group or an unsubstituted or substituted [1 ,3,4]thiadiazole group. A mono- or polycyclic ring-system according to the present invention means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more, e.g. 1 , 2 or 3, heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S. Preferably the polycyclic ring-system may comprise two rings that are condensed. The rings of the mono- or polycyclic ring-sytem are preferably 5- or 6-membered.

The term "condensed" according to the present invention means that a ring or ring- system is attached to another ring or ring-system, whereby the terms "annulated" or "annelated" are also used by those skilled in the art to designate this kind of attachment.

If one or more of the residues R³-R⁸ represents or comprises a saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic group, which is substituted by one or more, e.g. 1 , 2, 3 or 4, substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched d-β-alkoxy, branched or unbranched Ci-β-alkyI, branched or unbranched d-4-perfluoroalkoxy, branched or unbranched C1-4- perfluoroalkyl, oxo, amino, carboxy, amido, cyano, nitro, -SO₂NH₂, -CO-d-4-alkyl, - SO-Ci -₄-alkyl, -SO₂-Ci -₄-alkyl, -NH-SO₂-d-₄-alkyl , wherein the d-4-alkyl may in each case be branched or unbranched, and a phenyl group, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, oxo, CF₃ and a phenyl group.

If one or more of the residues R³-R⁸ represents or comprises a cycloaliphatic group, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of of N, O and S. Preferably a cycloaliphatic group may contain 1 , 2 or 3 heteratoms independently selected from the group consisting of N, O and S as ring members. Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing, optionally at least mono-substituted cycloaliphatic groups may preferably be selected from the group consisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyl and Morpholinyl.

If one or more of the residues R³-R⁸ comprises a mono- or polycyclic ring system, which is substituted by one or more, e.g. 1 , 2, 3, 4 or 5 substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched Ci_-6- alkoxy, branched or unbranched Ci-₆-alkyl, branched or unbranched Ci-₄- perfluoroalkoxy, branched or unbranched Ci-4-perfluoroalkyl, amino, carboxy, oxo, amido, cyano, nitro, -SO₂NH₂, -CO-C₁ ^-alkyl, -SO-Ci -4-alkyl, -SO₂-Ci-₄-alkyl, -NH- SO₂-C-ι-4-alkyl , wherein the Ci-4-alkyl may in each case be branched or unbranched, and a phenyl group, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF₃, oxo and a phenyl group.

If one or more of the residues R¹-R⁸ represents or comprises an aryl group, including a phenyl group, which is substituted by one or more, e.g. 1 , 2, 3, 4 or 5 substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of a halogen atom (e.g. F, Cl, Br, I), a linear or branched Ci-₆-alkyl group, a linear or branched Ci_-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-Ci -β-alkyl group, a cyano group, a nitro group, a carboxy group, a -CO-O-d-β-alkyl group, a -CO-

NR^AR^B- moiety, a -CO-NH-NR^cR^D-moiety, an -SH, an -S-Ci_6-alkyl group, an -SO-Ci. ₆-alkyl group, an -SOrd-β-alkyl group, a -Ci-β-alkylene-S-d-e-alkyl group, a -Ci_-6- alkylene-SO-Ci-β-alkyl group, a -Ci-e-alkylene-SOa-Ci-β-alkyl group, an -NH₂-moiety, an NHR'-moiety or an NR'R"-moiety, wherein R' and R" independently represent a linear or branched d-e-alkyl group, a d-β-alkyl group substituted by one or more hydroxy groups and a -Ci-₆-alkylene-NR^ER^F group,

whereby R^A, R^B, identical or different, represent hydrogen or a d-e-alkyl group, or R^A and R^B together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different, Ci_-6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,

R^c, R^D, identical or different, represent a hydrogen atom, a Ci-e-alkyl group, a -CO-O-Ci-β-alkyl group, a C_3-8-cycloalkyl group, a d-₆-alkylene-C₃-₈-cycloalkyl group, Ci-₆-alkylene-O-Ci-β-alkyl group or a C^-alkyl group substituted with one or more hydroxy groups, or R^c, R^D together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more substituents independently selected from the group consisting of Ci_-6 alkyl group, a -CO-Ci-₆-alkyl group, a -CO-O- Ci-β-alkyl group, a - CO-NH- Ci-₆-alkyl group, a -CS-NH- Ci-e-alkyl group, an oxo group, a Ci-₆-alkyl group substituted with one or more hydroxy groups, a Ci-β-alkylene-O-Ci-β-alkyl group and a -CO-NH₂ group and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member, and

wherein R^E, R^F, identical or different, represent hydrogen or a

group, or R^E and R^F together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different Ci_-6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member.

Preferred aryl groups, which may optionally be at least mono-substituted, are phenyl and naphthyl.

If one or more of the residues R³-R⁸ represents or comprises a heteroaryl group, which is substituted by one or more, e.g. 1, 2, 3, 4 or 5 substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of a halogen atom (e.g. F, Cl, Br, I), a linear or branched Ci-₆-alkyl group, a linear or branched Ci_-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-Ci-e-alkyl group, a cyano group, a carboxy group, a -CO-O-Ci ^-alkyl group, a -CO-NR^AR^B- moiety, a -CO-NH- NR^cR^D-moiety, an -S-d-6-alkyl group, an -SO-Ci-β-alkyI group, an -SO₂-Ci -β-alkyl group, a -d-β-alkylene-S-d-β-alkyl group, a -d-β-alkylene-SO-d-e-alkyl group, a -Ci- ₆-alkylene-SO₂-Ci-₆-alkyl group, a d-β-alkyl group substituted by one or more hydroxy groups and a -Ci-6-alkylene-NR^ER^F group,

whereby R^A, R^B, identical or different, represent hydrogen or a d-β-alkyl group, or R^A and R^B together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different, d-β alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,

R^c, R^D, identical or different, represent a hydrogen atom, a d-β-alkyl group, a -CO-O-Ci -₆-alkyl group, a C₃-₈-cycloalkyl group, a Ci-β-alkylene-Ca-β-cycloalkyl group, Ci-β-alkylene-O-d-β-alkyl group or a d-β-alkyl group substituted with one or more hydroxy groups, or R^c, R^D together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more substituents independently selected from the group consisting of Ci_-6 alkyl group, a -CO-Ci-β-alkyl group, a -CO-O-

group, a - CO-NH- d-β-alkyl group, a -CS-NH- d-β-alkyl group, an oxo group, a Ci-₆-alkyl group substituted with one or more hydroxy groups, a Ci-₆-alkylene-O-Ci-₆-alkyl group and a -CO-NH2 group and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member, and

wherein R^E, R^F, identical or different, represent hydrogen or a d-β-alkyl group, or R^E and R^F together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different Ci_-6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,

The heteroatoms, which are present as ring members in the heteroaryl radical, may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur. Preferably a heteroaryl radical may comprise 1 , 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.

Suitable heteroaryl groups, which may optionally be at least mono-substituted, may preferably be selected from the group consisting of thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, indolyl, chinolinyl, isochinolinyl, benzo[1 ,2,5]- thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl, imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably be selected from the group consisting of thienyl-, benzo[1 ,2,5]-thiodiazolyl, benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl, triazolyl and pyrazolyl.

If one or more of the residues R⁴-R⁸ represents or comprises a linear or branched, saturated or unsaturated aliphatic group such as an alkyl group, which is substituted by one or more, e.g. 1 , 2, 3, 4 or 5 substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched

branched or unbranched

branched or unbranched Ci-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO₂NH₂, -CO-Ci -4-alkyl, -SO-Ci -4-alkyl, -SO₂-Ci-4-alkyl, -NH-SO2-Ci-4-alkyl , wherein the Ci-4-alkyl may in each case be branched or unbranched, and a phenyl group, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃ and a phenyl group.

Preferred linear or branched, saturated or unsaturated aliphatic groups, which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.

If any of the residues R⁴-R⁸ represents or comprises a linear or branched alkylene group, said alkylene group may preferably be selected from the group consisting of - methylene -(CH₂)-, ethylene -(CH₂-CH₂)-, n-propylene -(CH₂-CH₂-CH₂)- or iso- propylene -(-C(CH₃)₂)-. Preferred are substituted pyrazoline compounds of general formula I given above, wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

R⁴ and R⁵, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, an -SO₂-R⁶- moiety, or an -NR⁷R⁸-moiety,

R⁶ represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring- system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, R⁷ and R⁸, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,

whereby preferably the following provisos (disclaimers) apply:

that R⁴ and R⁵ do not both represent a hydrogen atom, and that if one of the residues R⁴ and R⁵ represents a hydrogen atom or a linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic group, the other one of these residues R⁴ and R⁵ does not represent a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted or unsubstituted pyridazyl group, a substituted or unsubstituted pyrazinyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted phenethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group, which is condensed (attached) to at least one, optionally substituted ring or ringsystem, an -NH-phenyl-moiety, wherein the phenyl group may be at least mono-substituted, an unsubstituted or substituted thiazole group, or an unsubstituted or substituted [1 ,3,4]thiadiazole group.

Preferred are also substituted pyrazoline compounds of general formula I given above, wherein R¹ represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched

group, a linear or branched C_1-6-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R', SH, SR', SOR', SO₂R', NH₂, NHR', NR¹R", -(C=O)-NH₂, -(C=O)-NHR' and -(C=O)-NR¹R", whereby R' and R" for each substituent independently represent linear or branched Ci-6 alkyl, preferably R¹ represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, Cl₁ Br and CF3, more preferably R¹ represents a phenyl group, which is substituted with a chlorine atom in the 4-position, and R²-R⁸ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Also preferred are substituted pyrazoline compounds of general formula I given above, wherein R² represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched Ci-β-alkyl group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R', SH, SR', SOR', SO₂R', NH₂, NHR', NR¹R", -(C=O)-NH₂, -(C=O)-NHR' and -(C=O)-NR¹R" whereby R' and R" for each substituent independently represent linear or branched d-β alkyl, preferably R² represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, Cl, Br and CF₃, more preferably R² a phenyl group, which is di-substituted with two chlorine atoms in the 2- and 4-position, and R¹ and R³-R⁸ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Preference is also given to substituted pyrazoline compounds of general formula I given above, wherein R³ represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8 cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or R³ represents an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R³ represents an -NR⁴R⁵-moiety, preferably R³ represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C_3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R³ represents an -NR⁴R⁵-moiety, more preferably R³ represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, whereby each of these groups may be substituted with one or more Ci-e-alkyl groups, or R³ represents an -NR⁴R⁵-moiety and R¹, R² and R⁴-R⁸ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Furthermore, substituted pyrazoline compounds of general formula I given above are preferred, wherein R⁴ and R⁵, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted d-₆-aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C3-8- cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or an optionally at least mono- substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH₂-) or ethylene (-CH2-CH₂)-group, an -SO₂-R⁶-moiety, or an -N R⁷R⁸- moiety, preferably one of these residues R⁴ and R⁵ represents a hydrogen atom and the other one of these residues R⁴ and R⁵ represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C₃-₈-cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, an -SO₂-R⁶-moiety, or an -NR⁷R⁸- moiety, or R⁴ and R⁵, identical or different, each represent a d-β alkyl group, more preferably one of these residues R⁴ and R⁵ represents a hydrogen atom and the other one of these residues R⁴ and R⁵ represents an optionally at least mono- substituted pyrrolidinyl group, an optionally at least mono-substituted piperidinyl group, an optionally at least mono-substituted piperazinyl group, an optionally at least mono-substituted triazolyl group, an -SO₂-R⁶-moiety, or an -NR⁷R⁸-moiety, or R⁴ and R⁵, identical or different, represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a tert.-butyl group, and R¹- R³ and R⁶-R⁸ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Also preferred are substituted pyrazoline compounds of general formula I given above, wherein R⁶ represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted Ci_-6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C₃-₈ cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6- membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH₂-) or ethylene (-CH₂- CH₂)-group, preferably R⁶ represents a Ci-6-alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or a phenyl group, which is optionally substituted with one or more C1-6 alkyl groups, and R¹-R⁵, R⁷ and R⁸ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Moreover substituted pyrazoline compounds of general formula I given above are preferred, wherein R⁷ and R⁸, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C1.₆ aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C₃-β cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or an optionally at least mono- substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH₂)-group, preferably represent a hydrogen atom or a Ci_-6 alkyl radical, and R¹-R⁶ have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

Particularly preferred are compounds of general formula I given below,

wherein

R¹ represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position,

R² represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position,

R³ represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo- piperazinyl group, a morpholinyl group, or an -NR⁴R⁵-moiety, R⁴ represents a hydrogen atom or a linear or branched Ci-β-alkyl group,

R⁵ represents a linear or branched Ci-6 alkyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, whereby each of the heterocyclic rings may be substituted with one or more, identical or different,

groups, or an -SO₂-R⁶-moiety, and

R⁶ represents a phenyl group, which is optionally substituted with one or more C₁^ alkyl groups, which may be identical or different,

Most particularly preferred are substituted pyrazoline compounds selected from the group consisting of:

N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3- carboxamide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydiO-1 H-pyrazole-3-carboxylic acid-[1 ,2,4]-triazole-4-yl-amide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydiO-1 H-pyrazole-3-carboxylic acid-(4-methyl-piperazin-1-yl)-amide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid diethylamide,

[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-yl]-piperidine- 1-yl-methanone, N-[5-(4-Chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carbonyl]-4- methylphenylsufonamide,

optionally in the form of a corresponding N-oxide, or a corresponding salt, or a corresponding solvate.

In another aspect the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula I, according to which at least one benzaldehyde compound of general formula IV

(IV) wherein R¹ has the meaning given above, is reacted with a pyruvate compound of general formula (V)

(V), wherein G represents an OR group with R being a branched or unbranched Ci_-6 alkyl radical, preferably an ethyl radical, or G represents an O K group with K being a cation, preferably a monovalent cation, more preferably an alkali metal cation, even more preferably a sodium cation, to yield a compound of general formula (Vl)

wherein R¹ has the meaning given above, which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VII)

(VII) or a corresponding salt thereof, wherein RR²² hheas the meaning given above, under an inert atmosphere, to yield a compound of general formula (Villi)

(VIII) wherein R¹ and R² have the meaning as given above, which is optionally isolated and/or optionally purified, and optionally transferred under inert atmosphere to a compound of general formula (IX)

(IX) wherein the substituents R¹ and R² have the meaning given above and A represents a leaving group, via the reaction with an activating agent, said compound being optionally isolated and/or optionally purified, and at least one compound of general formula (Vl) is reacted with a compound of general formula R³H, wherein R³ represents an -NR⁴R⁵-moiety, wherein R⁴ and R⁵ have the meaning given above, to yield a substituted pyrazoline compound of general formula I, wherein R³ represents an -NR⁴R⁵-moiety, and/or at least one compound of general formula (IX) is reacted with a compound of the general formula R³H, in which R³ has the meaning given above to yield a compound of general formula (I) given above, which is optionally isolated and/or optionally purified.

The inventive process is also illustrated in scheme I given below:

Scheme I:

for R being different from -NR⁴R⁵

The reaction of the benzaldehyde compound of general formula IV with a pyruvate compound of general formula V is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996). The respective description is hereby incorporated by reference and forms part of the disclosure. Preferably sodium pyruvate may be used as the pyruvate compound. Preferably said reaction is carried out in a protic reaction medium such as a Ci_-4 alkyl alcohol or mixtures of these. Mixtures of such alcohols with water, e.g. ethanol/water may also be used. Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 ⁰C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours. Also preferred the reaction of the benzaldehyde compound of general formula IV with a pyruvate compound of general formula V is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001. The respective description is hereby incorporated by reference and forms part of the disclosure.

The reaction of the compound of general formula (Vl) with an optionally substituted phenyl hydrazin of general formula (VII) is preferably carried out in a suitable reaction medium such as Ci^-alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds. Also preferably, said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid. Furthermore, the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.

Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 ⁰C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.

The carboxylic group of the compound of general formula (VIII) may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art. Preferably the compounds of general formula (VIII) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a C₁-₄ alkyl ester, an activated ester such as p- nitrophenylester. Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)). If said activated compound of general formula (IX) is an acid chloride, it is preferably prepared by reaction of the corresponding acid of general formula (VIII) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent. Also preferably an additional solvent may be used. Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used. Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times from several minutes to several hours.

If said activated compound of general formula (IX) is a mixed anhydride, said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VIII) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent. The reaction of general formula (IX) with a compound of general formula HR³ to yield compounds of general formula I, wherein R³ represents an -NR⁴R⁵ moiety is preferably carried out in presence of a base such as triethylamine in a reaction medium such as methylenchloride. The temperature is preferably in the range from O⁰C to the boiling point of the reaction medium. The reaction time may vary over a broad range, e.g. from several hours to several days.

The reaction of general formula (IX) with a compound of general formula HR³ to yield compounds of general formula I, wherein R³ represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system may be carried out according to conventional methods well known to those skilled in the art, e.g. from Pascual, A., J. Prakt Chem., 1999, 341(7), 695-700; Lin, S. et al., Heterocycles, 2001 , 55(2), 265-277; Rao, P. et al., J. Org. Chem., 2000, 65(22), 7323-7344, Pearson D.E and Buehler, C.A., Synthesis, 1972, 533-542 and references cited therein. The respective descriptions are hereby incorporated by reference and form part of the present disclosure. Preferably said reaction is carried out in the presence of a Lewis acid, which is preferably selected from the group consisting of FeCb, ZnCb and AICI₃, in a suitable reaction medium such as toluene, benzene, tetrahydrofurane or similar. The temperature is preferably in teh range from O⁰C to the boiling point of the reaction medium, more preferably from 15 to 25 ⁰C. The reaction time may vary over a broad range, e.g. from several minutes to several hours. The afore mentioned reactions involving the synthesis of the 4,5-dihydro-pyrazole ring or the reaction of a compound comprising said ring are carried out under an inert atmosphere, preferably nitrogen or argon, to avoid oxidation of the ring-system. During the processes described above the protection of sensitive groups or of reagents may be necessary and/or desirable. The introduction of conventional protective groups as well as their removal may be performed by methods well-known to those skilled in the art. If the substituted pyrazoline compounds of general formula (I) themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractunalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis. In another aspect the present invention relates to the compound

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, in particular as an intermediate in a process for preparing substituted pyrazoline compounds of general formula (I). In a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula (I) and stereoisomers thereof, wherein at least one compound of general formula (I) having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media include, for example, any of the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid. In yet a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula (I) or stereoisomers thereof, wherein at least one compound of general formula (I) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH_nR₄-O]⁺, wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Ci-₄-alkyl-radical. Suitable reaction media are, for example, any of the ones given above. Solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula (I), of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.

Substituted pyrazoline compounds of general formula I, which comprise nitrogen- atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art. Those skilled in the art understand that the term substituted pyrazoline compounds as used herein is to be understood as encompassing derivatives such as ethers, esters and complexes of these compounds as well. The term "derivatives" as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation starting from an acting (active) compound to change (ameliorate for pharmaceutical use) any of its physico-chemical properties, especially a so-called prodrug, e.g. their esters and ethers. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002). The respective description is hereby incorporated by reference and forms part of the disclosure.

The purification and isolation of the inventive substituted pyrazoline compounds of general formula (I), of a corresponding stereoisomer, or salt, or N-oxide, or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization. The substituted pyrazoline compounds of general formula (I) given below, their stereoisomers, corresponding N-oxides, corresponding salts thereof and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments. It has been found that the substituted pyrazoline compounds of general formula I given below, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors. In particular, these pyrazoline compounds show little or no development of tolerance during treatment, particularly with respect to food intake, i.e. if the treatment is interrupted for a given period of time and then continued afterwards, the inventively used pyrazoline compounds will again show the desired effect. After ending the treatment with the pyrazoline compounds, the positive influence on the body weight is found to continue.

Furthermore, these pyrazoline compounds show relatively weak Herg channel affinity, thus a low risk of prolongation of the QT-interval is to be expected for these compounds.

In summary, the inventively used pyrazoline compounds are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient. In another preferred aspect of the invention, the invention relates to a pharmaceutical composition for the oral administration comprising at least one substituted pyrazoline compounds of the general formula Il

wherein

R¹ represents hydrogen or a linear or branched d-₄-alkyl group,

R², R³ and R⁴ independently of each other represent hydrogen, a linear or branched d-β-alkyl group, a linear or branched

group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^8', SH, SR^8', SOR^8', NH₂, NHR^8', NR⁸ R^9', -(C=O)-NH₂, -(C=O)-NHR^8' or -(C=O)-NR⁸R^9' whereby R^8' and R⁹ for each substituent independently represent linear or branched Ci_-6 alkyl, R⁵ and R⁶ independently of each other represent a linear or branched C-i-β- alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH₂F,

CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10',

NR^lu R^ηi , -(C=O)-NH₂, -(C=O)-NHR s1¹0"' and -(C=O)-NR 1¹0⁰'DRH¹¹' , whereby R >iⁱσ^υ and optionally R¹¹ for each substituent independently represent linear or branched Ci-6 alkyl;

R⁷ represents hydrogen, a linear or branched d-e-alkyl group, a linear or branched Ci-6-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰R^11', -(C=O)-NH₂, -(C=O)-

NHR^10' and -(C=O)-NR¹⁰ R^11', whereby R^10' and optionally R^11' for each substituent independently represent linear or branched Ci-6 alkyl; with the proviso that if R¹ and R⁷ are H and R⁵ and R⁶ both represent Cl in the 3- and 4-position of the phenyl ring neither of R² , R³ and R⁴ may represent F in the 4-position of the phenyl ring if the other two of R² , R³ and R⁴ both represent H; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof and nanoparticles for the production of a medicament for the prophylaxis and/or treatment of disorders related to the cannabinoid receptor system.

These compounds according to formula I had a surprising effect on the blood levels of diet relevant substances, e.g. Triglycerides.

With respect to compounds of general formula II, preferred are linear or branched, saturated or unsaturated aliphatic groups, which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl. In the context of this invention, alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. In these radicals, Ci_-2-alkyl represents C1- or C2-alkyl, Ci_-3-alkyl represents C1-, C2- or C3-alkyl, Ci-₄-alkyl represents C1-, C2-, C3- or C4-alkyl, d_-5-alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl, d-e-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, Ci._T-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, Ci-β-alkyI represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, Ci_i_O-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and Ci-i₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. Furthermore, C₃-4-cycloalkyl represents C3- or C4-cycloalkyl, C_3-5- cycloalkyl represents C3-, C4- or C5-cycloalkyl, C₃^-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C₃-₇-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C_3-8-cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C_4-5-cycloalkyl represents C4- or C5-cycloalkyl, C-j-β-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C₄-₇-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C_5-6-cycloalkyl represents C5- or C6-cycloalkyl and C_5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. In respect of cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O. However, mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system. The alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1 ,1-dimethylpropyl, 1 ,2- dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1 -methyl pentyl, cyclopropyl, 2- methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentyl methyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF2, CF₃ or CH2OH) as well as pyrazolinone, oxopyrazolinone, [1 ,4]-dioxane or dioxolane. Here, in connection with alkyl and cycloalkyl - unless expressly defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical by F, Cl, Br, I, NH2, SH or OH, "polysubstituted" radicals being understood as meaning that the replacement takes effect both on different and on the same atoms several times with the same or different substituents, for example three times on the same C atom, as in the case of CF₃, or at different places, as in the case of -CH(OH)-CH=CH-CHCI₂. Particularly preferred substituents here are F, Cl and OH. In respect of cycloalkyl, the hydrogen radical can also be replaced by OCi_-3-alkyl or Ci_-3-alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF₃, methoxy or ethoxy. The term (CH₂)3-6 is to be understood as meaning -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂- CH₂-, -CH₂-CH₂-CH₂-CH₂-CH₂- and -CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-, (CH₂)^ is to be understood as meaning -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂- and -CH₂-CH₂-CH₂-CH₂-, (CH₂)4-₅ is to be understood as meaning -CH₂-CH₂-CH₂-CH₂- and -CH₂-CH₂-CH₂- CH₂-CH₂-, etc.

An aryl radical is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or monosubstituted or polysubstituted.

A heteroaryl radical is understood as meaning heterocyclic ring systems which have at least one unsaturated ring and can contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and can also be mono- or polysubstituted. Examples which may be mentioned from the group of heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline. Here, in connection with aryl and heteroaryl, substituted is understood as meaning substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and/or Cl, a CF₃, a CN, an NO₂, an NRR, a Ci-e-alkyl (saturated), a d-e-alkoxy, a C_3-8- cycloalkoxy, a C3-8-cycloalkyl or a C_2-6-alkylene.

In a preferred embodiment of the invention for a compound according to formula Il at least one of R² , R³ or R⁴ represents hydrogen, while at least one of R² , R³ or R⁴ is different from hydrogen.

In a preferred embodiment of the invention for a compound according to formula Il R⁷ represents hydrogen.

In a preferred embodiment of the invention for a compound according to formula Il R², R³ and R⁴ independently of each other represent hydrogen, a linear or branched Ci_₆-alkyl group, a halogen atom, or CF₃, preferably R² , R³ and R⁴ independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF₃. In a preferred embodiment of the invention for a compound according to formula Il R⁵ and R⁶ independently of each other represent a linear or branched

group, a halogen atom, or CF₃, preferably R⁵ and R⁶ independently of each other represent methyl, ethyl, F, Cl₁ Br and CF₃.

In a preferred embodiment of the invention for a compound according to formula Il R² represents a chlorine atom in the 4-position of the phenyl ring, while R³ and R⁴ represent hydrogen.

In a preferred embodiment of the invention for a compound according to formula Il R⁵ and R⁶ each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R⁷ represents hydrogen.

In a preferred embodiment of the invention for a compound according to formula Il R¹ represents hydrogen, methyl or ethyl, preferably hydrogen. In a highly preferred further aspect the invention relates to a pharmaceutical composition for the oral administration comprising at least one compound of general formula Il represented by a compound of general formula III wherein

III

R¹ represents hydrogen or a linear or branched

group, R¹² or R¹³ independently of each other represent a linear or branched C1-₆- alkyl group, a linear or branched Ci-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, SH, NH₂, hydrogen, methyl, ethyl, F, Cl, Br and CF₃, R¹⁴ or R¹⁵ independently of each other represent a linear or branched C1-6- alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, SH, NH₂, methyl, ethyl, F, Cl, Br and CF₃, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.

These compounds according to formula Il had a surprising effect on the blood levels of diet relevant substances, e.g. Triglycerides.

In a preferred embodiment of the invention for a compound according to formula III

R¹² and R¹³ independently of each other represent hydrogen, a linear or branched Ci- ₆-alkyl group, a halogen atom, or CF₃, preferably R¹² and R¹³ independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF₃.

R¹⁴, and R¹⁵ independently of each other represent a linear or branched C-ι-₆-alkyl group, a halogen atom, or CF₃, preferably R¹⁴ and R¹⁵ independently of each other represent methyl, ethyl, F, Cl, Br and CF₃.

R¹³ represents Cl and R¹² represents hydrogen.

R¹⁴ and R¹⁵ each represent Cl. In a preferred embodiment of the invention for a compound according to formula III

R¹ represents hydrogen, methyl or ethyl, preferably hydrogen.

In another preferred embodiment the compound according to formula Il or III is selected from the group consisting of:

5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of its racemate or one of its enantiomers; a corresponding N-oxide, a corresponding salt or a corresponding solvate.

Another preferred embodiment of the invention covers also any prodrug of the compounds of the invention described above as well as any medicament comprising this and any use thereof; especially including their esters and ethers. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).

In another aspect the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula Il or III, wherein R¹ is hydrogen, given above, in that at least one benzaldehyde compound of general formula IV

(IV)

wherein R² , R³ and R⁴ have the meaning mentioned above, is reacted with a pyruvate compound of general formula (V)

(V)₁ wherein G represents an OR group with R being a branched or unbranched C₁.₆ alkyl radical or G represents an O K group with K being a cation, preferably an anorganic kation, more preferably an alkali metal kation, most preferably sodium, to yield a compound of general formula (Vl')

(Vl¹)

which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VH')

(VII-) or a corresponding salt thereof, wherein R⁵, R⁶ and R⁷ have the meaning mentioned above, under inert atmosphere, to yield a compound of general formula (VIII¹)

(VIII¹)

wherein R² , R³ , R⁴ , R⁵ , R⁶ and R⁷ have the meaning as given above, which is optionally isolated and/or optionally purified, and optionally esterified to an alkyl-ester if in the substituted pyrazoline compound of general formula I or Il according to the invention R¹ is a linear or branched C-ι-4-alfcyl group.

The inventive process is also illustrated in scheme I given below: Scheme I:

The reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula V is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11 ), 2229-33, (1996). The respective description is hereby incorporated by reference and forms part of the disclosure. Preferably said reaction is carried out in a protic reaction medium such as a Ci_-4 alkyl alcohol or mixtures of these.

Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 ⁰C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.

Also preferred the reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula V is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001. The respective description is hereby incorporated by reference and forms part of the disclosure.

The reaction of the compound of general formula (Vl¹) with an optionally substituted phenyl hydrazin of general formula (VM') is preferably carried out in a suitable reaction medium such as d-4-alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds. Also preferably, said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid. Furthermore, the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.

The carboxylic group of the compound of general formula (VIM') may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art. Preferably the compounds of general formula (VIII') are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci_-4 alkyl ester, an activated ester such as p- nitrophenylester. Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).

If said activated compound of general formula (VIII') is an acid chloride, it is preferably prepared by reaction of the corresponding acid of general formula (VIII') with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent. Also preferably an additional solvent may be used. Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used. Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times from several minutes to several hours.

If said activated compound of general formula (VIH') is a mixed anhydride, said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VIH') with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.

Following that the activated compound can be reacted with an alkyl-alcohol to arrive at compounds according to general formulas Il or III with R¹ being a a linear or branched Ci-4-alkyl group.

During the processes described above the protection of sensitive groups or of reagents may be necessary and/or desirable. The introduction of conventional protective groups as well as their removal may be performed by methods well-known to those skilled in the art.

If the substituted pyrazoline compounds of general formula Il or III themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractionalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.

In a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula Il or III and stereoisomers thereof, wherein at least one compound of general formula Il or III having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media include, for example, any of the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.

In yet a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula Il or III or stereoisomers thereof, wherein at least one compound of general formula Il or III having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH_nR^n]⁺, wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Ci-4-alkyl-radical. Suitable reaction media are, for example, any of the ones given above.

Solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula Il or III, of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.

Substituted pyrazoline compounds of general formula Il or III, which comprise nitrogen-atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art.

The purification and isolation of the inventive substituted pyrazoline compounds of general formula Il or III, of a corresponding stereoisomer, or salt, or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization. In another preferable aspect of the invention the pharmaceutical composition according to the invention is suitable for the modulation (regulation) of cannabinoid- receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.

Particularly preferably said pharmaceutical composition is suitable for the prophylaxis and/or treatment of psychosis.

Also particularly preferably said pharmaceutical composition is suitable for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity. The inventive medicament also seems to be active in the prophylaxis and/or treatment of appetency disorders, e.g. the pyrazoline compounds of general formula I also reduce the desire for sweets.

Also particularly preferably said pharmaceutical composition is suitable for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.

Particularly preferably said pharmaceutical composition is suitable for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.

Medicaments and/or drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.

The pharmaceutical composition according to the invention is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget^" s disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.

In an embodiment of the pharmaceutical composition according to the invention the medicament is for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type Il diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.

In an embodiment of the pharmaceutical composition according to the invention the composition is for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.

In an embodiment of the pharmaceutical composition according to the invention the composition is for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.

The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range fromi to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.

In a preferred aspect of the invention the pharmaceutical composition is in any of the following pharmaceutical forms (a), (b), (d), or (e) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients; or b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer; or d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients; or e) an inert core, with

(aa) a first layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients; (bb) a second layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients. In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (a) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients.

In a preferred embodiment of the invention in the pharmaceutical form (a) the pharmaceutical composition comprises:

0.5% to 40% by weight of compound of formula (I), (II) or (III)

0.05% to 0.5% by weight of sodium alkylsulfate, and 2.5% to 10% by weight of a disintegrant.

In a preferred embodiment of the invention in the pharmaceutical form (a) the pharmaceutical composition contains:

0.5% to 40% by weight of compound of formula (I), (II) or (III) 0.1 % to 0.4% by weight of sodium laurylsulfate,

5% to 8% by weight of crosslinked sodium carboxymethyl cellulose,

1 % to 10% by weight of binder,

0.2% to 5% by weight of lubricant, and a diluent in a sufficient amount for 100%.

In a preferred embodiment of the invention in the pharmaceutical form (a) the surfactant is added to the purified water in the process.

In a preferred embodiment of the invention in the pharmaceutical form (a) the composition is in the form of capsules, pellets, granules, tablets, sachets, powders, caplets, gels, multiparticulates such as granules, pellets, multipaticles, and the like, optionally compressed into tablets or filled into capsules.

In a preferred embodiment of the invention in the pharmaceutical form (a) the pharmaceutical composition is in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase compound of formula (I), (II) or (III) corn starch 30%

200 mesh lactose monohydrate 60.78% povidone K 30 2.53% crosslinked sodium carboxymethyl cellulose 5% Granulation sodium laurylsulfate 0.1% water QS External phase magnesium stearate 1%

Internal phase compound of formula (I), (II), (III) corn starch 30%

200 mesh lactose monohydrate 55.49% povidone K 30 2.53% crosslinked sodium carboxymethyl cellulose 5%

Granulation sodium laurylsulfate 0.1% water QS

External phase magnesium stearate 1%

Internal phase compound of formula (I), (II) or (III) corn starch 30%

200 mesh lactose monohydrate 43.73% povidone K 30 2.53% crosslinked sodium carboxymethyl cellulose 5% Granulation sodium laurylsulfate 0.1% water QS

External phase magnesium stearate 1%

Another preferred aspect of the invention relates to a process for the preparation of a pharmaceutical composition in the pharmaceutical form (a) in which: a) the active principle according to formula I, Il or III and the surfactant are mixed at room temperature optionally with a diluent, a binder and/or a coloring agent; b) the mixture is wetted with purified water; c) the resulting wet mass is dried and graded; and optionally d) a lubricant and, an antiadhesive, a flowing agent, a coloring agent and/or a flavoring agent are added to the resulting graded dry grains.

In a preferred embodiment of the process for the preparation of a pharmaceutical composition in the pharmaceutical form (a) the surfactant is incorporated in step b) instead of in step a).

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (b) and thus comprises: b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer.

A very preferred, separate aspect of the invention relates to a hydrogel-type sustained-release preparation comprising (1 ) at least one of the compounds of formula I, II, III, (2) at least one additive which insures a penetration of water into the core of the preparation and (3) at least one hydrogel forming polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the controlled release polymer is a sustained release polymer. In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on a soluble polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on an insoluble polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the sustained release polymer is based on a matrix-forming polymer.

In a preferred embodiment of the invention in the pharmaceutical form (b) the insoluble polymer is based on alkylcellulose, preferably ethylcellulose.

In a preferred embodiment of the invention in the pharmaceutical form (b) soluble polymer is based on a cellulose derivative.

In a preferred embodiment of the invention in the pharmaceutical form (b) the cellulose derivative is hydroxypropylmethylcellulose or hydroxypropylcellulose.

In a preferred embodiment of the invention in the pharmaceutical form (b) the matrix- forming polymer is based on a hydrogel-forming polymer.

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (c) and thus comprises: c) at least one additive which insures a penetration of water into the core of the preparation and at least one hydrogel forming polymer.

In a preferred embodiment of the invention the pharmaceutical form (c) is comprising (1) at least one compound of formula I₁ Il or III, (2) at least one additive which insures a penetration of water into the core of the preparation and (3) at least one hydrogel forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.

In a preferred embodiment of the invention in the pharmaceutical form (c) said additive which insures a penetration of water into the core of the preparation is at least one additive having a solubility that the volume of water required for dissolving 1 gram of said additive is not more than 5 ml.

In a preferred embodiment of the invention in the pharmaceutical form (c) said additive which insures a penetration of water into the core of the preparation is at least one additive having a solubility that the volume of water required for dissolving 1 gram of said additive is not more than 4 ml.

In a preferred embodiment of the invention in the pharmaceutical form (c) said hydrogel-forming polymer is either a polymer having an average molecular weight of not less than 2,000,000 or a polymer having a viscosity of not less than 1000 cps as measured at 1 % concentration in water at 25 DEG C, or a mixture of two or more of these polymers.

In a preferred embodiment of the invention in the pharmaceutical form (c) said hydrogel-forming polymer includes at least one polyethylene oxide.

In a preferred embodiment of the invention the pharmaceutical form (c) comprises (1) at least one compound of formula I, II, III in an amount of not more than 85% by weight based on the total preparation, (2) at least one additive which insures a penetration of water into the core of the preparation in an amount of from 5 to 80% by weight based on the total preparation, and (3) at least one hydrogel- forming polymer in an amount of from 10 to 95% by weight based on the total preparation.

In a preferred embodiment of the invention the pharmaceutical form (c) comprises (1) at least one compound of formula I, II, III in an amount of not more than 80% by weight based on the total preparation, (2) at least one additive which insures a penetration of water into the core of the preparation in an amount of from 5 to 60% by weight based on the total preparation, and (3) at least one hydrogel- forming polymer in an amount of from 15 to 90% by weight based on the total preparation.

In a preferred embodiment of the invention in the pharmaceutical form (a) the release of the active principle is controlled by pH.

In a preferred embodiment of the invention in the pharmaceutical form (a) the release of the active substance is controlled by a polymer whose dissolution is pH dependent.

In a preferred embodiment of the invention in the pharmaceutical form (c) the polymer is a gastric resistant polymer such as a co-polymerized methacrylic acid / methacrylic acid methyl esters.

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (d) and thus comprises: d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients.

In a preferred embodiment of the invention in the pharmaceutical form (d) the water soluble polymer comprises hydroxypropylmethylcellulose or hydroxypropylcellulose.

In a preferred embodiment of the invention the pharmaceutical form (d) has an enteric coating.

In a very preferred aspect of the invention the pharmaceutical composition is in the pharmaceutical form (e) and thus comprises: e) an inert core, with (aa) a first layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients;

In a preferred embodiment of the invention in the pharmaceutical form (e) the release of the active substance is controlled.

In a preferred embodiment of the invention in the pharmaceutical form (e) the controlled release is pH-dependent.

In a preferred embodiment of the invention in the pharmaceutical form (e) the pH- dependent controlled release is insured by an enteric polymer.

In a preferred embodiment of the invention in the pharmaceutical form (e) the enteric polymer is a gastric resistant polymer such as co-polymerized methacrylic acid / methacrylic acid methyl esters.

In a preferred embodiment of the invention in the pharmaceutical form (e) the controlled release formulation is a sustained release formulation.

Another preferred aspect of the invention is a pharmaceutical composition for oral administration of a compound of formula (I), (II) or (III) or a mixture thereof, for administration in form of caplets, gels, multiparticulates such as granules, pellets, multiparticles, and the like, optionally compressed into tablets or filled into capsules.

In general the pharmaceutical compositions according to the invention may also be formulated containing in addition one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may also additionally contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. The compositions may also - if suitable - take any convenient form, such as tablets, pellets, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release. The pharmaceutical excipients which can be used additionally for the pharmaceutical composition according to the present invention include especially a diluent, a binder and a lubricant. A flowing agent, an antiadhesive and, optionally, a coloring agent and/or a flavoring agent can also be added.

A study of the effects of incorporating wetting agents showed that a low concentration of surfactant like a sodium alkylsulfate considerably increases the wettability. It was found that by incorporating a surfactant in the formulation, the formulation dissolves rapidly and completely and with a good reproducibility of the results. According to the present invention, sodium alkylsulfate is understood as meaning a sodium (C8-C12)alkylsulfate, for example sodium octylsulfate or, preferably, sodium laurylsulfate.

The diluent used in the composition of the present invention can be one or more compounds which are capable of densifying the active principle to give the desired mass. The preferred diluents are inorganic phosphates such as calcium phosphates; sugars such as hydrated or anhydrous lactose, or mannitol; and cellulose or cellulose derivatives such as, for example, microcrystalline cellulose, starch, corn starch or pregelatinized starch. Lactose monohydrate, mannitol, microcrystalline cellulose and corn starch, used by themselves or in a mixture, for example a mixture of lactose monohydrate and corn starch, are very particularly preferred.

The binder employed in the composition of the present invention can be one or more compounds which are capable of densifying a compound of formula (I) by converting it to larger and denser particles with better flow properties. The preferred binders are alginic acid or sodium alginate; cellulose and cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or methyl cellulose; gelatin; acrylic acid polymers; and povidone, for example povidone K 30, which is a very particularly preferred binder. The binder is present in a proportion of 1% to 10% by weight in the pharmaceutical composition according to the invention.

The lubricant employed in the composition of the present invention can be one or more compounds which are capable of preventing the problems associated with the preparation of dry forms, such as the sticking and/or seizing problems which occur in the machines during compression or filling. The preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium laurylsulfate, sodium stearylfumarate, zinc stearate or stearic acid; hydrogenated vegetable oils, for example hydrogenated castor oil; polyalkylene glycols, especially polyethylene glycol; sodium benzoate; or talcum. Magnesium stearate is preferred according to the present invention. The lubricant is present in a proportion of 0.2% to 5% by weight in the pharmaceutical composition according to the invention.

The antiadhesive which may be employed in the composition of the present invention can be one or more compounds which are capable of reducing the sticky character of the formulation, for example of preventing adhesion to metal surfaces. The preferred antiadhesives are compounds containing silicon, for example silica or talcum. The antiadhesive can be present in a proportion of 0 to 5% by weight in the pharmaceutical composition according to the invention.

The flowing agent which may be employed in the composition of the present invention can be one or more compounds which are capable of facilitating the flow of the prepared formulation. The preferred flowing agents are compounds containing silicon, for example anhydrous colloidal silica or precipitated silica. The flowing agent can be present in a proportion of 0 to 15% by weight in the pharmaceutical composition according to the invention.

The disintegrating agent is understood as meaning cellulose or cellulose derivatives such as sodium carboxymethyl cellulose or crosslinked sodium carboxymethyl cellulose, crospovidone, pregelatinized starch or sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose being a preferred disintegrating agent.

When not explicitely mentioned otherwise, the percentage in weight of excipients and additives is always related to the active principle.

According to the present invention, the pharmaceutical compositions may be prepared by a wet granulation or by a layering process. Thus, for the wet granulation process, the internal phase, the active principle, the diluent, the binder, the disintegrating agent, the sodium alkylsulfate and, optionally, the coloring agent are mixed at room temperature and then wetted with the granulating liquid. The wet mass obtained is dried and then graded. The ingredient or ingredients of the external phase, namely the lubricant, possibly the antiadhesive, the flowing agent and, if appropriate, the coloring agent and/or the flavoring agent, are then added to the graded dry grains.

The layering process is characterized in that to an inert sugar/starch spherical core, a first layer is applied containing a mixture of the active ingredient, the diluent, the binder, the disintegrating agent, the sodium alkylsulfate and, optionally, the coloring agent, optionally followed by a second isolation layer formed by water soluble polymers and compatible excipients. Finally, a layer consisting of an enteric coating is applied.

As a result of extensive studies on the sustained-release of a drug, the inventors of the present invention also discovered that the release of a drug in the colon, which is low in water content, can be achieved by providing a preparation adapted to absorb water into its core to undergo substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine, and then move in the form of the gel down to the lower digestive tract. The present invention was achieved based on the above finding.

Thus, another aspect of the present invention relates to a hydrogel-type sustained- release preparation comprising (1) at least one drug, (2) an additive providing for a penetration of water into the core of the preparation, and (3) a hydrogel-forming polymer, which preparation undergoes a substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine and is capable of releasing a drug in the colon.

The term "substantially complete gelation" of the preparation as used in this specification refers to the state in which not less than about 70%, preferably not less than about 80%, of the preparation is gelled. Since even the colon can be utilized as a site of absorption, the sustained-release preparation of the present invention prolongs the absorption period of the drug to a remarkable extent and, hence, insures a steady blood level of the drug. Thus, the preparation of the present invention absorbs water during its stay in the upper digestive tract to undergo a substantially complete gelation and then moves down into the lower digestive tract with its surface being constantly eroded, and maintains drug release by further erosion in the lower digestive tract, with the result that a sustained and sufficient absorption of the drug is achieved even in the colon where little water is available.

The sustained-release preparation of the present invention is described in further detail hereinafter.

The drug or drugs which can be used in the preparation according to the present invention are not particularly limited in kind, provided that they are used for sustained-release system.

In order that these drugs may be readily absorbed in the colon which is low in water content, it is preferable to improve their solubilities in advance. Known techniques for improving the solubility of a drug which can be applied to hydrogel preparation can be employed. Among such techniques (solubilizing treatment) can be mentioned the method comprising adding a surfactant (e.g. polyoxyethylene-hydrogenated castor oils, polyoxy-ethylene-sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose fatty acid esters, etc.) and the method comprising preparing a solid dispersion of the drug and a solubilizer such as a polymer (e.g., a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc. or an enteric polymer such as carboxymethylethylcellulose (CMEC), hydroxypropylmethylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer (Eudragit L and S; the trade name of Rhom & Haas Co.), etc.). When the drug is a basic substance, the method comprising adding an organic acid such as citric acid, tartaric acid or the like can be employed. If necessary, the method involving the formation of a soluble salt or the method comprising forming a clathrate using cyclodextrin or the like can also be employed. These procedures for solubilization can be modified as necessary according to the particular drug.

The additive for allowing water to penetrate into the core of the preparation according to the present invention (this additive for insuring a penetration of water into the preparation core will hereinafter be referred to as "hydrophilic base") is such that the amount of water required to dissolve 1 g of the hydrophilic base is not more than 5 ml and preferably not more than 4 ml at the temperature of 20 +/- 5 DEG C. The higher the solubility of the hydrophilic base in water, the more effective is the base in allowing water into the core of the preparation. The hydrophilic base includes, inter alia, highly hydrophilic polymers such as polyethylene glycol (PEG; e.g. PEG400, PEG1500, PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats Co.) and polyvinylpyrrolidone (PVP; e.g. PVP K30, the trade name of BASF), sugar alcohols such as D-sorbitol, xylitol, etc., sugars such as sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40), glucose, etc., surfactants such as polyoxyethylene-hydrogenated castor oil (HCO; e.g. Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.), polyoxyethylene- polyoxypropylene glycol (e.g. Pluronic F68 produced by Asahi Denka Kogyo K.K.), polyoxyethylene-sorbitan high molecular fatty acid ester (Tween; e.g. Tween 80 produced by Kanto Kagaku K.K.), etc.; salts such as sodium chloride, magnesium chloride, etc., organic acids such as citric acid, tartaric acid, etc.; amino acids such as glycine, beta -alanine, lysine hydrochloride, etc.; and amino sugars such as meglumine.

Preferred ones are PEG6000, PVP, D-sorbitol, etc.

The proportion of such hydrophilic base depends on the characteristics of the drug (solubility, therapeutic efficacy, etc.) and content of the drug, solubility of the hydrophilic base itself, characteristics of the hydrogel-forming polymer used, the patient's condition at the time of administration and other factors. However, the proportion may preferably be a sufficient level to achieve a substantially complete gelation during the stay of the preparation in the upper digestive tract. The preparation stays in the upper digestive tract in a different period depending on the species and the individual but in about 2 hours after administration in the case of dogs and in about 4 to 5 hours after administration in the case of human (Br. J. din. Pharmac, (1988) 26, 435-443).For administration to human, the proportion may preferably be a sufficient level to achieve a substantially complete gelation in about 4 to 5 hours after administration. The proportion of the hydrophilic base is, therefore, generally about 5-80% by weight and preferably about 5-60% by weight based on the total weight of the preparation.

When the content of the hydrophilic base is too small, the necessary gelation into the core of the preparation does not proceed so that the release of the drug in the colon becomes insufficient. On the other hand, when the content of the hydrophilic base is excessive, the gelation proceeds in a shorter time but the resulting gel becomes so fragile that the release of the drug is too fast, thus failing to insure a sufficient sustained release. Moreover, because the amount of the base is large, the product becomes bulky.

The hydrogel-forming polymer mentioned above should have the physical characteristics, inclusive of viscosity in the gelled state, which permit the preparation of the present invention to retain its shape more or less during its travel down to the lower digestive tract, namely the colon, by withstanding the contractile forces of the digestive tract associated with the digestion of food.

The hvdrogel-forminq polymer which can be used in the preparation of the present invention is preferably a polymer showing a high viscosity on gelation. For example, a polymer showing a viscosity of not less than 1000 cps in 1% aqueous solution (at 25 DEG C) is particularly preferred.

The properties of the polymer depend on its molecular weight. The hydrogel-forming polymer which can be used in the present invention is preferably a substance of comparatively high molecular weight, viz. a polymer having an average molecular weight of not less than 2 x 10<6> and more preferably not less than 4 x 10<6>.

Among such polymers are polyethylene oxide (PEO) having a molecular weight of not less than 2 x 10<6> [e.g., Polyox WSR-303 (average mol. wt.: 7 x 10<6>; viscosity: 7500-10000 cps, 1% in H2O, 25 DEG C), Polyox WSR Coagulant (average mol. wt.: 5 x 10<6>; viscosity: 5500-7500 cps, under the same condition above), Polyox WSR-301 (average mol. wt.: 4 x 10<6>; viscosity: 1650-5500 cps, under the same condition above), Polyox WSR-N-60K (average mol. wt.: 2 x 10<6>; viscosity: 2000-4000 cps, 2% in H2O, 25 DEG C), all of which are trade names of Union Carbide Co.]; hydroxypropylmethylcellulose (HPMC) [e.g., Metolose 90SH100000 (viscosity: 4100-5600 cps., 1% in H2O, 20 DEG C), Metolose 90SH50000 (viscosity: 2900-3900 cps, under the same condition above), Metolose 90SH30000 (viscosity: 25000-35000 cps, 2% in H2O, 20 DEG C), all of which are trade names of Shin-Etsu Chemicals Co.]; sodium carboxymethylcellulose (CMC-Na) [e.g., Sanlose F-150MC (average mol. wt.: 2 x 10<5>; viscosity: 1200-1800 cps, 1% in H2O, 25 DEG C), Sanlose F-1000MC (average mol. wt.: 42 x 10<4>; viscosity: 8000-12000 cps, under the same condition above), Sanlose F-300MC (average mol. wt.: 3 x 10<5>; viscosity: 2500-3000 cps, under the same condition above), all of which are trade names of Nippon Seishi Co., Ltd.]; hydroxyethylcellulose (HEC) [e.g., HEC Daicel SE850 (average mol. wt.: 148 x 10<4>; viscosity: 2400-3000 cps, 1% in H2O, 25 DEG C), HEC Daicel SE900 (average mol. wt.: 156 x 10<4>; viscosity: 4000-5000 cps, under the same condition above), all of which are trade names of Daicel Chemical Industries]; carboxyvinyl polymers [e.g., Carbopol 940 (average mol. wt.: ca. 25 x 10<5>; B. F. Goodrich Chemical Co.) and so on.

The preferred is a PEO having an average molecular weight of not less than 2 x 10<6>. Where a continuous release of the drug over a long time, for example more than 12 hours, is required, a polymer having a higher molecular weight, preferably an average molecular weight of not less than 4 x 10<6>, or a higher viscosity, preferably a viscosity of not less than 3000 cps at a concentration of 1% in water at 25 DEG C, is preferable.

The above hydrogel-forming polymer may be used singly, or two or more kind(s) of the above hydrogel-forming polymers in mixture may be used. Or, the mixture of two or more kinds of any polymers, which mixture has characteristics suitable for the present invention, may be suitably used for the present invention.

In order to insure a release of the drug in the human colon, it is necessary that a portion of the preparation having undergone gelation still remain in the colon even as late as at least 6-8 hours, preferably at least 12 hours, after administration.

In order to provide a hydrogel-type preparation having such properties, although it depends on the volume of the preparation, the kind of polymer and the properties and amount of the drug and of the additive for insuring a penetration of water into the preparation core, it is generally preferable that the preparation contains 10-95 weight % (preferably, 15-90 weight %) of the hydrogel-forming polymer based upon the preparation weighing less than 600 mg, and one preparation contains not less than 70 mg per preparation and preferably not less than 100 mg per preparation of the hydrogel-forming polymer. If the amount of this polymer is less than the above- mentioned level, the preparation will not tolerate erosion in the digestive tract for a sufficiently long time and a sufficient sustained release may not be achieved.

Regarding the types and proportions of the hydrophilic base and hydrogel-forming polymer (the latter is hereinafter referred to as hydrogel-forming base), their usefulness has been established by the following experiments.

The liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents. Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.

The compositions of the present invention may also be administered topically or via a suppository.

The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day. Pharmacological Methods

I. In-vitro determination of affinity to CB1/CB2-Receptors

The in-vitro determination of the affinity of the inventive substituted pyrazoline compounds to CBi/CB₂-Rezeptors is carried out as described in the publication of Ruth A. Ross, Heather C. Brockie et al., "Agonist-inverse agonist characterization at CBi and CB₂ cannabinoid receptors of L-759633, L759656 and AM630", British Journal of Pharmacology, 126, 665-672, (1999), whereby the transfected human CBi and CB₂ receptors of Receptor Biology, Inc. are used. The radioligand used for both receptors is [³H]-CP55940. The respective parts of the description is hereby incorporated by reference and forms part of the present disclosure.

II. In-vivo bioassay system for determination of cannabinoid activity

Mouse tetrad model

Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are higly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.

The tetrad model is described, for example, in the publication of A. C. Howlett et al, International Union of Pharmacology XXVII. Classification of Cannabinoid Receptors, Pharmacol Rev 54, 161-202 , 2002 and David R. Compton et al., Jn-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A) inhibition of Tetrahydrocannbinol- induced Responses and Apparent Agonist

Activity", J. Pharmacol. Exp. Ther. 277 , 2, 586-594, 1996. The corresponding parts of the description are hereby incorporated by reference.

Material and Methods

Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.

Before testing in the behavioral procedures given below, mice are acclimatized to the experimental setting. Pre-Treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy. In order to determine the agonistic activty of the substance to be tested, the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.

In order to determine the antagonistic activity the identical procedure is used as for the determination of the agonistic effects, but with the difference that the substance to be evaluated for its antagonistic activity is injectected 5 minutes before the intravenous injection of 1.25 mg/kg Win-55,212 a known cannabinoid-receptor agonist.

Hot plate analgesia

The hot plate analgesia is determined according to the method described in Woolfe D. et al. ,,The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. The respective description is hereby incorporated by reference and forms part of the present disclosure.

The mice are placed on a hot plate (Harvard Analgesi meter) at 55 ± 0.5 ⁰C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B). The maximum time limit the mice are allowed to remain on the hot plate in absence of any painful response is 40 seconds in order to prevent skin damage. This period is called the cut-off time (PC).

Fifteen minuts after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).

The degree of analgesia is calculated from the formula :

% MPE of Analgesia = ( PT- B) / (PC-B) x 100

MPE = Maximum possible effect. Determination of sedation and ataxia

Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. ..Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975. The respective description is hereby incorporated by reference and forms part of the present disclosure.

The chosen scoring system is

0: no ataxia; 1: doubful;

2: obvious calmness and quiet; 3 pronounced ataxia;

prior to as well as after treatment.

The percentage of sedation is determined according to the formula:

% of sedation = arithmetic mean / 3 X 100

Hypothermia:

Hypothermia is determined according to the method described in David R. Compton et al. Jn-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A) Inhibition of Tetrahydrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277 , 2, 586-594, 1996. The respective description is hereby incorporated by reference and forms part of the present disclosure.

The base-line rectal temperatures are determined with a thermometer (YeIIo Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of > -2 ⁰C are considered to represent activity.

Catalepsy:

Catalepsy is determined according to the method described in Alpermann H. G. et al. ..Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is hereby incorporated by reference and forms part of the present disclosure.

The cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.

The chosen scoring system is:

Catalepsy for: more than 60 seconds = 6; 50 -60 seconds = 5, 40-50 seconds = 4, 30-40 seconds = 3, 20-30 seconds = 2, 5-10 seconds = 1 , and less than 5 seconds =0.

The percentage of catalepsy is determined according ot the following formula:

% Catalepsy = arithmetic mean / 6 X 100

III. In vivo testing for antiobesic activity

The in-vivo testing for antiobesic activity of the inventive pyrazoline compounds is carried out as described in the publication of G. Colombo et al., ..Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR 141716"; Life Sciences, 63 (8), 113-117, (1998). The respective part of the description is hereby incorporated by reference and forms part of the present disclosure.

IV. In vivo testing for antidepressant activity

The in-vivo testing for antidepressant activity of the inventive pyrazoline compounds in the water despair test is carried out as described in the publication of ET. Tzavara et al., ,,The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions"; Br. J. Pharmacol. 2003, 138(4):544:53. The respective part of the description is hereby incorporated by reference and forms part of the present disclosure.

The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

V. In-vivo testing for regulation of triglycerides in blood plasma The study was done using six weeks old male mice B6 Lep ob/ob, obtained from Charles River (France). Mice were divided in 3 groups : I (control), Il (vehicle), III (example 18).

Group I: The animals of the group I received the standard diet (D-12450B, Research

Diets, NJ, USA).

Group II: The animals of the groups Il and III were fed with a High Fat Diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).

Group III: The animals of the groups III were fed with a High Fat Diet (D-12492,

Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).

At the end of the feeding period of 7 weeks, it was started the treatment period (14 days): Group Il mice received the vehicle (10 ml/kg/day, po, of the aqueous solution of acacia gum, 5% W/V). Group III was administered with 30 mg/kg/day, po, of the inventive compound 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4,5-dihydro-pyrazole- 3-carboxylic acid according to Example 18. Group I didn't received any treatment. The three groups of mice had the same diet than in the previous period. At the end of the 14 days period of treatment, the blood levels of triglicerides of the animals were determined.

The analysis of the whole blood samples was done using test strips "Lipid panel" and the photometric Analyzer Cardio-Check Test System, from PA Instruments Polymer Technology Systems Indianapolis, IN-46268, USA (Distributed in Spain by Novalab lberica S.A.L, Madrid, Spain). Examples:

Example 1 :

1 mg Gelatin Capsule

A gelatin capsule prepared by wet granulation and having the following composition: Internal phase

N-piperidinyl-δ^-chloro-phenylJ-i^^-dichlorophenylH.δ-dihydro-I H-pyrazole-S- carboxamide 1 mg corn starch 51 mg

200 mesh lactose monohydrate 103.33mg povidone K 30 4.3mg crosslinked sodium carboxymethyl cellulose 8.5mg

Granulation sodium laurylsulfate 0.17mg purified water QS External phase magnesium stearate 1.7mg For a size 3 white-opaque gelatin capsule completed up to 170mg

Example 2:

10 mg Gelatin Capsule

A gelatin capsule prepared by wet granulation and having the following composition: compound N-[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-4-methyl-phenylsulfonamide 10 mg corn starch 51 mg 200 mesh lactose monohydrate 94.33 mg povidone K 30 4.3 mg crosslinked sodium carboxymethyl cellulose 8.5 mg

Granulation sodium laurylsulfate 0.17 mg purified water QS

External phase magnesium stearate 1.7 mg

For a size 3 white-opaque gelatin capsule completed up to 170 mg

Example 3:

30 mg Gelatin Capsule

A gelatin capsule prepared by wet granulation and having the following composition: compound 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carboxylic acid diethylamide 30 mg corn starch 51 mg

200 mesh lactose monohydrate 74.33 mg povidone K 30 4.3 mg crosslinked sodium carboxymethyl cellulose 8.5 mg Granulation sodium laurylsulfate 0.17 mg purified water QS External phase magnesium stearate 1.7 mg

For a size 3 white-opaque gelatin capsule completed up to 170 mg

Example 4:

30 mg Gelatin Capsule

A gelatin capsule prepared by wet granulation and having the following composition: compound [5-(4-Chloro-phenyl)-1-(2_I4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazol- 3-yl]-piperidin-1-yl-methanone 30 mg corn starch 51 mg

200 mesh lactose monohydrate 73.65 mg povidone K 304.3 mg crosslinked sodium carboxymethyl cellulose 8.5 mg Granulation sodium laurylsulfate 0.85 mg purified water QS

External phase magnesium stearate 1.7 mg For a size 3 white-opaque gelatin capsule completed up to 170 mg

Example 5:

1 mg tablet

compound 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carboxylic acid diethylamide 1 mg corn starch 50 mg

200 mesh lactose monohydrate 130 mg 6 cP hydroxypropyl methyl cellulose 6 mg crosslinked sodium carboxymethyl cellulose 10 mg Granulation sodium laurylsulfate 1 mg purified water QS External phase magnesium stearate 2 mg For a tablet completed up to 200 mg

Example 6:

10 mg tablet

Internal phase compound 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carboxylic acid diethylamide 10 mg corn starch 50mg

200 mesh lactose monohydrate 211.5 mg

6 cP hydroxypropyl methyl cellulose 9 mg sodium carboxymethyl starch 15 mg sodium laurylsulfate 1.5 mg

Granulation purified waterQS

External phase magnesium stearate 3 mg

For a tablet completed up to 300 mg

Example 7:

30 mg tablet

Internal phase compound N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4.5- dihydropyrazole-3-carboxamide 30 mg corn starch 80 mg

200 mesh lactose monohydrate 252 mg povidone K 30 12 mg crosslinked sodium carboxymethyl cellulose 20 mg sodium laurylsulfate 2 mg

Granulation purified water QS

External phase magnesium stearate 4 mg For a tablet completed up to 400 mg

Example 8

Pellets

In 580 g of deionized water, 75 g of 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5- dihydro-1 H-pyrazole-3-carboxylic acid-[1 ,2,4]triazol-4-yl amide (10.6%) and 70 g of hydroxypropylmethylcellulose, 20 mg crosslinked sodium carboxymethyl cellulose (2.8%) and 1 mg sodium laurylsulfate (0.14%) are dispersed. 490 g of inert uniform sugar/starch spheres (composition according to US pharmacopoeia) are introduced into a fluidized bed apparatus and the previous obtained dispersion is sprayed on the spheres. After spraying, the spheres are dried before applying the second layer. In 350 g of deionized water, 52 g of hydroxypropylmethylcellulose and 7 g of titanium dioxide are dispersed and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous step. After spraying, the spheres are dried before applying the third enteric coating layer.

In 280 g of deionized water, 290 g of a USP methacrylic acid copolymer (type C aqueous suspension), 13 g of triethylcitrate and 38,5 g of talc are dispersed, and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous step. After applying this final enteric coating layer the spheres (pellets) are dried.

Example 9 In a solvent mixture (dichloromethane-methanol) were dissolved 5-(4-Chloro-phenyl)- 1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid-[1 ,2,4]triazol-4-yl amide (CPTA), Tween 80 and CMEC and the solution was spray-dried using a spray dryer. The dried mixture was blended with POLYOX303 and the resulting composition was compression-molded using an oil press at a compression pressure of 0.8 ton/punch to provide tablets (SR) each measuring 8.0 mm in diameter and weighing 171.6 mg (CPTA content: 65 mg). Separately, CPTA and TC-5E were dissolved in a solvent mixture (dichloromethane-methanol) and using a Hi-Coater, this immediate-release component (QR; CPTA: 15 mg) was coated on the SR (CPTA: 65 mg) component to provide tablets each weighing 194.1 mg (CPTA: 80 mg).

Example 10

30 mg tablet

Internal phase

5-(4-chloro-phenyl)-1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazol-3-carboxylic acid 30 mg corn starch 80 mg

Granulation purified water QS

External phase magnesium stearate 4 mg For a tablet completed up to 400 mg Example 11 :

N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-clihyclro-1H-pyrazole-3- carboxamide a) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid

In a three neck flask p-chlorobenzaldehyde (13,3 g, 95 mmoles) and ethyl pyruvate (10 g, 86 mmoles) were dissolved in 150 ml of absolute ethanol.The solution was ice- cooled to 0⁰C and an aqueous solution of NaOH (3.8 g in 45 mL water) was added dropwise keeping the temperature below or equal to 10⁰C, whereby a yellow-orange colored precipitate was formed. The reaction mixture was stirred for 1 hour at 0⁰C and an additional 1.5 hours at room temperature (approximately 25 ⁰C). Afterwards the reaction mixture was cooled down to approximately 5°C and the insoluble sodium salt of 4-(4-chlorophenyl)-2-oxo-3-butenoic acid was isolated by filtration. The filtrate was left in the refrigerator overnight, whereby more precipitate is formed, which was filtered off, combined with the first fraction of the salt and washed with diethyl ether. The sodium salt of 4-(4-chlorophenyl)-2-oxo-3-butenoic acid was then treated with a solution of 2N HCI, stirred for some minutes and solid 4-(4- chlorophenyl)-2-oxo-3-butenoic acid was separated via filtration and dried to give 12.7 g of the desired product (70% of theoretical yield). IR (KBr, cm^"1 ) : 3500-2500, 1719,3, 1686,5, 1603,4, 1587,8, 1081 ,9. ¹H NMR(CDCI₃, D) : 7,4 (d, J=8,4Hz, 2H), 7,5 (d, J=16,1 Hz, 1 H), 7,6 (d, J=8,4Hz, 2H), 8,1(d, J=16,1 Hz, 1 H). b) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid

4-(4- chlorophenyl)-2-

oxo-3- butenoic acid obtained according to step a) (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 ⁰C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).

IR (KBr, cm ¹ ) : 3200-2200, 1668,4, 1458, 1251 ,4, 1104,8.

¹H NMR (CDCI₃, D) : 3,3 (dd, 1 H), 3,7 (dd, 1 H), 5,9 (dd, 1 H), 7,09-7,25 (m, 7H).

(c) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride

Under nitrogen atmosphere 5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid (2.5 g,

6.8 mmols) obtained according to step (b) was dissolved in 4 ml_ of in thionyl chloride and heated to reflux for 2.5 hours. The excess thionyl chloride is removed from the reaction mixture under reduced pressure and the resulting crude residue (2.6 g) is used without any further purification.

IR (KBr, cm ¹) : 1732,3, 1700, 1533,3, 1478,1, 1212,9, 826,6. d) N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3- carboxamide [this compound may also be referred to as 5-(4-Chloro-phenyl)-1-(2,4- dichloro-phenyl^.δ-dihydro-I H-pyrazole-S-carboxylic acid piperidin-1-ylamide or as

1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4,5-dihydro-N-(piperidin-1-yl)-1 H-pyrazole-

3-carboxamide]

Under nitrogen atmosphere N-aminopiperidine (0.6 ml_, 5.6 mmoles) and triethylamine (4 ml_) were dissolved in methylene chloride (25 ml_). The resulting mixture was ice-cooled down to 0⁰C and a solution of 5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c) in methylene chloride (15 ml_) was added dropwise. The resulting reaction mixture was stirred at room temperature (approximately 25 ⁰C) overnight. Afterwards the reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, then again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallized from ethanol. The crystallized solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallized product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of N-piperidinyl-5- (4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide having a melting point of 183-186°C. IR (KBr₁ cm ¹) : 3222,9, 2934,9, 1647,4, 1474,7, 1268,3, 815,6.

¹H NMR ( CDCI₃, D) : 1 ,4 (m, 2H), 1,7 (m, 4H), 2,8 (m, 4H), 3,3 (dd, J=6,1 y 18,3Hz, 1 H), 3,7 (dd, J=12,5 and 18,3 Hz, 1H), 5,7 (dd, J=6,1 and 12,5 Hz, 1 H), 7,0-7,2 (m, 6H), 7,4 (s, 1 H). The compounds according to the following examples 12-16 have been prepared analogously to the process described in Example 11. Example 12: δ-^-Chloro-phenyO-i-^^dichloro-phenylH.δ-dihydro-I H-pyrazole-S- carboxylic acid-[1 ,2,4]triazol-4-yl amide Melting point: 134-138 ⁰C. IR (KBr, cm ¹): 3448, 1686, 1477, 1243, 1091, 821.

¹H NMR(CDCI₃, D): 3,1 (dd, J=6,2 and 17,9Hz, 1 H), 3,7 (dd, J=12,3 and 17,9Hz, 1 H), 5,9 (dd, J=6,2 and 12,3 Hz, 1 H), 7,2-7,5 (m, 7H), 8,7 (s, 2H), 12,0 (bs, 1 H). Example 13: 5-(4-Chloro-phenyl)-1-(2_l4-dichloiO-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid-(4-methyl-piperazin-1-yl)-amide hydrochloride Melting point: 150-155⁰C. IR (KBr, cm ¹) : 3433, 1685, 1477, 1296, 1246, 1088, 1014, 825. ¹H NMR (CDCI₃, □): 2,7 (d, J=4,2Hz, 3H), 3,0-3,4 (m, 9H), 3,6 (dd, J=11 ,9 and

17,9 Hz, 1 H), 5,8 (dd, J=5,5 and 11 ,9 Hz, 1 H), 7,1 (d, J=8,4Hz, 2H), 7,25 (2d,

J= 8,4 and 8,7 Hz, 3H), 7,4 (d, J=2,2Hz, 1 H), 7,5 (d, J=8,7Hz, 1H), 9,8 (s, 1 H),

11 ,2 (bs). Example 14:

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carboxylic acid diethylamide

This compound was obtained in form of an oil.

IR (film, cm^'1) : 2974, 1621 , 1471 , 1274, 1092, 820. ¹H NMR (CDCI₃, D): 1 ,2 (m, 6H), 3,3-3,9 (m, 6H), 5,6 (dd, J=5,8 and 11 ,7 Hz,

1 H), 7-7,25 (m, 7H).

Example 15:

[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazol-3-yl]- piperidin-1 -yl-methanone Melting point: 105-110⁰C.

IR (KBr, cm ¹) : 2934, 1622, 1470, 1446, 1266, 1010, 817.

¹H NMR ( CDCI₃, D): 1 ,7 (m, 6H), 3,4 (dd, J=5,7 and 17,9Hz, 1 H), 3,7 (m, 3H),

3,9 (m, 2H), 5,6 (dd, J=6,1 y 11 ,9 Hz, 1 H), 7-7,25 (m, 7H).

Example 16: N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-4-methyl-phenylsulfonamide

This compound was obtained in form of an amorph solid.

IR (KBr, cm ¹) : 1697, 1481 , 1436, 1340, 1169, 1074, 853.

¹H NMR (CDCI₃, D): 2,4 (s, 3H), 3,2 (dd, J=6,6 and 18,3Hz, 1 H), 3,6 (dd, J=12,8 and 18,3Hz, 1 H), 5,8 (dd, J=6,6 and 12,8Hz, 1 H), 7 (d, J=8,2Hz, 2H), 7,2 (s, 1 H), 7,3-7,4

(m, 6H), 8 (d, J=8,1 Hz, 2H), 9 (s, 1 H).

Example 17:

N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydropyrazole-3-carboxamide Under nitrogen gas as an inert atmosphere N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice-cooled to 0 ⁰C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered. The filtered solution was evaporated to dryness and the crude product was purified via column chromatography yielding 78 mg (50 % of theoretical yield) of the N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4.5- dihydropyrazole-3-carboxamide in form of a white solid having a melting point of 115-

120 ⁰C.

IR (KBr, cm ¹): 3202, 1678, 1654, 1474, 1309, 1107.

¹H-NMR (CDCI₃, D): 1.6 (m, 2H), 1.8-2.0 (m, 4H), 2.55 (m, 2H), 3.3 (dd, J = 6.3 Hz and 18.2 Hz, 1 H), 3.7 (m, 3H), 5.8 (dd, J = 6.3 Hz and 12.5, Hz₁ 1 H), 7.0-7.3 (m, 7H), 8.5 (s, 1 H.)

Example 18:

5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid

The preparation of example 18 is already described in example 11 following steps a) and b).

Pharmacological Data:

I. In-vitro determination of affinity to

The affinity of the inventive substituted pyrazoline compounds to CB1/CB2 receptors was determined as described above. Some of the values obtained are given in the following table I:

Table I:

As can be seen from the values given in table 1 the inventive pyrazoline compounds are particularly suitable for regulating the CBrReceptor.

II. In-vivo bioassay system for determination of cannabinoid activity

The determinination of cannabinoid activity in-vivo was determined as described above. Some of the values obtained are given in the following table II:

Table II:

i.v. intravenous A: Hot-Plate test B: Hypothermia C: Catalepsy D: Sedation

As can be seen from the values given in table Il the inventive pyrazoline compounds show an antagonistic effect.

III. In-vivo testing for antiobesic activity

The in-vivo testing for antiobesic activity was carried out as described above, whereby three different groups of 10 rats each were treated as follows:

Group I:

Group was treated with vehicle, namely arabic gum (5 wt.-%) in water.

Group II:

The second group of rats was treated with the inventive compound N-piperidinyl-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide according to Example 11. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (10 mg/kg body weight).

Group III:

The third group of rats was treated with Amphetamine, an active ingredient known to reduce appetite. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (5 mg/kg body weight).

As can be seen from Figure 1 the body weight is lowered due to the administration of the inventive compound according to example 11 and this effect is also observed after the treatment is ended.

Figure 2 shows the reduction of food intake due to the administration of the inventive compound according to example 11. IV. In vivo testing for antidepressant activity

The in-vivo testing for antidepressant activity of the inventive pyrazoline compounds in the water despair test was carried out as described above. In particular, the compound according to example 11 displayed positive effects with respect to immobility time and struggling time.

IV. In-vivo testing for regulation of triglycerides in blood plasma

Compounds according to formulas Il (namely example 18) are inhibitors of high blood levels of triglicerides. This effect has been probed in obese mice fed with high fat diet.

The results obtained were the following :

(*) : p<0.05, Anova followed Bonferroni t-test, compared with Group I. NS : Not significant diference, compared with Group I.

The results showed that Group Il mice receiving high fat diet had significantly higher triglicerides blood levels than the control Group I. But the administration of the compound according to Example 18 (Group III) improved the triglicerides blood levels, which were not different of the levels of the group I, which received standard diet.

Claims

Claims:

1. A pharmaceutical composition for the oral administration comprising at least one compound of formula (I) :

(I)

wherein, R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

with the proviso that R⁴ and R⁵ do not both represent a hydrogen atom, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or a linear or branched, saturated or unsaturated, unsubstituted or substituted aliphatic radical, the other one of these residues R⁴ and R⁵ does not represent an unsubstituted or substituted thiazole group or an unsubstituted or substituted [1 ,3,4]thiadiazole group.

and/or

at least one compound of formula (II),

(H)

wherein

R¹ represents hydrogen or a linear or branched d^-alkyl group,

R² , R³ and R⁴ independently of each other represent hydrogen, a linear or branched Ci-₆-alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^8', SH, SR^8', SOR^8', SO₂R^8',

NH₂, NHR^8', NR⁸ R^9', -(C=O)-NH₂, -(C=O)-NHR^8' or -(C=O)-NR⁸R^9' whereby R^8' and R⁹ for each substituent independently represent linear or branched Ci_-6 alkyl,

R⁵ and R⁶ independently of each other represent a linear or branched Ci-₆-alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH₁ NO₂, -(C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰R^11', - (C=O)-NH₂, -(C=O)-NHR^10' and -(C=O)-NR¹⁰ R^11', whereby R^10' and optionally R¹¹ for each substituent independently represent linear or branched Ci-β alkyl;

R⁷ represents hydrogen, a linear or branched d-β-alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, - (C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰ R^11', -(C=O)-NH₂, -(C=O)- NHR^10' and -(C=O)-NR¹⁰R^11', whereby R^10' and optionally R^11' for each substituent independently represent linear or branched Ci_-6 alkyl;

with the proviso that if R¹ and R⁷ are H and R⁵ and R⁶ both represent Cl in the 3- and 4-position of the phenyl ring neither of R² , R³ and R⁴ may represent F in the 4-position of the phenyl ring if the other two of R² , R³ and R⁴ both represent H;

and/or

at least one compound of formula (III)

III

wherein

R¹ represents hydrogen or a linear or branched Ci-4-alkyl group,

R¹², R¹³, R¹⁴ or R¹⁵ independently of each other represent a linear or branched Ci-6-alkyl group, a linear or branched

group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, SH, NH₂, hydrogen, methyl, ethyl, F, Cl, Br and CF₃, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,

characterized in that the pharmaceutial composition is in any of the following pharmaceutical forms (a), (b), (c), (d), or (e) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients; or b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer; or c) at least one additive which insures a penetration of water into the core of the preparation and at least one hydrogel forming polymer; or d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients; or e) an inert core, with (aa) a first layer containing a compound of formula (I), (II), or (III), and optionally an inert water soluble polymer and optionally one or more pharmaceutical acceptable excipients;

2. A pharmaceutical composition according to claim 1 , characterized in that the composition comprises at least one compound of formula (I).

3. A pharmaceutical composition according to claim 2, characterized in that the compound of formula (I) is a compound wherein: wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

with the following provisos:

4. A pharmaceutical composition according to claims 2 or 3, characterized in that the compound of formula (I) is a compound wherein:

(0

wherein,

R³ represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an -NR⁴R⁵-moiety, R⁴ represents a hydrogen atom or a linear or branched d-β-alkyl group,

R⁵ represents a linear or branched Ci_-6 alkyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, whereby each of the heterocyclic rings may be substituted with one or more, identical or different, d-β-alkyl groups, or an -SO2- R⁶-moiety, and

R⁶ represents a phenyl group, which is optionally substituted with one or more

Ci-₆ alkyl groups, which may be identical or different, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and

0.05% to 0.5% by weight of the active principle of at least one surfactant and optionally one or more additional pharmaceutical excipients.

5. A pharmaceutical composition according to claims 2, 3 or 4, characterized in that the compound of formula (I) is a compound selected from:

• N-piperidinyl-5-(4-chloro-phenyl)-1-(2_l4-dichlorophenyl)-4,5-dihydro-1 H- pyrazole-3-carboxamide,

• 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carboxylic acid-[1 ,2,4]-triazole-4-yl-amide,

• 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydiO-1 H-pyrazole-3- carboxylic acid-(4-methyl-piperazin-1-yl)-amide,

• 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carboxylic acid diethylamide, • [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-yl]- piperidine-1 -yl-methanone,

• N-[5-(4-Chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-4-methylphenylsufonamide,

6. A pharmaceutical composition according to claim 1 , characterized in that the composition comprises at least one compound of formula (II),

wherein

R¹ represents hydrogen or a linear or branched Ci-4-alkyl group,

R² , R³ and R⁴ independently of each other represent hydrogen, a linear or branched d-β-alkyl group, a linear or branched d-e-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^8', SH, SR^8', SOR^8', SO₃R⁸¹T NH₂, NHR^8', NR⁸ R^9', -(C=O)-NH₂, -(C=O)-NHR^8' or -(C=O)-N R⁸R^9' whereby R^8' and R⁹ for each substituent independently represent linear or branched Ci_-6 alkyl,

R⁵ and R⁶ independently of each other represent a linear or branched d-β-alkyl group, a linear or branched Ci_₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, -(C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰R^11', - (C=O)-NH₂, -(C=O)-NHR^10' and -(C=O)-NR¹⁰R^11', whereby R^10' and optionally R¹¹ for each substituent independently represent linear or branched Ci-β alkyl;

R⁷ represents hydrogen, a linear or branched Ci-β-alkyI group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, - (C=O)-R^10', SH, SR^10', SOR^10', NH₂, NHR^10', NR¹⁰ R^11', -(C=O)-NH₂, -(C=O)- NHR^10' and -(C=O)-NR¹⁰R^11', whereby R^10' and optionally R^11' for each substituent independently represent linear or branched Ci_-6 alkyl;

7. A pharmaceutical composition according to claim 1 , characterized in that the composition comprises at least one compound of formula (III)

II

wherein

R¹ represents hydrogen or a linear or branched

group,

R¹², R¹³, R¹⁴ or R¹⁵ independently of each other represent a linear or branched d-β-alkyl group, a linear or branched Ci-₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH, NO₂, SH, NH₂, hydrogen, methyl, ethyl, F, Cl, Br and CF₃..

8. A pharmaceutical composition according to claim 7, characterized in that the compound of formula (III) is selected from:

9. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in any of the following pharmaceutical forms (a), (b), (d), or (e) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients; or b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer; or d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients; or e) an inert core, with

10. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in the pharmaceutical form (a) and thus comprises: a) 0.05% to 0.5% by weight of the active principle of a surfactant and optionally one or more additional pharmaceutical excipients.

11 A pharmaceutical composition according to claim 10 which comprises: 0.5% to 40% by weight of compound of formula (I), (II) or (III)

12. A pharmaceutical composition according to claim 10 which contains: 0.5% to 40% by weight of compound of formula (I), (II) or (III)

0.1% to 0.4% by weight of sodium laurylsulfate, 5% to 8% by weight of crosslinked sodium carboxymethyl cellulose, 1 % to 10% by weight of binder, 0.2% to 5% by weight of lubricant, and a diluent in a sufficient amount for 100%.

13. A pharmaceutical composition according to any one of claims 10 to 12 wherein the surfactant is added to the purified water in the process.

14. A pharmaceutical composition according to any one of claims 10 to 13 in the form of capsules, pellets, granules, tablets, sachets, powders, caplets, gels, multiparticulates such as granules, pellets, multipaticles, and the like, optionally compressed into tablets or filled into capsules.

15. A pharmaceutical composition according to claims 10 to 14 in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase compound of formula (I), (II) or (III) corn starch 30%

200 mesh lactose monohydrate 60.78% povidone K 302.53% crosslinked sodium carboxymethyl cellulose 5%

Granulation sodium laurylsulfate 0.1% water QS

External phase magnesium stearate 1%

16. A pharmaceutical composition according to claims 10 to 14 in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase compound of formula (I), (II), (III) corn starch 30%

200 mesh lactose monohydrate 55.49% povidone K 302.53% crosslinked sodium carboxymethyl cellulose 5% Granulation sodium laurylsulfate 0.1% water QS

External phase magnesium stearate 1%

17. A pharmaceutical composition according to claim 10 to 14 in the form of a gelatin capsule and having the following formulation, expressed in percentages by weight:

Internal phase compound of formula (I), (II) or (III) corn starch 30%

200 mesh lactose monohydrate 43.73% povidone K 30 2.53% crosslinked sodium carboxymethyl cellulose 5%

Granulation sodium laurylsulfate 0.1 % water QS

External phase magnesium stearate 1%

18. A process for the preparation of a pharmaceutical composition according to any one of claims 10 to 17, characterised in that: a) the active principle according to formula I, Il or III and the surfactant are mixed at room temperature optionally with a diluent, a binder and/or a coloring agent; b) the mixture is wetted with purified water; c) the resulting wet mass is dried and graded; and optionally d) a lubricant and, an antiadhesive, a flowing agent, a coloring agent and/or a flavoring agent are added to the resulting graded dry grains.

19.A process according to claim 18 for the preparation of a pharmaceutical composition according to any one of claims 1 to 10, characterised in that the surfactant is incorporated in step b) instead of in step a).

20. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in the pharmaceutical form (b) and thus comprises: b) an additive which insures a penetration of water into the core of the preparation and a controlled release polymer.

21. A controlled release formulation according to claim 20 wherein the controlled release polymer is a sustained release polymer.

22. A controlled release formulation according to claim 21 wherein the sustained release polymer is based on a soluble polymer.

23. A controlled release formulation according to claim 21 wherein the sustained release polymer is based on an insoluble polymer.

24. A controlled release formulation according to claim 22 or 23 wherein the sustained release polymer is based on a matrix-forming polymer.

25. A controlled release formulation according to claim 23 wherein the insoluble polymer is based on alkylcellulose, preferably ethylcellulose.

26. A controlled release formulation according to claim 22 wherein the soluble polymer is based on a cellulose derivative.

27. A controlled release formulation according to claim 26 wherein the cellulose derivative is hydroxypropylmethylcellulose or hydroxypropylcellulose.

28. A controlled release formulation according to claim 24 wherein the matrix-forming polymer is based on a hydrogel-forming polymer.

29. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in the pharmaceutical form (c) and thus comprises: c) at least one additive which insures a penetration of water into the core of the preparation and at least one hydrogel forming polymer.

30. A hydrogel-type sustained-release preparation according to claim 29 comprising (1 ) at least one compound of formula I, Il or III, (2) at least one additive which insures a penetration of water into the core of the preparation and (3) at least one hydrogel forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.

31 The hydrogel-type sustained-release preparation according to claim 30, wherein said additive which insures a penetration of water into the core of the preparation is at least one additive having a solubility that the volume of water required for dissolving 1 gram of said additive is not more than 5 ml.

32. The hydrogel-type sustained-release preparation according to claim 31 , wherein said additive which insures a penetration of water into the core of the preparation is at least one additive having a solubility that the volume of water required for dissolving 1 gram of said additive is not more than 4 ml.

33. The hydrogel-type sustained-release preparation according to claim 29, wherein said hydrogel-forming polymer is either a polymer having an average molecular weight of not less than 2,000,000 or a polymer having a viscosity of not less than 1000 cps as measured at 1% concentration in water at 25 DEG C, or a mixture of two or more of these polymers.

34. The hydrogel-type sustained-release preparation according to claim 29, wherein said hydrogel-forming polymer includes at least one polyethylene oxide.

35. The hydrogel-type sustained-release preparation according to any one of claims

29 to 36, which comprises (1) at least one compound of formula I, II, III in an amount of not more than 85% by weight based on the total preparation, (2) at least one additive which insures a penetration of water into the core of the preparation in an amount of from 5 to 80% by weight based on the total preparation, and (3) at least one hydrogel-forming polymer in an amount of from 10 to 95% by weight based on the total preparation.

36. The hydrogel-type sustained-release preparation according to any one of claims 29 to 35, which comprises (1 ) at least one compound of formula I, II, III in an amount of not more than 80% by weight based on the total preparation, (2) at least one additive which insures a penetration of water into the core of the preparation in an amount of from 5 to 60% by weight based on the total preparation, and (3) at least one hydrogel-forming polymer in an amount of from 15 to 90% by weight based on the total preparation.

37. A controlled release formulation according to claim 20 wherein the release of the active principle is controlled by pH.

38. A controlled release formulation according to claim 37 wherein the release of the active substance is controlled by a polymer whose dissolution is pH dependent.

39. A controlled release formulation according to claim 38 wherein the polymer is a gastric resistant polymer such as a co-polymerized methacrylic acid / methacrylic acid methyl esters.

40. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in the pharmaceutical form (d) and thus comprises: d) a nucleus formed by an inert core, an inert water soluble polymer and optionally pharmaceutical acceptable excipients.

41. A preparation according to claim 40 wherein the water soluble polymer comprises hydroxypropylmethylcellulose or hydroxypropylcellulose.

42. A preparation according to claim 40 which is enteric coated.

43. A pharmaceutical composition according to claim 1 , characterized in that the pharmaceutial composition is in the pharmaceutical form (e) and thus comprises: e) an inert core, with

44. A formulation according to claim 43 wherein the release of the active substance is controlled.

45. A formulation according to claim 44 wherein the controlled release is pH- dependent.

46. A formulation according to claim 45 wherein the pH-dependent controlled release is insured by an enteric polymer.

47. A formulation according to claim 46 wherein the enteric polymer is a gastric resistant polymer such as co-polymerized methacrylic acid / methacrylic acid methyl esters.

48. A formulation according to claim 44 wherein the controlled release formulation is a sustained release formulation.

49. A pharmaceutical composition for oral administration of a compound of formula

(I), (II) or (III) or a mixture thereof, for adminsitration in form of caplets, gels, multiparticulates such as granules, pellets, multiparticles, and the like, optionally compressed into tablets or filled into capsules.