Patent Application
20080161338
The invention relates to novel pyrrolodihydroisoquinoline derivatives, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
The International applications WO 02/48144, WO 03/014115, WO 03/014116, WO 03/014117 and WO 03/051877 disclose pyrrolodihydroisoquinoline derivatives with PDE10 inhibitory activity useful in cancer therapy.
The European application EP 1250923 discloses the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.
Additionally, the US applications US 2003/0008806, US 2003/0018047, US 2003/032579, US 2004/162293 and US 2004/162294 likewise disclose the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.
Yet additionally, the WO application WO 03/093499 also disclose the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.
The WO application WO 2005/120514 disclose methods to decrease body weight and/or body fat in animals, methods to treat non-insulin dependent diabetes (NIDDM), metabolic syndrome or glucose intolerance by administering a PDE10 inhibitor.
The WO application WO 2005/012485 relates to the treatment of diabetes, including type 2 diabetes, by administration of a PDE10 inhibitor.
The U.S. Pat. No. 5,965,575 discloses pyrrolodihydroisoquinoline derivatives as 5HT1B antagonists.
The International application WO 03/000269 disclose the use of PDE10A inhibitors for the treatment of neurodegenerative diseases, especially Parkinson's disease.
The International application WO 2005/003129 relates to pyrrolodihydroisoquinoline derivatives, which are efficacious inhibitors of PDE10.
The International application WO 2005/002579 relates to the use of a pyrrolo[2.1-a]isoquinoline structure-element as an integral part of the overall structure of compounds, which inhibit PDE10.
It has now been found that the pyrroloisoquinoline derivatives, which are described in greater details below, differ from prior art compounds by unanticipated structural features and have surprising and particularly advantageous properties.
The invention thus relates to compounds of formula I
in which
1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals.
2-4C-Alkyl represents a straight-chain or branched alkyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl radical.
1-6C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are the hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
1-4C-Alkylthio represents radicals which, in addition to the sulfur atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the ethylthio and the methylthio radicals.
2-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy radical.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the 3-7C-cycloalkylethyl radicals (e.g. the cyclohexylethyl radical), or the 3-7C-cycloalkylmethyl radicals (such as e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl, of which cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl are preferred).
As completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals may be mentioned. “Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy radicals are replaced by fluorine atoms.
1-4C-Alkoxy-2-4C-alkoxy represents one of the abovementioned 2-4C-alkoxy radicals, which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the 2-methoxyethoxy, 2-ethoxyethoxy and the 2-isopropoxyethoxy radicals.
1-4C-Alkoxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkyl radicals, which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the 2-methoxyethyl and the 2-isopropoxyethyl radicals.
1-4C-Alkoxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the 2-methoxyethyl and 2-isopropoxyethyl radicals.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy [—O—CH2—O—] and the ethylenedioxy [—O—CH2—CH2—O—] radicals.
As completely or predominantly fluorine-substituted 1-2C-alkylenedioxy bridge, for example, the difluoromethylenedioxy [—O—CF2—O—] radical may be mentioned. “Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-4C-alkylenedioxy radical are replaced by fluorine atoms.
Phenyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by a phenyl radical. Examples which may be mentioned are the phenethyl and the benzyl radicals.
1-4C-Alkoxycarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl and ethoxycarbonyl radicals.
1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
1-4C-Alkylene is a straight-chain alkylene radical such as, for example, the methylene (—CH2—) or, particularly, the trimethylene (—CH2—CH2—CH2—) or the tetramethylene (—CH2—CH2—CH2—CH2—) radical.
Halogen within the meaning of the invention is bromine and, preferably, chlorine and fluorine.
Hydroxy-2-4C-alkyl stands for one of the abovementioned 2-4C-alkyl radicals which is substituted by a hydroxyl group. Examples which may be mentioned are the 2-hydroxyethyl and 3-hydroxypropyl radicals.
Hydroxy-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxy radicals which is substituted by a hydroxyl group. Examples which may be mentioned are the 2-hydroxyethoxy and 3-hydroxypropoxy radicals.
Amino-2-4C-alkyl stands for one of the abovementioned 2-4C-alkyl radicals which is substituted by an amino group. Examples which may be mentioned are the 2-aminoethyl and 3-aminopropyl radicals.
Amino-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxy radicals which is substituted by an amino group. Examples which may be mentioned are the 2-aminoethoxy and 3-aminopropoxy radicals.
In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicals contain one or two of the abovementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is to be emphasized and here, in particular, dimethyl-, diethyl- and diisopropylamino.
Mono- or Di-1-4C-alkylamino-2-4C-alkyl stands for one of the abovementioned 2-4C-alkyl radicals which is substituted by one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the 2-dimethylaminoethyl and 3-dimethylaminopropyl radicals.
Mono- or Di-1-4C-alkylamino-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxy radicals which is substituted by one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the 2-dimethylaminoethoxy and 3-dimethylaminopropoxy radicals.
1-4C-Alkylsulfonyl is a sulfonyl group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example is the methanesulfonyl radical (CH3SO2—).
1-4C-Alkylsulfonylamino is an amino group which is substituted by one of the abovementioned 1-4C-alkylsulfonyl radicals. An example is the methanesulfonylamino radical (CH3SO2NH—).
Aryl radicals referred to herein, including those forming part of other groups or radicals, include phenyl or R711-substituted phenyl radicals.
Aryloxy stands for phenoxy or R711-substituted phenoxy.
Aryl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxy radicals, which is substituted by one of the abovementioned aryl radicals. Examples which may be mentioned are the 2-arylethoxy (e.g. phenethoxy) and the arylmethoxy (e.g. benzyloxy) radicals.
Aryloxy-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxy radicals, which is substituted by one of the abovementioned aryloxy radicals. An example which may be mentioned is the 2-aryloxyethoxy (e.g. 2-phenoxyethoxy) radical.
Aryloxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned aryloxy radicals. Examples which may be mentioned are the 2-aryloxyethyl (e.g. 2-phenoxyethyl) and the aryloxymethyl (e.g. phenoxymethyl) radicals.
Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropylaminocarbonyl radical.
Het1 refers to a 5- to 7-membered saturated heterocyclic ring radical comprising one nitrogen atom, to which R611 and R612 are bound, and, optionally, one further heteroatom selected from a group consisting of nitrogen, oxygen and sulfur, and optionally substituted by R613 on a ring nitrogen atom. Examples for Het1 include e.g. piperidin-1-yl, 4-methyl-piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, piperazin-1-yl, imidazolidin-1-yl, thiomorpholin-4-yl, homopiperidin-1-yl, homopiperazin-1-yl, 4-N-(1-4C-alkyl)-homopiperazin-1-yl or piperazinyl substituted on a ring nitrogen atom by R613 [4-N—(R613)-piperazin-1-yl] such as, for example, 4-N-(1-4C-alkyl)-piperazin-1-yl, 4-N-(hydroxy-2-4C-alkyl)-piperazin-1-yl, 4-N-(dimethylamino-2-4C-alkyl)-piperazin-1-yl, 4-N-(3-6C-cycloalkyl)-piperazin-1-yl, 4-N-formyl-piperazin-1-yl, 4-N-(pyridin-4-yl)-piperazin-1-yl, 4-N-(pyrimidin-2-yl)-piperazin-1-yl or 4-N-(3-6C-cycloalkylmethyl)-piperazin-1-yl.
Har refers to a monocyclic or fused bicyclic 5- to 10-membered partially or fully aromatic heterocyclic ring or ring system comprising one to four, particularly one to three, heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulphur.
The Har radical is bonded via a ring carbon atom to the adjacent pyrroloisoquinoline scaffold.
In one embodiment (embodiment a) Har refers to a monocyclic 5-membered fully aromatic heteroaryl radical comprising one to four heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulphur,
Exemplary Har radicals according to embodiment a may include, without being restricted to, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl or oxadiazolyl.
In another embodiment (embodiment b) Har refers to a monocyclic 6-membered fully aromatic heteroaryl radical comprising one or two nitrogen atoms.
Exemplary Har radicals according to embodiment b may include pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.
A Har radical according to embodiment a worthy to be mentioned is pyridinyl, such as e.g. pyridin-4-yl.
In another embodiment (embodiment c) Har refers to a fused bicyclic 9- or 10-membered fully aromatic heteroaryl radical comprising one to four, in particular one to three, in more particular one or two, heteroatoms, each of which is selected from a group consisting of nitrogen, oxygen and sulphur.
Exemplary Har radicals according to embodiment c may include, without being restricted to, the benzo-fused analogues of the Har radicals mentioned exemplarily above in embodiment a or b, such as, for example, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, indazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzothiazolyl or benzimidazolyl; or naphthyridinyl, phthalazinyl, imidazopyridinyl, purinyl, pteridinyl or imidazopyridazinyl.
The Har radicals according to embodiment c, which contain a benzene ring, can be attached to the parent molecular group via any ring carbon atom of the heteroatom containing ring or of the benzene ring.
Har radicals according to embodiment c worthy to be mentioned are indolyl, benzothiophenyl, or quinolinyl, such as e.g. indol-3-yl, benzothiophen-3-yl, or quinolin-4-yl.
In another embodiment (embodiment d) Har refers to a bicyclic partially aromatic heterocyclic radical made up of
Exemplary Har radicals according to embodiment d may include, without being restricted to, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzofuranyl, or chromanyl.
In another embodiment (embodiment e) Har refers to a stabile N-oxide derivative of any nitrogen-containing heteroaryl ring, particularly of any imino type nitrogen (═N—) containing heteroaryl ring, according to embodiment a or b.
Exemplary Har radicals according to embodiment d may include, without being restricted to, N-oxy-pyridinyl.
A Har radical according to embodiment c in particular worthy to be mentioned is 1N-oxy-pyridin-4-yl.
Naphthyl includes naphthalen-1-yl and naphthalen-2-yl.
N-(1-4C-alkyl)-piperazinyl stands for the piperazin-1-yl radical substituted by one of the abovementioned 1-4C-alkyl radicals on the 4N ring nitrogen atom.
The heterocyclic rings mentioned herein include, unless otherwise noted, all the possible isomeric forms thereof. Thus, for example, the heterocyclic rings mentioned herein include possible tautomers and the positional isomers thereof (such as e.g. the term pyridyl or pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl).
Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, at any possible position.
The substituents R1, R2 and/or R3 may be attached, unless otherwise noted, at any position of the benzo moiety of the pyrrolodihydroisoquinoline ring.
The given heterocyclic rings may be substituted, unless otherwise noted, by their substituents as mentioned herein at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom.
Heteroaryl rings containing imino-type ring nitrogen atoms (—N═) may be preferably not substituted (i.e. quaternized) on these imino-type ring nitrogen atoms by the mentioned substituents.
The substituents R71, R72 and/or R73 of the compounds according to this invention can be each attached in the ortho, meta or para position with respect to the binding position in which the phenyl ring is bonded to the pyrrolo moiety of the pyrrolodihydroisoquinoline ring, whereby in an embodiment of the present invention the attachment in the meta or in para position is to be emphasized.
When any variable occurs more than one time in any constituent, each definition is independent.
Suitable salts for compounds of the formula I—depending on substitution—are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-insoluble and, particularly, water-soluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation—depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases are—depending on substitution—also suitable. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of the compounds of formula I according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
According to expert's knowledge the compounds of formula I of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
Depending on substitution the compounds of formula I can be chiral compounds having, for example, chiral centers and/or chiral axes due to hindered rotation about single bonds. Chiral axes can be present in particular in those compounds according to the invention, in which R7 is a bicyclic ring, or a monocyclic ring substituted in the ortho position with respect to the binding position in which said monocyclic ring is bonded to the pyrrolo[2.1-a]isoquinoline ring system. Chiral centers can be, for example, -depending on the meaning of R4, R41, R5 and R51-located at position 5 and/or 6 of the pyrrolo[2.1-a]isoquinolin scaffold. The invention therefore includes all conceivable pure diastereomers and pure enantiomers and mixtures thereof in any mixing ratio including the racemates, as well as the salts thereof. The diastereomer mixtures can be separated into the individual isomers by standard methods, e.g. by chromatographic processes. The enantiomers can be separated in a known manner (e.g. by chromatographic processes on chiral phases or by resolution).
Therefore, e.g. the pure (5R)- and the pure (5S)-enantiomers, as well as mixtures thereof in any mixing ratio including the racemates, and the salts thereof, are part of this invention.
Compounds according to the present invention more worthy to be mentioned are those compounds of formula I,
in which
Compounds according to the present invention further more worthy to be mentioned are those compounds of formula I,
in which
Yet compounds according to the present invention further more worthy to be mentioned are those compounds of formula I,
in which
Compounds according to the present invention in particular worthy to be mentioned are those compounds of formula I,
in which
Yet compounds according to the present invention in particular worthy to be mentioned are those compounds of formula I,
in which
Compounds according to the present invention in more particular worthy to be mentioned are those compounds of formula I,
in which
Yet compounds according to the present invention in more particular worthy to be mentioned are those compounds of formula I,
in which
As exemplary compounds according to the present invention the following compounds of formula Ia
in which
As further exemplary compounds according to the present invention the following compounds of formula Ia
in which
As further exemplary compounds according to the present invention the following compounds of formula Ia
in which
Particular exemplary compounds according to the present invention may include, without being restricted thereto, any compound selected from
A special interest in the compounds according to this invention refers to those compounds of formula I which are included—within the scope of this invention—by one or, when possible, by more of the following special embodiments:
A special embodiment (embodiment 1) of the compounds according to this invention refers to those compounds of formula I, in which
none of R1, R2 and R3 is bound to the 10-position of the pyrrolo[2.1-a]isoquinoline ring.
Another special embodiment (embodiment 2) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 3) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 4) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 5) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 6) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 7) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 8) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 9) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 10) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 11) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 12) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 13) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 14) of the compounds according to this invention refers to those compounds of formula I, in which
Another special embodiment (embodiment 15) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 16) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 17) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 18) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 19) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 20) of the compounds according to the present invention refers to those compounds of formula I,
in which
Another special embodiment (embodiment 21) of the compounds according to this invention refers to those compounds of formula Ia
in which
Another special embodiment (embodiment 22) of the compounds according to this invention refers to those compounds of formula Ia as shown above, in which
It is to be understood that the present invention includes any or all possible combinations and subsets of the special embodiments defined hereinabove.
The compounds according to the present invention can be prepared as specified as follows, or in a manner described in the following examples, or according to art-known procedures, or analogously or similarly thereto.
As shown in reaction scheme 1, compounds of formula I, in which R1, R2, R3, R4, R41, R5, R51, R6, R7 and R8 have the meanings given above, and Het4 is an oxazolyl radical, can be obtained from corresponding amides of formula II by a cyclization reaction using compounds of formula III, in which R81 has the meanings given above and X is a suitable leaving group, such as e.g. bromine or, particularly, chlorine. This cyclization reaction can be carried out as it is known for the skilled person, or as described by way of example in the following examples, or analogously or similarly thereto.
As shown in reaction scheme 2, compounds of formula I, in which R1, R2, R3, R4, R41, R5, R51, R6, R7 and R8 have the meanings given above, and Het4 is an [1,2,4]oxazol-5-yl radical, can be obtained from corresponding ester compounds, particularly the methyl ester compounds of formula IV by a cyclization reaction using compounds of formula Va or Vb, in which R81 has the meanings given above, or a mixture of both. This cyclization reaction can be carried out as it is known for the skilled person, or as described by way of example in the following examples, or analogously or similarly thereto.
As shown in reaction scheme 3, compounds of formula I, in which R1, R2, R3, R4, R41, R5, R51, R6, R7 and R8 have the meanings given above, and Het4 is an [1,2,4]oxazol-3-yl radical, can be obtained from corresponding nitrile compounds of formula VI by reaction with hydroxylamine, acylation of the intermediate amidoxime using an activated carboxylic acid derivative of the formula R81C(O)Y, in which Y is a suitable leaving group, such as e.g. chlorine or an acyloxy leaving group (e.g. the R81C(O)—O— radical), and, finally, cyclization. In the case, if an anhydride of the formula R81C(O)Y, such as e.g. acetanhydride, is used, acylation and cyclization can be obtained in one step. The reaction steps mentioned can be carried out as it is known for the skilled person, or as described in J. Med. Chem. 1986, 29, 2174-2183, the disclosure of which is incorporated herein, or analogously or similarly thereto.
Compounds of formulae III, Va, Vb and R81C(O)Y are commercially available or can be obtained in a manner known to the skilled person from his/her expert knowledge and/or from literature.
The compounds of formula IV and VI can be obtained in an art-known manner, or in a manner described and shown as follows, or as disclosed in WO 02/48144, WO 03/014115, WO 03/014116, WO 03/014117 or WO 03/051877 (the disclosure of which is incorporated herein), or as described by way of example in the following examples, or analogously or similarly thereto. As shown in reaction scheme 4, in a first reaction step compounds of formula XIII, in which R1, R2, R3, R4, R41, R5 and R51 have the meanings indicated above, are reacted with compounds of formula XII, in which R′ is cyano or methoxycarbonyl, and L is a suitable leaving group, for example chlorine or an acyloxy radical (e.g. the R′—CH2—C(O)—O— radical), to give in the presence of a suitable organic or inorganic base corresponding compounds of formula XI.
Alternatively, compounds of formula XI are also accessible from compounds of formula XIII, in which R1, R2, R3, R4, R41, R5 and R51 have the meanings indicated above, and compounds of formula XII, in which R′ is cyano or methoxycarbonyl and L is hydroxyl, by reaction with amide bond linking reagents known to the person skilled in the art. Exemplary amide bond linking reagents known to the person skilled in the art which may be mentioned are, for example, the carbodiimides (e.g. dicyclohexylcarbodiimide or, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate), uronium salts [e.g. O′-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate or O-(benzotriazol-1-yl)-N,N,N′,N′tetramethyl-uronium-hexafluorophosphate] and N,N′-carbonyldiimidazole. In the scope of this invention preferred amide bond linking reagents are uronium salts and, particularly, carbodiimides, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
Said reactions are carried out under conditions known to the person skilled in the art or as described exemplarily in the following examples.
As shown in the next step, compounds of the formula IX, in which R1, R2, R3, R4, R41, R5 and R51 have the meanings indicated above and R′ is cyano or methoxycarbonyl, can be obtained by cyclocondensation of corresponding compounds of the formula XI. Said cyclocondensation reaction is carried out in a manner habitual per se to the person skilled in the art or as described by way of example in the following examples, according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing or dehydrating agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, at reduced temperature, or at room temperature, or at elevated temperature or at the boiling temperature of the solvent or condensing agent used.
Compounds of formula IX, in which R1, R2, R3, R4, R41, R5 and R51 have the meanings indicated above and R′ is methoxycarbonyl, are converted either with compounds of formulae VII, in which R7 has the meanings given above, and VIII, in which R6 is 1-6C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxycarbonyl, or with compounds of formula X, in which R7 has the meanings given above and R6 is 1-6C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxycarbonyl, optionally in a one pot synthesis and suitably in the presence of an inorganic or organic base (in particular a cyclic amine, e.g. piperidine) into the corresponding compounds of formula IV. In an analogous manner as described afore, compounds of formula IX, in which R1, R2, R3, R4, R41, R5 and R51 have the meanings indicated above and R′ is cyano, are converted into the corresponding compounds of formula VI.
Said conversion can be carried out as known to the skilled person or as described in the following examples or analogously or similarly thereto.
Compounds of formulae XIII, XII, VIII and VII are commercially available or can be obtained in a manner described in the following example or known to the skilled person from his/her expert knowledge and/or from literature, or analogously or similarly thereto.
Thus, e.g. compounds of formula XIII can be obtained starting from the corresponding benzaldehydes or acetophenons by a Henry reaction using the appropriate nitroalkane (e.g. nitromethane or nitroethane) and subsequent reduction of the nitro group and the double bond in a manner customary per se to the skilled person (using e.g. LiAlH4, see e.g. Zhurnal Organicheskoi Khimii, 1989, 25(7), 1477-82 or J. Org. Chem. 2005, 70(14), 5519-27)), or in analogy to the sequence described in J. Med. Chem. 1987, 30(10), 1914-1918.
The mentioned benzaldehydes and acetophenons are known or can be obtained in analogy to known procedures or as described in the following examples.
Compounds of formula X are known or are accessible by reaction of compounds of formula VII with compounds of formula VIII in the presence of a suitable organic or inorganic base in a manner customary per se to the skilled person.
Compounds of formula II are obtained from corresponding compounds of formula IV by an amidification reaction, which can be carried out analogously to procedures known to the skilled person or as described by way of example in the following examples.
Besides the above-described synthesis route to compounds of formula I, wherein the heterocyclic group attached to the 1-position of the pyrrolo[2.1-a]isoquinoline ring is built up in the final step, in an alternative synthesis rout this heterocyclic group can be built up on a previous stage, e.g. starting from compounds of formula IX.
Compounds of formula I obtained can be converted into further compounds of formula I by methods known to one of ordinary skill in the art. More specifically, for example, from compounds of the formula I, in which
The methods mentioned under a.) to h.) are expediently carried out analogously to the methods known to the person skilled in the art or as described by way of example in the following examples.
Optionally, compounds of the formula I can be converted into their salts, or, optionally, salts of the compounds of the formula I can be converted into the free compounds. Corresponding processes are habitual per se to the skilled person.
It is moreover known to the person skilled in the art that if there are a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in “Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3rd Ed.) or in “Protecting Groups (Thieme Foundations Organic Chemistry Series N Group” by P. Kocienski (Thieme Medical Publishers, 2000).
The isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
Suitably, the conversions mentioned in this invention can be carried out analogously or similarly to methods which are familiar per se to the person skilled in the art.
The person skilled in the art knows on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds of the formula I. All these other possible synthesis routes are also part of this invention.
The present invention also relates to intermediates and methods useful in synthesizing compounds according to this invention.
Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics or embodiments. As will be apparent to persons skilled in the art, modifications, analogies, variations, derivations, homologisations and adaptations to the described invention can be made on the base of the disclosure (e.g. the explicite, implicite or inherent disclosure) of the present invention without departing from the spirit and scope of this invention as defined by the scope of the appended claims.
The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula I, whose preparation is not explicitly described, can also be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.
In the examples, m.p. stands for melting point, h for hour(s), min for minutes, conc. for concentrated, satd. for saturated, MS for mass spectrum, M for molecular ion, other abbreviations have their meanings customary per se to the skilled person.
Unless otherwise noted, when the exemplary compounds mentioned expressis verbis herein contain a chirality center, they are described illustratively as racemic mixtures herein, without restricting this invention thereto. Accordingly, the pure enantiomers and the salts thereof are also part of the invention.
The compounds of formula I mentioned in the examples, particularly which are mentioned as final compounds, as well as their salts, stereoisomers and salts of the stereoisomers are a preferred subject of the invention.
A solution of 68 mg (918 μmol, 2.00 eq) N-hydroxy acetamidine and 55 mg (1.38 mmol, 3.00 eq) sodium hydride in 2 ml THF (and 150 mg molecular sieves) is heated to reflux for 1 h. A solution of 200 mg (459 μmol, 1.00 eq) (5RS)-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,5-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid methyl ester (compound A1) in THF is added. The mixture is heated to reflux for 24 h. Additional 68 mg acetamidine and 55 mg sodium hydride are added before heating to reflux for additional 4.5 h. Water is added and the solution is extracted with ethyl acetate. The organic layer is dried with magnesium sulfate and the solvent is removed at reduced pressure. After purification by column chromatography and washing with ethanol 21 mg of the title compound are obtained as a colorless solid.
M.p.: 182-184° C. MS: 459.8 (MH+)
The title compound can be prepared from compound A1 and N-hydroxy cyclopropanecarboxamidine analogously as described in Example 1.
M.p.: 174-175° C. MS: 485.8 (MH+)
The title compound can be prepared from compound A1 and N-hydroxy benzamidine analogously as described in Example 1.
M.p.: 203-206° C. MS: 522.2 (MH+)
The title compound can be prepared from (4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid methyl ester (compound A2) and N-hydroxy benzamidine analogously as described in Example 1.
M.p.: 191-193° C. MS: 508.2 (MH+)
The title compound can be prepared from (4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid methyl ester (compound A2) and N-hydroxy acetamidine analogously as described in Example 1.
M.p.: 218-221° C. MS: 445.9 (MH+)
A mixture of 5.00 mg (1.23 mmol, 1.00 eq) of 2-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid amide (compound A3), 300 μl (3.69 mmol, 3.00 eq) chloro acetone, 7.00 ml toluene and 7.00 ml THF are heated for 16 h to 120° C. in a sealed tube. The solvents are removed at reduced pressure and the residue is purified by column chromatography. After washing with ethanol 340 mg (62%) of the title compound are obtained as a white solid.
M.p.: 222-224° C. MS: 444.9 (MH+)
Analogously to a procedure described by Meyer in Liebigs Ann. Chem. 1981, 9, 1534-1544, (3RS)-(6,7-dimethoxy-3-methyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic acid methyl ester (compound B1) is reacted with nitro ethane and 4-hydroxy-3,5-dimethyl benzaldehyde to afford the title compound.
MS (M+H)=435.9; m.p.=177-179° C.
The preparation of the title compound is described in example 20 of WO 02/48144.
To a mixture of 1.40 g (26.1 mmol, 5.00 eq) ammonia chloride in 23 ml toluene at 0° C. are added dropwise 14.4 ml (28.7 mmol, 5.50 eq) of a 2 M solution of AlMe3 in toluene. The solution is stirred at room temperature for 1 h. A solution of 2.20 g (5.22 mmol, 1.00 eq) 2-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid methyl ester (compound A2) in 46 ml THF is added. The mixture is stirred at 80° C. for 16 h and cooled to room temperature. A 5 M aqueous solution of sodium hydroxide is added until the pH was basic. Water is added and the mixture was extracted with ethyl acetate. The organic layer is separated and dried with magnesium sulfate. The solvent is removed at reduced pressure and the residue is purified by column chromatography. 1.16 g (45%) of the title compound are obtained.
MS (M+H)=407.2; m.p.=229-231° C.
The title compound can be obtained by a Bischler-Napieralski reaction (e.g. Ber. 1893, 26, 1903) using N-{2-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]-ethyl}-malonamic acid methyl ester (compound C1) as the starting material.
The title compound can be prepared by a reaction of (RS)-2-(3,4-dimethoxy-phenyl)-1-methyl-ethylamine (compound D1) with methyl maloyl chloride in analogy to procedures in the literature (e.g. Benovsky et al., Tetrahedron Lett. 1997, 38, 8475-8478).
The title compound can be obtained starting from the corresponding benzaldehyde and nitroethane in analogy to a Henry reaction (e.g. Synthesis 1985 (5), 510-512) and subsequent reduction reaction (using e.g. LiAlH4 in THF).
Further compounds according to this invention can be prepared starting from compounds D2 to D5:
The title compound is commercially available.
2-[4-Methoxy-3-(2-methoxy-ethoxy)-phenyl)-ethylamine can be prepared by alkylation of 4-methoxy-3-hydroxy benzaldehyde with 2-bromomethyl ethyl ether (analogous to a procedure by Ashton et al., J. Med. Chem. 1994, 37, 1696-1703), followed by a sequence described by Shepard et al. in J. Org. Chem. 1952, 17, 568.
MS (M+H)=226.0
2-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-ethylamine can be prepared by difluoromethylation of 4-hydroxy-3-methoxy benzaldehyde with chloro difluoro methane according to a procedure published by Amschler et al. (WO97/28131), followed by a sequence described by Shepard et al. in J. Org. Chem. 1952, 17, 568.
MS (M+H)=217.6
2-[3-(1,1-Difluoro-methoxy)-4-methoxy-phenyl]-ethylamine can be prepared by difluoromethylation of 3-hydroxy-4-methoxy benzaldehyde with chloro difluoro methane according to a procedure published by Amschler et al. (WO97/28131), followed by a sequence described by Shepard et al. in J. Org. Chem. 1952, 17, 568.
MS (M+H)=217.7
Intracellular levels of the second messengers cAMP and cGMP are regulated by both their rates of synthesis by cyclases and their hydrolysis by phosphodiesterases. Of the 11 phosphodiesterase (PDE) isoenzymes which are presently known, PDE10 was described for the first time in 1999 (Soderling S H, Bayuga S J, Beavo J A. Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci USA. 1999 Jun. 8; 96(12):7071-6; Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem. 1999 Jun. 25; 274(26):18438-45; Loughney K, Snyder P B, Uher L, Rosman G J, Ferguson K, Florio V A. Isolation and characterization of PDE10A, a novel human 3′,5′-cyclic nucleotide phosphodiesterase. Gene. 1999 Jun. 24; 234(1):109-17). The first gene of this new PDE subfamily was designated PDE10A and the first splice variant was described as PDE10A1, according to the current nomenclature. Due to alternative splicing, other splice variants of PDE10A exist and have been described in the subsequent years (Kotera J, Fujishige K, Yuasa K, Omori K. Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP. Biochem Biophys Res Commun. 1999 Aug. 11; 261(3):551-7; Fujishige K, Kotera J, Omori K. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur J Biochem. 1999 December; 266(3):1118-27; Fujishige K, Kotera J, Yuasa K, Omori K. The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem. 2000 October; 267(19):5943-51). PDE10A has been described as a cyclic nucleotide phosphodiesterase exhibiting properties of a cAMP PDE and a cAMP-inhibited cGMP PDE.
Individual representatives of the PDE10 isoenzyme are characterized by being highly expressed in specific areas of the brain (striatum, putamen, caudate nucleus, cerebellum, thalamus), in testis, in kidney and in placenta.
Novel results have demonstrated that PDE10A expression is particularly prominently expressed in neurotransmitter/hormone secreting cells in brain, islets of Langerhans, pituitary and adrenal glands, see e.g. WO2005120474.
As cAMP is a well known stimulus for hormone/neurotransmitter release, it can be claimed that the neuroendocrine-specific mRNA expression of PDE10A reflects an important role in hormone/neurotransmitter secretion. For example, striatal expression and function of PDE10A has been associated with the regulation of dopaminergic neurotransmission (e.g. US 2003/0008806). Therefore, inhibition of PDE10A may be used for the treatment of disorders of the central nervous system (e.g. schizophrenia). Additionally, PDE10A inhibition in pancreatic beta cells might effect in a rise of cAMP and therefore induce or enforce insulin secretion. This effect may improve glucose homeostasis in type II diabetic patients.
Moreover it has been shown that pharmacological inhibition of PDE10 or a genetic knockout of the pde10A gene is an effective means of reducing body weight, reducing body fat, and treating disorders associated with increased adiposity. These results also demonstrated that PDE10 inhibitors are effective in treating disorders associated with NIDDM (non insulin dependent diabetes mellitus), glucose intolerance, insulin resistance and metabolic syndrome in addition to reducing body weight, body fat, and treating disorders associated with increased adiposity, see e.g. WO2005120514, the disclosure of which is incorporated herein.
Increased expression levels and activities of PDE10A in testis suggests that PDE10A may also contribute to spermatogenesis (Fujishige K et al., Eur J Biochem. 1999, 266:1118-27).
The compounds according to the invention have miscellaneous valuable pharmacological properties which make them commercially utilizable.
Thus, for example, the compounds according to this invention are PDE inhibitors.
Yet thus, for example, the compounds according to the invention are potent PDE10 inhibitors, some of which are apparently selective (e.g. by >10 or, particularly, >30 fold, or, for some advantage, >100 fold) among other PDE isoenzymes (such as e.g. PDEs 1A, 2A, 3A, 4B, 5A, 7A, 8A, 9A or 11A) whereby these selective compounds are particularly preferred in the context of the present invention.
The compounds according to the invention therefore can be employed as therapeutic agents for the treatment or prophylaxis of diseases in human and veterinary medicine; especially they are particular useful in the therapy of those diseases or conditions mentioned below.
Due to their potent and selective PDE10 inhibitory activity, the compounds according to the present invention may be, in a first facet of the present invention, of potential value in treating disorders of the central nervous system, in particular neurologic and psychiatric disorders, for example those mentioned in EP 1250923 and/or, in more particular, psychotic disorders, anxiety disorders, mood disorders or episodes, drug addiction, movement disorders or disorders comprising deficient cognition as a symptom (e.g. dementia, Parkinson's disease or Alzheimer's disease).
Furthermore, the compounds according to the present invention may be, in a second facet of the present invention, of potential value in treating certain disorders of the central nervous system, in particular neurologic and psychiatric disorders, for example those mentioned generically, specifically or exemplarily in EP 1250923, US 2003/0008806, US 2003/0018047, US 2003/032579, US 2004/162293, US 2004/162294 and/or WO03092499 (the disclosure of those applications is incorporated herein), such as, for example, anxiety or psychotic disorders, movement disorders, obsessive/compulsive disorders, drug addictions, cognition deficiency disorders, mood disorders or mood episodes, or neurodegenerative disorders.
In this context, examples of anxiety disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, panic disorder, agoraphobia, a specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, or generalized anxiety disorder.
Examples of psychotic disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, schizophrenia (for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder (for example of the delusional type or the depressive type), delusional disorder, substance-induced psychotic disorder (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine), personality disorder of the paranoid type, or personality disorder of the schizoid type.
Examples of movement disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, Parkinson's disease, or restless leg syndrome.
Examples of obsessive/compulsive disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, Tourette's syndrome, or other tic disorders.
Examples of drug addictions, which may be treated by the compounds according to the present invention, include, without being limited thereto, an alcohol, amphetamine, cocaine, or opiate addiction.
Examples of cognition deficiency disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia, delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, or age-related cognitive decline.
Examples of mood disorders or mood episodes, which may be treated by the compounds according to the present invention, include, without being limited thereto, a major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with a typical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder (for example bipolar I disorder, bipolar II disorder), or cyclothymic disorder.
Examples of neurodegenerative disorders, which may be treated by the compounds according to the present invention, include, without being limited thereto, Parkinson's disease, Huntington's disease, dementia (for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, or Fronto temperal Dementia), neurodegeneration associated with cerebral trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct, hypoglycemia-induced neurodegeneration, neurodegeneration associated with epileptic seizure, neurodegeneration associated with neurotoxin poisoning, or multi-system atrophy.
Yet in this context, the compounds according to the present invention may be of potential value for treating diseases or conditions, in which abnormal function of the basal ganglia has been implicated. Thus, abnormal function of the basal ganglia may be involved in disregulated motoric, appetitive and/or cognitive processes. Exemplary neuropsychiatric conditions, in which abnormal function of the basal ganglia has been implicated, are mentioned e.g. in EP 1250923, US 2003/0008806, US 2003/0018047, US 2003/032579, US 2004/162293, US 2004/162294 and/or WO03092499 (the disclosure of those applications is incorporated herein), such as e.g. psychosis, attention-deficit/hyperactivity disorder (ADHD) and related attentional disorders, depression, obsessive conpulsive disorders including Tourette's syndrome and other tic disorders, and substance abuse. Several neurological disorders including Parkinson's disease, restless leg syndrome and Huntington's disease can be also linked to basal ganglia dysfunction.
Still yet in this context, the compounds according to the present invention may be of potential value for improving cognition, powers of concentration, learning skills or hypermesia, in particular if the disorder is a symptom of dementia.
Yet furthermore, the compounds according to the present invention may be, in a third facet of the present invention, of potential value for regulating fertility, e.g. via reducing spermatogenesis and/or via reducing sperm motility.
Still yet furthermore, the compounds according to the present invention may be, in a fourth facet of the present invention, of potential value for treating diabetes, such as, for example, typ II diabetes, e.g. via augmenting glucose-induced insulin secretion.
A special interest in the compounds according to the present invention lies in their use in therapy of schizophrenia.
Another special interest in the compounds according to the present invention lies in their use in the therapy of psychotic disorders.
Another special interest in the compounds according to the present invention lies in their use in the therapy of drug addictions.
Furthermore, a special interest in the compounds according to the present invention lies in their properties which make them particularly useful in the therapy of diseases or conditions other than cancer. In this connection, a further special interest in the compounds according to the present invention lies in their reduced cytotoxic activity.
The invention further relates to a method for treating mammals, including humans, which/who are suffering from one of the abovementioned diseases and/or disorders. The method is characterized by the fact that a pharmacologically active and therapeutically effective and tolerated quantity of one or more of the compounds according to the invention is administered to the affected mammal.
The invention further relates to a method for inhibiting PDE10 comprising administering an effective amount of one or more compounds of the present invention to a mammal in need thereof.
The invention further relates to the compounds according to the invention for use in the treatment or prophylaxis of diseases, in particular said diseases and/or disorders.
The invention likewise relates to the use of the compounds according to the invention in the manufacture of pharmaceutical compositions which are employed for the treatment of said diseases or disorders.
The invention further relates to pharmaceutical compositions for the treatment or prophylaxis of the said diseases and/or disorders, which pharmaceutical compositions comprise one or more of the compounds according to the invention.
The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent.
The present invention further relates to combinations comprising one or more of the compounds according to this invention and pharmaceutically acceptable auxiliaries, excipients or vehicles, e.g. for use in the treatment of those conditions mentioned above.
The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions which can be used use in therapy of disorders responsive to inhibiting of PDE, such as e.g. PDE10.
The present invention further relates to compounds according to this invention having PDE, particularly PDE10, inhibiting properties.
The present invention further relates to pharmaceutical combinations or compositions according to this invention having PDE10 inhibiting properties.
The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention as sole active ingredient(s) and a pharmaceutically acceptable carrier or diluent in the manufacture of pharmaceutical products for therapy, amelioration or prophylaxis of the illnesses, diseases, disorders or conditions mentioned above.
Further, the present invention relates to the use of the compounds according to this invention in the manufacture of pharmaceutical compositions for treating psychotic disorders, anxiety disorders, mood disorders or episodes, drug addictions, movement disorders, cognition deficiency disorders, obsessive/compulsive disorders, or neurodegenerative disorders.
Yet further, the present invention relates to the use of the compounds according to this invention in the manufacture of pharmaceutical compositions for treating diabetes, including type 2 diabetes.
Still yet further, the present invention relates to a method for treating mammals, including humans, suffering from diabetes comprising administering to said mammal in need thereof a therapeutically effective and tolerable quantity of one or more compounds according to this invention.
Still yet further, the present invention relates to a method for treating mammals, including humans, suffering from psychotic disorders, anxiety disorders, mood disorders or episodes, drug addictions, movement disorders, cognition deficiency disorders, obsessive/compulsive disorders, or neurodegenerative disorders comprising administering to said mammal in need thereof a therapeutically effective and tolerable quantity of one or more compounds according to this invention.
In addition, the present invention further relates to a method for regulating fertility in a mammal, including human, comprising administering one or more compounds according to this invention to said mammal in need thereof.
In further addition, the present invention further relates to the use of the compounds according to this invention for inhibiting spermatogenesis and/or inhibiting sperm motility in a mammal, including human.
In yet further addition, the present invention further relates to the use of the compounds according to this invention for the manufacture of pharmaceutical compositions for regulating fertility in a mammal, including human.
Further on, the present invention further relates to a method to decrease body weight and/or body fat in animals, e.g. in the treatment of overweight or obese patients (e.g. humans or companion animals) or as means to produce leaner meet in food stock animals (e.g. cattle, chickens, pigs), comprising administering to a subject in need thereof an effective amount of one or more compounds according to this invention.
Further on, the present invention further relates to a method of treating a subject to reduce body fat or body weight, or to treat non-insulin dependent diabetes, metabolic syndrome, or glucose intolerance, comprising administering to a subject, including human, in need thereof (e.g. an overweight subject or an obese subject) a therapeutically effective and tolerable amount of one or more compounds according to this invention.
Further on, the present invention further relates to the use of the compounds according to this invention for the manufacture of pharmaceutical compositions for treating non-insulin dependent diabetes, metabolic syndrome, or glucose intolerance.
Further on, the present invention further relates to the use of the compounds according to this invention for the manufacture of pharmaceutical compositions for reducing body fat or body weight.
Further, the present invention relates to a method for inducing or enforcing insulin secretion in a mammal, including human, comprising administering to said mammal in need thereof a therapeutically effective and tolerable amount of one or more compounds according to this invention.
Further, the present invention further relates to the use of the compounds according to this invention for the manufacture of pharmaceutical compositions for inducing or enforcing insulin secretion.
The invention furthermore relates to a commercial product which consists of a customary secondary packaging means, a primary packaging means (for example an ampoule or a blister pack) which contains a pharmaceutical composition, and, if desired, a patient information leaflet, with the pharmaceutical composition exhibiting an antagonistic effect toward type 10 cyclic nucleotide phosphodiesterases (PDE10) and leading to the attenuation of the symptoms of diseases and/or disorders which are associated with type 10 cyclic nucleotide phosphodiesterases, and with reference being made, on the secondary packaging means and/or on the patient information leaflet of the commercial product, to the suitability of the pharmaceutical composition for use in the prophylaxis or treatment of diseases and/or disorders which are associated with type 10 cyclic nucleotide phosphodiesterases, and with the pharmaceutical composition comprising one or more compounds according to this invention. The secondary packaging means, the primary packaging means containing the pharmaceutical composition and the patient information leaflet otherwise correspond to what the skilled person would regard as being the standard for drugs of this nature.
The pharmaceutical compositions according to this invention are produced using methods with which the skilled person is familiar. When employed in pharmaceutical compositions, the compounds according to the invention (=active compounds) are either used as such or, preferably, in combination with suitable pharmaceutical auxiliaries or formulating agents, for example in the form of tablets, coated (e.g. sugar-coated) tablets, capsules, caplets, suppositories, patches (e.g. as TTS), plasters, emulsions, suspensions, gels or solutions, with the content of active compound advantageously being between 0.1 and 95%, and where, by the appropriate choice of the auxiliaries, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.
The person skilled in the art is familiar, on the basis of his/her knowledge, with auxiliaries, vehicles, formulating agents, carriers, diluents, adjuvants or excipients which are suitable to be used for the desired pharmaceutical formulations, preparations or compositions. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrines).
The administration of the compounds or pharmaceutical compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, inhalative, oral, nasal, parenteral, topical, transdermal and rectal delivery. Intravenous or, particularly oral delivery are preferred.
For the treatment of skin diseases, the compounds according to the invention are in particular administered in the form of those pharmaceutical compositions which are suitable for topical application. For the production of the pharmaceutical compositions, the compounds according to the invention (=active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
The pharmaceutical compositions according to the invention are prepared by processes known per se. The required dosage of the active compounds according to this invention can vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.01 to about 100 mg/kg body weight, conveniently administered, for example, in divided doses up to four times a day or in retard form.
The optimal dose and manner of administration of the active compounds necessary in each case can easily be determined by any person skilled in the art on the basis of his/her expert knowledge.
Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered separately, simultaneously, concurrently, sequentially or chronologically staggered with the compounds according to this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated.
The person skilled in the art is aware on the base of his/her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range.
Thus, e.g. the present invention further relates to a method of treating a subject to reduce body fat or body weight, or to treat non-insulin dependent diabetes, metabolic syndrome, or glucose intolerance, comprising administering to a subject, including human, in need thereof (e.g. an overweight subject or an obese subject) a therapeutically effective amount of one or more compounds according to this invention and further comprising administering a second therapeutic agent, such as e.g. an anti-obesity agent, which is e.g. selected from rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, peptide YY3-36, and analogs thereof.
Likewise, the present invention further relates to a kit comprising one or more compound according to this invention and instructions for administering the compound to a subject to reduce body fat, body weight, or to treat non non-insulin dependent diabetes, metabolic syndrome or glucose intolerance, in the subject; optionally, said kit further comprises a second therapeutic agent, such as e.g. an anti-obesity agent, which is e.g. selected from rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, peptide YY3-36, and analogs thereof.
Methods to determine the activity and selectivity of a phosphodiesterase inhibitor are known to the person skilled in the art. In this connection it may be mentioned, for example, the methods described by Thompson et al. (Adv Cycl Nucl Res 10: 69-92, 1979), Giembycz et al. (Br J Pharmacol 118:1945-1958, 1996) and the phosphodiesterase scintillation proximity assay of Amersham Pharmacia Biotech.
The PDE10A is cloned into pCR2.1-Topo (Invitrogen) via PCR from human whole brain cDNA using primers OZ 353 (5′-ACCATGTTGACAGATGAAAAAGTGAAGGC-3′) and OZ 317 (5′-TCAATCTTCAGATGCAGCTGCC-3′). The ORF encoding for the PDE10A is cut with EcoRV and BamHI and subcloned into SmaI and Bgl II of the expression vector pBP9 (Clontech). The encoded protein represents the PDE10A1 (GenBank Acc.-# AB020593) truncated at its N-terminus at aa 14.
The recombinant baculoviruses are prepared by means of homologous recombination in Sf9 insect cells. The expression plasmids are cotransfected with Bac-N-Blue (Invitrogen) or Baculo-Gold DNA (Pharmingen) using a standard protocol (Pharmingen). Wildtype virus-free recombinant virus supernatants are selected using plaque assay methods. After that, high-titre virus supernatants are prepared by amplifying 3 times. PDE10A1 is expressed in Sf21 cells by infecting 2×106 cells/ml with an MOI (multiplicity of infection) between 1 and 10 in serum-free SF900 medium (Life Technologies, Paisley, UK). Cells are cultured at 28° C., typically for 48 hours, after which they are pelleted for 5-10 min at 1000 g and 4° C. In spinner flasks, cells are cultured at a rotational speed of 75 rpm. The SF21 insect cells are resuspended, at a concentration of approx. 1×107 cells/ml, in ice-cold (4° C.) homogenization buffer (20 mM Tris, pH 8.2, containing the following additions: 140 mM NaCl, 3.8 mM KCl, 1 mM EGTA, 1 mM MgCl2, 10 mM β-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefabloc, 10 μM leupeptin, 10 μM pepstatin A, 5 μM trypsin inhibitor) and disrupted by ultrasonication on ice. The homogenate is then centrifuged for 10 min at 1000 g (4° C.) and the supernatant is stored at −80° C. until subsequent use (see below). The protein content is determined by the Bradford method (BioRad, Munich) using BSA as the standard.
The PDE10A activity is inhibited by said compounds in a modified SPA (scintillation proximity assay) test, supplied by Amersham Pharmacia Biotech (see procedural instructions “Phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090”), carried out in 96-well microtitre plates (MTPs). The test volume was 100 μl and contained 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg2+, 0.5 μM cAMP (including about 50,000 cpm of [3H]cAMP), 1 μl of the respective substance dilution in DMSO and sufficient recombinant PDE10A1 (1000×g supernatant, see above) to ensure that 15-20% of CAMP was converted under said experimental conditions. After a preincubation of 5 min at 37° C., the reaction is started by adding a substrate (CAMP) and the assays are incubated for a further 15 min; after that, they are stopped by adding SPA beads (50 μl). In accordance with the manufacturer's instructions, the SPA beads have previously been resuspended in water and diluted 1:3 (v/v) and added to IBMX (3 mM). After the beads have been sedimented (>30 min), the MTPs are analyzed in commercially available measuring appliances and the corresponding IC50 values of the compounds for the inhibition of PDE10A activity are determined from concentration-effect curves by means of non-linear regression.
Representative inhibitory values [inhibitory concentration as −logIC50 (mol/l)] which are determined in the aforementioned assay are shown in the following table A, in which the numbers of the compounds correspond to the numbers of the examples.
| Number | Date | Country | Kind |
|---|---|---|---|
| 05100154.4 | Jan 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP06/50167 | 1/11/2006 | WO | 00 | 8/16/2007 |
