DE10219294A1 - New substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, useful as cyclin-dependent kinase inhibitors for treating e.g. cancer, autoimmune diseases, cardiovascular diseases and neurodegenerative diseases - Google Patents

Abstract

Substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives (I) and their salts, tautomers, and isomers are new. Substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives of formula (I) and their salts, tautomers, and isomers are new. R1 = 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkoxy, 1-6C alkylthio, 3-12C cycloalkyl, 3-12C cycloalkenyl, 3-12C heterocycloalkyl, 3-12C heterocycloalkenyl, aryl or heteroaryl (all optionally substituted by one or more substituents); R2, R3 = H, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, or 1-6C alkoxy (all optionally substituted by one or more substituents; or R4, R5 = H or halo; 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl or 1-6C alkoxy (all optionally substituted by one or more substituents); or R4+R5 = carbonyl or cyclic 5-6-membered membered ring acetal having O, O; N, O; O, S; or S, S, and which is optionally substituted by 1-6C alkyl; or R2+R4 = 3-12C cycloalkyl or cycloalkenyl, both optionally substituted by one or more substituents; R6, R7 = H; 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl (all optionally substituted by one or more substituents); or R6+R7, R3+R5 = 3-12C cycloalkyl or 3-12C cycloalkenyl (both optionally substituted); or R5+R6 = a double bond; or R3+R5 = 3-12C cycloalkyl or 3-12 cycloalkenyl; or R2+R7 or R3+R6 or R2+R6 or R3+R7 = CH2; T = CH2, O, CH2=CH2, CHtriple bondCH, CH2OCH2, CHO, OCH2, CH(Me), or =CO (sic); and n = 0-6. An Independent claim is also included for an intermediate of formula (II).

Description

The invention relates to substituted N- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) - Derivatives, their manufacture and use as medicines for treatment various diseases.

The object of the present invention is to provide effective medicaments for treatment various diseases and processes for the production of these medicines provide.

DE 198 54 081 A1 and WO 00/31066 are substituted N-pyrazolyl- phenoxynicotinsäure- (thio) amides known, which are used as herbicides. These connections differ structurally from the compounds of the invention.

WO 01/12189 describes 3 (5) -amino-pyrazole derivatives and their use as pharmaceutical agent, in particular for the treatment of cancer and known cell proliferative diseases. These connections also differ differ from the compounds according to the invention by their structure, in particular on the pyrazole ring.

Amino-pyrazoles are known from WO 01/79198 and can be used as protein kinase inhibitors. On page 18 of the application, oxygen is defined as = O group in the definition of R ¹ as substituents on alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. This definition also includes substitution on the first carbon atom, ie the application also relates to compounds of the type


ie acylamino-pyrazoles. Such compounds are not exemplified in WO 01/79198.

Resynthesis of these compounds is analogous to that in WO 01/79198 described process resulted in the compounds of the invention, the acylamino-pyrazoles, not following the procedures described there have it made.

Furthermore, WO 02/12242 describes bicyclopyrazoles as kinase inhibitors known. However, these pyrazoles differ significantly from those compounds of the invention.

There is still a great need for effective drugs Treatment of cancer and other cell proliferative diseases as well as at the Representation of such connections.

It has now been found that compounds of the general formula I


in the
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ heterocycloalkyl, C ₃ -C ₁₂ - heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted or may be multiply substituted identically or differently,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ - C ₆ alkoxy, which can optionally be substituted one or more times, identically or differently,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may optionally be substituted one or more times, identically or differently, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal with O, O; N, O; O, S; or S, S, which may optionally be substituted by C ₁ -C ₆ alkyl, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which can optionally be substituted one or more times, identically or differently,
R ⁶ and R ^{7 are} identical or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, which may be one or more, identical or can be substituted differently, or together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which can optionally be substituted one or more times, identically or differently, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ⁵ and R ⁶ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which may optionally be substituted one or more times, identically or differently, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n stands for 0-6, and their tautomers, isomers and salts.

Under alkyl is in each case a straight-chain or branched alkyl radical, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Tert-butyl To understand butyl, pentyl, isopentyl or hexyl.

Under alkoxy is in each case a straight-chain or branched alkoxy radical, such as for example methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, Isobutyloxy, sec. Butyloxy, tert-butyloxy, pentyloxy, isopentyloxy or hexyloxy to understand.

Under alkylthio is a straight-chain or branched alkylthio radical, such as for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, Isobutylthio, sec. Butylthio, tert-butylthio, pentylthio, isopentylthio or hexylthio to understand.

Cycloalkyl includes monocyclic alkyl rings such as cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings such as norbornyl, To understand Adamantanyl, etc.

Cycloalkenyl is cyclobutenyl, cyclopentenyl, cyclohexenyl, Understand cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, the connection to both the double bond and the Single bonds can be made.

Halogen is to be understood as fluorine, chlorine, bromine or iodine.

Alkenyl is a straight-chain or branched alkenyl residue understand that contains 2-6, preferably 2-4 carbon atoms. For example the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en- 2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1- en-1-yl, but-1-en-3-yl, but-3-en-1-yl, allyl.

A straight-chain or branched alkynyl radical is in each case under alkynyl understand that contains 2-6, preferably 2-4 carbon atoms. For example the following radicals: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1- in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

The aryl radical comprises 3-12 carbon atoms and can in each case be benzo-condensed.

Examples include: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, Cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc.

The heteroaryl group comprises 3-16 ring atoms and can be used instead of Carbon one or more, identical or different heteroatoms, such as Contain oxygen, nitrogen or sulfur in the ring, and can be mono-, bi- or be tricyclic, and can additionally be benzo-fused in each case.

Examples include:
Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof such as e.g. B. benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as e.g. Quinolyl, isoquinolyl, etc .; or oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzene derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.

Heterocycloalkyl represents an alkyl ring comprising 3-12 carbon atoms, the one or more instead of carbon, the same or different Heteroatoms such as e.g. B. contains oxygen, sulfur or nitrogen. As heterocycloalkyl such. B. called: oxiranyl, oxethanyl, aziridinyl, Azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, Dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, Trithianyl, quinuclidinyl etc.

Heterocycloalkenyl represents a 3-12 carbon atom Alkyl ring, one or more, equal to or instead of carbon various heteroatoms, such as B. contains oxygen, sulfur or nitrogen, and which is partially saturated.

As heterocycloalkenyls such. B. called: Pyran, Thiin, Dihydroazet, etc.

Cyclic acetal stands for a ring, such as. B.


which may optionally be substituted with a C ₁ -C ₆ alkyl group.

The aryl and the heteroaryl group may each be mono- or polysubstituted, identically or differently, with hydroxy, halogen, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , C _1-6 alkylthio, halo _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, nitro, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or the group -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -CONH _2, -CONHCC ₁ - ₆ - Alkyl or -CON-di-C ₁ - ₆ alkyl, or may be substituted with a further aryl or heteroaryl radical, which may itself be substituted one or more times, identically or differently, with hydroxyl, halogen, amino , C _1-6 alkyl, C _1-6 - alkoxy, C ₁ - ₆ alkylthio, halo-C ₁ - ₆ alkyl, halo-C ₁ - ₆ alkoxy, C ₁ - ₆ alkoxycarbonyl, cyano, nitro , C ₁ - ₆ alkylcarbonyl, C _1-6 alkylsulphanyl, C _1-6 alkylsulphinyl, C ₁ - ₆ - alkylsulfonyl, or the group -C (O) C ₁ - ₆ alkyl, -NHCC _1-6 alkyl, -N-di-C _1-6 alkyl, -CONH _2, -CONHC _1-6 alkyl or -CON-di-C _1-6 alkyl may be substituted.

If an acidic function is contained, the physiologically acceptable salts are Salts of organic and inorganic bases suitable such as the good soluble alkali and alkaline earth salts as well as N-methyl-glucamine, dimethyl-glucamine, Ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, Serinol, Tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1- Amino-2,3,4-butanetriol.

If a basic function is included, the physiologically acceptable salts are included Suitable for organic and inorganic acids such as hydrochloric acid, sulfuric acid, Phosphoric acid, citric acid, tartaric acid, fumaric acid and the like. a.

Compounds of the general formula I in which
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ heterocycloalkyl, C ₃ -C ₁₂ - heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 - alkylthio, halo-C _1-6 alkyl, halo-C _1-6 -alkoxy, C _1-6 - alkoxycarbonyl, cyano, nitro, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or with the group -CHO, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N -di-C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl or -CON-di-C _1-6 alkyl may be substituted, or may be substituted with a further aryl or heteroaryl radical , which may itself be substituted one or more times, identically or differently,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ - C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, halogen, linear or branched C _1-6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which may optionally be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl , or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are} identical or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, which may be one or more, identical or may be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl, or together a C ₃ -C ₁₂ - Form cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently with hydroxyl, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts.

Compounds of the general formula I in which
R ^{1 is} linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ - C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ - heterocycloalkyl, C ₃ -C ₁₂ -Heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkoxycarbonyl, cyano, nitro, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or with the group -CHO, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N -di-C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl or -CON-di-C _1-6 alkyl may be substituted, or may be substituted with a further aryl or heteroaryl radical , which itself one or more times, identically or differently with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkyl, halo -C _1-6 alkoxy, C _1-6 alkoxycarbonyl, Cyano, nitro, C _1-6 alkylcarbonyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C ₁ -C ₆ alkylphenyl, C ₂ -C ₄ alkenylphenyl, C ₂ -C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl-C ₃ -C ₆ -cycloalklyl or with the group -COOH, -C (O) C _1-6 alkyl, -NHC _{1 -6-} alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , -CONHC _1-6 -alkyl or -CON-di-C _1-6 -alkyl may be substituted,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl can, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or may be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl, or together a C ₃ -C ₁₂ -Cycloalkyl- or C ₃ -C ₁₂ - cycloalkenyl ring, optionally one or more, the same or different with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts.

Those compounds of the general formula I in which
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, oxiranyl, oxethanyl, aziridinylidyllidolidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidol, azididylidolidol, azididylidolidol, azididylolidol, azididylolidol Piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, thiinyl, dihydroacetyl, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooktadienyl, fluorenyl, aylenylhenyl, fluoro, aylenylhenyl, fluoro, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluoro, adenyl Furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazi nyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenodinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl yl, phenoxazinyl or xanthenyl, which is optionally one or more, identical or different, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo-C _{1- 6} alkyl, halo-C _1-6 - alkoxy, C _1-6 alkoxycarbonyl, cyano, nitro, C _1-6 - alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or the group - CHO, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl or -CON-di -C _1-6 alkyl may be substituted, or may be substituted with a further aryl or heteroaryl radical, which may optionally itself be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkyl, H alo-C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, nitro, C _1-6 - alkylcarbonyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C ₁ - ₆ - alkylsulphonyl, C ₁ -C ₆ -alkylphenyl, C ₂ -C ₄ -alkenylphenyl, C ₂ -C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl- C ₃ -C ₆ -cycloalklyl or with the group - COOH, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -C (O) NH ₂ , -C (O) NHC _{1- 6} alkyl or -CON-di-C _1-6 alkyl may be substituted,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl can, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkenyl ring which may be one or more, identical or different, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or can be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or together a C ₃ -C ₇ -Cycloalkyl- or C ₃ -C ₇ - cycloalkenyl ring, optionally one or more, the same or different with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted,
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts.

Selected compounds are those compounds of the general formula I in which
R ^{1 is} C ₁ -C ₆ alkylthio, phenyl, biphenyl, thienyl, cyclopropyl, cyclohexyl, pyridyl, naphthyl, 1,3-benzodioxol-5-yl or isoxazolyl, which is optionally one or more, identical or different, with halogen, Amino, hydroxy, nitro, cyano, C ₁ -C ₆ alkylsulfonyl, C _1-6 alkyl, haloC _1-6 alkyl, C ₁ -C ₆ alkoxy, haloC _1-6 alkoxy, C _1-6 - alkylthio, with the group -CHO or -C (O) C ₁ - C ₆ alkyl, or with phenyl, thienyl, naphthyl, benzothiophenyl, benzodioxol-5-yl, biphenyl, phenyloxy, benzofuranyl, indolyl, pyridyl , Furanyl or pyrimidinyl, which may optionally be substituted one or more times, identically or differently with C ₁ -C ₆ alkyl, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo-C ₁ -C ₆ - alkoxy, amino, halogen, C ₁ -C ₆ alkylthio, C ₁ -C ₆ - alkylsulfonyl, cyano, hydroxy, C ₁ -C ₆ alkylphenyl, C ₂ -C ₄ alkenylphenyl, C ₂ -C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl-C ₃ -C ₆ -cycloalklyl or with the group -CHO, -C (O) NH ₂ or -C (O) -C ₁ -C ₆ alkyl, -N-di-C ₁ -C ₃ alkyl or -COOH may be substituted,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 represent} hydrogen or C _1-6 alkyl, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T represents the group -CH ₂ -, -CH ₂ -O-CH ₂ -, -CH (CH ₃ ) - or -CH ₂ O- and
n stands for 0-2, and their tautomers, isomers and salts.

• a) ein 1,4,5,6-Tetrahydro-cyclopentapyrazol-3-yl-amin der allgemeinen Formel II
  
  
  in der R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben,
  mit einer Verbindung der allgemeinen Formel III
  
  R¹-COX (III),
  
  in der R¹ die in der allgemeinen Formel I angegebene Bedeutung hat und X für Hydroxy, Fluor, Chlor, Brom oder eine Abgangsgruppe steht,
  zu Verbindungen der allgemeinen Formeln IVa und IVb
  
  
  in der R¹ die in der allgemeinen Formel I angegebene Bedeutung hat, umsetzt, die anschließend unter basischen Bedingungen selektiv zu den Verbindungen der allgemeinen Formel I hydrolysiert werden, oder
• b) ein 1,4,5,6-Tetrahydro-cyclopentapyrazol-3-yl-amin der allgemeinen Formel II
  
  
  in der R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben,
  mit einer Verbindung der allgemeinen Formel V
  
  R¹-CO-CCl₃ (V),
  
  in der R¹ die in der allgemeinen Formel I angegebenen Bedeutung hat, zu einer Verbindung der allgemeinen Formel I umsetzt, oder
• c) falls R¹ für ein 4-Halogenphenylacetyl-Rest in der Bedeutung der allgemeinen Formel I steht, eine Verbindung der allgemeinen Formeln VI oder VIa
  
  
  in denen R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben,
  
  
  für eine feste Phase steht und Y für Brom oder Jod steht, unter den Bedingungen einer Suzuki-Reaktion mit einer Boronsäure der allgemeinen Formel VIIa oder mit einem Boran der allgemeinen Formel VIIb
  
  
  in der R⁸ für Aryl oder Heteroaryl steht, zu einer Verbindung der allgemeinen Formeln Ia oder Ib,
  
  
  in der R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben, R⁸ für Aryl oder Heteroaryl steht und
  
  
  eine feste Phase bedeutet, umsetzt, wobei im Falle der an eine feste Phase gebundenen Verbindung die Abspaltung durch eine saure Hydrolyse erfolgt, oder
• d) eine Verbindung der allgemeinen Formeln VI oder VIa, in denen R¹ für ein 4- Halogenphenylacetyl-Rest steht,
  
  
  in denen R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben,
  
  
  eine feste Phase bedeutet und Y für Brom oder Jod steht, unter den Bedingungen einer Miyaura-Reaktion mit einem Diboronsäure-Derivat der allgemeinen Formel VIII
  
  
  zu Verbindungen der allgemeinen Formeln IX oder IXa
  
  
  in denen R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben und
  
  
  eine feste Phase bedeutet, umsetzt, und anschließend die Verbindungen der allgemeinen Formeln IX und IXa mit einer Verbindung der allgemeinen Formel X,
  
  R⁹Z (X),
  
  in der R⁹ für Aryl oder Heteroaryl und Z für Brom oder Jod steht, zu Verbindungen der allgemeinen Formeln Ic oder 1d
  
  
  in denen R², R³, R⁴, R⁵, R⁶ und R⁷ die in der allgemeinen Formel I angegebenen Bedeutungen haben,
  
  
  eine feste Phase bedeutet und R⁹ für Aryl oder Heteroaryl steht, umsetzt, und im Falle der an eine feste Phase gebundenen Verbindung die Abspaltung durch saure Hydrolyse erfolgt, oder
• e) eine Verbindung der allgemeinen Formel XI
  
  
  in der R¹ die in der allgemeinen Formel I angegebenen Bedeutungen hat, mit N-(1-Cyclopenten-1-yl)-morpholin der allgemeinen Formel XII
  
  
  zu Verbindungen der allgemeinen Formel XIII
  
  
  in der R¹ die in der allgemeinen Formel I angegebenen Bedeutungen hat, umsetzt, und anschließend die Verbindungen der allgemeinen Formel XIII mit Hydrazin zu Verbindungen der Formel I zyklisiert, oder
• f) eine Verbindung der allgemeinen Formel XIV,
  
  
  in der X für Sauerstoff oder Schwefel steht, mit einer Verbindung der allgemeinen Formel XV in Gegenwart starker Basen (z. B. Lithiumdiisopropylamid),
  
  R¹-COOR¹⁰ (XV),
  
  in der R¹ die in der allgemeinen Formel I angegebene Bedeutung hat und R¹⁰ für C₁-C₆-Alkyl steht, zu einer Verbindung der allgemeinen Formel I umsetzt.

The compounds of general formula I according to the invention are preferably prepared by:

• a) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of the general formula II
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I,
  with a compound of general formula III
  
  R ¹ -COX (III),
  
  in which R ^{1 has} the meaning given in the general formula I and X represents hydroxy, fluorine, chlorine, bromine or a leaving group,
  to compounds of the general formulas IVa and IVb
  
  
  in which R ^{1 has} the meaning given in the general formula I, which are then selectively hydrolyzed under basic conditions to give the compounds of the general formula I, or
• b) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of the general formula II
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I,
  with a compound of general formula V
  
  R ¹ -CO-CCl ₃ (V),
  
  in which R ^{1 has} the meaning given in general formula I, to give a compound of general formula I, or
• c) if R ^{1 is} a 4-halophenylacetyl radical as defined by the general formula I, a compound of the general formulas VI or VIa
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I,
  
  
  represents a solid phase and Y represents bromine or iodine, under the conditions of a Suzuki reaction with a boronic acid of the general formula VIIa or with a borane of the general formula VIIb
  
  
  in which R ^{8 represents} aryl or heteroaryl, to a compound of the general formulas Ia or Ib,
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I, R ^{8 is} aryl or heteroaryl and
  
  
  means a solid phase, wherein in the case of the compound bound to a solid phase the cleavage takes place by acid hydrolysis, or
• d) a compound of the general formulas VI or VIa in which R ^{1 represents} a 4-halophenylacetyl radical,
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I,
  
  
  means a solid phase and Y represents bromine or iodine, under the conditions of a Miyaura reaction with a diboronic acid derivative of the general formula VIII
  
  
  to compounds of the general formulas IX or IXa
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I and
  
  
  means a solid phase, and then reacting the compounds of the general formulas IX and IXa with a compound of the general formula X,
  
  R ⁹ Z (X),
  
  in which R ^{9 is} aryl or heteroaryl and Z is bromine or iodine, to compounds of the general formulas Ic or 1d
  
  
  in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I,
  
  
  denotes a solid phase and R ^{9 represents} aryl or heteroaryl, and, in the case of the compound bound to a solid phase, the cleavage takes place by acid hydrolysis, or
• e) a compound of the general formula XI
  
  
  in which R ^{1 has} the meanings given in the general formula I, with N- (1-cyclopenten-1-yl) morpholine of the general formula XII
  
  
  to compounds of the general formula XIII
  
  
  in which R ^{1 has} the meanings given in general formula I, and then cyclizes the compounds of general formula XIII with hydrazine to give compounds of formula I, or
• f) a compound of the general formula XIV,
  
  
  in which X represents oxygen or sulfur, with a compound of the general formula XV in the presence of strong bases (e.g. lithium diisopropylamide),
  
  R ¹ -COOR ¹⁰ (XV),
  
  in which R ^{1 has} the meaning given in the general formula I and R ^{10 is} C ₁ -C ₆ -alkyl, to give a compound of the general formula I.

Process variant a)

The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of the formula II with a compound of formula III can in the presence of a base such as triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or pyridine in a suitable one Solvents such as toluene, dichloromethane, chloroform, diethyl ether, Tetrahydrofuran, acetonitrile, dioxane or N, N-dimethylformamide in one Temperature between 0 ° C and the boiling point of the solvent be performed. It can also be one of those known from peptide chemistry Methods of amide formation are used.

The reaction of a compound of the general formulas IVa and IVb into one Compound of formula I can in the presence of a base such as sodium hydroxide, Potassium hydroxide, sodium carbonate, potassium carbonate or sodium methylate in one suitable solvents such as methanol, ethanol or a mixture of Methanol or ethanol can be carried out with water at room temperature.

Process variant b)

The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of the formula II with a compound of formula V to a compound of formula I can in Presence of a base such as triethylamine, N-methylmorpholine, N, N-diisopropylethylamine in a suitable solvent such as tetrahydrofuran, Acetonitrile, dioxane or N, N-dimethylformamide at a temperature between Room temperature and the boiling point of the solvent become.

Process variant c)

The Suzuki reaction of a compound of formula VI with a boronic acid of formula VII can in the presence of a base such as cesium fluoride, sodium carbonate or potassium carbonate and a catalyst such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd (OAc) ₂ / PPh ₃ in a suitable solvent such as dioxane, tetrahydrofuran, dimethoxyethane or a mixture of methanol and dimethoxyethane at a temperature between room temperature and the boiling point of the solvent.

Process variant d)

The Miyaura reaction of a compound of formula VI with a diboronic acid derivative of formula VIII to a compound of formula IX can in the presence of a base such as potassium acetate or triethylamine and a catalyst such as PdCl ₂ (diphenylphosphinoferrocene) or PdCl ₂ (PPh ₃ ) ₂ in a suitable solvent such as acetonitrile, dioxane, dimethoxyethane, dimethyl sulfoxide or N, N-dimethylformamide at a temperature between room temperature and the boiling point of the solvent.

The reaction of a compound of formula IX with a compound of formula X can be carried out in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate and a catalyst such as Pd (PPh ₃ ) ₄ or PdCl ₂ (PPh ₃ ) ₂ in a suitable solvent such as dioxane, tetrahydrofuran , Dimethoxyethan or N, N-Dimethylformamid be carried out at a temperature between room temperature and the boiling point of the solvent.

Process variant e)

The reaction of a compound of formula XI with N- (1-cyclopenten-1-yl) - Morpholine of the formula XII to a compound of the formula XIII can in one suitable solvents such as petroleum ether, ligroin, cyclohexane, hexane, pentane, Acetonitrile or dichloromethane at a temperature between room temperature and the boiling point of the solvent.

The reaction of a compound of formula XIII with hydrazine or hydrazine hydrate can in a suitable solvent such as methanol, ethanol or Tetrahydrofuran at a temperature between room temperature and the Boiling temperature of the solvent can be carried out.

Process variant f)

The reaction of a compound of formula XIV with a compound of formula XV to a compound of the formula I can be analogous to that in J. Heterocyclic Chem. 34, 1549 (1997).

The 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of the formula II is new and can be obtained by methods described in the literature, e.g. B. from Cyclopentanone thiosemicarbazone (J. Heterocyclic Chem. 34, 1549 (1997)) or from cyclopentanone-2-carbonitrile (J. Org. Chem., 52, 5538 (1987)).

The present invention thus also relates to compounds of the general formula II


in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I, as valuable intermediates for the preparation of the compounds of the general formula I according to the invention

The compounds of formulas III, V, VII, VIII, X, XI, XII, XIV and XV are either commercially available or can by methods known per se from the literature getting produced.

The compounds of formula I and the precursors for their preparation which are attached to a solid phase are bound, can be prepared by methods known per se become. Likewise, the elimination by acid hydrolysis to the free Connections are carried out according to known methods.

The compounds of the invention essentially inhibit cyclin-dependent kinases, whereupon their action, for example, against cancer, such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapy-induced alopecia and mucositis, cardiovascular diseases such as stenoses, arteriosclerosis and restenosis, infectious diseases, such as B. by unicellular parasites, such as Trypanosoma, Toxoplasma or Plasmodium, or caused by fungi, nephrological Diseases such as B. Glomerulonephritis, chronic neurodegenerative Diseases such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases such as ischemia of the brain and Neurotrauma, viral infections, such as B. cytomegalus infections, herpes, Hepatitis B and C, and HIV diseases based.

The present invention thus also relates to the use of Compounds according to the invention in these indications.

The eukaryotic cell division cycle represents the duplication of the genome and its Distribution to the daughter cells safely by having a coordinated and regulated Sequence of events iterates through. The cell cycle is divided into four successive phases divided: The G1 phase represents the time before the DNA replication in which the cell grows and is susceptible to external stimuli is. In the S phase the cell replicates its DNA and in the G2 phase it prepares anticipate entering mitosis. In the mitosis (M phase) the replicated DNA separated and cell division completed.

The Cyclin Dependent Kinases (CDKs), a family of Ser / Thr kinases whose Members bind a cyclin (Cyc) as a regulatory subunit to theirs Need activation, push the cell through the cell cycle. different CDK / Cyc pairs are active in the different phases of the cell cycle. For the fundamental function of the cell cycle are significant CDK / Cyc pairs for example CDK4 (6) / CycD, CDK2 / CycE, CDK2 / CycA, CDK1 / CycA and CDK1 / CycB. Some members of the CDK enzyme family have a regulatory function by affecting the activity of the aforementioned cell cycle CDKs while other members of the CDK enzyme family still have no specific function could be assigned. One of these, CDK5, is characterized by that it is an atypical, different from the cyclin regulatory Has subunit (p35) and its activity is highest in the brain.

The entry into the cell cycle and the passage of the "restriction point", which marks the independence of a cell from further growth signals for the completion of the started cell division, are controlled by the activity of the CDK4 (6) / CycD and CDK2 / CycE complexes. The main substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene. Rb is a transcriptional co-repressor protein. Rb binds and inactivates transcription factors of the E2F type, and forms transcriptional repressor complexes with histone deacetylases (HDAC) (Zhang HS et al. (2000) .Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI / SNF and Rb-hSWI / SNF. Cell 101, 79-89). The phosphorylation of Rb by CDKs releases bound E2F transcription factors and leads to transcriptional activation of genes, the products of which are required for DNA synthesis and progression through the S phase. In addition, Rb phosphorylation causes the Rb-HDAC complexes to dissolve, thereby activating additional genes. The phosphorylation of Rb by CDK's is equivalent to the exceeding of the "restriction point". For the progression through the S phase and its completion, the activity of the CDK2 / CycE and CDK2 / CycA complexes is necessary, e.g. B. the activity of the transcription factors of the E2F type is switched off by means of phosphorylation by CDK2 / CycA as soon as the cells have entered the S phase. After complete replication of the DNA, the CDK1 in complex with CycA or CycB controls the entry and the passage of phases G2 and M ( Fig. 1).

This is according to the extraordinary importance of the cell division cycle Going through the cycle strictly regulated and controlled. The enzymes that are for the Progression through the cycle is necessary at the right time be activated and also switched off again as soon as the corresponding Phase has passed. Lock the corresponding checkpoints progression through the cell cycle if DNA damage is detected, or DNA replication or the construction of the spindle apparatus has not yet been completed is.

The activity of the CDKs is controlled by various mechanisms, such as synthesis and Degradation of the cyclin, complexation of the CDKs with the corresponding ones Cyclins, phosphorylation and dephosphorylation of regulatory Thr and Tyr Residues, and the binding of natural inhibitory proteins, directly controlled. While the protein level of CDKs in a proliferating cell is relative is constant, the amount of the individual cyclines oscillates with the passage of the Cycle. For example, the expression of CycD during early G1 Phase stimulated by growth factors, and the expression of CycE after exceeding the "restriction point" by activating the E2F-type transcription factors induced. The cyclines themselves are made by Ubiquitin-mediated proteolysis degraded. Activating and inactivating Phosphorylation regulates the activity of the CDK's, for example phosphorylate CDK-activating kinases (CAKs) Thr160 / 161 of CDK1, whereas the family of Wee1 / Myt1 kinases CDK1 by phosphorylation inactivate Thr14 and Tyr15. This inactivating phosphorylation can be canceled by cdc25 phosphatases. Very significant is the regulation of the activity of the CDK / Cyc complexes by two families natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19). Members of the p21 Family bind to cyclin complexes of CDKs 1, 2, 4, 6, but only inhibit Complexes that contain CDK1 or CDK2. Are members of the p16 family specific inhibitors of the CDK4 and CDK6 complexes.

The lies above this complex direct regulation of the activity of the CDKs Control point regulation level. Control points allow the cell to do this to track the orderly progress of the individual phases during the cell cycle. The main checkpoints are at the transition from G1 to S and from G2 according to M. The G1 checkpoint ensures that the cell does not synthesize DNA starts with other cells or if she is not properly fed Substrate interacts correctly, and their DNA is intact. The G2 / M checkpoint poses the complete replication of the DNA and the structure of the mitotic spindle safe before the cell enters mitosis. The G1 checkpoint is from the Gene product of the p53 tumor suppressor gene activated. After detection of Changes in the metabolism or genomic integrity of the cell activated and can either stop cell cycle progression or apoptosis trigger. The transcriptional activation of CDK expression plays a role here Inhibitor protein p21 through p53 play a crucial role. A second branch of the G1 control point includes activation of ATM and Chk1 kinases after DNA Damage from UV light or ionizing radiation and finally the Phosphorylation and subsequent proteolytic degradation of the cdc25A Phosphatase (Milan N. et al. (2000). Rapid destruction of human cdc25A in response to DNA damage. Science 288, 1425-1429). This results in one Locking of the cell cycle because of the inhibitory phosphorylation of the CDKs is not removed. After activating the G2 / M checkpoint due to damage Both mechanisms are involved in the DNA in a similar way Stop progression through the cell cycle.

Loss of regulation of the cell cycle and loss of function of the Checkpoints are characteristics of tumor cells. The CDK-Rb signaling path is in Over 90% of human tumor cells affected by mutations. These mutations that eventually lead to inactivating phosphorylation of the RB, close the Overexpression of D and E cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of P16-type CDK inhibitors, as well as increased (p27) or decreased (CycD) Protein breakdown. The second group of genes caused by mutations in Tumor cells are hit encoding components of the control points. So is p53, which is essential for the G1 and G2 / M control points, is the most common mutated gene in human tumors (approx. 50%). In tumor cells without p53 Express mutation, it is often due to a greatly increased Protein degradation disabled. Similarly, the genes of others are for that Function of the control points of necessary proteins affected by mutations, for Example ATM (inactivating mutations) or cdc25 phosphatases (Overexpression).

Convincing experimental data suggest that CDK2 / Cyc complexes occupy a critical position during cell cycle progression: (1) Both dominant-negative forms of CDK2 and transcriptional repression CDK2 expression by anti-sense oligonucleotides stop the Cell cycle progression. (2) Inactivation of the CycA gene in mice is lethal. (3) Interfering with the function of the CDK2 / CycA complex in cells cell-permeable peptides led to tumor cell-selective apoptosis (Chen Y.N.P. et al. (1999). Selective killing of transformed cells by cyclin / cyclin dependent kinase 2 antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

Changes in cell cycle control don't just play a role in cancer a role. The cell cycle is characterized by a number of viruses, both by transforming, as through non-transforming, activated to multiply to allow the viruses in the host cell. The wrong entry into the cell cycle of normally post-mitotic cells is made with different related to neurodegenerative diseases.

The mechanisms of cell cycle regulation, their changes in diseases and a variety of approaches to developing inhibitors of the Cell cycle progression and specifically the CDKs have been seen in several Publications described in detail (Sielecki T. M. et al. (2000). Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J. Med. Chem. 43, 1-18; Fry D.W. & Garrett M.D. (2000). Inhibitors of cyclindependent kinases as therapeutic agents for the treatment of cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2, 40-59; Rosiania G.R. & Chang Y.T. (2000). Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al. (1999). Properties and potential applications of chemical inhibitors of cyclin dependent kinases. Pharmacol. Ther. 82, 279-284; Senderowicz A.M. & Sausville E.A. (2000). Preclinical and clinical development of cyclin dependent kinase modulators. J. Natl. Cancer Inst. 92, 376-387).

The use of the compounds according to the invention as pharmaceuticals brought this into the form of a pharmaceutical preparation, which in addition to the Active pharmaceutical ingredient suitable for enteral or parenteral administration, organic or inorganic inert carrier materials, such as water, Gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, contains vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories, Capsules or in liquid form, for example as solutions, suspensions or Emulsions are present. If necessary, they also contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for Change in osmotic pressure or buffer.

These pharmaceutical preparations are also the subject of the present Invention.

In particular, injection solutions or are for parenteral use Suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, suitable.

Surfactant auxiliaries such as salts of the Bile acids or animal or vegetable phospholipids, but also Mixtures thereof as well as liposomes or their components are used.

For oral use in particular tablets, coated tablets or capsules are included Talc and / or hydrocarbon carriers or binders, such as lactose, Corn or potato starch, suitable. The application can also be in liquid form take place, such as as juice, which may have a sweetener added.

The enteral, parenteral and oral applications are also a subject of the present invention.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and the like Factors vary. The daily dose is 0.5-1000 mg, preferably 50-200 mg, where the dose as a single dose to be administered or divided into 2 or several daily doses can be given.

The present invention also relates to the use of Compounds of general formula I, for the manufacture of a medicament for Treatment of cancer, autoimmune diseases, cardiovascular Diseases, chemotherapy-induced alopecia and mucositis, infectious Diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, with cancer solid tumors and leukemia, among autoimmune psoriasis, alopecia and multiple sclerosis, stenoses among cardiovascular diseases, Atherosclerosis and restenosis, among infectious diseases unicellular parasite-induced diseases, among nephrological Diseases glomerulonephritis, among chronic neurodegenerative Huntington's Disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, under acute neurodegenerative diseases ischemia of the brain and Neurotrauma, and among viral infections, cytomegalus infections, herpes, Hepatitis B or C, and HIV diseases are to be understood.

The present invention also relates to medicaments for Treatment of the diseases listed above, at least one Contain compound according to general formula I, as well as drugs with suitable formulation and carrier substances.

The compounds of general formula 1 according to the invention are under other excellent inhibitors of cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as the glycogen Synthase kinase (GSK-3β).

The following examples illustrate the preparation of the invention Compounds without restricting the invention to these examples.

Example 1.0 2- (3'-fluoro-biphenyl-4-yl) -N- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) - acetamide

230 mg of 2- (3'-fluorobiphenyl-4-yl) acetic acid are dissolved in 5 ml of tetrahydrofuran dissolved, mixed with 0.11 ml of oxalyl chloride and a drop of dimethylformamide and stirred for 2 hours at room temperature. 62 mg are added to this solution 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine added. The mixture will Stirred for 12 hours at room temperature and then concentrated. The The residue is extracted with ethyl acetate. The extract comes with Sodium bicarbonate solution and water washed over Magnesium sulfate dried and concentrated. The brown residue is in 5 ml Dissolved methanol and with 0.1 ml of a 30% sodium methylate solution added. It is stirred for 4 hours at room temperature and then concentrated. The residue is extracted with ethyl acetate. The extract comes with Sodium bicarbonate solution and sodium chloride solution washed over Magnesium sulfate dried and concentrated. It becomes a yellow resinous oil obtained, which is purified by HPLC. 2- (3'-Fluoro-biphenyl-4-yl) - N- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) acetamide of melting point 165-166 ° C.

Production of the starting material

1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine

5.3 g of cyclopentanone thiosemicarbazone are carefully added at 0 ° C. to a solution of lithium diisopropylamine in 200 ml of tetrahydrofuran (from 29 ml of diisopropylamine and 81 ml of 1.6 M n-butyllithium), the temperature rising to 30 ° C. The mixture is then stirred at room temperature for 2 hours. Then 150 ml of 4 N hydrochloric acid are carefully added dropwise (exothermic, H ₂ S evolution) and the mixture is heated under reflux for 30 minutes. It is then cooled to 5 ° C. and adjusted to pH 14 with sodium hydroxide solution. The aqueous phase is extracted three times with tetrahydrofuran / ethyl acetate 95: 5. The crude product is purified by column chromatography on silica gel with 1 l of ethyl acetate and 1 l of ethyl acetate / methanol 9: 1 with the addition of 3% triethylamine. 2.58 g of 1,4,5,6-tetrahydrocyclopentapyrazol-3-yl-amine with a melting point of 116-120 ° C. are obtained.

Production of the starting material 6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine

A mixture of 1-methylcyclopentanone (9.82 g, 100 mmol) and dimethylformamide-dimethylacetal (26 ml, 150 mmol) is heated at 110 ° C for 4.5 hours, concentrated and distilled in a Kugelrohr oven at 160-170 ° C / 2 mbar.
Yield: 7.7 g
MS-CI (NH3): 154

A solution of the enamine (7.65 g, 50 mmol) in methanol (50 ml) is mixed with hydroxylamine hydrochloride (3.47 g, 50 mmol), stirred for 1 hour at 50 ° C., mixed with diethyl ether, suction filtered and the mother liquor concentrated.
Yield: 6.08 g of isoxazole.
MS-EI: 124

A solution of the isoxazole (6.1 g, 50 mmol) in diethyl ether (100 ml) is added dropwise with 0.5 M sodium methylate solution in methanol (100 ml, 50 mmol) and the mixture is stirred at 23 ° C. for 24 hours. The solution is concentrated, the residue is cooled, cold water is carefully added, the mixture is stirred with diethyl ether and the organic phase is separated off. The alkaline water phase is brought to pH 1 with 6N hydrochloric acid (12 ml), extracted with diethyl ether (4 × 40 ml), the organic phase dried (Na ₂ SO ₄ ), filtered off and concentrated.
Yield: 4.6 g of 2-cyano-5-methylcyclopentanone.
MS-CI (NH3): 141
IR: 2240 cm-1 (CN), 1760 cm-1 (CO)

A solution of 2-cyano-5-methylcyclopentanone (1.23 g, 10 mmol) in ethanol (20 ml) is mixed with hydrazine hydrate (80% in water, 0.68 g, 10.8 mmol) at 23 ° C and 2.5 hours at 23 ° C touched. 4N HCl-dioxane solution (2.5 ml, 10 mmol) is added to this solution, the mixture is stirred at 23 ° C. for 1.5 hours, concentrated to half the volume and the precipitated hydrochloride is suctioned off. The mother liquor is concentrated, the residue is stirred in diethyl ether / ethanol, suction filtered and dried.
Yield: 780 mg of 6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine hydrochloride.
Mp 191 ° C (dec.)
MS-CI (NH3): 138
1H-NMR (d6-DMSO): 13.6 (br.s, NH), 6.9 (br.s, NH2), 3.1 (sext., J ≍ 7 Hz, 1H), 2.7-2.3 (m, 3H), 2.0 -1.9 (m, 1H), 1.18 (d, J = 6.7, 3H). Preparation of the protected aminopyrazoles Preparation of 3-amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazole-1-carboxylic acid tert-butyl ester and 3-amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2 -carboxylic acid tert-butyl ester

Process variant A

A mixture of 6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-ylamine (1.37 g, 10 mmol) in hexamethyldisilazane (25 ml) was added dropwise with ice cooling Trimethylsilyl chloride (11.4 ml, 90 mmol) was added and the mixture was stirred at 130 ° C. for 5 hours cooked. The resulting solution was concentrated on a Rotavap and the resulting one Residue distilled in a Kugelrohr oven at 140-150 ° C / 2 mbar.

The colorless oil obtained was dissolved in dry MeCN (30 ml), Boc ₂ O (1.53 g, 7 mmol) was added, the mixture was stirred at room temperature for 10 hours and at 50 ° C. for 2 hours, concentrated and diluted with ethyl acetate. The organic phase was washed with saturated aqueous NH ₄ Cl solution and saturated aqueous NaCl solution, dried (Na ₂ SO ₄ ), filtered, concentrated and chromatographed (gradient CH ₂ Cl ₂ → CH ₂ Cl ₂ : MeOH 95: 5) ,

yield 3-Amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazol-1-carboxylic acid tert-butyl ester

0.31 g (12%). ¹ H-NMR (CDCl ₃ ): 3.30 (sext., J ≍ 7.0, HC (6)), 2.92 (br. S, NH ₂ ), 2.75 (m, 1H), 2.60 (m, 1H), 2.1 ( m, 1H), 1.60 (s, tert.Bu), 1.22 (d, J = 7.1 Hz, Me).
MS-CI (C ₁₂ H ₁₉ N ₃ O ₂ ): 238 (100, [M + H] ⁺ ), 138 (78, [M-Boc + H] ⁺ ).

3-Amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazol-2-carboxylic acid tert-butyl ester

1.13 g (76%). ¹ H-NMR (CDCl ₃ ): 5.29 (br.s, NH ₂ ), 3.05 (sext., J ≍ 7.0, HC (6)), 2.55-2.30 (m, 3H), 1.88 (m, 1H), 1.63 (s, tert.Bu), 1.27 (d, J = 7.1 Hz, Me). MS-CI (C ₁₂ H ₁₉ N ₃ O ₂ ): 238 (55, [M + H] ⁺ ), 138 (100, [M-Boc + H] ⁺ ).

Process variant B

A mixture of KOH (450 mg, 8 mmol) in water (1.8 ml) and 6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-ylamine (1 mmol) in CH ₂ Cl ₂ (8 ml) was mixed with very vigorous stirring with a solution of Boc ₂ O (1.05 mmol) in CH ₂ Cl ₂ (1 ml) and until conversion was complete (TLC: CH ₂ Cl ₂ / MeOH 95: 5, Hex / AcOEt 1 : 1, Tol / EtOH 9: 1, about 1 hour). The phases were then separated, the organic phase washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated. After chromatographic purification (silica gel, gradient CH ₂ Cl ₂ → CH ₂ Cl ₂ : MeOH 95: 5), 0.029 g (12%) of 3-amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazole-1-carboxylic acid tert-butyl ester and 0.149 g (63%) 3-amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid tert-butyl ester obtained. The spectroscopic data agree with the compounds obtained according to process variant A.

In an analogous procedure according to procedure variant B are also manufactured:

3-Amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazol-1-carboxylic acid benylester

0.024 g (9%). ¹ H-NMR (CDCl ₃ ): 7.50-7.30 (m, 5H), 5.36 (s, PhCH ₂ ), 3.25 (sext., J ≍ 7.1, HC (6)), 2.99 (br.s, NH ₂ ) , 2.81-2.68 (m, 1H), 2.41-2.31 (m, 2H), 2.11-2.02 (m, 1H), 1.18 (d, J = 7.1 Hz, Me). MS-EI (C ₁₅ H ₁₇ N ₃ O ₂ ): 271 (18, [M] ⁺ ), 226 (15), 136 (10), 91 (100).

3-Amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazol-2-carboxylic acid benzyl ester

0.152 g (56%). ¹ H-NMR (CDCl ₃ ): 7.50-7.30 (m, 5H), 5.42 (d, J = 12.2, PhCH), 5.38 (d, J = 12.2, PhCH), 5.00 (br.s, NH ₂ ), 3.01 (sext. J ≍ 7.1, HC (6)), 2.58-2.31 (m, 3 H), 1.96-1.82 (m, 1H), 1.26 (d, J = 7.1, Me). MS-EI (C ₁₅ H ₁₇ N ₃ O ₂ ): 271 (25, [M] ⁺ ), 226 (22), 136 (25), 91 (100).

2-benzyl-6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-ylamine

0.114 g (50%). ¹ H-NMR (CDCl ₃ ): 7.36-7.12 (m, 5H), 5.20 (d, J = 12.1, PhCH), 5.16 (d, J = 12.1, PhCH), 3.26 (br.s, NH ₂ ), 3.01 (sext. J ≍ 7.0, HC (6)), 2.61-2.36 (m, 3 H), 1.99-1.82 (m, 1H), 1.27 (d, J = 7.1, Me). MS-CI (C ₁₄ H ₁₇ N ₃ ): 228 (100, [M + H] ⁺ ).

6-Methyl-2- (2-trimethylsilanyl-ethoxymethyl) -2,4,5,6-tetrahydro-cyclopentapyrazol-3-ylamine

0.139 g (54%). ¹ H-NMR (CDCl ₃ ): 5.11 (s, PhCH ₂ ), 3.58 (t, J ≍ 7.6, OCHCH ₂ ), 3.55 (t, J ≍ 7.6, OCHCH ₂ ), 3.32 (br.s, NH ₂ ) , 3.11 (sext., J ≍ 7.0, HC (6)), 2.78-2.66 (m, 1H), 2.54-2.35 (m, 2H), 2.12-2.01 (m, 1H), 1.24 (d, J = 7.1, Me), 0.91 (t, J ≍ 7.8, CH ₂ CHSiMe ₃ ), 0.90 (dd, J = 8.2, 6.3, CH ₂ CHSiMe ₃ ), -0.02 (s, 9H). MS-CI (C ₁₃ H ₂₅ N ₃ OSi): 268 (100, [M + H] ⁺ ). Preparation of 3- [2- (3'-acetyl-biphenyl-4-yl) acetylamino] -6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid benzyl ester

A solution of 3-amino-6-methyl-5,6-dihydro-4H cyclopentapyrazole-2-carboxylic acid benzyl ester (0.271 g, 1 mmol) and diisopropylethylamine (340 µl, 2 mmol) in CH ₂ Cl ₂ (5 ml) was added A solution of (3'-acetyl-biphenyl-4-yl) -acetyl chloride (1.1 mmol) in CH ₂ Cl ₂ (4 ml) was added dropwise at room temperature, the mixture was stirred for 12 hours, poured onto ice water and treated with CH ₂ Cl ₂ extracted. The organic phase was dried (Na ₂ SO ₄ ), filtered, concentrated and chromatographed (gradient CH ₂ Cl ₂ → CH ₂ Cl ₂ : MeOH 95: 5).
Yield: 0.365 g (72%). ¹ H NMR (CDCl ₃ ): 10.00 (br.s, NH), 8.20 (br.s, 1H), 7.91 (m, 1H), 7.75 (m, 1H), 7.61 (d, J = 7.0, 2H ), 7.60 (t, J ≍ 7.0, 1H), 7.42 (d, J = 7.0, 2H), 3.72 (s, PhCH ₂ ), 3.10 (br.s, 1H), 2.65 (s, 3H), 2.63- 2.49 (m, 3H), 1.90-1.82 (m, 1H), 1.14 (d, J = 6.9, Me). MS-EI (C ₃₁ H ₂₉ N ₃ O ₄ ): 507 (10, [M] ⁺ ), 373 (50), 209 (65), 165 (70), 137 (100). Preparation of 3- (2-biphenyl-4-yl-acetylamino) -6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid tert-butyl ester

A solution of 3-amino-6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid tert-butyl ester (0.475 g, 2 mmol) and diisopropylethylamine (681 µl, 4 mmol) in CH ₂ Cl ₂ (10 ml) was added dropwise at room temperature with a solution of biphenylacetic acid chloride (2.2 mmol) in CH ₂ Cl ₂ (4 ml), stirred for 12 hours, poured onto ice water and extracted with CH ₂ Cl ₂ . The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated. Crystallization of the residue from Et ₂ O (20 ml) gave 0.379 g of colorless crystals. Chromatographic purification of the mother liquor (silica gel, gradient CH ₂ Cl ₂ → CH ₂ Cl ₂ : MeOH 95: 5) gave a further 0.316 g of product.
Yield: 0.695 g (81%). Mp 141 ° C (dec.). ¹ H NMR (CDCl ₃ ): 10.35 (br.s, NH), 7.61-7.53 (m, 4H), 7.46-7.32 (m, 5H), 3.76 (s, PhCH ₂ ), 3.09-2.95 (m, 2H), 2.91-2.80 (m, 1H), 2.52-2.41 (m, 1H), 1.91-1.79 (m, 1H), 1.59 (s, tert-Bu), 1.27 (d, J = 7.1, Me). MS-CI (C ₂₆ H ₂₉ N ₃ O ₃ ): 432 (20, [M + H] ⁺ ), 332 (100, [M-Boc + H] ⁺ ).

The following are also produced in an analogous manner:

3- [2- (3'-methoxy-biphenyl-4-yl) acetylamino] -6-methyl-5,6-dihydro-4H- cyclopentapyrazol-2-carboxylic acid tert-butyl ester

Yield: 75%. ¹ H NMR (CDCl ₃ ): 10.15 (br.s, NH), 7.66 (d, 7.0, 2H), 7.41-7.31 (m, 3H), 7.16-7.08 (m, 2H), 6.88 (m, 1H ), 3.88 (s, OMe), 3.75 (s, PhCH ₂ ), 3.09-2.95 (m, 2H), 2.91-2.80 (m, 1H), 2.52-2.41 (m, 1H), 1.91-1.79 (m, 1H), 1.59 (s, tert Bu), 1.27 (d, J = 7.1, Me). MS-CI (C ₂₇ H ₃₁ N ₃ O): 461 (10, [M + H] ⁺ ), 361 (100, [M-Boc + H] ⁺ ).

3- (2- (3'-Fluoro-biphenyl-4-yl) acetylamino] -6-methyl-5,6-dihydro-4H- cyclopentapyrazol-2-carboxylic acid tert-butyl ester

Yield: 60%. ¹ H NMR (d ₆ -DMSO): 10.10 (br.s, NH), 7.62 (d, 7.0, 2H), 7.52-7.47 (m, 3H), 7.38 (d, J = 7.0, 2H), 7.15 (m, 1H), 3.79 (s, PhCH ₂ ), 2.95 (sext., J = 6.2, 1H), 2.52-2.41 (m, 3H), 1.81-1.72 (m, 1H), 1.52 (s, tert- Bu), 1.18 (d, J = 7.1, Me). MS-EI (C ₂₆ H ₂₈ FN ₃ O ₃ ): 449 (10, [M] ⁺ ), 349 (40, [M-Boc] ⁺ ), 185 (45), 137 (100).

6-Methyl-3- [2- (4-thiophen-3-yl-phenyl) acetylamino] -5,6-dihydro-4H- cyclopentapyrazol-2-carboxylic acid tert-butyl ester

Yield: 58%. ¹ H NMR (CDCl ₃ ): 10.12 (br.s, NH), 7.62 (d, 7.0, 2H), 7.41 (m, 1 H), 7.40-7.30 (m, 4H), 3.71 (s, PhCH ₂ ), 3.00 (m, 1H), 2.52-2.41 (m, 3H), 1.81-1.72 (m, 1H), 1.52 (s, tert-Bu), 1.18 (d, J = 7.1, Me). MS-EI (C ₂₄ H ₂₇ N ₃ O ₃ S): 337 (50, [M-Boc] ⁺ ), 200 (45), 173 (80), 137 (100).

Process variant C Preparation of the biaryl-pyrazole derivatives on the solid phase

The implementations on the fixed phase are done in a manual Synthesis robots from MultiSynTech, Germany.

1st stage

3.024 g of trityl resin (NovaBiochem, loading: 1.35 mmol / g, 4.08 mmol) are in 70 ml of dichloromethane / DMF mixture (6: 1) and swollen for 30 minutes. Then 1.42 g (4.44 mmol) of 2- (3-bromophenyl) -N- (1,4,5,6- tetrahydro-cyclopentapyrazol-3-yl) acetamide and 3 ml diisopropylethylamine add and shake the mixture for 3 days at room temperature.

For working up, the polymer is separated off via a frit. The first filtrate is collected separately and used in a slight excess Pyrazolamide after removal of the solvent using chromatographic purification reisolated.

The polymer is successively three times with 50 ml of DMF, methanol and Washed dichloromethane. Finally, the resin is at 40 ° C Drying freed of residues of adhering solvent. 4.029 g was isolated polymer-bound material that was used further.

In an analogous manner, polymer-bound 2- (4-bromophenyl) -N- (1,4,5,6- tetrahydro-cyclopentapyrazol-3-yl) acetamide. The load was here somewhat lower, so that in the subsequent stages 200 mg resin per reactor on Synthesis robots were used.

2nd stage

120 mg of resin (preparation see first stage) were placed in a reactor. 1.0 ml of arylboronic acid solution (0.4 M solution in DME / MeOH, 5: 1), 1.0 ml of CsF solution (0.8 M solution in DME / MeOH, 3: 1), 0 , 5 ml of Na ₂ CO ₃ solution (2.0 M in water) and 0.1 ml of freshly prepared tetrakis (triphenylphosphine) palladium (0) solution (0.1 M in THF) were added manually.

After the addition has ended, the batch is run over 18 hours at intervals (2 minutes Stirring, 58 minutes standstill) at 70 ° C. Then the approach three times with 2 ml DMF and then three times with 2 ml dichloromethane washed.

To complete the implementation, the process described above is still in progress repeated once with the same amounts.

3rd stage

To split off the products formed from the solid phase, this is done in the second Step obtained polymeric product with 1.5 ml of a 15% solution of Trifluoroacetic acid in dichloromethane (with the addition of 5 vol% triethylsilane) stirred for 90 minutes at room temperature. Then the polymer filtered and the residue again with 2 ml of THF and three times with 1.5 ml each Washed dichloromethane. The combined filtrates are concentrated and that Crude product purified by preparative HPLC.

The following compounds are also produced in an analogous manner.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =









R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =

R ¹ =



R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =

Ph = phenyl

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =



R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -



R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =



R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
R ¹ =

Ph = phenyl

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
R ¹ =















R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH (CH ₃ ) -
R ¹ =

Example 10.0 Preparation of 2- (3'-acetyl-biphenyl-4-yl) -N- (6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) acetamide

A solution of 3- [2- (3'-acetyl-biphenyl-4-yl) acetylamino] -6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid benzyl ester (125 mg, 0.25 mmol ) in EtOH (50 ml) is mixed with 10% -Pd / C (20 mg), hydrogenated for 2 h at room temperature under normal pressure, filtered, concentrated and dried.
Yield 66 mg (80%): ¹ H-NMR (d ₆ -DMSO): 11.90 (br.s, NH), 10.33 (br.s, NH), 8.18 (br.s, 1H), 7.92-7.88 ( m, 2H), 7.66 (d, J = 7.0, 2H), 7.62 (t, J ≍ 7.0, 1H), 7.41 (d, J = 7.0, 2H), 3.61 (s, PhCH ₂ ), 3.10 (br. s, 1H), 2.66 (s, 3H), 2.63-2.49 (m, 3H), 1.90-1.82 (m, 1H), 1.15 (d, J = 6.9, Me). MS-EI (C ₂₃ H ₂₃ N ₃ O ₂ ): 373 (50, [M] ⁺ ), 209 (50), 137 (100). Example 10.1 Preparation of 2-biphenyl-4-yl-N- (6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) acetamide

A solution of 3- (2-biphenyl-4-yl-acetylamino) -6-methyl-5,6-dihydro-4H-cyclopentapyrazole-2-carboxylic acid tert-butyl ester (0.475 g, 1.1 mmol) in dioxane (7 ml ) was added at room temperature with hydrochloric acid (4 N solution in dioxane, 0.55 ml, 2.2 mmol), stirred for 5 hours at room temperature and concentrated. The crystalline residue obtained was stirred for 10 minutes in aqueous 5% NaHCO ₃ solution (10 ml), filtered off and dried.
Yield: 0.29 g (80%). Mp 235-8 ° C. ¹ H-NMR (d ₆ -DMSO): 11.91 (br.s, NH), 10.30 (br.s, NH), 7.66-7.59 (m, 4H), 7.48-7.33 (m, 5H), 3.61 (s , PhCH ₂ ), 3.10 (br.s, 1H), 2.63-2.48 (m, 3H), 1.90-1.82 (m, 1H), 1.15 (d, J = 6.9, Me). MS-CI (C ₂₁ H ₂₁ N ₃ O): 332 (100, [M + H] ⁺ ).

The following connections are also produced in an analogous manner:

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ = hydrogen
R ⁷ = CH ₃
T = -CH ₂ -
n = 1
R ¹ =





R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
n = 1
T = -CH ₂ -
R ¹ =









R ² , R ³ , R ⁴ , R ⁶ and R ⁷ = hydrogen
R ⁵ = -CH ₃
n = 1
T = -CH ₂ -
R ¹ =





R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -



R ² , R ³ , R ⁴ , R ⁵ , R ⁵ and R ⁷ = hydrogen
T = -CH ₂ -
n = 1
R ¹ =



R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ = hydrogen
T = -CH ₂ -
n = 1
R ¹ =

Attempt to prepare the compounds of the invention analogously to the methods described in WO 01179198

With regard to the compounds generally described in WO 01/79198 it is examined whether the processes described there for the production of Use aminopyrazoles also for the acylaminopyrazoles according to the invention to let.

The reactions are carried out according to the general scheme 1 scheme 1

The compound mentioned under Example 8.6 was used as a production example selected.

On page 38 of WO 01/79198 three "General Reaction Schemes" are listed, all of which correspond to the reaction shown in Scheme 1.

The starting materials for this reaction are all commercially available and were obtained directly from the experiments used.

1. Production analogous to example 1 (a) on page 41 of WO 01/79198

0.76 ml (8.6 mmol) of cyclopentanone and 1.16 ml (8.6 mmol) of benzoyl isothiocyanate are reacted as described in Example 1 (a). After column chromatography, two fractions are isolated: fraction 1 107 mg of the compound of the structure

Fraction 2 417 mg of the compound of the structure

2. Production analogous to the precursor to Example 1 (j) on page 49 of the WO 01/79198

8.13 ml (8.13 mmol) lithium bis (trimethylsilyl) amide in tetrahydrofuran (THF) (45 ml), 0.6 ml (6.78 mmol) cyclopentanone in 30 ml THF, 1.1 ml (8.13 mmol) of benzoyl isothiocyanate, 60 ml of ethanol, 0.54 ml (11.15 mmol) of hydrazine hydrate and 15 drops of acetic acid are reacted as described. After column chromatography, several fractions are isolated: No fraction shows the sought peak [M + 1] of 228 m / e in the mass spectrum (CI). 3. Preparation of a reference standard analogous to Scheme 2 Scheme 2

spectroscopic properties

¹ H-NMR (DMSO): 11.98 (br.s, NH), 10.52 (br.s, NH), 7.98 (d, 2H), 7.51 (m, 3H), 2, 64 (m, 4H), 2.38 (q, 4H)
MS-CI (C ₁₃ H ₁₃ N ₃ O): 228 (100%, [M + 1]), 105 (8%)

2. Attempt to manufacture analogous to example 1 (a) on page 41 of WO 01/79198

0.38 ml (4.3 mmol) cyclopentanone and 0.58 ml (4.3 mmol) benzoyl isothiocyanate are implemented as described. There is no column chromatography carried out, but examined the raw product by means of analytical HPLC. It no product corresponding to the reference standard can be detected. The Molpeak is not found in the mass spectrum either.

It can be clearly seen from the results of the attempted synthesis that none of the described process variants results in the desired product.

The following examples describe the biological effects of compounds of the invention without the invention to these examples restrict.

Application example 1 CDK2 / CycE kinase assay

Recombinant CDK2 and CycE-GST fusion proteins, purified from Bakulovirus-infected insect cells (Sf9) were developed by Dr. Dieter Marmé, Clinic for Tumor biology Freiburg. Histone IIIS used as a kinase substrate was bought from Sigma.

CDK2 / CycE (50 ng / measuring point) was in assay buffer [50 mM Tris / HCl pH 8.0 for 15 min at 22 ° C. in the presence of various concentrations of test substances (0 μM, as well as within the range 0.01-100 μM). 10 mM MgCl ₂ , 0.1 mM Na ortho-vanadate, 1.0 mM dithiothreitol, 0.5 µM adenosine trisphosphate (ATP), 10 µg / measuring point histone IIIS, 0.2 µCi / measuring point ³³ P-gamma ATP, 0, 05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped by adding EDTA solution (250 mM, pH 8.0, 14 μl / measuring point).

10 μl of each reaction mixture were applied to P30 filter strips (Wallac), and ³³ P-ATP which had not been incorporated was removed by washing the filter strips three times for 10 min each in 0.5% strength phosphoric acid. After the filter strips had dried for 1 hour at 70 ° C., the filter strips were covered with scintillator strips (MeltiLex ™ A, Wallac) and baked at 90 ° C. for 1 hour. The amount of ³³ P incorporated (substrate phosphorylation) was determined by scintillation measurement in a gamma radiation measuring device (Wallac).

Example of use 2 proliferation assay

Cultivated human MCF7 tumor cells were plated at a density of 5000 cells / measuring point in a 96-well II multititer plate in 200 μl of the corresponding growth medium. After 24 hours, the cells of one plate (zero plate) were stained with crystal violet (see below), while the medium of the other plates was stained with fresh culture medium (200 μl) containing the test substances in various concentrations (0 μM and in the range 0.01) -30 µM; the final concentration of the solvent dimethyl sulfoxide was 0.5%) were replaced. The cells were incubated for 4 days in the presence of the test substances. The cell proliferation was determined by staining the cells with crystal violet: the cells were fixed for 15 min at room temperature by adding 20 .mu.l / measuring point of an 11% glutaraldehyde solution. After washing the fixed cells three times with water, the plates were dried at room temperature. The cells were stained by adding 100 μl / measuring point of a 0.1% crystal violet solution (pH adjusted to pH 3 by adding acetic acid). After washing the stained cells three times with water, the plates were dried at room temperature. The dye was dissolved by adding 100 ul / measuring point of a 10% acetic acid solution. The absorbance was determined photometrically at a wavelength of 595 nm. The percentage change in cell growth was calculated by normalizing the measured values to the absorbance values of the zero point plate (= 0%) and the absorbance of the untreated (0 μM) cells (= 100%).

Claims (15)

1. Compounds of the general formula I in which


in the
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ - C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ - heterocycloalkyl, C ₃ -C ₁₂ -Heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted or may be multiply substituted identically or differently,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which can optionally be substituted one or more times, identically or differently,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may optionally be substituted one or more times, identically or differently, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal with O, O; N, O; O, S; or S, S, which may optionally be substituted by C ₁ -C ₆ alkyl, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which can optionally be substituted one or more times, identically or differently,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or can be substituted differently, or together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which can optionally be substituted one or more times, identically or differently, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ³ and R ⁵ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring which may optionally be substituted one or more times, identically or differently, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts. 2. Compounds of general formula I, according to claim 1, in which
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ - C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ - heterocycloalkyl, C ₃ -C ₁₂ -Heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkoxycarbonyl, cyano, nitro, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or with the group -CHO, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N -di-C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl or -CON-di-C _1-6 alkyl may be substituted, or may be substituted with a further aryl or heteroaryl radical , which may itself be substituted one or more times, identically or differently,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl can, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or may be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl, or together a C ₃ -C ₁₂ -Cycloalkyl- or C ₃ -C ₁₂ - cycloalkenyl ring, optionally one or more, the same or different with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts. 3. Compounds of general formula I, according to claims 1 and 2, in the
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or C ₃ - C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ - heterocycloalkyl, C ₃ -C ₁₂ -Heterocycloalkenyl, aryl or heteroaryl, which is optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkoxycarbonyl, cyano, nitro, C, 4-alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 - alkylsulfonyl, or with the group -CHO, -C (O) C _1-6 - alkyl, -NHC _1-6 -alkyl, -N- di-C _1-6 -alkyl, -CONH ₂ , -CONHC _1-6 -alkyl or -CON-di-C _1-6 -alkyl may be substituted, or may be substituted by a further aryl or heteroaryl radical, which may be one or more, the same or different, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkyl, halo- C _1-6 alkoxy, C _1-6 alkoxycarbonyl, C yano, nitro, C _1-6 alkylcarbonyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C ₁ -C ₆ alkylphenyl, C ₂ -C ₄ -Alkenylphenyl, C ₂ - C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl-C ₃ -C ₆ -cycloalklyl or with the group -COOH, -C (O) C _1-6 -alkyl, -NHC _{1 -6-} alkyl, -N-di-C _1-6 -alkyl, -CONH ₂ , -CONHC _1-6 -alkyl or -CON-di-C _1-6 -alkyl may be substituted,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl can, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or may be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl, or together a C ₃ -C ₁₂ -Cycloalkyl- or C ₃ -C ₁₂ - cycloalkenyl ring, optionally one or more, the same or different with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted, or
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, - CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts. 4. Compounds of general formula I, according to claims 1 to 3, in the
R ^{1 is} linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio or cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, oxiranyl, oxethanyl, aziridinylidyllidolidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidlyl, azididylidolidol, azididylidolidol, azididylidolidol, azididylolidol, azididylolidol Piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, thiinyl, dihydroacetyl, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooktadienyl, fluorenyl, aylenylhenyl, fluoro, aylenylhenyl, fluoro, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluorenyl, adenyl, fluoro, adenyl Furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazi nyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenodinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl yl, phenoxazinyl or xanthenyl, which is optionally one or more, identical or different, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo-C _{1- 6} alkyl, halo-C _1-6 - alkoxy, C _1-6 alkoxycarbonyl, cyano, nitro, C _1-6 - alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, or the group - CHO, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl or -CON-di -C _1-6 alkyl may be substituted, or may be substituted with a further aryl or heteroaryl radical, which may optionally itself be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkyl, Halo-C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, nitro, C _1--6 alkylcarbonyl, C ₁₄ alkylsulfanyl, C ₁₄ alkylsulfinyl, C _1--6 alkylsulfonyl, C ₁ -C _6- alkylphenyl, C ₂ -C ₄ -alkenylphenyl, C ₂ -C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl- C ₃ -C ₆ -cycloalklyl or with the group -COOH, -C (O) C _1-6 alkyl, -NHC _1-6 alkyl, -N-di-C _1-6 alkyl, -C (O) NH ₂ , - (O) NHC _1-6 alkyl or -CON-di-C _1-6 alkyl may be substituted,
R ² and R ^{3 are the} same or different and are hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy, which optionally substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 -alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, halogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy , which may be substituted one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl can, or together represent a carbonyl group, or together a cyclic five- or six-ring acetal of the structure


form, or
R ² and R ⁴ together form a C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or may be substituted with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or
R ³ and R ⁵ together form a C ₃ -C ₁ cycloalkyl or C ₃ -C ₇ cycloalkenyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, C _1-6 alkoxy , or can be substituted by the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl,
R ⁶ and R ^{7 are the} same or different and represent hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, which may be one or more, identical or can be differently substituted with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 -alkyl or -N-di-C _1-6 -alkyl, or together a C ₃ -C ₇ -Cycloalkyl- or C ₃ -C ₇ - cycloalkenyl ring, optionally one or more, the same or different with hydroxy, halogen, amino, C _1-6 alkoxy, or with the group -NHC _1-6 alkyl or -N-di-C _1-6 alkyl may be substituted,
R ⁵ and R ⁶ optionally together form a double bond, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T for -CH ₂ -, -O-, -CH ₂ = CH ₂ -, -CH ~ CH-, -CH ₂ -O-CH ₂ -, -CH ₂ O-, -O-CH ₂ -, -CH (CH ₃ ) - or = CO stands and
n is 0-6, mean, and their tautomers, isomers and salts. 5. Compounds of general formula I, according to claims 1 to 4, in the
R ^{1 represents} C ₁ -C ₆ alkylthio, phenyl, biphenyl, thienyl, cyclopropyl, cyclohexyl, pyridyl, naphthyl, 1,3-benzodioxol-5-yl or isoxazolyl, which is optionally one or more, identical or different, with halogen , amino, hydroxy, nitro, cyano, C ₁ -C ₆ -alkylsulfonyl, C _1-6 alkyl, halo-C _1-6 - alkyl, C _1-6 alkoxy, halo-C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, with the group -CHO or -C (O) C ₁ - C ₆ alkyl, or with phenyl, thienyl, naphthyl, benzothiophenyl, benzodioxol-5-yl, biphenyl, phenyloxy, benzofuranyl, indolyl , Pyridyl, furanyl or pyrimidinyl may be substituted, which may be mono- or polysubstituted, identically or differently, with C ₁ -C ₆ alkyl, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo- C ₁ -C ₆ alkoxy, amino, halogen, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, cyano, hydroxy, C ₁ -C ₆ alkylphenyl, C ₂ -C ₄ alkenylphenyl, C ₂ -C ₄ -alkynylphenyl, C ₂ -C ₄ -alkynylpyridyl, C ₂ -C ₄ -alkynyl-C ₃ -C ₆ -cycloalklyl or with the group -CHO, -C (O) NH ₂ or -C (O) -C ₁ -C ₆ alkyl, -N-di-C ₁ -C ₃ alkyl or -COOH may be substituted,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 represent} hydrogen or C _1-6 alkyl, or
R ² and R ⁷ or
R ³ and R ⁶ or
R ² and R ⁶ or
R ³ and R ^{7 are connected} together via a -CH ₂ group,
T represents the group -CH ₂ -, -CH ₂ -O-CH ₂ -, -CH (CH ₃ ) - or -CH ₂ -O- and
n stands for 0-2, and their tautomers, isomers and salts. 6. Compounds of the general formula II,


in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in the general formula I, as intermediates for the preparation of the compounds of the general formula I according to the invention 7. Use of the compounds of general formula I, according to Claims 1 to 5 for the manufacture of a medicament for treatment of cancer, autoimmune diseases, chemotherapy-induced Alopecia and mucositis, cardiovascular diseases, infectious Diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections. 8. Use according to claim 7, characterized in that under cancer solid tumors and leukemia, among autoimmune psoriasis, Alopecia and multiple sclerosis, among cardiovascular diseases Stenoses, atherosclerosis and restenosis, among infectious Diseases caused by unicellular parasites, under nephrological diseases glomerulonephritis, under chronic neurodegenerative diseases Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, among acute neurodegenerative diseases Brain ischemia and neurotrauma, and among viral infections Cytomegalus infections, herpes, hepatitis B and C and HIV diseases are to be understood. 9. Medicament containing at least one compound according to Claims 1 to 5. 10. Medicament according to claim 9, for the treatment of cancer, Autoimmune diseases, cardiovascular diseases, infectious Diseases, nephrological diseases, neurodegenerative Diseases and viral infections. 11. Compounds according to claims 1 to 5 and pharmaceuticals according to the Claims 9 and 10 with suitable formulation and carrier substances. 12. Use of the compounds of general formula I, according to Claims 1 to 5, as inhibitors of the cyclin-dependent kinases. 13. Use according to claim 12, characterized in that the kinase CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9. 14. Use of the compounds of general formula I, according to Claims 1 to 5, as inhibitors of glycogen synthase kinase (GSK- 3β). 15. Use of the compounds of general formula I, according to Claims 1 to 5, in the form of a pharmaceutical preparation for enteral, parenteral and oral application.