MXPA99006580A

MXPA99006580A - Phthalazinones

Info

Publication number: MXPA99006580A
Application number: MXPA/A/1999/006580A
Authority: MX
Inventors: Van Der Mey Margaretha; Hatzelmann Armin; Beume Rolf; Boss Hildegard; Johanna Van Der Laan Ivonne; Timmerman Hendrik; Hafner Dietrich; Kley Hanspeter; Jan Sterk Geert
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh; Jan Sterk Geert
Priority date: 1997-01-15
Filing date: 1999-07-14
Publication date: 2000-01-21

Abstract

Compounds of formula (I) wherein R1, R2, R3, R4 and R5 have the meanings as given in the description are novel effective bronchial-therapeutics.

Description

FTALAZINONAS Field of Application of the Invention The invention relates to phthalazinones, which are used in the pharmaceutical industry for the production of medicines.

Known Technical Background International patent application WO 91/12251 describes phthalazinones having bronchodilating properties and properties for inhibiting thromboxane A2 synthase. The international patent application WO 94/12461 describes 3-aryl-pyridazin-6-one derivatives as selective inhibitors of PDE4.

Description of the Invention It has now been found that phthalazinones, which are described in more detail below, have surprising and particularly advantageous properties. The invention in this manner relates to compounds of the formula I: (i) wherein: R 1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R 2 is alkoxy of 1 to 8 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms , cycloalkylmethoxy of 3 to 7 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, -CmH2m-R7, - CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen (H), alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, polycycloalkyl of 7 to 10 carbon atoms, naphthyl, pyridyl, pyrazinyl , pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, indanyl, benzoxazolyl, benzothiazolyl or, oxazolyl, thiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, amino carbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, aminosulfonyl, mono - or dialkylaminosulfonyl of 1 to 4 carbon atoms, 4-methylphenylsulfonamido, tetrazol-5-yl, 2- (alkyl of 1 to 4 carbon atoms) tetrazol-5-yl or 2-benzyl-tetrazol-5-yl and, R62 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, cyano, nitro, nitroxy (-0-N02), carboxyl, carboxyphenyloxy, phenoxy, alkoxy 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms carbon, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, pi rroll or n-one or morpholinyl unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a radical phenyl, naphthyl, phenanthrenyl or anthracenyl unsubstituted or substituted by R81 and / or R82, wherein, R81 is hydroxyl, halogen, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, and R82 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl , isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, unsubstituted pyrrolyl, a radical 2- (alkyl of 1 to 4 carbon atoms) -thiazole-4 -yl, or a phenyl radical substituted by R 10 and / or R 11, wherein R 10 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxyl, carboxyalkyl of 1 to 4 atoms of carbon, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, aminocarbonyl or mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl, halogen, nitro , alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 2, and the salts of these compounds. One embodiment of the invention are the compounds of formula I, wherein: R 1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R 2 is alkoxy of 1 to 8 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R3 and R4 both are hydrogen or together form a additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen (H), alkyl of 1 to 8 carbon atoms, carbon, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, bornyl, norbornyl , adamantyl or a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, or halogen, and R62 is alkyl of 1 to 4 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, cyano, nitro, phenoxy, alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms, alkylcarbonyl from 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino , mono- or dialkylamino of 1 to 4 carbon atoms, or a piper radical idyl, piperazinyl, idr idrol or morpholinyl unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl, naphthyl, phenanthrenyl or anthracenyl radical unsubstituted or substituted by R81 and / or R82, where, R81 is hydroxyl, halogen, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, which is complete or predominantly substituted by fluorine, and R82 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, R9 is - CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, unsubstituted pyrrolyl, a 2- (C 1-4 -alkyl) -thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, nitro, alkyl, to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 atoms carbon, alkylcarbonylamino of 1 to 4 carbon atoms, aminocarbonyl or mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 atoms carbon, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 4, q is an integer from 0 to 2, and the salts of these compounds. Alkyl of 1 to 8 carbon atoms is a straight or branched chain alkyl radical having from 1 to 8 carbon atoms. Examples are the radicals octyl, heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylphenyl), neohexyl (3,3-dimethylbutyl), neopentyl (2,2-dimethylpropyl), pentyl, sopentyl (3- methylbutyl), 1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl. Alkyl of 1 to 4 carbon atoms is a straight or branched chain alkyl radical having from 1 to 4 carbon atoms. Examples thereof are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals. Alkoxy of 1 to 4 carbon atoms is a radical, which, in addition to the oxygen atom, contains a straight or branched chain alkyl radical having from 1 to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms, which can be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals. Alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, is, for example, the radical 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1,2,2-trifluoroethoxy and, in particular, the 1,1,1,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy and difluoromethoxy radical. Alkoxy of 1 to 8 carbon atoms is a radical, which in addition to the oxygen atom, contains a straight or branched chain alkyl radical having from 1 to 8 carbon atoms. Alkoxy radicals having from 1 to 8 carbon atoms, which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy radicals, (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy. Cycloalkyl of 3 to 7 carbon atoms represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred. Cycloalkylmethoxy of 3 to 7 carbon atoms represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of which the preferred ones are cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy. Cycloalkyl of 3 to 7 carbon atoms represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkylmethyl of 3 to 7 carbon atoms represents a methyl radical, which is substituted by one of the cycloalkyl radicals of 3 to 7 carbon atoms mentioned above.

Examples that may be mentioned are the cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl radicals. Alkenyl of 3 to 7 carbon atoms is a straight or branched chain alkenyl radical having from 3 to 7 carbon atoms. Preferred examples are the 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl) radicals. Alkynyl of 3 to 7 carbon atoms is a straight or branched chain alkynyl radical having from 3 to 7 carbon atoms. Preferred examples are 2-pentynyl, 2-butynyl, 3-butynyl and 2-propynyl (propargyl) radicals. Polycycloalkyl of 7 to 10 carbon atoms represents bicycloalkyl radicals of 7 to 10 carbon atoms or tricycloalkyl of 7 to 10 carbon atoms, such as, for example, bornyl, norbornyl or adamantyl. A phenylalkyl radical of 3 to 4 carbon atoms is, for example, the phenyl-1-en-3-yl radical. Halogen, within the meaning of the present invention, is bromine, chlorine and fluorine. Alkylcarbonyl of 1 to 4 carbon atoms is a group carbonyl to which is attached one of the above-mentioned alkyl radicals of 1 to 4 carbon atoms. An example is the acetyl radical (CH3C (0) -). The alkylcarbonyloxy radicals of 1 to 4 carbon atoms contain, in addition to the oxygen atom, one of the aforementioned alkylcarbonyl radicals of 1 to 4 carbon atoms. An example is the acetoxy radical (CH3C (0) -0-). An alkylcarbonylamino radical of 1 to 4 carbon atoms is, for example, the acetamido radical (-NH-C (0) -CH3). Alkoxycarbonyl of 1 to 4 carbon atoms is a carbonyl group to which one of the aforementioned alkoxy radicals of 1 to 4 carbon atoms is attached. Examples are the ethoxycarbonyl radicals (CH3CH20-C (0) -) and methoxycarbonyl (CH30-C- (O) -). The mono- or dialkylaminocarbonyl radicals having 1 to 4 carbon atoms are, for example, the methylaminocarbonyl, dimethylaminocarbonyl and diethylaminocarbonyl radicals. The mono- or dialkylamino radicals having 1 to 4 carbon atoms are, for example, the methylamino, dimethylamino and diethylamino radicals. Mono- or dialkylaminosulfonyl of 1 to 4 carbon atoms represents a sulfonyl group to which is attached one of the mono- or dialkylamino radicals of 1 to 4 carbon atoms mentioned above. Examples which may be mentioned are methylaminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl. Hydroxyalkyl of 1 to 4 carbon atoms represents one of the aforementioned alkyl radicals of 1 to 4 carbon atoms, which is substituted by hydroxyl. Examples which may be mentioned are the hydroxymethyl radical, the 2-hydroxyethyl radical or the 3-hydroxypropyl radical. Carboxyalkyl radicals of 1 to 4 carbon atoms are, for example, the carboxymethyl (-CH2COOH) and carboxyethyl (-CH2CH2COOH) radicals. The groups -CmH2m-, -CnH2n-, -CpH2p-, and -CqH2q-, can be straight or branched chain groups. Examples which may be mentioned for the group -CmH2m- are the octylene, so-heptylene (2-methyl-hexylene), hexylene, isohexylene (2-methylpentylene), neohexylene (2,2-dimethylbutylene), butylene, isobutylene, sec. -butylene, tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene and methylene. Examples that can be mentioned for the group -CpH2p- are the hexylene, isohexylene (2-methyl-pentylene), neohexylene (2,2-dithylenebutylene), butylene, isobutylene, sec-bitulene, tert-butylene, propylene, isopropylene, ethylene, 1 -methylmethylene and methylene. Examples which may be mentioned for the group -CmH2m- are the butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene and methylene groups. Examples which may be mentioned for the group -CqH2q are the ethylene, 1-methylmethylene and methylene groups. The group -CqH2q represents a covalent bond in the case that q is 0 (zero). The aza-heterocycles, which are a component (Ar) of the group of substituents defined as -CpH2p-Ar and contain the group -NH- (imino), such as, for example, pyrrole, imidazole, benzimidazole, benzotriazole or benzosuccinimide, they are preferably linked through their imino-nitrogen to the group -CpH2p- defined above. Suitable salts for the compounds of formula I, depending on the substitution, are all acid addition salts or all salts with bases. Particular mention is made of pharmacologically tolerable salts with inorganic or organic acids and bases commonly used in pharmacy. Suitable ones are, on the one hand, water-soluble acid salts which are insoluble in water with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, acid D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids being used in the preparation of salt, depending on whether it is related to a mono- or polybasic acid and depending on which salt is desired, in a quantitative ratio equimolar or one that differs from it.

On the other hand, salts with bases are also suitable, depending on the substitution. As examples of salts with bases are mentioned salts of lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium, here, too, the bases being used in the preparation of salt in an equimolar quantitative ratio or a different from this one Pharmacologically intolerable salts, which can be obtained, for example, as product processes during the preparation of the compounds according to the invention on an industrial scale, are converted to pharmacologically tolerable salts through processes known to those skilled in the art. . According to the knowledge of the experts, the compounds of the invention, as well as their salts, may contain, for example, when they are isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all the solvates and in particular all the hydrates of the compounds of the formula I, as well as all the solvates and in particular all the hydrates of the salts of the compounds of the invention. Formula I. The compounds of formula I that will be emphasized are those wherein: R 1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms which is complete or predominantly substituted by fluorine, R 2 is alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms or alkoxy of 1 to 2 carbon atoms which is completely or predominantly substituted by fluorine, R 3 and R 4 both are hydrogen or together form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, bornyl, norbornyl, adamantyl, naphthyl , pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 atoms carbon, nitro, halogen, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, aminocarbonyl, aminosulfonyl, mono- or dialkylaminosulfonyl of 1 to 4 carbon atoms, 4-methylphenylsuifonamido, tetrazole-5 -yl, 2- (alkyl of 1 to 4 carbon atoms) tetrazol-5-yl or 2-benzyl-tetrazol-5-yl and, R62 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms carbon, nitro or halogen, R7 is hydroxyl, halogen, carboxyl, nitroxy (-0-N02), phenoxy, carboxyphenoxy, alkoxy of 1 to 4 carbon atoms, aikilcarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl radical, or morpholinyl unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl or naphthyl radical unsubstituted or substituted by R81 and / or R82, wherein, R81 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 2 carbon atoms, which is completely or predominantly substituted by fluorine, and R82 is halogen, alkyl of 1 to 4 carbon atoms, or alkoxy from 1 to 4 carbon atoms, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, oxazolyl, unsubstituted thiazolyl, a 2- (alkyl of 1 to 2 carbon atoms) -thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein , R10 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxy, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, and R 11 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, m is an integer of 1 to 8, n is an integer of 1 to 4, p it is an integer from 1 to 6, q is an integer from 0 to 1, and the salts of these compounds. The compounds of formula I of the embodiment to which they can be emphasized are those wherein: R 1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms which is complete or predominantly substituted by fluorine, R 2 is C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyloxy, or C 1 -C 2 alkoxy which is completely or predominantly substituted by fluorine, R 3 and R 4 are both hydrogen or together form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, or an unsubstituted or substituted phenyl radical by R61 and / or R62, wherein, R61 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, or halogen, R62 is alkyl of 1 to 2 carbon atoms, nitro or halogen, R7 is hydroxyl, carboxyl, alkoxy of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl , mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, or morphine radical olinyl unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl or naphthyl radical unsubstituted or substituted by R81 and / or R82, wherein, R81 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms or alkoxy having 1 to 2 carbon atoms, which is completely or predominantly substituted by fluorine, and R82 is halogen, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, R9 is -CqH2q- phenyl, Ar is phenyl, naphthyl, pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, oxazolyl, unsubstituted thiazolyl, a 2- (alkyl of 1 to 2 carbon atoms) -thiazol-4-yl radical, or a phenyl radical substituted by R10 and / or R11, wherein, R10 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl ilo, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 4, is an integer from 0 to 1, and the salts of these compounds.

The compounds of formula I, which are particularly to be emphasized, are those wherein: R 1 is methoxy, ethoxy or difluoromethoxy, R 2 is alkoxy of 1 to 4 carbon atoms, difluoromethoxy, cycloalkoxy of 3 to 5 carbon atoms, or cycloalkylmethoxy of 3 to 5 carbon atoms, R3 and R4 both are hydrogen or together form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8 , -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkynyl of 3 to 4 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, adamantyl, pyridyl, quinoxaline, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, an unsubstituted or substituted phenyl radical by R61 and / or R62, wherein, R61 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxyl, carboxyalkyl of 1 to 2 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 2 carbon atoms, amino, aminosulfonyl, 4-methylphenylsulfonamido, 2- (alkyl of 1 to 2 carbon atoms) tetrazol-5-yl or 2-benzyltetrazol-5-yl, and R62 is alkyl of 1 to 2 carbon atoms or halogen, R7 is hydroxyl, halogen, carboxyl, nitroxy (-0-N02), phenoxy , carboxyphenyloxy, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, or unsubstituted morpholinyl radical or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon, carboxyl, aminocarbonyl or alkoxycarbonyl atoms of 1 to 4 carbon atoms, R8 is a phenyl or naphthyl radical unsubstituted or substituted by R81, wherein, R81 is halogen or alkoxy of 1 to 4 carbon atoms, R9 is -CqH2q -phenyl, Ar is phenyl, naphthyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, unsubstituted thiazolyl, a 2- (alkyl of 1 to 2 carbon atoms) -thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen , alkyl of 1 to 2 carbon atoms, trifluoromethyl, alkoxy of 1 to 2 carbon atoms, carboxyl, carboxyalkyl of 1 to 2 carbon atoms, or alkoxycarbonyl of 1 to 2 carbon atoms, and R11 is halogen, alkyl of 1 to 2 carbon atoms or alkoxy of 1 to 2 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 6, p is 1 or 2, q is 0 or 1, and the salts of these compounds. The compounds of formula I of the embodiment to which they are particularly emphasized are those wherein: R 1 is methoxy, ethoxy or difluoromethoxy, R 2 is alkoxy of 1 to 4 carbon atoms, difluoromethoxy or cycloalkoxy of 3 to 5 carbon atoms , R3 and R4 both are hydrogen or together form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen , alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkynyl of 3 to 4 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, or a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms or halogen, and R62 is alkyl of 1 to 2 carbon atoms or halogen, R7 is hydroxyl, carboxyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylamino minocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino from 1 to 4 carbon atoms, or a piperidyl, piperazinyl, or morpholinyl radical unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl or naphthyl radical unsubstituted or substituted by R81, wherein, R81 is halogen or alkoxy of 1 to 4 carbon atoms, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, benzotriazolyl, unsubstituted thiazolyl, a radical 2- (alkyl of 1 to 2 carbon atoms) -thiazole-4- ilo, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, alkyl of 1 to 2 carbon atoms, trifluoromethyl, alkoxy of 1 to 2 carbon atoms, carboxyl, carboxyalkyl of 1 to 2 carbon atoms, or alkoxycarbonyl of 1 to 2 carbon atoms, and R11 is halogen, 1 to 2 carbon atoms or alkoxy of 1 to 2 carbon atoms, m is an integer from 1 to 6, n is 1 or 2, p is 1 or 2, q is 0 or 1, and the salts of these compounds. Preferred compounds of the formula I are those wherein: R1 is methoxy or ethoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 both are hydrogen or together form an additional bond, R5 is R6, -CmH2m- R7, -CNH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, allyl, 2-propionyl, phenyl-trans-prop-1-en-3-yl, adamantyl, pyridyl, quinoxaline, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, a radical phenyl unsubstituted or substituted by R61, wherein, R61 is alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, amino, aminosulfonyl, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl, R7 is hydroxyl, halogen, carboxyl, nitroxy (-0-N02), phenoxy, carboxyphenyloxy, alkoxycarbonyl of 1 to 4 carbon atoms, amino, methylamino, dimethylamino, dimethylaminocarbonyl, 1-piperidyl or N -methyl-4-piperidyl, R8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R9 is -CqH2q-phenyl, Ar is phenyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, unsubstituted imidazolyl, a 2-methyl-thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, and R11 is methoxy, m is an integer from 1 to 8, n is 1, p is an integer from 1 to 6, q is 0, and the salts of these compounds. Preferred compounds of formula I of mode a are those wherein: R 1 is methoxy or ethoxy, R 2 is methoxy, ethoxy or cyclopentyloxy, R 3 and R 4 both are hydrogen or together they form an additional bond, R 5 is R 6, -C m H 2m- R7, -CNH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, allyl, 2-propionyl or phenyl-trans-prop-1-en-3-yl, R7 is hydroxyl, carboxyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms, dimethylamino, dimethylaminocarbonyl, 1- piperidyl or N-methyl-4-piperidyl, R8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R9 is -CqH2q-phenyl, Ar is phenyl, pyridyl, benzotriazolyl, unsubstituted, a 2-methyl-thiazol-4-yl radical, or a substituted phenyl radical by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, and R 11 is methoxy, m is an integer from 1 to 6, n is 1, p is 1 or 2, q is 0, and the salts of these compounds. Especially preferred compounds of the formula I are those wherein: R1 is methoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 both are hydrogen or together form an additional bond, R5 is R6, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, adamantyl , quinoxalinyl, benzothiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl or a phenyl radical unsubstituted or substituted by R61, wherein, R61 is alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, aminosulfonyl, 4-methylphenylsulfonamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazole -5-yl, R8 is phenyl or 2-naphthyl, Ar is phenyl, benzimidazolyl, N-benzosuccinimidyl, midazolyl, or a phenyl radical substituted by R10, wherein, R10 is hydroxyl, halogen, methoxy, trifluoromethyl or carboxyl, n is 1, p is an integer from 1 to 6, and the salts of these compounds. Especially preferred compounds of formula I of embodiment a are those wherein: R 1 is methoxy or ethoxy, R 2 is methoxy, ethoxy or cyclopentyloxy, R 3 and R 4 are both hydrogen or together form an additional bond, R 5 is R 6, -C m H 2m -R7, -CNH2n-C (0) R8, -CH2 (R9) 2 or -CpH2p-Ar, wherein, R6 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, allyl, 2-propionyl, phenyl or phenyl-trans-prop-1-en-3-yl, R7 is hydroxyl, carboxyl or phenoxy, R8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or naphthyl, R9 is -CqH2q-phenyl, Ar is phenyl, pyridyl, unsubstituted benzotriazolyl, a 2-methyl-thiazolyl-4-yl radical, or a phenyl radical substituted by R10 and / or R11, wherein, R10 is hydroxyl, halogen, methoxy , trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, and R11 is methoxy, m is an integer from 1 to 6, n is 1, p is 1 or 2, q is 0, and salts of these compounds. The compounds of the formula I are chiral compounds with chiral centers at positions 4a and 8a, Numeration Therefore, the invention includes all pure diastereomers and conceivable pure enantiomers, as well as all mixtures thereof, independent of the ratio, including the racemates. Preferred compounds are those in which the Hydrogen atoms at positions 4a and 8a have a cis configuration. Especially preferred in this respect are those compounds where the absolute configuration (according to Cahn's rules), Ingolg and Prelog) is S in position 4a and R in position 8a. The racemates can be divided to the corresponding enantiomers by methods known to one skilled in the art. Preferably, the racemic mixtures are separated into two diastereomers with the aid of an active optical separation agent in the stage of cyclohexanecarboxylic acids (starting compounds A, B, D and G) or 1,2,3,6- tetrahydrobenzoics (starting compounds C, E and F). As separating agents there may be mentioned, for example, active optical amines, such as the (+) - and (-) - forms of a-phenylethylamine and ephedrine, or the optical active alkaloids, cinchonine, cinchonidine and brucine. The invention also relates to a process for the preparation of compounds of the formula I and their salts. The process comprises: a) reacting keto acids of formula II: or one of its reactive derivatives wherein R1, R2, R3 and R4 have the meanings mentioned above, in a first step with hydrazine hydrate to compounds of the formula I: wherein R1, R2, R3 and R4 have the above-mentioned meanings and R5 represents hydrogen (H). If desired, these compounds can be reacted with alkylating agents of the formula R5-X, wherein R5 has the above-mentioned meanings [exception: R5 does not represent hydrogen (H)] and X represents a leaving group to give additional compounds of the formula I, wherein R1, R2, R3, R4 and R5 have the meanings mentioned above [exception: R5 does not represent hydrogen (H)]; b) reacting, alternately to process a), keto acids of the formula II or one of their reactive derivatives, wherein R1, R2, R3 and R4 have the meanings mentioned above with suitable hydrazine derivatives of the formula, R5-NH -NH2, wherein R5 has the meanings mentioned above [exception: R5 is not represented by (H)], to give compounds of the formula I, wherein R1, R2, R3, R4 and R5 have the meanings mentioned above [exception: R5 does not represent hydrogen (H)]. The conversion of the keto acids of the formula II or one of their reactive derivatives with hydrazine hydrate [according to process a)] respectively with any of the suitable hydrazine derivatives of the formula R5-NH-NH2 [according to process b)] is advantageously carried out with one to five equivalents of the hydrazine hydrate, respectively the hydrazine derivatives of the formula R5-NH-NH2, which can simultaneously be used as a solvent. However, it is more convenient to use an additional appropriate solvent. Inert solvents are preferably used alcohols such as methanol, isopropanol, n-butanol, isoamyl alcohol, glycols and their ethers, such as ethylene glycol, diethylene glycol, ethylene glycol, monomethyl or monoethyl ether, carboxylic acids, such as formic acid, acetic or propionic, mixtures of the aforementioned solvents, as well as mixtures with water, for example, aqueous ethanol, other ethers, especially water-soluble ethers such as tetrahydrofuran, dioxane or ethylene glycol dimethyl ether; also toluene or benzene, especially when the azeotropic distillation method is used to remove the water of reaction. The reaction temperatures suitably are between 0 and 200 ° C, preferably between 20 and 100 ° C; the reaction times of preference are between 1 to 48 hours.

Suitable reactive derivatives of the keto acids of the formula II, which may be mentioned in this context, are, for example, esters, especially methyl and ethyl esters, nitriles and halides, such as acid chlorides or acid bromides. These can be prepared, for example, starting from the corresponding keto acids of formula II, by methods that are known to those skilled in the art. The conversion of the compounds of the formula I, wherein R 1, R 2, R 3 and R 4 have the meanings mentioned above and R 5 represents hydrogen (H) with alkylating agents of the formula R 5 -X, wherein R 5 has the meanings mentioned above [with the exception of hydrogen (H)] and X represents a suitable leaving group, is carried out in a manner that is known to one skilled in the art. In a first step, the hydrogen atom (H) of the NH group of the compounds of the formula I, wherein R 5 represents a hydrogen atom (H) is removed through a base such as, for example, potassium carbonate , sodium hydroxide, sodium hydride, sodium methanolate, sodium ethanolate or butyl lithium, in a suitable inert solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or diethyl ether. The alkylation is then carried out by adding an appropriate alkylating agent of the formula R5-X. The bases of preference are used in more than one equimolar relation; the reaction temperature is preferably between 0 and 150 ° C. Examples of suitable leaving groups, X, which can be mentioned are halogen atoms, especially chlorine or activated hydroxyl groups by esterification (for example, with p-toluenesulfonic acid). Suitable alkylating agents of formula R 5 X are the, for example, iodomethane, 1-bromopropane, 2-bromopropane, 1-bromohexane, 3-bromopentane, cyclopentylbromide, bromomethyl-cyclohexane, chloromethylcyclopropane, cycloheptyl bromide, chloride allyl, propargyl bromide, 3-bromo-1-propanol, 6-bromohexanoic acid, 8-bromooctanoic acid, 2-bromethyl-N, N-dimethylamine, ethyl bromoacetate, 4-chloro-N-methylpiperidine, β-bromoacetophenone, diphenylchloromethane, 3-phenoxy-1-bromo propane, 1,4-dibromobutane, 1,6-dibromohexane, co-b-romo-4-chloro acetophenone, β-bromo-2-methoxyacetophenone, α-bromo-2'-acetonaphthone, 4-chloromethyl benzoic acid, 2-bromomethylbenzoic acid, 4-chloromethyl-phenylacetic acid, benzyl chloride, methoxybenzyl chloride, 2-chloride, 3-methoxybenzyl, 4-methoxybenzyl chloride, 3,5-dimethoxybenzyl chloride from chloride, 2 -trifluoromethylbenzyl, 2-chloro-benzyl chloride, 2-picolyl chloride, 3-picoliyl chloride, 4-pi co liyl chloride, 4 -chloromethyl-2-methylthiazole, 1-bromomethylbenztriazole, 2-bromoethyl ethylbenzene, 3-phenyl-2- [trans] propenyl chloride, 4-benzyloxybenzyl chloride and 2-benzyloxybenzyl chloride. Examples for suitable hydrazine derivatives of the formula R5-NH-NH2 are methylhydrazine, 4-heptylhydrazine, cyclohexylhydrazine, ciclooctilhidrazina, adamantilhidrazina, 2-hidrozietilhidrazina, 4-tert-butylhydrazine, phenylhydrazine, 2-methylphenyl, 4-tert-butylphenyl-hydrazine, 2-chlorophenyl, 3-hydrazinobenzoic acid, 4-hidrazinofenilacético, 2- (4-hydrazinophenyl) ethanol , 4-sulfonamidophenyl hydrazine, 4-nitrophenylhydrazine, 4- (2-ethyltetrazol-5-yl) phenylhydrazine, 2-benzyl-5- (4-hydrazinophenyl) tetrazole, benzylhydrazine, 2-bromophenyl-hydrazine, 4-chlorophenyl, 4 -fluorofenilhidrazina, 2,4-dichlorophenyl, 4-chloro-o-tolylhydrazine, 2, 5-dimethyl phenylhydrazine, 2,4-dinitrophenylhydrazine, 4-methoxyphenylhydrazine, 3-nitrophenylhydrazine, p-tolilh idrazina, 2-pyridylhydrazine, 2-indanilhidrazina , 2-hydrazino-1,4-benzodiazine, 2-hydrazino-benzothiazole, 4-hydrazinotetrahydropyran and 4-hydrazinotetrahydro-pyran. The keto acids of the formula II, wherein R1, R2, R3 and R4 have the meanings mentioned above, can be, for example, prepared from compounds of the formula III, wherein R1 and R2 have the meanings mentioned above and Z represents hydrogen (H) through Friedel-Crafts acylation with compounds of formula IV, wherein R3 and R4 have the meanings mentioned above. The Friedel-Crafts acylation is carried out in a manner that is known to those skilled in the art (for example, as described by M. Yamaguchi et al., J. Med. Chem. 36: 4052-4060, 1993 ) in the presence of a suitable catalyst, such as, for example, AICI3 ZnCl2, FeCl3 or iodide, in a suitable inert solvent, such as methylene chloride or nitrobenzene or another inert solvent such as diethyl ether, preferably at elevated temperature, especially to the point boiling of the solvent that is being used. Alternatively, the compounds of the formula II, wherein R 1, R 2, R 3 and R 4 have the meanings mentioned above, can be prepared from compounds of the formula III, wherein R 1 and R 2 have the meanings mentioned above and Z represents a Halogen atom through the reaction with compounds of the formula IV, wherein R 3 and R 4 have the meanings mentioned above. The reaction, which is mentioned in the preceding paragraph, is carried out in a manner that is known to those skilled in the art, for example: a) activating the compounds of the formula III, wherein R1, R2 and Z have the meanings mentioned above, through a lithium / halogen exchange reaction at low temperatures (preferably -60 to -100 ° C) in an appropriate inert solvent such as tetrahydrofuran or diethyl ether, preferably under an inert gas atmosphere, followed by the reaction of the lithiated compounds with cyclic carboxylic acid anhydrides of the formula IV, or b) converting the compounds of the formula III, wherein R1, R2 and Z have the meanings before mentioned, in a suitable inert solvent such as, for example, tetrahydrofuran or diethyl ether to the corresponding Grignard compounds of the formula II, wherein Z represents MgCl, MgBr, or Mgl, followed by the reaction of the Grignard compounds with acid anhydrides. cyclic carboxyl of the formula IV, wherein R3 and R4 have the meanings mentioned above. The compounds of the formula III, wherein R1 and R2 have the above-mentioned meanings and Z represents a hydrogen (H) or a halogen atom, are known or can be prepared by methods known to one skilled in the art. The compounds of the formula IV, wherein R 3 and R 4 have the meanings mentioned above are well known or can be prepared by methods known to one skilled in the art. In addition, it is possible to convert a functional group of a compound of formula I to another functional group through customary methods and reactions. Thus, if desired, the compounds of the formula I with suitable functional groups can be converted to other compounds of the formula I. For example, the compounds of the formula I, wherein R5 comprises an ester, can be converted to through acid or alkaline saponification, to the corresponding carboxylic acid or through reaction with an appropriate amine to the corresponding amide. In addition, the compounds of the formula I, wherein R5 comprises a reactive leaving group such as, for example, a halogen atom, can be converted to the corresponding amines through reaction with an appropriate amine. In addition, the compounds of the formula I, wherein R 2 comprises an acid labile ether linkage, such as, for example, the cyclopentyl-oxygen bond, can be converted through an acid ether cleavage reaction to the compounds of the formula I, wherein R2 represents a hydroxyl group. The renewed alkylation of this hydroxyl group with appropriate alkylation reagents further leads to compounds of the formula I. Suitable alkylation reagents may be mentioned in this context, for example, chlorodifluoromethane or cyclopropylmethyl chloride. Conveniently, conversions are made analogous to methods that are familiar per se to those skilled in the art, for example, in a manner that is described in the following examples. The substances according to the invention are isolated and purified in a manner known per se, for example, by distilling the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the usual purification methods, such as column chromatography on a suitable support material. The salts are obtained by dissolving the free compound in a suitable solvent, for example, in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the acid or desired base, or to which the desired acid or base is added later. The salts are obtained through filtration, reprecipitation, precipitation with a non-solvent for the addition salt or evaporating the solvent. The salts obtained can be converted through basification or through acidification to the free compounds, which, in turn, can be converted to the salts. In this way, the pharmacologically tolerable salts can be converted to pharmacologically tolerable salts. The following examples illustrate the invention in greater detail, without restricting it. Also, other compounds of the formula I, of which the preparation is not explicitly described, can be prepared in an analogous form or in a form that is known by one skilled in the art using customary preparation methods. In the examples p.f. represents melting point, min. minutes and THF is tetrahydrofuran. The compounds which are mentioned in the examples, as well as their salts, are preferred compounds of the invention.

EXAMPLES Final products 1. (cis) -4- (3,4-Pimetoxifenl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one A solution of 26 g of compound A (see starting compounds) ) and 19 g of hydrazine hydrate was refluxed for 4 hours in ethanol. After cooling to room temperature, the precipitate was filtered and dried. PJ. 170 ° C. 2. (trans) -4- (3,4-D-methoxyphenyl) -4a, 5.6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound B (see starting compounds) and hydrate of hydrazine, as described for compound 1. PJ. 143-146 ° C. 3. (cis) -4- (3,4-Dimethoxyphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from hydrazine hydrate and compound C (see starting compounds), as it was described for compound 1. PJ 173-174 ° C. 4. (cs) -4- (3-Cyclopentylloxy-4-methoxy-phenyl) -4a.5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound D (see starting compounds) and hydrazine hydrate, as described for compound 1. PJ 175-176 ° C. . (cis) -4- (3-Cyclopentylloxy-4-methoxyphenyl) -4a, 5,8,8a-tetra idro-2H-phthalazin-1-one Prepared from compound E (see starting compounds ) and hydrazine hydrate, as described for compound 1. PJ 166-168 ° C. 6- (cis) -4- (3-Ethoxy-4-methoxyphenyl) -4a, 5,8,8a-tetrar-idro-2H-phthalazin-1 -one Prepared from compound F (see starting compounds) and hydrazine hydrate, as described for compound 1. PJ 163-166 ° C. 7. (cis) -4- (3,4-Diethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound G (see starting compounds) and hydrazine hydrate , as described for compound 1. Purified through chromatography (dichloromethane). Crystallized from ethyl acetate. PJ 156-157 ° C. 8. (cis) -4- (3,4-Dimethoxyphenyl) -2-methyl-4a, 5,6,7,8,8a-hexa idro-2H-phthalazin-1 -one 6 mmoles of a 60% suspension were added of sodium hydride in mineral oil to a suspension of 5 mmoles of compound 1 in about 40 ml of dimethylformamide, under a nitrogen flow at room temperature. After stirring this mixture for 30 minutes, 7 mmoles of iodomethane were added and the resulting mixture was stirred for another 4 hours, after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). It was crystallized from petroleum ether (60-95 ° C). PJ. 110-112 ° C. 9. (cis) -4- (3,4-Dimethoxyphenyl) -2-etl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 1 and bromoethane, as described for compound 8. It was crystallized from methanol. PJ. 105-106 ° C. . (cis) -4- (3,4-D¡methoxy-phenyl) -2- (n-propyn-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one) from compound 1 and 1-bromopropane, as described for compound 8. It was purified by chromatography (dichloromethane), crystallized from petroleum ether (60-95 ° C), PJ 95-96 °. C. 11. (cis) -4- (3,4-Dimethoxyphenyl) -2- (n-hexyl) -4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 3 and 1-bromohexane, as described for compound 8. Purified through chromatography; it was crystallized from petroleum ether (60-80 ° C) at -20 ° C. PJ. 74-75 ° C. 12. (cis) -2-lsopropyl-4- (3,4-d¡methoxyphenol) -4a, 5.6.7,8,8a-hexahydro-2H-phthalazin-1 -one. Prepared from compound 2 and 2-Bromopropane, as described for compound 8. It was purified by chromatography (dichloromethane). It was crystallized from diethyl ether / petroleum ether (60-95 ° C). PJ. 79-81 ° C. 13. (cis) -4- (3,4-Dimethoxyphenyl) -2-isopro-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 3 and 2-bromopropane, as described for compound 8. It was crystallized and recrystallized from ethanol. PJ. 146-149 ° C. 14. (cis) -4- (3,4-Dimethoxyphenyl) -2- (tert-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one A mixture of 2 g of the compound A (see starting compounds), 5 g of t-butylhydrazine and 5 ml of triethylamine in toluene was heated for 20 hours in a Dean-Stark apparatus. It was purified by chromatography (dichloromethane) and crystallized from petroleum ether (60-95 ° C) at -20 ° C. PJ. 99-101 ° C. . (cis) -2- (3-Ethyl-propyl) -4- (3,4-dimethoxy-phenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and 3-bromopentane, as described for compound 8. It was purified by chromatography (dichloromethane). It was crystallized from methanol. PJ. 98-99 ° C. 16. (cs) -2- (4-Propyl-butyn-4- (3,4-dimethoxyphenyl) -4a.5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 3 and 4, heptylhydrazine, as described for compound 8. It was purified by chromatography and crystallized from petroleum ether (60-80 ° C).

PJ. 71-73 ° C. 17. (cis) -4- (3,4-Dimethoxypheni I) -2-cyclopentyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and cyclopentyl bromide , as described for compound 8. It was crystallized from methanol. PJ. 111-114 ° C. 18. (cis) -4- (3,4-Dimethoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 3 and cycloheptyl bromide, as described for Compound 8. Purified by chromatography (dichloromethane) and crystallized from diethyl ether. PJ. 131-133 ° C. 19. (cis) -4- (3-Ethoxy-4-methoxy-phenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one A solution of 0.5 g of compound 6, 0.8 g of K2CO3 and 0.3 g of ethyl iodide was stirred in 20 ml of N-methyl-pyrrolidinone for 4 hours at 70 ° C. After cooling to room temperature, the reaction mixture was poured into 200 ml of water and this mixture was extracted with diethyl ether. After drying over magnesium sulfate, the solvent was evaporated and the compound was crystallized from methanol. PJ. 124-127 ° C. . (cis) -4- (3-Difluo rom ethoxy -4-methoxy fe nyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one A solution of 1 g of compound H, 0.06 g of tetraethylaluminum bromide and 0.36 g of sodium hydroxide in 0.5 ml of water in 7 ml of dioxane at 80 ° C, was saturated for 30 minutes with chlorodifluoromethane. After cooling to room temperature, the dioxane was decanted and evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography. Crystallization from petroleum ether (60-80 ° C). PJ. 124-125 ° C. 21. (cis) -4- (3-Cyclopentyloxy-4-methoxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 5 and bromide of Cyclopentyl, as described for compound 8. Crystallized from diethyl ether. PJ. 144-145 ° C. 22. (cis) -4- (3,4-Dimethoxy-phenyl) -2-cyclohexyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound C (see starting compounds) and cyclohexylhydrazine, as described for compound 35. It was crystallized from methanol. PJ. 147-148 ° C. 23. (cis) -4- (3,4-D methoxy-enyl) -2-cyclohexyl-4a, 5,6,7,8,8-hexahydro-2H-phthalazin-1 -one Prepared from of compound 1 and cycloheptyl bromide, as described for compound 8. It was crystallized from diethyl ether. PJ. 102-104 ° C. 24. (cis) -4- (3-Cyclopentyloxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 4 and cycloheptyl bromide, as described for compound 8. It was crystallized from petroleum ether (60-80 ° C). PJ. 111-112 ° C. . (cis) -4- (3,4-Dimethoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 3 and cycloheptyl bromide, as described for Compound 105 was crystallized from methanol. PJ. 92-93 ° C. 26. (cis) -4- (3-Cyclopentyloxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 5 and cycloheptyl bromide, as described for compound 8. It was crystallized from petroleum ether (60-80 ° C). PJ. 106 ° C. 27. (cis) -4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5.8.8a-tetrahydro-2H-phthalazin-1-one A mixture of 1.4 g of compound 1, 0.4 g of cyclopropylmethyl chloride , 1.1 g of potassium iodide and 0.6 g of K2C03, was stirred in N-methylpyrrolidinone for 5 days at 60 ° C. The mixture was then partitioned between water and diethyl ether. The organic layer was dried over magnesium sulfate and evaporated. Purification through chromatography (petroleum ether / ethyl acetate, 4: 1). Crystallization from petroleum ether (60-80 ° C). PJ. 102-103 ° C. 28. (cs) -4- (3-Difluoromethoxy-4-methoxyphenyl) -2-cycloheptyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 1, as described for compound 20. It was crystallized from dichloromethane / petroleum ether (60-80 ° C). PJ. 83 ° C. 29. (cs) -4- (3,4-D-methoxyphenyl) -2-cyclooctyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 3 and Cyclooctyl hydrazine, as described for compound 35. Purified by chromatography (dichloromethane) and crystallized from petroleum ether (40-60 ° C). PJ. 75-77 ° C. . (cis) -4- (3,4-Dimethoxyphenyl) -2-adamantyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 3 and adamantylhydrazine hydrochloride, as described for compound 35. It was crystallized from methanol. PJ. 157-159 ° C. 31. (cs) -4- (3,4-Dimethoxyphenyl) -2-cyclopropylmethyl-4a, 5,8,8a-tetra idro-2H-phthalazin-1 -one Prepared from compound 3 and chloromethylcyclopropane, as described for compound 8. It was crystallized from diethyl ether and recrystallized from methanol. PJ. 142-145 ° C. 32. (cis) -2-C-hexymethylmethyl-4-yl-3,4-di methoxy-enyl) -4a, 5, 6, 7, 8, 8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and bromomethylcyclohexane, as described for compound 8. It was purified by chromatography (dichloromethane). It was crystallized from petroleum ether (60-95 ° C). PJ. 137-139 ° C. 33. (cis) -2-Allyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and allyl chloride, as described for compound 8. It was purified by chromatography (dichloromethane). It was crystallized from petroleum ether (60-95 ° C). PJ. 99-101 ° C. 34. (cis) -4- (3,4-Dimethoxyphenyl) -2-proparqyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 1 and propargyl bromide, as described for compound 8, using sodium ethanolate instead of sodium hydride. It was purified by chromatography (dichloromethane). It was crystallized from methanol. PJ. 118-121 ° C. . (cis) -4- (3,4-Dimethoxy-phenyl) -2- (2-hydroxy-1-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Una solution of 2 g of compound A (see starting compounds) and 2 g of hydroxyethylhydrazine in a mixture of 100 ml of 1-propanol and 5 ml of triethylamine was refluxed for 18 hours. After evaporating the solvent, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The compound was crystallized from diethyl ether and recrystallized from methanol (-20 ° C). PJ. 128-129 ° C. 36. (cis) -2- (3-Hydroxy-1-propyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from of compound 1 and 3-bromo-1-propanol, as described for compound 8. It was purified by chromatography (dichloromethane). It was crystallized from diethyl ether / petroleum ether (60-95 ° C). PJ. 94-97 ° C. 37. Ethyl- (cis) -4- (3,4-dimethoxy-phenyl-1-oxo-4a, 5,6,7,8,8a-hexahydro-1H-phthalazin-2-yl) acetic acid Prepared from compound 1 and ethyl bromoacetate, as described for compound 8. It was recrystallized from ethanol at -20 ° C. PJ. 97-99 ° C. 38. Acid (cis) -f 4- (3,4-d¡methoxyphen i I) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-yl) acetic were stirred 1.5 g of compound 37 in a mixture of 200 ml of 2N NaOH, 100 ml of THF and 200 ml of methanol for 3 hours at room temperature. After removing the organic solvents under reduced pressure, the solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and evaporated. The compound was crystallized from acetone / petroleum ether (60-95 ° C). PJ. 183-187 ° C. 39. Sodium salt of (cis) -6- (4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H -phthalazin-2-yl) hexanoic acid Prepared from compound 1 and 6-bromohexanoic acid, as described for compound 8, using 12 mmoles of sodium hydride instead of 6 mmoles. After evaporating the reaction mixture, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The aqueous solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. It was purified through chromatography (ethyl acetate). The compound (oil) was dissolved in diethyl ether. After the addition of a concentrated solution of sodium ethanolate, the precipitate was filtered and crystallized from methanol / ether. PJ. 140-143 ° C. 40. Acid (cis) -6-f4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-tetra h id ro-1 H-phthalazin-2-i I) hexanoic Prepared from compound 3 and 6-bromohexanoic acid, as described for compound 39. Purified through chromatography and crystallized from ether at -20 ° C. PJ. 97-99 ° C. 41. Acid (cis) -6-. { 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-i Poetan oico Prepared from compound 1 and 8-bromooctanoic acid, as described for compound 39. It was purified by chromatography. PJ. 90-91 ° C. 42. (cis) -4- (3,4-Dimethoxy-enyl) -2- (6-bromo-1-hexyl) -4a, 5, 6, 7, 8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 1 and 1,6-dibromohexane, as described for compound 58. It was purified by chromatography [ethyl acetate / petroleum ether (60-80 ° C), 1: 2]. It was crystallized from petroleum ether (60-80 ° C). PJ. 74-75 ° C. 43. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (6-amino-1-hexyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one fumarate Solution of 5 g of compound 42 in a mixture of 200 ml of methanol and 100 ml of tetrahydrofuran was saturated with ammonia and left for one week at room temperature. After evaporating the solvent, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The organic layer was evaporated and the compound was crystallized as fumarate from methanol / ethyl acetate. PJ. 127-129 ° C. 44. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (4-amnomethyl-1-butyl) -4a, 5,6,7,8,8a-exahydro-2H-phthalazine-1 hemifumarate ona Prepared from compound 58 and methylamin, as described for compound 46. It was purified by chromatography and crystallized as the hemifumarate from ethyl acetate. PJ. 108-111 ° C. 45. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (2-dimethylamido-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one fumarate Prepared from compound 1 and 2-bromoethyl-N, N-dimethylamine hydrobromide, as described for compound 8, using 12 mmoles of sodium hydride instead of 6 mmoles. It was purified by chromatography (ethyl acetate). It crystallized as the fumarate from ether. PJ. 74-76 ° C. 46. Fumarate (cis) -4- (3,4-dimethoxyphenyl) -2- (4-dimethylamino-1-butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one A solution of 2 g of compound 58 in 50 ml of a 30% solution of dimethylamine in ethanol was left for 18 hours at room temperature. After evaporating this mixture, the residue was purified by chromatography (ethyl acetate) and the compound was crystallized from ether as the fumarate. PJ. 119-121 ° C. 47. Oxalate of (cis) -4- (3,4-dimethoxyphenyl) -2- (6-dimethylamino-1-hexyl) -4a, 5,6,7,8, 8a-hexah id ro-2H-phthalazin-1 -one Prepared from compound 42, as described for compound 46. It was crystallized from acetone as the oxalate. PJ. 65-67 ° C. 48. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (4- (1-ptperidyl) -1-butyl) -4a, 5,6,7,8,8a-hexahydroxyhydrochloride 2H-phthalazin-1 -one Prepared from compound 58 and piperidine (in place of dimethylamine), as described for compound 46. It was purified by chromatography (ethyl acetate). It crystallized as the hydrochloride from diethyl ether. PJ. 63-68 ° C. 49. Fumarate (cis) -2- (N-Methylpiperidin-4-yl) -4- (3,4-dimethoxy-phenyl) -4a, 5, 6,7,8,8 a-hexah id ro-2H-phthalazin -1 -one A mixture of 10 mmoles of compuestol, 10 mmoles of 4-chloro-N-methylpiperidine hydrochloride and 20 mmoles of sodium hydride in dimethylformamide was heated for 150 hours at 120 ° C. After evaporating the reaction mixture, the residue was purified by chromatography (ethyl acetate, Jethylamine 10: 1). It was crystallized from tetrahydrofuran as the fumarate. PJ. 200 ° C (with decomposition). 50. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (2-nitroxy-1-ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one hydrochloride Mixture of 20 mmoles of acetic anhydride and 20 mmoles of nitric acid was added to a solution of 10 mmoles of compound 35 in 100 ml of dichloromethane at 0 ° C. After 30 minutes, 150 ml of water was added to the mixture and the organic layer was dried over magnesium sulfate and evaporated. Crystallization from ethyl acetate. PJ. 139-140 ° C. 51. (cis) -N, N-dimethyl-4- (4- (3,4-dimethoxy-phenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-yl) acetamide 5 mmoles of ethyl chloroformate were added to a mixture of 5 mmoles of compound 38 and 5 mmoles of triethylamine in dichloromethane at -20 ° C. After stirring this mixture for 30 minutes, a mixture of 6 mmoles of dimethylammonium chloride and 6 mmoles of triethylamine was added and the resulting mixture was stirred for 1 hour at room temperature, after which aqueous sodium carbonate was added to the reaction mixture. The layer organic was dried over magnesium sulfate and evaporated. It was crystallized from ethyl acetate / diethyl ether. PJ. 142-145 ° C. 52. (cis) -4- (3-, 4- Dimethoxy-spheryl) -2- (2-oxo-2-phenylethyl) -4a, 5-, 6, 7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and 2-bromoacetophenone, as described for compound 8. It was purified by chromatography [ethyl acetate: petroleum ether (60-80 ° C) / 1: 3]. It was crystallized from diethyl ether. PJ. 133-135 ° C. 53. (cis) -4- (3,4-Dimethoxyphenyl) -2-. { 2- (2-methoxyphenyl) -4a.5.6.7,8.8a-hexahydro-2H-phthalazin-1 -one A mixture of 2 g of compound 1 and 1 equivalent of sodium ethanolate in 30 ml of dimethylformamide was added to a mixture of 2 g of β-bromo-2-methoxyacetophenone in dimethylformamide. After 30 minutes, small portions of β-bromo-2-methoxyacetophenone (a total of 5 grams) and sodium ethanolate were added for 2 hours. Subsequently, the reaction mixture was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). It was crystallized from methanol. PJ. 93-96 ° C. 54. (cis) -2- (2- (4-Chlorophenyl) -2-oxoethyl) -4- (3,4-dimethoxyphenyl) -4a.5.6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from α-bromo-4-chloroacetophenone and compound 1, as described for compound 8. It was crystallized from methanol, PJ 142-144 ° C. 55. (cis) -4- (3,4-Dimethoxyphenin-2-f2- (2-naphth-2-oxoethyl) -4a, 5,6,7, 8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and a-bromo-2'-acetonaphthone, as described for compound 8. Purified by chromatography [ethyl acetate: petroleum ether (60-80 ° C) / 1: 3] It was crystallized from methanol at -20 ° C, PJ, 89-90 ° C. 56. (cis.-4J3.4-Dimethoxy-phenyl, -2-d-phenylmethyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and diphenylchloromethane , as described for compound 8. It was purified by chromatography (dichloromethane), crystallized from methanol, PJ 133-135 ° C. 57. (cis) -4- (3,4-Dimethoxyf in yl) -2- (3-phenoxy-1 -propi I) -4a, 5, 6, 7, 8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and 3-phenoxy-1-bromopropane, as described for compound 8. It was purified by chromatography (dichloromethane). It crystallized from ether of oil (60-80 ° C). PJ. 78-81 ° C. 58. (cis) -4- (3, 4-D methoxy in l) -2- (4-bromo-1 -buti I) -4a, 5, 6, 7, 8.8a-hexahydro-2H-phthalazin -1 -one 15 g of 1,4-dibromobutane was added to a mixture of 5.0 g of compound 1 and 1.0 g of sodium hydride in dimethylformamide. After stirring, the resulting mixture for 5 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). PJ. colorless oil. 1 H-NMR (CDCl 3): 1.20-1.97 (m, 1H, 7xcyclohexyl H, Br-C-CH 2 CH 2); 2.44-2.73 (m, 2H, 2xcyclohexyl H); 2.88-3.15 (m, 1H, cyclohexyl H); 3.49 (t, J = 6.0 Hz, 2H, Br-CH2); 3.72-4.12 (m, 8H, N-CH2, 2xO-CH3); 6.84 (d, J = 8.4 Hz, 1H, arom.H); 7.21 (dd, J = 2.0, 8.4 Hz, 1H, arom.H); 7.47 (d, J-2.0 Hz, 1H, arom.H). 59. (cis) -4- (3,4-Dimethoxyphenyl) -2-phenyl-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound A (see starting compounds) ) and phenylhydrazine, as described for compound 14. It was crystallized from ethyl acetate / petroleum ether (60-95 ° C). PJ. 122-124 ° C. 60. (cis) -4- (3,4-dimethoxyphenyl) -2-phenyl-4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound C (see starting compounds) ) and phenylhydrazine, as described for compound 35. It was crystallized from diethyl ether. PJ. 134-135 ° C. 61. (cis) -4- (3-Ethoxy-4-methoxyphenyl) -2-phenyl-4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound F (see compounds starting material) and phenylhydrazine, as described for compound 35. It was crystallized from diethyl ether at -20 ° C. PJ. 97-99 ° C. 62. (cis) -4- (3-Cyclopentyloxy-4-methoxyphenyl) -2-phenyl-4a, 5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from the compound E (see starting compounds) and phenylhydrazine, as described for compound 35. It was crystallized from methanol. PJ. 134-135 ° C. 63. (cis) -4- (3,4-Dimethoxyphenin-2- (2-methylphen-4a, 5,6,7,8,8a-tetrah id ro-2H-phthalazin-1 -one Prepared from compound C (see starting compounds) and 2-methylphenylhydrazine, as described for compound 35. It was crystallized from methanol, PJ 144-145 ° C. 64. (cis) -4- (3,4-Dimetox »phenyl) -2- (4-tert-butylphenin-4a.5,6,7,8,8a-tetrahydro-2H-phthalazin-1-one) Prepared from 4-tert-butylphenylhydrazine and compound C, as described for compound 35. After evaporation of the solvent, the compound was crystallized from ethanol, PJ 197-199 ° C. 65. (cis) -4- (3,4-Di methoxy-enyl) -2- (2-c I or rofenyl) -4a.5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from 4 chlorophenylhydrazine and compound C, as described for compound 35. It was crystallized from methanol. PJ. 131-134 ° C. 66. (cis) -4- (3,4-Dimethoxyphenyl) -2- (4-chlorophenyl) -4a, 5,8,8a-tetrahydro-2 Hf talazin-1 -one Prepared from 2- chlorophenylhydrazine and compound C, as described for compound 35. PJ. 140-141 ° C. 67. Acid (cis) -4. { 4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl) benzoic acid Prepared from compound C and 4-hydrazinobenzoic acid, as described for compound 35 It was purified by chromatography and crystallized from ethyl acetate. PJ. 198-199 ° C. 68. Acid (cis) -3. { 4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1-ftalazin-2-yl) benzoic acid Prepared from compound C and 3-hydrazinobenzoic acid, as described for Compound 35. Crystallized from ethyl acetate / petroleum ether (60-80 ° C). PJ. 185-186 ° C. 69. Benzoate of (cis) -n-Propyl-4-. { 4- (3,4-Dimethoxyphenyl) -1 -oxo-4a, 5,8,8a-tetrahydro-1 H-phthalazin-2-yl) A solution of 1 g of compound 67 and 1 g of p-toluenesulfonic acid in 100 ml of propanol was brought to reflux for 18 hours. After evaporating the solvent, the title compound was crystallized from methanol. PJ. 100-101 ° C. 70. (cis) -4- (3,4-D-methoxyphenyl) -2-. { 4- (2-hydroxyethyl) phenyl} -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound C and 2- (4-hydrazinophenyl) ethanol, as described for compound 35. It was crystallized from diethyl ether. PJ. 137-139 ° C. 71 Acid (cis) -4-. { 4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-yl) phenylacetic acid Prepared from compound C and 4-hydrazinophenylacetic acid, as described for compound 35. It was crystallized from diethyl ether. PJ. 162 ° C. 72. (cis) -4- (3,4-Dimethoxy-enyl) -2- (4-nitrofenyl) -4a.5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound C and 4 -nitrophenylhydrazine, as described for compound 35. It was crystallized from methanol. PJ. 179-182 ° C. 73. (cis) -4- (3,4-Dimethoxyphenyl) -2- (4-aminosulfonylphenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from 2 g of 4-sulfonamidophenylhydrazine and 3 g of compound C, as described for compound 35. After evaporating the solvent, the residue was crystallized from methanol and recrystallized from tetrahydrofuran / petroleum ether (60-80 ° C). PJ. 181-183 ° C. 74. (cis) -4- (3,4-Dimethoxyphenyl) -2- (4-aminophenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one A mixture of 35 mmoles of compound 35 and 15 g of iron in a mixture of 300 ml of ethanol and 80 ml of water at 65 ° C was treated with ml of 2N hydrochloric acid for 45 minutes. After filtration, the solvent was evaporated and the residue was washed with ethyl acetate. PJ. 183-185 ° C. 75. (cis) -4- (3,4-Dimethoxyphenyl) -2-f4- (4-methylphenylsulfonamido) phenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one. 20 mmoles of sodium chloride were added. p-toluenesulfonyl to a solution of 10 mmol of compound 74 in 100 ml of pyridine and the The resulting mixture was left overnight at room temperature. After evaporating the solvent, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. It was crystallized from methanol. PJ. 229-230 ° C. 76. (cs) -5-r4- (4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-phthalazin-2-yl-Ni-p-2-ethyltetrazole Prepared to Compound C and 4- (2-ethyltetrazol-5-yl) phenylhydrazine, as described for compound 35. Crystallized from diethyl ether, PJ 135-137 ° C. 77. (cis) -5-r4- | '4- (3,4-Dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-phthalazin-2-yl} phenyl-2-benzyl tet razol Prepared from compound C (see starting compounds) and compound N (see starting compounds), as described for compound 35. It was crystallized from methanol. PJ. 100-102 ° C. 78. (cis) -2-Benzyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one. 6 mmol of a 60% suspension was added. sodium hydride in mineral oil to a suspension of 5 mmol of compound 1 in about 40 ml of dimethylformamide, under a nitrogen flow at room temperature. After shaking this mixing for 30 minutes, 7 mmole of benzyl chloride was added and the resulting mixture was stirred for another 4 hours, after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from methanol. PJ. 117-118 ° C. 79. (trans) -2-Benzyl-4- (3,4-dimethoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one A mixture of 10 mmol of compound B (see compounds starting material) and 10 mmoles of benzylhydrazine hydrochloride in 100 ml of toluene was refluxed for 8 hours in a Dean-Stark apparatus. After cooling to room temperature, the mixture was washed with aqueous sodium carbonate, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography [ethyl acetate: petroleum ether (60-80 ° C) / 1: 3] and the compound was crystallized from diethyl ether. PJ. 86-88 ° C. 80. (cis) -2-Benzyl-4- (3,4-dimethoxy-enyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 3 and benzyl chloride, as it was described for compound 78. It was purified by chromatography [ethyl acetate: petroleum ether (60-80 ° C) / 1: 3]. It was crystallized from diethyl ether. PJ. 133-135 ° C. 81. (cis) -2-Benzyl-4- (3-cyclopentinyloxy-4-d-methoxyphenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 4 and benzyl chloride, as described for compound 78. Purified by chromatography [petroleum ether (60-80 ° C): ethyl acetate / 4: 1] and crystallized from petroleum ether (60- 95 ° C) / ethyl acetate. PJ. 91-92 ° C. 82. (cis) -2-Benzyl-4- (3,4-dimethoxyphenip-4a.5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 8 and benzyl chloride, as described for compound 78. Crystallized from petroleum ether (60-95 ° C), PJ 91-92 ° C. 83. Acid (cis) -4- (4- (3,4-dimethoxyphenyl) -1-oxo4-a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-yl methyl.} Benzo ico Prepared from compound 1 and 4-chloromethylbenzoic acid, as described for compound 78, using 12 mmoles of sodium hydride instead of 6 mmoles.After evaporation of the reaction mixture, the residue was divided between carbonate aqueous sodium and ethyl acetate.The aqueous solution was acidified with hydrochloric acid and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate and evaporated.The compound was purified through chromatography (ethyl acetate) and crystallized from diethyl ether, PJ 135- 139 ° C. 84. Hemieterate of (cis) -4- (4- (3-ethoxy-4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1 H-phthalazin-2-methylmethyl) benzoic acid Prepared to from compound 6 and 4-chloromethylbenzoic acid, as described for compound 83. It was crystallized from diethyl ether / petroleum ether (60-80 ° C). PJ. 132-133 ° C. 85. Acid (cis) -4- 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin -2-i I meti l > benzoic Prepared from compound 7 and 4-chloromethylbenzoic acid, as described for compound 83. Purified by chromatography (dichloromethane). It was crystallized from diethyl ether. PJ. 152-154 ° C. 86. Acid (cis) -4-. { 4- (3-Cyclopentyloxy-4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-ylmethyl) benzoic acid Prepared from compound 4 and 4-acid chloromethylbenzoic acid, as described for compound 83. It was crystallized from ethyl acetate. PJ. 189-190 ° C. 87. (Cis) -4-f4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,8,8a-tetrahydro-1H-phthalazin-2-ylmethyl) benzoic acid Prepared from compound 3 4 - acid chloromethylbenzoic acid, as described for compound 83. It was crystallized from ethyl acetate. PJ. 192-193 ° C. 88. Acid (cis) -3- (4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-ylmethyl) benzoic acid Prepared from compound 1 and 3-bromomethylbenzoic acid, as described for compound 83. Purified through chromatography (ethyl acetate). It was crystallized from diethyl ether. PJ. 133-136 ° C. 89. Acid (cis) -4-. { 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-ylmethyl) f-enylacetic Prepared from compound 1 and 4-chloromethylphenylacetic acid , as described for compound 83. It was purified by chromatography (ethyl acetate). It was crystallized from diethyl ether. PJ. 164-166 ° C. 90. (cis) -4- (3,4-Dimethoxyphenyl) -2- (2-methoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one. Prepared from compound 1 and sodium chloride. 2-methoxybenzyl, as described for compound 78. It was purified by chromatography (dichloromethane). It was crystallized from diethyl ether at -20 ° C. PJ. 96-99 ° C. 91. (cis) -4- (3,4-D i methoxy in i p-2- (3-methoxy benz I) -4a, 5, 6, 7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and 3-methoxybenzyl chloride, as described for compound 78. It was crystallized from methanol, PJ, 115 ° C. 92. (cs) -4- (3,4-Dimethoxyphenyl) -2- (4-methoxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from the compound 1 and 4-methoxybenzyl chloride, as described for compound 78. It was crystallized from diethyl ether. PJ. 77-78 ° C. 93. (cis) -4- (3,4-Dimethoxyphenyl) -2- (3,5-d-imethoxybenzyl) -4a, 5, 6, 7, 8, 8a-hexahydro-2H-phthalazin-1 -one. compound 1 and 3,5-dimethoxybenzyl chloride, as described for compound 78. Purified by chromatography (dichloromethane). It was crystallized from methanol. PJ. 114-117 ° C. 94. (cis) -4- (3,4-Dimethoxyphenyl) -2- (2-trifluoromethylbenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 1 and 2-trifluoromethylbenzyl chloride, as described for compound 78. Purified by chromatography (dichloromethane). It was crystallized from petroleum ether (60-95 ° C). PJ. 87-88 ° C. 95. (cis) -2- (2-CI, benzyl) -4- (3,4-di methoxy-enyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one. Compound 1 and 2-chlorobenzyl chloride, as described for compound 78. Purified by chromatography (dichloromethane). It was crystallized from petroleum ether (60-95 ° C). PJ. 101-104 ° C. 96. (cis) -4- (3,4-Dimethoxyphenyl) -2- (4-hydroxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 122 and Catalytic debenzylation in ethanol using 5% palladium on carbon. Crystallized from diethyl ether. PJ. 177-179 ° C. 97. (cis) -4- (3,4-D i methoxy in i I) -2- (2-h id roxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 126 through catalytic debenzylation, as described for compound 96. PJ. 132-133 ° C. 98. (cis) -4-. { Methyl 4- (3,4-dimethoxyphenyl) -1-oxo-4a, 5,6,7,8,8a-hexahydro-1 H-phthalazin-2-methyl) benzoate 3 ml of sodium chloride were added slowly thionyl to a solution of 1 g of compound 83 in methanol at -20 ° C. After the addition was complete, the mixture was stirred for 6 hours at room temperature and subsequently evaporated. The compound crystallized from diethyl ether at -20 ° C. PJ. 90-92 ° C. 99. (cis) -4- (3,4-Dimethoxyphenin-2- (2-pyridyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound C and 2-pyridylhydrazine chloride, as it was described for compound 35. It was purified by chromatography (ethyl acetate) and crystallized from ethyl acetate / diethyl ether, PJ 147-148 ° C. 100. (cis) -4- (3,4-D i methoxyphenyl) -2- (2-pyridylmethyl) -4a, 5, 6, 7,8,8 a-hexahydro-2H-phthalazin-1 -one Prepared to from compound 1 and 2-picolyl hydrochloride, as described for compound 105. It was crystallized from diethyl ether. PJ. 181-182 ° C. 101. (cis) -4- (3,4-Dimethoxy-enyl) -2- (2-pi ridi I met i I) -4a, 5, 8,8a -tetra h id ro-2H-phthalazin-1 -one Prepared from compound 3 and 3-picolyl hydrochloride, as described for compound 105. It was crystallized from diethyl ether. PJ. 146-147 ° C. 102. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (3-pyridylmethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one hydrochloride Prepared from the compound 1 and 3-picolyl hydrochloride, as described for compound 105. It was purified through chromatography (dichloromethane). It was crystallized from diethyl ether as the hydrochloride. PJ. 192-195 ° C. 103. (cis) -4- (3,4-Dimethoxy-enyl) -2- (3-pyridylmethyl) -4a, 5, 8,8a -tetra h id ro-2 Hf talazin-1 -one Prepared from the compound 3 and 3-phenylol hydrochloride, as described for compound 105. It was purified by chromatography (ethyl acetate). It was crystallized from diethyl ether. PJ. 117-120 ° C. 104. (cs) -4- (3,4-Dimethoxyphenin-2- (4-pyridylmethyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound 3 and hydrochloride of 4-picol ilo, as described for compound 105. It was purified by chromatography (ethyl acetate), crystallized from diethyl ether, PJ 121-124 ° C. 105. (cis) -4- (3,4-Dimethoxyphenyl) -2- (4-pyridylmethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from compound 1 and 4-picolyl hydrochloride, as described for compound 78, using 12 mmoles of sodium hydride instead of 6 mmoles. It was purified by chromatography (dichloromethane). It was crystallized from diethyl ether. PJ. 87-89 ° C. 106. (cis) -4- (3,4-Dimethoxyphenyl) -2- (2-yndalyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound C and hydrochloride 2 Indanylhydrazine, as described for compound 35. It was crystallized from methanol. PJ. 163-164 ° C. 107. (cis) -4- (3,4-Dimethoxyphenyl) -2- (1,4-benzodiazin-2-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from the compound C and 2-hydrazino-1,4-benzodiazine, as described for compound 35. Purified through chromatography and crystallized from diethyl ether. PJ. 154-156 ° C. 108. (cis) -4- (3,4-Pethoxyphenyl) -2- (2-benzothiazole-4a, 5,8,8a-tetrah id ro-2 Hf talazin-1 -one Prepared from compound C and 2-hydrazinobenzothiazole, as described for compound 35. It was crystallized from ethyl acetate / petroleum ether (60-80 ° C), PJ 176-177 ° C. 109. (cs) -4- (3,4-D¡methoxyphenyl) -2- (2-methythiazole-4-in-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one) from compound 1 and 4-chloromethyl-2-benzothiazole, as described for compound 35. Crystallized from ethyl acetate, PJ 135-137 ° C. 110. (cis) -2- (Benzotriazol-1-ylmethyl) -4- (3,4-dimethoxyphenyl) -4a, 5,6,7, 8,8a-hexahydro-2H-phthalazin-1 -one Prepared from the compound 1 and 1-bromomethylbenzotriazole, as described for compound 78, using sodium ethanolate in place of sodium hydride. It was purified by chromatography [ethyl acetate: petroleum ether (60-95 ° C) / 1: 2]. It was crystallized from methanol. PJ. 173-178 ° C. 111. (cis) -4- (3,4-Dimethoxyphenin-2- (2-phenylethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from 2-bromoethylbenzene and Compound 1, as described for compound 78. Purified by chromatography [ethyl acetate: petroleum ether (60-80 ° C / 1: 3] .Crystallized from methanol. ° C. 112. (Cis) -4- (3,4-dimethoxy-phenyl-2- (2-bromoetyp-4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one) hydrochloride A solution of 25 mmol of bromide in 10 ml of dichloromethane was added to a solution of 25 mmoles of triphenylphosphine in 50 ml of dichloromethane at 0 ° C under nitrogen flow, followed by the addition of 25 mmoles of compound 35 in 25 ml of dichloromethane. After the addition was complete, the mixture was stirred for 2 hours at room temperature, the reaction mixture was washed with aqueous sodium carbonate, dried over magnesium sulfate and evaporated. of methanol. PJ. 134-136 ° C. 113. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (2- (1-imidazolyl) ethyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one hydrochloride A solution of 2 g of compound 112 and 3 g of imidazole in methanol was left for 18 hours at room temperature. After evaporating the solvent, the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in ethyl acetate and filtered on silica. The compound was crystallized as the hydrochloride from tetrahydrofuran. PJ. 198-199 ° C. 114. (cs) -4- (3,4-Dimethoxyphenyl) -2- (4-bromo-1-butyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from the compound C and 1,4-dibromobutane, as described for compound 58. PJ. 105-106 ° C. 115. (Cis) -4- (3,4-dimethoxyphenyl) -2- hydrochloride. { 4- (1-imidazolyl) butyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 58, as described for compound 113. PJ. 210-212 ° C. 116. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (4- (1-imidazolyl) -1-butyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride Prepared from compound 144 and imidazole, as described for compound 113. The reaction mixture was evaporated and the residue was dissolved in 2N HCl. After extraction with dichloromethane and drying over magnesium sulfate, the solvent was evaporated. The residue was crystallized by treatment with ethyl acetate. PJ. 192-194 ° C. 117. (cis) -4- (3,4-Dimethoxyphenyl) -2- (6-bromo-1-hexyl) -4a.5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from the compound C and 1,6-dibromohexane, as described for compound 58. PJ. 55-56 ° C. 118. (Cis) -4- (3,4-Dimethoxyphenyl) -2- (6- (1-imidazolyl) -1-h ex-il-4a hydrochloride, 5,8,8a-tetrahydro-2 H -ftai azin- 1 -one Prepared from compound 117 and imidazole, as described for compound 113. Purified by chromatography and crystallized as the hydrochloride from tetrahydrofuran, PJ 183 ° C. 119. (Cis) -2-f6-benzimidazole) -1-hexyl hydrochloride} -4- (3,4-dimethoxy-phenyl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 117 and benzimidazole, as described for compound 113. It was purified from through chromatography (ethyl acetate) and crystallized as the hydrochloride. PJ. 67-70 ° C. 120. (cis) -N-r6- (4- (3,4-Dimethoxyphenipy-oxo-4a, 5,8,8a-tetrahydro-phthalazin-2-yl) hex] H phthalimide A mixture of 10 g of compound 117, g of phthalimide and 10 g of potassium carbonate was heated for 5 hours at 100 ° C. in DMF The mixture was diluted with water and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane) and crystallized from ethyl acetate / ether, PJ 104-105 ° C. 121. (cis) -4- (3,4-Dimethoxyphenyl-2- (3-phenyl-2-rtrans-1-propenyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared to from compound 1 and 3-phenyl-2- [transj-propenyl chloride, as described for compound 78. It was purified by chromatography (dichloromethane), crystallized from diethyl ether at -20 ° C. 76-79 ° C. 122. (cs) -4- (3,4-D-methoxyphenyl) -2- (4-benzyloxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1 -one Prepared from of compound 1 and 4-benzyloxybenzyl chloride, as described for compound 78. It was purified by chromatography (dichloromethane) and isolated as a colorless oil. 1 H-NMR (CDCl 3): 1.26-1.86 (m, 7H, 7x cyclohexyl H); 2.47-2.76 (m, 2H, 2x cyclohexyl H); 3.00-3.16 (m, 1H, cyclohexyl H); 3.93 (s, 6H, 2x O.CH3); 4.83-5.15 (m, 4H, N-CH2, 0-CH2); 6.80-6.97 (m, 3H, arom.H); 7.15-7.47 (m, 9H, arom.H). 123. Sodium salt of (cis) -2-r6- (4- (3,4-dimethoxyphenyl) -1 -oxo-4a, 5,8,8a-tetrahydroftalazin-2-yl) hexyloxy-1-benzoic acid A mixture of 4 g of compound 114, 3 g of ethyl salicylate and 3 g of potassium carbonate in 100 ml of DMF was heated for 2 hours at 100 ° C. After evaporating the reaction mixture, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The organic solvent was evaporated and the residue was dissolved in a mixture of 100 ml of methanol, 100 ml of tetrahydrofuran and 200 ml of 2N potassium hydroxide. The mixture was heated for 2 hours at 60 ° C and subsequently evaporated. After extraction with ethyl acetate, the compound was purified by chromatography and precipitated from ether with a solution of concentration of sodium ethanolate in ethanol. The crystallization from tetrahydrofuran / diethyl ether. PJ. 141-144 ° C. 124. (cis) -4- (3,4-Dimethoxyphenyl) -2- (tetrahydropyran-4-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from compound C and 4- Hydrazinotetrahydropyran, as described for compound 35. It was crystallized from methanol. PJ. 175-177 ° C. 125. (cs) -4- (3,4-Dimethoxy-phenyl-2- (tetrahydrothiopran-4-yl) -4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one. of compound C and 4-hydrazinotetrahydrothiopyran, as described for compound 35. It was crystallized from methanol, PJ 140-141 ° C. 126. (cis) -4- (3,4-Dimethoxyphenyl) -2- (2-benzyloxybenzyl) -4a, 5,6,7,8,8a-hexahydro-2H-phthalazin-1-one Prepared from compound 1 and 2-benzyloxybenzyl chloride, as described for compound 78. Purified through chromatography [ethyl acetate / petroleum ether (60-80 ° C), 1: 3]. PJ. colorless oil. 1 H-NMR (CDCl 3): 1.22-1.83 (m, 7H, 7x cyclohexyl H), 2.41-2.73 (m, 2H, 2x cyclohexyl H), 3.00-3.16 (m, 1H, cyclohexyl H), 3.91 (s, 3H, O-CH3), 3.93 (s, 3H, O-CH3), 4.83-5.16 (m, 4H, N -CH2, 0-CH2), 6.80-6.97 (m, 3H, Ar-H), 7.15-7.48 (m, 9H, Ar-H).

Compounds of Compound A. 2- (3,4-d-imethoxybenzoyl) Tetracyclohexane-carboxylic acid 0.5 mmol of 1,2-dimethoxybenzene was slowly added to a suspension of 0.5 mol of aluminum trichloride in one liter of dichloromethane at 0 ° C . After the addition was complete, cis-cyclohexane-1,2-dicarboxylic anhydride was added to the solution. After 8 hours of reflux, the solution was emptied on ice. The organic layer was dried over magnesium sulfate and evaporated. The residue was washed with diethyl ether and dried. PJ. 171-175 ° C.

B. 2- (3,4-Dimethoxybenzoyl) rtrans1-cyclohexanecarboxylic acid Prepared from trans-cyclohexane-1,2-dicarboxylic anhydride and 1,2-dimethoxybenzene, as described for compound A. PJ. 202-205 ° C.

C. 2- (3,4-Dimethoxybenzoyl) -1,2,3,6-tetrahydrobenzoic acid Prepared from 1,2-dimethoxybenzene anhydride and cis-1, 2,3,6-tetrahydrophthalic anhydride, as described for the compound A. PJ. 110-112 ° C.

D. 2- (3-Cyclopentoxy-4-methoxybenzoyl) -cis-cyclohexanecarboxylic acid 4-Bromo-2-cyclopentyloxy-1-methoxybenzene (16.3 g, 60 mmoles) in 200 ml of THF and cooled with an ethanol / N2 bath at -90 ° C. BuLi (41 ml, 66 mmol) was added portionwise, while maintaining the temperature below -80 ° C and stirred for another 15 minutes after the last addition. This mixture was then added rapidly under a nitrogen atmosphere to a cold solution (-90 ° C) of cis-1,2-cyclohexanedicarboxylic anhydride (11.1 g, 72 mmol) in 200 ml of THF. After stirring for 2 hours at -80 ° C, ammonium chloride was added and the reaction mixture was allowed to warm to room temperature. 300 ml of water were added and the inorganic layer was washed with 200 ml of ethyl acetate. The extracts The combined organics were washed with 300 ml of water and brine (2x300 ml), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography (petroleum ether (60-95 ° C) / ethyl acetate: 7/13) and crystallized from petroleum ether (60-95 ° C) / ethyl acetate to give the title compound (10.1 g) as a white solid. PJ. 120-121 ° C.

E. (cis) -2- (3-Cyclopentyloxy-4-methoxy-benzoyl) -1,2,3,6-tetrahydrobenzoic acid A solution of 100 ml of 1-nromo-3-cyclopentyloxy-4-methoxybenzene in Tetrahydrofuran was added slowly to a mixture of 1.1 equivalents of magnesium. After the addition was complete, the mixture was refluxed for 5 hours and left at room temperature for a further 18 hours. The mixture was added slowly to a solution of (cis) -1,2,3,6-tetrahydrophthalic anhydride in tetrahydrofuran at 0 ° C. After the addition was complete, the mixture was refluxed for 6 hours and left at room temperature for a further 18 hours, after which the reaction was quenched with ammonium chloride and the solvent was removed under reduced pressure. The residue was acidified with concentrated hydrochloric acid and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was filtered on silica. After evaporating this dichloromethane solution, the compound it was crystallized from diethyl ether. PJ. 114-115 ° C.

F. (Cis) -2- (3-Ethoxy-4-methoxybenzoyl) -1, 2,3,6-tetrahydro-benzoic acid Prepared from 1-bromo-3-ethoxy.4.methoxybenzene and tetrahydrophthalic anhydride, as described for compound D. PJ. 32-135 ° C.

G. 2- (3,4-Diethoxybenzoyl) acid Isicyclohexanecarboxylic acid Prepared from 1,2-diethoxybenzene and cis-hexahydrophthalic anhydride, as described for compound A. PJ. solid-low melting point. 1 H-NMR (CDCl 3): 1.28-2.27 (m, 14H, 8x cyclohexane H, 2x C-CH 3); 2.66 (quintet, J = 4.8 Hz, 1H, cyclohexane H); 3.91-3.97 (m, 1H, C-CH (O) -C); 4.01-4.25 (m, 4H, 2xO-CH2); 6.89 (d, J = 8.2Hz, 1H, arom.H); 7.48-7.53 (m, 2H, arom.H).

H. (cis) -4- (4-ethoxy-3-hydroxy-phenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one A solution of 3.3 g of compound 21 and 2 g of p-toluenesulfonic acid in 15 ml of toluene was refluxed for 4 hours. After cooling to room temperature, the mixture was washed with aqueous sodium carbonate, the toluene solution was dried over magnesium sulfate and evaporated. It was crystallized from diethyl ether / petroleum ether (60-80 ° C). PJ 142-144 ° C.

I. (cis) -4- (4-Methoxy-3-hydroxyphenyl) -2-cyclopentyl-4a, 5,8,8a-tetrahydro-2H-phthalazin-1 -one Prepared from compound 26, as described for the compound H. PJ. 171 ° C.

K. 5- (3-Nitrophennetetrazole A mixture of 14.8 g of 4-nitrobenzonitrile, 32 g of ammonium chloride and 39 g of sodium azide in 150 ml of DMF was heated for 2 hours at 120 ° C. evaporate the solvent, the residue was partitioned between 2N hydrochloric acid and ethyl acetate.The organic layer was dried and evaporated.The residue was washed with ether and dried PJ 101-102 ° C.

L. 2-Benzyl-5- (4-nitrophenyl) tet razol A mixture of 12 g of compound K, 20 g of potassium carbonate and 12 g of benzyl chloride in 100 ml of DMF was heated for 3 hours at 100 ° C. C. After evaporating the solvent, the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was washed with diethyl ether and dried. PJ. 139-141 ° C.

M. 2-Benzyl-5- (4-aminophenyl) tet razol Prepared from compound L, as described for compound 74. After evaporating the solvent, the residue was dissolved in ethyl acetate and this solution was washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The concentrated solution was filtered over silica and evaporated. The residue was washed with diethyl ether and dried. PJ. 130-132 ° C.

N. 2-Benzyl-5- (4-h! Drazinofen! P tet razol A solution of 1.9 g of sodium nitrite in 10 ml of concentrated hydrochloric acid was added slowly to a solution of 6.5 g of compound M in 20 ml of 2N hydrochloric acid This was followed by the addition of 17 g of tin dichloride dihydrate in 20 ml of water at 0 ° C. After 30 minutes, the precipitate was filtered, washed thoroughly with brine and dried. 185 ° C.

O. 2-Ethyl-5- (4-hydanatofenintetrazole) A mixture of 35 mmol of 2-ethyl-5- (4-nitrophenyl) tetrazole (prepared analogously to compound L) and 15 g of iron in a mixture of 300 ml of ethanol and 800 ml of water at 65 ° C, treated with 10 ml of 2N hydrochloric acid for 45 minutes.After filtering, the solvent was evaporated.The residue was washed with ethyl acetate and used without further purification in the Next step: A solution of 2.2 g of sodium nitrite in 10 ml of concentrated hydrochloric acid was slowly added to a solution of the residue mentioned above (2-ethyl-5- (4-aminophenyl) tetrazole) in 20 ml of concentrated hydrochloric acid. 2N This was followed by the addition of 22 g of tin dichloride dihydrate in 25 ml of water at 0 ° C. After 30 minutes, the mixture was extracted with tetrahydrofuran and ia.

The organic solution was washed once with a solution of sodium carbonate saturated with sodium chloride. The organic solution was dried over potassium carbonate and evaporated. The residue was used without purification in the next step.

Commercial Utility The compounds according to the invention have useful pharmacological properties, which make them industrially suitable. As inhibitors of cyclic nucleotide phosphodiesterase (PDE) (specifically of type 4), they are suitable, on the one hand, as therapeutic for the bronchi (for the treatment of airway obstructions that represent their dilating action, but also represent their action of increase in respiratory velocity or respiratory activation) and for the removal of erectile dysfunction that represents its vascular dilatation action, but, on the other hand, especially for the treatment of disorders, in particular of inflammatory nature, for example, of the respiratory tract (prophylaxis of asthma), skin, intestine, eyes, central nervous system (CNS) and joints, which are mediated through mediators such as histamine, PAF (platelet activation factor), arachidonic acid derivatives, such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta- and gamma-interf eron, tumor necrosis factor (TNF) or oxygen free radicals and protease. In this context, the compounds according to the invention are distinguished by low toxicity, good enteral absorption (high bioavailability), large therapeutic respiration and the absence of significant side effects. As for their PDE inhibitory properties, the compounds according to the invention can be used in medicine for human beings and veterinary as therapeutic, where they can be used, for example, for the treatment and prophylaxis of the following diseases: acute disorders and chronic respiratory tract (in particular, inflammatory and induced by allergen) of variable origin (bronchitis, allergic bronchitis, bronchial asthma); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburns, itching in the anogenital area, alopecia areata, hypertrophic scars , lupus erythematosus, follicular and extended pyoderma, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; disorders that are based on an excessive release of TNF and leukotrienes, for example, disorders of the arthritis type (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions), immune system disorders (AIDS, multiple sclerosis), types of shock (septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome and ARDS (respiratory distress syndrome in adults)) and also generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis); disorders that are based on false immunological, allergic and / or chronic reactions in the region of the upper respiratory tract (pharynx, nose) and adjacent regions (paranasal sinuses, eyes), such as allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and also nasal polyps; but also disorders of the heart, which can be treated through PDE inhibitors, such as heart failure, or disorders that can be treated in terms of the tissue relaxation action of PDE inhibitors, such as, for example. Erectile dysfunction or cramping of the kidneys and uterus in relation to kidney stones; and also central nervous system disease, such as depressions or arteriosclerotic dementia. The invention also relates to a method for the treatment of mammals, including humans, which suffer from one of the aforementioned diseases. The method is characterized in that a therapeutically active and pharmacologically effective and tolerable amount of one or more of the compounds according to the invention is administered to the diseased mammal. The invention furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the disease, in particular the aforementioned diseases. The invention also relates to the use of the compounds of according to the invention for the production of medicaments, which are used for the treatment and / or prophylaxis of the mentioned diseases. The invention also relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention. The drugs are prepared through processes, which are known per se and are familiar to those skilled in the art. As medicaments, the compounds according to the invention (= active compounds) are used either as such, or preferably in combination with suitable pharmaceutical auxiliaries, for example, in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the content of the active compound advantageously being between 0.1 and 95%. Those skilled in the art are familiar with the auxiliaries that are suitable for the desired pharmaceutical formulations in terms of their experienced knowledge. In addition, solvents, gel formers, ointment bases and other excipients of the active compound can be used, for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers or penetration promoters. For the treatment of respiratory tract disorders, the compounds according to the invention are preferably also ad ministered through inhalation. To do this, they are either administered directly as a powder (preferably in micronized form) or by atomization of solutions or suspensions containing them. With regard to the preparations and administration forms, reference is made, for example, to the details presented in the European patent 163 965. For the treatment of dermatoses, the compounds according to the invention can be administered in particular in the form of those medications that are suitable for topical administration. For the production of the medicaments, the compounds according to the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give the pharmaceutical formulations. Said pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, ointments, creams, pastes, gels or solutions. The medicaments according to the invention are prepared by processes known per se. The dose of the active compounds is carried out in the usual order of magnitude for the PDE inhibitors. The topical application forms (such as ointments) for the treatment of dermatoses in this manner contain the active compounds in a concentration of, for example, 0.1-99%. The dose for administration through inhalation is usually between 0.1 and 3 mg per day. The usual dose in the case of systemic therapy (p.o. or i.v.) is between 0. 03 and 3 mg / kg.

Biological Research In the investigation of the inhibition of PDE 4 in the cellular plane, the activation of inflammatory cells is attributed a particular importance. One example is FMLP (N-formyl-methionyl-leucyl-phenylalanine), induced by superoxide the production of neutrophilic granulocytes, which can be measured as chemiluminescence amplified by luminol. (Mc Phail LC, Strum SL, Leone PA and Sozzani S, The Neutrophil Respiratory Burst Mechanism, In "Immunology Series" 57: 47-76, 1992, ed. Coffey RG (Marcel Decker, Inc., New York-Basel-Hong Kong)). Substances that inhibit chemiluminescence and cytokine secretion and the secretion of pro-inflammatory mediators in inflammatory cells, in particular, neutrophilic and eosinophilic granulocytes, T-lymphocytes, monocytes and macrophages are those that inhibit PDE 4. This isoenzyme of families of Phosphodiesterase is particularly represented in granulocytes. Its inhibition leads to an increase in the concentration of intracellular cyclic AMP and in this way to the inhibition of cellular activation. The inhibition of PDE 4 through the substances according to the present invention in this way is a central indicator for the suppression of inflammatory processes. (Giembycz MA, Could Isoenzyme-Selective Phosphodiesterase Inhibitors Render Bronchiodilatory Theraphy Redundant in the Treatment of Bronchial Asthma ?. Biochem Pharmacol 43: 2031-2051, 1992; Torphy TJ et al., Phosphodiesterase Inhibitors: New Opportunities for the Treatment of Asthma. Thorax 46: 512-523, 1991; Schudt C et al., Zardaverine: A Cyclic AMP PDE 3/4 Inhibitor. In "New Drugs for Asthma Therapy", 379-402. Birkháuser Verlag Basel 1991; Schudt C et al., Influence of Selective Phosphodiesterase Inhibitors on Human Neutrophil Functions and Levéis of cAMP and Ca; Naunyn-Schmiedebergs Arch Pharmacol 344; 682-690, 1991; Nielson CP et al., Effects of Selective Phosphodiesterase Inhibitors on Polymorphonuclear Leucocyte Respiratory Burst. J. Allergy Clin Immunol 86: 801-808, 1990; Schade et al., The Specific Type 3 and 4 Phosphodiesterase Inhibitor Zardaverine Supress Formation of Tumor Necrosis Factor by Macrophages. European Journal of Pharmacology 230: 9-14, 1993).

Inhibition of PDE 4 Activity Methodology The activity test was carried out according to the Bauer and Schwabe method, which was adapted to microtitre plates (Naunyn-Schmiederberg's Arch. Pharmacol 311, 193-198, 1989). In this test, the PDE reaction is carried out in the first step. In the second step, the resulting 5 'nucleotide is separated to the uncharged nucleoside through the 5' nucleotidase of Crotalus Atrox snake venom. In the third step, the nucleoside is separated from the remaining loaded substrate in ion exchange columns. The columns were directly eluted to miniframes using 2 ml of 30 mM ammonium formate (pH 6.0), to which an additional 2 ml of synthetic fluid was added for counting. For the following compounds these values were determined [measured as -loglC50 (mol / 1)]. The numbers of the compounds correspond to the numbers of the examples. Compound 10-33, 40, 41, 50, 52-55.57, 59-64, 66-73, 75-82, 84, 86, 88-111, 115, 116, 118-121, 123-125.

Claims

1. - Compounds of the formula I: wherein: R 1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R 2 is alkoxy of 1 to 8 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms , cycloalkylmethoxy of 3 to 7 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, -CmH2m-R7, - CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen (H), alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, polycycloalkyl of 7 to 10 carbon atoms, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, indanyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or a phenyl radical unsubstituted or substituted by R61 and / or R62, in wherein, R61 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, amino carbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, aminosulfonyl, mono- or dialkylaminosulfonyl of 1 to 4 carbon atoms, 4-methylphenylsulfonamido, tetrazol-5-yl, 2- (alkyl of 1 to 4 carbon atoms) tetrazol-5-yl or 2-benzyl-tetrazol-5-yl and, R62 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, cyano, nitro, nitroxy (-0-N02), carboxyl, carboxyphenyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms , cycloalkylmethoxy of 3 to 7 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms carbon, or a piperidyl, piperazinyl, pi rro I id ini I oo morpholinyl unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, carbon or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is an unsubstituted or substituted phenyl, naphthyl, phenanthrenyl or anthracenyl radical by R81 and / or R82, wherein, R81 is hydroxyl, halogen, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms carbon, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 4 atoms carbon, which is complete or predominantly substituted by fluorine, and R82 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N- benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl nsubstituted, a 2- (C 1-4 -alkyl) -thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein R 10 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino from 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, aminocarbonyl or mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms or akoxy from 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 2, and the salts of these compounds .

2. Compounds of the formula I according to claim 1, wherein: R1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R2 is alkoxy of 1 to 8 carbon atoms, cycloalkoxy from 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms or alkoxy of 1 to 4 carbon atoms which is completely or predominantly substituted by fluorine, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, -CmH2m- R7, -CNH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen (H), alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms , cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, bornyl, norbornyl, adamantyl or an unsubstituted phenyl radical or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, or halogen, and R62 is alkyl of 1 to 4 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, cyano, nitro, phenoxy, alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 at 7 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl radical unsubstituted or substituted by R71 and / or R72, wherein R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms. carbon, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl, naphthyl, phenanthrenyl or anthracenyl radical unsubstituted or substituted by R81 and / or R82, wherein, R81 is hydroxyl, halogen, cyano, alkyl, to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino , mono- or dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, and R82 is hydroxyl, halogen, alkyl from 1 to 4 carbon atoms, alkoxy from 1 to 4 atoms carbon or alkoxy of 1 to 4 carbon atoms, which is completely or predominantly substituted by fluorine, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl , quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl unsubstituted, a 2- (alkyl of 1 to 4 carbon atoms) -thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono- dialkylamino of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, aminocarbonyl or mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 4, q is an integer from 0 to 2, and the salts of these compounds

3. Compounds of the formula I according to claim 1, wherein: R1 is alkoxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms which is completely or predominantly substituted by fluorine, R2 is alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkylmethoxy of 3 to 7 carbon atoms or C 1 -C 2 alkoxy which is completely or predominantly substituted by fluorine, R 3 and R 4 both are hydrogen or together form an additional bond, R 5 is R 6, -C m H 2m-R 7, -C n H 2n-C (0) R 8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, alkynyl of 3 to 7 atoms of carbon, phenyl-alkenyl of 3 to 4 carbon atoms, bornyl, norbornyl, adamantyl, naphthyl, pyridyl, quinoxalinyl, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiapyranyl or a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein, R61 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl from 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, aminocar bonyl, aminosulfonyl, mono- or dialkylaminosulfonyl of 1 to 4 carbon atoms, 4-methylphenylsulfonamido, tetrazol-5-yl, 2- (alkyl of 1 to 4 carbon atoms) tetrazol-5-yl or 2-benzyl-tetrazole- 5-y1 y, R62 is alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, nitro or halogen, R7 is hydroxyl, halogen, carboxyl, nitroxy (-0-N02), phenoxy, carboxyphenoxy, alkoxy from 1 to 4 carbon atoms, alkylcarbonyl 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, or morpholinyl radical unsubstituted or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is an unsubstituted or substituted phenyl or naphthyl radical by R81 and / or R82, wherein, R81 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl, alkylcarbonyloxy of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 2 atom s of carbon, which is completely or predominantly substituted by fluorine, and R82 is halogen, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl , pyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolium, N-benzosuccinimidyl, imidazolyl, oxazolyl, unsubstituted thiazolyl, a 2- (alkyl of 1 to 2 carbon atoms) -thiazol-4-yl, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms carbon, carboxyl, carboxyalkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, and R11 is hydroxyl, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 1, and the salts of these compounds.

4. Compounds of the formula I according to claim 1, wherein: R1 is methoxy, ethoxy or difluoromethoxy, R2 is alkoxy of 1 to 4 carbon atoms, difluoromethoxy, cycloalkoxy of 3 to 5 carbon atoms, or cycloalkylmethoxy from 3 to 5 carbon atoms, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar , wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkynyl of 3 to 4 carbon atoms, phenyl-alkenyl of 3 to 4 carbon atoms, adamantyl, pyridyl, quinoxaline, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, a phenyl radical unsubstituted or substituted by R61 and / or R62, wherein R61 is alkyl 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, nitro, halogen, carboxyl, carboxyalkyl of 1 to 2 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 2 carbon atoms, amino , aminosulfonyl, 4-methylphenylsulfonamido, 2- (alkyl of 1 to 2 carbon atoms) tetrazol-5-yl or 2-benzyltetrazol-5-yl, and R62 is alkyl of 1 to 2 carbon atoms or halogen, R7 is hydroxyl , halogen, carboxyl, nitroxy (-0-N02), phenoxy, carboxyphenyloxy, alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylaminocarbonyl of 1 to 4 carbon atoms, amino, mono- or dialkylamino of 1 to 4 carbon atoms, or a piperidyl, piperazinyl, or morpholinyl unsubstituid radical or substituted by R71 and / or R72, wherein, R71 is hydroxyl, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, and R72 is alkyl of 1 to 4 carbon atoms, carboxyl, aminocarbonyl or alkoxycarbonyl of 1 to 4 carbon atoms, R8 is a phenyl or naphthyl radical unsubstituted or substituted by R81, wherein R81 is halogen or alkoxy of 1 to 4 carbon atoms, R9 is -CqH2q-phenyl, Ar is phenyl, naphthyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, unsubstituted thiazolyl, a 2- (alkyl of 1 to 2 carbon atoms) -thiazol-4-yl, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, alkyl of 1 to 2 carbon atoms, trifluoromethyl, alkoxy of 1 to 2 atoms carbon, carboxyl, carboxyalkyl of 1 to 2 carbon atoms, or alkoxycarbonyl of 1 to 2 carbon atoms, and R11 is halogen, alkyl of 1 to 2 carbon atoms or alkoxy of 1 to 2 carbon atoms, m is a integer from 1 to 8, n is an integer from 1 to 6, p is 1 or 2, q is 0 or 1, and the salts of these compounds.

5. Compounds of the formula I according to claim 1, wherein: R1 is methoxy or ethoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, -CmH2m-R7, -CnH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, in wherein, R6 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, allyl, 2-propionyl, phenyl-trans-prop-1-en-3 -yl, adamantyl, pyridyl, quinoxaline, indanyl, benzothiazolyl, N-methylpiperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, a phenyl radical unsubstituted or substituted by R61, wherein, R61 is alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, amino, aminosulfonyl, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl, R7 is hydroxyl, halogen, carboxyl, nitroxy (-0-N02), phenoxy, carboxyphenyloxy , alkoxycarbonyl of 1 to 4 carbon atoms, amino, methylamino, dimethylamino, dimethylaminocarbonyl, 1-piperidyl or N-methyl-4-piperidyl, R8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or 2-naphthyl, R9 is -CqH2q -phenyl, Ar is phenyl, pyridyl, benzimidazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl unsubstituted or, a 2-methyl-thiazol-4-yl radical, or a phenyl radical substituted by R 10 and / or R 11, wherein, R 10 is hydroxyl, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, and R 11 is methoxy, m is an integer from 1 to 8, n is 1, p is an integer from 1 to 6, q is O, and the salts of these compounds.

6. Compounds of the formula I according to claim 1, wherein: R1 is methoxy, R2 is methoxy, ethoxy, difluoromethoxy, cyclopropylmethoxy or cyclopentyloxy, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6 , -CNH2n-C (0) R8, -CH (R9) 2 or -CpH2p-Ar, wherein, R6 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, adamantyl, quinoxalinyl, benzothiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl or a phenyl radical unsubstituted or substituted by R61, wherein, R61 is alkyl of 1 to 4 carbon atoms, nitro, halogen, carboxyl, carboxymethyl, hydroxyalkyl of 1 to 2 carbon atoms, aminosulfonyl, 4-methylphenylsulfonamido, 2-ethyltetrazol-5-yl or 2-benzyltetrazol-5-yl, R8 is phenyl or 2-naphthyl, Ar is phenyl, benzimidazolyl, N-benzosuccinimidyl, imidazolyl, or a phenyl radical substituted by R10, wherein, R10 is hydroxyl, halogen, methoxy, trifluoromethyl or carboxyl, n is 1, p is an integer from 1 to 6, and the salts of these compounds.

7. Compounds of the formula I according to claim 1, wherein: R1 is methoxy or ethoxy, R2 is methoxy, ethoxy or cyclopentyloxy, R3 and R4 both are hydrogen or together they form an additional bond, R5 is R6, - CmH2m-R7, -CnH2n-C (0) R8, -CH2 (R9) 2 or -CpH2p-Ar, wherein, R6 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, alio, 2-propionyl, phenyl or phenyl-trans-prop-1-en-3-yl, R7 is hydroxyl, carboxyl or phenoxy, R8 is phenyl, 2-methoxyphenyl, 4-chlorophenyl or -naphthyl, R9 is -CqH2q-phenyl, Ar is phenyl, pyridyl, unsubstituted benzotriazolyl, a 2-methyl-thiazolyl-4-yl radical, or a phenyl radical substituted by R10 and / or R11, wherein, R10 is hydroxyl, halogen, methoxy, trifluoromethyl, carboxyl, carboxymethyl or methoxycarbonyl, and R11 is methoxy, m is an integer from 1 to 6, n is 1, p is 1 or 2, q is 0, and salts of these compounds.

8. Medicaments containing one or more compounds according to claim 1 together with the usual pharmaceutical auxiliaries and / or vehicles.

9. The compounds according to claim 1 for use in the treatment of disease.

10. The use of the compounds according to claim 1 for the production of medicaments for the treatment of respiratory tract disorders.