KR20080074217A - New N-sulfamoyl-piperidineamides for the prevention or treatment of obesity and related conditions - Google Patents

Abstract

The present invention provides novel N-sulfamoyl-piperidineamides of formula (I) and their physiologically acceptable acid addition salts, pharmaceutical compositions comprising them, methods for their preparation, and obesity and incidental and And / or their use for the treatment of secondary diseases and / or conditions associated therewith.

Description

Novel N-Sulfamoyl-PIPERIDINEAMIDES FOR THE PROPHYLAXIS OR TREATMENT OF OBESITY AND RELATED CONDITIONS}

The present invention provides novel N-sulfamoyl-piperidineamides and their physiologically acceptable acid addition salts, pharmaceutical compositions comprising them, methods for their preparation, and their for the treatment of obesity and related conditions. It is about use.

WO 03/088908 discloses N-sulfamoyl-piperidineamides having a special substitution pattern in the piperidine ring. Perhaps the compounds disclosed in WO 03/088908 will be useful for the treatment of arrhythmia, 1 _Kur -related conditions, gastrointestinal disorders, diabetes, cognitive impairment and conditions associated with them.

US 2004/0167185 discloses several N-sulfamoyl-piperidineamides in the field of the treatment or prevention of cancer.

WO 02/07821 is known in mammals and humans for the discovery of compounds suitable for the treatment and / or prevention of obesity by inhibiting lipid biosynthesis via inhibition of carbonic anhydrases.

It is an object of the present invention to provide a novel medicament which can be obtained by a very effective and simple method for the treatment and / or prevention of obesity and its associated and / or secondary diseases or conditions.

Surprisingly, the fact that certain novel N-sulfamoyl-piperidinamides and their physiologically acceptable acid addition salts are suitable for the treatment and / or prevention of obesity and its associated and / or secondary diseases or conditions Turned out.

The present invention relates to compounds of general formula I and their physiologically acceptable acid addition salts:

R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; Alkylenearyl; Alkylene arylenealkyl; Alkylene arylene halogen; Alkylene aryleneoxyalkyl; Alkylene arylene dialkyl amines; Heteroaryl; Unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ;

R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or,

R1 and R2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and / or sulfur atoms; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl;

R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and optionally substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; Or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and Aryl, or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN.

Compounds of formula I are glaucoma, epilepsy, bipolar disorder, migraine, neuralgia, obesity, type II diabetes, metabolic syndrome, alcohol dependence, and / or cancer in mammals and humans, and secondary and / or secondary diseases It is suitable for the treatment and / or prevention of these or conditions.

More specifically, in the compound of Formula I, R1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Alkylene heteroaryl unsubstituted or substituted with halogen;

R2 is cycloalkyl; Aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; C0-alkylenearyl; CO-heteroaryl; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or;

R1 and R2 together Forms a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and / or sulfur atoms; May comprise one or two double bonds; It may also be substituted with alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also comprise a carbonyl group; Can also be condensed by aryl;

R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or

R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and also aryl It may be substituted by.

More specifically, in the compounds of Formula I, R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Selected from the group consisting of alkyleneheteroaryl substituted with halogen; R2 is alkylenealkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R 1 and R 2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and / or sulfur atom; And may optionally include one or two double bonds; It may also be substituted by alkyl, halogenalkyl, unsubstituted or by aryl and / or heteroaryl substituted by alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; Or R 3 and R 4 together form a ring selected from the group consisting of pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino.

In a particularly preferred embodiment of the invention, R 1 is only a hydrogen atom unless R 2 comprises a CO group.

In another particularly preferred embodiment of the invention, R 3 and R 4 are both hydrogen atoms.

In the compounds of the general formula (I) of the present invention or other compounds described as falling within the scope of the present invention, when the substituents are or include alkyl, cycloalkyl, alkylene, alkoxy, they may each be straight or branched chain, It may comprise 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms. Suitable substituents are methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene, ethylene, propylene, iso-propylene, butylene, iso-butyl Ethylene, tert-butylene, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, and tert-butoxy.

If the substituents of the compounds of formula I mean halogen, fluorine, chlorine, bromine or iodine are suitable. Chlorine and bromine are preferred.

When the substituents of the compound of formula I mean aryl, it means a monoaromatic ring system having the appropriate number of hydrogen atoms depending on the substitution pattern. However, condensed aryl systems and spiro aryl systems are also included within this definition. Suitable aryl substituents are phenyl, 1H-indene, 9H-fluorene, naphthalene, anthracene and phenanthrene.

In case the substituents of the compound of formula I mean heteroaryl, the aryl ring system is one in which at least one carbon atom from the aromatic ring system is substituted by a heteroatom selected from an oxygen atom and / or a nitrogen atom and / or a sulfur atom. it means. Suitable heteroaryls include pyrrole, furan, thiophene, indolizin, indole, isoindole, coumarone, thionaphthene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetra Sol, thiadiazole, pyridine, pyran, thiopyran, chinoline, isokinolin, pyridazine, pyrimidine, pyrazine and triazine.

Physiologically suitable acid addition salts of compounds of formula I are, for example, inorganic acids such as sulfuric acid, phosphoric acid, or hydrochloric acid, preferably hydrochloric acid, or lower acids such as, for example, malic acid, fumaric acid, lactic acid, tartaric acid, citric acid. Organic acids such as aliphatic monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids, or sulfonic acids such as lower alkanesulfonic acids such as, for example, methanesulfonic acid or trifluoromethanesulfonic acid, or p-toluenesulfonic acid. Typical salts of benzenesulfonic acid optionally substituted in the benzene ring by halogen or lower alkyl. Hydrochlorides of the compounds of general formula I are preferred.

Compounds of formula I and their physiologically acceptable acid addition salts, wherein R3 and R4 are not both hydrogen atoms, include compounds of formula II,

By reacting with sulfamoyl chloride of formula III

Obtaining a compound of formula IV,

The compound of formula IV is then reacted with amine H ₂ NR ₁ to obtain a compound of formula V,

The compound of formula V is further reacted with R 2 X, wherein X is selected from the group consisting of Cl, Br, and I to obtain a compound of formula I.

Alternatively, a compound of formula (I) in which neither R 3 nor R 4 is a hydrogen atom may be reacted with an amine HNR 1 R 2 to prepare a compound of formula (I).

Compounds of the general formula I, wherein R3 and R4 are both hydrogen atoms,

By reaction with a protecting group (PG), preferably sulfamoylchloride of formula VIa or a reagent of formula VIb, protected with tert-butyloxycarbonyl or benzyl,

To prepare a compound of formula (VII),

The compound of formula VIII is then reacted with amine H ₂ NR ₁ to prepare a compound of formula VIII,

The compound of formula (VII) is further reacted with R2X, wherein X is selected from the group consisting of Cl, Br, and I to prepare a compound of formula (VII),

Subsequently, under suitable conditions, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R 3 and R 4 are both hydrogen atoms. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, the protecting group can be removed by hydrogenation, preferably in the presence of a catalyst such as hydrogen and palladium.

Alternatively, the compound of formula I, wherein R 3 and R 4 are both hydrogen atoms, reacts the compound of formula X with amine HNR 1 R 2 to prepare a compound of formula X,

Subsequently, under suitable conditions, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I, wherein R3 and R4 are both hydrogen atoms. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, the protecting group can be removed by hydrogenation, preferably in the presence of a catalyst such as hydrogen and palladium.

The compound of the general formula (I) in which R ₂ comprises a methylene spacer CH ₂ represents a compound of general formula (X).

Reacted with the protective agent PG to prepare a compound of formula XI,

The compound of formula XI is then reacted with aldehyde R2'-CHO to prepare a compound of formula XII,

Wherein R 2 ′ is selected from the group consisting of alkyl; cycloalkyl; alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; alkylenealkoxy; and alkylenecycloalkyl

The protecting group PG of the compound of formula XII is then removed under suitable conditions and then the unprotected compound is reacted with sulfamoylchloride ClSO ₂ —NH ₂ to prepare a compound of formula I. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, the protecting group can be removed by hydrogenation, preferably in the presence of a catalyst such as hydrogen and palladium.

Alternatively, compounds of formula I wherein R ₂ comprises methylene spacer CH ₂ may be prepared by removing the protecting group PG of the compound of formula XII under suitable conditions, and the unprotected compound is then protected, preferably tert-butyl By reacting with sulfamoyl chloride of formula VIa or a reagent of formula VIb protected with a protecting group such as oxycarbonyl or benzyl,

Obtaining a compound of formula XIII,

Subsequently, under suitable conditions, the compound of formula I is prepared in which R 3 and R 4 are both hydrogen atoms by removing the protecting group PG from the obtained intermediate product. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, the protecting group can be removed by hydrogenation, preferably in the presence of a catalyst such as hydrogen and palladium.

As another alternative, a compound of formula I wherein R ₂ comprises a methylene spacer CH ₂ comprises a compound of formula X,

By reaction with the protective agent PG, to obtain a compound of the general formula XI,

Subsequently, the compound of formula XI is reacted with ketone R2'-COR1 'to obtain a compound of formula XIV,

Wherein R 1 ′ is alkyl; alkylenealkoxy; alkylenecycloalkyl; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearyleneoxyalkyl; alkylenearylenedialkylamine; and unsubstituted Or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ;

R2 'is alkyl; Cycloalkyl; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; And alkylenecycloalkyl)

Subsequently, under suitable conditions, the protecting group PG of the compound of formula XIV is removed and the unprotected compound is then protected with protecting group PG, preferably a protecting group such as tert-butyloxycarbonyl or benzyl, or sulfamoyl chloride of formula VIa React with the reagent of formula VIb,

Preparing a compound of formula XV,

Subsequently, under suitable conditions, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R 3 and R 4 are both hydrogen atoms. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid, and if the protecting group is benzyl, the protecting group is preferably subjected to hydrogenation in the presence of a catalyst such as hydrogen and palladium. Thus can be removed.

In addition, the compound of general formula (I) is a compound of general formula (II)

React with the protective agent PG to obtain a compound of the general formula

Subsequently, the compound of formula X 'is reacted with amine NHR1R2 to obtain a compound of formula X',

Subsequently, under suitable conditions, the protecting group PG of the compound of formula X 'is removed and the unprotected compound is reacted with sulfamide to produce the compound of formula I, or the compound of formula I by reacting with the compound of formula III Prepared or reacted with a compound of formula VIa or VIb to prepare a compound of formula XIX,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product under suitable conditions. If the protecting group is tert-butyloxycarbonyl, the protecting group can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, the protecting group can be removed by hydrogenation, preferably in the presence of a catalyst such as hydrogen and palladium.

In another embodiment, the compound of formula I is a compound of formula XVIIa,

Where R2 is a hydrogen atom

By reacting with a compound of formula XX,

Wherein R5 is alkyl; cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; unsubstituted or alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; and heteroaryl Is selected from the group)

Obtaining a compound of the general formula XXI,

Subsequently, under suitable conditions, the protecting group PG of the compound of formula XXI is removed and the unprotected compound is reacted with sulfamide to form a compound of formula I, or the compound of formula I by reacting with a compound of formula III Prepared or reacted with a compound of formula VIa or VIb to prepare a compound of formula XXII,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product under suitable conditions. If the protecting group is t-butyloxycarbonyl, it can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, it can be removed according to the hydrogenation reaction, preferably in the presence of a catalyst such as hydrogen and palladium.

In addition, the compound of the general formula I is a compound of the general formula X'a wherein R1

By reacting with a compound of formula XXIII,

Wherein R6 is selected from the group consisting of alkyl; unsubstituted or aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN)

Obtaining a compound of formula XXIV,

Subsequently, under suitable conditions, the protecting group PG of the compound of formula XXIV is removed and the unprotected compound is reacted with sulfamide to produce the compound of formula I, or the compound of formula I by reacting with the compound of formula III Prepared or reacted with a compound of formula VIa or VIb to prepare a compound of formula XXV,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product under suitable conditions. If the protecting group is tert-butyloxycarbonyl, it can be removed under acidic conditions, preferably in the presence of hydrochloric acid. If the protecting group is benzyl, it can be removed according to the hydrogenation reaction, preferably in the presence of a catalyst such as hydrogen and palladium.

In another embodiment of the invention, the compound of formula I is a compound of formula XI,

React with a compound of formula XXIII to obtain a compound of formula XXVI,

Subsequently, under suitable conditions, the protecting group PG of the compound of formula XXVI is removed and the unprotected compound is reacted with sulfamide to form a compound of formula I, or the compound of formula I by reacting with a compound of formula III Prepared or reacted with a compound of formula VIa or VIb to obtain a compound of formula XXIII,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product under suitable conditions. If the protecting group is tert-butyloxycarbonyl, it can be removed under acidic conditions, preferably in the presence of hydrochloric acid, and if the protecting group is benzyl, it is preferably in the presence of a catalyst such as hydrogen and palladium, hydrogenation Can be removed accordingly.

In another embodiment of the invention, the compound of formula I is a compound of formula

By reacting with a compound of the general formula

Obtain the compound of general formula XX ',

Subsequently, under suitable conditions, the compound of formula I is prepared by removing the protecting group PG of the compound of formula XX '. If the protecting group is tert-butyloxycarbonyl, it can be removed under acidic conditions, preferably in the presence of hydrochloric acid, and if the protecting group is benzyl, it is preferably in the presence of a catalyst such as hydrogen and palladium, hydrogenation Can be removed accordingly.

In another embodiment of the invention, the compound of formula I is a compound of formula XI,

React with a compound of the general formula

To obtain a compound of the general formula XXX,

Subsequently, under suitable conditions, the compound of formula XXXI is prepared by removing the protecting group PG of the compound of formula XXX,

Furthermore, the compound of formula XXXI is reacted with sulfamoyl chloride of formula III to prepare a compound of formula I, or the compound of formula XXXI is reacted with a compound of formula VIa or VIb to Preparing a compound,

Then, under suitable conditions, the compound of formula I is prepared by removing the protecting group PG of the compound of formula XXXII. If the protecting group is tert-butyloxycarbonyl, it can be removed under acidic conditions, preferably in the presence of hydrochloric acid, and if the protecting group is benzyl, it is preferably in the presence of a catalyst such as hydrogen and palladium, hydrogenation Can be removed accordingly.

If necessary, independently of the substitution patterns in R3 and R4, the free bases of the compounds of formula I obtained are converted into their physiologically acceptable acid addition salts, or with substitution patterns in R3 and R4 Independently, the acid addition salt of the obtained compound of formula I can be converted into the free base of the compound of formula I.

In another aspect, the invention also includes glaucoma, epilepsy, bipolar in a mammal or human, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a physiologically suitable acid addition salt thereof. A method of treating or preventing disorders, migraine, neuralgia, obesity, type II diabetes, metabolic syndrome, alcohol dependence and / or cancer, and incidental and / or secondary diseases or conditions.

Obesity according to the present invention is not limited to the medical definition of obesity, including preferred alternative definitions; It is meant to include any form of increase in body fat that causes an increase in body weight. Accordingly, the present invention also relates to non-medical weight loss, such as cosmetic weight loss, and generally includes improving the body shape. The term obesity also includes obesity and / or juvenile obesity caused by drugs.

According to the invention, diseases and conditions secondary to obesity and / or secondary in mammals and humans include, in particular, metabolic disorders and / or syndrome X and cardiovascular diseases.

As used herein, the term "metabolism" refers to hypertension, in particular arterial hypertension, in addition to abdominal obesity; Insulin resistance, in particular diabetes type II; Glucose tolerance; Complex symptoms of clinical findings, including dyslipoproteinaemia, especially hypertriglyceridemia accompanied by dyslipoproteinemia with low HDL-cholesterol levels, and hyperuricemia that can cause gout. The concept is all inclusive. Metabolic disorders are closely associated with insulin resistance, according to information from the American Heart Association. Some people are genetically susceptible to insulin resistance. Acquired factors such as excessive body fat and physical inactivity can cause insulin resistance and metabolic disorders in these people. Most of those who are insulin resistant are obese. The molecular mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and are considered to be very complex. The first group of people at risk of ongoing metabolic disorders have deficiencies in insulin action and suffer from diabetes, which is unable to maintain adequate levels of sugar in the blood. The second group is mainly people with hypertension, who have non-diabetic insulin resistance, but whose insulin resistance is offset by excessive insulin secretion. This symptom is known as hyperinsulinemia. The third group is heart attack survivors who, unlike high blood pressure, have hyperinsulinemia that does not show abnormal glucose levels. Metabolic disorders are becoming increasingly common in highly developed countries, such as the United States. In the United States, it is estimated that about 20-25% of American adults have metabolic disorders. There are no well established criteria for diagnosing metabolic disorders.

The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most widely used. According to this ATPIII standard, metabolic disorders can be identified when three or more of the following factors are present:

Abdominal obesity as measured by waist circumference (greater than -40 inches for men, greater than 35 inches for women)

Fasting blood triglycerides of 150 mg / dL or more

HDL cholesterol in blood (male-less than -40 mg / dL, female-less than -50 mg / dL)

Blood pressure over 130 / 85mmHg

Fasting blood glucose of 110 mg / dL or more

The term "X syndrome" is closely related to the term "metabolism" and is often referred to as the same disease or condition as the metabolic disorder. However, according to information from the American Heart Association, the term "X syndrome" also refers to a heart condition in which there is an electrocardiogram change that suggests chest pain and ischemic heart disease, but no signs of coronary artery disease are found by angiography. do. Patients with heart X syndrome often have dyslipidemia.

In general, the term "cardiovascular disease" associated with obesity is understood to mean coronary heart disease, which may cause, for example, heart failure, cerebrovascular disease, and peripheral obstructive arterial disease that may accompany an increased risk of stroke. do.

In addition, the compounds of formula I or their physiologically suitable acid addition salts are expected to be useful in the treatment of diabetic conditions or diseases not related to obesity, due to their inherent properties. Such diabetic conditions or diseases include, for example, type II diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, and the like.

Other diseases associated with obesity and / or secondary may be gallbladder disease such as gallstone formation, sleep apnea syndrome, orthopedic complications such as osteoarthritis and psychosocial disorders.

The compounds of formula I may also be useful as antispasmodics for the prevention or treatment of epilepsy in mammals and humans.

The compounds of general formula I according to the invention are inhibitors of mammalian carbonic anhydrase, in particular, such as human carbonic anhydrase isozymes of subtypes II and / or V.

Pharmacological Test Method

The numbers of the examples cited in the pharmacological test method are related to the following preparation examples.

1. Human Carbonic anhydrase  Isotope II ( hCA  Ⅱ) In vitro  control

Test compounds of Formula I were diluted in aqua bidest using an automatic pipette (CyBiWell ^® ) in 96 well microplates. 20 μl aliquots from the dilution plates were transferred to 96 well black assay plates with pipetting points (Tecan Genesis ^® ). In the second step, 148 μl (20 mM, pH7.4) of potassium phosphate buffer was added, and in the third step, 20 μl of enzyme solution (human carbonate dehydratase isozyme II derived from red blood cells dissolved in potassium phosphate buffer) (Sigma- the Aldrich) 1μl were incubated at room temperature for 60 minutes, the fluorescence signal (Tecan Ultra ^ⓐ fluorescence measurement at the end of the preincubation period (FLU-1); excitation wavelength: 280nm; emission wavelength: read 465nm) after preincubation time, 20 μl of aqueous monosylamide solution (1 mM monosylamide (Sigma-Aldrich) dissolved in hydrochloric acid) was added and the fluorescence signal was read every 10 minutes for 60 minutes at 37 ° C. For the calculation, the 60 minute time point (FLU-2) The total volume of the analyte mixture was equivalent to 208 μl The final concentration of carbonic anhydrase II was 10 ⁻⁷ M / L, the final concentration of monosylamide was 2.25 × 10 ^−6, and the final concentration of the compounds was 10 ^-8 M / L ~ 10 ^-5 M was / L. compound final concentration of DMSO as solvent is 0.1mM been Further, each of the micro plates, and comprises a blank (blank) without the compound and the enzyme, and the compound and Tox asleep imide (ethoxzolamide) comprises a control-free (to a final concentration of ^{5 × 10 -8 M / L)} . All data reflects one measurement: The data are presented as percent inhibition calculated by the following formula.

% Inhibition = 100 ((1- (FLU-2 _compound -FLU-2 _blank -FLU-1 _compound + FLU-1 _blank ) / (FLU-2 _control -FLU-2 _blank -FLU-1 _control -FLU-1 _blank) ))

Percent inhibition data for each compound and each final concentration were used for IC ₅₀ calculations using Prism4 software. Concentration coefficients of action were calculated by applying a prism algorithm for nonlinear curve-fit (type S dose response with various gradients and limits from 0 to 100).

In this test model, the test substance of formula Ⅰ shown in Table 1 below have IC _50, such as to The values are shown:

Table 1 In vitro hCA II Inhibitory Effects of Test Substances

2. Acute for Mice In vivo  Food intake test

Experiments were performed with male or female C57BI / 6 mice (n = 8-12 population per group). Mice were placed under conditions of repeated light / dark cycles (lit from 22:00) for 12/12 hours. The food (high calorie diet) and water were left free. Food intake and water consumption were measured daily. The test compound of formula I is suspended in 1% methylcellulose and 2% (v / v) poloxamer 188 (Lutrol F68 ^® ) in water, which is orally administered at a dose of 100 mg per kg body weight of mice per day. Was done. Half of the dose was administered between 7 am and 9 am and the other half was administered between 15 h and 15:30.

In the test model described above, as shown in Table 2 below, the 24 hour food intake rate of the animals was reduced due to the test substance compared to the control.

Table 2 Effect of Test Substances on Food Intake

The present invention also provides a pharmaceutical composition or medicament further comprising a pharmaceutically effective amount of a compound of Formula I or a physiologically acceptable acid addition salt thereof and conventional pharmaceutically acceptable auxiliaries and / or carriers.

Suitable pharmaceutically acceptable auxiliaries and / or carriers are well known to those skilled in the art and they are pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talc, cellulose, glucose, fructose (or other sugars), carbonic acid Magnesium, gelatin, oils, alcohols, surfactants, emulsifiers or water (preferably sterile water). The composition may be a mixture of the compositions, or may be a combination for simultaneous, separate or sequential use (including administration). The compounds according to the invention or their physiologically acceptable acid addition salts for use against the above-mentioned symptoms may be administered in any convenient manner, for example by oral administration (including inhalation), parenteral administration, mucosal administration (eg Oral, sublingual, nasal), rectal or transdermal administration, so that the composition may be formulated as appropriate. For oral administration, the compounds may be formulated in liquids or solids such as solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges. Liquid form preparations are generally in suspensions or solutions of the compounds of the invention or their physiologically acceptable acid addition salts in suitable aqueous or non-aqueous liquid carrier (s), for example water, ethanol, glycerin, polyethylene glycol or oils. Is done.

The formulation may also include suspending agents, preservatives, flavoring agents or coloring agents. Tablet compositions can be prepared by using any of the suitable pharmaceutical carrier (s) commonly used to prepare solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, fructose and microcrystalline cellulose. Capsule compositions can be prepared using conventional encapsulation processes. For example, standard carriers may be used to prepare powders, particulates or pellets comprising the active ingredient, which are then filled into hard gelatin capsules; Alternatively, dispersions or suspensions may be prepared using any suitable pharmaceutical carrier (s), such as aqueous gums, celluloses, silicates or oils, and the dispersions or suspensions may be filled into soft gelatin capsules. Compositions for oral administration can be designed to prevent degradation of their active ingredients while passing through the digestive tract, for example, by coating the tablet or capsule surface. Typical parenteral compositions are compounds of the present invention in sterile aqueous or non-aqueous carriers or parenterally acceptable oils such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil or their physiological It consists of a solution or suspension of an acid addition salt which is acceptable. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration. Nasal or oral compositions can be conveniently formulated into aerosols, drops, gels and powders.

Aerosol formulations typically comprise a solution or homogeneous suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are typically provided in aseptic single dose or multidose packages in a sealed container, which is a nebulizer It can take the form of a cartridge or a refill. Alternatively, the sealed container may be a single dose device such as a single-dose nasal inhaler or an aerosol doser equipped with a metering valve intended to be discarded once the contents in the container have been consumed. If the dosage form comprises an aerosol dispenser, it will include a pharmaceutically acceptable propellant. The aerosol dosage form may take the form of a pump nebulizer. Compositions suitable for oral or sublingual administration include tablets, rhombic tablets, and pastill, wherein the active ingredients are formulated with sugars and gum arabic, tragacanth gum, or carriers such as gelatin and glycerin. . Compositions for rectal or vaginal administration may conveniently be administered in suppository form (containing the basic substance of a conventional suppository such as cocoa butter), vaginal suppository, tablet formulation, foam or enema. Form. Compositions suitable for transdermal administration include injections including ointments, gels, patches and powder injections. Conveniently, the composition is in unit dosage form such as a tablet, capsule or ampoule. The pharmaceutical composition according to the invention can be used for obesity and its accompanying and / or secondary diseases; Other medical weight loss and non-medical weight loss; And / or for the prevention and / or treatment of diabetes conditions or diabetes.

The compounds of the present invention and their physiologically acceptable acid addition salts are generally administered as pharmaceutical compositions, which are important novel embodiments of the present invention, by the presence of the compounds disclosed herein. In an embodiment of the invention, there is provided a pharmaceutical pack or kit comprising one or more packaging (s) filled with one or more components of the pharmaceutical composition of the invention. Such packaging (s) may be provided to a government agency regulating the manufacture, use or sale of a pharmaceutical product, which reflects the method of use or approval by the manufacturer, user or distributor for administration to humans or animals. Various documents may be entailed, such as a notice in the form stipulated by.

Another aspect of the present invention provides a method of preparing a pharmaceutical composition as described. The method can be carried out by standard techniques known in the art, which include combining the compound according to the invention and a pharmaceutically acceptable adjuvant and / or carrier. The composition may be in tablet, liquid, capsule and powder or food form, for example in the form of a functional food. In the latter case, the food may itself function as a pharmaceutically acceptable carrier.

The compounds or compositions of the present invention are preferably administered to a patient in need thereof in an amount sufficient to prevent and / or treat the symptoms of the condition, disorder, or disease. For all aspects of the invention, in particular in medical terms, administration of the compound or composition is ultimately determined by the therapist, and includes the compound used, the type of animal, age, weight, severity of the condition, method of administration, side effects and / Or dosing regimen taking into account other contraindications. The range of specific dosages can be determined by clinical trials of the standard design, with a complete review of the patient's progress and recovery. Such clinical trials can be conducted by gradually increasing the dose, using a low percentage of the maximum dose that can be tolerated by the animal as the starting dose for humans. The physiologically acceptable compound of the present invention is usually, for example, the oral dose of the compound of formula I or a physiologically acceptable salt thereof calculated as a free base is 1 mg to 2000 mg, preferably 30 mg to A daily dose regimen of 1000 mg, eg 10 mg to 250 mg, or intravenous, subcutaneous, or intramuscular dose of 0.1 mg to 100 mg, preferably 0.1 mg to 50 mg, eg 1 mg to 25 mg (for adult patients). Will be administered 1 to 4 times per day. In addition, the compounds used according to the invention may be administered to children or adolescents, in which case individual dosing should be particularly tightly controlled by the therapist, usually in an amount less than that administered to an adult.

The compounds of the present invention will suitably be administered for a period of sustained treatment, for example at least one week, usually several weeks to months. The present invention also provides a cosmetic method for weight maintenance or cosmetic weight loss, comprising administering the compound according to another aspect of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent. Non-informative).

Preferably, the compound or composition is administered to a subject in need or need thereof in an amount sufficient to maintain weight or cosmetic weight loss.

In another aspect, the compounds of general formula I and their physiologically acceptable acid addition salts according to the invention include antidiabetic agents; Anti-obesity or appetite control agents; Cardiovascular actives, in particular antihypertensives; diuretic; Active agents that alter lipid concentration, in particular lipid lowering agents; And one or more active agents selected from active agents for the treatment and / or prevention of diabetes or the complications associated with the diabetes (as pharmaceutical combination compositions).

Suitable antidiabetic agents include, for example, insulin, amylin, GLP-1 and GLP-2 derivatives, such as those disclosed in WO 98/08871, and orally active hypoglycemic active ingredients. The orally active hypoglycemic active ingredient is preferably sulfonyl urea, for example tolbutamide, glybenclamide, glymepiride, glipizide, glyquidone, glyoxepide, glybomurid or Glyclazid; Biguanides such as metformin; Meglitinides such as repaglinide; β-3 adrenergic agonists; Oxadiazolidinedione; Glycosidase inhibitors, for example α-glycosidase inhibitors such as migliton or acarbose; Glucagon receptor antagonists, GLP-1 agonists, diazoxides or potassium channel openers such as those disclosed in WO 97/26265 or WO 99/03861; CB-1 (cannabinoid-1 receptor) antagonists / inverse agonists; Thiazolidinediones such as troglitazone, cyglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo- Insulin sensitizers such as 2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione; insulin receptor kinase activators; for example, glycogen kinase associated with stimulation of glucose synthesis and / or glycogen degradation Inhibitors of liver enzymes, such as and modulators of glucose uptake and glucose secretion.

Suitable anti-obesity or appetite modulators include one or more 5-HT (serotonin) carrier inhibitors, NE (norepinephrine) carrier inhibitors, CB-1 (cannabinoid-1 receptor) antagonists / reverse agonists, ghrelin antibodies, ghrelin antagonists, H3 (histamines) H3) antagonist / reverse agonist, MCH1R (melanin enrichment hormone 1R) antagonist, MCH2R (melanin enrichment hormone 2R) agonist / antagonist, NPY1 (neupeptide Y Y1) antagonist, NPY2 (neupeptide Y Y2) agonist, NPY5 (neuro) Peptide Y Y5) antagonists, leptin, leptin derivatives, opioid antagonists, orexin antagonists, BRS3 (bombesin receptor subtype 3) agonists, CCK-A (cholestokinin-A) agonists, CNTFs (cymbosine management factors), CNTF derivatives, Growth hormone secretagogue receptor (GHS) agonists, SHT2c (serotonin receptor 2c) agonists, Mc3r (melanocortin 3 receptor) agonists, Mc4r (melanocortin 4 receptor) agonists, monoamine reuptake inhibitors, serotonin ash Absorption inhibitors, GLP- 1 (glucagon-like peptide 1) agonist, topiramate, phytopam compound 57, ACC2 (acetyl-CoA carboxylase-2) inhibitor, β3 adrenergic agonist, DGAT1 (diacylglycerol acyltransferase 1) inhibitor, DGAT2 (diacylglycerol acyltransferase 2) inhibitors, FAS (fatty acid synthase) inhibitors, PDE (phosphodiesterase) inhibitors, thyroid hormone B agonists, UCP-1 (deconjugated protein 1), -2, or- 3 active agents, acyl-estrogens, glucocorticoid antagonists, 11 HSD-1 (11-βhydroxy steroid dehydrogenase type 1) inhibitors, SCD-1 (stearoyl-CoA desaturase-1) inhibitors, dipeptidyl Peptidase IV (DP-IV) inhibitors, lipase inhibitors, fatty acid carrier inhibitors, dicarboxylate carrier inhibitors, glucose carrier inhibitors, phosphate carrier inhibitors and pharmaceutically acceptable salts and esters thereof .

Suitable appetite modulators (appetite suppressants) include sibutramine or mono- and bismethylated active metabolites of sibutramine; Fenfluramine or dexfenfluramine; Marginol, diethylpropion or phentermine; Leptin or denatured leptin; Dexamphetamine and amphetamine.

Appropriate lipase inhibitor is orlistat, plate cleaners sour lipstatin (Streptomyces ethoxy tree shinny (Streptomyces The toxytricini) takes off) the lactone lipase inhibitors isolated from micro-organisms, such as everolimus B (Streptomyces Abu Ravi N-Sys (Streptomyce s aburaviensis) obtained load), synthetic derivatives of the following compounds from from; 2-oxy-4H-3,1-benzoxazin-4-one derivatives or structurally related compounds such as Alizyme's ATL-962; 2-amino -4H-3,1- benzoxazin-4-one derivative or a plant known to possess lipase inhibitory activity, extracts, for example, Alpinia operational scenario room extract, or 3-methyl ether of Rogaland (Alpinia officinarum) Long extract such as ( A. officinarum Derived).

Suitable CB ₁ Cannabinoid antagonists include limonabant, SLV319, SR147778 and CP-945598.

Suitable cardiovascular active agents include, but are not limited to, angiotensin II receptor antagonists such as abitesartan, benzyllosartan, candesartan, elisartan, embusartan, Enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteorin isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan (saprisartan), saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 057, Lusofarmaco LR-B / 081, Lusofarmaco LR B / 087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A -81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE -3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803 , EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KW-3433, L-158809, L -158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875 , LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U -96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM- 31472, ZD-6888, ZD-7155 and ZD-8731 or their physiologically acceptable salts, solvates, Prodrugs or esters; Daglutril; Non-selective α-adrenergic receptor antagonists such as tolazoline or phenoxybenzamine; Selective α-adrenergic receptor antagonists such as doxazosin, prazosin, terrazosin or urapidil; β-adrenergic receptor antagonists such as acebutorol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carrazolol, carteolol, serifrolol, mepindorol, metipranolol , Metoprolol, nadorol, oxprenolol, fenbutolol, pindorol, propranolol, sotarol and timolol; mixtures of α-adrenergic receptor antagonists and β-adrenergic receptor antagonists, such as carvedilol or rabetorol; Ganglion blockers such as reserpin or guanetidine; α2-adrenergic receptor agonists (including centrally acting α2-adrenergic receptor agonists) such as clonidine, guanfacin, guanabenz methyldopa and moxonidine; Renin-inhibitors such as alskiren; ACE-inhibitors such as benazepril, captopril, silazapril, enalapril, fosinopril, imidapril, ricinophril, moexipril, quinapril, perindopril, ramipril, spirapril or Transdorapril; Mixed or selective endothelin receptor antagonists such as atrasentane, bosentane, clazocentan, darsenentane, citaxentane, tezocentane, BMS-193884 or J-104132; Direct vasodilators such as diazoxide, dihydralazine, hydralazine or minoxidil; Mixed ACE / NEP-inhibitors such as omapatrylat; ECE-inhibitors such as FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; Selective NEP-inhibitors; Vasopressin antagonists, aldosterone receptor antagonists such as eplerenone or spironolactone; Angiotensin vaccine; And eurotensin II receptor antagonists.

Suitable diuretics are thiazide diuretics such as althiazide, bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, benzthiazide, Butiazide, chlorothiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlothiazide, paraflutizide (paraflutizide), polythiazide, teclothiazide, trichlormethiazide; Thiazide analogue diuretics such as chloraminofenamide, chlortalidone, clofenamide, clolopamide, cloloxolone, fenquizone, fenquizone, Indapamide, infamide, mefruside, metolazone, quinnethazone, tripamide, tripamide, xipamide; Cyclic diuretics such as azosemide, bumetanide, furosemide, pyretanide, torsemide; Potassium preservative diuretics such as amylolide, potassium cannolate, spironolactone, triamterene or their physiologically acceptable tautomers, salts, solvents Cargoes, prodrugs or esters.

Active agents that alter the appropriate lipid concentrations include antihyperlipidemic and anti-hyperlipidemic active ingredients such as HMGCoA reductase inhibitors, for example atorvastatin, berivastatin, cerivastatin, krillvastatin ( crilvastatin, fluvastatin, glenvastatin, glenvastatin, lovastatin, mevastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin ) Or their physiologically acceptable salts, solvates, prodrugs or esters; Cholesterol transport / intake inhibitors; Bile acid reuptake inhibitors or microsomal triglyceride transfer protein (MTP) inhibitors; Compounds that reduce food intake, PPAR (peroxysome proliferator-activated receptor) and RXR agonists and ATP dependent potassium channel activators of beta cells; Fibric acid such as bezafibrate, ciprofibrate, clofibrate, fenofibrate or gemfibrozil; Cholestyramine, cholstipol, probucol, ezetimibe and dextrothyroxine; HMGCoA synthase inhibitors, cholesterol absorption inhibitors, acyl coenzyme A-cholesterol acyl convertase (ACAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, squalene synthase inhibitors, antioxidants, PPAR α agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin-angiotensin inhibitors, microsomal triglyceride transfer inhibitors, bile acid reuptake inhibitors, PEAR8 agonists, triglyceride inhibitors, transcription regulators, squalene epoxidase inhibitors, low density lipoprotein receptors Compounds that alter lipid metabolism, such as inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 8 partial agonists, and niacin or niacin receptor agonists and pharmaceutically acceptable salts and esters thereof.

Further active agents suitable for use in combination with the compounds of general formula I according to the invention are CART agonists, H3 antagonists, TNF agonists, CRF agonists, CRFBP antagonists, eurocortin agonists, β3-agonists, MSH (Melanin cell stimulating hormone) agonists, serotonin-reuptake inhibitors, mixed serotonin- and noradrenaline reuptake inhibitors, 5HT modulators, MAO inhibitors, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, de-air proteins 2 or 3 modulators, leptin agonists, dopamine agonists (bromocriptine, doprexin), RXR modulators, hCNTF agonists and TR-beta-agonists.

Preferred pharmaceutical combination compositions according to the present invention include a combination of at least one compound of formula I with at least one biguanide; A combination of at least one compound of formula I with at least one fibric acid; A combination of at least one compound of Formula I with at least one HMGCoA reductase inhibitor; And a combination of at least one compound of Formula I and at least one insulin sensitizer.

Preferred compounds of formula I in combination with one or more of the above active agents include 4-phenyl-piperazine-1-sulfonic acid amide; 4- (2-Chloro-phenyl) -piperazine-1-sulfonic acid amide; 4- (2-methoxy-phenyl) -piperazine-1-sulfonic acid amide; 4-pyridin-4-yl-piperazine-1-sulfonic acid amide; 4-pyrimidin-2-yl-piperazine-1-sulfonic acid amide; 4- (4-fluoro-phenyl) -piperazine-1-sulfonic acid amide; 4- (4-Chloro-3-trifluoromethyl-phenyl) -piperazin-1-sulfonic acid amide and / or 4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -pipe Razin-1-sulfonic acid amide.

Preferred biguanides for combining with at least one compound of formula I are metformin.

Preferred fibric acids for combining with at least one compound of formula I are bezafibrate, ciprofibrate, clofibrate, fenofibrate and / or gemfibrozil to be. Most preferred is fenofibrate.

Preferred HMGCoA reductase inhibitors for combining with at least one compound of Formula I include atorvastatin, berivastatin, cerivastatin, crilvastatin, fluvastatin , Glenvastatin, lovastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and / or simvastatin or their physiologically Acceptable salts, solvates, prodrugs or esters. Most preferred are simvastatin, lovastatin and / or pravastatin.

Preferred insulin sensitizers for combining with at least one compound of formula I are thiazolidinediones, in particular troglitazone, ciglitazone, pioglitazone and / or rosiglitazone. . Most preferred are rosiglitazone and pioglitazone.

Further preferred combinations according to the present invention include combinations of 4-phenyl-piperazine-1-sulfonic acid amide with metformin; Combination of 4-phenyl-piperazine-1-sulfonic acid amide with fenofibrate; Combination of 4-phenyl-piperazine-1-sulfonic acid amide and simvastatin and combination of 4-phenyl-piperazine-1-sulfonic acid amide and rosiglitazone.

In one embodiment of the pharmaceutical combination composition according to the invention as described above, the compound of general formula I is combined with other active agents in one combined unit dosage form, eg, as a tablet or capsule, ie physical Obtained in the form of a combination and administered. In this combined unit dosage form, the compound of formula I and the other active agents can be prepared, for example, by the use of different layers in the tablet, for example inert interlayers known in the art; Or in the capsule, they may be separated from one another by other compartments. Corresponding active agents or pharmaceutically acceptable salts thereof may also be used in the form of their hydrates, or may include other solvents used for crystallization. Unit dosage forms, in particular fixed combinations of compounds of general formula I with one or more other active agents, are a preferred alternative to this embodiment.

In another embodiment, the compound of formula I and other active agents may be obtained and administered in two or more separate unit dosage forms, eg, two or more tablets or capsules that are physically separated from one another. Two or more separate unit dosage forms may be administered sequentially or sequentially (separately), eg, one by one in any order. Thus, the compound of formula 1 and other active agents may be administered simultaneously or in different times in any order throughout the day, with the optimal dosage regimen being typically determined by the therapist's prescription.

The following examples are intended to illustrate the invention in more detail, and do not limit the scope of the invention.

Example 1 :

Urea Analogs R1 = H, R2 = CO - NH - C ₆ H ₄ F ; boc = tert - Butyloxycarbonyl )

To a solution of 0.7 g of 1-fluoro-4-isocyanate benzene in 25 ml of dichloromethane, ice-cooled, 1.0 g of tert-butyl-4-aminopiperidine-1-carboxylate in 25 ml of dichloromethane under nitrogen atmosphere The solution was added dropwise. The mixture was stirred for 10 minutes at 0 ° C. and then for 16 hours at room temperature. The reaction mixture was diluted with water and washed with saturated aqueous NaCl solution. After separation, the organic layer is dried over sodium sulfate and evaporated under reduced pressure to give tert-butyl-4-{[[(4-fluorophenyl) -amino] -carbonyl] amino} -piperidine-1-carboxylate 1.6 g was obtained.

¹ H NMR (δ ppm, 400 MHz): 7.37 [2H], 7.04 [2H], 8.34 [1H, NH], 6.13 [1H, NH], 1.40 [9H].

1.6 g of tert-butyl-4-{[[(4-fluorophenyl) amino] carbonyl] amino} piperidine-1-carboxylate was dissolved in 50 ml of dichloromethane. After cooling the solution to 0 ° C., 2.3 ml of trifluoroacetic acid was added. After stirring for 40 hours at room temperature, the reaction mixture was evaporated under reduced pressure and treated twice with toluene. After vacuum drying, 2.4 g of 1- (4-fluorophenyl) -3-piperidin-4-yl-urea was obtained as the trifluoroacetic acid salt.

¹ H NMR (δ ppm, 400 MHz): 7.39 [2H], 7.05 [2H], 8.51 [1H, NH], 6.56 [1H, NH].

2.4 g of 1- (4-fluorophenyl) -3-piperidin-4-yl-urea-trifluoroacetate, 7 ml of triethylamine and 1.17 g of sulfamide are dissolved in 70 ml of dioxane, 5 It was refluxed (130 degreeC) for time. After removal of solvent under reduced pressure, the crude product was purified by flash chromatography using a mixture of dichloromethane / methanol 9: 1 as eluent. 1.0 g of 4-{[[(4-fluorophenyl) amino] -carbonyl] amino} piperidine-1-sulfonamide having a melting point of 219.6 to 221.2 ° C was obtained.

Example 2 :

Urea Analogs R1 = CH ₂ C ₆ H ₅ , R2 = CO - NH - C ₆ H ₅ ; boc = tert - Butyloxycarbonyl )

2.6 g of sodium acetate, 5.0 g of tert-butyl-4-aminopiperidine-1-carboxylate, 2.0 ml of acetic acid and 2.1 ml of benzaldehyde were mixed in 200 ml of THF and stirred at room temperature for 4 hours. After adding 8.8 g of trisacetoxy sodium borohydride, the mixture was stirred for 20 hours. The solvent was then removed under reduced pressure and the residue was dissolved in a mixture of methyl-tert-butylether and water. The aqueous layer was made basic with NaOH and extracted twice with methyl-tert-butylether. The combined organic layers were washed three times with 30 mL of 0.1N HCl and five times with 50 mL of 0.1N HCl. The aqueous layers were then combined, made basic with NaOH, and extracted twice with methyl-tert-butylether. The organic layers were washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated in vacuo. 4.9 g of tert-butyl-4- (benzylamino) piperidine-1-carboxylate were obtained as an oily product.

¹ H NMR (δ ppm, 400 MHz): 3.82 [s, 2H], 4.01 [2H], 2.81 [2H], 2.67 [1H], 1.86 [2H], 1.30 [2H], 1.45 [s, 9H].

To a solution of 0.187 ml of phenylisocyanate in 25 ml of dichloromethane, a solution of 0.5 g of tert-butyl-4- (benzylamino) piperidine-1-carboxylate in 20 ml of dichloromethane was added dropwise under ice cooling. After stirring for 5 hours at room temperature, the reaction mixture was washed three times with water and with saturated aqueous NaCl solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude product was crystallized with ethyl acetate / n-hexane in a freezer to give 0.55 g of tert-butyl-4-[(anilinocarbonyl) (benzyl) amino] piperidine-1-carboxylate.

¹ H NMR (δ ppm, 400 MHz): 4.61 [1H], 4.46 [s, 2H], 4.21 [2H], 2.83 [2H], 2.67 [1H], 1.83 [2H], 1.56 [2H], 1.44 [s , 9H].

Under ice-cooling, 0.94 ml of trifluoroacetic acid was added to a solution of 0.5 g of tert-butyl-4-[(anilino-carbonyl) (benzyl) amino] piperidine-1-carboxylate in 50 ml of dichloromethane. . After stirring for 16 hours at room temperature, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in a mixture of methyl-tert-butylether and water. The aqueous layer was made basic by addition of NaOH solution and extracted three times with methyl-tert-butylether. The combined methyl-tert-butylether layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated in vacuo to give 0.23 g of 1-benzyl-3-phenyl-1-piperidin-4yl-urea.

¹ H NMR (δ ppm, 400 MHz): 4.52 [1H], 4.52 [s, 2H], 3.13 [2H], 2.75 [2H], 1.84 [2H], 1.59 [2H].

0.2 g of 1-benzyl-3-phenyl-1-piperidin-4yl-urea and 0.075 g of sulfamide were dissolved in 50 ml of dioxane and refluxed for 5 hours. The reaction mixture was then concentrated in vacuo and the residue dissolved in water. After stirring for 3 hours, the residue was separated by filtration and stirred with methyl-tert-butylether. Filtration and drying in vacuo gave 0.23 g of crude product, which was purified by flash-chromatography using dichloromethane / methanol (19: 1) as eluent. 50 mg of pure 4-[(anilinocarbonyl)-(benzyl) amino] piperidine-1-sulfonamide was isolated (melting point: 188 ~ 189 ° C)

Example 3 :

Substituted amides ( R1 = CH3 ; R2 = C ₆ H ₁₁ ; boc = tert - Butyloxycarbonyl )

2.0 g of tert-butyl-4-oxopiperidine-1-carboxylate, 1.23 g of sodium acetate, 0.98 ml of acetic acid and 1.56 ml of N-methylcyclohexanamine were dissolved in 100 ml of THF and stirred at room temperature for 1 hour. did. Then 4.25 g of trisacetoxy sodium borohydride were added and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert-butylether. The aqueous layer was made basic and extracted twice with methyl-tert-butylether. Finally, the organic layer was washed twice with 0.1 N HCl, the aqueous layers were combined and made basic (pH = 10) by addition of NaOH solution. After extraction with methyl-tert-butylether (twice), the organic layer was dried over sodium sulfate and evaporated in vacuo. 1.3 g of oily tert-butyl-4- [cyclohexyl- (methyl) amino] piperidine-1-carboxylate were isolated and used without further purification.

¹ H NMR (δ ppm, 400 MHz): 4.12 [2H], 2.69 [2H], 2.63 [1H], 2.50 [1H], 2.23 [s, 3H], 1.45 [s, 9H].

1.25 g of tert-butyl-4- [cyclohexyl (methyl) amino] piperidine-1-carboxylate was dissolved in 100 ml of dichloromethane, treated with 3.0 ml of trifluoroacetic acid and stored at room temperature for 2 days. . The reaction mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert-butylether. The aqueous layer was saturated with sodium chloride and extracted three times with methyl-tert-butylether. The organic layer was dried over sodium sulfate and the solvent removed in vacuo to yield 0.8 g of N-cyclohexyl-N-methylpiperidin-4-amine, which was used without further purification.

¹ H NMR (δ ppm, 400 MHz): 3.12 [2H], 2.60 [1H], 2.59 [2H], 2.53 [1H], 2.26 [s, 3H].

0.8 g of N-cyclohexyl-N-methylpiperidin-4-amine and 0.47 g of sulfamide were dissolved in 70 ml of dioxane and refluxed for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert-butylether. The organic layer was washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated in vacuo to give 0.7 g of 4- [cyclohexyl (methyl) amino] piperidine-1-sulfonamide.

¹ H NMR (δ ppm, 400 MHz): 6.66 [s, 2H], 3.44 [2H], 2.52 [2H], 2.48 [1H], 2.48 [1H], 2.15 [s, 3H].

The amine was treated with HCl in isopropanol to make the hydrochloride, and the solvent was then evaporated. Melting point was determined to 240 ~ 242 ℃.

¹ H NMR (δ ppm, 400 MHz): 6.86 [2H], 3.34 [2H], 3.32 [s, 3H].

Example 4 :

Substituted amides ( R1 = H; R2 = C ₆ C ₁₁ ; boc = tert - Butyloxycarbonyl )

1.23 g of sodium acetate, 2.4 g of tert-butyl-4-aminopiperidine-1-carboxylate, 1.0 ml of acetic acid and 1.0 g of cyclohexanone were mixed in 150 ml of THF and stirred at room temperature for 3 hours. Then, 4.25 g of trisacetoxy sodium borohydride was added, and the reaction mixture was stirred at room temperature for 16 hours. After concentration of the reaction mixture under reduced pressure, the residue was taken up in a mixture of water and methyl-tert-butylether, which was made basic to pH 9 with sodium carbonate. The organic layer was washed four times with 0.1N HCl. The aqueous layer was then made basic with NaOH and extracted twice with methyl-tert-butylether.

The combined organic layers were washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated under reduced pressure to give 2.4 g of oily tert-butyl-4- (cyclohexylamino) piperidine-1-carboxylate.

¹ H NMR (δ ppm, 400 MHz): 4.03 [2H], 2.78 [2H], 2.74 [1H], 2.56 [1H], 1.83 [4H], 1.73 [2H], 1.45 [9H].

2.3 g of tert-butyl-4- (cyclohexylamino) piperidine-1-carboxylate was dissolved in 100 ml of dichloromethane and treated with 6.3 ml of trifluoroacetic acid under ice-cooling. After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and methyl-tert-butylether. The aqueous layer was made basic with NaOH and extracted five times with methyl-tert-butylether. The organic layer was then washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and the solvent removed in vacuo. 1.15 g of oily N-cyclohexyl-piperidin-4-amine was isolated and used without further purification.

¹ H NMR (δ ppm, 400 MHz): 3.08 [2H], 2.68 [1H], 2.60 [2H], 2.58 [1H], 1.85 [4H], 1.72 [2H].

1.1 g of N-cyclohexyl-piperidin-4-amine and 0.7 g of sulfamide were dissolved in 100 ml of dioxane and refluxed for 5 hours. The solvent was then removed under reduced pressure and the remaining residue was taken up in a mixture of water and dichloromethane. The organic layer was washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated in vacuo to give 0.8 g of 4- (cyclohexylamino) piperidine-1-sulfonamide.

¹ H NMR (δ ppm, 400 MHz): 6.83 [2H], 3.36 [2H], 2.59 [1H], 2.57 [2H], 2.48 [1H], 1.79 [4H].

The amine was treated with HCl in isopropanol to make hydrochloride, and the solvent was then evaporated. Melting point was determined to be 240 ℃ or more.

¹ H NMR (δ ppm, 400 MHz): 6.83 [2H], 3.53 [2H], 3.25 [1H], 3.08 [1H], 2.56 [2H], 2.10 [2H].

Example 5 :

Sulfonamides ( R1 = CH ₂ C ₆ H ₅ ; R2 = SO ₂ C ₆ H ₄ CH ₃ ; boc = tert - Butyloxycarbonyl )

1.5 g of tert-butyl-4-aminopiperidine-1-carboxylate and 1.13 ml of triethylamine were dissolved in 20 ml of dichloromethane. To this mixture, a solution of 1.57 g of p-toluenesulfonylchloride in 15 ml of dichloromethane was added under ice-cooling under a nitrogen atmosphere. The reaction mixture was then stirred for 2 days at room temperature. After washing with water, washing with sodium hydrogencarbonate solution, washing with water and washing with saturated aqueous NaCl solution, the organic layer was dried over sodium sulfate, evaporated in vacuo and dried in vacuo, then tert-butyl-4- { 2.6 g of [(4-methylphenyl) sulfonyl] amino} piperidine-1-carboxylate was obtained.

¹ H NMR (δ ppm, 400 MHz): 7.70 [2H], 7.67 [d, 1H], 7.39 [2H], 3.70 [2H], 3.13 [1H], 2.75 [1H], 2.39 [s, 3H], 1.36 [s, 9 H].

To a solution of 1.3 g of tert-butyl-4-{[(4-methylphenyl) sulfonyl] amino} piperidine-1-carboxylate in 40 ml of DMF, 0.62 g of potassium tert-butylate under nitrogen atmosphere under ice-cooling Was added. After 30 minutes, 0.69 g of benzylbromide in 5 ml of DMF was added dropwise. The mixture was stirred at rt for 20 h.

For work up, the solvent was removed under reduced pressure and the residue was taken in methyl-tert-butylether. The solution was washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and finally concentrated in vacuo. The crude product was purified by flash chromatography using a mixture of n-hexane and ethyl acetate (9: 1) as eluent. In addition to recovering 0.69 g of starting material, 0.51 g of tert-butyl-4- {benzyl [(4-methylphenyl) sulfonyl] amino} piperidine-1-carboxylate was isolated.

¹ H NMR (δ ppm, 400 MHz): 7.76 [2H], 7.41 [2H], 7.38 [2H], 7.33 [2H], 7.25 [1H], 4.39 [s, 2H], 3.86 [1H], 3.80 [2H ], 2.63 [2H], 2.41 [s, 3H], 1.31 [s, 9H].

0.5 g of tert-butyl-4- {benzyl [(4-methylphenyl) sulfonyl] amino} piperidine-1-carboxylate and 0.86 ml of trifluoroacetic acid were dissolved in 15 ml of dichloromethane and 60 hours at room temperature. Was stirred. The mixture was diluted with dichloromethane and stirred with 0.1N NaOH solution. The organic layer was then separated, treated with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated in vacuo to give 0.36 g of N-benzyl-4-methyl-N-piperidin-4-yl benzenesulfonamide. .

¹ H NMR (δ ppm, 400 MHz): 7.74 [2H], 7.40 [2H], 7.39 [2H], 7.34 [2H], 7.25 [1H], 4.40 [s, 2H], 3.69 [1H], 2.77 [2H ], 2.40 [s, 3 H], 2.31 [2 H].

0.36 g of N-benzyl-4-methyl-N-piperidin-4-yl benzenesulfonamide and 0.12 g of sulfamide were refluxed in 5 ml of dioxane for 8 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in methyl-tert-butylether, washed with water, washed with sodium carbonate solution, washed with water and washed with saturated aqueous NaCl solution. After drying over sodium sulfate, the organic layer was evaporated in vacuo to give 0.4 g of 4- {benzyl [(4-methylphenyl) sulfonyl] amino} piperidine-1-sulfonamide.

¹ H NMR (δ ppm, 400 MHz): 7.78 [2H], 7.41 [2H], 7.40 [2H], 7.35 [2H], 7.27 [1H], 6.67 [s, 2H], 4.42 [s, 2H], 3.70 [1H], 3.35 [2H], 2.43 [2H], 2.41 [s, 3H].

Example 6 :

Sulfonamides ( R1 and R2 Is Phenyl Make up a substituted piperazine system, boc = tert Butyloxycarbonyl)

2.0 g of tert-butyl-4-oxopiperidine-1-carboxylate, 1.23 g of sodium acetate, 0.98 ml of acetic acid and 1.83 ml of 1-phenylpiperazine were mixed in 150 ml of THF and stirred at room temperature for 2 hours. . Then, 4.25 g of trisacetoxy sodium borohydride was added and stirred for further 16 hours. For work up, the reaction mixture was concentrated in vacuo and the residue was poured into a mixture of methyl-tert-butylether and water. This mixture was made basic by addition of sodium carbonate solution (pH = 10). The organic layer was then washed six times with 0.1 N HCl and made basic by adding dilute NaOH solution to the aqueous layer (collected fractions 3, 4 and 5). After extraction with methyl-tert-butylether, the organic layer was washed with water, washed with saturated aqueous NaCl solution, dried over sodium sulfate and concentrated in vacuo. 2.0 g of tert-butyl-4- (4-phenylpiperazin-1-yl) piperidine-1-carboxylate was isolated.

¹ H NMR (δ ppm, 400 MHz): 7.26 [2H], 6.93 [2H], 6.85 [1H], 4.15 [2H], 3.20 [2H], 2.73 [2H], 2.72 [2H], 2.42 [1H], 1.46 [s, 9 H].

1.9 g of tert-butyl-4- (4-phenylpiperazin-1-yl) piperidine-1-carboxylate and 4.25 ml of trifluoroacetic acid were dissolved in 100 ml of dichloromethane and stirred for 24 hours. The reaction mixture was concentrated in vacuo and the remaining residue was taken up in a mixture of methyl-tert-butylether and water. After basifying with NaOH solution, the aqueous layer was extracted with methyl-tert-butylether. The precipitate in the aqueous layer was then separated by filtration, washed with water and dried in vacuo at 50 ° C. to give 0.67 g of 1-phenyl-4-piperidin-4-yl piperazine.

¹ H NMR (δ ppm, 400 MHz): 7.25 [2H], 6.93 [2H], 6.85 [1H], 3.21 [2H], 3.16 [2H], 2.73 [2H], 2.61 [2H], 2.38 [1H].

0.65 g of 1-phenyl-4-piperidin-4-yl piperazine and 0.30 g of sulfamide were dissolved in 50 mL of dioxane and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was taken up in water and precipitation started, which was completed by further stirring for 1 hour. After filtration, the precipitate was stirred for 1 h in the presence of dichloromethane, filtered again and vacuum dried at 50 ° C. 0.68 g of 4- (4-phenylpiperazin-1-yl) piperidine-1-sulfonamide was isolated.

¹ H NMR (δ ppm, 400 MHz): 7.20 [2H], 6.92 [2H], 6.76 [1H], 6.69 [s, 2H], 3.50 [2H], 3.11 [2H], 2.64 [2H], 2.54 [2H ], 2.31 [1 H].

This compound was converted to the corresponding HCl salt by treatment with HCl / isopropanol solution. Recrystallization gave 0.52 g of product. Melting Point: 222 ~ 227 ° C.

Example 7 :

Sulfonamide  Alternative introduction of functionality

To a solution of 4.36 ml of chlorosulfonyl isocyanate in 50 ml of ice-cold dichloromethane, a solution of 4.8 ml of tert-butanol in 50 ml of dichloromethane was added dropwise over 30 minutes. After stirring for 30 more minutes under cooling, the mixture was added dropwise to a solution of 7.68 g of 4-piperidone hydrate HCl-salt and 14.6 mL of triethylamine in 100 mL of dichloromethane. After stirring for 45 minutes under cooling, the reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane, washed three times with 0.1 N HCl (60 mL each) and with saturated aqueous NaCl solution. It was dried over sodium sulfate and the organic layer was concentrated in vacuo to give 7.2 g of crude product. Purification via flash chromatography using a mixture of dichloromethane / methanol (9: 1) as eluent gave 6.0 g of tert-butyl [(4-oxopiperidin-1-yl) sulfonyl] carbamate. .

¹ H NMR (δ ppm, 400 MHz, DMSO-d ₆ ): ¹ H-NMR: 3.56 [t, 4H], 2.44 [t, 4H], 1.42 [s, 9H].

Additional reaction steps as in any of the examples 1-6 described above.

Example 8 :

Sulfonamide  Alternative introduction of functionality

To a solution of 2.6 ml of tert-butanol in 20 ml of dichloromethane, 2.4 ml of chlorosulfonyl isocyanate was added dropwise over 15 minutes under ice cooling. After stirring for 15 minutes, 6.9 g of 4-dimethyl-amino pyridine was added. Cooling was removed and the reaction mixture was stirred at rt for 1 h, at which time a white precipitate formed. The mixture was diluted with 130 mL dichloromethane, washed several times with water and finally with saturated aqueous NaCl solution. After drying over sodium sulfate, the organic layer was concentrated in vacuo to give 6.4 g of crystalline reagent (tert-butoxycarbonyl) {[4- (dimethylimino) pyridin-1- (4H) -yl] sulfonyl} azaneide Got.

¹ H NMR (δ ppm, 400 MHz, CDCl ₃ ): 8.46 [d, 2H], 6.98 [d, 2H], 3.23 [s, 6H], 1.26 [s, 9H].

(tert-butoxycarbonyl) {[4- (dimethyliminoio) pyridin-1- (4H) -yl] sulfonyl} azaneide 0.5 g, 4-piperidone hydrate HCl-salt 0.26 g and 4-dimethylamino 0.205 g of pyridine was dissolved in 50 mL of dioxane and heated to 50 ° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane. After washing twice with dilute potassium hydrogensulfate solution, the organic layer was washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain 0.23 g of tert-butyl [(4-oxopiperidin-1-yl) sulfonyl] -carbamate. The combined aqueous layers were extracted with dichloromethane to afford an additional amount of 0.07 g of product.

¹ H NMR (δ ppm, 400 MHz, CDCl ₃ ): 3.74 [t, 4H], 2.58 [t, 4H], 1.49 [s, 9H].

Additional reaction steps as in any of the examples 1-6 described above.

Example 9 :

Substituted Sulfonamides

10 g (65 mmol) of piperidone hydrochloride and 7.7 mL (1.1 equiv, 71.6 mmol) of dimethylsulfamoyl chloride were dissolved in a mixture of acetone / water (1: 1, 400 mL). 20 mL (2.2 equiv, 143 mmol) of triethylamine was added and the reaction was stirred at rt for 4 days. Then the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was then washed with water, dried over magnesium sulfate and the solvent removed in vacuo to afford the desired sulfamide as a white solid (12.55 g, 95% yield).

¹ H NMR (δ ppm, 400 MHz, CDCl ₃ ): 2.49 (t, 4H, J = 6.24 Hz), 2.79 (s, 6H), 3.53 (t, 4H, J = 6.12 Hz).

0.35 g (1.7 mmol) of sulfamide from the above step was dissolved in 10 mL of dichloroethane, and then treated with 1.05 equivalents (1.78 mmol) of pentylamine and 1.5 equivalents (2.55 mmol) of trisacetoxy sodium borohydride. The reaction was stirred overnight at room temperature and then washed with 1M NaOH. The aqueous layer was extracted with ether. The combined organic layers were washed with saturated aqueous NaCl solution and then dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was placed on 0.5 g of polymer-supported toluenesulfonic acid. The resin was washed with MeOH and then with 2M ammonia in MeOH to recover pure amine.

¹ H NMR (δ ppm, 400 MHz, CDCl ₃ ): 0.69 (t, 3H, J = 7 Hz), 1.20 (m, 9H), 1.72 (m, 2H), 2.38 (m, 1H), 2.42 (t, 2H, J = 7 Hz), 2.60 (s, 6H ), 2.65 (td, 2H, J = 2, 13 Hz), 3.43 (2H, td, J = 3, 13 Hz).

¹³ C NMR (δ ppm, 400 MHz, CDCl ₃ ): 14.0, 22.6, 29.6, 30.1, 32.3, 38.2, 45.2, 46.9, 54.3.

0.036 mmol of the amine from this step was dissolved in 1 ml of dichloromethane and mixed with 1.5 equivalents of acetic acid chloride, 0.054 mmol and 0.054 mmol (1.5 equivalents, 15 mg) of polymer-supported triethylamine. The reaction was shaken for 3 days at room temperature before adding 0.054 mmol (1.5 equiv, 26 mg) of aminomethylated polystyrene to the reaction mixture. Then shaken another day. The resin was filtered off, rinsed with dichloromethane and the solvent was evaporated in vacuo to recover the desired sulfamide.

Example 10 :

Substituted sulfonamides ( boc = tert - Butyloxycarbonyl )

0.35 g (17.57 mmol) of tert-butyl-4-oxopiperidine-1-carboxylate was dissolved in 100 mL of dichloroethane, followed by 1.05 equivalent (18.44 mmol) of amine and trisacetoxy sodium borohydride 1.5 Equivalent weight (26.36 mmol) was added. The reaction was stirred at rt overnight. The reaction mixture was then washed with 1M NaOH and the aqueous layer was extracted with ether. The combined organic layers were washed with saturated aqueous NaCl solution, then dried over magnesium sulfate and the solvent was removed in vacuo to afford the desired pure amine-substituted piperidine.

18 mmol of the amine-substituted piperidine from this step were dissolved in 120 mL of dichloromethane and mixed with 19.8 mmol (1.1 equiv) of acid chloride and 27 mmol (3.76 mL, 1.5 equiv) of triethylamine. The reaction was stirred at rt for 3 days. The reaction mixture was then quenched with saturated aqueous NaCl solution and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude compound was eluted with 40-50% ethyl acetate / heptane and purified by flash chromatography to afford the desired carbonyl-substituted piperidine.

12.21 mmol of carbonyl-substituted piperidine from this step were dissolved in a 20% trifluoroacetic acid solution in 45 mL of dichloromethane. The reaction was stirred for 1 hour. The solvent was evaporated in vacuo to give the desired carbonyl-substituted piperidine as trifluoroacetic acid in quantitative yield. This compound was no longer purified and used as such in the next step.

0.84 mmol of carbonyl-substituted piperidine as trifluoroacetic acid from the above step was dissolved in 20 mL of dichloroethane and 9.51 mmol (3 g) of polymer-bound tetraalkylammonium carbonate was added to this mixture. The reaction was stirred for one day before the resin was filtered and rinsed with dichloromethane. Solvent was removed to obtain carbonyl-substituted piperidine as free base amine.

1.68 mmol (2 equiv) of tert-butanol was slowly added to a solution of 1.68 mmol (2 equiv, 0.145 mL) of chlorosulfonyl isocyanate in 10 mL of dichloromethane at 0 ° C. The reaction was allowed to warm to room temperature for 1 hour before cooling to 0 ° C. 0.47 mL (3.36 mmol, 4 equiv) of triethylamine was added to the reaction followed by the above free base amine in 5 mL of dichloromethane. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with 1N HCl, the organic layer was dried over magnesium sulphate and the solvent was evaporated in vacuo. The crude compound was purified by flash chromatography eluting with 50% ethyl acetate / heptane to give boc-protected sulfamamide as a white solid (0.185 g, 55% yield).

0.12 mmol of the boc-protected sulfamamide from this step was dissolved in 20% TFA in 1 ml of dichloromethane and the reaction was stirred for 2 hours. The solvent was evaporated in vacuo to give the desired final product of white solid as trifluoroacetic acid salt (42 mg) in quantitative yield.

Example 11 :

Hetero aryl-substituted sulfonamides ( boc = tert - Butyloxycarbonyl )

To a solution of 26 ml of tert-butanol in 200 ml of dichloromethane, 24 ml of chlorosulfonyl isocyanate was added dropwise over 90 minutes under ice cooling (5 ° C). After stirring for 60 minutes, 69 g of 4-dimethylamino pyridine was added in portions. Cooling was removed and the reaction mixture was stirred at rt for 1 h, at which time a white precipitate formed. The mixture was diluted with 200 mL of dichloromethane and washed with 500 mL of water. Then 1.1 l of dichloromethane were added and the resulting solution was washed four times with water (0.5 l each) and finally washed with brine. After drying over sodium sulfate, the organic layer was concentrated in vacuo to give (tert-butoxycarbonyl) {[4- (dimethyliminoo) pyridine-1 (4H)-, a crystalline reagent having a melting point of 180-181 ° C. Yl] sulfonyl} azanid.

¹ H-NMR (δ ppm, 400 MHz, CDCl ₃ ): 8.46 [d, 2], 6.98 [d, 2], 3.23 [s, 6], 1.26 [s, 9]

(tert-butoxycarbonyl) {[4- (dimethyliminoio) pyridin-1 (4H) -yl] sulfonyl} azanide 50 g, 4-piperidone hydrate HCl-salt 30.6 g and 4-dimethylamino pyridine 24.3 g was dissolved in 1.5 L of dioxane and heated at 55 ° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane. After three washes with dilute potassium hydrogensulfate solution, the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain 32.8 g of tert-butyl [(4-oxopiperidin-1-yl) sulfonyl] -carbamate having a melting point of 107 to 109 ° C.

¹ H NMR (δ ppm, 400 MHz, CDCl ₃ ): 3.74 [t, 4], 2.58 [t, 4], 1.49 [s, 9]

14 g of tert-butyl [(4-oxopiperidin-1-yl) sulfonyl] carbamate was dissolved in 600 mL of THF, and 5.7 g of 3-aminopyridine and 6.2 g of sodium acetate were added. 4.9 mL of acetic acid was added to this mixture, and 7.4 mL of tetraisopropyl ortho titanate was added, and then the reaction mixture was stirred at room temperature for 5 hours. Thereafter, 21.3 g of sodium trisacetoxy borohydride was added in portions, and stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was taken up in a mixture of dichloromethane and water. The aqueous layer and some solids were separated and stirred with dichloromethane. For better separation, the combined organic layers were treated in a centrifuge (4000 rpm). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give 20 g of pale green oil. Crystallized with MTB-E (100 mL), 8.34 g of pure tert-butyl {[4- (pyridin-3-ylamino) piperidin-1-yl] sulfonyl} carbamate with a melting point of 170 ° C. Got it.

¹ H NMR (δ ppm, 400 MHz, DMSO-d ₆ ): 10.92 [s, br, 1], 8.00 [d, 1], 7.76 [dd, 1], 7.11 [dd, 1], 7.02 [dd, 1], 3.62 [m, 2], 3.42 [m, 1] , 2.99 [m, 2], 1.97 [m, 2], 1.44 [s, 9], 1.38 [m, 2].

28.6 g of tert-butyl {[4- (pyridin-3-ylamino) piperidin-1-yl] sulfonyl} carbamate was almost completely dissolved in 1.5 l of dichloromethane, followed by 4- (trifluoromethyl 15 g of) -phenyl isocyanate was added. The reaction mixture was stirred at 40 ° C for 24 h. The reaction mixture was filtered (0.9 g of starting material was separated) and concentrated in vacuo. The residue was stirred in a mixture of 500 mL MTB-E and 500 mL water for 1 hour, at which time the product began to precipitate. The solid was separated by filtration, washed with MTB-E and water, and then vacuum dried at 60 캜. Tert-butyl {[4- (pyridin-3-yl {[4- (trifluoromethyl) phenyl] -carbamoyl} amino) -piperidin-1-yl] having a melting point of 145 ° C. (bubble) 41.4 g of sulfonyl} carbamate were isolated.

¹ H NMR (δ ppm, 400 MHz, DMSO-d ₆ ): 10.88 [s, br, 1], 8.61 [d, 1], 8,45 [dd, 1], 8,11 [s, 1], 7.70 [dd, 1], 7.61 [d, 2], 7.55 [ d, 2], 7.50 [dd, 1], 4.43 [m, 2], 3.67 [m, 1], 2.95 [m, 2], 1.92 [m, 2], 1.36 [s, 9], 1.22 [m , 2].

Tert-butyl {[4- (pyridin-3-yl {[4- (trifluoromethyl) phenyl] -carbamoyl} amino) -piperidin-1-yl] sulfonyl} carbamate in 100 ml of dichloromethane 1.8 ml of trifluoroacetic acid was added to 1.3 g of the solution. The mixture was stirred at rt for 30 h. The reaction mixture was then concentrated in vacuo and the resulting oily residue was taken up in MTB-E, whereby the product began to crystallize. After 2 hours, the solids were separated by filtration and then dried under reduced pressure. The resulting residue was stirred with a mixture of MTB-E and water. After some insoluble product (0.13 g) was removed, the organic layer was separated and washed with water and sodium hydrogencarbonate solution, at which time the product precipitated. The yield of the collected crystalline substance 4- (pyridin-3-yl {[4- (trifluoromethyl) phenyl] carbamoyl} -amino) piperidine-1-sulfonamide was 0.57 g, and was 188 ~ 191 ° C. Has a melting point of.

¹ H NMR (δ ppm, 400 MHz, DMSO-d ₆ ): 8.62 [d, 1], 8,47 [dd, 1], 8,14 [s, 1], 7.71 [dd, 1], 7.62 [d, 2], 7.55 [d, 2], 7.52 [dd, 1], 4.36 [m, 2], 3.50 [m, 1], 2.62 [m, 2], 1.93 [m, 2], 1.26 [m, 2].

The following compounds were prepared in excellent yields according to any one of Examples 1-8 described above.

Table 3: Additional Compounds of Formula I

Example  One: Example  Capsules comprising Compound I from 6

70 mg of compound I from Example 6

Corn Starch 60mg

Lactose 250mg

Small amount of ethyl acetate (= EA)

The actives, corn starch and lactose were processed into a homogeneous paste mixture using EA. The paste was ground and the resulting granules were placed in a suitable tray and dried at 45 ° C. to remove the solvent. The dried granules were passed through a grinder and mixed with the following additional aids in a blender.

Talc 5mg

Magnesium Stearate 5mg

Corn starch 10mg

It was then poured into 400 mg capsules (= capsule size 0).

Claims (17)

The following compounds of general formula I and their physiologically acceptable acid addition salts:

R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; Alkylenearyl; Alkylene arylenealkyl; Alkylene arylene halogen; Alkylene aryleneoxyalkyl; Alkylene arylene dialkyl amines; Heteroaryl; Unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or, R1 and R2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and / or sulfur atoms; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and optionally substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and aryl Or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN. The method of claim 1, R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Alkylene heteroaryl unsubstituted or substituted with halogen; R2 is cycloalkyl; Aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; C0-alkylenearyl; CO-heteroaryl; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R1 and R2 together Forms a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and / or sulfur atoms; May comprise one or two double bonds; It may also be substituted with alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also comprise a carbonyl group; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and also aryl Compound which can be substituted by. The method according to claim 1 or 2, R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Selected from the group consisting of alkyleneheteroaryl substituted with halogen; R2 is alkylenealkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R 1 and R 2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and / or sulfur atom; And may optionally include one or two double bonds; It may also be substituted by alkyl, halogenalkyl, unsubstituted or by aryl and / or heteroaryl substituted by alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or R 3 and R 4 together form a ring selected from the group consisting of pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino. The method according to any one of claims 1 to 3, If R2 does not comprise a CO group, then R1 is only a hydrogen atom. The method according to any one of claims 1 to 4, R 3 and R 4 are both hydrogen atoms. A pharmaceutical composition comprising the following (a) and (b): (a) a pharmaceutically effective amount of a compound of Formula I and its physiologically acceptable acid addition salt,

R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; Alkylenearyl; Alkylene arylenealkyl; Alkylene arylene halogen; Alkylene aryleneoxyalkyl; Alkylene arylene dialkyl amines; Heteroaryl; Unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or, R1 and R2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and / or sulfur atoms; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl; Heteroaryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and aryl Or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN; And (b) conventional pharmaceutically acceptable adjuvants and / or carriers. The method of claim 6, R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Alkylene heteroaryl unsubstituted or substituted with halogen; R2 is cycloalkyl; Aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; C0-alkylenearyl; CO-heteroaryl; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R1 and R2 together Forms a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and / or sulfur atoms; May comprise one or two double bonds; It may also be substituted with alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and also aryl A composition which can be substituted by. The method according to claim 6 or 7, R 1 is alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Selected from the group consisting of alkyleneheteroaryl substituted with halogen; R2 is alkylenealkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R 1 and R 2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and / or sulfur atom; And may optionally include one or two double bonds; It may also be substituted by alkyl, halogenalkyl, unsubstituted or by aryl and / or heteroaryl substituted by alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or And R 3 and R 4 together form a ring selected from the group consisting of pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino. The method according to any one of claims 6 to 8, If R2 does not comprise a CO group, then R1 is only a hydrogen atom. The method according to any one of claims 6 to 9, R 3 and R 4 are both hydrogen atoms. As a process for preparing the compound of the general formula (I) and its physiologically acceptable acid addition salts,

Wherein R 1 is a hydrogen atom; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; alkylenearyl; alkylene Arylenealkyl; alkylenearylenehalogen; alkylenearyleneoxyalkyl; alkylenearylenedialkylamine; heteroaryl; unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ Is selected from; R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or, R1 and R2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and / or sulfur atoms; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl; Heteroaryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and aryl Or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN); The method, a) a compound of formula II,

By reacting with sulfamoyl chloride of formula III

Obtaining a compound of formula IV,

The compound of formula IV is then reacted with amine H ₂ NR ₁ to obtain a compound of formula V,

The compound of formula I by reacting a compound of formula V with R2X wherein X is selected from the group consisting of Cl, Br and I

(Where R3 and R4 are not all hydrogen atoms) Manufactures or b) A compound of the general formula (I) by reacting a compound of the general formula (IV) with an amine HNR1R2

(Where R3 and R4 are not all hydrogen atoms) Manufactures or c) a compound of formula II,

By reaction with a sulfamoyl chloride of formula VIa or a reagent of formula VIb, protected by a protecting group PG, preferably tert-butyloxycarbonyl,

To prepare a compound of formula (VII),

The compound of formula V is then reacted with amine H ₂ NR ₁ to obtain a compound of formula V,

The compound of formula (VII) is further reacted with R2X, wherein X is selected from the group consisting of Cl, Br, and I to prepare a compound of formula (VII),

Subsequently, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R 3 and R 4 are both hydrogen atoms, or d) reacting a compound of formula VII with amine HNR1R2 to produce a compound of formula VII,

Subsequently, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R 3 and R 4 are both hydrogen atoms, or e) a compound of formula (VII),

Reacted with the protective agent PG to prepare a compound of formula XI,

The compound of formula XI is then reacted with aldehyde R2'-CHO to prepare a compound of formula XII,

Wherein R 2 ′ is selected from the group consisting of alkyl; cycloalkyl; alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; alkylenealkoxy; and alkylenecycloalkyl Subsequently, after removing the protecting group PG of the compound of Formula XII, the unprotected compound is reacted with sulfamoylchloride ClSO ₂ —NH ₂ to prepare a compound of Formula I wherein R ₂ comprises a methylene spacer CH ₂ ;  The protecting group PG of the compound of formula XII is removed and the unprotected compound is then reacted with sulfamoyl chloride of formula VIa or a reagent of formula VIb protected with a protecting group, preferably tert-butyloxycarbonyl,

To prepare a compound of formula XIII,

Subsequently, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R ₂ comprises a methylene spacer CH ₂ and R 3 and R 4 are both hydrogen atoms, or f) a compound of formula X,

By reaction with the protective agent PG, to obtain a compound of the general formula XI,

Subsequently, the compound of formula XI is reacted with ketone R2'-COR1 'to obtain a compound of formula XIV,

Wherein R 1 ′ is alkyl; alkylenealkoxy; alkylenecycloalkyl; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearyleneoxyalkyl; alkylenearylenedialkylamine; and unsubstituted Or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; R2 'is alkyl; Cycloalkyl; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; And alkylenecycloalkyl) The protecting group PG of the compound of formula XIV is then removed and the unprotected compound is then reacted with sulfamoylchloride of formula VIa or a reagent of formula VIb protected with protecting group PG, preferably tert-butyloxycarbonyl,

Preparing a compound of formula XV,

Subsequently, the protecting group PG is removed from the obtained intermediate product to prepare a compound of formula I wherein R ₂ comprises a methylene spacer CH ₂ and R 3 and R 4 are both hydrogen atoms, or g) a compound of formula II,

React with the protecting agent PG to obtain a compound of the general formula

Subsequently, the compound of formula X 'is reacted with amine NHR1R2 to obtain a compound of formula X',

Subsequently, the protecting group PG of the compound of formula X 'is removed, and then the unprotected compound is reacted with sulfamide to prepare a compound of formula I, or to react with a compound of formula III to prepare a compound of formula I, Or reacting with a compound of formula VIa or VIb to prepare a compound of formula XIX,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product, or h) a compound of formula XVIIa,

Where R2 is a hydrogen atom By reacting with a compound of formula XX,

Wherein R5 is alkyl; cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; unsubstituted or alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; and heteroaryl Is selected from the group) Obtaining a compound of the general formula XXI,

The protecting group PG of the compound of formula XXI is then removed and the unprotected compound is reacted with sulfamide to form a compound of formula I, or reacted with a compound of formula III to prepare a compound of formula I, or Reacting with a compound of formula VIa or VIb to prepare a compound of formula XXII,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product, or i) a compound of formula XVIIa,

Where R2 is a hydrogen atom By reacting with a compound of formula XXIII,

Wherein R6 is selected from the group consisting of alkyl; unsubstituted or aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN) Obtaining a compound of formula XXIV,

Subsequently, the protecting group PG of the compound of formula XXIV is removed and the unprotected compound is reacted with sulfamide to prepare a compound of formula I, or to react with a compound of formula III to prepare a compound of formula I, or Reacting with a compound of formula VIa or VIb to prepare a compound of formula XXV,

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product, or j) a compound of formula XI,

React with a compound of formula XXIII to obtain a compound of formula XXVI,

Subsequently, the protecting group PG of the compound of formula XXVI is removed and the unprotected compound is reacted with sulfamide to prepare a compound of formula I, or to react with a compound of formula III to prepare a compound of formula I, or React with a compound of formula VIa or VIb to obtain a compound of formula XX '

The compound of formula I is then prepared by removing the protecting group PG from the obtained intermediate product, or k) a compound of formula VII,

By reacting with a compound of formula XX,

Obtain the compound of general formula XX ',

The compound of formula I is then prepared by removing the protecting group PG of the compound of formula XX ', or l) a compound of formula XI,

React with a compound of the general formula

To obtain a compound of the general formula XXX,

The compound of formula XXXI is then obtained by removing the protecting group PG of the compound of formula XXX,

Furthermore, a compound of formula XXXI is prepared by reacting a compound of formula XXXI with sulfamoyl chloride of formula III, or a compound of formula XXXII by reacting with a compound of formula VIa or VIb,

A compound of formula I is then prepared by removing the protecting group PG of the compound of formula XXXII; And if necessary, convert the free base of the obtained compound of general formula (I) to their physiologically acceptable acid addition salt, or the physiologically acceptable acid addition salt of the compound of general formula (I) A compound of the general formula (I) and a method for preparing physiologically acceptable acid addition salts thereof, characterized by being converted to the free base of. The method of claim 11, R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Alkylene heteroaryl unsubstituted or substituted with halogen; R2 is cycloalkyl; Aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; C0-alkylenearyl; CO-heteroaryl; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R1 and R2 together Forms a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and / or sulfur atoms; May optionally include one or two double bonds; It may also be substituted with alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and also aryl Which can be substituted by The method of claim 11 or 12, R 1 is alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl; Alkylenearyl; Heteroaryl; Selected from the group consisting of alkyleneheteroaryl substituted with halogen; R2 is alkylenealkoxy; Alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylene aryl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; Is selected from the group consisting of SO ₂ -NH ₂ ; or; R 1 and R 2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and / or sulfur atom; And may optionally include one or two double bonds; It may also be substituted by alkyl, halogenalkyl, unsubstituted or by aryl and / or heteroaryl substituted by alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl; or R 3 and R 4 together form a ring selected from the group consisting of pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino. The method according to any one of claims 11 to 13, If R2 does not comprise a CO group, then R1 is only a hydrogen atom. The method according to any one of claims 11 to 14, R 3 and R 4 are both hydrogen atoms. Preventing and / or preventing glaucoma, epilepsy, bipolar disorder, migraine, neuralgia, obesity, type II diabetes, metabolic syndrome, alcohol dependence and / or cancer, and incidental and / or secondary diseases or conditions in mammals and humans Use of the following compounds of Formula I and their physiologically acceptable acid addition salts for the manufacture of a medicament for treatment and / or retardation:

R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyl; Aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; Alkylenearyl; Alkylene arylenealkyl; Alkylene arylene halogen; Alkylene aryleneoxyalkyl; Alkylene arylene dialkyl amines; Heteroaryl; Unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or, R1 and R2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and / or sulfur atoms; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl; Heteroaryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and aryl Or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN. Glaucoma, epilepsy, bipolar disorder, migraine, neuralgia, obesity in mammals and humans, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I and their physiologically acceptable acid addition salts Methods of treating or preventing type II diabetes, metabolic syndrome, alcohol dependence and / or cancer, and incidental and / or secondary diseases or conditions thereof:

R 1 is a hydrogen atom; Alkyl; Cycloalkyl; Alkylene alkoxy; Alkylenecycloalkyls; Aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF ₃ , CN; Alkylenearyl; Alkylene arylenealkyl; Alkylene arylene halogen; Alkylene aryleneoxyalkyl; Alkylene arylene dialkyl amines; Heteroaryl; Unsubstituted or alkyleneheteroaryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; R2 is cycloalkyl; Aryl unsubstituted or substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; Alkylenearyl unsubstituted or substituted but not substituted by furan or furanyl; Alkylene alkoxy; Alkylenecycloalkyl; Heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-alkylenearyl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF ₃ , CN; CO-O-alkyl; CO-O-cycloalkyl; CO-O-aryl substituted by alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-O-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF ₃ ; CO-NH-heteroaryl; SO ₂ -NH ₂ ; SO ₂ -alkyl; Unsubstituted or substituted from alkyl, alkoxy, halogen, CF ₃ , CN, SO ₂ -aryl; or, R 1 and R 2 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 additional heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and / or sulfur atom; Optionally may comprise one or two double bonds; Or may be substituted by alkyl, halogenalkyl, unsubstituted or aryl and / or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF ₃ ; May also include carbonyl groups; Can also be condensed by aryl; R3 and R4 are cycloalkyl including one or more heteroatoms selected from hydrogen atom, alkyl, cycloalkyl, nitrogen atom and / or oxygen atom; Cycloalkyl containing one or more heteroatoms selected from a nitrogen atom and / or an oxygen atom and optionally substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Aryl; Aryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Heteroaryl; Heteroaryl substituted with alkyl, alkoxy, halogen, CF ₃ , CN; Independently selected from the group consisting of alkylenearyl; or R 3 and R 4 together form a 5- or 6-membered ring, which ring may optionally comprise 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and / or oxygen atoms, and aryl Or alkyl, alkoxy, halogen, CF ₃ And aryl substituted with CN.