TW200927090A - Novel sulfamate compounds for medical use - Google Patents

Abstract

This invention relates to sulfamates of Formula I wherein R1 to R3 and n are defined in the claims, to medicaments comprising these compounds, to pharmaceutical compositions comprising these compounds, and to processes for the preparation of these compounds. The invention is also directed to the use of such compounds, medicaments and compositions, particularly to their use in administering them to patients to achieve a therapeutic effect.

Description

200927090 6. Technical Field of the Invention: The present invention relates to the field of pharmaceuticals and organic chemistry, and provides novel amino acid-reducing compounds, agents comprising the same, pharmaceutical compositions comprising the same, and preparation thereof Method of compound. The invention also relates to the use of such compounds and compositions: in particular, for the purpose of administering them to a patient for therapeutic purposes. [Prior Art] The use of amino acid as a pharmaceutical active ingredient in pharmaceuticals has been known for many years. European Patent No. EP 0 138 441 discloses sulfamic acid derivatives of the following general formula,

Wherein X is hydrazine or CH2, R1 is hydrazine or alkyl, R2 to R5 are hydrogen or alkyl, and when X is CH2, R4 and R5 may be combined to form a benzene ring, and when X is hydrazine, R2 and R3 are / or R4 and R5 together can form a methylenedioxy group. The conjugates of the type described are reported to exhibit anticonvulsant properties. European Patent Application ΕΡ 0 138 441 also describes the use of such compounds for the treatment of diseases such as epilepsy and glaucoma.

Other sulfamic acid derivatives for use in medicinal chemistry are disclosed by Maryanoff et al., J. Med. Chem. 1998, 41, 1315 to 1343. It has been reported that pyranose fructose sulfamic acid exhibits an anticonvulsant activity similar to that of phenytoin. The Topiramate study of the following general formula is used to treat a variety of medical conditions such as known representatives of children and adults with epilepsy. 3 200927090

In the child, Totatsu also attends Lennox-Gastaut syndrome (which causes seizures: and disorders of developmental delay). It is also approved by the Food and Drug Administration (FDA) and is currently used to prevent migraine. Neurologists use topiramate to treat stagnation' although it is not FDA-approved. The drug has been studied for the treatment of obesity, especially for lions to reduce gluttony and as a possible treatment for sputum. The drug is also used in clinical trials for the treatment of post-injury stress syndrome. - A preliminary study suggests that Protai may be effective for baby nodding. In May 2006, the National Institutes of Health on the Internet at http://www.dinicaltrials g〇v listed several items sponsored by or-··· to test the silky (4) off-axis and clusters. Study and use of headaches and uses. Other off-label use and research purposes of Topira include: m treatment of bulimia nervosa, obsessive-compulsive disorder, smoking cessation and treatment of neuropathology

Maryanoff et al., J. Med Chem 1987, 41, 88〇 to 887, also disclose Φ dibicyclic sulfamic acid.

However, its anticonvulsant activity has been reported to be very low. The present invention aims to provide a novel sulfamic acid which is very effective and can be obtained in a simple manner for the treatment and/or prevention of various diseases. 4 200927090 Some novel amino acides and their physiologically acceptable ones are now surprisingly found. Salts, hydrates, and solvates are suitable for the treatment and/or prevention of various diseases or conditions, such as obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, X syndrome, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, Sugar: urinary microangiopathy, diabetic macroangiopathy, islet tumor, familial hyperinsulin: hypoglycemia, male male alopecia, detrusor hyperactivity, hypertension, especially arterial sputum blood pressure, serum lipoprotein abnormalities, especially Is accompanied by the presence or absence of low HDL-cholesterol serum lipoprotein abnormalities of triglyceride, hyperuricemia, asthma, sputum glucose metabolism, especially insulin resistance, hyperglycemia and/or glucose intolerance, Neuroprotective, Parkinson's disease, Alzheimer's disease, pain relief, angina pectoris, arrhythmia, coronary motion痉挛, terminal vascular disease, cerebral vasospasm, appetite regulation, neurodegenerative, pain, including neuropathic pain and chronic pain, impotence, glaucoma, bipolar disorder, migraine, alcohol dependence, cancer and cardiovascular disease, including special departments Cardiac protection, heart numbness, coronary heart disease, cerebrovascular disease and peripheral arterial occlusive disease and its complications and/or secondary diseases or symptoms. [Contents] Φ Compounds of formula 1 have been found to be novel and suitable for treatment Different medical symptoms. The present invention relates to compounds of formula I and physiologically acceptable salts, hydrates and solvates thereof, 0

R3~(CH^r〇-s-NR1R2 I Ο wherein R1 and R2 are independently selected from the group consisting of hydrogen, C1_C8 alkyl, c4_cl〇cycloalkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl Optionally substituted with at least one substituent γ, and wherein the aryl and heteroaryl are optionally substituted with at least one substituent hydrazine, or wherein 5 200927090 R1 and R2 together form a -5 or 6-membered ring and may additionally Containing one to two heteroatoms independently selected from nitrogen, oxygen, and sulfur' and the 5 or 6-membered ring is optionally substituted with at least one substituent Y; R3 is selected from the group consisting of (lS, 2S, 5S)- 6,6-Dimethyl-bicyclo[3"ηhept-2-yl; :(Set, sink, 5, 6,6-dimethylbicyclo[3.1.1]hept-2-yl; (13 , 2 feet, 58) _6,6_dimercapto-r-ring-[3.1.1]hept-2-yl, (1 尺, 48)-bicyclo[2.2.1]hept-2-yl; (18,411 )_3-indenyl-bicyclo[2.2_1]hept-2-yl;bicyclo[2.2.2]oct-5-indol-2-yl; (4S)-bicyclo[2.2.1]hept-5-缔-2-yl; (1S, 2R, 4S)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl; ❹(1 ft, 28,4 ft)-1,7 , 7-trimethyl-bicyclo[2.2.1]hept-2-yl; and (1 ft, 211,411)-1,7,7-trimethylbicyclo-P.2.1]hept-2-yl; η 0 to 3; selection Lower group: alkyl, alkoxy, thioalkyl, aryl, co-aryl, heteroaryl, 'amino and carboxyalkyl; '' Ζ selected from the group consisting of alkyl, alkoxy, sulfur Alkenyl, halogen, aryl, CO-aryl, CN, heteroaryl and carboxyalkyl. The invention also relates to an agent comprising a compound of formula 1, a pharmaceutical composition comprising a compound of formula I, and a preparation of formula I The present invention also relates to the use of a compound of the formula I and a composition comprising a compound of the formula I, in particular for the administration of such a therapeutic effect to a patient. The invention particularly relates to a compound of the formula 1 Wherein R1 and R2 are independently selected from the group consisting of hydrogen and a C1-C8 alkyl group, wherein the C1_C8 alkyl group is optionally substituted with at least one substituent γ selected from the group consisting of C1-C4 alkyl, C1-C4 Alkoxy, C1-C4 thioalkyl, C6-C12 aryl, C〇-C6_C12 aryl, C6-C12 heteroaryl, amino and carboxy-C1-C4-alkyl. Preferred as R1 and R2 a compound of the formula I which is all hydrogen. In another embodiment of the invention, a preference is given to compounds in which η is 1 or 2', especially preference to 200927090 η is 1 in the present invention. In another embodiment, the compound is selected from the group consisting of: ~methylbicyclo[3.1.1]hept-2-yl]methylamino acid, 1 (1·Κ, 2^Κ, 5Κ^ )-6,6- ^*·"Tiangan~Methylbicyclo[3.1.1]hept-2-yl]methylsulfamic acid, [(lS,2S,5S)-6,6-二田甘me w < methyl bicyclo [3.1.1]hept-2-yl]ethylamino acid, /10 „methyl bicyclo[3.1,1]hept-2-yl]methylsulfamic acid , and (1R, 4S) - bicyclic - "2 2 η + ca. Heptyl-methylsulfamic acid, and (4S)-bicyclo[2.2.1]hept-5-en-2-yl.methyl-helium-glycolic acid. The most preferred compound of the present invention is

In another, A methyl bicyclo [3 · 1.1] heptyl] methyl sulfamic acid. 2. In her case, the invention relates to a medicament comprising a compound of formula I, or a pharmacological M hydrate or solvate thereof. The present invention relates to a pharmaceutical composition comprising: A) a pharmacologically effective amount of a compound of formula I or a pharmacologically acceptable salt, hydrate or solvate thereof as an active ingredient; Optionally, at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a pharmaceutical composition comprising: A) a pharmacologically effective amount of a compound; or a pharmacologically acceptable salt, anther or solvate thereof, as an active ingredient; and B) Optionally, at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable excipient. For the treatment of obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, X syndrome, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, islet tumor, familial insulin Hypoglycemia, male male alopecia, detrusor hyperactivity, hypertension, especially arterial hypertension, abnormal serum lipoprotein, especially accompanied by the presence/absence of hypoallergenic acid in the serum lipoprotein abnormality of 200927 90 HDL-cholesterol Glycerolemia, hyperuricemia, asthma, glucose metabolism, especially insulin resistance, hyperglycemia and/or glucose intolerance, neuroprotection, Parkinson's disease, Alzheimer's disease, analgesia, angina, arrhythmia Coronary artery spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegenerative, pain, including neuropathic pain and chronic pain, impotence, glaucoma, bipolar disorder, migraine, alcohol dependence, cancer and cardiovascular disease, Including special heart protection, heart itching, coronary heart disease 'cerebral blood Disease and peripheral arterial occlusive disease and its complications and / or secondary diseases or symptoms. The compound of the formula I of the present invention, and pharmacologically acceptable salts, hydrates and solvates thereof, have carbonic anhydrase inhibitory activity. It can be used to treat conditions involving carbonic anhydrase or by treatment of such enzymes. For example, for treatment and/or different diseases, such as obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, X syndrome, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microvessels Lesions, diabetic macroangiopathy, Tengdao tumor, family 'insulin hypoglycemia, male male show, detrusor function, high blood pressure, especially for arterial hypertension, serum lipoprotein abnormalities, accompanied by special fibers / does not appear

Pseudoalcoholic serum lipoprotein abnormality of hypertriglyceridemia, hyperuricemia, glucose metabolism 'special insulin resistance, hyperglycemia and / or glucose 棣 go to God Shenbao ^, Parkinson's disease, Azhai Motibus, pain relief, angina pectoris, palpebral artery spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, chemotherapy, pain, including neuropathic pain and chronic pain, impotence, vocal eye, migraine ^ fine dependence, cancer And money tube diseases, including special diseases I heart palsy, coronary heart disease, cerebrovascular disease and peripheral arterial obstruction and/or secondary diseases or symptoms. , mt, month < compound with carbonase inhibition activity. Inhibition of a compound of the invention; solubilization, for example, 'use-- or more of the assays described herein or in the art. 8 200927090. The isolation and purification of the compounds described herein, if desired, by any suitable separation or Purification methods, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or high pressure liquid chromatography, or a combination of these methods to achieve . Suitable separations and methods can be obtained from the preparation and examples. However, other equivalent separation or isolation methods can of course be used. The compounds of the present invention contain one or more asymmetric centers and thus appear as single mirror oxime isomers, mixtures of non-an image isomers, and individual non-image isomers. Depending on the nature of the different substituents, the molecule may have other asymmetric centers. The respective optical centers independently produce two optical isomers. Early sigma formation of such non-image isomers, or chromatographic separation thereof, can be accomplished as appropriate in the manner disclosed in the art. By deriving from, if necessary, the X-ray analytic method of the crystal product or crystal intermediate of the asymmetric center of the configuration is carried out. Can be loaded with the technology domain = to collect the compound racemic mixture pure as an ageing isomer, for example, the compound of the compound 2, the rotation of the compound, like the compound of the different frequency, to form a mixture of the lit matter, and then borrow Individual non-image-isomerized acidified fractional crystallization or riding methods are separated by standard methods. Coincidence includes the creation of a job like heterogeneity. Then Tongxian plus the cleavage of the chiral residue makes the non-image isomerization derivative servant I a pure mirror image isomer. It is also known by the chromatographic method using chiral fixation that the two races are directly separated from the racemic mixture: this method is a well-known technique in the field, using a pure starting material of a known configuration or The reagent is known as a polymorph of a compound of any of the compounds obtained by stereoselective synthesis of the compound by stereoselective synthesis: such an intention belongs to the invention of 200927090. Further, some of the compounds may form a solvate with water (i.e., hydrate) or a common organic solvent, and the formulation is also included in the scope of the present invention. Isotopically labeled compounds of formula I or their freshly acceptable salts, including the isotopically labeled formula [compounds, which are detectable by PET or SPECT, are also included within the scope of the invention. The same applies to the formula of the atomic label enriched with [13C]_, [MC], [3H]_, [18f]_, [125i]_: or its enantiomers, suitable for the receptor Binding or metabolic studies. Definitions The general terms used in the specification of the presently disclosed compounds have their usual meanings. As used herein, t-based is a monovalent saturated branched or straight hydrocarbon chain. Unless otherwise stated, the chain may contain from 1 to 18 carbon atoms. Representative of such a base are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tert-butylpentyl, isopentyl, neopentyl, tertiary pentane Base, hexyl, isohexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecanyl, ten Seven bases, eighteen bases, etc. In the preferred embodiment of the invention, the silk comprises from 1 to 8 bribe atoms. The same carbon content applies to the parent term "smoke ro" and applies to derivative terms such as "alkoxy" and "thioalkyl". The term "aryl" embraces monocyclic or fused bicyclic and polycyclic aryl groups including, but not limited to, the benzyl, 1,2,3,4-tetrahydro-naphthyl, naphthyl and alkoxy groups. The "heterocyclic group" includes a monocyclic or fused bicyclic and polycyclic aromatic ring system in which - or a plurality of carbon atoms are replaced by a hetero atom. The term "heteroaryl" includes, but is not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,lb][l,3pS4, carbyl, chew 4 Base, different ten records, "base, seam. Qinji is a bit of zirconyzine, 1,3,5-trisyl, octagonal, fluorenyl, fluorenyl, isomeric, benzo[b] thiol, u, 3, 4, Hydrogen isoindole, nodal base, nodal group, 200927090 benzo[b]thienyl, 2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl, benzo Thiazolyl, benzo[1,2,5]thia-diazolyl, indolyl, quinolyl, isoquinolinyl, oxazinyl, quinazolinyl, quinoxalinyl, , 8_naphthyridinyl, naphthyl, pteridinyl, oryl, and the like. "Halogen" means chlorine, fluorine, bromine or pyridine; "hetero" means "habric", "hetero: aryl" and the like to mean one or more N, hydrazine or S atoms. The term "substituted" means that a particular group or moiety carries one or more substituents. Any of these groups may carry multiple substituents and provide a wide variety of possible substituents which are independently selected and do not have to be identical. The term "unsubstituted" means that a particular group does not carry a substituent. "Optionally substituted" means that the alkyl or cycloalkyl group may or may not be further substituted by one or more groups Y, or the aryl group may or may not be further substituted by one or more groups z. &quot;Crystalline&quot; refers to different solid forms of the same compound, such as polymorphs, solvates, and amorphous forms. "Polymorph" is a crystal structure in which a compound can be crystallized in a different cell arrangement, all of which have the same elements. Polymorphism is caused by different crystallization conditions such as temperature, supersaturation level, presence of impurities, polarity of solvent, cooling rate, and polymorphisms usually have different diffraction patterns and solids. NMR spectrum 'infrared or Raman spectrum, melting point, density, hardness, crystal morphology, optical and electrical properties, stability and solubility. The recrystallization solution, crystallization rate, storage temperature, and other factors can lead to a crystal shape estimation advantage. The Y solvate is usually a crystal t containing a stoichiometric or non-stoichiometric amount of a solvent. Generally, in the crystallization, there is a tendency for the Wei compound to have a fixed molar ratio to dissolve in the solid of the knot 03. _ compound. When solvated 7, it forms a hydrate." The compound of the formula 1 and a pharmaceutically acceptable salt thereof may be present in the hydrate or the lysate (IV), and the female hydrate and the solvate are also included in the Japanese version. Examples thereof include (iv) hydrate, ]/4 hydrate, /2 aqueous monohydrate, hydrochloride 1/2 hydrate, dihydrochloride dihydrate, dihydrochloride 3/2 hydrate, and the like. The "amorphous" form is a non-long-range ordered amorphous material and usually does not provide a special powder X-ray diffraction pattern. The crystal form overview has been

Byrn (1995) and Martin (1995) describe. • Substitute, the term “independently” means when it is possible? When the species is substituted, they may be the same or different from each other. To provide a more concise description, some of the quantitative expressions provided herein are not defined by the term "about". It should be understood that whether or not the term "about" is used explicitly, the quantitative quantities provided herein mean the value of (10), and it also means that based on the common technology in the art, the _ given value is close to the health. It includes approximations due to experimental and/or measurement conditions for a given value such as this. The word "package" and variations of the word, such as "contains" or "includes", are not intended to be used in the context of the specification and the scope of the patent application. The compound of formula I may be administered as a pro-chemical, however it is preferred to be provided as a "pharmaceutical composition." According to another aspect, the present invention provides a secret composition comprising a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally together with one or more pharmaceutically acceptable carriers and/or at least A pharmaceutically acceptable excipient together. The carrier and excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject. The term "composition" as used herein, encompasses a product comprising a predetermined amount or percentage of a particular ingredient, and any product which is directly or indirectly obtained by combining a particular ingredient in a particular amount. With respect to pharmaceutical compositions, the term encompasses products comprising one or more active agents, and optionally carriers and/or adjuvants comprising inert ingredients, and combinations, complexations or aggregations of any of the two components, or Dissociation of one or more components, 12 200927090 or any product that reacts by other types of one or more components. In general, the pharmaceutical composition employs: the active ingredient is homogeneously: a carrier or a finely divided solid carrier or a combination of the two to be prepared, and, for example, =^ night = product processing is required. The pharmaceutical composition includes a course of disease or Symptoms produce sufficient active target compounds for the desired effect. Accordingly, the pharmaceutical group of the present invention == the compound of the present invention and optionally a pharmaceutically acceptable carrier and a mixture thereof - (4) "any composition. "Pharmaceutically acceptable" means that the carrier, the diluent, or the eliminator is not harmful to the recipient.

The affinity of the compound of the present invention as a carbonic anhydrase inhibitor is determined as follows. For the performance measured for a given compound of formula I, the theoretically least effective agent can be evaluated. In the case where the concentration of the compound is equal to twice the measured inhibition constant, it is possible that nearly 100% of the carbonic acid is occupied by the compound. The theoretical minimum effective dose is obtained by converting the concentration to mg compound/kg patient, assuming ideal bioavailability. Pharmacokinetics, pharmacodynamics, and other conditions may cause the actual dose to be higher or lower. The typical daily dosage of the active ingredient varies widely and depends on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and can be determined by the physician. The total daily dose administered to a patient, usually in a single dose or in a single dose, can be, for example, all of the active ingredients of formula I in an amount of from 0.001 to 10 mg/kg body weight per day. The dose is administered once to three times a day, or at a frequency required for efficacy, and for a period of at least two months, or typically at least six months or long, to a patient in need of treatment. The term "therapeutically effective amount" as used herein refers to a therapeutic agent that is used to treat a treatable condition by administering a composition of the present invention. The amount is sufficient to exhibit a detectable therapeutic or ameliorating effect in the tissue system, animal body or human body. Such effects can include, for example, treating the symptoms listed herein. The precise and effective amount for the subject depends on the weight and health of the subject, the symptoms of the treatment. 13 200927090 Essence and extent, therapist (researcher, veterinarian, pharmacist or other counselor, and the choice of route of administration) Therapy or combination therapy. Therefore 2) 3 is indeed effective. 4 疋 疋 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语 术语Pharmaceutically acceptable ^ 众所周知 is well known in the art. It can be prepared by finally isolating and purifying the compound of the present invention or by separately reacting it with a pharmaceutically acceptable non-toxic field or acid, so that inorganic or alkali and inorganic or organic acids are reacted separately (Berge, 1977). "Free radicals are regenerated by contact with a salt or test acid, and the parent cockroach is separated by conventional methods. The parent of the compound is in certain physical properties, such as in polar solvents: ς = = face, The various types are different, but it is the same as the parent form of the compound for the purpose of the present invention. The term "treatment" refers to the term "treatment", for example, any method of human disease. Including: (1) inhibiting the disease or symptoms, that is, inhibiting the shape. '(2) Reducing the disease or symptom 'because the symptoms are declining, or (7) terminating the disease, including the generally accepted meaning including preventing, preventing, inhibiting, delaying, terminating or reversing the progression, severity or symptoms. . The method of the invention comprises a drug treatment and/or a cake administration. As used herein, the term "drug therapy" is intended to include the manner in which lions, diagnosis and treatment are performed on the body or age of the human or other mammal. "Animal animals" include economically important animals such as cattle, sheep and pigs, special meat meats and livestock, sport animals, animals and humans, preferring the latter. The term "seeker" refers to an animal that is a therapeutic, observation, or test object. 14 200927090, prefers a mammal, and most favors humans. As used herein, "obesity" refers to a condition in which a person has a body mass index (BMI) of at least 3 inches, calculated as the square of weight/height (kg/m2). It is generally accepted that such persons having a BMI of at least 25.9 to less than 30 are overweight. Usually have a normal weight • These individuals have a BMI of 19.9 to less than 25.9. Obesity in this article may be due to any: cause, whether genetic or environmental. Examples of conditions that may cause obesity or obesity include overeating and overeating, polycystic ovarian disease, pharyngeal tumor, Prader-Willi syndrome, Fleulich syndrome ❹ (Frohlich's syndrome), type 2 diabetes, growth hormone deficiency, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced resting energy expenditure as a percentage of total fat-removing body weight, such as Children with acute lymphocytic leukemia. [Embodiment] Analytical method Nuclear magnetic resonance spectrum φ (lfi NMR and 13C NMR, APT) was measured in an indicating solution at 300 K unless otherwise stated 'Using Bruker Avance 500: 500 MHz, 13C: 125 MHz. Obtained from Cambridge Isotope Laboratories

The spectrum was measured in the dimethylated sub-sector of Ltd. The chemical shift (δ) from the low magnetic field of the tetradecyl calcined (1H, 13C) is provided in ppm. The coupling constant j is provided in Hz. The peak shape in the NMR spectrum is represented by the symbols "q" (quadruple peak), "dq" (double quadruple peak), "t" (triplet peak), "dt" (double triplet), and "d" (double) ♦), “dd” (double doublet), “s” (single peak), “bs” (wide single peak) and “m” (multiple peak). The melting point was recorded on a Biichi B-545 melting point apparatus. Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx software to obtain and recombine the data. The exact mass measurement is the excimer ion [M+H]+. All reactions involving moisture sensitive compounds or conditions are carried out in an anhydrous nitrogen atmosphere 15 200927090. Thin layer chromatography (TLC) was applied to a cerium oxide coated plastic sheet (Merclc precoated silicone 60 F254) to indicate the eluent to monitor the reaction. The chromatogram was examined by UV light (254 nm) or 12 visual inspection. All solvents were distilled before use. All other purchased chemicals are not: used for further purification. The present invention is not intended to limit the invention in any way. Other embodiments of the invention will be apparent to those skilled in the <RTIgt; The description and examples must be considered as illustrative only. Figure - Overview of a synthetic method of the compound of formula I: J 〇 al~~'n~~NR1R2 R3~(CH^TOH -^ R3—(cHi—〇—S—NR1R2 〇 ' ^π

11 III I Q Figure 1 In a preferred embodiment, the method of Figure 1 is carried out using a compound of formula II wherein R1 and R2 are both hydrogen and wherein Hal is chlorine. In another preferred embodiment, the method of Figure 1 is carried out using a general formula of hydrazine, which is selected from the group consisting of: [(lS, 2S, 5S)-6,6-dimethylbicyclo[3.1.1]hept-2-曱] sterol; [(1 Han '2 Han, 511)-6,6-dimethylbicyclo[3.1.1]-hept-2-yl]methanol; [(18,23,53)-6, 6-mono-T-bicyclo[3.1.1]hept-2-yl]ethanol, [(13,211,58)-6,6-dimethylbicyclo[3.1.1]heptyl]methanol, (1R, 4S )-bicyclo[2.2.1]heptan-2-yl-methanol, and (4S)-bicyclo[2·2.1] heptane-2-ylmethanol, preference [(18,28,58)_6,6_two Methyl bicyclo_[3.1.1]hept-2-yl]methanol. 16 200927090 The choice of the specific synthesis method depends on factors known to those skilled in the art such as the compatibility of the functional group with the reagent used, the possibility of using a protecting group, a catalyst, an activator and a coupling agent, and the presence of the final compound. Final structural characteristics. Pharmaceutically acceptable salts can be obtained by methods well known in the art, for example by mixing a compound of the invention with a suitable acid, such as a mineral or organic acid. Example 1: Synthesis of [(lS, 2S, 5S)-6,6 cf-based bicyclic Ru]hept-2-yl]methyl-aminotransacid-compound 1

Acryl chloride (1.67 g, 14.45 mmol) was added in one portion to [(18,28,58)-6,6-dimethylbicyclo[3丄1]hept-2-] A solution of methanol [(-)-trans-myroxylan] (1.115 g, 7.23 mmol) in anhydrous DMA (12 mL). The mixture was stirred at room temperature for 3 hours and then poured into 50 ml of cold saturated aqueous sodium chloride (br.). The resulting solution was extracted with EtOAc (3×25 mL). After concentrating under reduced pressure, the title compound was purified eluting eluting eluting eluting Sulfonic acid; mp 67-68 ° C; yield 92%. 1H NMR (DMSO-d6), δ: 0.82 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.20-1.38 (m, 2H), 1.53-1.63 (m, 1H), 1.69-1.79 ( m, 2H), 1.81-1.87 (m, 2H), 2.01-2.08 (m, 1H), 2.23-2.33 (m, 1H), 3.80 (d, J = 7.8 Hz, 2H, CHCH2OS〇2) ' 7.38 ( s, 2H, S02NH2). 13C NMR (DMSO-d6), δ: 17.23, 19.97, 22.88, 23.51, 26.44, 34.03, 38.74, 40.18, 41.51, 71.87°HR-MS (ESI, negative ion): 232.1011; ❹

17 200927090 Calculated as 232.1007 for C1()H18N03S (M-H)_. [a]d20 - 12, 4. (c=0,525 mol/L in methanol). Example 2: Synthesis [(1 public, 5)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl-sulfamic acid-compound 2

Ammoniasulfonyl chloride (1.67 g, 14.45 mmol) was added in one portion to [(1 R, 2R, 5R)-6,6-dimethylbicyclo[3.1.1]hept-2- stirred under 〇 °C. A solution of methanol [(+)-trans-myritol (1.115 g, 7.23 mmol) in anhydrous DMA (12 mL). The mixture was stirred at room temperature for 3 hours and then poured into 50 ml of cold saturated aqueous sodium chloride (brine). The resulting solution was extracted with EtOAc (3×25 mL). After concentrating under reduced pressure, the crude product was purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc Amino acid continued; mp 67-68 ° C; yield 89%. lH NMR (DMSO-d6), 5 : 〇.82 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.20-1.29 (m, 1H), 1.33 (d, J = 9.9 Hz, 1H) , 1.53-1.63 (m, 1H), 1.69-1.78 (m, 2H), I.8I-I.87 (m5 2H), 2.00-2.07 (m, 2H), 2.21-2.33 (m, 1H), 3.80 (d, J = 6.5 Hz, 2H, CHCH20S02), 7.38 (s, 2H, so2nh2). 13C NMR (DMSO-d6), 3: 17 22, 19 96, 22 87, 23 5〇, 26 43, 34 〇2, 38.74, 40.17, 41.50, 71.86. jjR-MS (ESI, negative ion): measured 232.1012; calculated for CwHuNC^S (M-H) is 232 1〇〇7. 200927090 [a ]D20 + 12,8. (c = 0,93 mol/L in methanol). Example 3: Preparation of [(18,28,58)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]ethyl •sulfamic acid-compound 3

Acryl chloride (〇.ll56g, 1mmol) was added to [(18,28,58)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]ethanol ([18.28,58)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]ethanol 0.0848, 0.5111111 〇 1) in a solution of anhydrous DMA (0.75 ml). The mixture was stirred at room temperature for 3 hours and then poured into a solution of 1 mL of cold saturated aqueous sodium chloride (br.). The resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with cold saturated aqueous sodium chloride (salt, 10 ml) and dried with EtOAc. After concentrating under reduced pressure, the crude product was purified by flash chromatography eluting with EtOAc (EtOAc: EtOAc: EtOAc Pure amino acid continued acid; mp Ο 49.5-51.5t:; yield 89%. !H NMR (DMSO-d6), δ : 0.80-0.92 (m, 1H), 0.99 (s, 3H, CH3), 1.17 (s, 3H, CH3), 1.40-1.53 (m, 1H), 1.63-2.13 (m, 8H), 2.23-2.40 (m, 1H), 4.01 (t, J = 6.6 Hz, 2H, CH2CH20S02), 7.36 (s, 2H, S02NH2) ° 13C NMR (DMSO-d6), &lt;5 : 21.30, 22.96, 25.90, 27.90, 32.95, 35.98, 36.60, 38.23, 40.74, 45.44, 67.72. HR-MS (ESI, negative ion): measured 246.1173; calculated for CuH^NOsS (M-Η)· was 246.1164. [α] 〇 20-19.3° (c=ll, DCM) ° Examples 4 to 6: Synthesis [(18, 2 team 58)_6,6-dimethylbicyclo[3.1.1]heptan-2-yl ] 19 200927090 Methyl sulfamic acid (Compound 4), (1R, 4S)-bicyclo[2.2.1]heptan-2-yl-methylamino acid (compound 5) and (4S)-one per [2.2 .1] G-5-sulfan-2-ylmethylamino acid (Compound 6) can be similarly used by [(18, 2 ft, 58)-6, 6-di, respectively, for the synthesis of compound 4. Methylbicyclo[3丄1]hept-2-yl]methanol for the synthesis of compound 5: (1R,4S)-monocyclo[2.2.1]hept-2-yl-methanol and for the synthesis of compound 6 Any of (4S)-bicyclo[2.2.1]hept-5-bine-r-2yl-nonanol was substituted for the alcohol as a starting material to prepare compounds 4 to 6.实施 Example 7: Formulation of Compound 1 for Animal Research For oral (po) administration, the compound is used as a wetting agent containing methyl ketone cellulose (m/m) and 〇. An excipient of poloxamer (p〇i〇xamer) nicknamed nonionic polyfluorene•ethylene-polyoxypropylene copolymer) is provided in the form of a suspension in water. The preparation was completed in a mortar with a mortar and the pH was adjusted to neutral conditions. For intraperitoneal (i.p.) administration: a small amount of glass beads was added to the required amount of solid compound 1 in the glass tube and the solid was vortexed for 2 minutes. After adding 1 ml of methylcellulose and 5% of mannitol in water, the compound was suspended in a vortex flow for 10 minutes. Finally adjust the pH to 7. For intravenous (i.v.) administration: The compound was dissolved in physiological saline (〇 9 % NaCl) and the pH was adjusted to 7. 7.1 Pharmacological Test Method The example number quoted in the pharmacological test method relates to the preparation examples described below. In vitro inhibition of human carbonic anhydride isoenzymes The test compound of formula I was diluted in a 96-well microplate using distillate water using an automated pipette (CyBiWell®). A 20 μl equivalent knife was applied to a 96-well black assay plate 20 200927090 from a different dilution plate using a pipetting console (Tecan Genesis®). In the second step, 148 μl potassium citrate buffer (20 mM, ρΗ7·4) was added, and as a third step, 20 μl of the enzyme solution (ΙμΜ human erythrocyte isoenzyme I (Sigma-Aldrich) from red blood cells or from Red blood cell human carbonase II (Sigma

❹

Aldrich) 'or recombinant human carbonic acid isoenzyme VB (R&amp;D Systems, dissolved in potassium citrate buffer) for 60 minutes at room temperature and read fluorescent signal at the end of pre-culture (FLU-1) (TecanUltra® Fluorescent Reader; excitation wavelength j80 nm; emission wavelength: 465 nm). After the pre-incubation time, a 20 μl aqueous sulfonamide solution (lmM dansamide (Sigma-Aldrich, dissolved in hydrochloric acid) was added] and the fluorescence signal was read at 3 r»c every 10 minutes for 60 minutes. Calculated using the light-time data of 60 minutes (FLU-2). The total volume of the analytical mixture totaled 208 μl. The final concentration of carbon-acid liver enzyme I is 1 (T7M / L 'the final concentration of carbonic anhydrase II is, the final concentration of carbonic anhydrase VB is 5xl (T6M / L 'the final concentration of dansamide is 1 〇 - 7 or 2 5^〇_6 or 5xl0·6 'and the final concentration of the compound is 10-7M/L and 1〇-6Μ/Ι^ as the compound solvent, the final concentration of DMSO is 〇·1%. Also included is a blank group containing no compound and enzyme, no compound and eszozolamide (final concentration 5xl〇_8M/L) as a control group for the calibration standard compound. All data are reflected in a single measurement. After the calculation, the data expression is % inhibition: ° % inhibition = l〇〇 ((l_(FLU-2 compound group _FLU_2 blank group hole called compound group + FLlM blank group) / (FLU-2 _-FLU-2 swFLXM _-FLU_l blank group)) The data of each compound and their respective final concentrations can be calculated by 4 software. By applying the pri 寅 algorithm to nonlinear regression (curve calculation of concentration for lag: variable slope) s _ quantity effect and _ factor / upper end: 100 and bottom 0 to obtain a concentration effect diagram. The test substance of I is shown in the test model 'below Lists the following formula i% inhibition provided disc information _1: In vitro inhibition of the test substance effects 21200927090 hCAII

Short-term in vivo feeding test in B-- \ ^ 7.3 mice

The study was performed in males (5 liters and 6 qi (n = group u). The mice were placed in a 12/12 hour light/dark cycle (22: 〇〇 lighting). Food (calorie diet) and water. Daily intake and water consumption were measured. The test compound of formula I was suspended in water with 1% methylcellulose and 1% (1%) of polozol I88 The drug was administered by oral gavage at a dose of 5 〇mg/kg/day for 3 days. Half dose was given at 8:00 to 1 ;; one half of the dose was taken from Η to 15 In the above test model, when compared with the control group, the test substance caused the animal to reduce the food intake for 72 hours as provided in the following Table 2. Branch 1: The influence of the test substance on the feeding 22 200927090 Ingestion [1 ___69.4% (3 days) of the control group 7.4 Effect on axonal exogenous effects of hippocampal neurons. Axon exogenous is an important parameter for evaluating the neurotrophic efficacy of compounds. Embryonic hippocampal nerve Compound 1 was tested for its ability to increase axonal exogenousness in cultures. Hippocampal neurons from Wistar male rats during pregnancy were treated with D. Dissociation by trypsinization (Tengin-EDTA, Gibco) for 30 minutes at 37 ° C in the presence of NAse I (Roche, Meylan) by addition of Dulbecci ^ DMEM containing 10% fetal bovine serum (Gibco); The reaction was terminated by Gibco's modified Eagle medium. The suspension was mashed using a pipette of i〇_mi and syringed using a 21G needle syringe and centrifuged at 35 〇Xg for 1 hr at room temperature. Suspension in a medium containing 2% B27 supplement (Gibco) and '2 mM ursolic acid (Gibco) in Neurobasal medium (Gibco). Calculated on a Neubauer blood cell counter using a phenol blue exclusion test (sigma) Viable cells were seeded on 30,000 cells each using a poly-L-lysine (Sigma) pre-coated Petri dish (Nimc). The cells were allowed to adhere for 2 hours and in a humidified incubator. Store at 37 ° C in a 5% carbon dioxide to 95% air atmosphere. ❹ Add the vehicle and various concentrations of test compound (ΙμΜ, 3μΜ, 1〇μΜ and 30μΜ) to the medium after adhesion. Includes BDNF ( 5〇ng/mh 3 7ηΜ) as a positive control for axon growth. Test compounds and controls And BNDF cultures were tested in parallel with independent cultures. After exposure of the neurons to the test compound for 3 days, the cultures were washed in phosphate buffered saline (PBS, Gibco) and used in 5% of PBS. Glutaraldehyde solid sputum. Photographs of several cells with axons without any branches were taken under various conditions using a digital camera (c〇〇ipix 5, Nikon) fixed on a microscope (Nikon, objective lens 4 () (~ So). Using an automatically calculated length imaging software (Image_Pr〇pius, French j to make the axon margin on the computer screen. 23 200927090 As expected, '50ng/ml BDNF treatment is associated with axonal growth from hippocampal neurons. The length of BNDF-stimulated axons grew from 105.7±3.2μηη (mean SEM; η=83) to Ι31.6±3.1μηη (η=79) with an average increase of 24.5μιη;

In the second culture, the BNDF-stimulated axon length grew from 109.3 ± 3.1 μηη (mean SEM; η = 86) to 118.7 ± 2.8 μηη (η = 82) with an average increase of 8.6 μιη. When the two cultures: the nutrients were normalized by the corresponding average control axon length, there was 16.4% BNDF induced growth. The potency of Compound 1 〇 As shown in Table 3, all of the tested concentrations of Compound 1 were associated with a significant increase in axon length. Compared to the control level, the axon exogenous effect was comparable for all test concentrations, increasing by 9% to 15%. The most effective concentration is 30 μΜ, which is comparable to the effect of BDNF .. Table 3: Effect of Compound 1 on axonal exogenous group Ν Average length (% of control group) compared with control conditions SEM Control group 169 100.0 2.0 BDNF (1.85 nM) 161 116.4 2.0 Compound 1 (1 μΜ) 171 110.9 2.3 Compound 1 (3 μΜ) 163 108.9 2.6 Compound 1 (1 μμΜ) 176 113.2 2.2 Compound 1 (30 μΜ) 166 114.5 2.4 In summary, this study demonstrates that Compound 1 is effective in promoting axonal exocytosis in hippocampal neurons. 7.5 Determination of anticonvulsant properties of test compounds by electroconvulsive threshold test (ECSTT) in mice Methods for determining convulsions or anticonvulsant activity are described in accordance with Swinyard et al. (J. 24 200927090)

Pharmacol. Exp. Ther. 1952' IM, 319-330). The pups were given ECS (DC, 0.4 s, 50 Hz) with a corneal electrode attached to a constant current electric shock (Ugo Basils Type 7801). Oral administration at doses of 1 〇, 3 〇, and 1 〇〇 mg/kg for 60 minutes after ECS • Test compound: The group in which the vehicle was orally administered 60 minutes before ECS was used as the control group. A tranquilizer (8 mg/kg orally) was administered as a positive anticonvulsant reference substance under the same experimental conditions. The treatment groups of 23 mice were exposed to ECS as follows: Animal n.丨 Exposure to ECS at 30 mA. If the animal η. 1 Exposing animal η 2 to a higher current of 40 mA without convulsions (tonic convulsions) for up to 5 seconds. If the animal η. 2 Still without convulsions, the current was further increased (1 mA higher) for the next animal until the first tonic convulsion was observed. Once the first tonic convulsion was observed, the ECS intensity was reduced by 5 mA for the next animal, and then the current intensity between the animals and animals was reduced or increased by 5 mA depending on whether the previous animal was convulsed or not. The minimum strength is 25mA and the highest intensity is 95mA. The threshold for electroconvulsive shock was determined as the mean current given in the last 20 mice. The results are represented as a percentage change from the control group. About 3 〇 ^ minutes after the animal convulsion test, it is necessary to record the number of deaths. The test was carried out by page inspection. A positive percentage change indicates an anticonvulsant effect. A negative percentage change indicates a convulsion-promoting effect. Quantitative data were analyzed using an unpaired Student&apos;s t test by comparing the treatment group to the vehicle control group. The number of data was analyzed using Fisher's exact probability test by comparing the treatment group with the vehicle control group. ϋ : Effect of Compound 1 and tranquilizer on mouse electroconvulsive shock (ECS) threshold test (20 pups per group) 25 200927090 Treatment of thousands of current intensity volts XmA) Death after ECS (mg/kg) Oral -60 minutes---****&quot;J mean sem P value compared with the control group % change • tr number excipient 36.5 + 1.0 .... 1 compound 1 (10) 40.0 soil 1.2 0.0334 + 10% 2 Compound 1 (30) 43.5 Soil 1.5 *11 0.0006 +19% 0 Compound 1 (100) 88.0 ± 2.1 &lt;0.0001 +141% 1 Stabilizer (8) 81.8 ± 3.0 *** &lt;0.0001 +124% 0

Students t test: NS = not significant; * = P &lt; 〇. 〇 5; *** = p &lt; 〇. 〇 (U. Fisher's exact test (death): unspecified = not obvious. (#): minimum = 30 mA; maximum = 95 mA. Compounds 1 (10, 30, and 100 mg/kg) administered orally 60 minutes prior to the test produced a dose-dependent and significant increase in the current threshold for sudden tonic convulsions at all three doses (respectively +10%, p&lt;〇.〇5; +19%, p&lt;0.001 and +141%, p&lt;0.001). Maximum effect obtained by oral administration at l〇〇mg/kg and anticonvulsant reference compound stability The effects of the agents were similar. These data indicate that Compound 1 has anti-epileptic properties. 7.6 Neuropathic Pain Test Caused by Diabetes 雄 In male Sprague Dawley rats (~2〇〇g), intravenous (tail) at a dose of 55 mg/kg Intravenous injection of streptomycin (STZ; Sigma, L, Isle D, Abeau Chesnes, France) in a buffered solution induced diabetic eSTZ was prepared in citrate buffer solution at pH 5 〇 〇 / / i. The group received the same volume of citrate buffer. The STZ injection day was considered the next day. After one week, the tail incision and blood were used. The instrument (solid blood glucose machine 'Roche Medical Instrument Co., Ltd., turned over) blood sugar level. Blood sugar > 260mg / dl of the rat is considered to have diabetes. (: =) =: sugar level of the way the rat is divided into 6 Group 1 〇 (4) Diuretic control group treated with paste, 26 200927090 2. ) STZ-treated diabetic group treated with vehicle (' ) to 5.) Oral administration at 10, 30 or 5 〇 mg/kg Compound 1 treated STZ treated diabetic group. 6.) STZ-treated diabetes treated with the positive reference compound morphine (3 mg/kg subcutaneous injection). : Compound 1 and vehicle (1% methylcellulose suspension) were orally administered 1 hour prior to the behavioral test. Morphine was injected subcutaneously 0.75 hours prior to the behavioral test. A second behavioral pain test was performed on day 10. ❹ The first day of the cold bath test:: Each animal is placed on a cold platform (1 to 4 ° C). Record the waiting time under the conditions of up to 3 sec before the first reaction (舔舐, move the paw, light jump). Compared with the time when the STZ-rat showed shortening (~10 seconds) before the first reaction, the animals in the control group could fortune 20 to 30 before the first reaction.

V seconds. This test is used to measure cold allodynia. Day Thirst Titer Plate (38 ° C_) Test: Animals are usually tested about 2 to 3 minutes after the cold bath test. Each animal was placed in a glass cylinder adjusted to a temperature plate of 38 ° C (Slide warmer MH6616; Euromedex; France). Record the waiting time for the first reaction (舔舐, move the paw, flick or jump to avoid heating). The cut-off time ® is set to 30 seconds. This test is used to measure hypersensitivity to hyperalgesia. A variant analysis (AN0VA) was performed on the data from the prepared parameters. Fisher's, s test is used to test the least significant difference value in pairs for comparison: the value of the value is still significant. The corresponding effector/control group was set to 100% and the STZ/excipient group was set to 0% inhibition to calculate the drug-induced inhibition of hyperalgesia and hyperalgesia caused by STZ-diabetes. 27 200927090 Treatment (mg/kg) % inhibition (compared with STZ/excipient group) Cold bath test warm plate test STZ/compound 1 (10) 62* 53 STZ/compound 1 (30) 58* 59* — STZ/ Compound 1 (50) 72* 64* — * Significant deviation from the STZ/excipitation group (p&lt;0.05): dose-dependent administration of Compound 1 (10, 30 and 50 mg/kg) orally 1 hour before the test And significantly inhibited the cold hyperalgesia caused by STZ-diabetes in the cold bath test on day 10. Compound 1 (30 and 50 mg/kg) administered orally 1 hour before the test dose-dependently and significantly inhibited the thermal hyperalgesia induced by STZ-diabetes in the warm plate test on day 10. These data indicate that Compound 1 has potential for neuropathic pain, particularly for diabetic neuropathic pain. Example 8: Pharmaceutical Formulations For clinical use, the compounds of formula I are formulated into pharmaceutical compositions which are important and novel embodiments of the present invention as they comprise the compounds disclosed herein, more specifically the particular compounds. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, pills, lozenges, dragees, throat lozenges, hard or soft capsules, powders, cachets, granules, suppositories, solutions, aqueous or oily suspensions. Liquids, emulsions, detergents, syrups, ointments, gels, pastes, creams, foams, inhalants, sprays, aerosols or dermatological patches and those disclosed herein or by those skilled in the art from this specification And other types apparent in the common sense of the art. The active ingredient, for example, may also be present in the form of an inclusion complex in the cyclodextrin, its ether or its ester. The composition can be administered orally, intravenously, subcutaneously, intratracheally, bronchially, intranasally, pulmonaryly, transdermally, orally, rectally, parenterally or otherwise. The pharmaceutical preparations comprise a mixture of at least one compound of the formula I and a pharmaceutically acceptable excipient, diluent and/or carrier. The total amount of active ingredients is suitably from 0.1% (w/w) to about 10% (w/w) of the formulation, suitably from 〇.5% to 5% (w/w), preference from 丨% to 25 Within the range of %(w/w). 28 200927090 The use of excipients such as liquid or solid, powdered ingredients by conventional means, such as liquid or solid fillers and synergists, solvents, emulsifiers, lubricants, flavoring agents, coloring agents and/or buffering substances which are commonly used in pharmaceuticals. The compounds of the invention are prepared in a suitable form for administration. Commonly used excipients include cerium carbonate 'cerium oxide, lactose, sucrose, 'sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, 1 starch, amylopectin, cellulose and its derivatives. , animal and vegetable oils such as cod liver oil, hollyhock, peanut or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol' and with disintegrants and lubricants such as magnesium stearate, stearic acid , φ stearin, sodium fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets were prepared using the following ingredients: Ingredient_mass (mg/tablet i?) Compound No. 1 10 Microcrystalline cellulose 200 Pyrogenic ceria 10 Stearic acid 10 Total 230 The ingredients were mixed and compressed into a single piece weighing 230 mg Tablets. The active ingredients are premixed with other inactive ingredients, respectively, prior to mixing to form the formulation. The active ingredients may also be mixed with one another prior to mixing with the inactive ingredients to form a formulation. A soft capsule may be prepared using a mixture capsule comprising the active ingredient of the present invention, vegetable oil, fat or other excipient suitable for soft capsules. Hard capsules may contain granules of the active ingredient. The hard capsules may also contain the active ingredient together with solid powdery ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Hard capsules can be prepared using the following ingredients: Ingredients ___mass (mg/abdominal sac) Compound No. 1 10 Dry starch 95 29 200927090 Magnesium stearate _____15 Total 120 The above ingredients are mixed and filled into a hard capsule of quantitative l2〇tng in. The dosage unit for rectal administration may be (1) a suppository form comprising an active substance mixed with a neutral fat base; (u) comprising an active substance and a vegetable oil, a paraffin oil 戋 * other suitable for gelatin rectal capsule formation The rectal capsule form of the gelatin mixture of the agent (iii) in the form of a prepared microenema; or (iv) in the form of a dried microenema formulation for immediate reconstitution in a suitable solvent prior to administration. Suppositories containing 1 mg of active ingredient can be prepared as follows: 匕 匕 - 詈 mg 詈 詈 詈 詈 詈 詈 詈 詈 詈 詈 詈 mg mg mg mg mg mg mg mg mg mg 化合物 化合物 化合物 化合物 化合物 化合物 化合物 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 2,000 The mesh is sieved and suspended in a preservative minimum: hot melted saturated fat-proof glycerin vinegar. The mixture is then poured into a suppository mold of a known capacity and allowed to cool. Liquid preparations can be syrups, elixirs, concentrated drops Or a suspension, i.e., a solution comprising the active quinone component and the remainder comprising, for example, a sugar or sugar alcohol and a mixture of ethanol, water, glycerol, propylene glycol and polypropylene glycol, or a suspension of the liquid. Internal preparation. Ingredient Compound No. 1 __ ig Arlatone GTM 100ml Ethanol 100ml Anise free 800ml The compound was dissolved in Arlatone GTM, ethanol and water, and then slowly diluted with added water. 30 200927090 If needed, this liquid preparation May contain colorants, flavoring agents, preservatives, saccharin and methine cellulose or other thickeners. Liquid preparations can also be in the form of dry powders. The preparation is prepared by reconstitution with a suitable solvent before use. The solution for parenteral administration can be prepared as a solution of the preparation of the present invention in a pharmaceutically acceptable solvent. The solutions may also contain a stable ingredient, a preservative. And/or a buffering ingredient. A solution for parenteral administration can also be prepared as a dry preparation, which is reconstituted with a suitable solvent before use. In an embodiment and without limitation, an active compound containing a preference is provided for A plurality of pharmaceutical compositions for systemic or topical administration. The compounds may be replaced (or added) with other guanidine compounds of the invention or a combination thereof. The concentration of the active ingredients may vary widely within the scope as discussed herein. The content and type of ingredients included are well known in the art.

Maryanoff et al., J. Med. Chem. 1998, 41, 1315 to 1343 〇

Maryanoff et al., J. Med. Chem 1987, 41, 880-887.

Berge, S.M.: "Pharmaceutical salts", J. Pharmaceutical Science, 66, 1-19 (1977).

Byrn et al., Pharmaceutical Research, 12(7), 945-954, 1995.

Martin, E.W. (Editor), "Remington: The Science and Practice of Pharmacy", Mack Publishing Company, 19th Edition, Easton, Pa, Vol 2, Chapter 83, 1447-1462, 1995. Cited patents and patent applications ΕΡ 0 138 441 31

Claims (1)

200927090 VII. Patent application scope: ι_ A compound of formula I, 0 R3 ~~|cH^~0-S-NR1R2 | Ο wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, Aryl and heteroaryl, the alkyl group and the cycloalkyl group are optionally substituted with at least one substituent Y, and the aryl and heteroaryl groups thereof are optionally substituted with at least one substituent Z, or R1 and Forming a 5- or 6-membered ring 'and may additionally comprise 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur' and said 5 or 6-membered ring is optionally substituted by at least one substituent γ R3 is selected from the group consisting of (18,28,53)-6,6-dimethyl-bicyclo[3.1.1]hept-2-yl; (set, 2 han, 511)-6,6-two Indenylbicyclo[3.1.1]heptan-2-yl; (18,211,53)_6,6-dimethyl-bicyclo-[3.U]heptyl-2-yl; (1R,4S)-bicyclic [2.2.1]Hept-2-yl; (lS,4R)-3-methyl-bicyclo[2.2.1]hept-2-yl;bicyclo[2.2.2]oct-5-indole-2- (4S)-bicyclo[2.2.1]hept-5-埽_2-yl; (13,211,48)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2- (1R'2S,4R)-1,7,7·trimethyl-bicyclo[2.2.1]heptan-2-yl; and (set,211,411)_1,7,7-trimethyl Ring [221] hept-2-yl; n is 0 to 3; fluorene is selected from the group consisting of alkyl, alkoxy, thioalkyl, aryl, CO aryl, heteroaryl, amino and carboxyalkyl 2 is selected from the group consisting of alkyl, alkoxy, thioalkyl, halogen, aryl, CO-aryl, CN, heteroaryl and carboxyalkyl; and pharmaceutically acceptable salts, hydrates thereof And solvates. * The compound according to claim 1, wherein R1 and R2 are independently selected from the group consisting of hydrogen and CrQ alkyl, the CVCs alkyl optionally being one selected from the group consisting of 32 200927090 Y substitution: CrC8 alkyl, crC8 alkoxy, CrCs thiopyranyl, C6-C12 aryl, CO-CVCi2 aryl, C6-C12 heteroaryl, gas group and carboxy-CVCV alkyl. The compound according to any one of claims 1 to 2, wherein both R1 and R2 are hydrogen. The compound according to any one of claims 1 to 3, wherein η is 1 or 2 and the preference η is 1. The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of: [(18,28,58)-6,6-dimethylbicyclo [3.1.1]Hept-2-yl]methylsulfamic acid, [(lR, 2R, 5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]nonylaminosulfonate Acid, [(lS, 2S, 5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl], ethylsulfamic acid, [(18, 2 ft, 58)-6, 6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl*-sulfamic acid, (1R,4S)-bicyclo-[2.2.1]hept-2-yl-methylaminosulfonate Acid, and (4S)-bicyclo[2.2.1]hept-5-indol-2-ylmethylsulfamic acid, preference [(lS,2S,5S)-6,6-dimethylbicyclo[3.1 .1]hept-2-yl]methylsulfamic acid. 6. A pharmaceutical agent comprising a compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt, hydrate or solvate thereof. A pharmaceutical composition comprising A) a pharmacologically effective amount of a compound of the formula I according to any one of claims 1 to 5, or a pharmacologically acceptable salt or hydrate thereof Or a solvate as an active ingredient; and B) optionally, at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable excipient. 8. The composition of claim 7, wherein the composition is in the form of a tablet, a pill, a lozenge, a dragee, a throat lozenge, a hard or soft capsule, a powder, a 33 200927090 capsule, a granule , suppositories, miscellaneous, aqueous or effluent, shaft, syrup, soft palate, gel, paste, emulsion, foam, inhalant, aerosol or dermal patch ❹ 9. According to paragraph 7 of the patent scope The composition, the secret treatment of obesity, type-type + type 2 diabetes, new generation syndrome, sputum syndrome, diabetes mellitus, pathological changes, diabetic retinopathy, diabetic kidney money, diabetic microangiopathy, diabetic macroangiopathy, Teng Island tumor, familial high insulin hypoglycemia, male male first, detrusor function, high blood pressure, especially for arterial hypertension, = lipoprotein abnormality, special serum with low HDL_cholesterol Protein abnormalities of hypertriglyceridemia, hyperuricemia, asthma, glucose metabolism, especially insulin resistance, hyperglycemia and / or glucose intolerance 'neuroprotection, Parkinson's disease, A Hyperthermia, analgesia, angina pectoris, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain, including neuropathic pain and chronic pain, impotence, optometry, bipolar disorder, Migraine 'alcohol dependence, cancer and cardiovascular disease, including special heart protection, heart itching, coronary heart disease, cerebrovascular disease and peripheral arterial occlusive disease and its complications and / or secondary diseases or symptoms. 10. A process for the preparation of a compound of the formula I according to any one of claims 1 to 5, characterized in that the compound of the formula 〇Hal+NR1R2 丨_0, wherein Hal represents halogen, It is selected from chlorine and bromine, prefers chlorine, and reacts with an alcohol of the formula RR3—(cH^V〇h HI provides a compound of the formula I. U. The method according to claim 10 of the patent application' wherein R1 and R2 All of them are hydrogen, 34 200927090 and Hal is chlorine. 12. The method according to any one of the above claims, wherein the compound is selected from the group consisting of: [(1, 5__2) Thiol-based bicyclo[31'-g- 2-----methanol; [(10) ice called dimethyl bicyclo is called Parkengchun A 2; 1 (15, 58) Miao dimethyl bicyclo [3丄1] heptyl ]ethanol; L2 ?·6'6·dimethyldiene. U]hept-2-yl]methanol; (1R,4S)_bicyclo[2m2_yl-methanol and bicyclo[221]heptan (4) _6,6nmi spectroscopy (4). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Preparation of a medicament for treatment and/or Or obesity, type-type diabetes, type 2 diabetes, metabolic syndrome, X syndrome, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, island tumor Sexual high islet pure blood glucose, detrusor function several times blood pressure 'especially for arterial hypertension, serum lipoprotein abnormalities, especially with the presence or absence of low HDL_cholesterol serum lipoprotein abnormal high triglyceride Hypertension, hyperuricemia, asthma, glucose metabolism, especially insulin resistance, hyperglycemia and/or glucose intolerance, neuroprotection, Parkinson's disease, Alzheimer's disease, analgesia, angina, arrhythmia, Coronary artery lean, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegenerative, pain, including neuropathic pain and chronic pain, impotence, glaucoma, noisy, migraine, alcohol dependence, cancer and cardiovascular disease, It includes special heart protection, heart itching, coronary heart disease, cerebrovascular disease and peripheral arterial occlusive disease. a complication of the compound or a physiologically acceptable salt, hydrate or solvate thereof, according to any one of the above claims. For the treatment of obesity, 35th 200927090 ❹ 15. ❹ i diabetes 1 bribery, metabolic syndrome, X syndrome, diabetes = nerve (four), diabetic dependent lesions, diabetic nephropathy, diabetes micro = lesions, diabetic macroangiopathy, Tengdao tumor, familial high insulin and low blood, knee male male genital area, detrusor machine (four), high blood pressure, especially for arterial traits, u-protein abnormalities, especially with or without low ribs The blood π-fat egg from abnormal high triglyceride, hyperuricemia, asthma, glucose metabolism, especially 姨 素 resistance, hyperglycemia and / or glucose intolerance, = protection, Parkinson's disease , Alzheimer's disease, pain relief, angina pectoris, arrhythmia ¥, coronary stenosis, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegenerative, pain _, including neuropathic pain and chronic pain, yang Itching, glaucoma, transposition, migraine, transfer dependence, cancer and vascular disease, including special heart protection, cardiac paralysis, coronary heart disease, cerebrovascular disease and peripheral arterial occlusive disease and its complications and / or secondary Disease or symptom. 'Oral therapy or prevention of obesity in mammals or humans, type 1 diabetes, type 1 diabetes, metabolic syndrome, sputum syndrome, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetes Vascular lesions, islet tumors, familial hyperinsulinemia, male male alopecia, detrusor hyperactivity, hypertension, especially arterial hypertension, abnormal serum lipoprotein, especially with or without mHDL_cholesterol High serum triglyceride, hyperuricemia, asthma, glucose metabolism, especially insulin resistance, hyperglycemia and/or glucose intolerance, neuroprotection, Parkinson's disease, Alzheimer's disease , analgesia, angina pectoris, arrhythmia, coronary artery spasm, terminal jk tube disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain, including neuropathic pain and chronic pain, impotence, glaucoma, bipolar disorder, migraine, alcohol dependence , cancer and cardiovascular disease, including special heart protection, heart palsy, crown A method of heart disease, cerebrovascular disease, and peripheral arterial occlusive disease, and concurrent complications and/or secondary disease or condition, comprising treating a therapeutically effective amount according to any one of claims 1 to 5 of the patent application scope The compound of formula r is administered to a subject in need thereof, optionally together with pharmaceutically acceptable excipients and/or carriers. 16. Use of the sputum according to any one of the application patents to the fifth to fifth 200927090 Compound or physiologically acceptable salt, hydrate and solvate thereof (4) for treating and/or preventing mammals, prefer human obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, X syndrome, diabetes Neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, islet tumor, familial hyperinsulinemia, male male alopecia, detrusor function redundancy, hypertension, especially high arterial Abnormal blood pressure and serum lipoprotein, especially high triglycerideemia, hyperuricemia, asthma, glucose metabolism, especially insulin resistance, hyperglycemia, and the presence or absence of low HDL-cholesterol serum lipoprotein abnormalities / or glucose intolerance, neuroprotection, Parkinson's disease, Alzheimer's disease, pain relief, heart, colic, arrhythmia, coronary stenosis, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, Pain, including neuropathic pain and chronic pain, impotence, glaucoma, bipolar disorder, migraine = Fine dependence, cancer and vascular diseases ^ '^ care of their dirty bag (iv) protection, the heart itch, coronary heart disease, cerebrovascular disease and peripheral arterial occlusive disease and its symptoms and / or secondary diseases or symptoms. A 37 200927090 IV. Designation of the representative representative: (1) The representative representative of the case is: (). (2) A brief description of the symbol of the representative figure: There is no drawing in this case. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: