UA74879C2 - Condesated bicyclic or tricyclic amino acids - Google Patents

Abstract

The compounds of the instant invention are bicyclic or tricyclic amino acids useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, arthritis, neuropatho-logical disorders, sleep disorders, visceral pain disorders, and gastrointestinal disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included.

Description

Description of the invention

The present invention relates to new cyclic amine derivatives suitable as pharmaceutical agents, a method for their preparation, pharmaceutical compositions containing them, and their use for the treatment of the conditions described below. The invention also relates to bicyclic and tricyclic ketones, which are suitable as intermediate compounds for the preparation of the above-mentioned compounds.

Gabapentin (Neurontin(K)) is an anticonvulsant agent used to treat epilepsy and which has recently been shown to be useful in the treatment of neurogenic pain. It is 70 1-(aminomethyl)cyclohexylacetic acid of the structural formula:

MN, co

Gabapentin is one of a number of compounds of the formula с нам-сСнНА-сС-сн.-сСООВК 7 7 У 2 | o (o) in which B is hydrogen or lower alkyl and n is 4, 5 or 6. such compounds are described in patent 0.5. uh-

Mo4,024,175 and patent 0.5. Mo4,087,544) on the basis of a separate application. They are used to protect against seizures caused by thiosemicarbazide; to protect against seizures caused by Cardiazol; cerebral so diseases, epilepsy, fainting attacks, hypokinesia and craniocerebral injuries; and improvement of mental activity. The compounds are suitable for the treatment of elderly patients. The disclosures of the above two patents are incorporated herein by reference. in.

International Application Publication No. MUO 99/21824), the content of which is also incorporated herein by reference, discloses other cyclic amino acids that are useful in the treatment of epilepsy, brain injury, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, "gastrointestinal disorders such as irritable bowel syndrome (IB5): and inflammation, especially arthritis.

The described compounds include compounds of the formula: c) and nm so

And" 2

And: In! 7 2 sh K VE their ne EZ (ee) 20 a so and their salts, in which: K means hydrogen or lower alkyl; and c' to Bz each independently selected from hydrogen, linear or branched alkyl having from 1 to 6 carbon atoms, phenyl, benzyl, fluorine, chlorine, bromine, dihydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -СОоН, - СО»В 5, -СНСОЗН, -СНСО»В 5, "ОВ, where В? means linear or branched alkyl having from 1 to 6 carbon atoms, phenyl or benzyl, radicals (F) from B! to EZ at the same time do not mean hydrogen. ka IInternational patent publication MoU/O01289781, which corresponds to (patent application OB Mob0/160725), describes a number of new bicyclic amino acids, their pharmaceutically acceptable salts and their prodrugs of the formula: 60 b5

НОМ Ссо.Нн 2 2 Н.М СсоО.Н НхМ

Nam o son 2 h0b0N in ch og (СНО) 70 (СН (СНО)п 2 (СНо)п

І ц Ш І in which n is an integer from 1 to 4, in which there are stereocenters, each center can be independently K or 5, the preferred compounds are compounds of the formulas I-M above, in which n is an integer from 2 to 4. The described compounds are suitable for the treatment of many diseases, including epilepsy, fainting fits, hypokinesia, craniocerebral diseases, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders and sleep disorders. Certain compounds described in this patent have high activity as measured in radioligand binding assays using | Nigabapentin and A»5 subunit derived from pig brain tissue |bee M.5., Vgom/p U. R., OivvapauaKke M. OO. KO. OPoga 9., Tpygiom K., MMosadgii H.M.,

U. Visi. Specialist, 1996; 271: 5879-5776). The results for some compounds are shown in the following table:

Table p

TABLE 1 (8)

Compound Structure 020 binding affinity t (22) (o, Za, Bo)(3-Aminomethyl-: 20 | on m bicyclo|3.2.0)hept-3-yl)-. and M 0.038 s acetic acid "

Goi y(te,5VCHZ-aminomethyl-Ox OH - bicycloi3.2.0)hept-Zyl)- MH, acetic acid, «: shi c z (10,Za,5a)(3-Aminomethyl-no Mn. bicycloi3.2. O)hept-Z-yl)- t 0.332 75 | acetic acid -I sh" (oo) (Patent application MoER 01400214.1| describes the use of compounds of formulas I-IM, given above, for - 50 prevention and treatment of visceral pain and gastrointestinal diseases.

Certain analogues of the above-mentioned compounds, derived, for example, from 1-aminomethyl)cyclopentanoacetic acid, (Che) which are obtained by condensation of a 3- or 4-membered ring with a cyclopentane ring and which are substituted by one or more substituents, show similar high activity. Also, amino acids based on bicyclo|3.2.F)heptane, bicyclo|4.2.0)octane and bicyclo|5.2.O|nonane, in which amino and carboxyl residues are attached to one of the atoms of a four-membered ring, show high activity.

The present invention relates to bicyclic amino acid analogs and derivatives thereof, prodrugs, and pharmaceutically i) acceptable salts and solvates suitable for the treatment of many disorders, including epilepsy, syncope, hypokinesia, craniocerebral disorders, neurodegenerative disorders, depression, anxiety, panic, pain, sleep disorders, osteoarthritis, rheumatoid arthritis and neuropathological disorders. The compounds of the invention may also be suitable for the treatment of visceral pain, functional disorders of the large intestine, such as gastroesophageal reflux, dyspepsia, irritable bowel syndrome and functional abdominal pain syndrome, and inflammatory diseases of the large intestine, such as Crohn's disease, ileitis and ulcerative colitis, and other types of visceral pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis. They may also be suitable for treating premenstrual syndrome. 65 They are compounds of any of the general formulas below:

by me, I CAN, by me, but by me,

Kk me 2 I with x tag. son of MRS SHEE

Yany ki da ki Kk2 (y (v au (M) yiv nor; Mn, NOH NM, NOYU vn, no pe iz, tag, "i y di vi vi Vi 2 v2 k2 2 (M) (M) (m) MID s i E og U si yo; sha n; (22) zo ah) so ikh" (khy) sh

NOYU MN, p

Нн M nos chn, pod Mn, no, r o; | n. |: Z -I NO ey y chan chens T Ky nos sh shk what miy so hmm hih xx xx - 50 eeyutuye no 7 no F

Gee! che, te ih) ХХХ ХМ ХК ХК 60 where are B and VC? each independently selected from H, linear or branched alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl and benzyl, provided that, except in the case of a cyclooctane compound of formula (XM4), B! and B? at the same time do not mean hydrogen.

Suitable compounds (including their salts, solvates and prodrugs) are: ((1kK,55)-3-Aminomethyl-1,5-dimethylbicyclo|3.2.F|hept-3-yl)ioacetic acid; bo ((15,5K)-3-Aminomethyl-1,5-dimethylbicyclo/3.2.F|hept-3-yl)ioacetic acid;

((1kK,55)-3-Aminomethyl-6b,b6-dimethylbicyclo!|3.1.0|hex-3-yl)acetic acid; ((15,5K)-3-Aminomethyl-6b,6-dimethylbicyclo!/3.1.0|hex-3-yl)acetic acid; ((15,25,5K)-2-Aminomethyl-6b,6-dimethylbicyclo!|3.1.0|hex-2-yl)acetic acid; (1kK,25,55)-2-Aminomethyl-6b,6-dimethylbicyclo!/3.1.0|hex-2-yl)acetic acid; (15,2k,5K)-2-Aminomethyl-6,b-dimethylbicycloyl|3.1.0|hex-2-yl)acetic acid; (1k,2kK,55)-2-Aminomethyl-b,b-dimethylbicycloi|3.1.0|hex-2-yl)acetic acid; ((1kK,5K,65)-6-Aminomethylbicyclo!/3.2.0|hept-b-yl)acetic acid; ((15,55,65)-6-Aminomethylbicyclo!|3.2.0)hept-b-yl)acetic acid; 70 ((1kK,5K,6K)-6-Aminomethylbicycloi|3.2.0Hept-b-yl)acetic acid; ((15,55,6K)-6-Aminomethylbicyclo!|3.2.O|hept-b-yl)acetic acid; cis-(15,2K,45,5K)-3-Aminomethyl-2,4-dimethylbicyclo!/3.2.0|hept-3-yl)acetic acid; trans-(15,2K,45,5K)-3-Aminomethyl-2,4-dimethylbicyclo!/3.2.0|hept-3-yl)acetic acid; (15,5k,65,7K)-3-Aminomethyl-6b,7-dimethylbicycloyl|3.2.0)hept-3-yl)acetic acid; (15,5k,6K,75)-3-Aminomethyl-6b,7-dimethylbicycloyl|3.2.0)hept-3-yl)acetic acid; (1K,25,55)-7-Aminomethyl-3,3-dimethyltricycloyl3.3.0.F|oct-7-yl)acetic acid; ((1k,6K,75)-7-Aminomethylbicyclo|4.2.F)oct-7-yl)acetic acid; ((15,65,75)-7-Aminomethylbicyclo|4.2.F)oct-7-yl)acetic acid; (1k,6K,7Kk)-7-Aminomethylbicycloi|4.2.F|oct-7-yl)acetic acid; ((15,65,7K)-7-Aminomethyloxychloi|4.2.F|oct-7-yl)acetic acid; (1kK,7k,85)-8-Aminomethylbicyclo!|5.2.F|non-8-yl)/ acetic acid; 7 ((15,75,85)-8-Aminomethylbicyclo!/|5.2.O|non-8-yl)acetic acid; (1k,7kK,8Kk)-8-Aminomethylbicyclo!|5.2.0|non-8-yl)acetic acid; and ((15,75,8K)-8-Aminomethylbicyclo|5.2.O|non-8-yl)acetic acid. high school

Preferred compounds (including their salts, solvates and prodrugs) are:

I(1K,5K,65)-6--"Aminomethyl)bicyclo!|3.2.0Hept-6b-yl|acetic acid; i)

I15,55,6K)-6-(Aminomethyl)bicyclo!|3.2.O|hept-b-yl|acetic acid;

I(1k5,5Kk5,6K5)-6-(Aminomethyl)bicyclo!|3.2.0)hept-6-yl acetic acid;

I1k5,bk5,75K)-7-"Aminomethyl)bicyclo|4.2.0|oct-7-yl|acetic acid; and He!zo I1k5,bKk5,7k5)-7--"Aminomethyl)bicyclo|4.2.0 |oct-7-yl|acetic acid.

A particularly preferred compound (including salts, solvates and prodrugs) is

I(1K,5K,65)-6--"Aminomethyl)bicyclo!/3.2.0Hept-6b-yl|acetic acid.

These compounds can exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, which may contain isotopic substituents (eg, 020, db-acetone, 46-UOM50O), are equivalent to unsolvated forms and are also within the scope of the present invention.

Certain compounds of the present invention have one or more choral centers, and each center can exist in

K(B) or 5(I) configuration. The present invention encompasses all enantiomeric and epimeric forms, as well as suitable mixtures thereof. Separation of diastereoisomers or cis- and trans-isomers can be carried out according to standard techniques, for example, by fractional crystallization, chromatography or HPLC of a stereoisomeric mixture from a compound of the present invention or a suitable salt or derivative thereof, the individual enantiomer of the compound of the invention can also be obtained from the corresponding of an optically pure intermediate or by separation, such as HPLC, ;" of the appropriate racemic mixture using a suitable chiral filler or fractional crystallization of diastereoisomeric salts formed by the interaction of the appropriate racemic mixture with a suitable optically active acid or base, if necessary. -I The present invention also includes all suitable isotopic species of a compound of the invention or a pharmaceutically acceptable salt thereof, isotopic species of a compound of the invention or a pharmaceutically acceptable salt thereof are defined as a pi compound or a salt thereof in which at least one atom is replaced by an atom having the same atomic room, but

Go! an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be included in the compounds of the invention and their pharmaceutically acceptable salts are isotopes of hydrogen, carbon, nitrogen, oxygen,

Phosphorus, sulfur, fluorine and chlorine, such as 2Н, ЗН, 19С, ис, 15М, 170, 180, 31р, 32р, 355, 18Е and З6СИ|, respectively. (Che) Certain isotopic varieties of the compounds of the invention and their pharmaceutically acceptable salts, for example, those in which radioactive isotopes such as ZN or 7C are incorporated, are suitable as drugs and/or for studying substrate distribution in tissues. Particular preference is given to isotopes of tritium, i.e., H, and carbon-14, i.e., 14C, due to their ease of obtaining and ability to detect. In addition, substitution with isotopes,

HF) such as deuterium, i.e., H, may have certain therapeutic advantages due to their greater metabolic stability, such as increased half-life or use at reduced doses, and thus may be preferable in some cases. Isotopic varieties of the compounds of the invention and their pharmaceutically acceptable salts of the present invention in general can be obtained by conventional techniques, such as, 60 explanatory techniques or preparation described in the Examples and Preparative Examples below using suitable isotopic varieties of the corresponding reagents.

Since amino acids are amphoteric, pharmacologically compatible salts may be salts of suitable non-toxic inorganic or organic acids or bases. Suitable acid addition salts are hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, sulfate, bisulfate, nitrate, bo phosphate, hydrophosphate, acetate, fumarate, aspartate, besylate, bicarbonate/carbonate, camsylate, U and I-lactate, OO and I-tartrate, edsylate, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucoronate, 2-napsylate, tosylate, gibenzate, nicotinate, isothianate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate salt Suitable base salts are obtained from bases that form non-toxic salts, examples being sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine, meglymine, and diethylamine. Salts with quaternary ammonium ions, for example, with tetramethylammonium ion, can also be obtained. The compounds of the invention can be obtained in the form of a zwitterion.

A suitable salt of the compounds of this invention is the hydrochloride salt. For information on suitable salts (|see 70 Wegode et al., U. R/Layap. Zsi., 66,1-19,1977|.

Also, the scope of the compounds of this invention includes all their polymorphic forms.

The scope of this invention also includes prodrug forms of the above-mentioned compounds. The effectiveness of an orally administered drug depends on the efficiency of the drug's passage through the mucous epithelium and its stability during the passage of the gastrointestinal tract. Drugs that are 7/5 effective after parenteral administration but are less effective when administered orally, or whose plasma half-life is considered too short, can be chemically modified into a prodrug form. Prodrugs are drugs that can be chemically modified and that can be biologically inactive at their site of action, but that can be degraded or modified by one or more enzymes or other processes to form the parent bisactive form. Such chemically modified drugs or prodrugs should have different pharmacokinetic parameters compared to the original substance, the possibility of easier absorption through the mucous epithelium, better salt formation and/or solubility, improved systemic stability (for example, to increase half-life in plasma). Such chemical modifications can be (1) Ester or amide derivatives that can be cleaved by, for example, esterases or lipases. For ester derivatives, esters are obtained from a fragment of a carboxylic acid, molecules of a medicinal substance by known methods. For amide derivatives, the amide can be obtained from the carboxylic acid fragment or the amine fragment of the drug molecule by known methods. i) (2) Peptides that can be recognized by specific or non-specific proteinases. The peptide can be combined with a drug substance molecule by forming an amide bond with an amine or carboxylic acid fragment of the drug substance molecule by known methods. Gee! (3) Derivatives that accumulate at the site of their action due to the process of membrane selectivity of the prodrug form or modified prodrug form. - (4) Any combination from 1 to 3. co

It will be clear to a specialist in this field in the future that certain fragments known to specialists as "pro-fragments", for example, such as are described in "Oevidp oyi Rgodgydv" ("Development of prodrugs") by N. Vypadaag "(E)zemieg) 1985 , can be placed on the corresponding functional groups, if such functional groups are present in the compounds of the invention, also forming "prodrugs". In addition, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are included in the scope of the invention.

Studies have shown that the oral absorption of certain prodrugs can be increased by receiving a "soft" quaternary salt. A quaternary salt is called a "soft" quaternary salt because, unlike "ordinary quaternary salts, for example, B-M'(CH3z)z, it can release the active medicinal substance during hydrolysis. "Soft" quaternary salts have useful physical properties compared to the main medicinal substances or their salts. Compared to other salts, such as hydrochloride salts, the solubility in water may be increased, but more importantly, the absorption of the medicinal substance from the intestine may be increased.

Absorption increases probably due to the fact that "soft" quaternary salt has the properties of a surface-active substance and is able to form micelles and non-ionized ion pairs with bile acids and the like, which are able to penetrate the intestinal epithelium more effectively. After absorption, prodrugs are quickly hydrolyzed with the release of the active medicinal substance. e Aminoacyl-glycol and -lactate esters are known as prodrugs of amino acids |MMegptshii S.G., Spetivigu apa (ee) Ipdivigu (Chemistry and Industry), 1980: 433-435). The carbonyl group of amino acids can be esterified by known methods. Prodrugs and soft drugs are known in the art (Raiyutipo E., Ogydvoi Shche Eshige (Medicines 7 of the future), 1990; 15(4): 361-368). The two latter works are incorporated herein by reference. (Che) The invention also relates to the therapeutic use of these compounds as agents for the treatment or relief of symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, the disease

Alzheimer's, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. The present invention also encompasses the treatment of neurodegenerative disorders known as acute brain injury. Such damages include, but are not limited to: stroke, head injury and asphyxiation, stroke applies

F, cerebrovascular disease and may also be referred to as cerebrovascular injury (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also included are transient cerebral ischemic attacks and other cerebrovascular problems associated with ischemia. These vascular disorders may occur in patients who have undergone carotid endarterectomy or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography, etc. Other cases include head trauma, spinal cord injury, or damage from general hypoxia. , hypoglycemia, hypotension, as well as similar injuries observed in the process of embolism, hyperfusion, and hypoxia. The invention would be useful in a number of cases, for example, 65 in the process of cardiac bypass, in cases of intracranial hemorrhage, with perinatal asphyxia, with cardiac arrest and epileptic state.

One skilled in the art will be able to determine the appropriate situation in which subjects are at risk, for example, of stroke, for treatment with the methods of the present invention.

The compositions of the invention are also useful for the treatment of acute and chronic pain. Acute pain is usually short-lived and associated with hyperfunction of the sympathetic nervous system. Examples are post-operative pain such as after tooth extraction, migraine, headache, trigeminal neuralgia and allodynia. Chronic pain is usually defined as pain that lasts from 3 to 6 months and includes somatogenic and psychogenic pain. Examples of chronic pain include pain associated with musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, seronegative (non-rheumatoid) arthropathies, 70 non-articular rheumatism and periarticular disorders, and pain associated with cancer , peripheral neuropathy and post-herpetic neuralgia, another pain is noniceptive pain. Also, other pain caused by damage or infection of peripheral sensory nerves. It includes but is not limited to pain from peripheral nerve injury, herpes infection, diabetes, causalgia, plexus avulsion, neuroma, amputation, and vasculitis. Neuropathic pain is also caused by damage to the /5 nerve as a result of chronic alcoholism, hypertension, hypothyroidism, uremia, or hypovitaminosis. Neuropathic pain includes, but is not limited to, pain caused by nerve damage, such as diabetic pain.

Psychogenic pain is pain caused by non-organic sources, such as low back pain, atypical facial pain and chronic headache, other types of pain: inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legs syndrome, acute herpetic pain and postherpetic neuralgia, causalgia, brachial plexus avulsion, occipital neuralgia, gout, phantom limb pain, burn pain and other forms of neuralgia, neuropathic and idiopathic pain syndrome.

The compositions of the invention are expected to be useful in depression. Depression can be the result of an organic disease, secondary to loss of personality, or idiopathic first, there is a strong tendency for familial manifestations of some forms of depression, which points to a mechanistic cause for at least some forms of depression. The diagnosis of depression is based primarily on the quantitative change in the mood of patients. These mood assessments are generally performed by a physician or neurophysiologist using an approved rating scale, such as i) the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Numerous other scales have been developed to quantify and measure mood changes in depressed patients, such as insomnia, attention deficits, hypoergy, feelings of worthlessness, and guilt. Standards for the diagnosis of Ge! of depression, as well as all psychiatric diagnoses, collected in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), referred to as the OZM-IM-K Handbook, published by the American Psychiatric Association, - 1994.

The compounds of the invention are expected to be useful in the treatment of visceral pain and gastrointestinal disorders. Viscera covers the organs of the abdominal cavity. These organs include the genitals, the spleen, and part of the digestive system. Pain related to the viscera can be divided into gastrointestinal (digestive) pain and non-digestive visceral pain. They usually occur with gastrointestinal disorders, including functional bowel disorders and inflammatory bowel disease. These gastrointestinal disorders include a wide range of conditions that are currently only moderately controlled, including functional bowel disorders: gastro-oesophageal reflux, dyspepsia, irritable bowel syndrome « | functional abdominal pain syndrome, and inflammatory bowel diseases: Crohn's disease, ileitis, and plv) with nonspecific ulcerative colitis, all of which regularly cause visceral pain. It was recently shown that . with these pathologies, in particular, irritable bowel syndrome and dyspepsia, the threshold of visceral pain and? decreased, indicating visceral hypersensitivity. other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis.

Some drugs are known to act selectively on gastrointestinal disorders associated with hypersensitivity -I (IRapyipo M. U. (1998) Medicines 56: 11-21). Available pain management falls into two main categories: (1) nonsteroidal anti-inflammatory drugs used to treat moderate pain, but whose therapeutic use is limited by gastrointestinal side effects (gastric erosion, peptic ulceration, inflammation

Go! duodenum and colon); (2) morphine and opioids used to treat moderate to severe pain, but their therapeutic use is limited by undesirable side effects, including constipation, respiratory depression, tolerance, and potential for abuse.

Ge) The compositions of the invention are expected to be useful in the treatment of anxiety and panic as shown by standard pharmacological procedures.

Thus, according to a further aspect of the present invention, the use of a compound selected from formulas (I) - (XXU) as a medicament is described.

A still further aspect relates to the use of a compound selected from formula (I) - (XXM) in the manufacture of (F) a medicament for the treatment of a disease selected from epilepsy, syncope, hypokinesia, craniocerebral disorders, neurodegenerative disorders, depression, anxiety , panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain due to functional bowel disorders, inflammatory bowel disease, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.

In an alternative aspect, a method of treating diseases selected from epilepsy, syncope, hypokinesia, craniocerebral disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, 65 neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel disease, pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis, comprising administering a therapeutically effective amount of a compound selected from formula (1I)-(-(XXM) to a mammal, who needs said treatment.

The biological activity of the compounds of the invention can be measured by a radioligand binding study using I'NI gabapentin and A»5 subunits isolated from the brain tissue of a pig |(bee M. 5., Vhom/n 4). R.,

Oivzapauake M. SHO. K., Opoga 9, Tpiyom/ K., MMosagy G. M. AOMAMSEOMAMSE 3. Vioi. Specialist, 1996; 271: 5879-5776). Results can be expressed in µM values. or nM A»b binding affinity.

The compounds of this invention may be administered in combination or alone, simultaneously or sequentially, with one or more other pharmacologically active agents. Acceptable agents, especially for pain management, 70 include: () Opioid analgesics: morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine; (i) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, 75 fenbufen, fenoprofen, flufenizal, flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozine, phenylbutazone , piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts; (ii) Barbiturates such as amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metabarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiopental and their pharmaceutically acceptable salts; (m) Benzodiazepines with a sedative effect, such as chlordiazepoxide, chlorazepam, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts, (y) Well antagonists with a sedative effect, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts; He (mi) Various sedatives such as glutethimide, 2-methyl-2-propyl-1,3-propanediol-dicarbamate, methaqualone, (5) dichloralphenazone and their pharmaceutically acceptable salts; (my) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadine and their pharmaceutically acceptable salts, (my) MMOA receptor antagonists, for example dextromethorphan ((i)-33-hydroxy-M-methylmorphinan) and its F) 3 metabolite dextrorphan ((i) /-33-hydroxy-M-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone | and m cis-4-phosphonomethyl)-2-piperidinecarboxylic acid and their pharmaceutically acceptable salts; (their) Alpha-adrenergic active compounds such as doxazosin, tamsulosin, clonidine (« and (ee) 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2 -yl)-5-(2-pyridyl)quinazoline; « (C Tricyclic antidepressants such as desipramine, imipramine, amitriptyline and nortriptyline; (xi) Anticonvulsants such as carbamazepine, gabapentin, pregabalin and valproate; - (xii) inhibitors serotonin reuptake inhibitors, such as rluoxetine, paroxetine, citalopram, and sertraline; (chii) Mixed norepinephrine-serotonin reuptake inhibitors, such as milnacipran, venlafaxine, and duloxetine; (chem) norepinephrine reuptake inhibitors, such as reboxetine; (hm) Antagonists tachykinin, especially MK-3, MKk-2 and MK-1, such as antagonists - c (AK,9K)-7-IZ,5-bis(trifluoromethyl)benzyl-8,9,10,11-tetrahydro-9- methyl-5-(4-methylphenyl)-7H-(1,41-diazo-ycin-(2,1-9) 1, 7|naphthyridine-6-13-dione (TAK-637), ,» 5-I (2K,35)-2-K1K)-1-3,5-bis(trifluoromethyl)phenyl|ethoxy-3-(4-fluorophenyl)-4-morpholinyl|methyl/i-1,2- dihydro-ZH-1, 2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3-(2-methoxy-5-trifluoromethoxy)phenyl|methylamino|-2-phenyl-piperidine (25, 35); -and (hui) Muscarinic antagonists, such as oxybutine, toterodine, propiverine, tropesium chloride, and darifenacin; (chemicals) phosphodiesterase inhibitors, such as sildenafil, vardenafil and Cialis (Trademark); (chemicals) COX-2 inhibitors such as celecoxib, rofecoxib and valdecoxib; (ee) (xix) Non-selective COX inhibitors (mainly gastrointestinal protectors), such as nitroflubiprofen (HnStT-1026); -1 50 (0) Analgesics, in particular paracetamol; (xxi) Neuroleptics such as droperidol; iChe) (xhii) Agonists of MAPIPPoia-receptors, such as resinferatoxin; (xxii) Beta-adrenergic compounds such as propranolol; (xchem) Local anesthetics, such as mexiletine; (xhu) Corticosteroids such as dexamethasone; o (xhui) Agonists and antagonists of serotonin receptors; (khmii) Cholinergic (nicotinic) analgesics; and where (khmii) Various agents, such as, Tramadol "U;

The combination of compounds of this invention and other therapeutic agents may be administered separately, sequentially, or simultaneously. Thus, the present invention extends to a kit containing a compound of formulas (I) - (XXM), one or more other therapeutic agents, such as those mentioned above, and a suitable container.

The compositions of the invention may be administered alone, but will generally be administered in admixture with an acceptable pharmaceutical excipient, diluent, or carrier selected in accordance with the route of administration and standards of pharmaceutical practice. If necessary, other auxiliary agents can be added. Auxiliary agents are preservatives, antioxidants, flavorings or dyes. The compounds of the invention can be formulated in the form of rapid, delayed, modified, sustained, pulse or controlled release compositions.

Compositions of the invention can be prescribed, for example, but not limited to the following ways: orally, buccally or sublingually in the form of tablets, capsules, multi- and nano-particles, gels, films (including mucoadhesive), powders, ovules, elixirs, pills, chewable forms, solutions, suspensions and aerosols.

The compounds of the invention may also be administered as osmotic forms or as high energy dispersions or as coated particles or as rapidly dissolving, rapidly disintegrating forms as described

Shpapo and Spep in Avzpieu Rybiisayop, 2001. The compounds of the invention can be prescribed as crystalline or amorphous products dried by lyophilization or spray. Acceptable formulations of the compounds of the invention may be in a hydrophilic or hydrophobic matrix, in a complex of ion exchange resins, in a shell or unshelled form, and 7/0 other types as described (US 6,106,864). as desired Such pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (predominantly corn, potato or tapioca), mannitol, disintegrants such as, sodium starch glycolate, croscarmellose sodium, and certain silicate complexes and granulate binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, triglycerides, hydroxypropylcellulose, sucrose bentonite, sorbitol, gelatin, and copper. Additionally, lubricating agents may be added to solid formulations such as magnesium stearate, stearic acid, glyceryl behenate, polyethylene glycol and talc or wetting agents such as sodium lauryl sulfate Additionally, polymers such as carbohydrates, phospholipids and proteins may be included.

Dosage forms that quickly disperse or dissolve may contain the following components: 2o aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavoring, polyethylene glycol, aerosil, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol or xylitol. The term dispersion or dissolution, as used herein in reference to rapidly dispersible or soluble dosage forms, depends on the solubility of the substance used, i.e. when the substance is insoluble, a rapidly dispersible dosage form may be prepared and when the substance is soluble, a fast-dissolving form. and)

A solid dosage form, such as a tablet, is produced by a standard process such as direct compression or wet, dry granulation, melt granulation, melt cooling, and extrusion. The core of the tablet, which may be mono or multilayer, may be coated with appropriate coatings known in the art.

Solid compositions of this type can also be used as fillers in capsules, such as - gelatin, starch or hydroxypropylmethylcellulose capsules. Preferred excipients in this regard include lactose, starch, cellulose or 5 high molecular weight polyethylene glycols. Liquid compositions can be used as fillers for soft or hard capsules, such as gelatin capsules. For water and -

From oil suspensions, solutions, syrups or elixirs, the compounds of the invention can be combined with various sweeteners or flavors, dyes, emulsifiers or suspenders and solvents, such as water, ethanol, propylene glycol, methyl cellulose, alginic acid or sodium alginate, glycerin, oils, hydrocolloid agents and their combinations. In addition, compositions containing these compounds and excipients can be presented as a dry product for mixing with water or other acceptable carriers before use. Liquid forms of preparations include solutions, suspensions, and emulsions, for example, aqueous or aqueous solutions of propylene glycol. For parenteral injections, liquid preparations can be formed in an aqueous solution; polyethylene glycol. Aqueous solutions acceptable for oral use may be prepared by dissolving the active ingredient in water and adding acceptable colors, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic resins, gums, methylcellulose, sodium carboxymethylcellulose and other known dispersants.

Go! The compositions of the invention can also be administered by injection, that is, intravenously, intramuscularly, 5r Intradermally, intraduodenally or intraperitoneally, intraarterially, intrathecally,

Sh- intraventricular, intraurethral, intrasternal, intracranial, intraspinal or subcutaneous, or they

Ge) can be prescribed as an infusion, needleless injector or implantation. For such parenteral administration, it is preferable to use in the form of a sterile aqueous solution, suspension or emulsion, which may contain other substances known in the art, for example, a sufficient amount of salts or carbohydrates such as glucose, to make the solution isotonic with blood. Aqueous solutions should be appropriately buffered (preferably to a pH of 3 to 9) if necessary. For some forms of parenteral administration, they can

F) to be used in the form of a sterile non-aqueous system such as non-volatile oils, including mono- or diglycerides and fatty acids, including oleic acid. The production of acceptable parenteral compositions under sterile conditions, for example by lyophilization, is easily performed by standard pharmaceutical methods, as is known to specialists. Alternatively, the active ingredient may be in powder form to form a parenteral composition with a carrier (sterile pyrogen-free water) prior to use.

Also, the compounds of the invention can be administered intranasally or by inhalation. They are conveniently delivered in the form of a dry powder (alone or in the form of a dry mixture, for example a dry mixture with lactose, or a mixed component particle, for example with phospholipids) by a dry powder inhaler or an aerosol spray, 65 represented by a sealed container, a pump, a nebulizer (mainly used, electrohydrodynamic nebulizer, for the formation of fog) or nebulizer with or without the use of an acceptable carrier gas, for example, dichlorotetrafluoroethane, dichlorodifluoromethane, trichlorofluoromethane, a hydrofluoroalkane such as o 1,1,1,2-t-etrafluoroethane /(NEA 134A (Ggorgovel brand|) or 1 ,1,1,2,3,3,3-heptafluoropropane (NEA 227EA (trade mark)), carbon dioxide, perfluorinated

Hydrocarbon such as Perflubron (trademark) or other acceptable gas. In the case of a pressurized aerosol, the dosage unit may be defined by a valve to deliver a metered amount.

Hermetic container, pump, spray, nebulizer or nebulizer may contain a solution or suspension of the active compound, for example using a mixture of ethanol (optionally, aqueous ethanol) or an acceptable dispersant, solubilizer or prologer and carrier gas, may additionally contain a lubricant such as Sorbitan 7/0 trioleate Capsules, blisters, cartridges (made for example of gelatin or hydroxypropyl methylcellulose for use in an inhaler or insufflator may be formed containing a powder mixture of a compound of the invention, an acceptable powder base such as lactose or starch and a functionality modifier such as 1-lycine, mannitol or stearate magnesium

Before using the composition as a dry powder or suspension for inhalation, the compound of the invention will be 7/5 micronized to a size suitable for inhalation (usually less than 5 microns). Micronization is achieved by a range of methods, such as spiral jet grinding, supercritical fluid crystallization, dry spraying.

An acceptable solution composition for use in an electrohydrodynamic nebulizer to make a fine mist may contain from mcg to 10mg of a compound of the invention per actuation and the actuation volume may vary from 17 to 100µl. A typical composition may include a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents can be used instead of propylene glycol, such as glycerin or polyethylene glycol.

Alternatively, the compositions of the invention can be administered topically to the skin, mucous membrane, transdermally, for example, in the form of a gel, hydrogel, lotion, solution, cream, ointment, powder, dressing material, foam, film, plaque, implant, sponge, fibers , bandage, microemulsions and their combinations. For such applications, the compositions of the invention may be suspended or dissolved in, for example, i) a mixture of one or more of the following: mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene polyoxypropylene, emulsifying wax, non-lectic oils, including synthetic mono- or diglycerides , and fatty acids, including oleic acid, sorbitan monostearate, polyethylene glycol, Ge! zo liquid paraffin, polysorbate 60, cetyl esters of waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol. Alternatively, penetration enhancers may be used. The following can also be used: polymers, carbohydrates, proteins, phospholipids in the form of nanoparticles (such as nasal or salt liposomes) or suspended or dissolved. Additionally, they can be delivered using iontophoresis, phonophoresis, and sonophoresis. "

Alternatively, the compositions of the invention can be administered rectally, for example in the form of a suppository or a pessary. They can also be prescribed vaginally. For example, these compositions can be made by mixing the substance with acceptable inert excipients, such as cocoa butter, synthetic glyceride esters, or polyethylene glycols, which are solid at ordinary temperatures but become liquid or dissolve in the cavity, releasing the active ingredient. "

The compositions of the invention can also be prescribed as ophthalmic dosage forms. For ophthalmic use, from c compositions can be formed as micronized suspensions in isotonic, pH-adjusted, sterile physiological solution, or, preferably, as solutions in isotonic, pH-adjusted, sterile;" physiological solution. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer (eg, hydroxypropylmethyl-, hydroxyethyl-, methyl cellulose), or heteropolysaccharide polymers may be added. Alternatively, they can be formulated as ointments on -I petroleum jelly or mineral oil, incorporated into biodegradable by microorganisms (absorbable gel sponges, collagen) or non-biodegradable (silicone) implants, laminated plates, drops, lenses, etc. or delivered via corpuscular or vesicular systems such as niosomes or liposomes. Compositions

Go! may be optionally combined with a preservative such as benzalkonium chloride. Alternatively, they can be delivered using iontophoresis. They can also be prescribed in the form of ear forms, using for example, but not limited to drops.

Ge) Compositions of the invention can also be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with molecules. Formation of a drug-cyclodextrin complex may alter solubility, dissolution rate, masked taste, bioavailability, or stability properties. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Alternatively, for the direct complexation of the medication with (F, cyclodextrin) can be used as auxiliaries: carrier, solvent or solubilizer. Examples of acceptable alpha-, beta- and gamma-cyclodextrins that are commonly used are described (in UUO-A-91/11172,

MO-A-94/02518 and UMO-A-98/551481. The term "administration" includes delivery by viral or non-viral methods. Viral delivery mechanisms include, but are not limited to, adenoviral vectors, adeno-associated virus (AAM) vectors, herpesvirus vectors, retroviral vectors, lentiviral vectors, and baculovirus vectors. Non-viral delivery mechanisms include lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic amphiphilic substances (SEAzv) and their combinations. Routes of administration for such 65 delivery mechanisms include, but are not limited to: mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the drug is divided into single doses, which contain a suitable amount of the active component. A unit dosage form may be packaged, the package containing discrete amounts of the drug, such as packaged tablets, capsules, and powders in bottles or ampoules. Also, the unit dosage forms can be capsules, tablets, sachets or lozenges, or they can be a suitable amount of each of these packaged forms. The amount of the active ingredient in a single dosage form can be varied or adjusted from 0.1 mg to 1 g according to the specific application and effectiveness of the active ingredient. In medical use, the drug can be prescribed three times a day, as, for example, capsules of 100 or ZOOmg. In therapeutic use, 7/0 Compositions used in the pharmaceutical method of the present invention are administered in an initial dose of approximately 0.01mg to approximately 10Omg/kg per day. A daily dose range of from about 0.01 mg to about 10 ug/kg is preferred. The dosage, however, may vary depending on the needs of the patient, the severity of the condition to be treated, and the compound used. Determining the appropriate dosage for a specific case is within the competence of a specialist. In general, treatment is started with small doses that are less than /5 the optimal dose of the compound. After that, the dosage is increased in small amounts until the optimal effect for these cases is achieved. For convenience, the total daily dosage can be divided and, if desired, can be taken in portions throughout the day.

The pharmaceutical composition according to the present invention may, if necessary, also contain one or more other compatible therapeutic agents. In particular, the composition can be combined with any one or more compounds suitable for the treatment of pain, such as the compounds listed above. Thus, the present invention relates to a pharmaceutical composition containing a compound selected from the compounds of formulas (1I)-(XXM), one or more other pharmacologically active agents and one or more pharmaceutically acceptable carriers.

General methods of sch

The above-mentioned compounds can be synthesized from ketones (1)-(12) below, in which B and B? have the same meanings that were indicated above: (o) in (ee) " and - - . and? -i sh» (ee) -i iChe) ime) 60 b5

1 -d2 ki Kk: (1) (2) 1 2

Vive t y v1 ko (3) (4) (5) (6) scho o o o . vi "h" TSO U F i. 2 i- s (7) (6) (8) (10) « m. o v; with Sl x shi - (11) (12) and?

It is believed that the intermediate compounds of the formulas (1)-(6) indicated above are novel and constitute a further aspect of this invention. Particularly preferred intermediate ketones according to the present invention are compounds selected from: -I sh» (ee) - 50 3e)

F) name) 60 b5 o- o - (from) (4a) and (52)

Me. Me (Z Ho" and O (ba) Me (7a)

Various methods of synthesis of the above ketones are described below:

A. Synthesis of ketones 1-12 s (1) Synthesis of ketones of type (1). o (o. (o) ich-

NO1 zh" -n-y2 so "

For example: rch- o

З ОМе тон ЯТОМв « s dome -on --OMa g» 13 9 14 15

V. t" so I? Zh s -1 50 mmeOo,s nok Ga so mes, and nos i 18 17 16

F) who me. . 60 g gy o - and that 65 19

(a) The known diester (13) is reduced to diol (14), for example, with lithium aluminum hydride in an organic solvent, for example, tetrahydrofuran or diethyl ether at a temperature from 02C to the boiling point. (5) Diol (14) is added to a solution of methylsulfonyl chloride in pyridine or triethylamine in dichloromethane at a temperature from -602C to 402C to obtain dimesylate of formula (15). (c) Dimesylate (15) is added to a solution of lithium aluminum hydride in a solvent such as tetrahydrofuran or diethyl ether at a temperature from 02C to the boiling point to give the alkene of formula (16). (4) Alkene (16), given above, is added to a mixture of carbon tetrachloride or ethyl acetate and acetonitrile, to which water, sodium periodate and 70 ruthenium chloride (I) are added and stirred at a temperature from 402C to 802C to obtain the carboxylic acid of formula (17) ; or to a mixture of potassium permanganate in water and dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium chloride to give (17). (e) Carboxylic acid (17) is added to a mixture of an alcohol, such as methanol, and a concentrated acid, such as sulfuric acid or hydrochloric acid, at room temperature to the boiling point to give a diester of formula (8). (0 The diester (18) above is added to a strong base such as sodium hydride or potassium tert-butoxide in a solvent such as tetrahydrofuran at boiling temperature to give the ketone (19). (9) Ketone (19) ), specified above, is added to a mixture of dimethylsulfoxide and water at a temperature of 100-1809C to obtain a ketone of formula (20). (2) Synthesis of ketones of type (4) and (5). c (8) (22) zo ki k2 I 2 cha 4 5 so

Example: "

TYA v. Jean nn « in - - In, .

I» 21 22 23 -I gch On (ee) - 50 i 3e) 24 25 26 (F; (a) Known alkene (21), see V. O. Kgateg, R. Yu. Vapei, 9U. At. Spec. bos, 1972, 94, 3934), mixed with an organoborane such as disiamylborane, texylborane or 9-BVM in a solvent such as diethyl ether or tetrahydrofuran at a temperature from 09C to room temperature. The obtained organoborane is mixed with a solution of concentrated sodium hydroxide and hydrogen peroxide to obtain the alcohol of formula (22). (c) The alcohol (22) is oxidized, for example, with an oxidizing agent such as chromium trioxide, pyridinium dichromate, and pyridinium chlorochromate in a solvent such as dichloromethane or acetone to give the ketone of formula (23).

A similar process can be used for the ketone (25), except that the starting material is the known alkene (24), see V. O. Kgateg, R. Oyu. Vapei, earlier. 65 (3). Synthesis of ketones of type (3)

at

WITH

Example:

I yuininrchnny ie ty Dir 7 27 28 29 (a) Known ketone (27), see patent application 05 60/160725), is added to a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide, followed by the addition of a methylating agent such as methyl iodide in a solvent such as tetrahydrofuran or diethyl ether at a temperature between -1009C and at room temperature to obtain the ketone of formula (28). (o) (B) The ketone of formula (46) above is further methylated with a methylating agent such as methyl iodide in the presence of a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide in a solvent such as tetrahydrofuran or diethyl ether, at a temperature between -1002C and room Fuzo temperature to obtain the ketone of formula (29). (4). Synthesis of ketones of type (9) and (10). about

E. and a Z 10 z and ketones are known compounds, see Y. U. ep, Y. ove;, Teiapeidgop I!etsegv, ,; ,; ; b. with Tsi and I M. mm. sp. g. sp. Teipaney Yei 1990, 31, 4467; S "z Notsyde, A. M. Egizdce-Nezbaiip, A. MosKe!i, Y. Orpozel, 9). R. YuOesieged, G. Septaiip, M. Map Meegzzspe, -). At.

Spent os, 1982, 104, 2920).

Such ketones can also be obtained from a known unsaturated ketone of the general formula (76) -I sh» (ee) - 50 c o (76) by reduction by hydrogenation with a suitable catalyst, such as Pa/C in a suitable solvent, such as ethyl acetate. about (5). Synthesis of ketones of type (2). name) 60

Ki 2 b5 2

Example:

Me. Me

And Me. Me o7zagto but he yours. And som kV 31 32

Me. "Me Me. uMe Me Me from paragraph chan 35 according to Z3 zv Me. /Me Me cm (8) and nn nina oi g so,Me | oh oh and

ZB 37 them. her . . . . c (a) The known carbamate (30), see MU. Mop deg BZaaY, K. Keippagai, N. M. Zeiidepzrippeg, u. 5iam/y, N.

Otsazi, Iieridv App. Spet., 1989, 703; 7. SecComis, K. Maiimis, 9U. Zepr. SPpet 5Bos., 1988, 53, 595), "reduce using lithium aluminum hydride in a solvent, such as tetrahydrofuran or diethyl ether, at a temperature from 02C to the boiling point to obtain diol (31). (B) Diol (31) is added to methylsulfonyl chloride in pyridine or triethylamine in dichloromethane at a temperature from -602C to 402 to obtain dimesylate of formula (32). (c) Dimesylate (32) is added to a solution of sodium or potassium cyanide in a solvent such as tetrahydrofuran, diethyl ether, dimethylsulfoxide, or dimethylformamide, at a temperature from 09 to the boiling point of c. Che) with the preparation of dicyanide of structure (33). and (c) Dicyanide (33) is added to a concentrated solution of potassium or sodium hydroxide at a temperature from 509 °C to the boiling point to give the diacid (34). (a) The diacid (34) is esterified to diester (35) by adding: to a mixture iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or -I 1,4-dioxane, to which is added a base such as 1,8-diazabicyclo|5.4.0)undec-7-ene (OB), triethylamine or 1,5-diazabicyclo|4.3.P|non-5-ene (OBM), and stirred at a temperature from -402C to 1102C; or to a mixture of methanol and a concentrated acid, such as sulfuric acid or hydrochloric acid, at (ee) at a temperature in the range from 02C to 1002; or -1 50 to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from 402C to 1009C; or to diazomethane in a solvent such as benzene, toluene, dichloromethane at a temperature from -402C to 4096. also (e) Diester (35) is added to a strong base, such as sodium or potassium hydride or tert-butoxide ka lithium in a solvent such as tetrahydrofuran at boiling point to give a ketone (36). () Ketone (36) is added to a mixture of dimethyl sulfoxide and water at a temperature of 100-1802C to obtain 22 ketone of formula (37).

F! (6). Synthesis of ketones of type 7 and 8 i.e.) 7 in c

Kk AK 7 V 65 Ketones of this type can be obtained using a ruthenium complex, see Z-MU Rak, 9-N. Zop, 5-G.

Keith, K. N. ANp, Teigapedgop: Azutteigu, 1999,10,1903).

For example: Fr

Towns. in Me

Me o

And also from Me. Where I. 2 ligand (a)

The known alkene (38), see N. Mizpiuata, M. Moi, N. Maizitoio, 5. V. Ragk, K. Moi, U. At. Spent 5os., 1994, 116, 2223), was mixed with a ruthenium catalyst, such as SI oKsh(pibox-ip(CHn-CH»e) in a solvent such as dichloromethane or chloroform at a temperature from 02С to room temperature with the result ketone structure (39). t 2

Inny schi Ya s S - chi y s 25 . 40 a 42 o (n) (a) Known alcohol (40), (see M. Avati, Vy. Spet. bos. Orp., 1990, 63, 721; T. Za, M. Soyuny, U.

Uuakabrauzni, T. Erzizaula, Teigapyedgop Ieyege, 1983, 24, 4123), mixed with diiodomethane and with alkylzinc, Ge»! such as dimethylzinc or diethylzinc, or by zinc-copper vapor in a solvent such as toluene or benzene at a temperature from -602C to the boiling point to obtain the alcohol of formula (41). - (B) An alcohol of formula (41) is added to an oxidizing agent such as chromium trioxide, pyridinium dichromate (ee) or pyridinium chlorochromate in a solvent such as dichloromethane or acetone to give a ketone of formula h (42). (7). Synthesis of ketones of type (6). ich- shi s;" with" V

I. 6 sh»

For example: (ee) - 50

F) from 43 44 60 The known ketone (43), see MU. A. MMislak, O. I. spivieg, Teiapedtop Ieitseg5, 1986, 27, 5331; Yu. I.

Zspyzieg, U. Egikwep, u). Oh Speth, 1979, 44, 4254), mixed with diiodomethane and alkylzinc, dimethylzinc or diethylzinc, or zinc-copper vapor in a solvent, such as toluene or benzene, at a temperature from -609C to the boiling point to obtain a ketone of structure (44). (8). Synthesis of ketones of type (11) and (12) b5 o o st se (11) (2) 70 Preparation of ketone of structure (11) can be found in the following sources:

Oedipus, Tospio. Rgeragaiop oi bBisusio(4.2. Phosiap-7-opez (Preparation of bicyclo|4.2.0|octan-7-ones). (Miida(a

Oaidaki Kusikiodakiby Kiuo, Zpigep Kadaki Nep (1973), 15 26-33).

Magko, Ivimap; Kopztapv, Vhypo; Nezbraip-Rgizdape, Appe Magie; Yuitavs, Zierpape; Opose, I eop; Egpwi, Weab

Sgetsshieg, Napv. IpigatoIesshag (2-2) susioadaiiope oi Keiiepez ap Kefepitipisht extra (o oieypv 75 (Intramolecular (242) cycloaddition of ketenes and ketenimine salts to olefins). U. At. Spect. 5 vol. (1985), 107(7), 2192-4 ).

Spep, Pap Jopo; OSrpozvel, Ieop. 5itsau oh spiga! aihiyagez god She ipigatoIesshag (2-2| susioadayomp oi a Keifepitipisht za (o ap oieiipis doshbie ropd. A pem/ azutteiiis zupipeviz oi susiorshapopev. (Study of chiral auxiliaries for intramolecular (2-2| cycloaddition of a ketenimine salt to an olefinic double bond ).

The preparation of the ketone of structure (12) can be found in Magko et al., cited above.

B. Conversion of ketones as starting substances into amino acids of the invention

The above ketones can be converted to amino acids using one of the following general methods A-E, as shown below for ketone (1), in which B-B2-methyl. with

Method A: o and | "yby-t m

I A so ES -MO, 20 aBa 455 so « | and - : : « : so o yu fd and d. things ode -

E 5 s H -H, : -MyaU

I» av "- ac (a) The ketone (20) is converted to the unsaturated ester (452) by reaction with a trialkylphosphonoacetate, such as, -I triethylphosphonoacetate, in the presence of a base. Suitable bases include sodium hydride, potassium hydride, lithium or sodium-or potassium hexamethyldisilazide, butyllithium or potassium tert-butoxide The reaction can be carried out in a non-polar aprotic organic solvent such as tetrahydrofuran, dimethylformamide, diethyl (ee) ether or dimethylsulfoxide at a temperature in the range of -782C to 10020. (B) To the unsaturated nitromethane is added to the ester (45a) by the addition reaction of Mispaya! in the presence of a base and a polar aprotic organic solvent at a temperature from -202C to 1002 with the formation of nitroester (455). Suitable bases are tetrabutylammonium fluorides, tetramethylguanidine, 1,5-diazabicyclo| 4,3,P|non-5-ene, 1,8-diazabicyclo|5,4,FTundec-7-ene, sodium or potassium alkoxide, such as potassium tert-butoxide, potassium carbonate, sodium hydride or potassium fluoride. Suitable organic solution solvents include tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, dichloromethane, chloroform, or tetrachloromethane. o (c) Reduction of the nitroester (455) and ring closure by the reaction of the resulting amino group with an ester group leads to the formation of a cyclic lactam (45c). The hydrogenation can be carried out in the presence of a catalyst such as Raney Nissel, palladium on carbon or rhodium catalyst, or another catalyst containing nickel or palladium, in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, because 1,4-dioxane, chloroform or diethyl ether at a temperature in the range from 202C to 80960. (4) Hydrolysis of a cyclic lactam (45c), for example, using aqueous hydrochloric acid with a concentration of 0.01M to 12M and optionally in the presence of ( Its solvent, such as 1,4-dioxane, acetic acid or water, gives the amino acid (46).

Method B: b5

Oh and oh! action eat SM inn zi i drink ipiinininiv Dy. as ? 20 : cm : cm tA - 48

Her EI; x t -

M - : «irin : Son : o 49 (a) Ketone (20) is condensed with an alkyl cyanoacetate, for example, ethyl cyanoacetate, in an organic solvent selected from toluene, benzene, xylenes, or m-heptane, to which acetic acid and β-alanine are added or ammonium acetate or piperidine. The mixture is stirred at a temperature of 09Сb to 15097 with the removal of water, using, for example, a Dean-Stark nozzle or activated molecular sieves, to obtain the cyanoester of formula (47). c (B) Cyanoester (47) is converted to dicyanide (48) by treatment with potassium cyanide or sodium cyanide in water (He) or ethanol or methanol. Boil the mixture and remove the water using, for example, a Dean-Stark nozzle. (c) The cyanomethyl group of the dicyanide (48) is converted to the ethoxycarbonylmethyl group by reaction with ethanol in toluene or benzene saturated with hydrochloric acid gas. The reaction temperature can range from -3022; to 4090, b" (4) The cyano group of the obtained cyanoester (49) is reduced by hydrogenation in methanol, ethanol or ethyl acetate, using a catalyst such as nickel, palladium, platinum or rhodium, at a temperature from 159 to 602C, followed by ring closure get lactam (50). (e) Hydrolysis of lactam (50), for example, using aqueous hydrochloric acid with a concentration from 0.01M to 12M It is optional in the presence of a solvent such as 1,4-dioxane, acetic acid or water, 3o amino acid is obtained (51). in

Method C.

I AM

І : : « s si a RA yar r nyny І ш шщ s E SO, Z so E zn

I'm 47 beats 53 and? - She, she, etc

Mo in fshk:

Е со К ши 5 СХож у m; Ф со и зе и O;Me І "Me -yu 5 s: "di

N k Ka de) : dream

BI

60 (a) The cyanoester (47) is added to a mixture of benzylmagnesium chloride, -bromide, or -iodide in a dry solvent, for example, tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diegyl ether, or tert-butyl methyl ether at a temperature from -1002C to 11023 to obtain the cyanoester of formula (52). (c) The cyano group of the cyanoester (52) is removed with a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent such as ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane, or diethylene glycol. The mixture is stirred at a temperature from 252C to 25022 to obtain the carboxylic acid of formula (53). (c) The carboxyl group of the acid (53) is protected by conversion to its alkyl ester with 1-6 carbon atoms in the alkyl residue, for example, to the methyl ester (54). For this, the acid (53) can be added: to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene or 1,4-dioxane, to which is added a base such as 1,8-diazabicyclo|5.4.0Iundec-7 -ene (OB), triethylamine or 1,5-diazabicyclo|4.3.F|non-5-ene (OBM), and stir at a temperature from -402С to 1102С; or to a mixture of methanol and a concentrated acid, such as sulfuric acid or hydrochloric acid, at a temperature ranging from 02C to 1002C; or to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from -402C to 1002C; or to diazomethane in a solvent such as benzene, toluene, dichloromethane, at a temperature from -402C to 4020. (4) The phenyl group of the obtained ester (54) is oxidized to the carboxyl group by treatment with sodium periodate and ruthenium chloride (I) in a mixture of tetrachloride carbon or ethyl acetate and acetonitrile to which water is added. The mixture is stirred at a temperature from 402С to 802С with the production of carboxylic acid (55). (e) The carboxyl group of the acid (55) is converted into isocyanate by adding to the mixture a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl ether or n-heptane, to which diphenylphosphorylazide (OPPA) is added ) and mixed at a temperature from 02C to 15022 to obtain the isocyanate of formula (26); or to ethyl chloroformate or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at -409C to 782C followed by addition of sodium azide in water and tetrahydrofuran or acetone followed by addition of toluene or benzene and boiling They are cooked with a reflux condenser. (0) The isocyanate and ester groups of compound (56) are simultaneously hydrolyzed to amino and carboxyl groups, for example, with the help of aqueous hydrochloric acid with a concentration of 0.01M to 12M, optionally in the presence of a solvent such as 1.4 -dioxane, acetic acid or water, with the amino acid (57). Ge)

Method 0: 7 tep x -erRV Her (o) inn and chu Km zi

In a dream tt o: A Wasps: owls

NC x 58 and 2 so

With « | and -

Y I : « gy So,Me GO, Me and u- 2 рн e 2 i son s t son t soOL-Vo s : E 2 g СсО,Vu " 62 vd 7" vo

I. e E : t» BZh dove GTuitoon nin - t so yah

H: МН, с 7 83 "essay (а) At the first stage of protection of the carboxyl group of acid (53), it is converted into chloride (58) by reaction at a temperature from -402С to 1102С, for example, with oxalyl chloride or thionyl chloride in an aprotic organic solvent, for example, dichloromethane, chloroform, diethyl ether, toluene, or tert/P-butyl methyl ether, to which is added 0.01 mol.bo to 1Omol.bo M,M-dimethylformamide (OME).ime) (B) Chloroanhydride (58) is converted into its tert-butyl ester, for example, by reaction with tert-butyl alcohol in an aprotic organic solvent, such as dichloromethane, chloroform, 60 diethyl ether, toluene or tert-butyl methyl ether, to which is added M,M-isopropylethylamine (OIREA) or triethylamine. The reaction mixture is stirred at a temperature from -409C to 1109 to obtain an ester of the formula (59). (c) The phenyl group of the ester (59) is oxidized to a carboxyl group by interaction with sodium periodate and ruthenium chloride (III) in a mixture of carbon tetrachloride or ethyl acetate and acetonitrile, to which water is added. because the mixture is stirred at a temperature from 402С to 802С with the production of carboxylic acid (60).

(4) The carboxyl group of the acid (60) is converted to an ester group by adding: to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1,4-dioxane, to which is added a base such as 1,8- diazabicyclo|5.4.0Iundec-7-ene (OB), triethylamine or 1,5-diazabicyclo|4.3.F|non-5-ene (OBM), and stir at a temperature from -409C to 11022 to obtain an ester of the formula (61) ; or to a mixture of methanol and a concentrated acid, such as sulfuric acid or hydrochloric acid, at a temperature ranging from 02C to 1002C; or to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from -402C to 1002C; or to diazomethane in a solvent such as benzene, toluene, dichloromethane at a temperature of -402C to 4020. (e) the tert-Butoxy group is removed from the diester (61) by reaction with trifluoroacetic acid in a solvent such as dichloromethane, chloroform, 1, 4-dioxane, tetrahydrofuran, diethyl ether or tert-butyl methyl ether. The reaction mixture is stirred at a temperature from -402C to 1109 to obtain the carboxylic acid of formula (62). (0) The ester group of the acid (62) is converted to the isocyanate (63) by adding: to a mixture of a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl ether or n-heptane, to which add diphenylphosphorylazide (ORPA) and stir at a temperature from 02С to 15092С; or to ethyl chloroformate or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at -409C to 782C followed by addition of sodium azide in water and tetrahydrofuran or acetone followed by addition of toluene or benzene and boiling They are cooked with a reflux condenser. (9) By simultaneous hydrolysis of the isocyanate and hexadecane groups of compound (63), for example, with aqueous hydrochloric acid at a concentration of 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water, amino acid (64) is obtained. Gee)

Method E: ik SM DN di: g en - Yar

Y So, l so, : son 4 MS 65 t vv so « | -

And - : i-th

І I і і во нин nt lush fa pp fa shsh s : son g Sso,Me : SOo,Me

I" vo o bv 767 (a) The cyanoester (47) is reacted with allylmagnesium chloride or -bromide, or 2-butenylmagnesium chloride and dialkylzinc, such as dimethylzinc, or a copper (I) salt, such as copper (I) iodide or cyanide copper (I), in and dry organic solvent, for example, tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl "" ether or tert-butyl methyl ether, at a temperature from -10092C to 11097 to obtain an unsaturated additive product of the formula (65). (c) The cyano group of the addition product (65) is removed by reaction with a base, for example, potassium hydroxide -I 250, sodium hydroxide, lithium hydroxide or cesium hydroxide, in an organic solvent selected from ethylene glycol, 2-methoxyethyl ether, 1,4- dioxane or diethylene glycol. The reaction mixture is stirred at a temperature from 252C to 2502, obtaining the carboxylic acid of formula (66). (c) The carboxyl group of the acid (66) is converted to an ester group by adding: to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 59 1,4-dioxane, to which is added a base such as 1,8- diazabicyclo|5.4.0Iundec-7-ene (OB), triethylamine or

HF) 1,5-diazabicyclo|4.3.F|non-5-ene (OVM), and mixed at a temperature from -402C to 11092 to obtain ester d) of formula (67); or to a mixture of methanol and a concentrated acid, such as sulfuric acid or hydrochloric acid, at a temperature ranging from 02C to 1009C; or to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from -402C to 1002C; or to diazomethane in a solvent such as benzene, toluene, dichloromethane at a temperature from -402C to 4020. (4) The unsaturated ester group (67) is oxidized with sodium periodate and ruthenium chloride (II) in a mixture of carbon tetrachloride or ethyl acetate and acetonitrile, to which water is added. The mixture is stirred at a temperature from 402C to 802C to obtain the carboxylic acid of formula (68). (e) Carboxylic acid (68) is converted to amino acid (69) as mentioned in method C

The above ketones can also be converted to an amino acid using one of the general R-G methods, as shown below for group (9) ketone.

The method is "pol, with fu rr tea ach and Ya. to, "nn,

So, Eh! со,н Со 15 (70) (71) (72) (a) The ketone is converted into the nitroester (70) according to the methods described above. (B) The nitro ester (70) is hydrolyzed with a suitable base such as aqueous sodium hydroxide to give 20 Nitro acid 72).

Method b c 25 pin "7 MO 2 MH, (22) z kos so. so, cha (73) (74) (75) so " (a) The unsaturated ester (73), in which K is benzyl or diphenylmethyl, can be prepared from ketone 3o according to any of the general methods described above.c (c) The nitroester (74) is converted to the amino acid (75) by reduction by catalytic hydrogenation in a suitable solvent.

The compounds of the invention can alternatively be obtained from known unsaturated modifications of the ketone of type (8), as shown below in methods H and I: C

Method H s;" z o z mo, mo, --

(76) (77) (18) (79) (80) (a) The ketone (76) is converted to the unsaturated nitroester (78) according to the general methods previously described. (B) The nitroester (78) is hydrolyzed with a suitable base, such as aqueous sodium hydroxide, to give the nitro acid (79), which is reduced by hydrogenation, for example, H 5 with a palladium-on-charcoal catalyst in a suitable solvent, such as ethanol, with obtaining amino acid (80).

GF) Method I name) 60 b5

2 I o b; mo, Tv, ko,C so, so,n (76) and (81) (82 (83) (a) The unsaturated nitroester (82) can be obtained from the ketone (76) in accordance with the methods generally described earlier. ( B) The nitroester (82) is converted into the amino acid (83) by reduction by catalytic hydrogenation in a suitable solvent.

A pharmaceutically acceptable salt of a compound of the invention may be readily prepared by mixing solutions of the compound of the invention and the required acid or base, as appropriate. The salt can be precipitated out of solution and collected by filtration or can be isolated by evaporation of the solvent.

With reference to the general techniques described above, it will be readily understood by one skilled in the art that when protecting groups are present, they will generally be interchangeable with other protecting groups of a similar nature, for example, when an acidic group is described as being protected by an ethyl group, it may readily be replaced by any any suitable alkyl group, for example, Si. a group in Balkal.

It will be understood by one skilled in the art that the specific steps in the general methods presented herein above may be suitably combined in any other manner not shown herein to produce compound c according to the present invention. at

Thus, in brief, the invention covers: (І) a compound of the formula I-XXM or a pharmaceutically acceptable salt, solvate, polymorph or prodrug form; (i) a method of obtaining a compound of formula I-XXM or its pharmaceutically acceptable salt, solvate, polymorph Me) or prodrug form; ich- (iii) a pharmaceutical composition, which includes a compound of the formula I-XXM or its pharmaceutically acceptable salt, solvate, polymorph or prodrug form, together with a pharmaceutically acceptable excipient, diluent or carrier; (im) a compound of the formula I-XXM or its pharmaceutically acceptable salt, solvate, polymorphic form, "g prodrug form or their composition for use as a medicine;

Zo (M) use of a compound of the formula I-XXM or its pharmaceutically acceptable salt, solvate, polymorphic form, prodrug form or their composition for the production of a medicament for the treatment of any of the conditions mentioned above; (mi) the use of a compound of formula I-XXM or its pharmaceutically acceptable salt, solvate, polymorphic form, prodrug form or composition thereof for the manufacture of a medicament for the treatment of any of the conditions mentioned above; With (my) a method of treatment in a mammal of any of the conditions mentioned above, including treatment of said "" mammal with an effective amount of a compound of formula I-XXM or its pharmaceutically acceptable salt, solvate, " polymorph form, pro dosage form or composition ; (my) new intermediate compounds of formulas (Ia), (4a)-(7a), (70), (71), (73), (74), (77)-(79), (81) or (82) ; (their) method of treating any of the conditions mentioned above, which consists in administering to a patient in need of such treatment, simultaneously, separately or sequentially, a combination of a compound of formula I-XXM and an additional agent of analgesia; (b) using a combination of a compound of formula I-XXM and an additional therapeutic agent to produce a medicament for the treatment of any condition mentioned above; and -I 20 (xi) a product that contains a compound of formula I-XXM and an additional therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of any of the conditions mentioned earlier.

The present invention is illustrated by the following non-limiting examples and intermediates.

Example 1

I(1kK,5K,65)-6-(Aminomethyl)bicyclo/|3.2.F|hept-6-UCacetic acid hydrochloride

F) name) 60 per b5 dream

Isocyanate from preparative example 9 (approximately 9.33 mmol) and 6M hydrochloric acid (30 ml) were boiled for 18 hours. The mixture was left to cool, diluted with water (bOml) and extracted with dichloromethane (2x5Oml). The aqueous phase was concentrated under reduced pressure to obtain a yellow solid, which was washed with ethyl acetate and acetonitrile to obtain 0.92 g of the title compound as a white solid. "H-NMR (400 MHz, 4a6-0OM80): 5-7.94 (ZM, sho), 3.15 (IN, d), 3.07 (1H, d), 2.72 (1H, sq), 2.46 (1H, m), 2.42 (1Н, d), 2.33 (1Н, d), 1.98 (1Н, m), 1.80-1.64 (2Н, m), 1.59 (1Н, m), 1.48-1.28 (ЗН, m), 1.23(1Н, dd ).

NRMS (HIAT): t/2 (MN-NSY) 7,184.

RHMS (Rhodidu 0053 (Zmyu), column 150mmx4.bmm (inner diameter), 20-10095 acetonitrile and 0.196 formic acid) retention time - 4.34 minutes, 10095 purity.

IAR (c-0.127 in methanol)--12.49

Microanalysis: Found: C, 54.64; H, 8.19; M, 6.42. С10Н47МО». NSI calculated C, 54.67; H, 8.26; M, 6.389050.

Melting point (RegKkeep EIteg О5С7): 19896.

Alternatively:

LA example

(1K,5K,65)-6-(aminomethyl)bicyclo|3.2.0)hept-6-ylacetic acid hydrochloride

The nitro acid of preparative example 32 (2.0g; 9.4mmol) in (or 1:1 IPS:NO or 1:11 Mesm:nNO (4Oml; 2Oml/g)) was hydrogenated using 1095 Ra/s (0.2g; 0.1g/g) at 502C and 60 r for 18 h. The reaction mixture was filtered through Seille and the filter cake was washed with 1:11 IPS:NO or 111 Mesm:NO (20 mL). The combined filtrates and washings were concentrated in vacuo and azeotroped to dryness with with an additional amount of IPS or Mesm, obtaining the title compound as a white crystalline solid (1.52G).

Example 18

Hydrochloride (1K,5K,65)-6-(aminomethyl)bicyclo|3.2.0)hept-6-ylacetic acid Ge)

The lactam of preparative example 33 (4.70 g, 28.44 mmol) and hydrochloric acid (57 ml of a 6 M solution) were boiled together for two hours. The mixture was allowed to cool and then diluted with water (bOml). The aqueous layer was washed with dichloromethane (2x1O0Oml), filtered and then evaporated under reduced pressure. The obtained yellowish solid was triturated with ethyl acetate and recrystallized using Ф mixture of acetonitrile:water 1:1 to give the title compound (4.51g). -

Example 1C

I(1kK,5K,65)-6-(Aminomethyl)bicyclo!/3.2.F|hept-b-yl)acetic acid (Zwitter-ion) so

Amino acid hydrochloride of Example 1 (2.2 g) was dissolved in 7.25 ml of HNO (3.3 ml/g). The pH of the solution was brought up to 7.5, first with the help of 1.bml of an aqueous solution of MAOOH, and at the end with a few drops of 0.1M aqueous MMAON. m

The precipitated zwitter ion was stirred for 8 hours at a temperature of 82C, the suspension was filtered and the residue was washed with ice-cold water (bml). The water-moistened sediment formed on the filter was suspended in

IPS (115 ml) and boiled for 10 minutes. After cooling to ambient temperature, the suspension was filtered and the residue was washed with IPS (bml). The precipitate on the filter was resuspended in IPS (15 ml), boiled for 20 minutes and cooled to ambient temperature. The suspension was filtered, the residue was washed with IPS (bml) and dried in a vacuum at 402 to constant weight to obtain the title compound as a solid crystalline substance (1.4 g). Melting point (Regkip Eiteg OST): 20826. from Example 2

Hydrochloride of (15,55,6K)-6-Aminomethyl)bicyclo!|3.2.0Ihept-6b-yl|acetic acid: i» zh B.Ya so shk che 00 MN, No zh y- t "son 2

Isocyanate from Preparative Example 12 (approximately 11.0 mmol) and 6M hydrochloric acid (30 ml) were boiled for 16 hours. The mixture was left to cool, diluted with water (100 ml) and extracted with dichloromethane (2x5 ml). The aqueous phase was concentrated under reduced pressure to obtain a yellow solid and co-washed with ethyl acetate and acetonitrile to obtain 0.94 g of the title compound as a white solid. 60 "H-NMR (400 MHz, a6-0M80): 5-7.94 (ZH, sho), 3.15 (IN, d), 3.07 (1H, d), 2.72 (1H, sq), 2.46 (1H, m), 2.42 (1Н, d), 2.33 (1Н, d), 1.98 (1Н, m), 1.80-1.64 (2Н, m), 1.59 (1Н, m), 1.48-1.28 (ЗН, m), 1.23(1Н, dd).

NRMS (HIAT): t/2 (МН-НСО 184.

PHMS (Rhodidu 0053 (Zmk), column 150mmx4.bmm (internal diam.), 20-10095 acetonitrile and 0.195 formic acid) retention time -4.34 min., 10095 purity. for IAIr (c-0.35 in methanol) -- 13.02

Example C

(1К5,5К5,6К5)-6-(aminomethyl)bicyclo|3.2.0)hept-b-yl|acetic acid hydrochloride

SN) te 70 Son

Isocyanate from preparative example 17 (approximately 2.7 µmol) and 6 M hydrochloric acid (15 ml) were boiled at 72 for 18 hours. The mixture was allowed to cool, diluted with water (bOml) and extracted with dichloromethane (3x5Oml). The aqueous phase was concentrated under reduced pressure to obtain a yellow solid, which was washed with ethyl acetate and acetonitrile to obtain 0.45 g of the title compound as a white solid. "H-NMR (400Mhz, a6-0OM50): 5-7.84 (ZH, shs), 2.92 (1H, d), 2.85 (1H, d), 2.75 (1H, t), 2.69 (1H, d), 2.59 720 (TN, d), 2.39 (1Н, t), 1.81-1.62 (4Н, m), 1.41-1.30 (4Н, m).

NRMS (HIAT): t/2 (MN-NSI) 1184

PHMS (Rhodidu 0053 (Zmk), column 150mmx4.bmm (internal diam.), 20-10095 acetonitrile and 0.195 formic acid) retention time -4.27 min., 99.895 purity. high school

Example 4

K1K5,6K5,75K)-7-(aminomethyl)bicyclo|4.2.F|oct-7-yl|acetic acid hydrochloride o g FU yiv Son - chik so

Kai (n-) in | | | | and -

The lactam from preparative example 22 (3.20g, 17.9mmol) was heated to boiling in 1,4-dioxane (15ml) and bM

NSI (5 Oml). After 4 hours, the mixture was cooled to room temperature and washed with dichloromethane (2x3Oml). The aqueous phase was collected and the solvent was removed in vacuo. The residue was triturated with ethyl acetate and the resulting solid was collected by filtration and dried in vacuo to give 2.74 g of the title compound as a white solid. - s "NA-NMR (400MHz, 020): 3.24 (2Н, m), 2.58 (2Н, s), 2.39 (1Н, m), 2.03 (IN, m), 1.76 (2Н, m), 1.59-1.10 "from (7H, m), 0.96 (1H, m). " NRMS (HIAT): t/2 (MN-NSI) 3198.

Example 5

Hydrochloride K1K5,6K5,7k5)-7-(aminomethyl)bicyclo|4.2.F|oct-7-yl|acetic acid -I i MH..He / 2 boche -1 50 pr i Son i (no) oo Diphenylphosphorylazide (0.4 mL, 1.98 mmol) was added with stirring to a solution of triethylamine (0.28 mL,

Gee! 2.03mmol) and the acid of preparative example 29 (0.47g, 1.9bmmol approximately) in toluene (15ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 16 hours and then heated to 3592 for 1 hour. The mixture was left to cool, diluted with ethyl acetate (bOml), washed with a saturated aqueous solution of sodium bicarbonate (2x1O0Oml), saturated salt solution and dried (М9505). Solvent 60 was removed under reduced pressure and the resulting yellow oil was heated to boiling in EM NSI (20ml). After 18 hours, the mixture was cooled to room temperature and washed with dichloromethane (2xbOml) and diethyl ether (bOml). The aqueous phase was collected and the solvent was removed in vacuo. The residue was triturated with ethyl acetate and the resulting solid was collected by filtration and dried in vacuo to give 0.304 g of the title compound as a white solid. bo "H-NMR (400 MHz, as-0OM50): 3.04 (1H, d), 2.99 (1H, d), 2.68 (1H, d), 2.62 (1H, d), 1.98 (1H, m), 1.83

(IN, t), 1.69-1.28 (9Н, m), 1.00 (1Н, m).

NRMS (HIAT): t/2 (MN-NS) 1198.

Preparative example 1 (1K5,5K5)-Bicycloyl3.2.0)heptan-b-one

To a solution of bicyclo|3.2.F|hept-2-en-b-one (12 mL, 111.3 mmol) in ethyl acetate (10 O mL) was added palladium (g, 75 1095 wt./wt. on charcoal) and the mixture was hydrogenated for b hours at 302 and 483 kPa (7Or.5.i). The reaction mixture was filtered and the solvent was removed under reduced pressure to give 12.1 g of the title compound as a colorless oil. utah (filkausm"! 1777.

TN-NMR (400 MHz, SOSIv): 5-3.54 (1Н, m), 3.19 (IN, ddd), 2.88 (IN, m), 2.49 (1Н, ddd), 2.04 (1Н, m), 1.91-1.49 ( BN, m).

Preparative example TA (1K,5K)-Bicycloi3.2.F|heptan-6-one c o (22) o i-

A solution of (1K,5K)-bicyclo|3.2.0)hept-2-en-6-one (50.0g; 462mmol) in E(Ac (375ml) was hydrogenated using co

Tooth Ra/C (5.0g) with 5095 moisture at bOrg for 8 hours at ambient temperature. "AND

The reaction mixture was filtered through Seille, and the filtrate was concentrated in vacuo to give 41.3 g of the title compound as a colorless oil. - 7H-NMR (400MGu, SOSI»v): 5-3.55 (1H, w), 3.20 (1H, m), 2.90 (1H, m), 2.50 (1H, m), 2.0-1.5 (BN, m) . "Reference: EROO74856

Preparative example 2 « 20 Ethyl (2E/2)-(1К5,5К5)-bicyclo!|3.2.0)hept-b-ylidene(cyano)ethanoate - with z z. 5 sc) - I m 5. AsO (ee)

M MS

-AND

Ge) Ketone from Preparative Example 1 (22.4g, 204.1mmol), ethyl cyanoacetate (21.7ml, 204.1mmol), ammonium acetate (15.7g, 204.1mmol) and glacial acetic acid (11.7ml, 204.1mmol) were boiled in toluene ( 220 ml): using the YuOeap-ziagk nozzle. After 8 hours, the mixture was left to cool and diluted with ethyl acetate (300ml), washed with water (3x150ml), saturated salt solution and dried (Ma9504). The solvent was evaporated under reduced pressure. The residue was chromatographed (5iO", heptane/ethyl acetate, from 95:5 to 7:3) to give Zbog

F) 6:4 mixture of isomers of the title compound in the form of a yellow solid. ime) utah(film/cm"! 2225, 1725, 1640.

TN-NMR (400 MHz, SOSIv): 5 (essential isomer) -4.26 (2Н, m), 3.64 (1Н, m), 3.36 (1Н, ddd), 2.96 (1TN, m), 60 2.70 (1Н, dt) , 2.11 (1Н, m), (1.92-1.58, 5Н, m), 1.32 (ЗН, m); 5 (secondary isomer)-4.26 (2Н, m), 3.85 (1Н, m), 3.15 (1Н, ddd), 2.96 (1Н, m), 2.52 (1Н, dt, 920.0, 4.4), 2.02 (1Н, m ), (1.92-1.58, 5Н, m), 1.32 (ЗН, m).

NRMS (HIAT): пп/2 |M-NI 204.

Preparation example Z

Ethyl KI1K5,5K5,6K5)-6-benzylbicycloi|3.2.0Ihept-6b-ylI(cyano)dacetate b5 i.

Sk) -RV is so and Mo

The cyanoester from preparative example 2 (10.0g, 48.7mmol) in THF (bOml) was added with stirring for 1 hour to a solution of benzylmagnesium chloride (7v8ml of a 1M solution in ether, 7vmmol) in THF (100ml) at 75.-789C in an argon atmosphere. After stirring for 2 hours at the same temperature, the reaction was stopped by adding a saturated solution of ammonium chloride (40 ml). The mixture was allowed to warm to room temperature and diluted hydrochloric acid (15 Oml) was added. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with saturated saline, dried (Mao5O)) and the solvent was evaporated under reduced pressure to give the title compound as a mixture of diastereoisomers as a yellow oil, which was used without purification in the next step. utah (filmkausm"! 22471741.

NRMS (HIAT): pp/2 |M-NI 296.

Preparatory example 4

I(1Kk5,5Kk5,65K)-6-benzylbicyclo!/3.2.0|hept-6-yl|acetic acid with (8) (ni-) (22) pla

Ri te s m.

A mixture of diastereomeric cyanoesters from preparative example C (20.3g, 68.4mmol) and potassium hydroxide (23.0g, 410.4mmol) was heated to 1602 in ethylene glycol (350ml) for 38 hours. After that, the mixture was left to cool and hydrochloric acid (300 ml) was carefully added. The mixture was extracted with ethyl acetate (3 x 200 ml) and the combined organic fractions were washed with saturated salt solution, dried (Mo95O)) and the solvent was removed under reduced pressure. The residue was chromatographed (5105, heptane/ethyl acetate, 8:2) to give 14 g of the title compound as a racemic mixture of diastereomers as a white solid. xz" utah (film)/cm"! 3344, 1704. 7TN-NMR (400MHz, SOCIz): 5-7.31-7.22 (BN, w. 3.02 (1H, d), 2.97 (1H, d), 2.64 (2H . t/x (M-NO 243.

Preparatory example 5

ChK» (1K,5K,65)-6-benzylbicycloi|3.2.0)hept-b-yl|acetic acid (ee) - 50 3e) i, 5 RA

F) 60 (8)-(4-)-a-Methylbenzylamine (6.67g, 55mmol) was added with stirring to a solution of a racemic mixture of acid from preparative example 4 (24g, 98.2mmol) dissolved in ethyl acetate. Acidic salt precipitated from the solution as a white solid. This salt was recrystallized three times from ethyl acetate to obtain 8.5 g of acid salt. An additional amount of 8.5 g of acid salt was obtained by further recrystallization of the residue. The first part of the obtained salt was transferred to dichloromethane, washed with dilute hydrochloric acid, a saturated 65 salt solution and dried (Ma95O)). The solvent was evaporated under reduced pressure to give 5.0 g of the title compound as a white solid.

NRI S | Spigaised OO, column 250x4.bmm (Mobile phase: 90905 hexane, 1095 IPS with a content of 0.595 TFC)); Holding time-5. 1 minute (9495 ee).

IAIr (c-1.13 in chloroform)--20.29

The second part of the salt was transferred to dichloromethane, washed with dilute hydrochloric acid, a saturated salt solution and dried (Ma5O)4) to obtain additional 5 g of acid 86905 ee.

Similarly received:

Preparatory example 6

15,55,6K)-6-benzylbicyclo!|3.2.0Hept-6b-yl|acetic acid tora ra 7 C-y sho

E Pv son by recrystallization of the salt formed by the addition of (5)-(-)-A-methylbenzylamine.

NRI S (Spigaise! 00 250X54.bmm column (Mobile phase: 9095 hexane, 10956 IPS with a content of 0.5956 TFC)): Retention time - 4.2 minutes (95965 ee).

IAIr (c-1.0 in chloroform) - 17.39 Ge

Preparatory example 7 (5)

Methyl (1K,5K,65)-6-benzylbicycloyl|3.2.0)hept-6b-yl|acetate (22) ychin (ee)

RE h z» SO, Me i

Trimethylsilyldiazomethane (17.7 ml of a 2M solution in hexane, 35.4 mmol) was added dropwise with stirring to a solution of the acid of preparative example 5 (7.85 g, 32.1 mmol) in a mixture of toluene (9 ml) and methanol (22.5 ml) at 02С in an argon atmosphere. The mixture was allowed to warm to room temperature and was stirred for 4-6 hours. The solvent was removed under reduced pressure and the residue was transferred to ethyl acetate (150 ml), washed with saturated sodium bicarbonate solution (150 mL), dilute hydrochloric acid (100 mL), saturated salt solution and dried (Ma5O). The solvent was removed under reduced pressure. The residue was chromatographed (51O», heptane/ethyl acetate, 9:1) to obtain 7.0 g of the title compound in the form of a colorless oil. m. 3.67 (ZH, c), 2.97 (1H, d), 2.92 (1H, d), 2.65-2.60 (2H, m), t» 2.26 (1H, d), 2.18 (1H, d), 2.08 ( 1H, m), 1.82-1.52 (ZN, m), 1.48-1.22 (AN, m). for NRMS (HIAT): t/g2 (МНА259.

IAir (c-0.11 in methanol)--24.19, -i Preparative example 8 c I 1kK,5K,65)-6-(2-Methoxy-2-oxoethyl)bicycloi|3.2.0Ihept-b-yl|acetic acid o you, name) so,n 60

SO, Me

The ester from Preparative Example 7 (7.0g, 27.1mmol) and sodium periodate (81.1g, 379.3mmol) were stirred together in ethyl acetate (100ml), acetonitrile (100ml) and water (150ml) for 5 minutes. The mixture was cooled to 5 02 and ruthenium (III) chloride hydrate (0.11 g, 0.54 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. Diethyl ether (15 mL) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (200ml) was added to the mixture, which was then extracted with ethyl acetate (3x100ml). United organic; the fractions were washed with saturated sodium thiosulfate solution, saturated salt solution, dried (M9505) and the solvent was evaporated under reduced pressure to obtain the title compound as a yellow oil. utach (film)/cm"! 1733, 1715. "NA-NMR (400 MHz, SOSIz): 5-3.65 (ZM, s), 2.82-2.76 (ZN, m), 2.55-2.49 (ZN, m), 2.05 (1Н, m), 1.81 (1Н, m), 1.73-1.69 (2Н, m), 1.49-1.28 (4Н, m).

NRMS (HIAT): ti/g (M-NI 225.

Preparatory example 9

Methyl MKI1K,5K,65)-6-(Isocyanatomethyl)bicyclo|3.2.0Ihept-b-yl|acetate as 2 сО,Me

Diphenylphosphorylazide (8.45 mL, 39.2 mmol) was added with stirring to a solution of triethylamine (5 mL, 40.4 mmol) and the acid from Preparative Example 8 (8.78 g, 38.8 mmol) in toluene (8 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 3 hours and then heated to 35923 for 1.5 hours. The mixture was left to cool, diluted with ethyl acetate (150 ml), washed with a saturated aqueous sodium bicarbonate solution (150 ml), saturated salt solution and dried (Mo950O4). The solvent was removed under reduced pressure to give 8.7 g of the title compound as a yellow oil. utah(filmkausm"! 2265, 2171, 1733. Ge)

Preparative example 10 Kc

Methyl ((15,55,6K)-6-benzylbicyclo|3.2.O|hept-6-yl|acetate c

Here

And what J

Her RA "iy SO,Me that s;" Trimethylsilyldiazomethane (5.7 ml of a 2M solution in hexane, 11.4 mmol) was added dropwise to a solution of the acid from Preparative Example 6 (2.77 g, 11.3 mmol) in a mixture with toluene (30 ml) and methanol (7.5 ml) at 02C in an argon atmosphere while stirring. . The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100ml), washed with saturated sodium bicarbonate solution (100ml), dilute hydrochloric acid (1000ml), saturated salt solution and dried (M9505). The solvent was evaporated under reduced pressure. The residue was chromatographed (5105, heptane/ethyl acetate, 9:1) to give 2.84 g of the title compound as a colorless oil. ate "NA-NMR (400 MHz, SOSI8): 5-2.28-7.21 (BM, m), 3.67 (ZH, s), 2.97 (1H, d), 2.92 (1H, du), 2.65-2.60 (2H, 3e) M), 2.26 (1H, d), 2.18 (1H, d), 2.08 (1H, m), 1.82-1.52 (ZH, m), 1.48-1.22 (AN, m);

IAIr (c-0.11 in methanol) - 23.19

Preparatory example 11

15,55,6K)-6-(2-methoxy-2-oxoethyl)bicyclo|3.2.0Ihept-b-yl|acetic acid

Ф) r o t 7 7 - y GP yoboNn and so Me

Ester from Preparative Example 10 (7.0g, 27.1mmol) and sodium periodate (81.1g, 379.mmol) were stirred together in a mixture of ethyl acetate (100ml), acetonitrile (100ml) and water (1500ml) for 5 minutes. The mixture was cooled to 09 and ruthenium (I) chloride hydrate (0.11 g, 0.B54 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. Diethyl ether (1500 ml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (200ml) was added to the mixture and then the mixture was extracted with ethyl acetate (3x100ml). The combined organic fractions were washed with saturated sodium thiosulfate solution, saturated salt solution, dried (Mo9505) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil. "NA-NMR (400 MHz; SOSIz): 5-3.65 (ZM, s), 2.82-2.76 (ZH, m), 2.55-2.49 (ZH, m), 2.05 (1H, m), 1.81 (1H, m) , 1.73-1.69 (2Н, m), 1.49-1.28 (4Н, m).

Preparatory example 12

Methyl ((15,55,6K)-6-(isocyanatomethyl)bicyclo|3.2.O|hept-6-yl)|acetate 18 rech i Kia)

SsO, Me

Diphenylphosphorylazide (2.4ml, 11.1mmol) was added with stirring to a solution of triethylamine (1.bml, 11.4mmol) and acid from Preparative Example 11 (11.0mmol approximately) in toluene (30ml) at room (o) temperature under a nitrogen atmosphere. The mixture was boiled for 2 hours. The mixture was left to cool, diluted with ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium bicarbonate (2 x 15 Oml), a saturated salt solution and dried (Ma5O)). The solvent was removed under reduced pressure to give the title compound as a yellow oil. utah (film)/cm"! 2265, 2151, 1734. -

Preparative example 13 ee) tert-Butyl (1К5,5К5,65К)-6-benzylbicyclo!|3.2.0)hept-6-yl|acetate « - (no)

Man

RA - p

Oxalyl chloride (0.92 ml, 10.Bmmol) was added dropwise to a solution of the acid from Preparative Example 4 (2.34g, 9.58mmol) in dichloromethane (30.Bml) at 09C in an argon atmosphere while stirring. Carefully - dimethylformamide (0.3ml) was added and the mixture was allowed to warm to room temperature, then they were stirred for the next 4 hours. The solvent was removed in vacuo and the residue was diluted with dichloromethane (20 mL). In an argon atmosphere, 2-methylpropan-1-ol (1 mL) in dichloromethane (20 mL) was carefully added to the reaction mixture, then diisopropylethylamine (2.5 mL, 14.4 mmol) was added. The mixture was stirred for 17 hours and then -I 20 was transferred to ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate (2x200Oml) and dried (Ma5O)). The solvent was removed under reduced pressure and the residue was chromatographed (50", with heptane/ethyl acetate 95:5) to give the title compound (2.40g) as a yellow oil. utah (film kausm"! 1727. 5 TN-NMR (400 MHz, SOSIv): 8-7.28-7.21 (BN, sho RI), 2.98 (1H, d), 2.92 (1H, d), 2.64-2.56 (2H, m ), 2.16 (1Н, d), 2.09 (1Н, d), 2.04 (1Н, m), 1.80-1.50 (ЗН, m), 1.48 (9Н, с), 1.47-1.20 (АН, m). (Ф ) Preparative example 14 ko I1k5,5Kk5,65K)-6-(2-tert-Butoxy-2-oxoethyl)bicyclo|3.2.0)hept-b-yl|Ioacetic acid 60 b5 g.) aa son to OWL

The ester from Preparative Example 13 (2.4g, 7.99mmol) and sodium periodate (23.93g, 111.8mmol) were stirred together in ethyl acetate (24ml), acetonitrile (24ml) and water (Zbml) for 5 minutes. The mixture was cooled to 09C and ruthenium (I) chloride hydrate (0.033g, 0.1 mmol) was added to the reaction mixture.

The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. Diethyl ether (bOml) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (150ml) was added to the mixture and then extracted with ethyl acetate (3x100ml). The combined organic fractions were washed with a saturated salt solution, dried (NaCl) and the solvent was evaporated under reduced pressure to give the title compound (1.78g, 8390) as a yellow oil. udak (filkausm"! 1728, 1714.

TN-NMR (400 MHz, SOSIv8): 8-2.78 (1H, 5), 2.71 (1H, d), 2.43 (1H, d), 2.38 (1H, d), 2.01 (1H, m), 1.86-1.64 ( ЗН, m), 1.52-1.36 (6Н, m), 1.45 (ОН, с).

NRMS (HIAT): pp/2 |M-NI 267. p

Preparatory example 15 o

Methyl ester (1К5,5К5,65К)-6-(2-tert-butoxy-2-oxoethyl)bicyclo!|3.2.0Ihept-b-yl|acetic acid (22) Oh, Me "And with SO-You in

Trimethylsilyldiazomethane (4.3ml of a 2M solution in hexane, 8.mmol) was added dropwise with stirring to a solution of acid from Preparative Example 14 (1.78g, 6.6mmol) in a mixture with toluene (24ml) and methanol (bml) at 092С in an atmosphere argon The mixture was allowed to warm to room temperature and stirred for 24 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (100 ml), diluted hydrochloric acid (100 ml), saturated salt solution (100 ml) and dried (Ma5O). The solvent was evaporated under reduced pressure to obtain the "title compound" in the form of a yellow oil.

Preparative example 16 g" I1k5,5Kk5,6K5)-6-(2-Methoxy-2-oxoethyl)bicyclo|3.2.O|hept-6-yl|acetic acid (ee) - 50 te (not) "a

SoO.Me about SON with -

Trifluoroacetic acid (ml) was added dropwise with stirring to a solution of the ester from the preparation in Example 15 (approx. 6.63 mmol) in dichloromethane (1 bml) at 09C. The mixture was allowed to warm to room temperature and stirred for an additional 17 hours. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate until neutral pH was reached and extracted with dichloromethane (5 Oml). Then it was re-acidified to pH 4 with dilute hydrochloric acid. The mixture was then extracted with dichloromethane (2x5Oml). The combined organic fractions were washed with saturated salt solution, dried (MaSO)) and the solvent 65 was removed under reduced pressure. The residue was purified by chromatography (SO 5, 8:2 to 6:4 heptane/ethyl acetate) to obtain 0.63 g of the title compound as a colorless oil.

utach (film)/cm"! 3200, 1738, 1705. "H-NMR (400MHz, SOSIv): 5-68 (ZM, s), 2.84-2.73 (ZN, m), 2.61-2.48 (ZN, m) , 2.03 (1Н, m), 1.80 (1Н, m), 1.79-1.32 (6Н, m).

NRMS (HIAT): pp/2 |M-NI 225.

Preparative example 17

Methyl ((1K5,5K5,6K5)-6-(isocyanatomethyl)bicyclo!|3.2.0)hept-6-yl|acetate (e-) naked and CO. Me mSo

Diphenylphosphorylazide (0.61ml, 2.82mmol), triethylamine (0.40ml, 2.90mmol) and acid from Preparative Example 16 (0.63g, 2.79mmol) were boiled in toluene (15ml) for 6 hours. The mixture was allowed to cool and diluted with ethyl acetate (bOml). The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (15 Oml), a saturated salt solution and dried (MaSO)). The solvent was removed under reduced pressure to give the title compound as a yellow oil.

KEheptane-ethyl acetate, 9:1) 0.36. in utah (filkausm"! 2259, 2171, 1736. p

Preparative example 18 (o) (1k5,65k)-8.8-Dichlorobicyclo|4.2.F)octan-7-one o F zo y, Kk (He) : si Fo « si i -

Copper sulfate (II) (2.0g, 8.0mol) was dissolved in water (/bml) and added to zinc dust (30g). The mixture was stirred for 2 hours. The mixture was filtered and the solid was collected, washed twice with acetone and dried in vacuo at 1002 for 24 hours. A portion of activated zinc (8.0 g) was added to a solution of cyclohexane (1 Oml, 98.9 mmol) in diethyl ether (18380 ml). Trichloroacetyl chloride (10.48 mL, 93.96 mmol) in diethyl ether (20 mL) was added at a rate to maintain the mixture at boiling. After C c addition was completed, the mixture was heated to boiling for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether (5 Oml) and carefully poured into a saturated aqueous solution of sodium bicarbonate. The mixture was acidified with 2M HCl and the organic phase was separated. The ether extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate. The organic phase was collected, dried (Ma5O)) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc:heptane 1:9) to obtain 8.62 g of the title compound in the form of a clear oil. (film)/cm"! 2939, 1802. so 7H-NMR (400MGu, SOSI»v): 5-3.94 (1H, w), 2.95 (1H, m), 2.18-1.82 (2H, m), 1.80-1.20 (6H, m).

Preparative example 19 - and (1K5,6K5)-Bicyclo|4.2.F|octan-7-one with Sha x Fi; (and

F) (1k5,65k)-8,8-dichlorobicyclo|4.2.0|octan-7-one (preparative example 18) (8.60g, 44.bmol) was heated to boiling in acetic acid (10Oml) with zinc dust ( 29.0g, 44bmmol). After 4 hours, the mixture was cooled to room temperature, diluted with diethyl ether (200ml) and washed with 2M Mahon (2x1000ml) and then with 60 saturated aqueous solution of MansSoOz (4x100ml). The ether phase was collected, dried (M9505) and the solvent was removed under reduced pressure to obtain 4.79 g of the title compound as a clear oil. utach(film)/cm"! 2930, 1776. 7H-NMR (400MGu, SOSIz): 5-3.27 (1M, m), 3.12 (1H, m), 2.42 (2H, m), 2.20-1.02 ( VN, m). 65 Preparative example 20

Ethyl (22/E)-(1K5,6K5)-bicyclo|4.2.F|oct-7-ylideneoctanoate

"swarm? - (no)

Sodium hydride (6095 dispersion in oil, 1.46g, 36.bmmol) was suspended in dry tetrahydrofuran (150ml) and cooled to 092. Triethylphosphonoacetate (7.bbml, 38.5mmol) was added and the mixture was stirred at 09C 70 for 15 minutes. Then a solution of (1K5,6K5)-bicyclo|4.2.F|octan-7-one (preparative example 19) (4.78 g, 38.5 mmol) in THF (20 ml) was added and the mixture was stirred at 02С. After 1 hour, the mixture was allowed to warm to room temperature, diluted with ethyl acetate (200 ml) and washed with 2M HCl (2 x 150 ml). The organic phase was collected, dried (Mo9505) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, E(JuAc:heptane 3:20)) to obtain 5.49 g of the title compound in the form of a clear oil. ): 5-5.63 sa 5.58 (AN total - E/7 isomers, 2хм), 4.15 (2Н, m), 3.38-2.98 (2Н, m), 2.79-2.35 (2Н, m), 2.13-1.05 (11Н, m).

NRMS (HIAT): t/ (MN")195.

Preparative example 21

Ethyl (1k5.6Kk5,75K)-7-(nitromethyl)bicyclo|4.2.0|oct-7-yl|acetate mo, scho o CO eyes

C se) Ph- (27/E)-(1K5,6K5)-Bicyclo|4.2.0oct-7-ylidenethanoate (preparative example 20) (5.47 g, 28.2 mmol) was heated to 602C in tetrahydrofuran (5 Oml) with nitromethane ( 3.05ml, 56.4mmol) and tetrabutylammonium fluoride (1M in THF, 42ml, 42.0mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (200ml) and washed with 2M HCl (2x100ml) and then with saturated salt solution. The organic phase was collected, dried (MazO)) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, -

EtOAc:heptane 1:9) to obtain 4.73 g of the title compound in the form of a clear oil. utah (film kausm"! 1182, 1547, 1731, 2936. 7TN-NMR (400MHz, SOSIv): 5-4.83 (2M, m), 4.12 (2H, sq), 2.66 (2H, m), 2.57 (1H, m ), 2.22 (1Н, m), 2.05 « 40. AN, m), 1.86 (TN, m), 1.76-1.91 (7Н, m), 1.26 (ЗН, t), 1.10 (1Н, m). NRMS ( HIAT): t/2 (MH 256. shsh s Preparative example 22 xu (15,65,7K)-Spiro|bicyclo|4.2.Phoctan-7.3-pyrrolidin|-5'-one i

N

M

- ro t" and "As so (thi-) - 20 or iChe) Ethyl o MKI1kK5,6bKk5,75K)-7-(nitromethyl)bicyclo|4.2.0|oct-7-yl|Iacetate (preparative example 21) ( 4.70g, 18.4mmol) was shaken in methanol (1500ml) at 309C over a Raney nickel catalyst in an atmosphere of hydrogen gas at 483kPa (7Or.5.i.). After 4 hours, the catalyst was removed by filtration through Celite and 22 the solvent was removed under reduced pressure to give 3.23 g of the compound indicated in the title in the form of a transparent

Gee! butter: which hardens on standing. 2919, 1712, 1677. 7H-NMR (400 Mg, SOSI»z): 5-5.61 (1M, sho), 3.46 (2H, m), 2.42 (2H, m), 2.18-1.01 ( 12H, m).

NRMS (HIAT): t/ (MN-)180. because Preparative example 23

Ethyl (2Е/2)-(1кК5,6К5)-bicyclo|4.2.F|oct-7-ylidene(cyano)ethanoate b5

M

2 "pheno

C (he) 10 Ketone from preparative example 19 (2.85g, 23.00mmol), ethyl cyanoacetate (2.45ml, 23.0mmol), ammonium acetate (1.77g, 23.0mmol) and glacial acetic acid (1.32ml) were boiled in toluene (40 ml) using a trap

Dean Stark. After 6 hours, the mixture was left to cool and diluted with ethyl acetate (150 ml), washed with water (50 ml), saturated salt solution and dried (Ma5O5). The solvent was evaporated under reduced pressure.

The residue was chromatographed (5iO»5, heptane/ethyl acetate, 4:11) to obtain 2.76 g of a mixture of cyanoesters in the form of a yellow solid. "H-NMR (400 MHz, SOCIz): 5 (is the main isomer); 4.26 (2H, yuk), 3.36 (1IN, m), 3.02 (2H, m), 2.58 (1H, m), 1.30-2.18 (8H, m), 1.33 (ZH, m). (Uebasic isomer) -4.25 (2H, k), 3.48 (1H, m), 3.23 (2H, m), 2.58 (1H, m), 1.30-2.18 (8H, m ), 1.32 (ZN, t).

Preparative example 24

Ethyl K1K5,6K5,7kB5)-7-benzylbicyclo|4.2.Phoct-7-ylcyano)acetate

Ri

I, | and about

Sai syu » s) i cha

The cyanoester from preparative example 23 (2.75 g, 12.5 mmol) in THF (bOml) was added for about 1 hour with stirring to a solution of benzylmagnesium chloride (200 ml of a 1M solution in ether, 20 mmol) in THF (20 ml) at -782С in an argon atmosphere. After stirring for 2 hours at this temperature, the mixture was quenched by adding saturated ammonium chloride solution (1 Oml). The mixture was allowed to warm to room temperature, and M dilute hydrochloric acid (0 mL) was added. The aqueous layer was extracted with ethyl acetate (3x4Oml). The combined organic layers were washed with saturated salt solution, dried (Ma5O)) and the solvent was evaporated under reduced pressure to obtain a mixture of diastereomeric cyanoesters. The residue was chromatographed (510 5, heptane/ethyl acetate, 4:1) to obtain 3.53 g of a mixture of diastereomeric cyanoesters in the form of a clear oil. "20 KkKheptane-ethyl acetate, 4:1)-0.30 - s utah (film)/cm"! 2247, 1740. t Preparative example 25 "" I1k5,bKk5,75K)-7-benzylbicyclo|4.2.F)oct-7 -yl|acetic acid t RA -I o shi SOo,n so | we - and 50 Kt (ee) 3e)

A mixture of diastereomeric cyanoesters from preparative example 24 (3.52 g, 11.3 mmol) and potassium hydroxide (3.8 g, 67.9 mmol) was heated to 16092 in ethylene glycol (Ubml) for 72 hours. After that, the mixture was left to cool and dilute hydrochloric acid was carefully added until the solution became acidic: which was determined by pH paper. The mixture was extracted with ethyl acetate (3x100ml) and the combined organic fractions were washed (F, saturated salt solution), dried (Ma95O5) and the solvent was evaporated under reduced pressure. diastereomeric acid in the form of a yellow oil. in TN-NMR (400 MHz, SOSIv): 5-7.31-7.22 (BM, m), 3.08 (1H, d), 3.00 (IN, d), 2.56 (1H, m), 2.44 (1H, d), 2.38 (1H, d), 2.25 (1H, m), 1.98 (1H, m), 1.75 (1H, t), 1.71-1.30 (7H, m), 1.10 (1H, m) .

NRMS (E5): pp/2 (M-NI 257.

Preparative example 26 tert-Butyl (1K5,6K5,75K)-7-benzylbicyclo|4.2.F|oct-7-yl|acetate b5

RA ate | OWLS chn hu" (m) 70 Oxalyl chloride (0.b/ml, 7.6b2mmol) was added dropwise with stirring to a solution of the acid from preparative example 25 (1.79g, 6.93mmol) in dichloromethane (25ml) in a nitrogen atmosphere at 09C. It was added dimethylformamide (0.25 mL) carefully, and the mixture was allowed to warm to room temperature, after which it was stirred for an additional 4 h. The solvent was removed in vacuo and the residue was diluted with dichloromethane (2 O mL). To the reaction mixture under argon was carefully added 2-methylpropan-1-ol ( U9ml) in 75% dichloromethane (20ml) followed by the addition of diisopropylethylamine (1.8ml, 10.4mmol). The mixture was stirred for 18 hours and then saturated aqueous sodium bicarbonate solution (30ml) was added. The mixture was extracted with ethyl acetate (3x50ml) and the combined organic fractions were washed saturated salt solution and dried (M9503). The solvent was removed under reduced pressure and the residue was chromatographed (5% O, heptane/ethyl acetate 98:2) to give the ester (2.42g). "NA-NMR (400MHz, SOCIv): 5-7.33- 7.19 (5M, m), 3.05 (1H, d), 2.96 (1H, d), 2.53 (1H, m), 2.30-2.18 (ZH, m), 1.90 (1H, m), 1.72 (1H, t) , 1.65-1.55 (2Н, m), 1.48 (9Н, с), 1.47-1.00 (6Н, m).

Preparation example 27

I(1k5,bKk5,75K)-7-(2-tert-Butoxy-2-oxoethyl)bicyclo|4.2.F)oct-7-yl|acetic acid ch 8-7 so,n 5; y y OWLS know (o)

S (n/-) t s

The ester from Preparative Example 26 (6.93mmol) and sodium periodate (20.75g, 97.02mmol) were stirred together in ethyl acetate (20ml), acetonitrile (20ml) and water (30ml) for 5 minutes. The mixture was cooled to 02C and ruthenium (I) chloride hydrate (0.03g, 0.14mmol) was added to the reaction mixture. The reaction mixture was left to warm to room temperature and was stirred for 24 hours. Diethyl ether (10 mL) was added and the mixture was stirred for 40 minutes. Dilute hydrochloric acid (1500ml) was added to the mixture and then extracted with ethyl acetate (3x100ml). The combined organic fractions were washed with a saturated salt solution, dried (M959), and the solvent was evaporated under reduced pressure to obtain 0.64 g of acid. - then TN-NMR (400 MHz, SOSIv): 5-2.84 (1M, d), 2.75 (1H, d), 2.61-2.48 (ZH, m), 2.17 (1H, m), 1.95-1.80 (ZH, s m), 1.78-1.30 (7Н, m), 1.44 (9Н, с). :z" Preparative example 28

Methyl ester (1К5,6К5,75К)-6-(2-tert-Butoxy-2-oxoethyl)bicyclo|4.2.F|oct-7-yl|acetic acid - CO,Me and CsOl-Vu i (ee) i that, on 2 -I so -7 SK)

Trimethylsilyldiazomethane (1.2 mL of a 2M solution in hexane, 2.4 mmol) was added dropwise with stirring to a solution of the acid from Preparative Example 27 (0.64 g, 2.28 mmol) in a mixture of toluene (1 mL) and methanol (2.5 mL) at 02 in an argon atmosphere. The mixture was allowed to warm to room temperature and was stirred for 16 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution (100 mL), dilute hydrochloric acid (100 mL), saturated salt solution, and dried (NaOH). The solvent was evaporated under reduced pressure to obtain 0.65 g of etcher in the form of a yellow oil. 7TH-NMR (400 MHz, SOSIz): 8-3.66 (ZM, s), 2.83 (1IN, d), 2.74 (1H, d), 2.57 (1H, d), 2.49 (1H, d), 2.15 (IN, m), 1.94-1.78 (ЗН, m), 1.72-1.06 (8Н, m), 1.43 (9Н, с).

Preparative example 29

I1k5,bKk5,5K)-7-(2-Methoxy-2-oxoethyl)bicyclo|4.2.0|oct-7-yl|acetic acid b5 lyso,H for

WITH (-)

Trifluoroacetic acid (3 mL) was added dropwise with stirring to a solution from Preparative Example 28 (0.65 g, 2.19 mmol) in dichloromethane (3 mL) at 09C. The mixture was allowed to warm to room temperature and stirred for an additional 16 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate (50 ml). The aqueous layer was acidified to pH 4A with 7/5 diluted hydrochloric acid and then extracted with ethyl acetate (2 x 5 Oml). The combined organic fractions were washed with saturated salt solution, dried (MazO)) and the solvent was removed under reduced pressure. The residue was purified by chromatography (51С-2, 6:4 heptane/ethyl acetate) to obtain 0.47 g of acid as a yellow oil. NA-NMR (400 MHz, SOCI3): 5-3.67 (3M, s), 2.84 (1H, d), 2.78 (1H, d), 2.74 (1H, d), 2.66 (1H, d), 2.49 (1H, m), 2.14 (1H, m), 1.95-1.81 (2H, m), 1.70 (1H , m), 1.63 (1Н, m), 1.55-1.30 (5Н, m), 1.07 (1Н, m).

Preparation example 30

Ethyl (2E)-(1K,5K)-bicyclo[3.2.0]hept-6-ylidene acetate/ethyl (22)-(1K,5K)-bicyclo[3.2.0]hept-b-ylideneacetate with (8) in me )

СО со н н

A solution of triethylphosphonoacetate (53.4g; 238.3mmol) in THF (25ml) was added to a suspension of 6095 dispersion of sodium hydride (9.53g; 238.3mmol) in THF (75ml), maintaining the temperature in the range of 5-159C. A solution of y-(1K,5K)-bicyclo|3.2.0)hepatan-b6-one (preparative example TA) (25g, 226.0mol) in THF (150ml) was added, maintaining the temperature in the range of 5-159C. The reaction mixture was stirred at ambient temperature for 30 minutes and then water (10 mL) was added. The phases were separated and the organic layer, which contained the compound specified in the title, was used directly in the next stage. With t0 7TN-NMR (400MHz, SOSIv): 5-5.55 (1M, d), 4.15 (2H, yu), 3.40 (IN, m), 3.20 (IN, m), 2.90 (1H, m), 2.55 s (IN, m), 1.8-1.5 (5Н, m), 1.30 (ЗН, t). with Preparative example 31

Ethyl (1K,5K,65)-I6-(nitromethyl)bicyclo!|3.2.0)hept-6-ylI|acetate -I sh» (ee) kak, z Mo, 3e) so 59 Solution in THF of the compound from the preparative of example 30 (40.9 g of the compound in a total volume of 225 ml) was diluted

HF) THF (27Oml). TVAR.ZNYO (93.1g; 295.0mmol) and Memo" (453.9mmol) were added and the solution was heated at boiling point 7 for 4 hours. The reaction mixture was cooled and concentrated under reduced pressure. Toluene (30ml) was added and the two-phase mixture was washed with water (165ml), 2M aq. NSI (165ml 1O0Oml) and then with an additional amount of water (165ml). The toluene layer containing the product was dried over Mo950O and concentrated under reduced pressure to give the title compound as a red/brown oil (90965 (2 stage)). 7TH-NMR (400MHz, SOSIv): 5-4.80 (2M, m), 4.15 (2H, m), 2.85 (IN, m), 2.65 (1H, m), 2.55 (2H, m), 2.20 (IN, m), 1.9-1.4 (7Н, m), 1.25 (ЗН, т). 65 Preparative example 32 (1kK,5K,65)-I(6-(nitromethyl)bicyclo!|3.2.0)hept-6-yl|ioacetic acid mac, mo, i son

A solution of the nitroester from Preparative Example 31 (200g; 828.9mmol) in THF (1.Ol) was combined with 2M aq.

Mahon (1.04L; 2.08mol) and stirred at ambient temperature for 18 hours.

The two-phase mixture was diluted with toluene (500 ml) and the layers were separated. The pH of the aqueous layer was adjusted to a value of 1-3 with the help of concentrated aqueous HCl and extracted with CH»Y» (1.0l-600ml). The dichloromethane layers containing the combined product were concentrated under reduced pressure to give the title compound as an orange oil which solidified on standing (163.4g). 7TH-NMR (400MHz, SOSIv): 5-4.80 (2M, m), 2.85 (1IN, m), 2.60 (ЗН, m), 2.20 (1Н, m), 1.85 (1Н, m), 1.70 (2Н, m), 1.6-1.4(4Н, m).

Preparative example 33 (1k5,5K5,65K)-Spiro|bicyclo|3.2.0)heptan-6b,3'-pyrrolidine|-5'-one c o pu

MN F ich- o (se)

The nitroester from Preparative Example 31 (13.0 g, 53.9 μmol) was shaken in methanol (125 mL) at 259 over a porous nickel catalyst in an atmosphere of hydrogen gas at 345 kPa (50 r.v.i.). After 24 hours, their catalyst was removed by filtration through Arbocell and the solvent was removed under reduced pressure. The residue was then chromatographed (5%, ethyl acetate) to give the lactam (4.76 g). "H-NMR (400 MHz, SOSIz): 5-5.86 (1M, shs), 3.40 (2H, s), 2.79-2.70 (1H, m), 2.54-2.47 (1H, m), 2.32 (1H, "

D), 2.12 (1Н, t), 2.03 (1Н, d), 1.86-1.60 (ЗН, m), 1.57-1.38 (4Н, m).

Microanalysis: Obtained: C, 72.48; H, 9.15; M, 8.43. С.оН/5МО: calculated С, 72.69; H, 9.15; M, 8.4896. o) c IAIro-28.42 (252C) "» Examples of Pharmaceutical Compositions " In the following examples, the active compound can be any compound of formula I-XXM and/or its pharmaceutically acceptable salt, solvate or physiologically functional derivative. (Y) Composition of tablets is. The following compositions A and B can be obtained by wet granulation of the ingredients from (a) to (c) and from i" (a) to (d) with povidone solution, followed by the addition of magnesium stearate and tableting.

Composition A (ee)

0 more

Fo fupovidonv. 00000015

GF! With 1 voi de Composition V vo 11111011 |mptabletka mptabletka

DAMOIRNIOYI 11010606 65 (vupovidonvya. 11101161 (I) Magnesium stearate B 3

Composition C rose and nn ET

The following compositions O and E can be obtained by direct pressing of the mixed ingredients. Lactose used in formulation E is lactose of the direct pressing type. 19 Composition Yu 1 mtosleti oyu

Composition Е с 0 меласлотаи о

F zo 1voo m

Composition E (Composition of controlled release) h o pnya - zv m «

PP 1tov 2 i- The composition can be obtained by wet granulation of ingredients (a)-(c) with povidone solution, followed by the addition of magnesium stearate and pressing.

Composition o (Enteric-coated tablets)

Tablets with an enteric coating can be obtained from composition C by coating tablets in the amount of 25 mg/tablet. an enteral polymer, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Etsagaidiya I). With the exception of Etsagadia HER, these polymers can also include up to 1095 (from

Go) the weight of the used polymer) plasticizer to prevent the destruction of the membrane in the process of 5r Use or storage. Suitable plasticizers are diethyl phthalate, and tributyl citrate and triacetin. w- Composition H (Tablets of controlled release with an enteric coating)

Ge) Tablets with an enteric coating from composition E can be obtained by coating the tablets with an enteric polymer in the amount of BOmg/tablet., such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Ecydagadia I). With the exception of Etchagadia I, these polymers may also include up to 1095 (by weight of the polymer used) of plasticizer to prevent membrane breakdown during the process

F) use or storage. Suitable plasticizers are diethyl phthalate, tributyl citrate and triacetin. ka (ii) Compositions of capsules

Composition A 60 Capsules can be obtained by mixing the ingredients of the above-mentioned composition O and filling hard gelatin capsules consisting of two parts with the resulting mixture. Composition B (given below) can be obtained in a similar way.

Composition B and (a) Active ingredient 250 -To-

at

The composition of S

Since then and 11 1vo

Capsules can be prepared by dispersing the active ingredient in lecetin and peanut butter and filling soft, elastic gelatin capsules with the dispersion. 19 Composition Yu Mata, 20 Yavo

Capsules can be obtained by melting macrogol 4000 BP, then dispersing the active ingredient in the melt and filling it into hard gelatin capsules consisting of two parts. EM 25 Composition E (Capsules of controlled release) about 0 units)

F zo te p TE so

Formulation of controlled-release capsules can be obtained by forming a mixture of ingredients t 35 (a)-(c) using a syringe machine with subsequent spheronization and drying of the obtained material. what-

The dried granules are covered with a controlled release membrane (4) and filled with hard gelatin capsules consisting of two parts.

Composition E (Enteral capsules) « 4 1 noytou) With p. » - 1vvB t- The composition for enteral capsules can be obtained by forming a mixture of ingredients (a)-(c) with

Go) using a syringe machine followed by spheronization and drying of the obtained material. Dried 5p granules are covered with an enteric membrane (a), which contains a plasticizer (e), and are filled with hard gelatin capsules consisting of two parts.

Ge) Composition o (Enteric-coated capsules of controlled release)

Enteral capsules from composition E can be obtained by coating the granules of controlled release with an enteral polymer in the amount of 5mg/capsule, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or anionic polymers of methacrylic acid methyl ester of methacrylic acid (Etsagadiyi Y). With the exception of Etsagadia Her, a plasticizer to prevent the breakdown (F) of the membrane during use or storage. Suitable plasticizers are diethyl phthalate, tributyl citrate and triacetin. (iii) Compositions for intravenous injection 60

Active ingredient 0.250g

Sterile pyrogenic phosphate buffer (рНеО,0) up to 1 Oml

The active ingredient is dissolved in most of the phosphate buffer at 35-40 C, then brought to the required volume and filtered through a sterile microporous filter into sterile glass bottles with a volume of 65 10 ml (Type 1), which are hermetically closed with sterile bottle caps and an additional means that -d41-

warns against unauthorized opening. im) composition for intramuscular injections

Active ingredient 0.20 g

Benzyl alcohol O1og

Glycofurol 751 1.45 g

Water for injections 4.5. to Z, 0 Oml

The active ingredient is dissolved in glycofurol. Then add benzyl alcohol, dissolve and add water to Zml. Then the mixture is filtered through a sterile microporous filter and sealed in sterile Zml glass ampoules (Type 1). (m) syrup composition

Active ingredient 0.25g

Sorbitol solution 1.50 g

Glycerin 1, god

Sodium benzoate 0.0 OBg

Flavoring agent 0.0125 ml

Purified water 4.5. up to 5.00 ml

Sodium benzoate is dissolved in a portion of purified water and a sorbitol solution is added. Add the active ingredient and dissolve. The resulting solution is mixed with glycerin and then brought to the required volume with purified water. (mi) composition of suppositories with 0 mpoupovzhoriu o

PP of the 1st (22)

One fifth of UMierzo! NI5 is melted in a steam-jacketed tank at a maximum temperature of 4592. The active ingredient is sieved through a 200 (t sieve and added to the molten base with stirring, using a Zymegzop equipped with a cutting head, until a homogeneous 00 dispersion is obtained. While maintaining the mixture at 459, add the remaining UMyerzo! NO15 to the suspension, which is stirred until a homogeneous mixture is obtained. The homogeneous suspension is then passed through a 250 |t stainless steel sieve and

With constant stirring, leave to cool to 40 2C. At a temperature of 38-409C, aliquots of (2.02 g) of the mixture is filled into suitable plastic molds and the suppositories are left to cool to room temperature. (my) Composition of pessaries « with 0 pessaries -; The above-mentioned ingredients are completely mixed, and pessaries are obtained by pressing the resulting mixture. (my) Transdermal composition (ee)

Active ingredient 200mg and Alcohol OR O ml (Che) Hydroxyethyl cellulose

The active ingredient and OBR alcohol are gelatinized with hydroxyethyl cellulose and incorporated into transdermal products with a surface area of 10 cm7.

Biological Data i) Compounds of Examples 1 and 4 were tested in the radioligand binding assays described herein and determined to have binding affinities of 46.8 and bOONM, respectively. for

Claims (1)

The formula of the invention 1. Compound of any formula I - ХХМ b5 -d42- nos mn, nose MN. But MN, / gi |, Ke str B ee 7 W in! in: p ( CT to no MN. nos MN. 2 no,s MN, I I and p sh-V! t in: 2 r and in r: (m that sl m rn (5 no,s chn nya - nes - y v! Ve U Ho doya y I ? E: r t" s o SA) SA 0 nm 2 Na Nam F no so "I 0 ih SK) M- nNozh Noze 2 Me; nos MN, 2 Mn; ve. Met in , і "Ko, ey - s;" Kk shya TK R 2 SCM (KM) 75 no MN, nos mn, and y K nom m KE . but, with her (ee) byu | Z -I 50 and Wed in! re v Ha IJ OO) osv ol nom nom o nom ih kh NO m nos young shchi y i 3 60 Still x ХХ my ikhk) S 65 -A3- N.M nam Nm g s no,s I; nose | Fa But What -. сх оосИ) as NM , - nos 2 a У) where В! and 2 each independently selected from hydrogen, linear or branched alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl and benzyl, provided that, except in the case of a cyclooctane compound of the formula (CHMI), EB and K2 simultaneously do not mean hydrogen, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug form thereof. 2. The compound according to claim 1, in which V tav? both mean methyl. C. The compound according to claim 1 or 2 or its salt, solvate or its prodrug form, selected from the group consisting of: сч ((1К,55)-3-aminomethyl-1,5-dimethylbicyclo|3.2.0)hept -Z-yl)acetic acid; o ((15,5K)-3-aminomethyl-1,5-dimethylbicyclo|3.2.0)hept-3-yl)acetic acid; ((1K,55)-3-aminomethyl-β,β6-dimethylbicyclo!|3.1.0|hex-3-yl)acetic acid; ((15,5K)-3-aminomethyl-β,β6-dimethylbicyclo!|3.1.0|hex-3-yl)acetic acid; ((15,25,5K)-2-aminomethyl-β,β6-dimethylbicyclo!|3.1.0|hex-2-yl)acetic acid; F 3o (1kK,25,55)-2-aminomethyl-b,b6-dimethylbicyclo!|3.1.0|hex-2-yl)acetic acid; - (15,2kK,5K)-2-aminomethyl-b,b6-dimethylbicyclo!/3.1.0|hex-2-yl)acetic acid; (1kK,2kK,55)-2-aminomethyl-b,b-dimethylbicyclo!/3.1.0|hex-2-yl)acetic acid; co ((1K,5K,65)-6-aminomethylbicyclo!/3.2.0|hept-b-yl)acetic acid; "And ((15,55,65)-6-aminomethylbicycloi|3.2.0)hept-b-yl)acetic acid; ((1K,5K,6K)-6-aminomethylbicyclo!/3.2.0)|hept-b-yl)acetic acid; - ((15,55,6K)-6-aminomethylbicyclo|3.2.0)hept-b-yl)acetic acid; cis-(15,2K,45,5K)-3-aminomethyl-2,4-dimethylbicyclo|3.2.O)hept-3-yl)acetic acid; trans-(15,2K,45,5K)-3-aminomethyl-2,4-dimethylbicyclo!|3.2.0|hept-3-yl)acetic acid; di(15,5k,65,7K)-3-aminomethyl-b,7-dimethylbicyclo!|3.2.0|hept-3-yl)acetic acid; with (15,5k,6K,75)-3-aminomethyl-b,7-dimethylbicyclo!|3.2.0|hept-3-yl)acetic acid; c (1K,25,55)-7-aminomethyl-3,3-dimethyltricycloyl3.3.0.F|oct-7-yl)acetic acid; :z" ((1k,6Kk,75)-7-aminomethylbicyclo|4.2.F|oct-7-yl)acetic acid; ((15,65,75)-7-aminomethylbicyclo|4.2.0|oct-7-yl)acetic acid; (1k,6K,7Kk)-7-aminomethylbicyclo|4.2.F|oct-7-yl)acetic acid; - 15 ((15,65,7K)-7-aminomethylbicyclo|4.2.0|oct-7-yl)acetic acid; ((1kK,7k,85)-8-aminomethylbicyclo!|5.2.F|non-8-yl)acetic acid; t» (15,75,85)-8-aminomethylbicyclo|5.2.0|non-8-yl)acetic acid; because ((1kK,7kK,8Kk)-8-aminomethylbicyclo!|5.2.0Inon-8-yl)/acetic acid and ((15,75,8K)-8-aminomethylbicyclo!/|5.2.O|non-8- il)acetic acid. - and 20 4. The compound according to any of claims 1-3 or its salt, solvate or its prodrug form, selected from the group consisting of: I 1K,5K,65)-6-(aminomethyl)bicyclo/ |3.2.F|hept-b-yl|acetic acid; I15,55,6K)-6-(aminomethyl)bicyclo|3.2.0)hept-b-yl|acetic acid; I1k5,5Kk5,6K5)-6-(aminomethyl)bicyclo!|3.2.0)hept-b-yl|ioacetic acid; I1k5,bKk5,75K)-7-(aminomethyl)bicyclo|4.2.0|oct-7-yl|acetic acid; and HF) I1k5,bKk5,7k5)-7-(aminomethyl)bicyclo|4.2.0|oct-7-yl|acetic acid. 7 5. The compound according to any of claims 1-4 or its salt, solvate or its prodrug form, which is I(1K,5K,65)-6-(aminomethyl)bicyclo|3.2.F|hept-b-yl Acetic acid. 6. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1-5 60 and a pharmaceutically acceptable carrier. 7. A method of treating a disease selected from epilepsy, fainting attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders , inflammatory bowel disease, pain associated with dysmenorrhea, 65 pelvic pain, cystitis and pancreatitis, which comprises administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-5. 8. The method according to claim 7, in which the disease is neuropathic pain. 9. The method of obtaining the compound according to any of claims 1-5, which consists of the following stages: (i) acid hydrolysis of the corresponding isocyanate derivative/derivative (C4-C8) alkyl ester of carboxylic acid; (ii) hydrolysis of the corresponding cyclic lactam; (ii) recovery of the corresponding nitro/acid derivative, which may be optionally unsaturated; or (m) reduction of the corresponding nitro derivative/derivative benzyl- or diphenylmethyl ester, which may be optionally unsaturated. 0. и и и 0. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 2, 15.02.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s shchi 6) (o) cha (ee) « and - - with . and? -I sh» (ee) -I iChe) ime) 60 b5