6-amino-morphinane derivatives and uses thereof

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 6-amino-morphinane derivatives of formula I wherein meanings of R1-R4 and X are as defined in specification; composition based on the same having analgesic action, and uses thereof as high active analgesics.

EFFECT: new high active analgesics.

9 cl, 4 tbl, 5 ex

 

This invention relates to a class of compounds 6-aminomorpholine, which can be used as highly active analgesics. This invention also relates to pharmaceutically acceptable salts and easily accessible derivatives (e.g. esters or Amida amino acid derivatives), method of their production and their use in obtaining pharmaceutical products.

The existence of opioid receptors as receptors of the Central nervous system (CNS), which carry an analgesic effect, clearly proved. These receptors are divided into three subtypes: m, k and d. Activation of these receptors by opioids provides an analgesic effect. Activation of m-receptors gives the greatest analgesic effect as of the effective analgesics apply certain morphinane with functional groups of the oxygen at position 6 (morphine, Oxymorphone, hydromorphone, and so on). In recent time, there was a significant study of the relationship between structure and activity in this class of substances.

In Journal of Medical Chemistry 1984, 27, pp. 1575-1579 describes the various 14-methoxypropan-6-ones with different substituents in position 3. These derivatives show higher analgesic effect compared to their 14-hydroxy analogues.

A detailed study of 5-methyloxymorphone (= 14-hydroxy-5-methyl is hydromorphone) described in Helvetica Chimica Acta (1988, 71, pp. 1801-1804), showed that the introduction of the 5-methyl group reduces agonist to the opioid characteristics Oxymorphone.

Further study of 14-alkoxyimino-6-ones described in Helvetica Chimica Acta 1989, 72, pp. 1233-1239, it evaluate the effects of different substituents in position 3 and the nitrogen of the amino group.

In the description DE 3412727 presents 14-alkoxy-N-methylmorphinan-6-ones (14-O-allyloxyphenyl) c higher activity compared to their 14-hydroxy analogues.

It was recently revealed the existence of opioid receptors in the peripheral system (e.g., bones, joints, cartilage, muscles and so on). It is shown that anesthesia can also be made through such peripheral opioid receptors (C. Stein, New Engl. J. Med. 1995, 332, pp. 1685-1690). This requires only a small dose of opioid (eg, morphine), which is injected directly into the damaged tissue by injection. A little dose not cause any side effects in the Central nervous system. Analgesic effect was observed especially during the treatment of inflammation and neuropathic pain (R. Likar et al., Brit. J. Anaesth. 1999, 83, pp. 241-244; V. Kayser et al., Neurosci. 1995, 64, 537-545). The route of administration (injection) is a significant lack of treatment. Repeated injections into the damaged tissue or joint associated with the risk of bleeding, infection or damage to the cartilage. Analge the automatic effective substances, which have only limited access to the Central nervous system (due to the fact that they can't overcome, or overcome only to a minor extent, the blood-brain barrier) and can be administered systemically or orally, are of great interest.

The object of this invention to provide a highly active analgesics, which preferably have limited access to the CNS and which preferably are perifericheskie, not centrally, and which can preferably be administered systemically or orally. Substances that are promising in light of the above, are substances that have exclusively peripheral analgesic effect, without the side effects that occur when the Central action.

This invention solves the above problem by objects of independent items. Preferred options are given in the dependent clauses.

This invention is a highly active compounds of formula (I)

in which the substituents have the following meaning: R1: hydrogen; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C1-C6monohydroxyethyl; C2-C6dihydroxyethyl; C3-C6three is hydroxyalkyl; With4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil.

Nitrogen attached to R1can also be stereoselectivity two substituents R1that may be the same or different and have the above definition, and where the second quaternaire Deputy can also be set hydroxyl, oxyl (N-oxide), and alkoxyl.

R2provided the following definitions X: hydrogen; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C1-C6monohydroxyethyl; C2-C6dihydroxyethyl; With3-C6trihydroxysilyl; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; C2-C6alkanoyl; C3-C6alkanoyl; C3-C6alkanoyl; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkanoyl is a C1-C6alkanoyl; C9-C16arylalkyl, where the aryl is a C6-C10aryl and alkanoyl is a C3-C6alkanoyl; C9-C16arylalkyl, where the aryl is a C6-C10aryl and Akinola is a C3-C6alkanoyl.

R 3: C1-C6alkyl; C2-C6alkenyl; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; alkoxyalkyl, where alkoxy is1-C6alkoxy and alkyl is C1-C6alkyl; CO2(C1-C6alkyl); CO2H; CH2HE.

R4provided the following definitions Y: hydrogen; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16Ari is quinil, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; C2-C6alkanoyl; C3-C6alkanoyl; C3-C6alkanoyl; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkanoyl is a C1-C6alkanoyl; C9-C16arylalkyl, where the aryl is a C6-C10aryl and alkanoyl is a C3-C6alkanoyl; C9-C16arylalkyl, where the aryl is a C6-C10aryl and Akinola is a C3-C6alkanoyl; iminomethyl, formamidines,1-C6-N-alkyl - and N,N'-dialkylamides; C2-C6-N-alkenyl - and N,N'-dialkanolamine; C2-C6-N-quinil - and N,N'-dialkylanilines; C4-C16-N-cycloalkenyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16-N-cycloalkylcarbonyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16-N-cycloalkylcarbonyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7With 16-N-arylalkyl - and N,N'-diarylethylenes, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl.

R5and R6that may be the same or different: hydrogen; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; further, R5and R6that may be the same or different, CH(A)CO2B, where a is hydrogen; hydroxyl; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; amino; C1-C6alkylamino; guanidino; C1-C6alkyl-CO2In; and where b is hydrogen; C1-C30-preferably With1-C6by alkyl; C2-C30-preferably With2-C6alkenyl; C2-C30-preferably With2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is 3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; phenyl; substituted phenyl; CH2CCA-C1-C6by alkyl; CH(C1-C6alkyl)OCO-C1-C6by alkyl; CH2LLC-C1-C6by alkyl; CH(C1-C6alkyl)LLC-C1-C6by alkyl; CH2CON(C1-C6by alkyl)2; SN(C1-C6alkyl)CON(C1-C6by alkyl)2; phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)stands; then, SN(A)SO3B, where a and b are such as defined above; R5and R6that may be the same or different, can be iminomethyl, formamidines,1-C6-N-alkyl - and N,N'-dialkylimidazolium; C2-C6-N-alkenyl - and N,N'-dialkanolamine; C2-C6-N-quinil - and N,N'-dia is kinformation; With4-C16-N-cycloalkenyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C3-C16-N-cycloalkylcarbonyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16-N-cycloalkylcarbonyl - and N,N'-dicyclohexylcarbodiimide where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16-N-arylalkyl - and N,N'-diarylalkylarsines, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16-N-arylalkyl - and N,N'-dialliltiokarbamidom, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16-N-arylalkyl - and N,N'-diallinginformation, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; C2-C7-N-allyloxycarbonyl - and N,N'-bis(allyloxycarbonyl)formamidine; C3-C8-N-alkenylacyl - and N,N'-bis(alkenylacyl)formamidine; C3-C8-N-alkyloxyaryl - and N,N'-bis(alkyloxyalkyl)formamidine; C8-C17-N-aryl is alkyloxyaryl - and N,N'-bis(arylalkylamine)formamidine, where the aryl is a C6-C10aryl, alkyloxy is a C1-C6alkyloxy; C9-C17-N-arylalkylamine - and N,N'-bis(arylalkylamine)formamidine, where the aryl is a C6-C10aryl, alkenylacyl is a C2-C6alkenylamine; C9-C17-N-arylalkylamine - and N,N'-bis(allucinazioni) formamidine, where the aryl is a C6-C10aryl, alkyloxy is a C2-C6alkyloxy; C2-C7-N-alkanoyl - and N,N'-dialkylimidazolium; C3-C8-N-alkanoyl - and N,N'-dialkanolamine; C3-C8-N-alkanoyl - and N,N'-dialkylamino; C8-C16-N-arylalkyl - and N,N'-dialliltiokarbamidom, where the aryl is a C6-C10aryl and alkanoyl is a C2-C6alkanoyl; C9-C16-N-arylalkyl - and N,N'-dialliltiokarbamidom, where the aryl is a C6-C10aryl and alkanoyl is a C3-C6alkanoyl; C9-C16-N-arylalkyl - and N,N'-dialliltiokarbamidom, where the aryl is a C6-C10aryl and Akinola is a C3-C6alkanoyl; R5and R6that may be the same or different, can be 4,5-dihydro-1H-imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 4,56,7-tetrahydro-1H-[1,3]diazepin-2-yl.

X is oxygen, sulfur or methylene, or group (X-R2is N.

Y is oxygen or the group (Y-R4is N.

This invention also includes pharmaceutically acceptable acid additive salts and easily accessible derivatives (e.g. esters or amides of amino acid derivatives) of compounds of formula (I).

In this invention, the terms alkyl, alkenyl and quinil include both branched and unbranched alkyl, alkeline and alkyline group, and mono-, di - and trihydroxytoluene branched and unbranched alkyl, alkeline and alkyline group. The aryl may be substituted or mono-, di - or triamese, where the substituents may be independently selected from hydroxy, halogen, nitro, cyano, thiocyanate, trifloromethyl,1-C3of alkyl, C1-C3alkoxy, CO2H, CONH2, CO2(C1-C3the alkyl), CONH(C1-C3the alkyl), CON(C1-C3the alkyl)2WITH(C1-C3the alkyl); amino; and (C1-C3-monoalkyl)amino, (C1-C3-dialkyl)amino, C5-C6cyclooctylamino; and (C1-C3alkanoyl)amido, SH, SO3H, SO3(C1-C3the alkyl), SO2(C1-C3the alkyl), SO(C1-C3the alkyl), C1-C3alkylthio or1-C3Alcano the tio. Definitions listed above for alkyl, alkenyl, quinil and aryl, valid for all substituents in the description.

Compounds in accordance with this invention include pharmaceutically and pharmacologically acceptable salts of the compounds of formula (I). In accordance with this invention are suitable as inorganic and organic salts. Examples of suitable inorganic salts in accordance with this invention include hydrochloride, hydrobromide, sulphates, phosphates and tetrafluoroborate. Possible organic salts are, for example, acetates, tartratami, lactates, benzoate, stearates, pamoate, methansulfonate, salicylates, fumarate, maleates, succinate, aspartate, citrates, oxalates, triptoreline and orotate.

As usual pharmaceutically acceptable additive salts preferred acid additive salts, particularly preferred hydrochloride, hydrobromide, tetrafluoroborate and triptoreline. X and Y are preferably oxygen. Preferably R1is alkyl such as defined above, in particular the stands or ethyl, where preferred is methyl, or cycloalkylation, preferably by cyclopropylmethyl. R2preferably is not H and is not a group that forms an ester with X. on the Contrary, preferred is entrusted other definitions for R 2such as given in paragraph 1, particularly preferred is alkyl such as defined above, particularly preferred are methyl, ethyl and propyl, not necessarily substituted, for example, phenyl group, for example, with 3 phenylpropene group (for example, otherwise, the preferred R2also is arylalkyl group, in particular 3-phenylpropyl). Particularly preferably, both R1and R2at the same time were alkyl, in particular or both at the same time were stands or stands (R1) and ethyl (R2). Even more preferred combination of R1and R2is cycloalkenyl, in particular cyclopropylmethyl for R1and arylalkyl, preferably phenylpropyl for R2. R3and R4in each case preferably are hydrogen or alkyl, particularly preferred alkyl group is methyl. In addition, the preferred R4is C(N-Boc) - (NH-Boc). R5and R6preferably chosen so that one was H and the other one was different from N, where the moiety other than H, preferably is not halogenated. R5and R6preferably choose, independently from each other, from hydrogen, CH2COOC(CH3)3CH2COOH, CH(CH3)COOC(CH3), CH(CH3)COOH, CH(CH2Ph)OOC(CH 3)3CH(CH2Ph)COOH, C(N-Boc) - NH-BOC and C(NH)NH2where R6preferably is H and R5preferably is one of the groups listed above or is N. Also preferably, when R5and R6both are N.

In a particularly preferred embodiment, X and Y are oxygen. Then, preferably, R1is stands and cyclopropylmethyl, and R2is alkyl and arylalkyl, in particular the stands and 3-phenylpropyl, and R3, R4and R6are hydrogen. Preferably R5then choose from tert-butoxycarbonylmethyl, hydroxycarbonylmethyl, 2-(tert-butoxycarbonylamino), 2-(hydroxycarbonylmethyl), 2-(tert-butoxycarbonyl-1-phenylethyl), 2-(hydroxycarbonyl-2-phenylethyl), hydrogen, benzyl (R6also is a benzyl group), N,N'-bis-(tert-butoxycarbonyl)formamidine and formamidine.

Particularly preferred variant of the present invention is a compound of formula I selected from:

tert-butyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid

tert-butyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-acetic acid

(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid

(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-b-ylamino)-acetic acid

tert-butyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-propionic acid

tert-butyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-propionic acid

(2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-propionic acid

(2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-propionic acid

tert-butyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-3'-phenylpropionic acid

tert-butyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-3'-phenylpropionic acid

(2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-3'-phenylpropionate acid

(2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-3'-phenylpropionate acid

6a-amino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol

6b-dibenzylamino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol

6b-amino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol

4,5a-epoxy-6b-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-ol

4,5a-epoxy-6b-guanidine-14b-methoxy-17-methylmorphinan-3-ol

4,5a-epoxy-6a-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-ol

4,5a-epoxy-6a-guanidine-14b-methoxy-17-methylmorphinan-3-ol

1,3-bis(tert-butoxycarbonyl)-2-{4,5a-EPoX is-6b-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-yl}-isomotion

1,3-bis(tert-butoxycarbonyl)-2-{4,5a-epoxy-6a-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-yl}-isomotion

the dihydrochloride of ethyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid

the dihydrochloride of ethyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-acetic acid

tert-butyl ether (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6a-ylamino)-acetic acid

tert-butyl ether (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6b-ylamino)-acetic acid

bis(tetrafluoroborate) (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6a-ylamino)-acetic acid

bis(tetrafluoroborate) (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6b-ylamino)-acetic acid

tert-butyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3,14b-digidroksimorfinan-6b-ylamino)-3-phenylpropionic acid

bis(tetrafluoroborate) (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3,14b-digidroksimorfinan-6b-ylamino)-3-phenylpropionic acid

tert-butyl ether {17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6a-ylamino}-acetic acid

tert-butyl ether {17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6a-ylamino}-acetic acid

tert-butyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-what eliprodil)oxy]-morphinan-6a-ylamino)-3-phenylpropionic acid

the dihydrochloride {17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6b-ylamino}-acetic acid.

It was found that the compounds in accordance with this invention are effective ligands for opioid receptor type 6-aminomorpholine and demonstrate high potential therapeutic use as analgesics, as immunomodulators with immunostimulating or immunosuppressive effect, as a medicinal anti-cancer agents, inhibitors of inflammation, as Antirheumatic agents, diuretics, means reducing appetite, as an Antidiarrhoeal agent, anesthetic or as a neuroprotective active substances.

Connection represented in the claims, are potentially useful for the treatment of pain, functional bowel disorders, such as abdominal pain, bowel obstruction (ileus) or persistent constipation, for the treatment of mammals, particularly humans, to treat the disease, Raynaud's disease, for treating disorders caused by narrowing of blood vessels for the treatment of dysmenorrhea, angina, myocardial infarction, emphysema, bronchial spasms, chronic obstructive bronchitis, rheumatic disorders, nephropathy, nephritis in combination with rheumatic disease, for treatment the tumors, vaahtoniemi, Addison disease, cirrhosis, chronic inflammation of the small and large intestine (for example, irritable bowel syndrome - irritable bowel, ulcerative colitis, Crohn's disease, syndrome, for example, opiates, cocaine, or alcohol, or for the treatment of mental illness, such as dysphoria or schizophrenia.

Compounds in accordance with this invention suitable for use to obtain drugs for the treatment of pain, including acute and chronic pain, or pain in the locomotor apparatus, such as pain in the neck, back, hip, knee, shoulder or militias pain, for the treatment of complex syndromes peripheral pain, phantom pain, facial neuralgia, rheumatalgia, cancer pain, pain from burns, pain after an accident, pain due to chronic inflammation, viscerally, headaches, such as, for example, pulling a headache, associated cervical headache or migraine, Central pain after injuries such as paraplegia or thalamic damage, nerve pain such as neuralgia with shingles, neuralgia after shingles, ischemic pain, such as angina or occlusion of peripheral arteries, postoperative pain, neuropathic pain, such as pain when diabetica the coy neuropathy, pain after viral infection or pain after nerve injury.

Pharmaceutical compositions in accordance with this invention, which contain the compound in accordance with this invention and/or its pharmaceutically acceptable salt as an active ingredient together with a pharmaceutically acceptable carrier suitable for treating conditions specified in this specification.

Application in accordance with this invention includes the use as an analgesic, an immunomodulator, an antineoplastic agent, an antiproliferative agent, an anti-inflammatory agent, Antirheumatic agent, a diuretic, a means of reducing appetite, Antidiarrhoeal tools, anesthetic, neuroprotective substances and active substances for the prevention and treatment of intestinal obstruction (ileus).

The preferred application is receiving medications for treatment of pain, functional bowel disease, disease Raynaud's syndrome, for treating disorders caused by narrowing of blood vessels, angina, myocardial infarction, emphysema, bronchial spasms, chronic obstructive bronchitis, rheumatic disorders (including rheumatoid arthritis, osteoarthritis, osteoarthritis, spondylos, lumbago, lupus erythematosus, spondylarthropathy), netropa the AI, jade in combination with rheumatic disease for the treatment of tumors, cancer, vaahtoniemi, Addison disease, cirrhosis, chronic inflammation of the small and large intestine (for example, irritable bowel syndrome - irritable bowel, ulcerative colitis, Crohn's disease), for the treatment of abuse of drugs, mental illness, erectile dysfunction and/or to suppress the rejection of grafts after transplantation mammals, especially humans.

It has been unexpectedly found that the compounds in accordance with this invention is not able to overcome the blood-brain barrier or overcome it in a slight degree, so they are of particular interest for use as perifericheskie effective therapeutic tools, such as medicines for the treatment of pain, rheumatic therapy, suppression of rejection of organs after transplantation in mammals, preferably humans, for the treatment of erectile dysfunction. Limited access to the Central nervous system provides a significantly reduced risk of side effects related to the Central side effects such as nausea, vomiting, sedation, dizziness, confusion, respiratory depression and mania.

In addition,it has been unexpectedly discovered, the compounds in accordance with this invention are quite effective analgesic period. This allows you to reduce the dose and enter the medication less frequently, which leads to a lower risk of side effects and low toxicity, and also gives a greater willingness of the patient to take medicines.

Getting connections

Compounds in accordance with this invention, which are represented by the formula (I)can be obtained in the following ways :

From thebaine formula (II)

this compound interacts with diallylsulfide, alcelaphinae persulphate, alcelaphinae alkylsulfonate, alcelaphinae arylsulfonate, alkylhalogenide, aralkylated, aralkylamines alkylsulfonate, aralkylamines arylsulfonate, arylalkylamines, esters of Harborview acid or similar compounds in solvents such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether or the like, in the presence of a strong base such as n-utility, diethylamid lithium, diisopropylamide lithium or the like, at low temperatures (-20 to -80° (C) (see Boden et al., J. Org. Chem., volume 47, pp. 1347-1349, 1982; Schmidhammer et al., Helv. Chim. Acta, volume 71, pages 642-647, 1988; Gates et al., J. Org. Chem., volume 54, pp. 972-975, 1984) with receipt the m compounds of the formula (III) where R 3is1-C6by alkyl; C2-C6alkenyl; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; alkoxyalkyl, where alkoxy is1-C6alkoxy and alkyl is C1-C6alkyl; CO2(C1-C6by alkyl); CO2N.

The compounds of formula (III) or thebaine (formula (II)) can be transformed into the corresponding 14-hydroxycotinine formula (IV)

where R3is hydrogen; C1-C6by alkyl; C2-C6alkenyl; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; alkoxyalkyl, where alkoxy is1-C6alkoxy and alkyl is C1-C6alkyl; CO2(C1-C6by alkyl). This reaction is carried out with permorming acid (see H. Schmidhammer et al., Helv. Chim. Acta, vol 71, pp. 1801-1804, 1988), m-chloroperbenzoic acid or the like acid when those whom peraturan from 0 to 60° C., the Preferred method is the reaction with permorming acid at a temperature from 0 to 40°C.

Such 14-hydroxycotinine formula (IV) is further subjected to interaction with diallylsulfide, alkylhalogenide, alkanolamide, alkylhalogenide, arylalkylamine, arylalkylamines, arylalkylamine or chloroformate, in solvents such as N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) in the presence of a strong base such as sodium hydride, potassium hydride or sodium amide, to obtain the compounds of formula (V),

where R3the same as defined above; and R2is hydrogen; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl With 8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; C2-C6alkanoyl; C3-C6alkanoyl; C3-C6Akinola; C7-C16arylalkenes, where the aryl is a C6-C10aryl and alkanoyl is a C1-C6alkanoyl; C9-C16arylalkenes, where the aryl is a C6-C10aryl and alkanoyl is a C3-C6alkanoyl; C9-C16arylalkenes, where the aryl is a C6-C10aryl and Akinola is a C3-C6alkanoyl.

These compounds are then reduced to compounds of the formula (VI)using catalytic hydrogenation with a catalyst such as Pd/C, PdO, Pd/Al2O3Pt/C, PtO2Pt/Al2O3or the like, in solvents, such as alcohols, a mixture of alcohol/water, glacial acetic acid or the like,

where R2and R3such as defined above.

Further N-demethylation is carried out with chloroformiate or bromocyanogen in solvents such as 1,2-dichloromethane, chloroform or the like, to obtain the compounds of formula (VII)

where R1is the CO2CH(Cl)CH3, CO2CH=CH2, CO2CH2CCl3, CO2CH2CH3, CO2Ph, CN, or the like; and R2and R3such as defined above.

The carbamates of the formula (VII) share or by heating at the boiling point under reflux in alcohols (1-hareticantem) or the addition of hydrogen halides) or halogen followed by heating at the boiling point under reflux in alcohols (for vinylcarbazole), obtaining cyanamide formula (VII) acid or alkaline hydrolysis, to obtain the N-Nor compounds of the formula (VIII),

in which R2and R3such as defined above.

N-alkylation of compounds of formula (VIII) is carried out with alkylhalogenide, diallylsulfide, alkanolamide, alkylhalogenide, cycloalkylcarbonyl, cycloalkylcarbonyl, arylalkylamine, arylalkylamines, arylalkylamine or the like, in solvents such as dichloromethane, chloroform or N,N-dimethylformamide, in the presence of a base such as sodium bicarbonate, potassium carbonate, triethylamine or the like, and obtaining compounds of formula (IX),

where R2and R3such as defined above; and R1yavlyaetsyasredstvom; With1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil.

The separation of these compounds of the formula (IX) tribromide boron (in the solvent dichloromethane or chloroform) at a temperature of 0°, 48% Hydrobromic acid (heated at the boiling point under reflux)with alkanethiolate sodium in a solvent such as N,N-dimethylformamide) or with other well-known reagents for the separation of the ether gives a phenolic compound of the formula (X),

where R1, R2and R3such as defined above.

3-O alkylation of compounds of formula (X) is carried out with alkylhalogenide, diallylsulfide, alkanolamide, alkylhalogenide, cycloalkylcarbonyl, cycloalkylcarbonyl, arylalkylamine, arylalkylamines, arylalkylamine or the like, in solvents such as dichloromethane, chloroform, acetone or N,N-dimethylformamide, in the presence of a base such as sodium bicarbonate, potassium carbonate, triethylamine or the like; 3-acylation of compounds of formula (X) are halides, carboxylic acids, anhydrides of carboxylic acids or the like, in the presence of solvents such as dichloromethane, chloroform, acetone or N,N-dimethylformamide, pyridine or the like, to obtain the compounds of formula (XI),

where R1, R2and R3such as defined above; R4is1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; the 5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; C1-C6alkanoyl; C3-C6alkanoyl; C3-C6Akinola; C7-C16arylalkenes, where the aryl is a C6-C10aryl and alkanoyl is a C1-C6alkanoyl; C9-C16arylalkenes, where the aryl is a C6-C10aryl and alkanoyl is a C3-C6alkanoyl and C9-C16arylalkenes, where the aryl is a C6-C10aryl and Akinola is a C3-C6alkanoyl.

The compounds of formula (XI) is subjected to interaction with ammonium acetate, primary and secondary amines, hydrochloride hydroxyamino, amino acids, esters of amino acids or the like, in solvents, such as alcohols, N,N-dimethylformamide or toluene, to obtain Iminov formula (XII) and the salts Imin the I of the formula (XIII),

in which R1, R2, R3and R4such as defined above; and R5and R6that may be the same or different, are hydrogen, hydroxyl, C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; CH(A)CO2B, where a is hydrogen; hydroxyl; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is the 3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; amino; C1-C6alkylamino; guanidino; C1-C6alkylguanine; C1-C6alkyl-CO2In; and where b is hydrogen; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cyclo what Kilom is a C 3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil.

Recovery Iminov and salts imine spend hydride complexes of metals, such as alumalite lithium, lithium borohydride, sodium borohydride and cyanoborohydride sodium or the like, the alcohols berateragentur or similar) in tetrahydrofuran (THF), with cyclohexene or cyclohexadiene or the like in the presence of a hydrogenation catalyst such as Pd/C with hydrogen in the presence of a hydrogenation catalyst such as Pd/C, PdO, Pd/Al2O3Pt/C, Pt/C (AU cu), PtO2Pt/Al2O3, Rh/C, Rh/Al2O3or the like, in solvents, such as alcohols, glacial acetic acid or the like, to obtain the corresponding amines of formula (XIV),

in which R1, R2, R3and R4such as defined above; and R5and R6that may be the same or different, I had are hydrogen, With1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; CH(A)CO2B, where a is hydrogen; hydroxyl; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C65-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; amino; C1-C6alkylamino; guanidino; C1-C6alkylguanine; C1-C6alkyl-CO2In; and where b is hydrogen; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; the 8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil. These compounds correspond to compounds of the formula (I) in accordance with this invention,

where R1, R2, R3, R4, R5and R6such as defined above, and X and Y are oxygen.

If R5and R6in the compounds of formula (I) in accordance with this invention are hydrogen and X and Y are oxygen, 6-amino compounds of formula (XV),

in which R1, R2, R3and R4such as defined above, can be subjected to interaction with agents guanidinium, such as N,N'-bis-(tert-butoxycarbonyl)-S-methylisothiazoline, in the presence of salts, such as mercury chloride(II), silver nitrate or the like, and bases, such as triethylamine, N-ethyldiethanolamine or the like, in solvents such as N,N-dimethylformamide or the like, and, depending on the number of used agent guanidinium, obtaining or compounds of the formula (XVI), or compounds of the formula (XVIa),

in to is that R 1, R2, R3and R4such as defined above; and R5and R6that may be the same or different, are hydrogen; a protecting group, such as, for example, tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z); C2-C7-allyloxycarbonyl; C3-C8-alkanolammonium; C3-C8-alkyloxyalkyl; C8-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkyloxy is a C1-C6alkyloxy; C9-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkenylacyl is a C2-C6alkenylamine; C9-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkyloxy is a C2-C6alkyloxy; C2-C7-alkanoyl; C8-C17-arcanorum, where the aryl is a C6-C10aryl and alkyl is C2-C7alkyl; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6 alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil.

Subsequent cleavage of the protective groups (R5, R6) acids such as galogenovodorodov acid, triperoxonane acid, tetraberlinia acid or the like, in solvents such as dichloromethane, diethyl ether, alcohols, mixtures of alcohol/water or similar, gives compound 6-guanidine formula (XVII),

in which R1, R2, R3and R4such as defined above. These compounds correspond to compounds of the formula (I) in accordance with this invention in which R1, R2, R3and R4such as defined above and R5is formamidines, R6is hydrogen, X and Y are oxygen.

If R5and R6in the compounds of formula (I) in accordance with this invention which are hydrogen and X and Y are oxygen, the 6-amino compound of the formula (XV),

in which R1, R2, R3and R4such as defined above, can be subjected to interaction with, for example, N-acyl-2-(methylmercapto)-2-imidazoline (which may be easily commercially available hydroiodide 2-(methylmercapto)-2-imidazoline; see Mundla et al., Tetrahedron Lett., volume 41, page 6563, 2000) or the like, in solvents such as acetic acid, acetic acid/ethanol 1:10; acetic acid/isopropanol 1:10 or similar, to obtain the compounds of formula (XVIII),

in which R1, R2, R3and R4such as defined above; and R5is a hydrogen; a protecting group, such as, for example, tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z); C2-C7-allyloxycarbonyl; C3-C8-alkanolammonium; C3-C8-alkyloxyalkyl; C8-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkyloxy is a C1-C6alkyloxy; C9-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkenylacyl is a C2-C6alkenylamine; C9-C17-arylalkylamines, where the aryl is a C6-C10aryl, alkyloxy the C is C 2-C6alkyloxy; C2-C7-alkanoyl; C8-C17-arcanorum, where the aryl is a C6-C10aryl and alkyl is C2-C7alkyl; C1-C6by alkyl; C2-C6alkenyl; C2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; n = number of from 2 to 4.

Subsequent cleavage of the protective group (R5) is conducted by heating at the boiling point under reflux compounds of the formula (XVIII) in solvents such as acetic acid/ethanol 1:10, acetic who iSlate/isopropanol 1:10, methanol/water 3:1 or the like, to obtain the compounds of formula (XIX)

in which R1, R2, R3and R4such as defined above; n is the number of from 2 to 4. These compounds correspond to compounds of the formula (I) in accordance with this invention in which R1, R2, R3and R4such as defined above, and R5is 4,5-dihydro-1H-imidazol-2-yl (n=2), 1,4,5,6-tetrahydropyrimidin-2-yl (n=3) or 4,5,6,7-tetrahydro-1H-[1,3]diazepin-2-yl (n=4), R6is hydrogen and X and Y are oxygen.

An alternative way to start from compounds of the formula (XX), in which R1and R3such as defined above (see, for example, the formula (IX) (see Weiss et al., J. Amer. Chem Soc., volume 77, page 5891, 1955; Lijima et al., J. Med. Chem., volume 21, pages 398-400, 1978; Coop et al., J. Org. Chem., volume 63, page 4392-4396, 1988; Schmidhammer et al., Helv. Chim Acta, volume 71, pp. 1801-1804, 1988; Schmidhammer et al., Helv. Chim Acta, volume 73, pages 1986-1990, 1990).

Ketones of the formula (XX) is subjected to interaction in the presence of acid, such as methanesulfonate or the like, with ethylene glycol (as a reagent and solvent) to obtain compounds of the formula (XXI),

in which R1and R3such as defined above.

Introduction 3-Oh protective group in the compounds of formula (XXI) is carried out, for example, with OSU of benzylchloride or trialkylsilanes, in solvents such as dichloromethane, chloroform, acetone or N,N-dimethylformamide or the like, in the presence of a base such as sodium bicarbonate, potassium carbonate, triethylamine or the like, to obtain the compounds of formula (XXII),

in which R1and R3such as defined above; R4is a protective group such as benzyl, three(C1-C6-alkyl)silyl or Tris(C7-C16-arylalkyl)silyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl.

These 14-hydroxycodone then subjected to interaction with diallylsulfide, alkylhalogenide, alkanolamide, alkylhalogenide, arylalkylamine, arylalkylamines, arylalkylamine or chloroformiate in solvents such as N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) in the presence of a strong base such as sodium hydride, potassium hydride or sodium amide, to obtain the compounds of formula (XXIII),

in which R1, R2and R3such as defined above (see, for example, the formula (IX)), R4such as defined in the formula (XXII). If R2and R4are benzyl, the compounds of formula (XXI) may be directly subjected to the reaction with two equivalents of gasoline is bromide in DMF in the presence of sodium hydride, obtaining 3,14-O-dibenzyl derivatives of the formula (XXIII)in which R2and R4are benzyl and R1and R3such as defined above.

Acidic cleavage of the 3-Oh protective group and Catalinas functional group of compounds of formula (XXIII) is carried out in one stage with an acid, such as hydrochloric acid in methanol, tetraberlinia acid in dichloromethane, triperoxonane acid, to obtain the compounds of formula (X) (see 1st way)

in which R1, R2and R3such as defined above.

An alternative to this, if R4in the compounds of formula (XXIII) is benzyl, by hydrogenolysis of 3-O-benzyl connection with gaseous hydrogen in the presence of a catalyst such as Pd/C, PdO, Pd/Al2O3Pt/C, PtO2Pt/Al2O3or the like, in solvents, such as alcohols, a mixture of alcohol/water, glacial acetic acid or the like, followed by acid hydrolysis Catalinas functional group in position 6, for example with methanol and concentrated hydrochloric acid to obtain the compounds of formula (X).

The compounds of formula (X) is subjected to interaction in accordance with the first method, through the connection formulas (XI)-(XIV), with compounds of formula (I) in accordance with this invention.

In performance is undertaken following examples detail the formation of compounds in accordance with this invention.

Example 1

Synthesis of tert-butyl methyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid (compound 1) and tert-butyl methyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-acetic acid (compound 2)

The solution of the hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim Acta 1990, vol 71, pp. 1779-1783) (2,36 g, 5,96 mmol) and hydrochloride of glycine tert-butyl ester (1,11 g, 6.62 mmol) in absolute Meon (100 ml) is stirred for 1 hour in an atmosphere of N2at room temperature. Then added dropwise a solution of NaCNBH3(0.55 g, is 8.75 mmol) in Meon (50 ml) for 20 min, and the solution is stirred in an atmosphere of N2at room temperature. After 19 h add H2O (20 ml) and the mixture is evaporated. The residue is mixed with H2O (400 ml), alkalinized with concentrated ammonia, saturated with NaCl and extracted with Et2O (1 x 100 ml 3 x 50 ml). The combined organic phases are washed with H2About (1 x 200 ml) and saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. The aqueous phase is extracted with CH2Cl2/ISO-D 4:1 (1 x 100 ml 3 x 50 ml). The combined organic phases are treated as described above for the ethereal phases. After the first extraction (Et2O) gain of 1.05 g of a yellow oil containing two products (connection 1 and connection 2). the donkey second extraction (CH 2Cl2/ISO-D) get to 0.72 g of yellow oil containing, in addition to the two products, the corresponding 6-hydroxy. Two products are separated and purified HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1).

Connection 1: yield 0.28 g (11%) orange foamy resin. IR (KBr): 3407 (OH), 1731 (C=O) cm-1;1H-NMR (CDCl3): δ 6,66 (d, J=8,1, 1 arene. H); 6.48 in (d, J=8,1, 1 arene. H); of 5.05 (s, W, OH-C(3), -NH-C(6)); the 4.65 (d, J=3,6, H-C(5)); of 3.42 (s, C(6)-NH-CH2-); is 3.21 (s, CH3O-C(14)); a 2.36 (s, CH3N); 1,43 (C, -COOC(CH3)3); CI-M: m/z 431 (M++1).

Connection 2: output 0,63 g (24%) of a yellow foam resin. IR (KBr): 3421 (OH), 1729 (C=O) cm-1;1H-NMR (CDCl3): δ of 6.68 (d, J=8,0, 1 arene. H); 6,53 (d, J=8,0, 1 arene. H); 4,71 (s, W, OH-C(3)C(6)-NH-); 4,47 (d, J=7,0, H-C(5)); of 3.48 (d, J=17,3, 1H, C(6)-NH-CH2-); of 3.32 (d, J=17,3, 1H, C(6)-NH-CH2-); 3,19 (s, CH3O-C(14)); 2,42 (s, CH3N); of 1.42 (s, -COOC(CH3)3); CI-MS: m/z 431 (M++1).

Example 2

Synthesis Queen of triptoreline (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid (compound 3 · 1,5 TN)

A mixture of compound 1 (0.18 g, 0.42 mmol) and 30% triperoxonane acid (TFA) in CH2Cl2(7 ml) was stirred at room temperature for 9 h and evaporated. The residue (0.26 g orange foamy resin) is crystallized from ISO-D/Et2O/MeOH. The expected bis(triptorelin) is e get but instead receive a single triptorelin, which confirms several elemental analyses. The yield of 0.13 g (57%) of beige connections 3 · 1,5 TN: TPL > 190°C (decomp.); IR (KBr): 3428 (OH), 1677 (C=O) cm-1;1H-NMR (D2O): δ make 6.90 (d, J=8,4, 1 arene. H); for 6.81 (d, J=8,4, 1 arene. H); 4,47 (DD,3J=3,0,4J=1,0, H-C(5)); a 3.87 (d, J=1,4, C(6)-NH-CH2-); at 3.35 (s, CH3O-C(14)); 2,94 (s, CH3N); ESI-MS: m/z 375 (M++1).

Example 3

Synthesis Queen of triptoreline (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-acetic acid (compound 4 · 1,5 TN)

A mixture of compound 2 (a 0.30 g, 0.70 mmol) and 30% triperoxonane acid (TFA) in CH2Cl2(11 ml) was stirred at room temperature for 5 h and evaporated. The residue (0,43 g orange foamy resin) is crystallized from ISO-D/Et2O/MeOH. The expected bis(triptorelin) do not receive, but instead get a single triptorelin, which confirms several elemental analyses. Yield 0.21 g (55%) of beige connections 4 · 1,5 TN: TPL > 210°C (decomp.); IR (KBr): 3419 (OH), 1677 (C=O) cm-1;1H-NMR (D2O): δ 6,89 (d, J=8,6, 1 arene. H); 6,83 (d, J=8,6, 1 arene. H); the 4.90 (d, J=7,8, H-C(5)); of 4.04 (s, C(6)-NH-CH2-); of 3.32 (s, CH3O-C(14)); 2.91 in (s, CH3N); ESI-MS: m/z 375 (M++1).

Example 4

Synthesis of tert-butyl methyl ether (2'S)-2'-(4,5a-epoxy-3-is hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-propionic acid (compound 5) and tert-buterbaugh ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-propionic acid (compound 6)

The mixture hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim. Acta 1990, vol 71, pp. 1779-1783) (2,54 g, 6,41 mmol) and hydrochloride of L-alanine tert-butyl ester (1.75 g, 9,63 mmol) in absolute EtOH (100 ml), N-ethyldiethanolamine (2.8 ml, 16,07 mmol) and molecular sieves (2.8 g) is stirred for 5 hours in an atmosphere of N2at room temperature. Then added dropwise a solution of NaCNBH3(0.51 g, 8,12 mmol) in EtOH (20 ml) for 20 min, and the solution is stirred in an atmosphere of N2at room temperature. Two days later add the H2O (5 ml) and the mixture is evaporated. The residue is mixed with H2O (200 ml) and extracted with Et2O (2 x 100 ml 2 x 50 ml). The combined organic phases are washed with saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. The aqueous phase is extracted with CH2Cl2(2 x 100 ml 2 x 50 ml). The combined organic phases are treated as described above for the ethereal phases. From the first extraction (Et2O) gain of 1.34 g of yellow oil containing two product (compound 5 and compound 6). From the second extraction (CH2Cl2) gain of 0.68 g of yellow oil containing, in addition to the two products, the corresponding 6-hydroxy. Two products are separated and purified HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1). Compound 5 crystallized from methanol, and only what about the analytical quantity (50 mg) of compound 6 can be crystallized from ISO-D, the residue (0.75 g) obtained as a white foamy resin.

Compound 5: yield 0.32 g (11%) of colorless crystals. TPL 196-200°C; IR (KBr): 3203 (OH), 1729 (C=O) cm-1;1H-NMR (CDCl3): δ 6,69 (d, J=8,2, 1 arene. H); 6,47 (d, J=8,2, 1 arene. H); 4,70 (d, J=3.2, and H-C(5)); 3,55 (kV, J=6,8, C(6)-NH-CH(CH3)-); 3,19 (s, CH3O-C(14)); 2,35 (s, CH3N); 1,47(C, -COOC(CH3)3); of 1.26 (d, J=6,8, C(6)-NH-CH(CH3)-); CI-MS: m/z 445 (M++1).

Compound 6: yield of 0.80 g (24%) colourless crystals or white foamy resin. TPL 235-240°C (decomp.); IR (KBr): 3423 (OH), 1722 (C=O) cm-1;1H-NMR (CDCl3): δ 6,69 (d, J=8,0, 1 arene. H); is 6.54 (d, J=8,2, 1 arene. H); 4,39 (d, J=7,2, H-C(5)); of 3.32 (q, J=7,0, C(6)-NH-CH(CH3)-); 3,20 (s, CH3O-C(14)); 2,39 (s, CH3N); of 1.41 (s, -COOC(CH3)3); of 1.26 (d, J=6,8, C(6)-NH-CH(CH3)-); CI-MS: m/z 445 (M++1).

Example 5

Synthesis of bis(tetrafluoroborate) (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-propionic acid (compound 7 · 2 HBF4)

A solution of compound 5 (0,30 g, 0.70 mmol) in CH2Cl2(3 ml) is stirred with 54% terraforming acid (HBF4in Et2O (0.33 ml, 2,39 mmol) and the mixture is treated with ultrasound for 1 hour at room temperature. The precipitate is filtered off and dried. Yield 0.21 g (79%) of a white compound 7 · 2 HBF4: TPL > 290°C (decomp.); IR (KBr): 3423 (OH), 1741 (C=O), 1064 (B-F cm -1;1H-NMR (D2O): δ make 6.90 (d, J=8,0, 1 arene. H); for 6.81 (d, J=8,0, 1 arene. H); 5,02 (d, J=2,8, H-C(5)); 4,24 (kV, J=7,0, C(6)-NH-CH(CH3)-); at 3.35 (s, CH3O-C(14)); 2,94 (s, CH3N); and 1.63 (d, J=7,0, C(6)-NH-CH(CH3)-).

Example 6

Synthesis of bis(tetrafluoroborate) (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-propionic acid (compound 8 · 2 HBF4)

A solution of compound 6 (0.25 g, 0,56 mmol) in CH2Cl2(4 ml) is stirred with 54% terraforming acid (HBF4in Et2O (0,39 ml, to 2.85 mmol) and the mixture is treated with ultrasound for 1 hour at room temperature. The precipitate is filtered off and dried. Yield 0.28 g (89%) of a white compound 8 · 2 HBF4: TPL > 290°C (decomp.); IR (KBr): 3423 (OH), 1720 (C=O), 1083 (B-F) cm-1;1H-NMR (D2O): δ 6,87 (s, 2 arene. H); a 4.86 (d, J=7,6, H-C(5)); or 4.31 (q, J=7,0, C(6)-NH-CH(CH3)-); to 3.33 (s, CH3O-C(14)); 2,92 (s, CH3N); 1,58 (d, J=7,0, C(6)-NH-CH(CH3)-).

Example 7

Synthesis of tert-butyl methyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-3'-phenylpropionic acid (compound 9) and tert-butyl methyl ether (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-3'-phenylpropionic acid (compound 10)

The mixture hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim. Acta 190, volume 71, pp. 1779-1783) (2.70 g, for 6.81 mmol) and hydrochloride of L-phenylalanine tert-butyl ester (2,74 g, as 10.63 mmol) in absolute EtOH (150 ml), N-ethyldiethanolamine (3.04 from ml, 17,49 mmol) and molecular sieves (3.0 g) is stirred for 2.5 hours in an atmosphere of N2at room temperature. Then added dropwise a solution of NaCNBH3(0,47 g of 7.48 mmol) in EtOH (20 ml) for 20 min and the solution stirred in an atmosphere of N2at room temperature. After three days, add H2About (10 ml) and the mixture is evaporated. The residue is mixed with H2O (300 ml) and extracted with CH2Cl2(1 x 100 ml 4 x 50 ml). The combined organic phases are filtered through Celite, washed with saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. Gain of 3.96 g of a yellow oil, from which each of the two products get pure using HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1). of 0.68 g of starting compound (14-O-methyloxymorphone) restore as a brown foamy resin.

Compound 9: yield 0.34 g (10%) of an orange foam resin: IR (KBr): 3336 (OH), 1725 (C=O) cm-1;1H-NMR (CDCl3): δ 7,31-7,17 (m, 5 arene. H); of 6.71 (d, J=8,0, 1 arene. H); 6,47 (d, J=8,0, 1 arene. H); 4,71 (d, J=3.2, and H-C(5)); of 3.77 at 3.69 (m, C(6)-NH-CH(CH2Ph)-); 3,12 (s, CH3O-C(14)); 2,94-2,90 (m, C(6)-NH-CH(CH2Ph)-); 2,35 (s, CH3N); 1,32 (C, -COOC(CH3)3); CI-MS: m/z 521 (M++1).

The connection 10: you are the od 0,81 g (23%) of an orange foam resin: IR (KBr): 3409 (OH), 1724 (C=O) cm-1;1H-NMR (CDCl3): δ 7,29-7,17 (m, 5 arene. H); 6,70 (d, J=8,0, 1 arene. H); is 6.54 (d, J=8,0, 1 arene. H); 4,39 (d, J=7,4, H-C(5)); 3,51-of 3.43 (m, C(6)-NH-CH(CH2Ph)-); 3,20 (s, CH3O-C(14)); 2,98-2,78 (m, C(6)-NH-CH(CH2Ph); 2,44 (s, CH3N); 1,28 (C, -COOC(CH3)3); CI-MS: m/z 521 (M++1).

Example 8

Synthesis of bis(tetrafluoroborate) (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-3'-phenylpropionic acid (compound 11 · 2 HBF4)

A solution of compound 9 (0.16 g, 0.31 mmol) in CH2Cl2(3 ml) is stirred with 54% terraforming acid (HBF4in Et2O (0.25 ml, is 1.81 mmol) and the mixture is treated with ultrasound for 30 min at room temperature. The mixture is then evaporated, the residue (0.21 g orange oil) is dissolved in N2O and dried by freezing. Yield 0.18 g (90%) of a white lyophilisate:1H-NMR (D2O): δ 7,46-to 7.35 (m, 5 arene. H); 6,86 (d, J=8,2, 1 arene. H); 6,77 (d, J=8,2, 1 arene. H); the 4.90 (d, J=3,4, H-C(5)); to 4.46 (t, J=6,8, C(6)-NH-CH(CH2Ph)-); at 3.35 (d, J=6,8, C(6)-NH-CH(CH2Ph)-); of 3.25 (s, CH3O-C(14)); 2,90 (C, C3N).

Example 9

Synthesis of bis(tetrafluoroborate) (2'S)-2'-(4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-3'-phenylpropionic acid (compound 12 · 2 HBF4)

A solution of compound 10 (0,41 g of 0.79 mmol) in CH2Cl2(5 ml) paramesh who live with 54% terraforming acid (HBF 4in Et2O (0,60 ml, 4.35 mmol) and the mixture is treated with ultrasound for 30 min at room temperature. The mixture is then evaporated, the residue (0.54 g orange oil) is dissolved in N2O and dried by freezing. Output 0,46 g (90%) of a white lyophilisate:1H-NMR (D2O): δ 7,28 (s, 5 arene. H); to 6.88 (d, J=8,4, 1 arene. H); for 6.81 (d, J=8,4, 1 arene. H); a 4.83 (d, J=7,6, H-C(5)); of 4.54 (t, J=7,0, C(6)-NH-CH(CH2Ph)-); of 3.25 (s, CH3O-C(14)); 2,86 (s, CH3N).

Example 10

Synthesis of 6a-amino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol (compound 13)

The mixture hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim Acta 1990, vol 71, pp. 1779-1783) (6,22 g, 15,70 mmol), ammonium acetate (12.00 g, 156 mmol), NaCNBH3(0,81 g of 7.64 mmol) and absolute Meon (100 ml) is stirred for 23 h in an atmosphere of N2at room temperature. Then the solution is acidified (beige precipitate) with concentrated HCl and the mixture is evaporated. The residue is dissolved in N2(550 ml) and extracted with CH2Cl2(1 x 200 mg) to remove components that are insoluble in water. The aqueous phase is alkalinized with concentrated ammonia, saturated with NaCl and extracted with CH2Cl2/ISO-D 4:1 (2 x 250 ml 3 x 125 ml). The combined organic phases are washed with saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. The residue after evaporation (beige crystals) paracrystal izbivaut from methanol. The output of 1.95 g (39%) of white powder: TPL > 300°C (decomp.); IR (KBr): 3421 (OH) cm-1;1H-NMR (Me2SO-d6): δ 6,55 (d, J=8,0, 1 arene. H); of 6.29 (d, J=8,0, 1 arene. H); to 4.33 (DD,3J=4,0,4J=0,8, H-C(5)); to 3.38 (s, W, OH-C(3), NH2-C(6)); 3,13 (s, CH3O-C(14)); 2,24 (s, CH3N); CI-MS: m/z 317 (M++1).

Example 11

Synthesis of 6b-dibenzylamino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol (compound 14)

The mixture hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim Acta 1990, vol 71, pp. 1779-1783) (2.00 g, of 5.05 mmol) in Meon/N2About 9:1 (80 ml) is mixed with silver benzoate (1,17 g, 5,11 mmol) and stirred for 90 minutes at a temperature of 40°C. the precipitate of silver bromide is filtered off and the filtrate is evaporated. The residue is mixed with EtOH/toluene 2:3 (50 ml) and the solvent is sucked off. Thus, the gain of 2.35 g of 14-O-methyloxymorphone in the form of a yellow foam resin. It is mixed with toluene (250 ml), benzoic acid (0,93 g, 7.62 mmol), dibenzylamine (1,49 g, rate of 7.54 mmol) and the monohydrate of p-toluenesulfonic acid on the tip of a spatula, and the mixture is heated at boiling temperature under reflux for 20 h with the use of a water separator. Then the solution reduces to a volume of 50 ml, add absolute EtOH (220 ml), NaCNBH3(0,30 g, 4.77 mmol) and molecular sieves, and the solution is stirred for 6 hours in an atmosphere of N2at room t is mperature. The mixture is diluted with Meon (100 ml), filtered and the filtrate is evaporated. The residue is mixed with H2(550 ml), alkalinized with concentrated ammonia and extracted with CH2Cl2(1 x 200 ml, 3 x 100 ml). The combined organic phases are washed with H2About (5 x 300 ml) and saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. The residue after evaporation (2,42 g of brown oil) is recrystallized from methanol. The output of 1.43 g (57%) of beige crystals: TPL 124 to 128°C; IR (KBr): 3178 (OH) cm-1;1H-NMR (CDCl3): δ 7,45-7,20 (m, 10 arene. H); 6,56 (d, J=8,1, 1 arene. H); 6,44 (d, J=8,1, 1 arene. H); 4.72 in (d, J=6,8, H-C(5)); a 3.87 (d, J=14,0, 2H, (PhCH2)2N-C(6)); 3,61 (d, J=14,0, 2 H, (PhCH2)2N-C(6)); 3,20 (s, CH3O-C(14)); 2,34 (s, CH3N); CI-MS: m/z 497 (M++1).

Example 12

Synthesis of 6b-amino-4,5a-epoxy-14b-methoxy-17-methylmorphinan-3-ol (compound 15).

A mixture of compound 14 (1,02 g, 2.05 mmol), 10% Pd/C catalyst (0.52 g), cyclohexene (30 ml) and absolute Meon (30 ml) is heated at boiling temperature under reflux for 16 h in an atmosphere of N2. Then the catalyst is filtered off and the filtrate is evaporated. The residue (0.66 g of a white foamy resin) is crystallized from ISO-D/Et2O 1:1 (2 ml). Yield: 0.33 g (42%) of beige crystals: TPL > 235-239°C; IR (KBr): 3348 (OH) cm-1;1H-NMR (CDCl3): δ 6,62 (d, J=8,0, 1 arene. H); 6,54 (who, J=8,0, 1 arene. H); 4.26 deaths (d, J=7,0, H-C(5)); 3,22 (s, CH3O-C(14)); a 2.36 (s, CH3N); CI-MS: m/z 317 (M++1).

Example 13

Synthesis of 4,5a-epoxy-6b-[N,N'-bis(tert-butoxycarbonyl) guanidino]-14b-methoxy-17-methylmorphinan-3-ol (compound 16)

A solution of compound 15 (0,94 g of 2.97 mmol), N,N'-bis-(tert-butoxycarbonyl)-S-methylisoleucine (0,92 g, 3,17 mmol) and N-ethyldiethanolamine (of 0.58 ml of 3.33 mmol) in absolute N,N-dimethylformamide (40 ml) is mixed with silver nitrate (0.54 g, 3,18 mmol) and the mixture is stirred for 4 hours. Then mercaptan silver is filtered through Celite and washed with CH2Cl2(4 x 50 ml). The filtrate was washed with N2About (10 x 150 ml) and saturated NaCl solution (2 x 150 ml), dried (Na2SO4) and evaporated. Thus, the gain of 1.46 g of yellow foam resin, which purify HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH/conc. ammonia 95:4,5:0,5). Output: 0,77 g (46%) green foamy resin:1H-NMR (CDCl3): δ 11,49 (s, sh, NH-COO - (CH3)3); 8,59 (d, J=8,0, C(6)-NH-); of 6.71 (d, J=8,4, 1 arene. H); 6,56 (d, J =8,4, 1 arene. H); to 4.41 (d, J=7,2, H-C(5)); 3,22 (s, CH3O-C(14)); of 2.38 (s, CH3N); is 1.51 (s, s (N3)3), 1,47 (C, C(CH3)3).

Example 14

Synthesis dihydrochloride 4,5a-epoxy-6b-guanidine-14b-methoxy-17-methylmorphinan-3-ol (compound 17 · 2 HCl)

A solution of compound 16 (50 mg, 0,089 the mol) in Et 2O (3 ml) is mixed through the transparent acidic reaction mixture with ethereal HCl and 4 drops of N2O. the Mixture is treated with ultrasound for one hour at room temperature and then evaporated. The residue (40 mg white foamy resin) was dissolved in N2O and dried by freezing. Yield: 30 mg (79%) of compound 17 · 2 HCl as a white lyophilisate:1H-NMR (CDCl3): δ 9,59 (s, OH-C(3)); 9,29 (s, sh, NH+); 8,53 (d, J=8,0, C(6)-NH-); 7,29 (s, W, C(6)-NH-C(NH2)2+), is 6.78 (d, J=8,1, 1 arene. H); 6,69 (d, J=8,1, 1 arene. H); of 4.49 (d, J=7,2, H-C(5)); 3,26 (s, CH3O-C(14)); 2,84 (s, CH3N).

Example 15

Synthesis of 4,5a-epoxy-6a-[N,N'-bis(tert-butoxycarbonyl)-guanidino]-14b-methoxy-17-methylmorphinan-3-ol (compound 18)

A solution of compound 13 (1,00 g, and 3.16 mmol), N,N'-bis-(tert-butoxycarbonyl)-S-methylisoleucine (1,00 g, 3,44 mmol) and N-ethyldiethanolamine (of 0.60 ml, 3,44 mmol) in absolute N,N-dimethylformamide (60 ml) is mixed with silver nitrate (0.55 g, 3,24 mmol) and the mixture is stirred for 1.5 hours. Then salt of the mercaptan and silver is filtered through Celite and washed with CH2Cl2(4 x 50 ml). The filtrate was washed with N2About (6 x 200 ml) and saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. Thus, the gain of 1.85 g of yellow oil, which was purified HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1). Output:0,67 g (38%) of a white foamy resin: 1H-NMR (CDCl3): δ 11,53 (s, sh, NH-COO - (CH3)3); 8,81 (d, J=8,0, C(6)-NH-); of 6.73 (d, J=8,2, 1 arene. H); 6,56 (d, J=8,2, 1 arene. H); of 4.66 (DD,3J=2,6,4J=1,6, H-C(5)); of 3.25 (s, CH3O-C(14)); 2,35 (s, CH3N); a 1.50 (s, 2 x C (N3)3).

Example 16

Synthesis dihydrochloride 4,5a-epoxy-6a-guanidine-14b-methoxy-17-methylmorphinan-3-ol (compound 19 · 2 HCl)

A solution of compound 18 (50 mg, 0,089 mmol) in Et2O (3 ml) is mixed through the transparent acidic reaction mixture with ethereal HCl and 4 drops of N2O. the Mixture is treated with ultrasound for 1.5 hours at room temperature and then evaporated. The residue (40 mg white foamy resin) was dissolved in N2O and dried by freezing. Yield: 35 mg (92%) of compound 19 · 2 HCl as a white lyophilisate:1H-NMR (CDCl3): δ 9,29 (s, sh, NH+); 9,20 (s, OH-C(3)); EUR 7.57 (d, J=8,8, C(6)-NH-); 7,46 (s, W, C(6)-NH-C(NH2)2+), 6,76 (d, J=8,1, 1 arene. H); 6,62 (d, J=8,1, 1 arene. H); 4,70 (d, J=4,0, H-C(5)); to 3.36 (s, CH3O-C(14)); 2,88 (s, CH3N).

Example 17

Synthesis of 1,3-bis(tert-butoxycarbonyl)-2-{4,5a-epoxy-6b-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-yl}-isomotion (compound 20)

A solution of compound 15 (0.12 g, 0.38 mmol), N,N'-bis-(tert-butoxycarbonyl)-S-methylisoleucine (0.24 g, 0.83 mmol) and triethylamine (of 0.12 ml, 0.86 mmol) in abs the currency of N,N-dimethylformamide (4 ml) is mixed with silver nitrate (0.14 g, 0.82 mmol) and the mixture is stirred for 17 hours. Then salt of the mercaptan and silver is filtered through Celite and washed with CH2Cl2(4 x 50 ml). The filtrate was washed with N2About (5 x 200 ml) and saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. Thus, the gain of 0.10 g of a yellow foam resin, which purify HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH/conc. ammonia 100:5:0.5 to). Yield: 45 mg (15%) of a white foamy resin:1H-NMR (CDCl3): δ 11,54 (s, NH-COO - (CH3)3; 10,44 (s, sh, NH-COO - (CH3)3); 8,59 (d, J=8,8, C(6)-NH-); 6,91 (d, J=8,0, 1 arene. H); only 6.64 (d, J=8,0, 1 arene. H); 4,51 (d, J=4,4, H-C(5)); or 3.28 (s, CH3O-C(14)); is 2.37 (s, CH3N); is 1.51 (s, 2 x C (N3)3, of 1.47(s, 2 x C (N3)3). FAB-MS: m/z 801 (M++1).

Example 18

Synthesis of 1,3-bis(tert-butoxycarbonyl)-2-{4,5a-epoxy-6a-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14b-methoxy-17-methylmorphinan-3-yl}-isomotion (compound 21)

A solution of compound 13 (0.50 g, was 1.58 mmol), N,N'-bis-(tert-butoxycarbonyl)-S-methylisoleucine (1,00 g, 3.54 mmol) and triethylamine (0.5 ml, 4,94 mmol) in absolute N,N-dimethylformamide (15 ml) is mixed with silver nitrate (0,58 g of 3.12 mmol) and the mixture is stirred for 20 hours. Then salt of the mercaptan and silver is filtered through Celite and washed with CH2Cl2(5 x 50 ml). The filtrate was washed with N2About (5 x 200 ml)and saturated NaCl solution (1 x 200 ml), dried (Na2SO4) and evaporated. Thus, the gain of 1.14 g of yellow foam resin, which purify HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH,conc. ammonia 100:5:0.5 to). Yield: 0.75 g (62%) of a white foamy resin:1H-NMR (CDCl3): δ to 11.56 (s, NH-COO - (CH3)3; 10,69 (s, sh, NH-COO - (CH3)3); 8,68 (d, J=8,8, C(6)-NH-); 6,87 (d, J=8,0, 1 arene. H); 6,66 (d, J=8,0, 1 arene. H); 4,63 (d, J=3,6, H-C(5)); of 3.27 (s, CH3O-C(14)); a 2.36 (s, CH3N); is 1.51 (s, 4 x C(CH3)3), ESI-MS: m/z 801 (M++1).

Example 19

Synthesis of ethyl ester dihydrochloride (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6a-ylamino)-acetic acid (compound 22 · 2 HCl) and the dihydrochloride of ethyl ether (4,5a-epoxy-3-hydroxy-14b-methoxy-17-methylmorphinan-6b-ylamino)-acetic acid (compound 23 · 2 HCl)

The mixture hydrobromide 14-O-methyloxymorphone (H. Schmidhammer et al., Helv. Chim. Acta 1990, vol 71, pp. 1779-1783) (2.00 g, of 5.05 mmol), hydrochloride of the ethyl ester of glycine (1.06 g, to 7.59 mmol), absolute EtOH (100 ml), triethylamine (1.8 ml, 12,91 mmol) and molecular sieves (2.5 g) is stirred for 3.5 hours in an atmosphere of N2at room temperature. Then several portions add NaCNBH3(0,49 g, 7,80 mmol) and the solution stirred in an atmosphere of N2at room temperature. After 4 days add H2O (5 ml) and the mixture is evaporated. The residue is mixed with H2 O (200 ml) and extracted with CH2Cl2(2 x 100 ml 2 x 50 ml). The combined organic phases are washed with saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and evaporated to obtain 0,76 g of brown oil. Two products are separated and purified by HPLC (p=4 bar, silica gel 60, CH2Cl2/MeOH 10:2). They are then dissolved in a small amount of the Meon and turn in dihydrochloride ethereal HCl. Because no crystallization connection 22 · 2 HCl, the solvent is sucked off, the residue is dissolved in N2O and dried by freezing. The mother solution of compound 23 · 2 HCl also is evaporated, the residue is dissolved in N2O and dried by freezing.

The connection 22 · 2 HCl: yield 0.20 g (8%) yellow lyophilisate: IR (KBr): 3423 (OH), 1743 (C=O) cm-1;1H-NMR (DMSO-d6): δ 9,81, 9,50, 9,34 (3C, 4H, OH, NH+, NH2+), for 6.81 (d, J=8,1, 1 arene. H); only 6.64 (d, J =8,1, 1 arene. H); 4,50 (d, J=3,6, H-C(5)); to 4.23 (q, J=6,9, -COOCH2CH3); 3,13 (s, CH3O-C(14)); 2,88 (d, J=4,4, CH3N); of 1.26 (t, J=6,9, -COOCH2CH3).

The connection 23 · 2 HCl: yield 0.20 g (8%) white crystals (0.11 g) and yellow lyophilisate (0.09 g): TPL > 200°C (decomp.); IR (KBr): 3413 (OH), 1745 (C=O) cm-1;1H-NMR (DMSO-d6): δ 10,02, being 9.61, 9,51 (3C, 4H, OH, NH+, NH2+), PC 6.82 (d, J=8,0, 1 arene. H); 6,70 (d, J=8,0, 1 arene. H); 4,95 (d, J=7,4, H-C(5)); 4,22 (kV, J=7,0, -COOCH2CH3); 3,26 (s, CH3OC(14)); 2,85 (s, CH3N); 1,25 (t, J=7,0, -COOCH2CH3).

Example 20

Synthesis of tert-butyl methyl ether (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6a-ylamino)-acetic acid (compound 24) and tert-butyl methyl ether (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6b-ylamino)-acetic acid (compound 25)

A mixture of 14-O-ethoxypropane (H. Schmidhammer, R. Krassnig, Sci. Pharm. 1990, volume 58, pages 255-257) (1,02 g, to 3.09 mmol), hydrochloride of glycine tert-butyl ester (0.7 g, 4,63 mmol), absolute EtOH (100 ml), N-ethyldiethanolamine (0.9 ml, 5.0 mmol) and molecular sieves (2 g) is stirred for 3 hours in an atmosphere of N2at room temperature. Then added dropwise a solution of NaCNBH3(0.25 g, 3,98 mmol) in ethanol (20 ml) and the solution stirred in an atmosphere of N2at room temperature. After 2 days, add H2O (5 ml), filtered through Celite and the mixture is evaporated. The residue is mixed with H2O (150 ml) and extracted with Et2O (2 x 100 ml 1 x 80 ml, 2 x 50 ml). The combined organic phases are washed with saturated NaCl solution (3 x 100 ml), dried (Na2SO4) and evaporated. The aqueous phase is extracted with CH2Cl2/ISO-D 4:1 (2 x 100 ml). The combined organic phases are treated as described above for the ethereal phases. From the first extraction (Et2O) gain of 1.05 g of a yellow foam resin and the second extracts and (CH 2Cl2/ISO-D) obtain 0.17 g of a white foamy resin. Two products are separated and purified HPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1).

Compound 24: yield 0.09 g (7%) white foam resin: IR (KBr): 3425 (OH), 1735 (C=O) cm-1;1H-NMR (CDCl3): δ 6,66 (d, J=8,0, 1 arene. H); 6,47 (d, J=8,0, 1 arene. H); and 4.68 (d, J=2,6, H-C(5)); of 3.43 (s, C(6)-NH-CH2-); 2,32 (s, CH3N); 1,45 (s, -COOC(CH3)3); to 1.15 (t, J=7,0, C(14)-OCH2CH3); CI-MS: m/z 445 (M++1).

Compound 25: exit at 0.19 g (14%) white foam resin: IR (KBr): 3440 (OH), 1734 (C=O) cm-1;1H-NMR (CDCl3): δ to 6.67 (d, J=8,0, 1 arene. H); 6,53 (d, J=8,0, 1 arene. H); 4,48 (d, J=7,0, H-C(5)); 3,50 (d, J=17,2, 1H, C(6)-NH-CH2-); 3,23 (d, J=17,2, 1H, C(6)-NH-CH2-); 2,33 (s, CH3N); the 1.44 (s, -COOC(CH3)3); to 1.19 (t, j=7,0, C(14)-OCH2CH3); CI-MS: m/z 445 (M++1).

Example 21

Synthesis of bis(tetrafluoroborate) (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6a-ylamino)-acetic acid (compound 26 · 2 HBF4)

A solution of compound 24 (0.05 g, 0.11 mmol) in CH2Cl2(3 ml) is stirred with 54% terraforming acid (HBF4in Et2O (0,08 ml) and the mixture is treated with ultrasound for 15 minutes at room temperature. The precipitate is filtered off and dried. Yield 0.03 g (53%) of a white compound 3 · 2 HBF4: TPL > 286°C (decomp.); IR (KBr): 3466 (OH), 1735 (C=O), 1067 (-F) cm -1;1H-NMR (D2O): δ make 6.90 (d, J=8,0, 1 arene. H); for 6.81 (d, J=8,0, 1 arene. H); 5,07 (d, J=3,6, H-C(5)); was 4.02 (s, C(6)-NH-CH2-); 2,96 (s, CH3N); to 1.24 (t, J=7,0, C(14)-OCH2CH3); ESI-MS: m/z 389 (M++1).

Example 22

Synthesis of bis(tetrafluoroborate) (4,5a-epoxy-3-hydroxy-14b-ethoxy-17-methylmorphinan-6b-ylamino)-acetic acid (compound 27 · 2 HBF4)

A solution of compound 25 (0.10 g, 0.22 mmol) in CH2Cl2(6 ml) is stirred with 54% terraforming acid (HBF4in Et2O (0.16 ml) and the mixture is treated with ultrasound for 15 minutes at room temperature. The precipitate is filtered off and dried. Yield 0.09 g (73%) of a white compound 3 · 2 HBF4: TPL > 280°C (decomp.); IR (KBr): 3426 (OH), 1758 (C=O), 1064 (B-F) cm-1;1H-NMR (D2O): δ make 6.90 (d, J=8,0, 1 arene. H); 6,85 (d, J=8,0, 1 arene. H); to 4.92 (d, J=7,6, H-C(5)); a 4.03 (s, C(6)-NH-CH2-); to 2.94 (s, CH3N); of 1.29 (t, J=6,8, C(14)-OCH2CH3); ESI-MS: m/z 389 (M++1).

Example 23

Synthesis of tert-butyl methyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3,14b-digidroksimorfinan-6b-ylamino)-3-phenylpropionic acid (compound 28)

A mixture of naltrexone hydrochloride (UK patent GB 1119270, 1968) (5,46 g, 13,23 mmol) and hydrochloride of L-phenylalanine tert-butyl ester (5,46 g, 21,18 mmol) in absolute EtOH (250 ml), N-ethyldiethanolamine the (6 ml, to 43.4 mmol) and molecular sieves (5 g) is stirred for 6 hours in an atmosphere of N2at room temperature. Then add NaCNBH3(0,91 g, 14, 48mm mmol) and the solution stirred in an atmosphere of N2at room temperature. After 6 days add H2O (20 ml), filtered and the filtrate is evaporated. The residue is mixed with H2O (300 ml), alkalinized conc. ammonia and extracted with CH2Cl2(1 x 100 ml 4 x 50 ml). The combined organic phases are washed with H2About (2 x 200 ml), dried (Na2SO4) and evaporated. From the obtained after evaporation residue (8.44 grams) 2 g clean circular chromatography (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:1:0.1 to 150:2,5:0,2). Yield 0.33 g (19% relative to the entire crude product) of pure compound 28 as a white foam resin:1H-NMR (DMSO-d6): δ 8,98 (s, OH-C(3)), 7,22 (m, 5 arene. H), 6,56 (d, J=8,0, 1 arene. H); 6,46 (d, J=8,0, 1 arene. H); 4,78 (s, OH-C(14)); 4,14 (d, J=6,0, H-C(5)); of 1.20 (s, -COOC(CH3)3); 0,84 (m, CH (cyclopropyl)); 0,47 (m, CH2(cyclopropyl)); 0,09 (m, CH2(cyclopropyl)); CI-MS: m/z 547(M++1).

Example 24

Synthesis of bis(terpersonal) (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3,14b-digidroksimorfinan-6b-ylamino)-3-phenylpropionic acid (compound 29 · 2 HBF4)

A solution of compound 28 (0.18 g, 0.33 mmol) in CH2Cl2(5 ml) displaced the more with 54% terraforming acid (HBF 4in Et2O (0,22 ml) and the mixture stirred for 1 h at a temperature of 0aboutC. the precipitate is filtered off and dried. The crude product is purified by circular chromatography (silica gel 60, CH2Cl2/MeOH 7:3 to 3:7, then only the Meon). Yield 0.06 g (27%) of pure compound 29 · 2 HBF4in the form of a yellow foam resin:1H-NMR (DMSO-d6): δ 7,17 (m, 5 arene. H), of 6.45 (d, J=8,2, 1 arene. H); 6,35 (d, J=8,2, 1 arene. H); to 4.73 (s, OH-C(14)); 4,08 (d, J=7,4, H-C(5)); 0,80 (m, CH (cyclopropyl)); 0,44 (m, CH2(cyclopropyl)); 0,09 (m, CH2(cyclopropyl)); HR-FAB-MS: m/z calculated for C29H35N5About5(M++1): 491,2536 found 491,2540.

Example 25

Synthesis of 3-benzyloxy-17-cyclopropylmethyl-4,5a-epoxy-14b-hydroxymorphinan-6-Spiro-2'-1,3-dioxolane (compound 30)

A mixture of 17-cyclopropyl-4,5a-epoxy-3,14b-digidroksimorfinan-6-Spiro-2'-dioxolane (H. Schmidhammer et al., Heterocycles 1998, vol 49, PP 489-497) (6,90 g, 17,90 mmol), K2CO3(6,70 g, 48,48 mmol), benzylbromide (2,34 ml, 19,66 mmol) and absolute DMF (70 ml) is stirred for 21 h in an atmosphere of N2at room temperature. Inorganic substances are filtered off, washed with CH2Cl2and the filtrate is evaporated. The residue (yellow crystals) is recrystallized from Meon. Output 7,37 g (87%) of pure compound 30 in the form of yellow crystals. TPL 130-131°C; IR (KBr): 3352(OH) cm -1;1H-NMR (CDCl3): δ 7,42-7,27 (m, 5 arene. H); to 6.75 (d, J=8,3, 1 arene. H); is 6.54 (d, J=8,3, 1 arene. H); to 5.17 (d, J=11,7, OCH2Ph), 5,10 (d, J=11,7, OCH2Ph), 4,58 (s, H-C(5)); 4,19-to 3.73 (m, C(6)-0-CH2-CH2-0-C(6)); CI-MS: m/z 476 (M++1).

Example 26

Synthesis of hydrochloride of 3-benzyloxy-17-cyclopropylmethyl-4,5a-epoxy-14b-{[(E)-3-phenylprop-2-enyl]oxy}morphinan-6-Spiro-2'-1,3-dioxolane (compound 31 · HCl)

A mixture of compound 30 (4,00 g to 8.41 mmol)in absolute DMF (50 ml), NaH (0,60 g, 25,23 mmol, from 1,00 g of 60% NaH dispersion after repeated washing with petroleum ether) is stirred for 20 minutes in an atmosphere of N2at a temperature of 0°C. and Then added dropwise a solution of innamibia (2.15 g, of 10.93 mmol) in DMF (20 ml) and the mixture stirred for 3 h at room temperature in an atmosphere of N2. After decomposition of the excess NaH careful addition of small pieces of ice, the mixture was poured into 400 ml of N2O and extracted with CH2Cl2(4 x 75 ml). The combined organic phases are washed with H2About (5 x 300 ml) and saturated NaCl solution (1 x 100 ml), dried (Na2SO4) and evaporated. The residue after evaporation (5,25 g orange oil) is purified by chromatography on a column (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:2:0,5). Yield 1.86 g (37%) of pure compound 31. For analytical purposes 0.2 g dissolved in ether and soedinenie · HCl precipitated as Krasnogo powder ethereal HCl solution. TPL 133-136°;1H-NMR (DMSO-d6): δ 8,33 (sh, NH+); 7,53-of 7.24 (m, 10 arene. H); 6,93 (d, J=8,4, 1 arene. H); 6,72 of 6.68 (m, 1 arene. H, 2 Alef., H); 5,15 (s, OCH2Ph); the 4.65 (s, H-C(5)); or 4.31-is 4.21 (m, C(6)-O-CH2-CH2-O-C(6)); 1,09 (m, CH (cyclopropyl)); 0,72 to 0.44 (m, 2 x CH2(cyclopropyl)); CI-MS: m/z 592 (M++1).

Example 27

Synthesis of hydrochloride 17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[3-(phenylpropyl)oxy]morphinan-6-Spiro-2'-1,3-dioxolane (compound 32 · HCl)

A mixture of compound 31 (0,89 g and 1.51 mmol), Meon (50 ml), THF (15 ml) and 10% Pd/C (90 mg) hydronaut at room temperature and a pressure of 30 lb/inch2(206,8 kPa) for 2 hours. Then the catalyst is filtered off and the filtrate is evaporated. The residue after evaporation (1.0 g, yellow oil) is purified by chromatography on a column (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:5:0.5 to). The yield of 0.41 g (53%) of pure compound 32. For analytical purposes 70 mg dissolved in ether and the connection 32 · HCl precipitated as a white powder by the addition of ethereal HCl. TPL 158-162°;1H-NMR (DMSO-d6): δ 9,24 (s, OH); 7,79 (sh, NH+); 7,35-7,19 (m, 5 arene. H); of 6.68 (d, J=8,0, 1 arene. H); to 6.57 (d, J=8,0, 1 arene. H); 4,51 (s, H-C(5)); or 4.31-is 4.21 (m, C(6)-O-CH2-CH2-O-C(6)); CI-MS: m/z 504 (M++1).

Example 28

Synthesis of hydrochloride 17-cyclo is mobiletel-4,5a-epoxy-3-hydroxy-14b-[3-(phenylpropyl)oxy]morphinan-6-she (compound 33 · HCl)

A solution of compound 32 (4,00 g, 7,94 mmol) in 28 ml Meon and 12 ml of conc. HCl is heated at the boiling point under reflux for 1.5 h, then poured into 100 ml of ice/water and alkalinized conc. the ammonia. The mixture is extracted with CH2Cl2(4 x 100 ml), the combined organic phases are washed with water (2 x 100 ml) and saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and evaporated. The residue after evaporation (3,98 g of brown oil) is purified by chromatography on a column (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:3:0,5). The output of 3.05 g (83%) of pure compound 33. For analytical purposes 90 mg dissolved in ether and the connection 33 · HCl precipitated as colorless crystals by the addition of ethereal HCl. TPL 220-230°;1H-NMR (DMSO-d6): δ 9,52 (s, OH); to 8.20 (s, NH+); 7,30-to 7.18 (m, 5 arene. H); of 6.71 (d, J=8,0, 1 arene. H); only 6.64 (d, J=8,0, 1 arene. H); 4,89 (s, H-C(5)); CI-MS: m/z 460 (M++1).

Example 29

Synthesis of tert-butyl methyl ether {17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6a-ylamino}-acetic acid (compound 34) and tert-butyl methyl ether {17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6b-ylamino}-acetic acid (compound 35)

A mixture of compound 33 (0.7 g, of 1.41 mmol), hydrochloride of glycine tert-butyl ester (0,26 is, 1.55 mmol), absolute EtOH (20 ml), triethylamine (0,49 ml of 3.53 mmol) and molecular sieves (0.7 g) is stirred for 23 hours in an atmosphere of N2at room temperature. Then add NaCNBH3(0,13 g 2,07 mmol) and the solution stirred in an atmosphere of N2at room temperature. After 3 days add H2O (5 ml), filtered and the filtrate is evaporated. The residue is mixed with H2O (20 ml), alkalinized with concentrated ammonia and extracted with CH2Cl2(1 x 50 ml 3 x 30 ml). The combined organic phases are washed with saturated NaCl solution (3 x 200 ml), dried (Na2SO4) and evaporated. The residue after evaporation (of 0.62 g of brown oil) is separated and purified by chromatography on a column (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:2:0,5).

Compound 34: yield 70 mg (9%).1H-NMR (CDCl3): δ 7,28-7,16 (m, 5 arene. H); to 6.67 (d, J=8,1, 1 arene. H); 6,45 (d, J=8,1, 1 arene. H); 4,70 (d, J=3,4, H-C(5)); of 1.44 (s, -COOC (N3)3); CI-MS: m/z 575 (M++1).

Compound 35: yield 40 mg (5%).1H-NMR (DMSO-d6): δ 8,96 (s, OH); 7,31-7,16 (m, 5 arene. H); is 6.54 (d, J=8,3, 1 arene. H); 6,45 (d, J=8,3, 1 arene. H); 4.25 in (d, J=6,6, H-C(5)); of 1.39 (s, -COOC(CH3)3); CI-MS: m/z 575 (M++1).

Example 30

Synthesis of tert-butyl methyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]morphinan-6a-ylamino)-3-phenylpropionic acid (compound 36) and tert-bout the gross ether (2'S)-2'-(17-cyclopropylmethyl-4,5a-epoxy-3-hydroxy-14b-[(3-phenylpropyl)oxy]morphinan-6b-ylamino)-3-phenylpropionic acid (compound 37)

A mixture of compound 33 (0.7 g, of 1.41 mmol), hydrochloride of L-phenylalanine tert-butyl ester (0.55 g, 2,13 mmol), absolute EtOH (20 ml), triethylamine (0,49 ml of 3.53 mmol) and molecular sieves (0.7 g) is stirred for 23 hours in an atmosphere of N2at room temperature. Then add NaCNBH3(0,13 g 2,07 mmol) and the solution stirred in an atmosphere of N2at room temperature. After 4 days add H2O (5 ml), filtered, and the filtrate is evaporated. The residue is mixed with H2O (20 ml), alkalinized conc. ammonia and extracted with CH2Cl2(1 x 50 ml 3 x 30 ml). The combined organic phases are washed with saturated NaCl solution (3 x 100 ml), dried (Na2SO4) and evaporated. The residue after evaporation (brown oil) is separated and purified by chromatography on a column (silica gel 60, CH2Cl2/MeOH/conc. ammonia 250:2:0,5).

The connection 36: yield 70 mg (7%).1H-NMR (DMSO-d6): δ of 8.90 (s, OH); 7,31 for 7.12 (m, 5 arene. H); 6,56 (d, J=8,2, 1 arene. H); 6,40 (d, J=8,2, 1 arene. H); to 4.52 (d, J=3,6, H-C(5)); 1,22 (C, -COOC(CH3)3); CI-MS: m/z 665 (M++1).

Compound 37: yield 0.33 g (35%).1H-NMR (DMSO-d6): δ 8,98 (s, OH); 7,27-7,13 (m, 5 arene. H); is 6.54 (d, J=8,0, 1 arene. H); 6,44 (d, J=8,0, 1 arene. H); is 4.21 (d, J=7,0, H-C(5)); of 1.20 (s, -COOC(CH3)3); CI-MS: m/z 665 (M++1).

Example 31

Synthesis dihydrochloride {17-cyclopropylmethyl-4,5a-EPO is si-3-hydroxy-14b-[(3-phenylpropyl)oxy]-morphinan-6b-ylamino}-acetic acid (compound 38 · 2 HCl)

A mixture of compound 35 (40 mg, 0.07 mmol) and 4M HCl in dioxane (2 ml) is heated at the boiling point under reflux for 6 hours the Precipitate is filtered off and dried. Yield 10 mg (24%) of a white compound 38 · 2 HCl:1H-NMR (D2O): δ 7,38-7,26 (m, 5 arene. H); 6.89 in (d, J=8,0, 1 arene. H); 6,83 (d, J=8,0, 1 arene. H); 4,91 (d, J=7,4, H-C(5)); 4,00 (C(6)-NH-CH2-).

Example 32

Studies of binding to opioid receptors

Studies of binding to opioid receptors spend on homogenizate rat brain using [3H]DAMGO (agonist m-receptor) as radioligand, in strict accordance with the earlier publication (M. Spetea et al., Neurochemical Research, 1998, volume 23, pages 1213-1218).

Compounds 1-4, 7, 8, 11, 16, 17, 22, 23 and 38 show a very high affinity for m-opioid receptors, which are mainly responsible for analgesia (table 1). Compared with them, morphine clearly shows a lower affinity for m-opioid receptors.

0,90
Table 1< / br>
Studies of binding to opioid receptors of compounds 1-4, 7, 8, 11, 16, 17, 22, 23 and 38 and morphine
ConnectionKi(nm) (μreceptor)
10,48
21,30
3
40,83
70,77
81,90
110,95
160,61
170,25
220,21
230,80
380,24
Morphine6,55

Example 33

Test for analgesia

Testing conducted on rats ("test OTDELENIE tail of the rat"). This test is carried out as described in the literature (Zs. Fürst et al., Eur. J. Pharmacol. 1993, vol 236, pp. 209-215).

Compounds 3, 4, 7 and 8 showed a very high analgesic effect. Connection 4 68 times more active than morphine in a subcutaneous (SC) and 238 times more active than morphine when intracerebroventricular introduction (ITC) (table 2). High performance PC/IVC ratio for compounds 3, 4, 7 and 8 show that, compared to morphine, these compounds are mainly distributed in the peripheral system, and mainly have an analgesic effect on the periphery. These figures indicate that compound 3 can overcome the blood-brain barrier only in very limited quantities, and its efficiency is, therefore, primarily evident at the periphery (outside the Central nervous with the system). This significantly reduces the number of side effects that are related to the Central side effects such as nausea, vomiting, sedation, dizziness, confusion, respiratory depression and mania.

Compounds 3 and 4 show a much longer effective analgesic period compared with morphine. While compound 3 (0.5 μg/rat) and 4 (0.25 microgram/rat) showed 100% analgesic effect even after 120 minutes, morphine (50 mg/rat) reduced to 20% after 120 minutes (table 3). Compounds 3 and 4 still show 90% of the analgesic effect even after 180 minutes.

Table 2< / br>
The test for movement of the tail of the rat" for compounds 3, 4, 7, 8 and morphine
ConnectionED50(ug/kg, PCand)ED50(ug/kg, DOIb)PC/DOI
3860,49176
4280,4267
71000,75133
85000,67 746
Morphine190010019
andPC = subcutaneous injection,bDOI = intracerebroventricular introduction
Table 3< / br>
Analgesic effect (%) of compounds 3, 4 and morphine in 10, 20, 30, 60, 120 and 180 minutes in the test for OTDELENIE tail of the rat" after intracerebroventricular introduction
Compound (μg/ratand)10203060120180 minutes
3 (0,5)46625910010090
4 (0,25)61747610010090
Morphine (50)5791745920BUTb
andthe weight of the tested rats in each case is 120 grams

bBUT = not specified

Example 34

Test Randall-Selitto

Test Randall-Selitto (L.O. Randall and J.J. Selitto, Arch. Int. Pharmacodyn. 1957, the om 111, pages 409-419) is used to study the analgesic actions caused by carrageenan hyperalgesia right hind paws of the rat. Thus, the measured latent period of abstinence hind legs" (LAZ, the latent period of abstinence right hind legs) during mechanical stimulation (e.g., I. Bileviciute-Ljungar and M. Spetea, Br. J. Pharmacol. 2001, volume 132, pages 252-258).

Compounds 4 and reference connection to the Central action, 14-methoxymetopon (Zs. Fürst et al., Eur. J. Pharmacol. 1993, vol 236, pages 209-215), show a significant analgesic effect at a dose in each case 20 μg/kg after subcutaneous injection (increase latency period for otdergivanija hind legs (OSL), at least 100% accept as a significant analgesic effect). While compound 4 shows the lasting effect (approximately 14 hours), the effect of 14-methoxymetopon much shorter and is 2 hours.

Exceptional peripheral analgesic effect of compound 4 is proved by the following test. Analgesic effect of compound 4 (20 mg/kg) completely neutralized by subcutaneous injection of a selective antagonist of peripheral opioid actions methiodide naloxone (equivalent), while on the analgesic action 14-methoxymetopon (20 mg/kg) subcutaneous administration of a selective antagonist opioi the and peripheral actions of methiodide naloxone (equivalent) is not affected. This is proof that the analgesic effect of compound 14 is achieved through peripheral opioid receptors, whereas the analgesic action 14-methoxymetopon achieved through opioid receptors of the Central nervous system. Therefore, we can conclude that compound 4 can not cross the blood brain barrier and, therefore, may not cause adverse effects in the Central nervous system (e.g., respiratory depression, dizziness, confusion, sedation, drowsiness and mania).

Example 35

Test for respiratory depression in rats

In this test, a measured volume of respiration and the respiratory rate had shot rats.

Compounds 3 and 4 examine on the subject of the ability to cause respiratory depression (see table 4). When subcutaneous injection (SC) of compounds 3 and 4 in order to have begun respiratory depression, require a very high dose. While at intracerebroventricular introduction (DOI) respiratory depression occurs at much lower doses for compounds 3 and 4 is characterized by a very high ratio PC/DOI (1205 ACC. 1190). PC/DOI ratio for morphine and fentanyl significantly lower (34 ACC. 0,2).

While analgesic values ED50(the test for OTDELENIE tail of the rat") is very similar to the values of the ED 50in the test for respiratory depression after intracerebroventricular introduction, these values differ significantly percutaneously. If high values of the ED50when testing for respiratory depression after subcutaneous injection of compounds 3 and 4 are comparable to the low values of the ED50in "the test for OTDELENIE tail of the rat", we can understand that for the initiation of respiratory depression, a necessary dose of compound 3, 12 times more than that to achieve the analgesic actions. To connect 4 a necessary dose of higher than 18 times. Therefore, doses of the compounds 3 and 4 needed to achieve the analgesic action may not cause respiratory depression.

Table 4< / br>
The test for respiratory depression in rats" for compounds 3 and 4, morphine and fentanyl
ConnectionED50(ug/kg, PCand)ED50(ug/kg, DOIb)PC/DOI
310000,831205
45000,421190
Fentanyl251250,2
Morphine28008334
andPC = subcutaneous injection,b DOI = intracerebroventricular introduction

Example 36

Definition protivoallergicheskogo actions

Rats carry out two tests:

a) test von Frey (mechanical allodynia)

b) test on allodynia in cold water (thermal allodynia)

Tests include models for testing the action of the substance on neuropathic pain. In both tests around isyanova nerve was ligated vessels (G.J. Bennett and Y.K. Xie, Pain 1988, volume 33, 87-107).

a) test von Frey (mechanical allodynia)

A slight pressure (from 2 to 60 g) attached to the rear paw of rats (200-250 g), using the hairs von Frey and examine the latency period of otdergivanija hind legs at different time intervals (5, 15, 30 and 60 minutes after administration of the substance). The test substance enters through intraplant (CPS).

Compound 4 shows a significant protivoallergicheskoe action in a dose of 100 μg/rat after subcutaneous administration (increased latency period of otdergivanija hind legs, at least 100% take in as considerable protivoallergicheskogo actions). Antagonist of peripheral opioid actions methiodide naloxone (IPL) will neutralize almost protivoallergicheskoe action connections 4.

b) test on allodynia in cold water (thermal allodynia)

Thermal stimulation (cold water) used the t to initiate otdergivanija hind paws of rats (200-300 g). After 5, 15 and 30 min after administration of the substance) measure the latency period of otdergivanija hind legs (J.C. Hunter et al., Eur. J. Pharmacol., 1997, vol 324, 153-160). The test substance enters through intraplant (CPS).

Compound 4 shows a significant protivoallergicheskoe action in a dose of 100 μg/rat after subcutaneous administration (increased latency period of otdergivanija hind legs, at least 100% take in as considerable protivoallergicheskogo actions). Antagonist of peripheral opioid actions methiodide naloxone (IPL) will neutralize almost protivoallergicheskoe action connections 4.

1. The compounds of formula (I)

in which the substituents have the following meanings:

R1: hydrogen; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C1-C6monohydroxyethyl; C2-C6dihydroxyethyl; C3-C6trihydroxysilyl; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl, C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10qi is loukil and quinil is a C 2-C6quinil;

R2: C1-C6alkyl, C1-C6monohydroxyethyl; C2-C6dihydroxyethyl; C3-C6trihydroxysilyl; C2-C6alkenyl; C2-C6quinil; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl, C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl;

R3: hydrogen;

R4: hydrogen; C1-C6-N-alkyl - and N,N'-dialkylamides;

R5and R6that may be the same or different: hydrogen; SN(A)CO2where a is hydrogen; hydroxyl; C1-C6alkyl; C2-C6alkenyl; C2-C6quinil; C4-C16cycloalkenyl where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl, C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cloacal and alkenyl is a C 2-C6alkenyl; C5-C16cycloalkylcarbonyl where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; C7-C16arylalkyl, where the aryl is a C6-C10aryl and alkyl is C1-C6alkyl, C8-C16arylalkyl, where the aryl is a C6-C10aryl and alkenyl is a C2-C6alkenyl; C8-C16arylalkyl, where the aryl is a C6-C10aryl and quinil is a C2-C6quinil; guanidino; and where b is hydrogen, C1-C30-, preferably C1-C6by alkyl; C2-C30-preferably With2-C6alkenyl; C2-C30-preferably With2-C6the quinil; C4-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkyl is C1-C6alkyl, C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and alkenyl is a C2-C6alkenyl; C5-C16cycloalkylation where cycloalkyl is a C3-C10cycloalkyl and quinil is a C2-C6quinil; formamidines, C1-C6-N-alkyl - and N,N'-dialkylimidazolium;

X is oxygen, and Y is CI the activated oxygen;

and their pharmaceutically acceptable acid additive salt.

2. Compounds according to claim 1, selected from the group including

tributyl ether (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-acetic acid

tributyl ether (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-acetic acid

(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-acetic acid

(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-acetic acid

tributyl ether (2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-propionic acid

tributyl ether (2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-propionic acid

(2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-propionic acid

(2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-propionic acid

tributyl ether (2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-3'-phenylpropionic acid

tributyl ether (2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-3' -phenylpropionic acid

(2'S)-2'-(4,5± -epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-3'-phenylpropionate acid

(2'S)-2'-(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-ylamino)-3'-phenylpropionate acid

6α-amino-4,5α-epoxy-14β-methoxy-17-methylmorphinan-3-ol

6α-dibenzylamino-4,5α-epoxy-14β-methoxy-17-methylmorphinan-3-ol

6β-amino-4,5α-epoxy-14β-methoxy-17-methylmorphinan-3-ol

4,5α-epoxy-6β-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14β-methoxy-17-methylmorphinan-3-ol

4,5α-epoxy-6β-guanidine-14β-methoxy-17-methylmorphinan-3-ol

4,5α-epoxy-6α-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14β-methoxy-17-methylmorphinan-3-ol

4,5α-epoxy-6α-guanidine-14β-methoxy-17-methylmorphinan-3-ol

1,3-bis(tert-butoxycarbonyl)-2-{4,5α-epoxy-6β-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14β-methoxy-17-methylmorphinan-3-yl}-isomotion

1,3-bis(tert-butoxycarbonyl)-2-{4,5α-epoxy-6α-[N,N'-bis(tert-butoxycarbonyl)guanidino]-14β-methoxy-17-methylmorphinan-3-yl}-isomotion

the dihydrochloride of ethyl ether (4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-ylamino)-acetic acid

the dihydrochloride of ethyl ether (4,5α-epoxy-3-hydroxy-14β-methoxy-17-meillor the Inan-6β -ylamino)-acetic acid

tributyl ether (4,5α-epoxy-3-hydroxy-14β-ethoxy-17-methylmorphinan-6α-ylamino)-acetic acid

tributyl ether (4,5α-epoxy-3-hydroxy-14β-ethoxy-17-methylmorphinan-6β-ylamino)-acetic acid

bis(tetrafluoroborate) (4,5α-epoxy-3-hydroxy-14β-ethoxy-17-methylmorphinan-6α-ylamino)-acetic acid

bis(tetrafluoroborate) (4,5α-epoxy-3-hydroxy-14β-ethoxy-17-methylmorphinan-6β-ylamino)-acetic acid

tributyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5α-epoxy-3,14β-digidroksimorfinan-6β-ylamino)-3-phenylpropionic acid

bis(tetrafluoroborate) (2'S)-2'-(17-cyclopropylmethyl-4,5α-epoxy-3,14β-digidroksimorfinan-6β-ylamino)-3-phenylpropionic acid

tributyl ether {17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-[(3-phenylpropyl)oxy]-morphinan-6α-ylamino}-acetic acid

tributyl ether {17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-[(3-phenylpropyl)oxy]-morphinan-6α-ylamino}-acetic acid

tributyl ether (2'S)-2'-(17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-[(3-phenylpropyl)oxy]-morphinan-6α-ylamino)-3-phenylpropionic acid

the dihydrochloride{17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-[(3-phenylpropyl)oxy]morphinan-6β -ylamino}-acetic acid,

or any pharmaceutically acceptable salt.

3. The composition having an analgesic action, including a connection according to claim 1 or 2, and/or its pharmaceutically acceptable acid additive salt, and pharmaceutically acceptable carrier.

4. The compound according to any one of claims 1 or 2 as a medicine.

5. The use of compounds according to claim 1 or 2 to obtain medicines used to treat pain.

6. The use of compounds according to claim 1 or 2 to obtain drugs for the treatment of intestinal diseases, in particular chronic inflammation of the small and large bowel (irritable bowel syndrome - irritable bowel, ulcerative colitis, Crohn's disease), diarrhea, constipation.

7. The use of compounds according to claim 1 or 2 to obtain drugs for the treatment of rheumatic diseases, including rheumatoid arthritis, osteoarthritis, arthrosis, spondylos, lumbago, systemic lupus erythematosus, spondyloarthropathy.

8. The use of compounds according to claim 1 or 2 to obtain drugs for the treatment of tumors and cancers, and also to suppress the rejection of grafts after transplantation, and for the prevention and treatment of intestinal obstruction (ileus).

9. The use of compounds according to claim 1 or 2 to obtain the medication is the main tool for the treatment of the syndrome drugs for example, opiates, cocaine, or alcohol, or for treatment of mental illness.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

FIELD: experimental medicine, neurphysiology, neurosurgery.

SUBSTANCE: the present innovation deals with stimulating the growth of nerve tissue. Method for stimulating the regeneration of damaged peripheral nerve in experimental animals after operation on cutting and suturing deals with introduction of medicinal preparations chosen from group-B vitamins and anti-cholinesterase preparations. Additionally, in post-surgical period animals should be intramuscularly injected with neurotoxin of parti-colored scorpion's venom at the dosage of about 40-50 mcg/kg once during 2 d for 30-40 d by repeating the course twice or thrice at interval of 20-30 d. The innovation provides accelerated regeneration process and increased volume of regenerating nerve fibers in peripheral nerve.

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4 dwg, 3 ex, 1 tbl

FIELD: medicine, orthopedics.

SUBSTANCE: one should fulfill certain tests, for example digital compression test, elevation test and others to evaluate pain syndrome according to a 5-point scale. If, as a result of these tests, the intensity of pain syndrome is increased up to 2-4 points and paresthesia occurs it is necessary to introduce about 25-35 mg kenalog 40 into painful site and at decreased pain syndrome up to 0-1 points one should diagnose peripheral tunnel syndrome. The innovation enables to differentiate peripheral tunnel syndromes against neurological manifestations of vertebral osteochondrosis.

EFFECT: higher efficiency and accuracy of diagnostics.

1 ex

FIELD: medicine, neurology, pediatrics.

SUBSTANCE: method involves administration of aminolone in the dose 0.25-0.5 g, 2-3 times per a day for 6-8 months, cerebrolysine in the dose 1.0-1.2 ml by intramuscular route, course 15-20 injections, mydocalm in the dose 50-75 mg, 2 times per a day for 1-1.5 month, vitamin B12 in the dose 150-300 mcg, course 15-20 injections wherein injections of vitamin B12 and cerebrolysine are alternated in each other day; in 1.5 month after onset of this treatment prefizone in the dose 1 ml by intramuscular route is administrated every day, course 15-20 injections, pyrogenal in the dose 100-200 MTD is administrated by course 15-20 injections and curative physical culture is carried out with heat procedure in sauna (dry bath) for 3 months, and after termination of medicinal therapy hyppotherapy is carried out for 3-5 months for each other day. Method allows straightening the kyphoscoliotic carriage and to improve joins mobility due to increase of the motions volume in them. Invention can be used in treatment of spastic diplegia in infantile cerebral paralysis.

EFFECT: improved treatment method.

3 ex

FIELD: medicine, ophthalmology.

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EFFECT: improved and enhanced treatment method.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying substituted benzenesulfonylureas and -thioureas of the formula (I) for preparing a medicinal agent used for treatment and prophylaxis of disturbances in vegetative nervous system. In particular, invention relates to treatment and prophylaxis of disturbances associated with vagus nerve, for example, in cardiovascular diseases, and to applying compounds of the formula (I) in combination with beta-receptor blocking agents. Also, invention relates to products and pharmaceutical compositions that comprise at least one substance among compounds of the formula (I) and at least one beta-receptor blocking agent, and to new compounds also. Invention provides enhancing effectiveness in treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

22 cl, 2 tbl, 6 ex

FIELD: medicine, pediatrics.

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EFFECT: higher efficiency of therapy.

2 ex

The invention relates to medicine, in particular to endocrinology, and for the treatment of complications of diabetes - neuropathy

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FIELD: medicine.

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EFFECT: improved conditions for carrying out hypotensive anesthesia; reduced intraoperative blood losses.

FIELD: medicine, surgery.

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EFFECT: higher efficiency of prophylaxis.

1 ex

FIELD: medicine, therapy, neurology.

SUBSTANCE: method involves subcutaneous injection of heparin over the painful locus in the dose 50-120 IU diluted in 2 ml of water or in 0.5-1% solution of Novocain or lidocaine. This mixture is administrated as a single dose 1-30 ml followed by compression of subcutaneous infiltrate up to its disappearance. Method provides enhancing effectiveness of anesthetization based on the combined using small doses of heparin and topical anesthetics. Invention can be used in treatment of painful syndromes of neurogenous and inflammatory genesis.

EFFECT: improved method of anesthetization.

2 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out lumbar puncture below L2 with lidocaine subsequently introduced into subarachnoid space before carrying out operation. The surgical intervention being ended, 3-5 ml of liquor is sucked. The suction is carried out by means of repeated lumbar punctures, by means of catheter preliminarily introduced into subarachnoid space.

EFFECT: reduced risk of neurotoxic complications; reduced frequency of development transient neurological disorders.

3 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to anhydrous, antifungal, lubricating gel compositions comprising polyhydric alcohol, gelatinizing agent and an antifungal azole compound, and to a method for treatment of a patient with fungal infections comprising administration of indicated composition in a patient. Compositions shows the excellent warming and lubricating effect after its applying on skin and mucosal tissues and provides the effective treatment of fungal infections.

EFFECT: improved and valuable properties of compositions.

21 cl, 2 tbl, 11 dwg, 9 ex

FIELD: medicine, surgery, traumatology, anesthesiology, physiotherapy, curative physical training.

SUBSTANCE: before carrying out curative physical training it is necessary to fulfill anesthesia of brachial plexus at the side of affected limb due to injecting pharmacological solution consisted of 45 ml 0.5%-lidocaine solution and 0.3 ml 1%-adrenaline solution; anesthesia should be fulfilled twice or thrice per the course of curative physical training in 5-6 d; curative physical training should be started in 1.5-2 h after anesthesia. The present innovation increases the volume of movements due to removing muscular hypertension, improving muscular circulation in area of the lesion that, in its turn, prevents complications in tissues of areas of operated limb, it, also, increases efficiency of curative physical training and shortens restorative period 2-fold.

EFFECT: higher efficiency of rehabilitation.

2 ex, 4 tbl

FIELD: medicine, endoscopic surgery.

SUBSTANCE: the present innovation deals with treating traumas of organs of thoracic cavity. For this purpose, at the side of the lesion in V intercostal area along posterior axillary line one should apply a thoracoscope, then through jugular fossa at the root of a lung at the side of predominant lesion one should introduce a polyvinyl chloride catheter through which one should carry out a 2-h-long infusion of 0.25%-novocaine at the rate of 10 drops/min during the 1st h. At the absence of Horner's syndrome at the side of the lesion 1 h after the onset of infusion it is necessary to increase the tempo of infusion up to 15 drops/min. At observing Horner's syndrome the tempo of infusion should be remained the same. Anesthetization should be repeated thrice for 5 d. The innovation enables to provide prolonged blockade of reflexogenous areas of mediastinum, regulate the volume of applied anesthetic depending upon the efficiency of observed analgesia and, also, decrease stress impact of curative procedures due to high accuracy of blockades without carrying out thoracotomy.

EFFECT: higher efficiency.

2 ex

FIELD: medicine, surgery.

SUBSTANCE: one should register initial temperature values on the moment of performing spinal anesthesia with lidocaine and, also, its values on the moment of observed increased temperature values and during the next 5 min; and in case of increased temperature and its progressive growth during the next 5-min-long periods of survey at first at a sick limb and several minutes later - at a healthy limb it is possible to conclude upon lateral localization of disk hernia.

EFFECT: higher efficiency and accuracy of diagnostics.

3 ex

FIELD: medicine; surgery, nephrology; neurology; clinical pharmacology.

SUBSTANCE: method can be used at injection introductions of medicinal aids into deep layers of soft tissues of lumbar area. Ultrasonic detector is applied to selected area. Area to be found in depth of tissues is detected by means of device on the screen. Different areas of skin are subject to periodical pressing by finger and appearance of wave-shaped reversible changes in skin is observed on screen under point of pressing. Part of skin is marked for injection introduction from which part the deformation wave reaches selected area more precise. Distance from skin to the area is measured and needle is introduced for the depth. 1-1,5 ml of solution is pressed out of syringe. Correctness of introduction is estimated from ultrasonic visualization of localization point which appears in tissues of medicinal infiltrate. Procedure is repeated till correct introduction is performed and that the required medicinal solutions are introduced.

EFFECT: improved precision; prevention of complications.

1 ex

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