Carbamate derivatives used for pain treatment

FIELD: organic chemistry, medicine, clinical pharmacology.

SUBSTANCE: invention relates to agents used in treatment of pain. Method involves administration to a patient the effective dose of enantiomer of compounds of the formula (Ib) or the formula (IIb) or their mixture. Method provides the antihyperanalgesic effect in acute and chronic pain.

EFFECT: valuable medicinal properties of derivatives.

5 cl, 1 tbl

 

Cross-reference to related applications

This application claims the benefits of provisional application serial number 60/271,888, filed February 27, 2001, which is an integral part of the present description by reference.

The technical field

This invention relates to a method of applying the derived carbamate for the treatment of pain. In particular, this invention relates to a method of using halogenated derivatives of 2-phenyl-1,2-ethanediol of monocarbonate or dicarbamate for the treatment of pain.

Prior art

The pain is usually defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage (L Wileman, Advances in pain management, Scrip Report, 2000).

Acute pain is a physiological response to noxious chemical, thermal or mechanical stimulus, which can be associated with surgery, trauma or acute illness. The above conditions include, but are not limited to, post-operative pain; injuries related to sports medicine; carpal tunnel syndrome, burns, musculoskeletal sprains and injuries, tendon and muscle damage, pain in the neck-shoulder syndrome, dyspepsia, stomach ulcers, duodenal ulcer, renal colic, pain in gall bladder pain gall-amandoi disease, dysmenorrhoea, endometriosis, obstetric pain, rheumatic pain or toothache.

Chronic pain is pain condition outside the common causes of injury or disease and may be a consequence of inflammation or painful flowing stages of a serious, progressive disease. Various types of chronic pain include, but are not limited to, headache, migraine, trigeminal neuralgia, TMJ syndrome, fibromyalgia, osteoarthritis, rheumatoid arthritis, pain in the bone tissue caused by osteoarthritis, osteoporosis, metastatic bone or unknown causes, gout, fibrositis, myofascial pain, compression of the brachial plexus and subclavian artery attached to the muscles in the area of the first rib and the clavicle (thoracic outlet syndromes), pain in the upper or lower back (where the back pain is due to a systemic, localized or primary spine disease (radiculopathy),pain in the pelvic area, pain in the chest cardiac origin, pain in the chest deserticola origin, pain associated with spinal cord injury, Central post-stroke pain, pain due to malignant tumour, pain, AIDS-related pain in sickle cell enemy is or geriatric pain.

Anticonvulsant drugs have been used effectively for the treatment of pain, since 1940, when it was shown that phenytoin, originally used to treat epilepsy, has a beneficial effect on trigeminal neuralgia. There is evidence suggesting that carbamazepine, clonazepam, valproic acid, gabapentin, lamotrigine and topiramate, originally developed as anti-convulsants for the treatment of epilepsy, show, all, effectiveness against a variety of chronic pain, including trigeminal, glossopharyngeal, top-laryngeal (superior laryngeal) and post-herpetic neuralgia, tablecheck pain, phantom pain, prophylaxis of migraine, multiple sclerosis, thalamic syndrome, diabetic neuropathy and neuropathic pain (Swerdlow M, Anticonvulsant drugs and chronic pain, Clin. Neuropharmacol., 1984,7, 51-82; Andrea B, The use of anticonvulsants in neurological conditions other than epilepsy: A review of the evidence from randomized controlled trials, CNS Drugs, 1999,11, 1, 61-82; Leslie M, Nonepileptic uses of gabapentin, Epilepsia, 1999,40 (Suppl. 6), S66 - S72; Hansen HC, Treatment of chronic pain with antiepileptic drugs: a new era, Southern Medical Journal, 1999,92, 7, 642-9). Anticonvulsants reduce neuronal excitability due to its neurohabilitation properties that may contribute to their effectiveness in the treatment of pain, as pain signals are transmitted from notiz is Perov to the cortex through the specific (ascending afferent conductive path throughout the spinal cord, brain stem and diencephalon.

In U.S. patent No. 3265728 Bossinger and others (whose description is incorporated into this description by reference) discloses derivatives of substituted phenylalkylamines represented by the formula:

where R1represents either a carbamate or allylcarbamate containing alkyl group of 1 to 3 carbon atoms; R2represents either hydrogen, hydroxy, alkyl, or hydroxyalkyl containing from 1 to 2 carbon atoms; R3represents either hydrogen, or alkyl containing from 1 to 2 carbon atoms; and X may be halogen, stands, methoxy, phenyl, nitro or amino.

In U.S. patent No. 3313692 Bossinger and others (whose description is incorporated into this description by reference) disclose a method of inducing uspokaivajushe actions and muscle relaxation by carbamates, by introducing a compound of the formula:

where W represents an aliphatic radical containing less than 4 carbon atoms, where R1represents an aromatic radical, R2represents hydrogen or an alkyl radical containing less than 4 carbon atoms, and X represents hydrogen or hydroxy, or alkoxy and alkyl radicals containing less than 4 carbon atoms, or the radical:

in which B represents the radical of the organic the CSOs amine group, consisting of heterocyclic, ureido, hydrazine radicals and radical-N(R3)2where R3represents hydrogen or an alkyl radical containing less than 4 carbon atoms.

In addition, Choi and others in U.S. patent No. 6103759 (the description of which is incorporated into this description by reference) discloses optically pure form halogen-substituted 2-phenyl-1,2-ethanediol of monocarbonate and dicarbamate, effective for the treatment and prevention of disorders of the Central nervous system, including convulsion, epilepsy, stroke and muscle spasm; and as useful for the treatment of diseases of the Central nervous system, in particular as anti-convulsants, protevoepilepticakih, neuroprotective funds and muscle relaxants that act on the Central nervous system, having the formula:

where one enantiomer predominates and where the phenyl ring is substituted at position X from one to five halogen atoms selected from fluorine, chlorine, bromine or iodine, and R1, R2, R3, R4, R5and R6each selected from hydrogen and straight or branched alkyl groups with from one to four carbon atoms, optionally substituted phenyl group with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, amino, nitro and cyano. Was the described pure enantiomers and enantiomeric mixtures, in which one enantiomer predominates in the mixture of compounds represented by the aforementioned formulas; preferably one enantiomer predominates in the range of about 90% or more and most preferably in the range of about 98% or more.

Halogen-substituted 2-phenyl-1,2-candiacervus formula (I) or formula (II) have not previously been described as compounds useful for the treatment of pain. Recent preclinical studies revealed previously unrecognized pharmacological properties, confirming that the compound of formula (I) or formula (II) is useful for the treatment of pain. Accordingly, the present invention is to provide methods of using compounds of formula (I) or formula (II) for the treatment of pain.

A brief statement of the substance of the invention

The present invention relates to a method of treating pain comprising the administration to a subject in need of such treatment, a therapeutically effective amount of a compound selected from the group consisting of the compounds of formula (I) and compounds of formula (II):

where

phenyl substituted at position X from one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine; and

R1,R2, R3, R4, R5and R6independently selected from g is uppy, consisting of hydrogen and C1-C4of alkyl; where C1-C4alkyl optionally substituted phenyl (where the phenyl optionally substituted by substituents independently selected from the group consisting of halogen, C1-C4of alkyl, C1-C4alkoxy, amino, nitro and cyano).

Variants of embodiments of the invention include a method of treating pain comprising the administration to a subject in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected from the group consisting of compounds of the formula (I) and formula (II).

Variants of embodiments of the invention include the use of compounds selected from the group consisting of compounds of the formula (I) and formula (II), to obtain drugs for treating pain in a subject in need of such treatment.

Embodiments of the method include the use of an enantiomer selected from the group consisting of compounds of the formula (I) and formula (II) or enantiomeric mixture wherein one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates. For enantiomeric mixtures, where one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates, preferably, when one enantiomer selected the C group, consisting of compounds of the formula (I) and formula (II)predominates in the range of about 90% or more. More preferably, when one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates in the range of about 98% or more.

A detailed description of the invention

The present invention relates to a method of treating pain comprising the administration to a subject in need of such treatment, a therapeutically effective amount of compounds from the group selected from the group consisting of compounds of the formula (I) and formula (II):

where

phenyl substituted at position X from one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine; and

R1,R2, R3, R4, R5and R6independently selected from the group consisting of hydrogen and C1-C4of alkyl; where C1-C4alkyl optionally substituted phenyl (where the phenyl optionally substituted by substituents independently selected from the group consisting of halogen, C1-C4of alkyl, C1-C4alkoxy, amino, nitro and cyano).

The present invention includes the use of compounds selected from the group consisting of compounds of the formula (I) and formula (II), where X represents chlorine; preferably when X is substituted in anthopology the phenyl ring.

In addition, the present invention includes the use of compounds selected from the group consisting of compounds of the formula (I) and formula (II), where R1, R2, R3, R4, R5and R6preferably selected from hydrogen.

A variant embodiment of the proposed method includes the use of the enantiomer selected from the group consisting of compounds of the formula (I) and formula (II) or enantiomeric mixture in which one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates, where X represents chlorine; preferably X substituted in anthopology phenyl rings.

The proposed method also includes applying enantiomer selected from the group consisting of compounds of the formula (I) and formula (II) or enantiomeric mixture wherein one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates, where R1, R2, R3, R4, R5and R6preferably selected from hydrogen.

For enantiomeric mixtures, where one enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates, preferably when the enantiomer selected from the group consisting of compounds of the formula (I) and formula (II)predominates in the range of about 90% or more. More preferably, when the enantiomer selected from the group consisting of compounds of the formula (I) and formula (II), prevails within about 98% or more.

A variant of implementation of the present method includes the use of the enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa) or enantiomeric mixture wherein one enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa)prevails:

where

phenyl substituted at position X from one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine; and,

R1,R2, R3, R4, R5and R6independently selected from the group consisting of hydrogen and C1-C4of alkyl; where C1-C4alkyl optionally substituted phenyl (where the phenyl optionally substituted by substituents independently selected from the group consisting of halogen, C1-C4of alkyl, C1-C4alkoxy, amino, nitro and cyano).

The present method includes the use of the enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa) or enantiomeric mixture in which one enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa)prevails, where X represents chlorine; preferably X substituted in anthopology phenyl rings.

In addition, the present method includes the use of enantiomer selected and the group, consisting of compounds of the formula (Ia) and formula (IIa) or enantiomeric mixture wherein one enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa)prevails, where R1, R2, R3, R4, R5and R6preferably selected from hydrogen.

For enantiomeric mixtures, where one enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa) is, preferably, when the enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa), is predominant in the range of about 90% or more. More preferably, when the enantiomer selected from the group consisting of compounds of the formula (Ia) and formula (IIa), is predominant in the range of about 98% or more.

A variant embodiment of the present method includes a method of treating pain comprising the administration to a subject in need of such treatment, a therapeutically effective amount of an enantiomer selected from the group consisting of compounds of the formula (Ib) and formula (IIb) or enantiomeric mixture wherein one enantiomer selected from the group consisting of compounds of the formula (Ib) and formula (IIb)prevails:

For enantiomeric mixtures, where one enantiomer selected from the group consisting of compounds of the formula (Ib) and formula (IIb), predominates, preferably, when enantion the R, selected from the group consisting of compounds of the formula (Ib) and formula (IIb), is predominant in the range of about 90% or more. More preferably, when the enantiomer selected from the group consisting of compounds of the formula (Ib) and formula (IIb), is predominant in the range of about 98% or more.

There may be other crystalline forms according to the present invention, it is understood that these forms are included in the scope of protection of the present invention.

For specialists in this area it is obvious that the compounds of the present invention are present in the form of the racemates, enantiomers and enantiomeric mixtures. The carbamate enantiomer selected from the group consisting of compounds of the formula (I), formula (II), formula (Ia), formula (IIa), formula (Ib) and formula (IIb), contains an asymmetric chiral carbon atom at the benzyl position, which represents an aliphatic carbon adjacent to the phenyl ring (indicated by the asterisk in the structural formula).

Compounds of the present invention can be obtained as described Bossinger in vysheupomyanutom patent '728 (the description of which is included in the present invention by reference), the patent '692 (the description of which is included in the present invention by reference) and Choi in the patent '759 (the description of which is included in the present invention by reference).

It is implied that defined the e of any substituent or variable at a given position in a molecule is independent of its definitions elsewhere in that molecule. Obviously, deputies and forms of substitution in the molecule of the compounds of this invention can be readily selected by the person skilled in the art to provide compounds that are chemically stable and which can be easily synthesized by methods known in this field, as well as methods set forth below.

The present invention provides a method of treating pain in a subject in need thereof. Examples of pain include, and are not the limitation, pain that is mediated by the Central nervous system, pain that is mediated by the peripheral nervous system, pain, which is caused by damage to the structural tissue, pain that is caused by damage to the soft tissue, or pain that is caused by progressive disease. The pain associated with involvement of the Central nervous system, peripheral nervous system, damage to structural tissue damage soft tissue and with progressive disease includes acute pain or chronic pain.

Acute pain includes pain caused by acute injury, trauma, disease or surgery (for example, an operation to open the chest, including open-heart surgery or bypass surgery). In addition, acute pain includes, and the following is not a limitation, paleoposition the Yu pain, renal colic, pain in the gall bladder, the pain of gall-stone disease, obstetric pain, rheumatic pain, toothache, or pain caused by injuries related to sports medicine, carpal tunnel syndrome, burns, musculoskeletal sprains and injuries, tendon and muscle injuries, pain in the neck-shoulder syndrome, dyspepsia, gastric ulcer, duodenal ulcer, dysmenorrhea or endometriosis.

Chronic pain includes pain caused by inflammatory disease, osteoarthritis, rheumatoid arthritis, or as a complication, a painful condition following disease, acute injury or trauma. In addition, chronic pain includes, but is not limited to the following, pain in the upper or lower back (chosen from back pain, which is the result of systemic, localized or primary spine disease (selected from radiculopathy), pain in bone tissue (selected from the pain in the bone tissue caused by osteoarthritis, osteoporosis, metastatic bone or unknown reasons), pain in the pelvis, pain, assotsiirovannuyu with spinal cord injury, pain in the chest cardiac origin, pain in the chest deserticola origin, Central pain after UDA the and, myofascial pain, pain in malignant tumors, pain, AIDS pain in sickle-cell anemia, geriatric pain or pain caused by headache, migraine, trigeminal neuralgia, TMJ syndrome, fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, gout, fibrositis or compression of the brachial plexus and subclavian artery attached to the muscles in the area of the first rib and clavicle.

An example of the method of the present invention includes an introduction to the subject a therapeutically effective amount of a compound selected from the group consisting of compounds of the formula (I) and formula (II), pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound selected from the group consisting of compounds of the formula (I) and formula (II). The method of the present invention also includes the use of compounds selected from the group consisting of compounds of the formula (I) and formula (II), to obtain drugs for the treatment of pain.

Another example of the method of the present invention includes an introduction to the subject a therapeutically effective amount of a compound selected from the group consisting of compounds of the formula (I) and formula (II) or pharmaceutical composition thereof, in combination with one or more of the means used by the La treatment of pain.

A compound selected from the group consisting of compounds of the formula (I) and formula (II), or pharmaceutical composition comprising them, can be applied using any conventional route of administration, including, but not limited to, oral, pulmonary, intraperitoneal (V.B.), intravenous (I.V), intramuscular (VM), subcutaneous (P.K.), transdermal, buccal, nasal, sublingual, ocular, rectal and vaginal. In addition, the introduction directly into the nervous system, may include, but following paths are not limited to, intracerebrally, intraventricularly, intracerebroventricularly, vnutriobolochechnoe, intracisternally, intraspinally or peripherally routes of administration by delivery via intracranial or vnutriarterialnah needles or catheters equipped with a pumping device or without pump devices.Specialists in this field it is obvious that for use in the present invention is suitable can be any dose or frequency of administration, which provides the above-described therapeutic effect.

A therapeutically effective amount of a compound selected from the group consisting of compounds of the formula (I) and formula (II), or pharmaceutical compositions containing them, may be from about 0.01 mg/kg/dose to about 100 mg/kg/dose. Preferably, therapeu the automatic effective amount may be from about 0.01 mg/kg/dose to about 25 mg/kg/dose. More preferably, therapeutically effective amount may be from about 0.01 mg/kg/dose to about 10 mg/kg/dose. Most preferably, therapeutically effective amount may be from about 0.01 mg/kg/dose to about 5 mg/kg/dose. In this regard, for the subject, for example, having an average weight of 70 kg, a therapeutically effective amount of the active ingredient contained in the dosage unit (e.g. tablet, capsule, powder, injection, suppository, teaspoonful and the like)described above, may be from about 1 mg/day to about 7,000 mg/day.

The dosages, however, may vary depending on the needs of stakeholders (including factors relating to the specific subject to be treated, including the age of the subject, the body weight and diet, the activity of the drug, development of state of the disease, and time and method of administration) and the use of specific compounds of formula (I) or formula (II), or pharmaceutical compositions containing them.

Optimal dosages to be introduction, can be easily defined by the experts in this field and is determined by the need to adapt the dose until an appropriate therapeutic level. You can use either a daily injection, or posterities dosing.Preferably, for the treatment of pain Conn the General formula (I) or formula (II) or containing pharmaceutical composition is administered orally or parenterally.

According to the methods of the present invention, the compound of formula (I) or formula (II) or containing pharmaceutical composition can be entered separately, at different times during the course of treatment, or both, in the split of the combined forms or single combination forms. Mainly, a compound selected from the group consisting of compounds of the formula (I) and formula (II) or containing pharmaceutical compositions can be entered as a single daily dose or the total daily dosage by continuous delivery or in the form of parts divided doses two, three or four times a day. It should be borne in mind that the present invention covers all such methods and diagrams are continuous, simultaneous or changing treatment and the term "introducing" shall be construed accordingly.

The term "subject" refers to an animal, preferably a mammal, most preferably the person who was the object of treatment, observation or experiment.

The term "therapeutically effective amount" means such amount of active compound or pharmaceutical agent that causes a biological or medicinal response in a tissue system, animal or human that is expected by the researcher, veterinarian, physician or other clinics the Ohm, which includes alleviation of the symptoms of the disease or disorder to be treated.

The term "composition", as implied, covers the product, including specific components in specific amounts, as well as any product which results, directly or indirectly, combinations of specific components in specific amounts.

To obtain the pharmaceutical composition of the present invention, the compound of formula (I) or formula (II) as an active ingredient is mixed with a pharmaceutical carrier according to conventional methods adopted to obtain pharmaceutical preparations with obtaining a homogeneous mixture, with the above media may take a variety of forms depending on the type of dosage forms of the drug that is required for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers well known in this field. Descriptions of some of the above-mentioned pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of great Britain.

Methods of formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised an Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Preferably, the pharmaceutical composition is in the form of standard dosage forms such as tablet, pill, capsule, caplet, gelatin capsule, pellet, granule, powder, sterile parenteral solutions or suspensions, metered aerosol or liquid spray, drops, ampoules, autoinjector device or suppository for the introduction of oral, intranasal, sublingual, intraocular, transdermal, parenteral, rectal, and vaginal routes, through inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month or may be adapted to provide preparation for intramuscular injection.

To obtain a pharmaceutical composition having a solid dosage form for oral administration such as tablet, pill, capsule, caplet, gelatin capsule, pellet, granule or powder (each includes compositions immediate release specified time-release and sustained-release), suitable carriers and additives (excipients) include, but are not limited the tsya, diluents, granulating tools, lubricants, binders, substances promoting sliding, dezintegriruetsja tools, etc. If desired, tablets may be coated with a sugar shell, gelatinous membrane, film or intersolubility coating using conventional methods.

In the case of production of solid dosage forms, the principal active ingredient is mixed with a pharmaceutical carrier (e.g., conventional components for tabletting (auxiliary substances such as diluents, binders, adhesives, disintegrators, lubricants, anti-adhesive means and substances that contribute to sliding). In chewing solid dosage forms to improve the palatability of oral dosage forms can be added sweeteners and corrigentov. Furthermore, in a solid dosage form for ease of identification of the medicinal product or for aesthetic purposes may be added or applied dyes and coatings. The aforementioned carriers is mixed with the pharmaceutically active component, providing accurate, appropriate dose pharmaceutically active component with a therapeutic profile release.

To obtain a pharmaceutical composition having a liquid dosage form for oral, local and parenteral administration, can IP alsowhat any of the usual pharmaceutical media or fillers. So, for liquid dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions and solutions, can be used suitable carriers and additives include, but are not limited to, pharmaceutically acceptable humectants, dispersing funds, flocculants, thickeners, pH regulating means (i.e. buffers), osmotic means, dyes, giving a taste, flavorings, preservatives (i.e. to prevent microbial growth) and a liquid filler. Not all of the above components may be required for each liquid dosage forms. Liquid forms for administration by oral or by injection, which may be included new compositions of the present invention include, but are not limited to, aqueous solutions, suitable flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as oil of cotton seeds, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical excipients.

Biological experimental example

Activity of the compounds of formula (I) and formula (II)used to treat pain, were evaluated in the following experimental example, which, as implied, is illustrating, but not limiting on the TES invention.

The model of Bennett (Chronic anabolic damage (trauma))

The Bennett model is to impose loosely ligation (alloying) of the sciatic nerve in rats (Bennett GJ and Xie YK, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 1988, 33, 87-107). Although the pharmacological profile of spontaneous pain, protective posture (body position) and allodynia (the smaller of the two) is similar to the profile of clinical neuropathic pain, loosely chronic ligature of the sciatic nerve in the model of Bennett causes higher thermal hyperalgesia than mechanical allodynia due to its inflammatory mechanism. Loosely ligature causes the compression/swelling with subsequent inflammation at the site of ligation, a condition most typically associated with different types of pain. Behavioral response to the ligature is manifested in one of the symptoms of hyperalgesia. Accordingly, anti-hyperalgesia reduces chronic symptoms of pain hypersensitivity. Therefore, the model of Bennett used to assess antinociceptive pain (Cui JG, Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy, Pain, 2000, 88 (3), 239-248; Lovell JA, Changes in Spinal Serotonin Turnover Mediate Age-Related Differences in the Behavioral Manifestations of Peripheral Nerve Injury, Pharmacol. Biochem. Behav., 2000, 66 (4), 873-878; Yasuda T, The novel analgesic compound OT-7100 [5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5a]pyrimidine] attenuates mechanical nociceptive responses in animal modes of acute and peripheral neuropathic hyperalgesia, J. Pharmacol., 1999, 79(1), 65-73; Toda K, Antinociceptive effects of neurotropin in a rat model of painful peripheral mononeuropathy, Life Sci., 1998, 62 (10), 913-921; Munglani R, Neuropeptide changes persist in spinal cord despite resolving hyperalgesia in a rat model of mononeuropathy, Brain Res., 1996, 743, 1(2), 102-108).

The enantiomer of formula (Ib) and formula (IIb) were evaluated in the model of Bennett on their effectiveness in States of pain in 3 doses (10, 30 and 100 mg/kg, per os, n=8 animals per treatment). The effect of antihyperalgesic was evaluated at 30, 60 and 90 minutes after oral dose.

Rats (weighing 180-220 g) were subjected to anesthesia (sodium pentobarbital, 40 mg/kg, VB.) and then the incision was made at the level of the mid thigh to expose the General left sciatic nerve. Four ligatures, located at a distance of 1 mm from each other, were loosely superimposed around the sciatic nerve. Then the wound was suture. Rats did V.M. injection of 50,000 IU of penicillin and provided an opportunity to recover from this operation. After at least one week after surgery, when a chronic condition is fully established, rats with undamaged and damaged hind legs, sequentially subjected to thermal stimulation. Device (UgoBasil, Reference: 7371) consists of 6 individual boxes of acrylic (organic glass) (17×13×13 cm), placed on an elevated glass platform. The rat was put into the box is provided the ability to adapt within 10 minutes. Then under the undamaged and damaged the rear legs have focused mobile infrared radiation source (setting 20) and automatically register latency otdergivanija (withdrawal) feet in seconds. The test was carried out blind. The increased latency in the treated animals compared to control animals (those that received only filler) were expressed as % efficiency (action) medicinal product. Data were analyzed by comparing the damaged group, the treated and control groups using unpaired student test.

The results in the Table demonstrate that the enantiomers of formula (Ib) and formula (IIb) have protivogipertonicheskoe action in relation to the call to thermal stimulation (** represents the value of p<0,01, where the change of d% indicates the effectiveness of the enantiomer of formula (Ib) and formula (IIb) compared with the control-filler).

Table

Protivogipergonichesky efficiency (Efficient in %)
Dose (mg/kg)30 min60 min90 min
(Ib)(IIb)(Ib)(IIb)(Ib) (IIb)
10--791215350
305961109318**107182**
3004348314**198**15169

Although the above description discloses the basic principles of the present invention in the preferred specific examples of its implementation, it should be borne in mind that these examples are illustrative and that the implementation of the invention in practice covers all of the usual variations, adaptations and/or modifications made to him within the scope of the following claims and their equivalents.

1. The way antihyperalgesic impacts, including introduction to the subject in need of treatment, the enantiomer of formula Ib, or formula IIb, or a mixture thereof in therapeutically effective amounts.

2. The method according to claim 1, where one enantiomer selected from the group consisting of formula Ib or IIb, prevails within 90% or more.

3. The method according to claim 1, where one enantiomer selected from the group consisting of formula Ib or formula IIb, prevails within 98% or more.

4. The method according to claim 1, where the pain is selected is from acute pain or chronic pain.

5. The method according to claim 1, where therapeutically effective amount is from 0.01 to 100 mg/kg/day.



 

Same patents:

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: medicine, resuscitation.

SUBSTANCE: one should obtain the values on head's vertical position, pulmonary ventilation, efforts coming to organs of controlling and parameters of cabin's hermetic nature. A transport driver should get the information on irregular extreme situation, one should supply 100% oxygen. In case of acute respiratory insufficiency at the background of spontaneous respiration, in case of acute pain, high heart beating or gunshot wound it is necessary to perform additional electrostimulation of the muscles that actively participate in respiration act, with amplitude-frequency-modulated triangular series of impulses at impact duration being 1.5-2.0 sec at pause being about 3-4 sec. Moreover, electrostimulation should be combined with anesthesia performed due to automatic injection of medicinal preparation into biologically active point Tan'-Chzhun along with the intake of therapeutic dosage of an antiaggregant, a thrombolytic, a nitropreparation, beta-adrenoblocking agent and low-molecular heparin. Automatic pharmacoinjection should be conducted manually as a transport driver desired, and in critical situation - due to distance-controlled operation; moreover, injection should be fulfilled perpendicularly for the depth not exceeding 0.5-0.6 cm. The innovation increases the number of preparations applied in extreme situations to rescue a transport driver.

EFFECT: higher efficiency of rescue activity.

3 cl, 1 dwg

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

New compounds // 2258703

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I):

wherein R1 is taken among phenyl or pyridinyl and wherein each phenyl ring R1 or pyridinyl ring R1 can be substituted additionally and independently with chlorine, fluorine, bromine and iodine atom at any position of indicated ring, and also to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition based on these compounds eliciting δ-agonistic activity and to a method for pain treatment. Invention provides preparing new compounds of the formula (I) used in applying for pain treatment and for manufacturing drugs for this purpose.

EFFECT: valuable medicinal properties of new compounds.

8 cl, 3 tbl, 4 ex

FIELD: chemistry of heterocyclic compounds, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (promedol) used extensively as an analgetic medicinal agent. Method involves reaction of 1,2,5-trimethylpiperidone-4 with aromatic compound of alkaline or earth-alkaline metal that is carried out at temperature from -10°C to -100°C and wherein 1-1.15 mol of aromatic compound of alkaline or earth-alkaline metal, in particular, phenyllithium or phenylmagnesium bromide is used per 1 mol of 1,2,5-trimethylpiperidone-4 followed by two-fold treatment with propionyl chloride. Invention provides enhancing yield of promedol.

EFFECT: improved preparing method.

5 cl, 8 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes analgesic compositions containing buprenorphine in the level of subclinic analgesic doses in combination with naloxone, naltrexone or nalmephene. The mass ratio buprenorphine to naloxone is in the range from 12.5:1 to 27.5:1, and the mass ratio buprenorphine to naltrexone or to nalmephene is in the range from 12.5:1 to 22.5:1. Compositions are prepared as the parenteral or sublingual medicinal formulation or as a medicinal formulation that can be delivered through mucosa. Analgesic effect of buprenorphine is enhanced by low dose of naloxone, naltrexone or nalmephene.

EFFECT: enhanced effectiveness of compositions, valuable medicinal properties.

7 cl, 3 dwg, 21 ex

FIELD: organic chemistry, veterinary science.

SUBSTANCE: invention describes using aminoacetonitrile compounds of the formula (I): wherein Ar1 and Ar2 mean independently of one another unsubstituted phenyl or phenyl substituted with halide; Q means -C(R1)(R2) wherein R1 and R2 or independently of one another mean hydrogen atom, or in common with carbon atom to which they are bound form (C2-C6)-alkylene; d = 1; R3 means hydrogen atom, (C1-C6)-alkyl or (C2-C6)-alkynyl; each among R4, R5, R6, R7 and R8 means independently of one another hydrogen atom, (C1-C6)-alkyl or (C3-C6)-cycloalkyl; or R4 and R5 mean in common (C2-C6)-alkylene; W means oxygen atom; a and b mean independently of one another 0 or 1, and optionally of their enantiomers in control of endoparasitic pests in warm-blooded productive cattle and domestic animals. Also, the invention describes the composition and a method for control of endoparasitic pests. Above said compounds are used for control of endoparasites, especially, helminthes in warm-blooded productive cattle and in domestic animals.

EFFECT: valuable properties of compounds.

6 cl, 3 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition possessing capacity to release the therapeutically effective dose of active substance rivastigmin and showing the time-controlled pattern. The pharmaceutical composition is designated for treatment of patients suffering with Alzheimer's diseases dementia from small to middle severity degree. Compositions show safety and time-controlled release pattern of active substance rivastigmin.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 2 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): and formula (II): , and to their esters that can be used for treatment of the cellular proliferation disorders. Also, invention relates to a pharmaceutical composition used for modulation of cellular proliferation and comprising compound of the formula (I) or its ester.

EFFECT: valuable medicinal property of compounds and composition.

62 cl, 2 tbl, 25 dwg, 58 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I) inhibiting tumor growth and angiogenesis wherein each R2 and R3 represents independently hydrogen atom (H), (C1-C4)-alkyl; each X2 and X3 represents independently (C1-C4)-perfluoroalkyl; A represents hydrogen atom (H) or a covalent bond; t represents a whole number 0 or 1 under condition that if A represents hydrogen atom (H) then t = 0, and if A represents a covalent bond then t = 1. Also, invention relates to a pharmaceutical composition and method for inhibition of the tumor growth.

EFFECT: valuable medicinal properties of composition.

32 cl, 3 sch, 5 dwg, 19 ex

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with applying the compound of formula I

for treating neuropathic pains. This compound I (retigabin) is of high efficiency in treating allodynia, hyperalgesia-conditioned pains, neuropathic pain in case of diabetic neuropathy, neuropathic pain at migraine. The compound suggested is low toxic being of high bioavailability.

EFFECT: higher efficiency of therapy.

6 cl, 1 tbl

FIELD: medicine, surgery.

SUBSTANCE: method involves administration of verapamil solution in the amount 20-30 mg by intraperitoneal route by spraying method on visceral and parietal peritoneum on the final stage of operation. Invention promotes to reducing frequency in formation and relapse of post-operative adhesions. Invention can be used for prophylaxis of post-operative adhesions.

EFFECT: improved method for prophylaxis.

2 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

The invention relates to medicine and can be used in the treatment of nephropathy in children in the neonatal period
The invention relates to medicine and can be used in the treatment of nephropathy in children in the neonatal period

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

Up!