HK1068794A - Novel use of combined 5-ht1a agonists and selective serotonin reuptake inhibitors - Google Patents

Description

Combined 5-HT1ANovel use of agonists and selective 5-hydroxytryptamine reuptake inhibitors

The present invention relates to a combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) and 5-HT_1AUse of a receptor agonist compound in the manufacture of a medicament for the treatment of chronic pain.

The invention relates in particular to a combination of 5-HT_1AUse of an agonist and a selective 5-hydroxytryptamine reuptake inhibitor for the manufacture of a medicament for the treatment of chronic pain, wherein said compound is selected from the group consisting of 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof.

1- [4- (5-cyanoindol-3-yl) butyl is known from the US patent US5,532,241]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof (US5,532,241, column 7, lines 30 to 58) and a process for the preparation thereof (US5,532,241, example 4). In this patent selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRI) and 5-HT as a combination are described_1AReceptor agonismAgents the compounds referred to herein. Accordingly, disclosed herein is 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of: depressive disorders, including subtype disorders, primarily depressive disorders and melancholic disorders; anxiety disorders; psychiatric disorders such as psychosis, schizophrenia or schizoaffective disorder; cerebral infarction, such as stroke and cerebral ischemia; CNS diseases such as stress; therapies for the treatment of side effects in hypertension (e.g., using alpha-methyldopa); and 1- [4- (5-cyanoindol-3-yl) butyl is disclosed]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable acid addition salt thereof for the preparation of a medicament for the prevention and treatment of brain diseases. In addition, the use of these compounds in endocrinology and gynecology is described, for example, their use in the treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome or undesirable postpartum lactation.

3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl is known from EP 0736525]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof (EP 0736525, page 3, line 5, 26 and page 8, line 28 to page 9, line 12) and a process for its preparation (EP 0736525, example 1). They exhibit in particular an action on the central nervous system, in particular 5-HT_1AExcitability and 5-HT-resorption inhibition. They are therefore suitable for the treatment of disorders of the central nervous system, such as stress, depression and/or side effects in the treatment of psychosis and hypertension. In addition, the use of these compounds in endocrinology and gynecology, for example in the treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome or undesirable postpartum lactation; and further described herein are the use of these compounds in the prevention and treatment of brain diseases, particularly the treatment of cerebral infarction (stroke) sequelae, such as stroke and cerebral ischemia, similar to certain ergot alkaloids in geriatric conditions.

The inventionThe subject matter of (1) is to provide a combined 5-HT_1AAgonist and selective 5-hydroxytryptamine reuptake inhibitor compounds, particularly 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine and physiologically acceptable salts or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile and physiologically acceptable salts thereof.

It has been found that a combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) and 5-HT_1AAgonists, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof is also active against pain, especially chronic pain.

U.S. Pat. No. 5,5,532,241 discloses piperazines such as 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine and their physiologically acceptable acid addition salts with analgesic action. However, the use of such piperazines in the treatment of pain, particularly in the treatment of chronic pain, has not been disclosed.

The analgesic effect disclosed does not necessarily result in an effective treatment of chronic pain. Acute pain is a normal sensation produced in the nervous system that makes an individual aware of a possible injury. Chronic pain results from the persistent onset of pain signals in the nervous system after the initial damage or injury has disappeared. Chronic pain can occur without any evidence of past injury or physical damage, so-called psychogenic pain.

The term pain as used herein shall refer to all types of pain. Preferably the term refers to all types of chronic pain, including nociceptive pain, neuropathic pain, psychogenic pain and mixed pain types (nociceptive and neuropathic pain components). It includes in particular but is not limited to diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, post-operative pain, chronic back pain, sciatica, neck and back pain, tension headache, cluster headache, daily chronic headache, herpetic neuralgia and postherpetic neuralgia, facial and oral neuralgia and myofascial pain syndromes, pseudolimb pain, residual limb pain and paraplegia pain, dental pain, opioid-resistant pain, post-operative pain including cardiac surgery and mastectomy, exertion and parturition pain, post-partum pain, post-stroke pain, angina pectoris, genitourinary pain including pelvic pain and cystitis and vaginal vestibulitis and testicular pain, irritable bowel syndrome, premenstrual pain syndrome, pain due to burns and chemical or sun exposure, and bone-damaging pain.

The subtypes of nociceptive pain are somatic pain and visceral pain.

Somatic pain includes inflammatory pain, post-operative pain, chronic back pain, neck and low back pain, cluster pain, dental pain, exertion and childbirth pain, post-partum pain, pain due to burns and chemical or sun exposure, and bone injury pain. Visceral pain includes cancer pain, post-operative pain including cardiac surgery, angina, genitourinary pain including pelvic pain and cystitis, and vaginal vestibulitis and testicular pain, and premenstrual pain syndrome. Subtypes of neuropathic pain are diabetic neuropathy, cancer pain, neurogenic pain, central pain, sciatica, herpetic neuralgia, post-herpetic neuralgia, facial and oral neuralgia, pseudolimb pain, residual limb pain and paraplegia pain, opioid-resistant pain, post-operative pain including mastectomy, and post-stroke pain. The subtypes of psychogenic pain are chronic headache and tension headache each day. Subtypes of mixed headache-like are cancer Pain, myofascial Pain syndrome and tension headache (e.g., McCaffery M, Pasero C., Clinical Manual of Pain p19 St. louis: Mosby 1999; Merskek H and Bogduk (eds.) Chronic Pain Classification of Chronic Pain, 2 nd edition, IASP Task Force on Taxomy, p 209. 214, IASP Press, Seattle 1994; The Merck Manual, 14 th part, 167, "Pain" (Pain), 17 th edition Merck & Co 1999).

The effectiveness of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) in various pain indications has been demonstrated in animals and humans.

For example, SSRIs have been shown to potentiate the action of conventional opioid analgesics and to be effective themselves in acute, inflammatory and neuropathic pain in various animal models (e.g., Messing et al, psychopharmacology communications 1975, 1: 511. sup. Pharmacol, Commun.). 521; Hynes et al, Life sciences (Life sciences 1985, 36: 2317. sup. 2323; Larsen and Arnt, Integrated Pharmacology and toxicology reports (Acta Pharmacol Toxicol. Copenh.). 1985, 57: 345. sup. Pharmacol; Larsen and Hyttel, Pharmacol. Copenh.). 1985, 57: 214. sup. Pharmacol 218; Yamamoto et al, Nippon Yakuku Pharma 351, Zhiass 351, 94. 1986; Biotech., Clematis Pharmacol et al., Pharmacol., 1986. sup. 35; Solomon et al, Biotech., Pharmacol., 189, 1986. 75. sup. 1986, Pharmacol., 189; clinical pharmacology, 1986. 1986, 1986. sup. 1986, Biotech.),32; Solomon.), 48: 411-416; for example, Schreiber et al, neuropsychiatric pharmacology in Europe (Eur. Neuropsychromermacol.) 1996, 6: 281 and 284; korzeniewska et al, pharmacological and biochemical effects (pharmacol. biochem. behav.)1998, 59: 331-338; luger et al, Pharmacol, Toxicol 1999, 85: 263-268, Sawynom et al, Pain 1999, 82: 149-158, McCleane, Pain 2000, 85: 311-312.

SSRIs are also effective in experimental Pain in healthy volunteers (Coquoz et al, Schweiz. Med. Wochenschr.1991, 121: 1843-1845; Coquoz et al, clinical drug therapy (Clin. Pharmacol. Ther.)1993, 54: 339 344) and more particularly in patients with various chronic pains such as headache (tension headache), diabetic neuropathy, spontaneous Pain, backache, pseudolimb Pain, rheumatic Pain, irritable bowel syndrome, premenstrual Pain syndrome or diffuse or mixed Pain syndromes (e.g. radicular Pain, atypical chest Pain) (e.g. Theesen and Marsh, P1989, 23: 572-dash 574; Sindrrup et al, Pain (Pain)1990, 42: 135-dash 144; Sindrrup et al, drug therapy monitoring (Ther. Drugt. Patch. 1991; clinical drug therapy (Psuch. Clithi.341, Psuch. 19913; Bouch et al, clinical drug therapy (Psuch. 341, Psuch. 76; Psuch. 76), 6 (supplement 5); 5-12; Power-Smith and Turkington, journal of psychiatry in the united kingdom (br.j. psychiatry)1993, 163: 105-106; manna et al, Headache (Headeace) 1994, 34: 44-49; langemark and Olesen, Headache (Headache)1994, 34: 20-24; finally, the annual book of drug therapy (ann. pharmacother.) 1994; 28: 1359-; saper et al, Headache (Headache)1994, 34: 497-502; gruber et al, north american clinical psychiatry (psychiatr. clin. north am.)1996, 19: 351- > 369; rani et al, "narcotic analgesics" (aneth. analg.)1966, 83: 371-; McQuay et al, Pain (Pain)1996, 68: 217-227; jung et al, journal of international genetics and drugs (j.gen.lnn.med.) 1997, 12: 384-389; abramson and Garfin, Pain (Pain)1999, 83: 137-145; baraczka et al, Orv.Hetil.1997, 138: 2605 and 2607; o' Mally et al, j.fam.pract.1999, 48: 80-990; ciaramella et al, Minerva Anestesol.2000, 66: 55-61; ansari, harv.rev.psychiatry 2000, 7: 257-277).

Moreover, SSRIs are the most frequently used drugs in depressive disorders with high concomitant incidence for depression and pain and even they may share common etiologies (e.g., Ekselius et al, J. Rehabil. Med. 1997, 29: 91-96; Max et al, J. New England. J. Med. 1992, 326: 1250-.

Finally, selective 5-hydroxytryptamine 5-HT_1AReceptor agonists reduce pain in models of acute and chronic pain and inflammatory pain in animals (e.g., Fasmer et al, pharmacological and biochemical effects 1986, 25: 883-888; Bragin et al, Pain (Pain)1989, 36: 257- > 261; giordano and Rogers, Pain (Pain)1989, 39: 109-113; murphy and Zemlan, Neuropharmacology (Neuropharmacology)1990, 29: 463 and 468; crisp et al, genetics (gen. pharmacol.)1991, 22: 247-; danzebrink and Gebhart, Brain studies (Brain Res) 1991, 538: 64-75; glide and Hole, Neuropharmacology (Neuropharmacology)1991, 30: 727-731; giordano and Rogers, Pain (Pain)1992, 50: 365-; mjellem et al, neurological reports (Neuroreport)1992, 3: 1061-1064; eide and Hole, headache (Cephalagia)1993, 13: 75-85; korneyev and Seredenin, life sciences (life sci) 1993, 52: 997-; cervo et al, journal of european pharmacology (eur.j. pharmacol.)1994, 263: 187-191; xu et al, journal of pharmacological experimental therapy (j. pharmacol. exp. ther.)1994, 269: 1182-; sanchez et al, neurological reports (Neuroreport)1995, 6: 2585-2588; millan et al, brain action research (behav. brain Res.)1996, 73: 69-77; robles et al, J.Eur. Pharmacol 1996, 295: 181-188; galeoti et al, pharmacological and biochemical effects (pharmacol. biochem. behav.) (1997), 57: 835-841; rouzade et al, "science of digestive disorders" (digest. dis. sci.)1998, 43: 2048-2054; jain and Kulkarni, "methods for pharmacological approaches in clinical trials" (meth.find.exp.clin.pharmacol.)1999, 21: 161-165; shannon and Lutz, Psychopharmacology (Psychopharmacology)2000, 149: 93-97). To our knowledge, the lack of selective 5-HT in the market_1AAgonists have not yet achieved clinical effects in pain patients.

Thus, as in 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine and its salts or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitriles and salts thereof recognized 5-hydroxytryptamine reuptake inhibiting properties and 5-hydroxytryptamine 5-HT_1ACombinations of agonist properties in the treatment of chronic pain conditions or in the treatment of hypersensitivity to pain signals, hyperalgesia, allodynia, increased perception of pain and increased memory in painThe other diseases of action represent advantages over SSRIs alone.

Accordingly, the present invention relates to the combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) and 5-HT_1AUse of a receptor agonist compound in the manufacture of a medicament for the treatment of chronic pain.

The invention therefore relates to the use of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment of chronic pain.

The invention further relates to the use of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the treatment of chronic pain.

A preferred salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine is 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride.

The invention therefore relates to the use of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine as the physiologically acceptable salt, in the manufacture of a medicament for the treatment of chronic pain, is the hydrochloride salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine.

A preferred salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile is 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile hydrochloride.

The invention therefore relates to the use of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile, a physiologically acceptable salt thereof, in which the hydrochloride salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile, for the preparation of a medicament for the treatment of chronic pain.

In addition, the invention relates to a selection comprising at least one combinationSex 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRI) and 5-HT_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof, together with at least one solid, liquid or semi-solid excipient or adjuvant for use in the treatment of chronic pain.

The invention therefore provides a pharmaceutical preparation for the treatment of pain, characterized in that it contains at least 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine or one of its pharmaceutically acceptable salts.

The invention therefore provides a pharmaceutical preparation for the treatment of pain, characterized in that it contains at least 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile or one of its pharmaceutically acceptable salts.

The selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) in combination with 5-HT according to the present invention are preferably administered in a manner similar to other known commercially available pain-treating agents, such as duloxetine (duloxetine)_1AA receptor agonist compound. The unit dose generally contains from 0.1 to 1000mg, preferably from about 0.1 to 500mg, in particular 5, 10, 20, 30, 40, 50, 100, 150, 200, 250 and 300 mg. The composition may be administered once or several times, for example 2, 3 or 4 times per day. The daily dosage is about 0.01-50mg/kg body weight. However, the specific dose for each patient depends on various factors, for example, on the activity of the specific compound used, body weight, general health, sex, diet, time and route of administration, rate of excretion, combination of drug substances and the severity of the particular disease to which the therapy is directed. Oral administration is preferred, but non-oral (peroral) routes of administration (e.g. intravenous or transdermal) may also be used.

Preferably, a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT is used_1AReceptor agonists, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzoFuran-5-yl-piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile, or a physiologically acceptable salt thereof, is used for the treatment of chronic pain. Preferred nociceptive pain indications are inflammation and post-operative pain.

Accordingly, the present invention relates to a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and a 5-HT_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof for use in the preparation of a medicament for the treatment of nociceptive pain.

Preferably, a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT is used_1AReceptor agonists, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile, or a physiologically acceptable salt thereof, is used for the treatment of chronic pain. Preferred neuropathic pain indications are neuropathic pain and facial and oral neuralgia.

Accordingly, the present invention relates to a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and a 5-HT_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof for use in the manufacture of a medicament for the treatment of neurogenic pain.

In addition, a combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRI) and 5-HT has been found_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof is further useful for the treatment of other diseases where hypersensitization is present with respect to pain signals, hyperalgesia, allodynia, enhanced perception of pain and enhanced memory of pain. The preferred indication is irritable bowel syndrome.

Irritable Bowel Syndrome (IBS) is a common bowel disorder that causes spastic pain, gas regurgitation, bloating and altered bowel habits. The cause of IBS is not known, but it is generally thought to be caused by emotional conflicts or stress. IBS is a so-called functional disorder because there is no sign of disease when the colon is examined. People with IBS often have spastic abdominal pain with painful constipation or diarrhea.

Accordingly, the present invention relates to a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and a 5-HT_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof for use in the preparation of a medicament for the treatment of inflammatory bowel syndrome.

A preferred salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine is 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride.

Accordingly, the present invention relates to the use of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine, wherein the pharmaceutically acceptable salt is the hydrochloride salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine, for the manufacture of a medicament for the treatment of irritable bowel syndrome.

A preferred salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile is the hydrochloride salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile.

Accordingly, the present invention relates to the use of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of irritable bowel syndrome, wherein the hydrochloride salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile.

In addition, the present invention relates to compositions comprising at least one selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) in combination with a 5-HT inhibitor_1AReceptor agonist compounds, in particular 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof, together with at least one solid, liquid or semi-solid excipient or adjuvant, for use in the treatment of irritable bowel syndrome.

The invention therefore provides a pharmaceutical preparation for the treatment of irritable bowel syndrome, characterized in that it contains at least 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine or one of its pharmaceutically acceptable salts.

The invention therefore provides a pharmaceutical preparation for the treatment of irritable bowel syndrome, characterized in that it contains at least 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile or one of its pharmaceutically acceptable salts.

The selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) in combination with the present invention are preferably administered in a manner similar to other known commercially available formulations for the treatment of Irritable Bowel Syndrome (IBS)_1AA receptor agonist compound. The unit dose generally contains from 0.1 to 1000mg, preferably from about 0.1 to 500mg, in particular 5, 10 and 20 mg. The composition may be administered once daily. The daily dosage is about 0.01-10mg/kg body weight. However, the specific dose for each patient depends on various factors, for example, on the activity of the specific compound used, body weight, general health, sex, diet, time and route of administration, rate of excretion, combination of drug substances and the severity of the particular disease to which the therapy is directed. Oral administration is preferred, and non-oral (perora) administration may also be usedl) route of administration (e.g., intravenous or transdermal).

The pharmaceutical preparations for the treatment of pain or preferably for IBS can be used as medicaments in human or veterinary medicine.

The preparation method of the pharmaceutical preparation for treating chronic pain is characterized in that 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile, or a physiologically acceptable salt thereof, in combination with a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRis) and 5-HT_1AThe receptor agonist compounds are converted into suitable dosage forms containing at least one solid, liquid or semi-solid or auxiliary agent.

Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. buccal), parenteral or topical administration and which do not react with 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine and/or one of its biocompatible salts, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. Dosage forms for oral administration, in particular tablets, pills, sugar-coated tablets, capsules, powders, granules, syrups, liquids or drops; dosage forms for rectal administration, in particular suppositories; formulations for parenteral administration are, in particular, solutions in solvents, preferably oils or aqueous solutions, and also suspensions, emulsions or implants; and the topical dosage form is transdermal plaster, ointment, cream or powder. It is also possible to lyophilize 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine and/or one of its pharmaceutically acceptable salts and to use the resulting lyophilizates, for example, for the preparation of injectable products. The above formulations may be in sterile form and/or comprise auxiliaries, such as glidants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, colorants, fragrances and/or other active substances, for example one or more vitamins.

If desired, the formulation may be designed as a sustained release formulation of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a biocompatible salt thereof.

The following examples relate to 5-HT for the purposes of the illustrative combination_1AAn animal model of the effectiveness of an agonist and a 5-hydroxytryptamine reuptake inhibitor.

Example 1: procedure for testing acute analgesic Properties for pain relief in mice and rats

1. Hot plate tests on mice or rats (J.Pharmacol. exp. Ther.)1953, 107: 385-:

the mice or rats were placed on a hot metal plate maintained at 54 ℃ for mice or 52 ℃ for rats, which was surrounded by a plexiglas cylinder (height: 13 cm; diameter: 19 cm). The latency of the first licking (maximum: 30 seconds) was determined.

2. Tail flick tests (J. Pharmacol. Exp. Ther.)1941, 72: 74-79, performed on mice or rats as described by D' Amour and Smith:

the animal's tail is heated by a hot light source. The latency before the animals withdraw their tail was determined (maximum: 15 seconds for mice and 30 seconds for rats).

3. Shock susceptibility testing of mice or rats described by Escalier et al (journal of european pharmacology (eur.j. pharmacol.)1981, 74: 1-7):

each animal was placed on a grid plate connected to an electric shock generator that delivered a brief electric shock to the animal's paw. The shock was delivered 3 times at 1mA current intensity for a period of 0.5 seconds each.

The shock interval is 30 seconds. The response to electroshock was quantified using a scale incorporating 3 parameters: jump, vocalization, and escape (each parameter scores 0, 1, or 2). The total score of all 3 parameters obtained from 3 shocks was taken as a measure of susceptibility to electrical shock.

4. The shock titration Test (ShockTitration Test) was performed as described by Weiss and Laties (european journal of pharmacology 1961, 131: 120-129):

the device consists of a standard sound-attenuating peel box (Skinner) (23 x 21 x 18cm) fitted with a household light source, a lever and a grid base plate connected to a programmed shock-applying generator (Imetronic). The skinning box is connected with an MED and PC operation system for controlling experiments and automatically collects data. Rats were first trained in the laboratory to press the lever in order to terminate shock (0.8mA) given 5 seconds apart (escape training). They were then trained to control the electric shock intensity by pressing the lever (30 steps: 0.03-0.9 mA). When the rat presses the lever in the presence of a shock, the shock is terminated and returns to the next lower intensity after 5 seconds. If the rat does not respond during the shock presence, the shock is automatically terminated after 5 seconds and returns to the next higher intensity after 5 seconds (shock titration). Pressing the lever between shocks (reaction within the test) has no result. Each training session lasted 15 minutes and began at the 10 th amperage level (0.3 mA). Animals received vehicle administration of test compound 60 minutes prior to each time frame. Two behavioral measures were taken: the median shock level (nociception threshold) for each rat was defined as the current intensity above and below which the animal received 50% of the shock and the internal test response as the number of lever presses that occurred between the presence of the shock. Drug testing was performed on animals that reached a stable baseline condition for two consecutive weeks. Drug test sessions were administered twice weekly, with no drug used for at least one training session between drug test sessions. Animals were tested (training and trial period) for 5 days per week (monday to friday). The expiration period was 15 minutes later, as described above. Each animal served as its own control and received all selected treatments and controls (vehicle) during the respective test period. The order of treatment is determined by the step of ensuring an even distribution over the different treatment times. Each animal was always tested in the same peeling box in the same order and at the same time of day.

5. Phenylbenzoquinone and acetic acid writhing in mice as described by Hendershot et al (J.Pharmacol. Exp. Ther.)1959, 125: 237-240):

mice were injected with benzoquinone (PBQ) (1.25mg/kg intraperitoneally) or acetic acid (0.5% intraperitoneally). This treatment induced a recognizable writhing response in control animals. The number of wriggling was counted for 10 minutes starting 5 minutes after PBQ or acetic acid injection.

Oral administration of 30mg/kg 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride reduced the number of writhes by 82%.

Example 2: procedure for testing pain relief characteristics associated with anti-inflammatory Process in mice and rats

1. Formalin paw test in mice or rats as described by Wheeler-Aceto et al (Psychopharmacology 1991, 104: 35-44):

5% formalin (25 ul for mice and 50ul for rats) was intraplanted into the left hind paw of the animal. This treatment induced a recognizable withdrawal response in control animals. The number of flinches was counted in mice for 10 minutes starting immediately after formalin injection (early) and again for 5 minutes or in rats for 15 minutes starting 20 minutes after injection.

Oral administration of 30mg/kg of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride reduced the formalin-induced pain response by 79%.

Example 3: procedure for testing the characteristics of pain relief and anti-inflammatory/antipyretic properties associated with anti-inflammatory Process in mice and rats

1. Carrageenan edema test in rats as described by Winter et al (Proc. Soc. exp. biol. Med.)1962, 111: 544-:

the carrageenan solution was injected into the lower surface of the right hind paw of the animal (0.75 mg/paw in 0.05ml of physiological saline). Rats were continuously given thermal and tactile stimulation of both the non-inflamed and inflamed hind paws after 2 hours. For thermal stimulation, the device (Ugo Basile, Reference: 7371) consists of 6 independent plexiglas boxes (17X 11X 13cm) placed on a raised glass plate. Rats were placed in boxes and left free to habituate for 10 minutes. An active infrared light source (set at 20) was then focused in the non-inflamed and inflamed hind paw and the paw withdrawal latency was automatically recorded. The retraction of the paw blocks the reflected light and switches off the counter and light source. To prevent tissue damage, if no reaction was observed, the test was terminated after 45 seconds. For tactile stimulation, animals were placed under an inverted plexiglas box (17 × 11 × 13cm) on the grid floor. An electrical Von Frey probe tip with increased pressure was then applied to the non-inflamed and inflamed hind paw and the force required to induce paw withdrawal was automatically recorded. This step was performed 3 times and the mean force/paw was calculated to give a basal score for each animal. After 3.5 hours the animals were sacrificed by cervical dislocation and the hind paws were sliced and weighed. Increased paw weight (edema) is indicative of inflammation. The latter step can also be used for mice.

2. Yeast Hyperthermia (Yeast Hyperthermia) test as described by Teotino et al (J.Med.chem.)1963, 6: 248):

the rectal temperature of the animal was first measured using a rectal probe. They were then injected with a yeast suspension (512mg/kg subcutaneously). The test substance was administered after 8 hours. The rectal temperature of the mice was determined immediately before the test substance was administered and again after 60 and 120 minutes.

Example 4: procedure for testing pain relief characteristics in chronic pain and inflammation in ratsMethod for preparing a Chinese medicinal composition

1. Chronic inflammatory pain tests (freund's adjuvant test) performed on rats as described by Whiteley (Current Protocols in pharmacology), Wiley, New York, 5.5, 1999):

injection of Freund's adjuvant into rats induced chronic clinical signs of polyarthritis with pain. Rats were weighed on day 1 and a suspension of mycobacterium butyrate (freund's adjuvant) was injected intradermally into the proximal quarter of the tail (1mg in 0.1ml mineral oil). Sham control group received similar injections of mineral oil. On day 18, when the chronic state was completely established, the rats were weighed again and evaluated for clinical symptoms of inflammation. Then both of their hindpaws are subjected to continuous thermal and tactile stimulation. For clinical signs, inflammation was scored on a 5-point scale (0-4) for each paw and tails on a 4-point scale (0-3), i.e., the highest score of 19 per animal. For thermal stimulation, the device (Ugo Basile, Reference: 7371) consists of 6 independent plexiglas cassettes (17X 11X 13cm) placed on a raised glass plate. Rats were placed in boxes and left free to habituate for 10 minutes. A moving infrared light source (set at 20) was then focused in each hind paw and the paw withdrawal latency was automatically recorded. The retraction of the paw blocks the reflected light and switches off the counter and light source. To prevent tissue damage, if no reaction was observed, the test was terminated after 45 seconds. For tactile stimulation, animals were placed under an inverted plexiglas box (17 × 11 × 13cm) on the grid floor. An electrical Von Frey probe (Bioseb, Model 1610) tip with increasing pressure was then applied to each hind paw and the force required to induce paw withdrawal was automatically recorded. This step was performed 3 times and the mean force/paw was calculated to give a basal score for each animal. All animals were tactile stimulated prior to receiving drug treatment and assigned to treatment groups matched based on their pain response.

2. Neuropathic Pain tests (Chung's test) were performed on rats as described by Kim and Chung (Pain 1992, 50: 355-363):

tightening of spinal nerves in rats is associated with hyperalgesia, allodynia and spontaneous pain and thus constitutes a model for peripheral neuropathic pain in humans. Anti-hyperalgesics alleviate these chronic symptoms of pain hypersensitivity. Rats (40 mg/kg intraperitoneal sodium pentobarbital) were anesthetized (180-220g) and incisions were made at the L4-S2 level to expose the left L5 and L6 spinal nerves. Each nerve was tied with ligature around it. The wound is then sutured closed. Rats received an intramuscular injection of 50000 IU penicillin and allowed to recover. At least 2 weeks after surgery, when the chronic state was fully established, both the undamaged and the damaged hind paws of the rats were subjected to thermal and tactile stimulation. For thermal stimulation, the device (Ugo Basile, Reference: 7371) consists of 6 independent plexiglas cassettes (17X 11X 13cm) placed on a raised glass plate. Rats were placed in boxes and left free to habituate for 10 minutes. A moving infrared light source (set at 20) was then focused in the undamaged and damaged hind paws and the paw withdrawal latency was automatically recorded. The retraction of the paw blocks the reflected light and switches off the counter and light source. To prevent tissue damage, if no reaction was observed, the test was terminated after 45 seconds. For tactile stimulation, animals were placed in an inverted plexiglas box (17 × 11 × 13cm) on the grid floor. An electric Von Frey probe tip with increasing pressure was then applied to the undamaged and damaged hind paws and the force required to induce paw withdrawal was automatically recorded. This step was performed 3 times and the mean force/paw was calculated to give a basal score for each animal. All animals were tactile stimulated prior to receiving drug treatment and assigned to treatment groups matched based on their pain response.

The following examples relate to pharmaceutical products:

example A: small bottle

100g of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT with 2N hydrochloric acid_1AA solution of the receptor agonist compound and 5g of disodium hydrogen phosphate in 3 liters of double distilled water is adjusted to pH6.5, sterile filtered, filtered into vials, lyophilized under sterile conditions and sealed to sterileAnd (4) molding. Each vial contained 5mg of active ingredient.

Example B: suppository

20g of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT_1AA mixture of receptor agonist compounds was melted with 100g of soy lecithin and 1400g of cocoa butter and the mixture was poured into a mold and kept cool. Each suppository comprises 20mg of active ingredient.

Example C: solutions of

Selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRI) and 5-HT combined from 1g_1AReceptor agonist compound, 9.38g NaH₂PO₄·2H₂O、28.48gNa₂HPO₄·12H₂O and 0.1g benzalkonium chloride were dissolved in 940ml double distilled water to prepare a solution. The pH was adjusted to 6.8 and the solution was made up to 1 liter and sterilized by irradiation. The solution can be used in the form of eye drops.

Example D: ointment

Combining 500mg of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT under sterile conditions_1AThe compound of the receptor agonist was mixed with 99.5g of petrolatum.

Example E: tablet formulation

1kg of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT was used in a conventional manner_1AA mixture of the compound for the receptor agonist, 4kg lactose, 1.2kg potato starch, 0.2kg talc and 0.1kg magnesium stearate was tableted so that each tablet contained 10mg of active ingredient.

Example F: sugar-coated tablet

The mixture is compressed in a similar manner to example E and the tablets are subsequently coated in a conventional manner with a coating material such as sucrose, potato starch, talc, tragacanth and a coloring agent.

Example G: capsule

2kg of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT was used in a conventional manner_1AThe compound of the receptor agonist is filled into hard capsules so that each capsule contains 20mg of the active ingredient.

Example H: ampoule (CN)

1kg of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT_1AA solution of a compound of a receptor agonist in 60 liters of double distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed into sterile dosage forms. Each ampoule contains 10mg of active ingredient.

Example I: inhalation spray

14g of a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and 5-HT_1AThe compound of the receptor agonist was dissolved in 10 liters of isotonic NaCl solution and the solution was charged into a commercially available pump-operated spray container. The solution is sprayed into the oral cavity or nose. One start (about 0.1ml) corresponds to about 0.14 mg.

Claims (10)

1. Combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) and 5-HT_1AUse of a receptor agonist compound in the manufacture of a medicament for the treatment of chronic pain.

2. Use according to claim 1, wherein the selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) and 5-HT are used in combination_1AThe receptor agonist compound is selected from 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazine) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof.

3. The use of claim 2, wherein the physiologically acceptable salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine is 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride.

4. Use according to claim 2, wherein the physiologically acceptable salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile is 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile hydrochloride.

5. Pharmaceutical preparation for the treatment of chronic pain, characterized in that it comprises a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and a 5-HT_1AAt least one compound of a receptor agonist.

6. Combination of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRis) and 5-HT_1AUse of a receptor agonist compound in the manufacture of a medicament for the treatment of irritable bowel syndrome.

7. Use according to claim 6, wherein the selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) and 5-HT are used in combination_1AThe receptor agonist compound is selected from 1- [4- (5-cyanoindol-3-yl) butyl]-4- (2-carbamoyl-benzofuran-5-yl) -piperazine or a physiologically acceptable salt thereof or 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl]-butyl } -1H-indole-5-carbonitrile or a physiologically acceptable salt thereof.

8. The use of claim 7, wherein the physiologically acceptable salt of 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine is 1- [4- (5-cyanoindol-3-yl) butyl ] -4- (2-carbamoyl-benzofuran-5-yl) -piperazine hydrochloride.

9. The use of claim 7 wherein the physiologically acceptable salt of 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile is 3- {4- [4- (4-cyano-phenyl) -piperazin-1-yl ] -butyl } -1H-indole-5-carbonitrile hydrochloride.

10. Pharmaceutical preparation for the treatment of irritable bowel syndrome, characterized in that it comprises a combination of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) and a 5-HT_1AAt least one compound of a receptor agonist.