WO2005107744A1 - Nerve damage - Google Patents

Abstract

Present invention is directed to a novel medicament for medical treatment of nerve compression or nerve entrapment, such as carpal tunnel syndrome (CTS) or ulnar tunnel syndrome (UTS). More particularly it involves the use of aminoketones derivatives of phloroglucinol, to prevent, retard and ameliorate a nerve compression, a nerve entrapment or traumatic or physical nerve injury and the associated syndromes or axonal degeneration. Such aminoketone derivatives are preferably 2’,4’,6’-triemthoxy-4 (1-pyrrolidinyl) butyrophenone or pharmacologically acceptable salts and/or functional derivatives thereof. The medicament to prevent, retard and ameliorate a nerve compression, nerve entrapment or physical nerve injury syndromes can furthermore comprise magnesium (Mg), its pharmacologically acceptable salt or its derivatives, such as magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate chelated magnesium, magnesium EAP in an amount sufficient to treat, to prevent, to retard, to ameliorate of to cure physical or traumatic nerve injury, nerve compression or nerve entrapment and the associated syndromes or axonal degeneration.

Description

NERVE DAMAGE

FIELD OF THE INVENTION

Present invention is directed to a novel medicament for medical treatment of physical nerve injuries, in particular nerve compression or nerve entrapment, such as carpal tunnel syndrome (CTS) or ulnar tunnel syndrome (UTS). More particularly it involves the use of aminoketones derivatives of phloroglucinol (C6H6O3), to prevent, retard and ameliorate a nerve compression, a nerve entrapment or traumatic or physical injury of the nerve and the associated syndromes or axonal degeneration. Such aminoketone derivatives are preferably 2',4',6'-triemthoxy-4 (1- pyrrolidinyl) butyrophenone or pharmacologically acceptable salts and/or functional derivatives thereof. The medicament to prevent, retard and ameliorate nerve compression, nerve entrapment or traumatic nerve injury syndromes can furthermore comprise magnesium (Mg), its pharmacologically acceptable salt or its derivatives, such as magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate chelated magnesium, magnesium EAP in a amount sufficient to treat, to prevent, to retard, to ameliorate or to cure traumatic or physical injury of the nerve, nerve compression or nerve entrapment and the associated syndromes or axonal degeneration.

BACKGROUND OF THE INVENTION

Present invention involves a medicinal treatment of physical nerve injuries, more particularly nerve entrapment or nerve compression.

Nerve entrapment involves a group of syndromes resulting from entrapment or compression of a short segment of a nerve at a specific site. The nerve is particular vulnerable to entrapment or compression where it passes through a fibro-osseous tunnel or an opening in fibrous or muscular tissue.

Such entrapment neuropathies have generally common features such as the pain, which is usually ever-present, and activity increases the pain; discomfort after activity and relief after rest is not usually seen as in tendonitis or bursitis and there is a retrograde pain distribution. Pain is typically the predominant feature of entrapment neuropathies. In sensory nerve dysfunction the pain may be sharp, burning, with associated parasthesias. Altered sensation will be present such as hyperesthesia, or hypoesthesia. Motor involvement may present as sharp or dull pain, often poorly localised, with or without atrophy.

Nerve entrapment or nerve compression syndromes are usually diagnosed with a combination of history and physical examination and clinical electromyography (EMG) consisting of nerve conduction studies (NCS) and needle electromyography (needle EMG) of the nerves suspected to be entrapped or compressed. Decreased nerve conduction across the compression or entrapment site is usually noted. Nerve conduction studies by monitoring the action potential while stimulating different regions of the nerve may be used to help localise the level of physical injury and entrapment. The examiner looks for a change in amplitude or conduction velocity.

Among the many sorts of nerve entrapments are entrapments of various nervous at various sites some are listen in Table 1. The two most common forms of peripheral nerve entrapment are carpal tunnel syndrome and ulnar tunnel syndrome. These are of a group of disorders categorised by several different terms such as repetitive stress injuries, cumulative trauma disorders, overuse syndromes, chronic upper limb pain syndrome or repetitive motion disorder.

The occurrence of nerve entrapment syndromes is frequent. For instance of the most common diagnosed nerve entrapment, carpal tunnel syndrome, a British study of 1988 demonstrates that between 7% and 16% of the population experience it. According to a 2001 report from the Bureau of Labour Statistics, carpal tunnel syndrome was associated with the longest average time away from work. In USA occupation-related causes of carpal tunnel syndrome have been reported to have a severe impact on American businesses. Workers with carpal tunnel syndrome become easily fatigued, experience pain and discomfort, and may not perform up to par. The medical costs and loss of productivity because of carpal tunnel syndrome would in USA average $29,000 per injured worker. The only treatment of nerve entrapment syndromes such as carpal tunnel syndrome and ulnar tunnel syndrome with proven benefits so far is surgical treatment. Nerve decompression by surgery is since many years the most common practice of treatment and has become a standard of care (Semple JC and Cargill AO. Lancet 1969 1: 918-919). There are three release surgical procedures common practice all with particular advantages or disadvantages: standard open release surgery, limited incision release and endoscopic release surgery (Brown L.G. and Wright J.G. Bone Joint Surg. Am. 2003 May 85-A (5): 964; Klein R.D. et al. Plast. Reconstr. Surg. 2003 Apr. 15, 111 (5): 1616 - 22; Serra L. et al. Minim Invasiv. Neurosurg. 2003 Mar. 46 (1) 11 - 5; Rutch D.S. et al. J. South Orthop. Assoc. 2002 11 (3) 144 - 7; Kiymaz N. et al. Minim Invasive Neurosurg. 2002 Dec. 45 (4) 228 - 30; Chow J.C. and Hantes M.E. J. Hand. Surg. 2002 Nov. 27 (6) 10011-8 and Ferdinand R.D. et al. J. Bone Joint. Surg. 2002 Apr. 84(3): 375 - 9). Surgery does not cure all patients. If it permanently cuts ligaments in the wrists some wrist strength may be lost.

Current medicinal treatments which induce pain relief for nerve entrapment syndromes are the use of painkillers of the group of nonsteroidal anti-inflammatory drugs (NSAIDs), such as the drugs of the group comprising aspirin, ibuprofen, naproxen, ketoprofen, diclofenac and tolmetin. They may help to reduce swelling and pain and may induce improvement in clinical and electromyographic parameters (Celiker R. et al Am. J. Phys. Med. Rehabil. 2002 Mar; 8 1 (3): 182 - 6). However long-term use of NSAID's is the second most common cause of ulcers and there is some evidence that over long term NSAIDs may actually damage joint cartilage. Sometimes diuretics, such as trichlormethiazide, are used to reduce fluid in the body to treat nerve entrapment. However, studies are not reporting any significant benefits with these agents. In fact some studies demonstrate that neither the NSAID nor the diuretic was any more effective than a placebo (Chang MH, et al. Neurology. 1998 Aug; 51 (2): 390-3 and Nakasato Y.R. J. Okla State Med. Assoc. 2003 Mar. 96 (3): 113 - 5).

Sometimes corticosteroid (such as cortisone or prednisolone) are injected on the place of nerve entrapment. Corticosteroids are known to reduce inflammation and may shrink the swollen tissues and relieve pressure on the nerve (van Gijn J. and Staal A. Ned. Tijdschrift voor

Geneeskunde 2002 May 25, 146 (21): 981 - 5). In many cases steroid injections provide only a temporary relief. On the other hand corticosteroids can have serious side effects if used for long periods. The long-term risks of this treatment for corticosteroids are currently unknown.

Present invention and the subject matter herein claimed and disclosed have thus solved the above mentioned long-felt needs in the art since it demonstrates that a medicament comprising buflomedil (2',4',6^,-trimethoxy-4-(l-pyrrolidinyl) butyrophenone) or a pharmaceutical acceptable salts or a functional derivative thereof and a medicament further comprising magnesium or a pharmaceutically acceptable salt or functional derivatives can be used to decrease pain or discomfort cause by nerve entrapment or nerve compression and moreover can be used to prevent, retard and ameliorate nerve entrapment or nerve compression without surgery.

We found that a medicament comprising the aminoketone derivative, buflomedil (2',4',6'- trimethoxy-4-(l-pyrrolidinyl) butyrophenone can ameliorate or cure nerve entrapment syndrome and that such medicament comprising the aminoketone derivative, buflomedil (2',4',6'- trimethoxy-4-(l-pyrrolidinyl) butyrophenone) can be combined with magnesium to even treat more efficiently nerve entrapment syndromes.

The aminoketone derivative derivatives of phloroglucinol with the general structure formula I:

wherein each Rl, R2 and R3, are the same or different, and represent methyl or ethyl, and n is 3, or a nontoxic acid addition salt thereof and in particular buflomedil or 2',4',6'-trimethoxy-4-(l- pyrrolidinyl) butyrophenone (Registry Number: 55837-25-7, Formula: C17 H25 N O4;

CA Index Name: 1-Butanone, 4-(l-pyrrolidinyl)-l-(2,4,6-trimethoxyphenyl)- (9CI); Other Names: Buflomedil) and is describable by the structure formula II :

and buflomedil Hcl (Registry Number: 35543-24-9, Formula: C17 H25 N 04 . CI H, CA Index Name: 1-Butanone, 4-(l-pyrrolidinyl)-l -(2,4,6 - trimethoxyphenyl)- , hydrochloride (9CI); Other Names: Bufedil; Buflan; Buflocit; Buflomedil hydrochloride; Buflonat; Fonzylane; Irrodan; Irrodan R; LL 1656; Lofton; Loftyl; Provas), and is describable by the structure formula III:

^• HC1 have currently been used as a vasodilator to treat vasculorpathy and diabetic angiopathy (e.g. arteriosclerosis, diabetes or endoangioitis obliterans). The aminoketone derivatives of phloroglucinol and in particular the compounds 4-(pyrrolidinyl)-l(2,4,6-trimethoxyphenyl)- 1- butanone; 2',4',6'-trimethoxy-4-(r-pyπOlidinyl) butyrophenone; (2,4,6- trimethoxyphenyl) (3- pyrrolidinopropyl)ketone and buflomedil (BFL) and its derivative CRL 41034 (CAS Registry No. 138230-22-5, Fundam Clin Pharmacol 1990;4(5):52) are classified as peripheral vasodilators and are also widely used for improving microcirculation. Drugs of this type having the general formula C17H26C1NO4 are fully described in the DE-A-2,122,144 (1971) in US-A-3,895,030 (1971) and in Italian patent No. IT- A- 1,120,968, which is hereby included by reference. Methods of synthesis of these compounds have for instance been described by Jiang, Ye and Zhang,

Rong-Jiu., Zhongguo Yiyao Gongye Zazhi (1999), 30(2), 58-59. ZYGZEA 1001-8255 and by Cirere Dotti, Xavier. (1986) in ES 539108 Al 1986 05 16 and in US-A-3,895,030 (1971).

Magnesium on the other hand is involved in more than 300 different enzymatic reactions, including carbohydrate utilisation, ATP metabolism, muscle contraction, transmembrane ion transport, and the synthesis of fat, protein, and nucleic acids.

ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

Carpal tunnel syndrome (CTS) is the most common diagnosed entrapment syndrome in the upper extremity and has already been recognised for many years (Phalen GS J. Bone Joint Surg. Am 1966; 48:211-228). CTS is a syndrome associated with axonal degeneration (Cactano MR Arq. Neuropsiquitar. 2003 Mar. 61 (1) 48-50) caused by compression or entrapment of the median nerve, more particularly median nerve entrapment at the wrist manifested by characteristic signs and symptoms. It can be diagnosed clinically. Complains are for instance numbness, tingling, and pain in the arm, hand, and fingers. Usually, CTS is considered a disorder caused by chronic, repetitive, work-related upper extremity stress, physical injury repetitive stress, or other conditions that cause the tissues around the median nerve to become swollen (Masear V.R. et al, J. Hand Surg Am. 1986; 11: 222-227). It occurs either when the protective lining of the tendons within the carpal tunnel becomes swollen or when the ligament that forms the roof becomes thicker and broader. CTS is estimated to account for over 41% of these repetitive motion disorders. Researchers have defined six key risk factors in the workplace for the development of CTS as: 1) repetition; 2) high force; 3) awkward joint posture; 4) direct pressure; 5) vibration; and 6) prolonged constrained posture. Some experts believe that incorrect posture may play a large role in the development of carpal tunnel syndrome, particularly in people who work at computer and other types of keyboards. Carpal tunnel syndrome involves symptoms such as pain in distal, palmar surface of wrist or arm with distal radiation into thumb, index and middle finger and proximal radiation into arm, shoulder and neck, gradually increasing night pain (95% of patients), increase in wrist swelling with inactivity, wrist flexion at night, paresthesias along median nerve course (palmar surface), electrical sensation or dysesthesias. It commonly involves only index and middle fingers and may affect all median innervated 3.5 fingers. In CTS, the well known discriminating clinical/orthopedic tests include phalens test, tinels tap, two point discrimination for sensory loss, muscle testing for thumb adduction, and opponens weakness, as well as thenar atrophy. Both the Phalen and the percussion (Hoffman-Tinel) test are considered to be the classic diagnostic tests for CTS. Electrophysiologic evaluation typically consists of measuring denervation patterns on EMG.

Ulnar tunnel syndrome (UTS) is the second most common upper extremity compression neurodegeneration of which ulnar neurodegeneration at the elbow (UNE) or cubital tunnel syndrome (CTS) is the most common ulnar tunnel syndrome. Cubital tunnel syndrome occurs when the ulnar nerve, which passes through the cubital tunnel (a tunnel of muscle, ligament, and bone) on the inside of the elbow, becomes irritated due to injury or pressure. The condition may occur when a person frequently bends the elbows (such as when pulling, reaching, or lifting), constantly leans on the elbow, or sustains a direct injury to the area. Ulnar nerve lesions at the elbow are for instance the most common nerve injury in baseball pitching. Due to the mechanism of throwing and the action of the flexor carpi ulnaris on the medial epicondyle at or near the cubital tunnel, the ulnar nerve may get entrapped. The symptoms are usually gradual in onset with the most common complaint being hand clumsiness and weakness. Pain may also be present, but the difficulty with hand control is more often seen. Very often this syndrome is associated with difficulty doing fine hand and/or finger movements. Sensory examination may reveal loss of light touch, or in milder cases, decrease in two-point discrimination. Clinicians have recognised UNE at least since the nineteenth century (Panas J. Arch. Gen. Med. 1878; 2:5- 15, Osborne GV. J. Bone Joint Surg. Am 1957; 39B:782 and Buzzard EF Lancet 1922; 17: 1336 - 1342). There are four different sites of potential ulnar compression in the region of the elbow, from proximal to distal: the medial intermuscular septum, the retroepicondylar groove, the humeroulnar arcade (HUA: the aponeurotic band which joins the two heads of the flexor carpi ulnaris muscle), and at the point of exit of the nerve from the flexor carpi ulnaris. Lesions in the ulnar groove account for most cases; HUA compression is also common (Cambell W.W. Muscle Nerve 23:450-452, 2000). The exit compression syndrome is infrequent, but can be recognised regularly if one is sensitive to its existence. Compression by the medial intermuscular septum (arcade of Struthers) proximal to the elbow is rare. The original description of HUA compression is generally attributed to Buzzard's report in 1922 and Osborne's report in 1957 (Buzzard E.F. Lancet 1922 17: 1336 - 1342 and Osborne GV. J. Bone Joint Surg. Am 1957 39B :782).

Guyon's canal syndrome, (Felix Guyon, 1831-1920, French surgeon) is an ulnar entrapment syndrome of the wrist caused by compression of the ulnar nerve at the site where the nerve enters the palm through the ulnar tunnel (canal of Guyon). This disorder is also termed the ulnar tunnel syndrome. This ulnar nerve injury at the canal of Guyon is common to cyclists. This occurs due to the grip on the handlebars putting excessive pressure on the ulnar nerve. Most frequently entrapment of the ulnar nerve in Guyon's canal results from the presence of ganglia or from trauma, including accidents, athletic activities and fractures of the hook of the hamate. This syndrome is also known as an ulnar nerve entrapment at the wrist. At the wrist, the ulnar nerve enters Guyon's canal along with the ulnar artery, which runs just lateral to the nerve. This canal runs along the lower edge of the palm, on the little finger side of the hand. In the middle of the canal, the ulnar nerve splits into its two terminal branches (deep and superficial) that go on to the palm, ring and little fingers.

Other common nerve entrapment syndromes include: 1) Pronator syndrome, an entrapment of the median nerve at the elbow resulting from compression of the median nerve where it passes between the two heads of the pronator teres muscle and under the flexor digitorum sublimis muscle in the antecubital area; 2) Anterior interosseous nerve syndrome (Kiloh Nevin syndrome or Kiloh - nevin syndrome from Leslie Gordon Kiloh, 20th century, Australian physician and

Samuel Nevin, 20th century, English neurologist), a disorder that results from compression of the anterior interosseous nerve, a branch of the radial nerve, leading to weakness of the thumb and index finger. The syndrome is also known as the anterior interosseous nerve syndrome and may be idiopathic or occur as a result of aberrant fibrous bands, after fractures of the radius or humerus, or in association with thrombosed vessels or enlarged bursae; 3) Entrapment of the

Suprascapular Nerve, a nerve entrapment syndrome with typically deep aching pain in the area of the lateral and posterior shoulder. The suprascapular nerve may get entrapped in sports such as baseball, volleyball, weight training and fencing in the area of the suprascapular notch or spinoglenoid notch; and 4) Radial tunnel syndrome, an entrapment of the radial nerve at its bifurcation point at the elbow at the arcade of Frohse, or at the fibrous margin of the supinator muscle.

Table 1. Some nerve entrapment or nerve compression syndromes.

The basic pathophysiology, anatomy and diagnosis of these and other specific causes of nerve injury, nerve entrapment, nerve compression and the syndromes thereof have been well described in the profession literature and in the scientific literature (Slater R.R. Journal of the Southern Orthopaedic Association Vol. 8 No. 3 1999; Jablecki C.K. et al. Neurology 58, June 2002; Trumble T.E. et al. The Journal of Bone & Joint Surgery Vol. 84- A No. 7 July 2002; Netscher D.T. Plast. Reconstr. Surg. 2003 May 1; 111 (6): 2020-2; Carpal Tunnel Syndrome and Other Disorders of the Median Nerve (2nd Edition) R.B. Rosenbaum J.L. Ochoa; Butterworth Heinemann, 2002, 400 pp.; Gay R.E. et al., Journal of Hand Surgery 2003 Mar. 28 (2) 250-4; Wilson J.K. and Sevier T.L. Disabil. Rehabil. 2003 Feb 4, 25 (3): 113 - 9.; Padua L. et al. Clin. Orthop. 2002 Feb. 395 128 - 34; Commandre F. Pathologie Arbarticulaire, Agence VLOO, Copyright 1977 Schering Corporation U.S.A. Depot legal 4e trimester 1977; HM Childress. CORR. Vol 108, 1975. p 168-170; EB Toby et al. J. Hand Surg. Vol 23-A. 1998. p 992-997; Gilliatt RW. The Physiology of Peripheral Nerve Disease. 1st Edition. Edited by Sumner AJ. Philadelphia: WB Saunders Company; 1980. pp. 316-339; Thomas PK, Holdorff B. Peripheral Neuropathy. 3rd Edition. Edited by Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (editors). Philadelphia: WB Saunders Company; 1993. pp. 990-1013; Stewart JD. Focal Peripheral Neuropathies. 3rd Edition. Philadelphia: Lippincott Williams & Wilkins; 2000; Kline DG, Hudson AR. Nerve Injuries. Operative Results for Major Nerve Injuries, Entrapments, and Tumors. 1st Edition. Philadelphia: WB Saunders Company; 1995; Rempel D., et. al. Am J Public Health 1998; 88:1447-1451; Jablecki C.K., et al. Report of the American Association of Electrodiagnostic Medicine, American Academy of Neurology, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2002; 58:1589- 1592 and Gerritsen A. A. M.et al. JAMA 2002; 288:1245-1251).

The invention thus involves a novel medicament and treatment of an entrapment or compression of nerves of the group consisting of median, ulnar, radial, suprascapular, plantar and interdigital, posterior tibial, common peroneal, lateral femoral cutaneous, femoral, obturator, sciatic and brachial plexus, more particularly by the use of aminoketones derivatives of phloroglucinol. The aminoketone derivatives of phloroglucinol can be of the general structure formula I:

wherein each Rl, R2 and R3, are the same or different, and represent methyl or ethyl, and n is 3, or a non-toxic addition thereof. The acid addition salt can be a salt of hydrochloric, hydrobromic, hydroiodic, sulphuric, phosporic, oxalic, fumaric, maleic, malic, citric, ascorbic, cyclohexylsulphamic, benzoic, glutamic or aspartic acid and in particular it can be the compounds 2^,,4',6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone; 1-Butanone, 4-(l-pyrrolidinyl)- 1 -(2,4,6 - trimethoxyphenyl)- , hydrochloride; 2',4',6'-triethoxy-4-(l-pyrrolidinyl) butyrophenone; 1-Butanone, 4-(l-pyrrolidinyl)-l -(2,4,6 - triethoxyphenyl)- , hydrochloride or a non-toxic acid addition thereof.

Furthermore the present invention involves the treatment of a disease of the group consisting of pronator syndrome, anterior interosseous nerve syndrome (Kiloh Nevin syndrome), carpal tunnel syndrome, sublimis syndrome (pseudo-carpal tunnel syndrome), cubital tunnel syndrome (tardy ulnar palsy), ulnar tunnel syndrome (Guyons canal syndrome), Saturday night palsy (sleep palsy), posterior interosseous nerve syndrome, morions metatarsalgia, tarsal tunnel syndrome, meralgia paraesthetica, piriformis syndrome, thoracic outlet syndrome (scalenus anticus syndrome), calceneal nerve compression, peroneal nerve compression, thoracic outlet syndrome, tarsal tunnel syndrome, radial nerve compression, calcaneal nerve compression, heel pain due to compression of the calcaneal nerve, peroneal nerve compression, deep peroneal nerve, entrapment on the dorsum of the foot and ankle, pain over the top of the foot due to an entrapment of the deep peroneal nerve.

In a preferred embodiment 2', 4', 6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone or p-desmethyl- 2',4',6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone, their hydrochloride or any pharmaceutically acceptable salt or derivatives there of may administered orally in a regime of 5 to 5000 mg/patient/day, more preferably 20 to 1000 mg/patient/day, and yet more preferably 150 to 800 mg/patient/day and most preferably 300 to 600 mg/patient/day. A possible daily dose can for instance be 7 to 10 mg/kg body weight. The active compound may be delivered as a solid medicine in pill or tablet form and alternatively as liquid, semi-solid. The parenteral administration form may be an isotonic injection solution. The daily dose parenteral dose could be 3 to 6 mg/kg body weight.

Oral dosage forms are preferred for those therapeutic agents that are orally active, and include tablets, capsules, caplets, solutions, suspensions and/or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts, e.g., in Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, A.R., Ed. (Lippincott, Williams and Wilkins, 2000). Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed.

Tablets may be manufactured using standard tablet processing procedures and equipment. One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like. As an alternative to direct compression, tablets can be prepared using wet- granulation or dry-granulation processes. Tablets may also be moulded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred.

In addition to the active agent(s), then, tablets prepared for oral administration using the method of the invention will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilisers, surfactants, colouring agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinised starch), gelatine, sugars _.(including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size tablet is ultimately provided.

Suitable diluents include lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, magnesium stearate and stearic acid. Stearates, if present, preferably represent at no more than approximately 2 wt. % of the drug-containing core.

Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. Stabilisers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions. Surfactants may be anionic, cationic, amphoteric or non-ionic surface active agents.

The dosage form may also be a capsule, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets). Suitable capsules may be either hard or soft, and are generally made of gelatine, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatine capsules are preferably sealed, such as with gelatine bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, which describes materials and methods for preparing encapsulated pharmaceuticals. If the active agent-containing composition is present within the capsule in liquid form, a liquid carrier is necessary to dissolve the active agent(s). The carrier must be compatible with the capsule material and all components of the pharmaceutical composition, and must be suitable for ingestion.

Solid dosage forms, whether tablets, capsules, caplets, or particulates, may, if desired, be coated so as to provide for delayed release. Dosage forms with delayed release coatings may be manufactured using standard coating procedures and equipment. Such procedures are known to those skilled in the art and described in the pertinent texts, e.g., in Remington, supra. Generally, after preparation of the solid dosage form, a delayed release coating composition is applied using a coating pan, an airless spray technique, fluidised bed coating equipment, or the like. Delayed release coating compositions comprise a polymeric material, e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof. A pharmaceutical prepn. in perorally administrable form containing hydrophobized granules of buflomedil-HCl coated with an acrylic acid polymer and/or a cellulose ether or cellulose ether deriv. to mask the bitter taste of the drug without delaying its release in the digestive tract has for instance been described by Dϋrr Manfred and Gajdos Benedikt in WO9427596.

Sustained release dosage forms provide for drug release over an extended time period, and may or may not be delayed release. Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolysable) material such as an, insoluble plastic, a hydrophilic polymer, or a fatty compound, or by coating a solid, drug containing dosage form with such a material. Insoluble plastic matrices may be comprised of, for example, polyvinyl chloride or polyethylene. Hydrophilic polymers useful for providing a sustained release coating or matrix cellulosic polymers include, without limitation: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (sold under the tradename Eudragit RS) preferred; vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylenevinyl acetate copolymers; zein; and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butyl stearate. Fatty compounds for use as a sustained release matrix material include, but are not limited to, waxes generally (e.g., camauba wax) and glyceryl tristearate.

Alternatively transepidermal effective amounts of 2',4',6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone or of p-desme yl-2',4',6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone, their hydrochloride or any pharmaceutically acceptable salt or derivatives thereof may be administered topically on the respective nerve entrapment areas. The transdermal administration of 2',4',6'- trimethoxy-4-(l-pyrrolidinyl) butyrophenone or of p-desmethyl-2^,,4',6^l-trimethoxy-4-(l- pyrrolidinyl) butyrophenone, their hydrochloride or any pharmaceutically acceptable salt or derivatives thereof can be transdermal electromotive administration, the transdermal absorption being accelerated by use of an electrode-drug receptacle attached to the patients. For such topical treatment the pharmaceutical product can be used as liquid, semi-solid or solid medicine. Liquid medicines are solutions, suspensions, emulsions or dispersions of the above-cited active ingredients or combinations of active ingredients as drops, tinctures and sprays. As semi-solid medicines, for example, gels, ointments, creams and foams are used while, for example, powders, toilet powders, granulates, pellets and microcapsules are used as solid medicines. If the pharmaceutical product containing as active ingredient 2',4',6'-trimethoxy-4-(l- pyrrolidinyl) butyrophenone, its hydrochloride or any pharmaceutically acceptable salt or derivatives thereof, is used as a liquid, it is recommended to use as far as possible irritation-free diluting agents, as for example water, monovalent alcohols, especially ethanol, polyvalent alcohols, especially glycerine and/or propanediol, polyglycols, especially polyethylene glycols and/or miglyols, glycerine formal, dimethylisosorbide, natural and synthetic oils and/or esters.

For the production of semi-solid products, as for example gels, ointments, creams and foams, in addition to the above-cited diluting agents basic materials, as for example bentonite, veegum, guar flour and or cellulose derivatives, especially methylcellulose and/or caboxymethylcellulose, are suitable. The buflomedil hydrochloride, maleate and/or alkali and/or alkaline earth salts may be in the form of a physico-chemical complex with a phospholipid selected from the group consisting of lecithin, cephalin, phosphatidylserine, phosphoinositide, and phosphatidic acid, or mixtures thereof in the form of a cream, an ointment, a pomade, a gel, or an emulsion to the area to be treated. The process of manufacture of such complexes has been described by Bertini Curri in US5,280,020.

Furthermore, instead of the above-cited basic materials or in addition to these materials polymers of vinylalcohol and vinylpyrrolidone, alginates, pectines, polyacrylates, solid and/or liquid polyethylenglycols, paraffins, fatty alcohols, vaseline and/or waxes, fatty acids and/or fatty acid esters are used. It is possible to use the above-cited active ingredients without filler for the production of solid products, as for example powders, toilet powder, granulates, pellets and microcapsules. The pharmaceutical product described here is especially suited for the attention of such of the above-described diseases which are in a very progressed stage so that at first an increased concentration of active ingredients is necessary. With less serious disease conditions or with progressive healing of the disease such embodiments of the solid pharmaceutical product are used which contain fillers, as for example colloidal silicic acid, powdered soapstone, milk sugar, starch powder, sugar, cellulose derivatives, gelatine, metal oxides and/or metal salts, wherein the concentration of the active ingredient or of the combination of active ingredients varies between 0.001% by weight and 50% by weight. A suitable kind of pharmaceutical form may be a topical deliver form of the above-described active ingredient, which is made by the application of the solid, liquid or semi-solid pharmaceutical product onto a gauze strip, a compress or a plaster so that such a gauze strip, such a compress or such a plaster then is only locally applied onto the spot which is to be treated. The pharmaceutical product can be filled into the known receptacles, as for example bottles, tubes, toilet powder boxes and baby powder boxes as well as seal edge bags, which are possibly provided with metering means, as for example droplet forming means, metering valves or metering chambers.

Buflomedil hydrochloride is synonym of 4-(l-Pyrrolidinyl)-l-(2,4,6-tr-methoxyphenyl)-l- butanone has CAS Number 55837-25-7 and molecular Formula: C17H25NO4 ^• HC1 and is describable by the structure formula as displayed in structure formula III of this application.

For the manufacture of the pharmaceutical product of present examples the 2', 4',6'-trimethoxy-4- (1-pyrrolidinyl) butyrophenone indicated above was used. Instead of the 2',4',6'-trimethoxy-4-(l- pyrrolidinyl) butyrophenone or in addition to it salts, especially the corresponding hydrochloride, maleate and/or alkali and/or alkaline earth salts of the 2',4^l,6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone, which can be sulphated and/or sulfonated on the aromatic moiety and/or the pyrrolidine moiety, can be used for the manufacture of the pharmaceutical product. The pharmaceutical products which can be used for the treatment of nerve entrapment, in addition to the above-cited active ingredients or instead of the above-cited ingredients, can also contain derivatives, preferably pharmacologically active metabolic products (metabolites), of the 2',4',6'- trimethoxy-4-( 1-pyrrolidinyl) butyrophenone, especially the p-desmethyl-2',4',6'-trimethoxy-4-(l- pyrrolidinyl) butyrophenone.

The pharmaceutical compound buflomedil may be administered as the hydrochloride, maleate and/or alkali and/or alkaline earth salts. It may be bound to a cation-exchange resin for instance a buflomedil resinate complex. Buflomedil hydrochloride can for instance be bound to cation- exchange resins by soaking the resin in an aqueous solution of the drug, which renders it particularly suitable for oral administration. Process for making a taste-masked buflomedil resinate are described by R. A. Honeysett et al. "Taste-masked buflomedil preparation" in EP0501763.

2', 4', 6'-triemthoxy-4 (1-pyrrolidinyl) butyrophenone, to which the examples of present invention relates is marketed as buflomedil hydrochloride. It is a peripheral vasodilator which has been sold under the trade names BUFENE (I.C.I.), LOFTIL (ABBOT), BUFLAN (PIERREL), IRRODAN (BIOMEDICA FOSCANA) and FLOMED (PULITZER). Amongst the other aminoketones which are classified as peripheral vasodilators and which are more widely used in the treatment of functional and organic peripheral vasculopathy are for instance aminoketone derivatives of phloroglucinol such as 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl)-l-butanone; 2', 4', 6'- trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone; (2,4,6-triethoxyphenyl) (3- diethylaminopropyl) ketone; (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof with pharmaceutically acceptable acids can be used to treat nerve entrapment or compression or the associated syndromes or axonal degeneration or to manufacture a medicament to treat nerve entrapment or nerve compression and physical nerve injuries. The synthesis of these structures have been described in German Pat. 2,122,144 (1971), in U.S. Pat. No. 3,895,030 (1971) and in Italian patent No. 1,120,968. And their use can be within the scope of present invention. These compounds are known to act as vasodilator agent with calcium antagonistic and alpha-adrenoceptor action.

Buflomedil, for instance, is a competitive inhibitor of alpha-adrenergic receptors and acts as a non-specific calcium antagonist. As a vasodilator, it acts via mechanisms of alpha-adrenoceptor blockade and calcium-mobilisation-blocking. Buflomedil is a competitive inhibitor of alpha- adrenergic receptors, not selective for either the alpha- 1- or alpha-2-adrenergic receptor subtype. Addition of buflomedil can totally block the vasoconstriction elicited by phenylephrine.

Buflomedil hydrochloride improves perfusion in the impaired microcirculation of the peripheral and central vascular beds. The vascular activity of buflomedil is related to the two pharmacological components: an alpha- 1 effect and alpha-2 adrenolytic and to a direct action on the microcirculatory structures related to an effect on the calcium uptake at the membrane level of the perivacular myocytes. By its adrenolytic non-specific alpha action, buflomedil is opposed locally to the vasoconstriction effect adrenaline in for instance response to stress or to cold. This action is found primarily in these arteries which have abundant alpha-receptors such as the muscular peripheral arteries of the distribution system. By its calcium-channel-blocking action properties buflomedil opens the contracted pre-capillary sphincters and thus restores a functional microcirculation.

An embodiment of present invention is a method of treating of physical nerve injury, nerve compression or nerve entrapment and the associated syndromes or axonal degeneration, which comprises treating an affected patient with a therapeutically effective amount of a pharmaceutical composition containing as active ingredient a therapeutically effective amount of alpha- adrenoceptor antagonist (competitive inhibitor of a alpha-adrenergic receptors) and a calcium antagonist (calcium-channel-blocker) or a compound which comprises both properties.

Calcium calcium blockers are widely used as vasodilator drug. Their mechanism by which they act as vasodilator is based on a calcium-antagonistic effect whereby they interfere with the transmembrane transfer of calcium in the smooth arterial muscles or act on platelet sludging and on erythrocyte deformability. Despite the various chemical structures of calcium channel blockers, they have one primary mode of action. The cells e.g. cardiac or myocytes release calcium ions through subcellular structures and thereby activate the contractile proteins. A calcium selective channel allows the influx of calcium ions from the extracellular space into the cell, which also triggers the release of calcium from the cell structure. The calcium channel blockers block the calcium selective channel, and hence act primarily as a vasodilator. Potent calcium channel blockers, other than the aminoketone derivates, with marked vasodilator action are 3,5-pyridinedicarboxylic acid, l,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)- dimethyl ester; l,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl) methyl 2-(methyl (phenylmethyl) amino) -3,5- pyridinecarboxylic acid ethyl ester, brovincamine (Tanaka, Y., Arzneimittelforschung, 44, 803- 8), nifedipine, testosterone (K.M. English et al. J. Endocrinol. Invest. 2002, 25: 455-458), Felodipine . Cohn, J. N. et al. Circulation 96: 856-863). Various others calcium channel blockers used or under investigation to widen the blood vessels are felodipine, amlodipine, nifedipine, verapamil HC1, nicardipine HC1, diltiazem HC1, aranidipine, atosiban, barnidipine, cilnidipine, docosahexaenoic acid, efonidipine HCL, fasudil, isradipine, lacidipine, lercanidipine, lomerizine, manidipine, nifelan, nilvadipine, nimodipine, teczem, verelan, plendil, nisoldipine, bepridil HC1, NS-7, NW-1015, SB-237376, SL-34.0829-08, terodiline, R-verapamil, bisaramil, CAI, ipenoxazone, JTV-519, S-312d, SD-3212, tamolarizine, TA-993, vintoperol, YM-430, CHF- 1521, elgodipine, nitrendipine, furnidipine, L-651582, oxodipine, ranolazine, AE-0047, azelnidipine, dotarizine, lemildipine, pranidipine, semotiadil, temiverine HC1, tenosal, vatanidipine HC1, and ziconotide. They can without limitation be used within the scope of this invention.

The adrenoceptor family was first divided into two subtypes, the a- and b-adrenoceptors, as determined by pharmacological studies in isolated tissue (Ahlquist, 1948). A quarter of a century later, the a-adrenoceptors were further subdivided based on their anatomical location, with the a- adrenoceptors located on peripheral sympathetic nerve terminals designated a2 adrenoceptors, and those located post-synaptically designated al-adrenoceptors (Langer, 1974). This anatomical classification rapidly gave way to the identification of pharmacological differences between the a-adrenoceptors, notably the ability of yohimbine and rauwolscine to act as a2-adrenoceptor antagonists. Subsequent studies using pharmacological and molecular biology techniques have further subdivided the alpha adrenoceptor family; three subtypes within each group have now been cloned and pharmacologically characterised. The al-adrenoceptor subtypes have been classified as the al A-, alB- and alD-adrenoceptors and the a2-adrenoceptors have been classified as the a2A- (a2D- species variation of the human a2A-), a2B- and a2C-adrenoceptors.

Alpha-adrenoceptor antagonist or adrenolytic antagonists with a non-specific alpha action, which are currently used as a pharmaceutical are for instance: cetiedil (of Innothera), dihydroergocristine (Poli), dihydroergotamine (bioMerieux-Pierre Fabre), dihydroxyacetone (Vinas), etoperidone, Angelini (Wyeth), labetalol (GlaxoSmithKline), trimazosin (Pfizer), ciclonicate (Poli), dapiprazole (Angelini), amosulalol (Yamanouchi), arotinolol (Sumitomo), naftopidil (Hoffmann-La Roche), terazosin (Abbott), urapidil (Altana), phentolamine (Zonagen), phentolamine (Novartis), dihydroergotamine SR (Ethypharm), Alpha-dihydroergocryptine (Poli). Nonselective alpha-adrenergic antagonists currently underdevelopment are for instance Naftidrofuryl SR (Ethypharm), dihydroergotamine (POZEN), AGN- 195795 (ACADIA), ergotamine (Sheffield), dihydroergotamine, (Sheffield). They can without limitation be used within the scope of this invention.

Present invention thus involves a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising inhibiting the alpha receptors in the arteries and calcium-channel-blocking of the myocytes at the segment said nerve entrapment.

Furthermore the present invention involves a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising a calcium channel blockers and an alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein calcium channel blockers and alpha-adrenoceptor antagonist is a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof

The invention also involves a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising a calcium channel blockers and an alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein calcium channel blockers and alpha-adrenoceptor antagonist is an aminoketone derivatives of phloroglucinol selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(r-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof

Yet an other embodiment of present invention is a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising a calcium channel blockers and an alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein calcium antagonist (calcium blocker) and alpha- adrenoceptor antagonist is an aminoketone derivatives of phloroglucinol of the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl)- 1-butanone, 2',4',6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone and (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone.

The invention involves furthermore a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising a calcium channel blockers and an alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein calcium channel blockers and alpha-adrenoceptor antagonist is 2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'-trimethoxy-4-(l- pyrrolidinyl) butyrophenone or the addition salts thereof

The invention involves furthermore a method of treating, preventing or ameliorating nerve entrapment disorders in a subject comprising: (a) administration to said subject an effective amount of a calcium channel blockers and (b) co-administration to said subject an effective amount of alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein said calcium channel blockers is selected of the group consisting of felodipine, amlodipine, nifedipine, verapamil HC1, nicardipine HC1, diltiazem HC1, aranidipine, atosiban, barnidipine, cilnidipine, docosahexaenoic acid, efonidipine HCL, fasudil, isradipine, lacidipine, lercanidipine, lomerizine, manidipine, nifelan, nilvadipine, nimodipine, teczem, verelan, plendil, nisoldipine, bepridil HC1, NS-7, NW- 1015, SB-237376, SL-34.0829-08, terodiline, R- verapamil, bisaramil, CAI, ipenoxazone, JTV- 519, S-312d, SD-3212, tamolarizine, TA-993, vintoperol, YM-430, CHF-1521, elgodipine, nitrendipine, furnidipine, L-651582, oxodipine, ranolazine, AE-0047, azelnidipine, dotarizine, lemildipine, pranidipine, semotiadil, temiverine HC1, tenosal, vatanidipine HC1, and ziconotide and said alpha-adrenoceptor antagonist is selected from the group consisting of cetiedil, dihydroergocristine, dihydroergotamine, dihydroxyacetone, etoperidone, Angelini, labetalol, trimazosin, ciclonicate, dapiprazole, amosulalol, arotinolol, naftopidil, terazosin, urapidil, phentolamine, phentolamine, dihydroergotamine SR, Alpha-dihydroergocryptine, Naftidrofuryl SR, dihydroergotamine, AGN- 195795, ergotamine, dihydroergotamine.

The invention may also concern to the use of the compounds and the combination of said compounds with adrenolytic antagonists and calcium channel blocking properties, mentioned above, to manufacture a medicament for treating, preventing or ameliorating nerve entrapment disorders.

Magnesium which in an example of present invention has been combined buflomedil and had been found to enhance the cure of nerve entrapment or nerve compression syndrome. Magnesium is the fourth most abundant cation in the body, following calcium, sodium, and potassium, and the second most abundant intracellular cation (after potassium). It is involved in more than 300 different enzymatic reactions, including carbohydrate utilisation, ATP metabolism, muscle contraction, transmembrane ion transport, and the synthesis of fat, protein, and nucleic acids. Magnesium is thus a physiologic necessity, but can also used as a pharmacological compound. Magnesium is, for instance also considered to be a natural calcium-channel blocker and has vasodilator properties and is an inhibitor of vascular smooth muscle cell contraction (Shechter M., et al. Circulation. 2000 Nov 7;102(19):2353-8).

An embodiment of present invention is method of treating of physical or traumatic nerve injury, nerve compression or entrapment and the associated syndromes or axonal degeneration, which comprises treating an affected patient with a therapeutically effective amount of a pharmaceutical composition containing as active ingredient a therapeutically effective amount of aminoketones derivatives of phloroglucinol and preferably a aminoketones derivatives selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone; 2', 4', 6'-trimethoxy-4- (l'-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone; (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone; (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino)methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone or their pharmaceutically acceptable salts and most preferably 2', 4', 6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl- 2',4',6'-trimethoxy-4-(l-pyrrolidinyl) butyrophenone, in the form of their hydrochloride or any pharmaceutically acceptable salt of the active ingredient. The active ingredient may be orally or parenterally administered. Pharmaceutical compositions according to the invention can be periodically administered to a mammalian patient (e.g., a human patient), in need of such treatment, to promote neuronal regeneration and functional recovery and thereby to treat damage to peripheral nerves caused by physical injury or surgical repair. The compounds of present invention are thus useful to enhance regeneration of the injured peripheral nerve. The present invention thus involves a method of promoting nerve regeneration in a mammal having a peripheral nerve injury, the method comprising: administering to the mammal a pharmaceutical composition comprising a nerve regenerating stimulating amount of the compounds of present invention. The compounds of present invention can also be used to enhance motor recovery following physical peripheral nerve injury or surgical repair.

To further enhance injured nerve repair the compounds of present invention may be combined with known neurotrophic factors, which have been shown to play an essential throphic role in the development, maintenance and regulation of neuronal function such as for instance ciliary neurotrophic factor, glial growth factors (glial mitogenic factors), schwann cell mitogenic factors or the nerve growth factors (NGF) and other members of the NGF family.

The peripheral nervous system consists of those nerve cells that extend axonal processes outside the spinal cord and brain. The principle nerve cell types in the peripheral nervous system are primary motor neurons innervating skeletal muscle and controlling movement, autonomic neurons (both sympathetic and parasympathetic) innervating the cardiovascular system and other internal organs and regulating their function, and sensory neurons innervating sensory receptors throughout the body and conveying sensations including pain and proprioception. Conditions that compromise the survival and proper function of one or more of these types of peripheral nerve cells cause peripheral nerve damage. Such damage may occur through physical injury, which causes the degeneration of the axonal processes of peripheral nerve cells that pass through or near the site of injury. A particular form of nerve injury, beside entrapment nerve injury, which can be treated by the compoimds of present invention, is cold injured peripheral nerve injury, for instance trench foot, which is a particular risk for homeless, adventure tourism and for soldiers in winter or mountain area. Another particular form of nerve injury treatable by present can be high energy transfer injuries, nerve injury associated with electrical injury or nerve elongation for instance from leg lengthening surgery. The treatment of peripheral nerve damage caused by physical injury includes the ability to reverse permanent peripheral nerve damage and the ability to enhance naturally occurring recovery processes by either speeding up such processes or by affecting a more complete recovery from the peripheral nerve damage. The prevention of peripheral nerve damage includes the ability to totally prevent nerve damage against the effects of conditions that typically lead to peripheral nerve damage, as well as the ability to lessen the extent of peripheral nerve damage associated with such conditions.

Pharmaceutical compositions are provided as are combination therapies with other agents such as anti-inflammatory drugs, growth factors, and agents useful in the treatment of neuropathic pain. The use of the methods of the present invention are also contemplated with other treatment regimens used to treat patients having carpal tunnel syndrome.

Date of the present invention there is a teaching that the aminoketone derivative of phloroglucinol of present invention can be used to enhance the nerve repairing or protecting effect of growth factors, morphogens or neuronal protective agents on nerve injuries.

The aminoketone derivative of phloroglucinol of present invention are particularly suitable to be combined with the aminoketone derivative of phloroglucinol of present invention for treating nerve injuries. One possible treatment for treating nerve injuries, in particular nerve entrapment and physical nerve injuries can be a combination of aminoketone derivative of phloroglucinol of present invention with morphogen," "bone morphogen," "bone morphogenic protein," "BMP," "morphogenic protein" and "morphogenetic protein" all embrace the class of proteins typified by human osteogenic protein 1 (hOP-1). For ease of description, hOP-1 is considered a representative morphogen. It will be appreciated that OP-1 is merely representative of the TGF-β subclass of true tissue morphogens and is not intended to limit the description. Other known and useful morphogens include, but are not limited to, BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP- 13, BMP-15, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, GDF- 10, GDF-11, GDF-12, 60A, NODAL, UNrVIN, SCREW, ADMP, and NEURAL, and morphogenically-active amino acid variants of any thereof. Morphogen polypeptide sequences, as well as relevant chemical and physical properties, of naturally-occurring and/or synthetic morphogens have been disclosed for OP-1 and OP-2 in U.S. Pat. NOS. 5,011,691, 5,266,683, Ozkaynak, et al, EMBO J. 9: 2085-2093 (1990); OP-3: WO 94/10203 (PCT US93/10520); BMP-2, BMP-3, and BMP-4: WO 88/00205, Wozney, et al., Science 242: 1528-1534 (1988); BMP-5 and BMP-6: Celeste, et al., PNAS 87: 9843-9847 (1991) ; Vgr-1: Lyons, et al., PNAS 86: 4554-4558 (1989); DPP: Padgett, et al., Nature 325: 81- 84 (1987); Vg-1: Weeks Cell 51: 861- 867 (1987); BMP-9: WO 95/33830 (PCT/US95/07084); BMP-10: WO 94/26893 (PCT US94/05290); BMP-11: WO 94/26892 (PCT US94/05288); BMP- 12: WO 95/16035 (PCT/US94/14030); BMP-13: WO 95/16035 (PCTAJS94/14030); GDF-1: WO 92/00382 (PCT US91/04096) and Lee, et al., PNAS 88: 4250-4254 (1991); GDF-8: WO 94/21681 (PCT/US94/03019); GDF-9: WO 94/15966 (PCT/US94/00685); GDF-10: WO 95/10539 (PCT/US94/11440); GDF-11: WO 96/01845 (PCT/US95/08543); BMP-15: WO 96/36710 (PCT/US96/06540); MP121: WO 96/01316 (PCT/EP95/02552); GDF-5 (CDMP-1, MP52): WO 94/15949 (PCT/US94/00657) and WO 96/14335 (PCT US94/12814) and WO 93/16099 (PCT/EP93/00350); GDF-6 (CDMP-2, BMP-13): WO 95/01801 (PCT/US94/07762) and WO 96/14335 and WO 95/10635 (PCT/US94/ 14030); GDF-7 (CDMP-3, BMP-12): WO 95/10802 (PCT US94/07799) and WO 95/10635 (PCT/US94/14030). In another embodiment, useful proteins include biologically active biosynthetic constructs, including novel biosynthetic morphogenic proteins and chimeric proteins designed using sequences from two or more known morphogens. See also the biosynthetic constructs disclosed in U.S. Pat. No. 5,011,691, the disclosure of which is incorporated herein by reference (e.g., COP-1, COP-3, COP-4, COP-5, COP-7, and COP-16).

The aminoketone derivative of phloroglucinol of present invention are particularly suitable to be combined with neuronal protective agents such as the Calcium Channel blockers (Nimodipine or Flunarizine), the Calcium chelators (DP-b99, Free radical scavengers, Ebselen or Tiralazad), the GABA agonists (Clomethiazole), the Glutamate antagonists (AMPA antagonists, GYKI 52466, NBQX, YM90K, YM872 or ZK-200775), Kainate antagonists such as SYM 2081, NMDA antagonists (Competitive such as CGS 19755 (Selfotel) or NMDA channel blockers such as Aptiganel (Cerestat), CP 101,606, Dextrorphan, Dextromethorphan, Magnesium, Memantine, MK 801, Remacemide or NPS 1506); Polyamine site antagonists (Eliprodil or Ifenprodil), Growth factors (Fibroblast growth factor), Leukocyte adhesion inhibitors, Nitric oxide inhibitor (Lubeluzole), Opioid antagonists (Naloxone or Nalmefene), Phosphatidylcholine precursor (Citicholine (CDP-choline)), Serotonin agonist (BAYX 3072), Idebenone, Citicoline, Potassium channel openers, or Sodium channel blockers (Fosphenytoin, Lubeluzole or 619C89) to prevent, ameliorate or cure nerve injuries, in particular entrapment and physical nerve injuries.

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention can be combined with known neurotrophic factors, which have been shown to play an essential throphic role in the development, maintenance and regulation of neuronal function such as for instance ciliary neurotrophic factor (CNTF), glial growth factors (glial mitogenic factors), schwann cell mitogenic factors, the nerve growth factors (NGF) and other members of the NGF family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or platelet-derived growth factor (PDGF). Progressive CNS degeneration or degeneration of the motor cells in the spinal cord and the brain can be treated or retarded by combining compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3- pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6- triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl- piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof with compounds selected from the group consisting of Free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), platelet-derived growth factor (PDGF), non-competitive antagonists of glutamate such as for instance l-(l-(2-thienyl)cyclohexyl)piperidine (TCP), superoxide dismutases, adenosine agonists such as cyclohexyladenosine (CHA), Gamma-amino butyric acid (GABA) and GABA-mimetic drugs, non-NMDA receptor antagonist such as 2,3- dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), green tea polyphenol (-)- epigallocatechin-3-gallate, NAALADase inhibitors such 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), small molecule inhibitors of cyclin-dependent kinases (CDKs), cyclooxygenase 2 (COX-2) inhibitors alone or in combination with creatine, (lR)-l-benzo [b] thiophen-5-yl-2-[2- (diethylamino) ethoxy] ethan-1-ol hydrochloride (T-588), riluzole (an inhibitor of glutamate transmission), phosphodiesterase (PDE) inhibitors such as the selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) and the nonselective PDE inhibitor aminophylline. To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention can be combined with known neuroprotective compounds such as the compounds of the group consisting of free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN); non-competitive antagonists of glutamate such as for instance l-(l-(2- thienyl)cyclohexyl)piperidine (TCP) or topiramate, peroxide dismutases, adenosine agonists such as cyclohexyladenosine (CHA), Gamma-amino butyric acid (GABA) and GABA-mimetic drugs, non-NMDA receptor antagonist such as 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), the green tea polyphenol (-)-epigallocatechin-3-gallate, NAALADase inhibitors such 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), small molecule inhibitors of cyclin- dependent kinases (CDKs), cyclooxygenase 2 (COX-2) inhibitors alone or in combination with creatine, (lR)-l-benzo [b] thiophen-5-yl-2-[2-(diethylamino) ethoxy] ethan-1-ol hydrochloride (T-588), riluzole, an inhibitor of glutamate transmission and drug used in amyotrophic lateral sclerosis (ALS), Cardiotrophin-1 (CT-1), nocycline, cyclin-dependent kinase CDK selective inhibitors (CDKIs) and phosphodiesterase (PDE) inhibitors such as the selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as the nonselective PDE inhibitor (aminophylline).

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention, in particular the compounds selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(l'-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piρerazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof may in particular be combined with VEGF homologous , which have been shown to play a role in mediated survival signals to motor neurons or motor neuron protection. The compounds of present invention may for instance be combined with for instance VEGF A, VEGFB or PLGF. Or the compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6- trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6- trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β- hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3- pyrrolidinopropyl) ketone of which preferably their salts thereof may be combined with a compound selected of the group consisting of minocycline, Neurontin (gabapentin), Neurodex (dextrometho han hydrobromide + quinidine sulfate), tamoxifen, Topamax (opiramate), CoQIO, PC-01, Celebrex (celecoxib), Indinavir, buspirone, oxandrolone, creatine, NAALADase, neotrophin and Rilutek (riluzole).

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention or the compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(l'-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3- piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6- trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6- triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof can in particular be combined with LAX-101 or Rilutek (riluzole).

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries, the aminoketone derivative of phloroglucinol of present invention, in particular the compounds selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof may in particular be combined with of the group consisting of interferon beta- lb, interferon beta- la, glatiramer acetate and mitoxantrone. MS can also be treated by combining compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-1rimethoxy-4-(r-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3- pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6- triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl- piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof with a compound selected from the group consisting of Antegren (natalizumab), the adenosine deaminase inhibitor Cladribine and the immunomodulator Campath (alemtuzumab).

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention, in particular the compounds selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof may in particular be combined with an AChE inhibitor, for instance an AChE inhibitor selected of the group consisting of Exelon (rivastigmine), Aricept (donepezil), Reminyl (galantamine), Ebixa (memantine), zanapezil, phenserine and ganstigmine. To further retard the progression of Alzheimer's disease (AD) the compounds selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3- piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6- trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6- triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof can also be combined with a Neurotrophic agents for instance compound selected of the group consisting of the Cere (Cerebrolysin), xaliproden and Neofrofin or with the compounds selected of the group consisting of NS-2330 (a^' monoamine re-uptake inhibitor), memantine, Alzene SR-3, Colostrinin, rofecoxib and n acetyl-1-carnitine.

To further enhance the prevention, retardation, amelioration or cure of nerve injuries, in particular entrapment and physical nerve injuries the aminoketone derivative of phloroglucinol of present invention, in particular the compounds selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2 4 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof can in particular be combined with a compound of the group consisting of Sinemet (levodopa + carbidopa), Madopar (levodopa + benserazide), Mirapex (pramipexole), Cabaser/Dostinex (cabergoline), Requip (ropinirole), Eldepryl (selegiline) and Comtan (entacapone).

The use of such aminoketone derivatives of phloroglucinol of present invention and more particularly the aminoketone derivatives of phloroglucinol selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trimethoxyphenyl) (3-piρeridinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof or the hydrochloride form or any pharmaceutical acceptable salts thereof in comibation with above mentioned nerve growth factors, morphogens or neuronal protective agents used to treat a CNS degenerative disease can be particularly suitable for the preparation of a pharmaceutical composition with enhanced prevention or amelioration of nerve injury caused by a CNS degenerative diseases, such as a motor neuron disease (MND), for instance Materal Sclerosis (ALS), Primary Lateral Sclerosis, (PLS), Progressive Muscular Atrophy (PMA) or spinal-bulbar muscular atrophy, Alzheimer's disease, Huntington's disease or Parkinsons disease.

Examples

Example 1 Treatment of a patient with typical symptoms of ulnar nerve compression or entrapment.

A 42 years old male patient with a body mass index of 2.84 kg/m2 and no history of rheumatoid arthritis or diabetes had a symptomatic history of a feeling that his left hand was swollen and numbness in the fingertips of the little finger and the left site of the ring finger of the left hand, which he described as tingling or needle pricks. This progressed in what he described as being an aching to burning pain in the hand that in several cases awoke him from sleep and was later on followed with a lost of sensation and clumsiness in the left hand.

The patient was subjected to a physical examination and was diagnosed for an ulnar tunnel syndrome. A sensation test (pinpricking) located the lost of sensation in the little finger and the ulnar innervated site of the ring finger. Weakness of the little finger and weakness of the hand grip was confirmed respectively by a strength test. The Tinel's sign from de median nerve were indicative for an ulnar tunnel syndrome at the left hand. The patient had some complains of pain in the right hand but the sensation, strength and Tinel's test was negative. The patient was subjected to a clinical electromyography (EMG) investigation. A nerve conduction study demonstrated ulnar neurodegeneration at the left site with especially a sensory axonal degeneration. At the rights site there was no convincing deviation.

The patient received a daily dose of 600 mg of Buflomedil which was taken preorally at midday. After 62 treatment days the patient regained sensation in the little finger and the left site of the ring finger, there was no burning pain in the hand anymore and the patient slept well. There only was as what the patient described as a light sensation of tingling in the little finger and the left part of the ring finger. For a consequent 50 days the patient received at midday a peroral treatment of a daily dose of 600 mg of buflomedil and a 450 mg magnesium oxide. Subsequently physical examination could not demonstrate ulnar tunnel syndrome. Nerve conduction studies (NCS) of the ulnar nerve demonstrated an improvement of the ulnaris neurodegeneration. Especially the conduction velocity left ulnar nerve was improved.

Example 2 Treatment of a patient with typical symptoms of median nerve compression or entrapment

A 77 years old male with no history of rheumatoid arthritis or diabetes presented with complains of recurrent pain in the wrist and the hand at both left and rights site and complains first of waking in the middle of the night with pain and later a feeling that the whole hand is asleep. Other complaints included numbness while using the hand for gripping activities. These symptoms were more expressed at the right site. At right the pain was eminating up the forearm to the shoulder. The doctor diagnosed the patient for carpal tunnel syndrome. The patient had pain in the distribution of the median nerve. The little finger had no signs of numbness. The Tinel's sign test (tap over volar carpal ligament) reproduced pain and tingling along median nerve course, while the Carpal Compression Test (pressing thumbs for 30 sec over carpal tunnel) and Phalen's Maneuver Phalen's Test (One minute acute wrist flexion against resistance) reproduced symptoms of carpal tunnel syndrome. Electrodiagnosis confirmed carpal tunnel syndrome. There was a slowing of conduction across right carpal tunnel region for the sensory fibers of the right median nerve. For the median nerve at the right site a prolonged sensory terminal latency was measured and a prolonged mixed latency in mid palm and wrist was measured.

For 30 days the patient received a daily oral dose of 600 mg of buflomedyl and 450 mg of magnesium oxide, which had been taken in the evening. After treatment the patient no complains of the above described symptoms, the physical examination did not demonstrate carpal tunnel syndrome anymore. Thirteen months later the patient had yet no complains or clinical signs of carpal tunnel syndrome and was subjected to a clinical electromyographical examination. The electrodiagnosis did not display denervation patterns of the median nerve. The nerve conduction velocity test displayed normal median nerve conductivity in the right upper extremity and normal needle EMG of C7 muscles at the right site. There were no arguments to conclude carpal tunnel syndrome.

SUMMARY OF THE INVENTION

Present invention involves the use of a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure nerve entrapment. Yet another embodiment of present invention involves the use of a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof in combination with magnesium, its pharmaceutically acceptable salt or its derivatives for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure nerve entrapment.

The aminoketone derivatives of phloroglucinol for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure nerve entrapment can be a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3- piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6- trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6- triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof. In yet another embodiment of present invention the aminoketone derivatives of phloroglucinol is a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl)- 1- butanone, 2',4',6'-trimethoxy-4-( -pyrrolidinyl) butyrophenone and (2,4,6-trimethoxyphenyl) (3- pyrrolidinopropyl) ketone or the aminoketone derivatives of phloroglucinol is 2',4',6'-trimethoxy- 4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or the addition salts thereof.

In yet another embodiment of present invention the aminoketone derivatives of phloroglucinol for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure nerve entrapment is 2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone bound to a cation-exchange resin.

These compositions may further comprise a pharmaceutically acceptable carrier. The magnesium salt or derivative can be a compound selected from the group consisting of magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate, chelated magnesium and magnesium EAP.

The above mentioned compounds or a combination thereof may be used for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure a disorder of nerve entrapment or nerve compression which causes axonal degeneration or nerve entrapment syndrome. The above mentioned compounds may also be used to manufacture a medicament for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure a nerve entrapment syndrome of the group consisting of median nerve, ulnar nerve, radial nerve, suprascapular nerve, plantar nerve, interdigital nerve, posterior tibial nerve, common peroneal nerve, lateral femoral cutaneous nerve, obturator nerve, sciatic nerve, calcaneal nerve, peroneal nerve, deep peroneal nerve and brachial plexus or a disorder of a nerve entrapment syndrome which is of the group consisting of pronator syndrome, anterior interosseous nerve syndrome (Kiloh nevin syndrome), carpal tunnel syndrome, sublimis syndrome (Pseudo-carpal tunnel syndrome), cubital tunnel syndrome (Tardy ulnar palsy), ulnar tunnel syndrome (Guyons canal syndrome), cubital tunnel syndrome, Saturday night palsy (sleep palsy), posterior interosseous nerve syndrome, morions metatarsalgia, tarsal tunnel syndrome, meralgia paraesthetica, piriformis syndrome, thoracic outlet syndrome (Scalenus anticus syndrome), thoracic outlet syndrome and tarsal tunnel syndrome.

The above mentioned aminoketone derivative of phloroglucinol and magnesium compounds or a combination thereof can be to manufacture a medicament for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure a disorders of nerve of the group consisting of physical injury, repetitive stress injuries, chronic stress injuries, cumulative trauma disorders, overuse syndromes, chronic upper limb pain syndrome and repetitive motion disorder.

Another aspect of present invention is the use of a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof for the preparation of a pharmaceutical composition for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure damage to peripheral nerves caused by physical injury or surgical repair. The pharmaceutical composition to prevent, ameliorate or cure damage to peripheral nerves caused by physical injury or surgical repair may further comprising a pharmaceutically acceptable carrier and may further comprise magnesium, its pharmaceutically acceptable salt or its derivatives. The magnesium salt or derivative suitable for this invention is a compound selected from the group consisting of magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate, chelated magnesium and magnesium EAP.

The aminoketone derivatives of phloroglucinol for the above mentioned use can be a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(r-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3- pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6- triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl- piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof. It can be a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6-trimethoxyphenyl)- 1-butanone, 2',4',6'-trimethoxy-4-(r- pyrrolidinyl) butyrophenone and (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone. The aminoketone derivatives of phloroglucinol for the above mentioned use can be 2',4',6'- trimethoxy-4-( 1 -pyrrolidinyl) butyrophenone, p-desmethyl-2',4',6'-trimethoxy-4-( 1 -pyrrolidinyl) butyrophenone or 4-(3 -methyl-piperidin- 1 -yl)- 1 -(2,4,6-trimethoxy-phenyl)-butan- 1 -one Or the addition salts thereof.

In another embodiment of present invention 2',4',6'-trimethoxy-4-(l -pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone bound to a cation-exchange resin for the preparation of a pharmaceutical composition for the treatment of damage to peripheral nerves caused by physical injury or surgical repair.

The above mentioned compounds or a combination thereof may be used for the preparation of a pharmaceutical composition to prevent, ameliorate or cure or for use in a treatment to prevent, ameliorate or cure a disorder of physical nerve injury wherein the damage to peripheral nerves causes axonal degeneration.

The invention further involves a method of preventing, ameliorating or curing nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising any of the above mentioned a aminoketone derivatives of phloroglucinol or an hydrochloride form or any pharmaceutical acceptable salts thereof.

Yet another aspect of present invention is method of treating or ameliorating damage to peripheral nerves caused by physical injury or surgical repair in a subject comprising administering to said subject an effective amount of a composition comprising any of the above mentioned aminoketone derivatives of phloroglucinol or an hydrochloride form or any pharmaceutical acceptable salts thereof.

Also an aspect of present invention is a method of preventing, ameliorating or curing nerve entrapment disorders in a subject comprising administering to said subject an effective amount of a composition comprising a calcium channel blockers and an alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein calcium channel blockers and alpha-adrenoceptor antagonist is a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof. This calcium channel blockers and alpha-adrenoceptor antagonist can be an aminoketone derivatives of phloroglucinol selected from the group consisting of 4- (pyrrolidinyl)-l (2,4,6-trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(l '-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6- Trϊmethoxyphenyl) (3-piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6-trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof. Or this calcium channel blockers and alpha-adrenoceptor antagonist is an aminoketone derivatives of phloroglucinol of the group consisting of 4-(pyrrolidinyl)-l (2,4,6- trimethoxyphenyl)- 1-butanone, 2',4',6'-trimethoxy-4-(l '-pyrrolidinyl) butyrophenone and (2,4,6- trimethoxyphenyl) (3-pyrrolidinopropyl) ketone. Or this calcium channel blockers and an alpha- adrenoceptor antagonist (adrenolytic antagonists) wherein calcium channel blockers and alpha- adrenoceptor antagonist is 2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl- 2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or the addition salts thereof.

Yet another aspect of present invention is a method of preventing, ameliorating or curing nerve entrapment disorders in a subject comprising: (a) administration to said subject an effective amount of a calcium channel blockers and (b) co-administration to said subject an effective amount of alpha-adrenoceptor antagonist (adrenolytic antagonists) wherein said calcium channel blockers is selected of the group consisting of felodipine, amlodipine, nifedipine, verapamil HCl, nicardipine HCl, diltiazem HCl, aranidipine, atosiban, barnidipine, cilnidipine, docosahexaenoic acid, efonidipine HCL, fasudil, isradipine, lacidipine, lercanidipine, lomerizine, manidipine, nifelan, nilvadipine, nimodipine, teczem, verelan, plendil, nisoldipine, bepridil HCl, NS-7, NW- 1015, SB-237376, SL-34.0829-08, terodiline, R-verapamil, bisaramil, CAI, ipenoxazone, JTV- 519, S-312d, SD-3212, tamolarizine, TA-993, vintoperol, YM-430, CHF-1521, elgodipine, nitrendipine, furnidipine, L-651582, oxodipine, ranolazine, AE-0047, azelnidipine, dotarizine, lemildipine, pranidipine, semotiadil, temiverine HCl, tenosal, vatanidipine HCl, and ziconotide and said alpha-adrenoceptor antagonist is selected from the group consisting of cetiedil, dihydroergocristine, dihydroergotamine, dihydroxyacetone, etoperidone, Angelini, labetalol, trimazosin, ciclonicate, dapiprazole, amosulalol, arotinolol, naftopidil, terazosin, urapidil, phentolamine, phentolamine, dihydroergotamine SR, Alpha-dihydroergocryptine, Naftidrofuryl SR, dihydroergotamine, AGN- 195795, ergotamine, dihydroergotamine.

Claims

NERVE DAMAGECLAIMSWhat is claimed is:

1. Use of a aminoketone derivative of phloroglucinol or the hydrochloride form or any pharmaceutical acceptable salts thereof for the preparation of a pharmaceutical composition to treat, prevent or ameliorate a physical nerve injury.

2. Use of the aminoketone derivatives of phloroglucinol of the claims 1 and 2, wherein the derivative has the general structure I:

wherein each Rl, R2 and R3, are the same or different, and represent methyl or ethyl, and n is 3, or a non-toxic acid addition salt thereof.

3. Use of the aminoketone derivatives according to the claims 1 and 2, for the preparation of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

4. Use of the aminoketone derivatives of the claims 1 and 2 with magnesium, its pharmaceutically acceptable salt or its derivatives for the preparation of a pharmaceutical composition to treat or ameliorate nerve entrapment.

5. The use of claim 4, wherein the magnesium salt or derivative is a compound selected from the group consisting of magnesium oxide, magnesium aspartate, magnesium sulphate, magnesium citrate, chelated magnesium and magnesium EAP.

-> 3

6. The use of any of the claims 1 to 6, wherein the aminoketone derivatives of phloroglucinol is a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6- trimethoxyphenyl) -1-butanone, 2', 4', 6'-trimethoxy-4-(l '-pyrrolidinyl) butyrophenone; (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone, (2,4,6-Trimethoxyphenyl) (3- piperidinopropyl) ketone, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl) ketone, (2,4,6- trimethoxyphenyl) [4-β-hydroxyethyl-piperazino) methyl] ketone dihydrochloride and (2,4,6- triethoxyphenyl) (3-pyrrolidinopropyl) ketone of which preferably their salts thereof

7. The use of any of the claims 1 to 6, wherein the aminoketone derivatives of phloroglucinol is a compound selected from the group consisting of 4-(pyrrolidinyl)-l (2,4,6- trimethoxyphenyl)- 1-butanone, 2',4',6'-trimethoxy-4-(l '-pyrrolidinyl) butyrophenone and (2,4,6-trimethoxyphenyl) (3-pyrrolidinopropyl) ketone.

8. The use of any of the claims 1 to 6, wherein the aminoketone derivatives of phloroglucinol is 2',4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'- trimethoxy-4-(l- pyrrolidinyl) butyrophenone or the addition salts thereof .

9. The use of 2^,,4',6'-trimethoxy-4-( 1-pyrrolidinyl) butyrophenone or p-desmethyl-2',4',6'- trimethoxy-4-( 1-pyrrolidinyl) butyrophenone of claim 7, bound to a cation-exchange resin for the preparation of a pharmaceutical composition for the treatment nerve entrapment.

10. The use of claims 1 to 9, wherein the nerve entrapment or nerve compression causes axonal degeneration.

11. The use of claim 1 to 10, wherein the nerve entrapment is a nerve entrapment syndrome

12. The use of claim 11, wherein the nerve entrapment syndrome is of the group consisting of median nerve, ulnar nerve, radial nerve, suprascapular nerve, plantar nerve, interdigital nerve, posterior tibial nerve, common peroneal nerve, lateral femoral cutaneous nerve, obturator nerve, sciatic nerve, calcaneal nerve, peroneal nerve, deep peroneal nerve and brachial plexus.

13. The use of claim 11, wherein the nerve entrapment syndrome is of the group consisting of pronator syndrome, anterior interosseous nerve syndrome (Kiloh nevin syndrome), carpal tunnel syndrome, sublimis syndrome (Pseudo-carpal tunnel syndrome), cubital tunnel syndrome (Tardy ulnar palsy), ulnar tunnel syndrome (Guyons canal syndrome), cubital tunnel syndrome, Saturday night palsy (sleep palsy), posterior interosseous nerve syndrome, morions metatarsalgia, tarsal tunnel syndrome, meralgia paraesthetica, piriformis syndrome,

tj O thoracic outlet syndrome (Scalenus anticus syndrome), thoracic outlet syndrome and tarsal tunnel syndrome

14. Use of a aminoketone derivative of phloroglucinol of the claims 1 to 8 for the preparation of a pharmaceutical composition to treat, prevent or ameliorate a disorders of nerve of the group consisting of physical injury, repetitive stress injuries, chronic stress injuries, cumulative trauma disorders, overuse syndromes, chronic upper limb pain syndrome and repetitive motion disorder.

15. Use of a aminoketone derivative of phloroglucinol of the claims 1 to 8 for the preparation of a pharmaceutical composition to treat, prevent or ameliorate a disorders of nerve of the group consisting of physical injury, repetitive stress injuries, chronic stress injuries, cumulative trauma disorders, overuse syndromes, chronic upper limb pain syndrome and repetitive motion disorder further comprising nerve growth factors, morphogens or neuronal protective agents.

16. Use of a aminoketone derivative of phloroglucinol of the claims 1 to 8 in a treatment of a disorders of nerve of the group consisting of physical injury, repetitive stress injuries, chronic stress injuries, cumulative trauma disorders, overuse syndromes, chronic upper limb pain syndrome and repetitive motion disorder.

17. A method of treating, preventing or ameliorating nerve entrapment disorders or physical nerve injury in a subject comprising administering to said subject an effective amount of a composition comprising a aminoketone derivatives of phloroglucinol of any of the claims 1 to 8 or an hydrochloride form or any pharmaceutical acceptable salts thereof.

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