CN1043610C - Novel treatment - Google Patents

Novel treatment Download PDF

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Publication number
CN1043610C
CN1043610C CN93116874A CN93116874A CN1043610C CN 1043610 C CN1043610 C CN 1043610C CN 93116874 A CN93116874 A CN 93116874A CN 93116874 A CN93116874 A CN 93116874A CN 1043610 C CN1043610 C CN 1043610C
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CN
China
Prior art keywords
chemical compound
treatment
purposes
administration
cyclopropyl methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CN93116874A
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Chinese (zh)
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CN1114880A (en
Inventor
B·A·施派泽
K·G·艾利斯
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication of CN1114880A publication Critical patent/CN1114880A/en
Application granted granted Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes in mammals, such as humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic, non-toxic amount of Compound 1 (1,3-dicyclopropymethyl-8-amino-xanthine).

Description

New therapeutic agent
The chemical compound that the present invention relates to treat and/or prevent the method for obesity or treatment type and be used for this method.
European patent application publication No. 0389282 has been described formula (A) chemical compound: Or its pharmaceutically acceptable salt that is fit to, wherein R 1And R 2Represent alkyl or formula (a) part respectively:
-(CH 2) mA (a) wherein m represents 0 or integer 1,2, or 3, the A representative replaces or unsubstituted cyclic hydrocarbon radical, condition is to work as R 1R during represent methylidene 2It or not methyl; With
R3a represents halogen atom, nitro, or group-NR 4R 5R wherein 4And R 5Represent hydrogen respectively, alkyl or alkyl-carbonyl or R 4And R 5Form a heterocyclic radical that replaces arbitrarily with the nitrogen that is connected them.
The example 9 of EP903030930.0 is 1, the amino xanthine (after this preferably as chemical compound 1) of 3-bicyclic methyl propyl-8-.
Chemical compound with treatment cerebrovascular and neuronal degeneration disease activity has been described especially and as the phosphodiesterase inhibitor that improves ring AMP level in European application numbers 90303093.0.
We are surprised to find the absorption that chemical compound 1 can increase the consumption of energy and also can reduce food now, so it comprises that for the treatment mammal people's obesity is of great use.
It is that effectively therefore to treat type be effective that chemical compounds I also demonstrates for improving insulin sensitivity.
Therefore, the invention provides a kind of mammal that treats and/or prevents, as the method for people's obesity or treatment type, this method comprises and will treat and/or prevent effective dose and/or prevention that the mammal that needs is given in chemical compound 1 administration of nontoxic amount.
The present invention also is provided for treating and/or preventing the chemical compound 1 of obesity or treatment type.
Another aspect of the present invention provide a kind of be used for the treatment of and/or prevent obesity or the treatment type pharmaceutical composition, said composition comprises chemical compound 1 and pharmaceutically acceptable carrier.
The present invention also on the one hand provides chemical compound 1 to be used to prepare to treat and/or prevent the purposes of the sick medicine of obesity or treatment II type sugar.
Mammal is given in administration can pass through oral or parenterai administration.
The effective dose of treatment of obesity or type is according to general factor such as mammiferous person's character, and the order of severity and the body weight of the state of an illness decide.Then, unit dose contains 0.1 to 200mg usually for example 5 to 50mg or 1 to the chemical compound 1 of 20mg.Unit dose is usually with once a day or more than single administration, every day 1,2,3 for example, 4,5 or 6 times, more generally every day 1-4 time, therefore be generally 0.5 to 500mg for the total daily dose of 70Kg adult, for example 50 to 250mg or 10 arrive 150mg, be that its scope is about 0.001 to 10mg/Kg/ days, more generally 1 to 3mg/Kg/ days or 0.2 to 2.5mg/Kg/ days, for example 0.7 to 2mg/Kg/ days.
Preferably, chemical compound 1 is with the units dosage composition form administration, as the oral or non-intestinal compositions of unit dose.
By being mixed with this compositions and adopting suitable oral or parenterai administration, as being tablet, capsule, oral liquid, powder, granule, lozenge, recombinant powder, but injection and infusion solution or suspension emulsion.Orally administered composition is preferred, and molding port oral compositions particularly is because they are more convenient for common use.
Oral tablet and capsule exist with unit dose usually, and contain conventional excipients such as binding agent, filler, and diluent becomes tablet, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent.Tablet can carry out coating according to known method of the prior art.
Available suitable filler comprises cellulose, mannitol, lactose and other similar filler.The disintegrating agent that is fit to comprises starch, polyvinylpyrrolidone and starch derivatives such as Explotab.The lubricant that is fit to comprises for example magnesium stearate.The pharmaceutically acceptable wetting agent that is fit to comprises sodium laurylsulfate.
Methods such as these solid oral compositions can mix by conventional, fill, and are in blocks prepare.Can use the remix operation to utilize a large amount of filleies to disperse the activating agent of whole compositions.Certainly, this operation is a routine techniques.
For example, oral liquid can be aqueous solution or oily suspension, solution, and emulsion, the form of syrup or elixir, or exist with dryed product, before use with water or other appropriate excipients remix.This liquid preparation can contain conventional additives such as suspending agent, for example Sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, stearic acid aluminium glue or hydrogenation edible fat.Emulsifying agent, lecithin for example, single oleic acid sorbitan ester, or Radix Acaciae senegalis; Non-water excipient (can comprise edible oil), almond oil for example, fractionated coconut oil, grease such as glyceride, propylene glycol, or ethanol; Antiseptic, for example right-methyl hydroxybenzoate or propyl ester or sorbic acid; And to contain conventional flavoring agent or coloring agent if desired.
Oral formulations also comprises conventional extended release preparation such as tablet or contains the granule of enteric coating.
For parenterai administration, can prepare the liquid unit doses form that contains chemical compound 1 and sterilization excipient.According to excipient and concentration, the chemical compound 1 also solubilized that both can suspend.Non-intestinal solution usually by with compound dissolution in excipient and be filled into suitable bottle or ampoule bottle and sealing preceding filtration sterilization.With adjuvant such as local anesthetic, it also is favourable in the excipient that antiseptic and buffer agent are dissolved in.In order to improve stability, compositions freezing and vacuum after being filled into bottle can be removed and anhydrate.
The also available essentially identical method preparation of non-intestinal suspension is except being suspended in chemical compound in the excipient rather than dissolving and sterilize by being exposed in the oxirane before in being suspended in the sterilization excipient.Advantageously, in compositions, also comprise surfactant or wetting agent, so that the uniform distribution of favourable chemical compound.
Following pharmacological datum has proved the in test activity of chemical compound 1, and this test explanation chemical compound is for the potential purposes of treatment of obesity.The pharmacological datum test procedure
Experimental animal is 12 male and 12 female Sprague-Dawley Mus (body weight 200-270g, about 8-10 age in week).
Mus is fed SQC Mus and mice and is kept diet number 1; Diet and water can at will obtain.
Temperature and relative humidity are remained on 21 ± 2 ℃ and 55 ± 10% respectively, and 12 hours lights were given in brilliance control at per 24 hours.
After adaptation in 6 days, animal is divided into two groups (matched group and treatment groups) by stratified random, to obtain the group that average weight approximately equates.Every group contains 6 male Mus and 6 female Mus.Mus is stayed in together for 3 one group.
After benchmark was observed in 4 days, all animals are being begun administration on the same day.With all animals administers once a day, totally 10 days.
Test compound is organized oral administration with the suspending agent of 1% methylcellulose of 1mg/Kg/ days dosage levels to treatment by gavage.
Animal is carried out administration with the constant dosage volume of 1ml/100g body weight.The same dose volume of control animals is given excipient separately.
Absorption record every day of food and water.Body weight between 1. groups (g) compares the sky as a result
Male treatment of control group group 1 average 269.3 266.8NS
% poor--1
S.D. 9.6 4.1
(N) (6) (6) 11 meansigma methodss 318.3 268.5 *
% poor--16
S.D. 13.7 12.0
(N) (6) (6)
Female 1 meansigma methods, 210.3 206.8NS
% poor--2
S.D. 5.4 3.0
(N) (6) (6) 11 meansigma methodss 227.8 211.2 *
% poor--7
S.D. 12.4 8.5
(N) % difference in (6) (6) is calculated on the data basis that does not round up.For Student " t "-test (the 2-tail) significant level: *P＜0.05 *The inapparent NT of P＜0.01NS not between 2. groups of test body weight increase (g) relatively
Treatment of control group group sky
Male 1-11 meansigma methods 49.0 1.7 *
% poor--97
S.D. 10.1 9.4
(N) (6) (6)
Female 1-11 meansigma methods 17.5 4.3 *
% poor--75
S.D 9.5 7.5
(N) % difference in (6) (6) is to calculate on the data basis that does not round up.For Student " t "-test (the 2-tail) significant level: *P＜0.05 *Food consumption relatively between＜0.013. group
(g/ animal/sky)
Treatment of control group group sky
Male 1-10 meansigma methods 28.7 22.1
% poor--23
(N) (2) (2)
Female 1-10 meansigma methods 21.5 19.9
% poor--7
(N) % difference in (2) (2) is calculated on the data basis that does not round up.4. water consumption is compared between the group
(g/ animal/sky)
Treatment of control group group sky
Male 1-10 meansigma methods 30.6 27.5
% poor--10
(N) (2) (2)
Female 1-10 meansigma methods 25.6 30.0
% poor-+17
(N) % difference in (2) (2) is calculated on the data basis that does not round up.1. food intake in 19 of Mus hours
Arbitrarily feed ball shape food and single being placed in the illumination circulation with male Sprague-Dawley Mus (420-550g), lamp is closed from 6pm-6am.With chemical compound 1 or excipient in the 2.30pm administration and from this moment measuring the absorption of food and the change of body weight to second day 10am.The result is meansigma methods ± SEM (n=6).Chemical compound 1 dosage 015 (mg/Kg p.o.) food intake (g) 25.0 ± 2.3 11.0 ± 3.5 13.8 ± 2.8 1Body weight loss (g) 1.0 ± 1.9 27.0 ± 1.2 132.0 ± 3.4 11P＜0.001 comparative control is worth the food intake in 20 hours of 2. mices
Arbitrarily feed ball shape food with female CFLP mice (29-37g) and also be placed in pairs in the illumination circulation, lamp is closed from 6pm-6am from 6pm.Chemical compound 1 or excipient are measured food intake and body weight change in the 2pm administration and in following 20 hours.The result is meansigma methods ± SEM5 (food intake) or meansigma methods ± SEM10 (body weight).12.1 ± 10.5 ± 6.5 ± 5.4 ± 4.2 ± every couple (g) 1.2 1.1 1.5 of chemical compound 1 dosage 0 0.3 135 (mg/Kg p.o) food intake *1.0 *0.8 * *Body weight loss (g) 0.94 ± 1.50 ± 2.71 ± 3.77 ± 4.45 ±
0.25 0.32 0.71 * 0.29 *** 0.57
*P＜0.05; *P＜0.01, * *P＜0.001 comparative control
Value.3. mice food intake in 4 hours
Female CFLP mice (22-34g) is placed and feeds ball shape food in pairs.Make them in 1 all endoadaptation illumination circulations, 12 from 12 noon to night on this lamp is closed.Between 11.30am to 12.15pm with chemical compound 1 or excipient administration and (3.30pm to 4.15pm) food intake after estimating 4 hours.The result is meansigma methods ± SEM (n=5).5.83 ± 5.14 ± 4.88 ± 3.80 ± 3.06 ± 2.74 ± every couple (g) 0.25 0.39 0.25 of chemical compound 10 0.03 0.1 0.3 1.0 3.0 dosage (mg/Kg p.o) food intake *0.36 *0.17 * *0.31 * *Toxicity
Do not produce unfavorable toxicology effect in the above in the test of mentioning.The physical qualification of experimental animal discloses for treatment and does not show any side reaction.

Claims (5)

1. chemical compound 1, and the amino xanthic purposes of 3-two-cyclopropyl methyl-8-, this purposes comprise this chemical compound is used to make as treating and/or preventing obesity or being used as the medicine for the treatment of type.
2. according to the purposes of claim 1, comprising with 1, the amino xanthine of 3-two-cyclopropyl methyl-8-is used to make the medicine that is suitable for oral medication or parenterai administration treatment.
3. according to the purposes of claim 1, wherein 1, the amino xanthine of 3-two-cyclopropyl methyl-8-is to use in the form of pharmaceutical composition with unit dose.
4. according to the purposes of claim 3, wherein this unit dose contain 0.1 to 200mg 1, the amino xanthine of 3-two-cyclopropyl methyl-8-.
5. according to the purposes of claim 3, wherein this unit dose contain 5 to 50mg or 1 to 20mg 1, the amino xanthine of 3-two-cyclopropyl methyl-8-.
CN93116874A 1992-07-23 1993-07-22 Novel treatment Expired - Lifetime CN1043610C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9215633.0 1992-07-23
GB929215633A GB9215633D0 (en) 1992-07-23 1992-07-23 Novel treatment

Publications (2)

Publication Number Publication Date
CN1114880A CN1114880A (en) 1996-01-17
CN1043610C true CN1043610C (en) 1999-06-16

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EP (1) EP0651642A1 (en)
JP (1) JPH07509456A (en)
CN (1) CN1043610C (en)
AU (1) AU4714393A (en)
GB (1) GB9215633D0 (en)
MX (1) MX9304435A (en)
TW (1) TW258663B (en)
WO (1) WO1994002150A1 (en)
ZA (1) ZA935339B (en)

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WO2003004496A1 (en) * 2001-07-03 2003-01-16 Novo Nordisk A/S Dpp-iv-inhibiting purine derivatives for the treatment of diabetes
US6869947B2 (en) 2001-07-03 2005-03-22 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
JP2005509603A (en) * 2001-09-19 2005-04-14 ノボ　ノルディスク　アクティーゼルスカブ Heterocyclic compounds that are inhibitors of the DPP-IV enzyme
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
DE10254304A1 (en) * 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
MXPA06002521A (en) 2003-09-05 2006-06-20 Altana Pharma Ag Use of pde4 inhibitors for the treatment of diabetes mellitus.
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004030502A1 (en) 2004-06-24 2006-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel imidazoles and triazoles, their preparation and use as medicines
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
NZ560269A (en) 2005-03-08 2010-12-24 Nycomed Gmbh Roflumilast for the treatment of diabetes mellitus
DE102005035891A1 (en) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
NZ619413A (en) 2006-05-04 2015-08-28 Boehringer Ingelheim Int Polymorphs of a dpp-iv enzyme inhibitor
AR071175A1 (en) 2008-04-03 2010-06-02 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO
BRPI0916997A2 (en) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh DPP-4 INHIBITOR AND ITS USE
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BRPI0919288A2 (en) 2008-09-10 2015-12-15 Boehring Ingelheim Internat Gmbh combination therapy for treatment of diabetes and related conditions.
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
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AR074990A1 (en) 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
KR20210033559A (en) 2009-11-27 2021-03-26 베링거 인겔하임 인터내셔날 게엠베하 Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
CN102946875A (en) 2010-05-05 2013-02-27 贝林格尔.英格海姆国际有限公司 Combination therapy
EP3124041A1 (en) 2010-06-24 2017-02-01 Boehringer Ingelheim International GmbH Diabetes therapy
AR083878A1 (en) 2010-11-15 2013-03-27 Boehringer Ingelheim Int VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD
AU2012285904C1 (en) 2011-07-15 2017-08-31 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0389282A2 (en) * 1989-03-23 1990-09-26 BEECHAM - WUELFING GmbH & Co. KG Xanthinederivatives, process for their preparation and their pharmaceutical use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0389282A2 (en) * 1989-03-23 1990-09-26 BEECHAM - WUELFING GmbH & Co. KG Xanthinederivatives, process for their preparation and their pharmaceutical use

Also Published As

Publication number Publication date
EP0651642A1 (en) 1995-05-10
GB9215633D0 (en) 1992-09-09
JPH07509456A (en) 1995-10-19
ZA935339B (en) 1995-01-18
CN1114880A (en) 1996-01-17
AU4714393A (en) 1994-02-14
WO1994002150A1 (en) 1994-02-03
TW258663B (en) 1995-10-01
MX9304435A (en) 1994-04-29

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