US20060205806A1 - Synergistic combination - Google Patents
Synergistic combination Download PDFInfo
- Publication number
- US20060205806A1 US20060205806A1 US11/433,419 US43341906A US2006205806A1 US 20060205806 A1 US20060205806 A1 US 20060205806A1 US 43341906 A US43341906 A US 43341906A US 2006205806 A1 US2006205806 A1 US 2006205806A1
- Authority
- US
- United States
- Prior art keywords
- salt
- solvate
- hydrate
- hydroxy
- pde inhibitor
- 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.)
- Abandoned
Links
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- 239000003112 inhibitor Substances 0.000 claims abstract description 19
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- 239000000048 adrenergic agonist Substances 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 17
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- 238000000034 method Methods 0.000 claims description 14
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- SYCWERNQGSKYAG-QVRIGTRMSA-N hydron;8-hydroxy-5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]-1h-quinolin-2-one;chloride Chemical compound Cl.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 SYCWERNQGSKYAG-QVRIGTRMSA-N 0.000 description 1
- TWTMQRXNAZGSCE-UHFFFAOYSA-N hydron;[6-(methylamino)-1-(2-methylpropanoyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl] 2-methylpropanoate;chloride Chemical compound Cl.C1=CC(OC(=O)C(C)C)=C(OC(=O)C(C)C)C2=C1CC(NC)CC2 TWTMQRXNAZGSCE-UHFFFAOYSA-N 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
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- 230000003014 reinforcing effect Effects 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
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- 125000006850 spacer group Chemical group 0.000 description 1
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- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- 229950010448 tolafentrine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- HJMQDJPMQIHLPB-UHFFFAOYSA-N zardaverine Chemical compound C1=C(OC(F)F)C(OC)=CC(C2=NNC(=O)C=C2)=C1 HJMQDJPMQIHLPB-UHFFFAOYSA-N 0.000 description 1
- 229950001080 zardaverine Drugs 0.000 description 1
Classifications
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- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Definitions
- the invention relates to the combination of certain known active compounds for therapeutic purposes.
- the substances used in the combination according to the invention are known active compounds from the PDE inhibitors class and active compounds from the ⁇ 2 adrenoceptor agonists class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
- the invention thus relates to the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and a ⁇ 2 adrenoceptor agonist in the treatment of respiratory tract disorders.
- PDE inhibitors which can be used as respiratory tract therapeutics in the sense of the present invention are those compounds which slow the breakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a relative increase in the intracellular concentration of cAMP or cGMP.
- Possible PDE inhibitors within the meaning of the present invention are primarily those substances which are to be considered part of the PDE4 inhibitor class and those substances which can be designated as mixed types of PDE3/4 inhibitors.
- those PDE inhibitors may be mentioned which are described or claimed in the following patent applications and patents: DE 1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811, EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP 08
- PDE inhibitors are shown on the following pages with the aid of their formulae:
- PDE inhibitors to be emphasized which are selected from the abovementioned compounds and which may be mentioned are the active compounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine, BYK-33043, CC-3052, CDP-840, CI-1018, cipamfylline, CP-220629, CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifyliine, piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597, RS-25344-000, SB-207499,
- the compounds preferred from the group of the abovementioned PDE inhibitors are arofylline, cipamfylline, D4418, filaminast, ibudilast, laprafylline, ORG-20241, piclamilast, rolipram, SB-207499, tibenelast and V-11294A.
- the compounds particularly preferred are BYK-33043 and in particular roflumilast.
- ⁇ 2 adrenoceptor agonists which may particularly be mentioned are those selectively acting substances which only have a slight cardiac action and therefore are also employed in therapy, in particular in the oral therapy of respiratory tract disorders.
- ⁇ 2 adrenoceptor agonists which may be mentioned are, for example: AR-C68397AA, broxaterol, CHF-1035, HOKU-81, ibuterol, KUL-1248, soterenol, meluadrine, TA-2005, tiaramide, salbutamol, levosalbutamol, tulobuterol, terbutaline, carbuterol, pirbuterol, reproterol, clenbuterol, fenoterol, hexoprenaline, orciprenaline, isoprenaline, formoterol, salmeterol, rimiterol, procaterol, bambuterol, bitolterol and mabuterol.
- ⁇ 2 adrenoceptor agonists such as clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol and reproterol are preferred. Particularly preferred are the so-called long acting ⁇ 2 adrenoceptor agonists, such as salmeterol.
- the PDE inhibitors and the ⁇ 2 adrenoceptor agonists can be present as such or in chemically bonded form. It is understood hereby that the active compounds mentioned can also be present, for example, in the form of their pharmacologically tolerable salts and/or as solvates (e.g. hydrates), and/or in the form of their N-oxides etc.
- Suitable pharmacologically tolerable salts here are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyly benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation—depending on whether it is a mono- or polybasic acid and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
- the active compounds mentioned can also be present as pure enantio
- Respiratory tract disorders which may be mentioned are in particular allergen- and inflammation-induced bronchial disorders (bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD), which can be treated by the combination according to the invention also in the sense of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).
- allergen- and inflammation-induced bronchial disorders bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD
- Combined use or “combination” within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (directly in succession or else alternatively at a relatively large time interval) in a manner which is known per se and customary.
- ⁇ 2 adrenoceptor agdnist is preferably administered by inhalation in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 ⁇ m, advantageously of 2 to 6 ⁇ m.
- Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
- the active compounds are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the active compounds compared with the norm.
- the O 2 adrenoceptor agonist (depending on potency) is administered in a dose of, for example, 0.002 to 2.0 mg per day on administration by inhalation.
- the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
- propellants e.g. Frigen in the case of metered aerosols
- surface-active substances e.g. Frigen in the case of metered aerosols
- emulsifiers emulsifiers
- stabilizers emulsifiers
- preservatives e.g., emulsifiers, stabilizers, preservatives
- flavorings e.g. lactose in the case of powder inhalers
- fillers e.g. lactose in the case of powder inhalers
- the ⁇ 2 adrenoceptor agonist is administered in a daily dose of, for example, 0.05 to 60 mg.
- the PDE inhibitors it is possible in the case of oral administration to vary the doses—depending on the active compound—within a wide range, it being possible, as bounds, to start from a dose of 1-2000 ⁇ g/kg of body weight.
- the dose is in the range from 2-20 ⁇ g/kg of body weight.
- the PDE inhibitors to be administered orally are formulated—if appropriate together with the ⁇ 2 adrenoceptor agonists—to give medicaments according to processes known per se and familiar to the person skilled in the art.
- the pharmacologically active compounds are employed as medicaments, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form).
- oral administration of both active compounds according to the invention are oral administration forms, e.g. tablets or capsules, in which one part of the ⁇ 2 adrenoceptor agonist and the PDE inhibitor is present in non sustained-release form and a further, preferably larger part, of the ⁇ 2 adrenoceptor agonist is present in sustained-release form.
- excipients or vehicles are suitable for the desired pharmaceutical formulations.
- solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyciodextrins).
- Non-challenged, only sensitized animals were used as baseline control.
- the drugs (thoroughly mixed with lactose) or the placebo control (lactose) were administered intratracheally (i.t.) as dry powders 1 h before OVA-challenge. 48 h later, OVA-challenged or non-challenged animals were anaesthetized and bronchoalveolar lavage (BAL) was performed using 3 ⁇ 4 ml BAL buffer per animal. The number of total cells and eosinophils in the BAL fluid, and the concentration of protein in the cell-free BAL fluid were determined. Drug-induced relative changes were calculated and statistically analyzed by the Jonckheere Terpstra test.
Abstract
The invention relates to the combined administration of PDE inhibitors and β2 adrenoceptor agonists for the treatment of respiratory disorders.
Description
- The invention relates to the combination of certain known active compounds for therapeutic purposes.
- The substances used in the combination according to the invention are known active compounds from the PDE inhibitors class and active compounds from the β2 adrenoceptor agonists class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
- It is the object of the present invention to make available respiratory tract therapeutics which fulfill the following conditions:
- Good antiinflammatory action
- Marked bronchorelaxation and -dilatation
- Good oral availability, at least with respect to the PDE inhibitor
- Minor side effects
- Good suitability for long-term therapy
- Favorable influence on bronchial hyperreactivity.
- It has now been found that the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and of a β2 adrenoceptor agonist outstandingly fulfills the abovementioned conditions.
- The invention thus relates to the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and a β2 adrenoceptor agonist in the treatment of respiratory tract disorders.
- PDE inhibitors which can be used as respiratory tract therapeutics in the sense of the present invention are those compounds which slow the breakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a relative increase in the intracellular concentration of cAMP or cGMP.
- Possible PDE inhibitors within the meaning of the present invention are primarily those substances which are to be considered part of the PDE4 inhibitor class and those substances which can be designated as mixed types of PDE3/4 inhibitors. By way of example, those PDE inhibitors may be mentioned which are described or claimed in the following patent applications and patents: DE 1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811, EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP 92234389, JP 94329652, JP 95010875, JP 98072415, JP 98147585, U.S. Pat. No. 5,703,098, U.S. Pat. No. 5,739,144, WO 9117991, WO 9200968, WO 9212961, WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO 9319720, WO 9319747, WO 9319749, WO 9319751, WO 9325517, WO 9402465, WO 9412461, WO 9420455, WO 9422852, WO 9427947, WO 9501338, WO 9501980, WO 9503794, WO 9504045, WO 9504046, WO 9505386, WO 9508534, WO 9509623, WO 9509624, WO 9509627, WO 9509836, WO 9514667, WO 9514680, WO 9514681, WO 9517392, WO 9517399, WO 9519362, WO 9520578, WO 9522520, WO 9524381, WO 9527692, WO 9535281, WO 9535283, WO 9535284, WO 9600218, WO 9601825, WO 9606843, WO 9611690, WO 9611917, WO 9612720, WO 9631486, WO 9631487, WO 9635683, WO 9636595, WO 9636596, WO 9636611, WO 9636625, WO 9636638, WO 9638150, WO 9639408, WO 9640636, WO 9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345, WO 9712895, WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO 9722586, WO 9723457, WO 9723460, WO 9723461, WO 9724117, WO 9724355, WO 9725312, WO 9728131, WO 9730999, WO 9731000, WO 9732853, WO 9735854, WO 9736905, WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO 9748697, WO 9804534, WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830, WO 9808841, WO 9808844, WO 9809946, WO 9809961, WO 9811113, WO 9814448, WO 9818796, WO 9821208, WO 9822453, WO 9845268, WO 9855481, WO 9856756, WO 9905111, WO 9905112, WO 9505113, WO 9906404 and WO 9918095. Those PDE inhibitors are to be emphasized which are claimed in the patent applications or patents EP 0393500, EP 0510562, EP 0553174, WO 9501338, WO 9603399, WO 9636625, WO 9636626, WO 9735854, WO 9821208, WO 9831674, WO 9840382, WO 9855481, WO 9905111, WO 9905112, WO 9905113, WO 9931071 and WO 9931090. Substances having good oral availability are preferred here.
-
- No hydrogen atoms are indicated in the above formulae. —O is accordingly-OH, —N is NH2. Methyl groups, e.g. on the oxygen atoms, are indicated by lines.
- PDE inhibitors to be emphasized which are selected from the abovementioned compounds and which may be mentioned are the active compounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine, BYK-33043, CC-3052, CDP-840, CI-1018, cipamfylline, CP-220629, CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifyliine, piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597, RS-25344-000, SB-207499, SB-210667, SB-211572, SB-211600, SB-212066, SB-212179, SDZ-ISQ-844, SDZ-MNS-949, SKF-107806, SQ-20006, T-2585, T440, tibenelast, tolafentrine, UCB-29646, V-11294A, YM-58997, YM-976 and zardaverine.
- The compounds preferred from the group of the abovementioned PDE inhibitors are arofylline, cipamfylline, D4418, filaminast, ibudilast, laprafylline, ORG-20241, piclamilast, rolipram, SB-207499, tibenelast and V-11294A. The compounds particularly preferred are BYK-33043 and in particular roflumilast.
- β2 adrenoceptor agonists which may particularly be mentioned are those selectively acting substances which only have a slight cardiac action and therefore are also employed in therapy, in particular in the oral therapy of respiratory tract disorders. β2 adrenoceptor agonists which may be mentioned are, for example: AR-C68397AA, broxaterol, CHF-1035, HOKU-81, ibuterol, KUL-1248, soterenol, meluadrine, TA-2005, tiaramide, salbutamol, levosalbutamol, tulobuterol, terbutaline, carbuterol, pirbuterol, reproterol, clenbuterol, fenoterol, hexoprenaline, orciprenaline, isoprenaline, formoterol, salmeterol, rimiterol, procaterol, bambuterol, bitolterol and mabuterol. The orally readily available β2 adrenoceptor agonists such as clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol and reproterol are preferred. Particularly preferred are the so-called long acting β2 adrenoceptor agonists, such as salmeterol.
- The PDE inhibitors and the β2 adrenoceptor agonists can be present as such or in chemically bonded form. It is understood hereby that the active compounds mentioned can also be present, for example, in the form of their pharmacologically tolerable salts and/or as solvates (e.g. hydrates), and/or in the form of their N-oxides etc. Suitable pharmacologically tolerable salts here are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyly benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation—depending on whether it is a mono- or polybasic acid and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom. Furthermore, the active compounds mentioned can also be present as pure enantiomers or as enantiomer mixtures in any mixing ratio.
- Respiratory tract disorders which may be mentioned are in particular allergen- and inflammation-induced bronchial disorders (bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD), which can be treated by the combination according to the invention also in the sense of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).
- “Combined use” or “combination” within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (directly in succession or else alternatively at a relatively large time interval) in a manner which is known per se and customary.
- Within the meaning of the present invention, “use” is preferably understood as meaning the oral administration of both active compounds. If only the PDE inhibitor is administered orally, “use” with respect to the β2 adrenoceptor agonist is understood in particular as meaning topical application in inhalatory form. For this, the β2 adrenoceptor agdnist is preferably administered by inhalation in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.
- Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
- The active compounds are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the active compounds compared with the norm. Customarily, the O2 adrenoceptor agonist (depending on potency) is administered in a dose of, for example, 0.002 to 2.0 mg per day on administration by inhalation.
- Depending on the inhaler system used, in addition to the active compounds the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
- For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is as right as possible for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®)), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described in European Patent Application EP 0 505 321), using which an optimal administration of active compound can be achieved.
- In the case of the oral administration of the β2 adrenoceptor agonists together with the PDE inhibitor, which is the preferred administration form, the β2 adrenoceptor agonist is administered in a daily dose of, for example, 0.05 to 60 mg. For the PDE inhibitors, it is possible in the case of oral administration to vary the doses—depending on the active compound—within a wide range, it being possible, as bounds, to start from a dose of 1-2000 μg/kg of body weight. In the case of the administration of the preferred PDE inhibitor roflumilast, the dose is in the range from 2-20 μg/kg of body weight.
- The PDE inhibitors to be administered orally are formulated—if appropriate together with the β2 adrenoceptor agonists—to give medicaments according to processes known per se and familiar to the person skilled in the art. The pharmacologically active compounds are employed as medicaments, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form). Particularly worthy of mention within the meaning of the combined, oral administration of both active compounds according to the invention are oral administration forms, e.g. tablets or capsules, in which one part of the β2 adrenoceptor agonist and the PDE inhibitor is present in non sustained-release form and a further, preferably larger part, of the β2 adrenoceptor agonist is present in sustained-release form.
- The person skilled in the art is familiar on the basis of his/her expert knowledge with which excipients or vehicles are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyciodextrins).
- Model
- Late Inflammatory Airway Reaction in the Ovalbumin-sensitizedl-challenged Brown-Norway Rat Anti-inflammatory activity of Roflumilast, Pumafentrine (BYK-33043), and Salmeterol was determined in ovalbumin (OVA)-sensitized and OVA-challenged Brown Norway rats. Sensitization was done by simultaneous injection of Bordetella pertussis suspension i.p. and OVA/AHG suspension s.c. on day 1, 14 and 21. 28 days after start of sensitization, conscious Brown-Norway rats were challenged by inhalation of the aerosolized OVA solution for 1 h (˜20 ml/h). Non-challenged, only sensitized animals were used as baseline control. The drugs (thoroughly mixed with lactose) or the placebo control (lactose) were administered intratracheally (i.t.) as dry powders 1 h before OVA-challenge. 48 h later, OVA-challenged or non-challenged animals were anaesthetized and bronchoalveolar lavage (BAL) was performed using 3×4 ml BAL buffer per animal. The number of total cells and eosinophils in the BAL fluid, and the concentration of protein in the cell-free BAL fluid were determined. Drug-induced relative changes were calculated and statistically analyzed by the Jonckheere Terpstra test.
- Results
% Inhibition of Infiltration/Accumulation PDE3/4 Dose Appl. [Median/Mean ± SEM] Compound IC50 [μmol] [μmol/kg] Route N Total cells EOS Protein Roflumilast >10/0.0007 0.3 it 8 −25 −15 −8 −37.6 ± 26.7 −22 ± 25.7 −22.3 ± 25.5 Pumafentrine 0.028/0.007 3 it 8 −19 −26 17 −39.1 ± 30.5 −28.5 ± 30.1 23.5 ± 10.6 Salmeterol 3 it 8 19 39 44 6.3 ± 17.9 31 ± 14.8 37.5 ± 16.2 Salmeterol/ 3/0.3 it 8 50 67** 59** Roflumilast 34.5 ± 21.1 61.1 ± 7.9** 50.8 ± 13.6** Salmeterol/ 3/3 it 8 56* 85** 75** Pumafentrin 58.1 ± 12.3* 83 ± 3.7** 67.1 ± 11.1**
*p < 0.05, **p < 0.01 v.s. untreated, OVA-challenged control groups
- The PDE inhibitors Roflumilast (PDE4 inhibitor) and Pumafentrine (PDE3>4 inhibitor) administered at doses of 0.3 μmol/kg and 3 μmol/kg i.t., respectively, did not show any significant effects on cell infiltration and protein accumulation. The negative values obtained (trend: amplification of inflammation) fall into the range of biological variability of the model and therefore, no significance must be attached to these data.
- In contrast, the long-acting p2-adrenergic receptor agonist Salmeterol given at a dose of 3 μmol/kg i.t exhibited inhibitory effects on total cell and eosinophil influx into alveolar space and protein levels in BAL fluid. However, the data failed to reach significance.
- Co-administration of the PDE inhibitor Roflumilast or Pumafentrine with Salmeterol resulted in synergistic effects compared to administration of every compound alone, i.e. both PDE inhibitors combined with the β2 agonist displayed a significant inhibition of eosinophilia and reduction of protein concentration in the BAL fluid. The combination of the PDE3/4 inhibitor Pumafentrine and Salmeterol was more efficacious on all parameters measured (difference was not significant), and additionally, showed a significant effect on inhibition of total cell influx into the alveolar space.
Claims (19)
1-12. (canceled)
13. A pharmaceutical composition comprising a PDE inhibitor, which is to be administered orally, from the PDE4 or PDE3/4 inhibitors group combined with a β2 adrenoceptor agonist in fixed or free combination, wherein said PDE inhibitor is selected from the group consisting of roflumilast; BYK-33043; AWD-12-281; SB-207499; arofylline; ibudilast; a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof; an N-oxide of roflumilast; and an N-oxide of BYK-33043;
and wherein said β2 adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); (R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline); 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine (pirbuterol); (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (formoterol); (+)-4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3benzenedimethanol (salmeterol); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.
14. The pharmaceutical composition as claimed in claim 13 , which is a fixed oral combination.
15. The pharmaceutical composition as claimed in claim 13 , wherein the PDE inhibitor is a compound selected from the group consisting of arofylline; ibudilast; SB-207499; and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.
16. The pharmaceutical composition as claimed in claim 13 , wherein the PDE inhibitor is BYK-33043 or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of BYK-33043.
17. The pharmaceutical composition as claimed in claim 13 , wherein the PDE inhibitor is BYK-33043 or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of BYK-33043, and the β2 adrenoceptor agonist is (±)-4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3benzenedimethanol (salmeterol) or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.
18. The pharmaceutical composition as claimed in claim 13 , which additionally contains an excipient selected from the group consisting of propellants, surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers, solvents, gel-forming agents, tablet excipients, antioxidants, dispersants, antifoams, flavor corrigents, solubilizers, colorants or permeation promoters, and completing agents.
19. A method of treating a respiratory tract disorder in a patient, comprising administering a therapeutically effective amount of a PDE inhibitor from the PDE4- or PDE3/4 inhibitors group in combination with a β2 adrenoceptor agonist to said patient, wherein said PDE inhibitor is administered orally, wherein said PDE inhibitor is selected from the group consisting of roflumilast; BYK-33043; AWD-12-281; SB-207499; arofylline; ibudilast; a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof; an N-oxide of roflumilast; and an N-oxide of BYK-330439; and wherein said β2 adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); (R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline); 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine (pirbuterol); (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (formoterol); (±)-4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.
20. The method of claim 19 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.
21. The method of claim 20 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.
22. The method of claim 19 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered simultaneously.
23. The method of claim 19 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered more or less simultaneously.
24. The method of claim 19 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered in succession.
25. A method of treating a respiratory tract disorder in a patient, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition as claimed in claim 17 .
26. The method of claim 25 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.
27. The method of claim 26 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.
28. The method of claim 25 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered simultaneously.
29. The method of claim 25 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered more or less simultaneously.
30. The method of claim 25 , wherein the PDE inhibitor and the β2 adrenoceptor agonist are administered in succession.
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US8367829B2 (en) | 2010-05-10 | 2013-02-05 | Gilead Sciences, Inc. | Bi-functional pyrazolopyridine compounds |
US8394829B2 (en) | 2010-05-10 | 2013-03-12 | Gilead Sciences, Inc. | Bi-functional quinoline analogs |
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