Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes

专利摘要:
The present invention relates to compounds of the formula (1.0.0) which are useful as inhibitors of PDE4 in the treatment of diseases regulated by activation and degranulation of eosinophils, especially asthma, chronic bronchitis and chronic obstructive pulmonary disease. In the formula, j is 0 or 1, and when j is 0, n must be 2; k is 0 or 1; m is 0, 1 or 2; n is 1 or 2; W 1 is -O-, -S (= 0) t -where t is 0, 1 or 2 or -N (R 3 )-; W 2 is —O—CR A R B — or absent; Y is = C (R 1 a )-or-[N⇒ (O) k ]-, where k is 0 or 1; R A and R B are —H substituted with 0 to 3 substituents R 10 ; -F; -CF 3 ; - (C 1 -C 4) alkyl; -(C 3 -C 7 ) cycloalkyl; Phenyl; Or benzyl or form a spiro residue only when R A and R B are taken together but m is 1; R C and R D have the same meaning as R A and R B , except that one of them must be -H; R 1 and R 2 are -H, -F, -Cl, -CN, -NO 2 ,-(C 1 -C 4 ) alkyl,-(C 2 -C 4 ) alkynyl, fluorinated- (C 1 -C 3 ) alkyl, -OR 16 and -C (═O) NR 22 a R 22 b ; R 3 is H, — (C 1 -C 3 ) alkyl, phenyl, benzyl or —OR 16 ; R 4 , R 5 and R 6 together with other meanings Can form; Q 1 , Q 2 and Z are as defined herein.
公开号:KR20030074761A
申请号:KR10-2003-7010074
申请日:2001-12-06
公开日:2003-09-19
发明作者:로버트 제임스 챔버스；토마스 빅터 마지；안토니 마팻
申请人:화이자 프로덕츠 인크.；
IPC主号:

专利说明:

Nicotinamide biaryl derivative useful as inhibitor of PD4 isozyme {NICOTINAMIDE BIARYL DERIVATIVES USEFUL AS INHIBITORS OF PDE4 ISOZYMES}
[1] 1.0 Notes on co-pending applications
[2] Disclosed is a nicotinamide derivative useful for the treatment of inflammation, respiratory and allergic diseases and symptoms, as it has the biological activity of selective PDE4 isozyme inhibitors, and provisional application No. 60/043403, filed April 4, 1997, agent To WOT 98/45268, filed Oct. 15, 1998, filed Mar. 10, 1998, which claims priority to Revenue Number PC9762, now abandoned, Representative Revision No. PC9762A. See co-pending international applications and US applications. The disclosure disclosed in the above-mentioned application does not teach at the skill level of those skilled in the art an unexpectedly high level of inhibition choice for the novel compounds of the invention or the PDE4 isozymes possessed by the new compounds.
[3] In addition, co-pending application No. 09 / 345,185, which discloses an N-substituted nicotinamide derivative and a method for preparing the same, claiming provisional application No. 60 / 105,120 (filed Oct. 21, 1998, Rep. No. PC10096). (Filed June 30, 1999, Reagent No. PC10096A).
[4] Agent No. PC11712, filed on the same date as this application, which also contains another class of nicotinamide derivatives useful as inhibitors of PDE4 isozyme; PC11848; PC11893; PC11894; Reference is made to co-pending applications of PC11895 and PC11896. All disclosures of this co-pending application are hereby fully incorporated by reference.
[5] 2.0 Background
[6] 3 ', 5'-cyclic nucleotide phosphodiesterases (PDEs) comprise many types of enzymes that are divided into 11 or more families that are structurally, biochemically and pharmacologically different from each other. Enzymes in each family are commonly referred to as isozymes or isozymes. A total of more than 15 gene products are included in this class, and further diversity occurs due to the different splicing and post-trnaslational processes of these gene products. The present invention primarily relates to four gene products of four families of PDEs (ie PDE4A, PDE4B, PDE4C and PDE4D). These enzymes are collectively referred to as isoforms or subtypes with PDE4 isozyme. The following will discuss in more detail the genomic organization, molecular structure and enzyme activity, different splicing, transcriptional regulation and phosphorylation, distribution and expression, and selective inhibition of PDE4 isozyme subtypes.
[7] PDE4 is characterized by selective high affinity hydrolytic degradation of adenosine 3 ', 5'-cyclic monophosphate (cAMP), a secondary messenger cyclic nucleotide, and selectivity for inhibition by rolipram . A number of selective inhibitors of PDE4 have recently been discovered and beneficial drug effects from this inhibition have been observed in many disease models. See, for example, Torphy et al., Environ. Health Perspect. 102 Suppl. 10-79-84, 1994; Duplantier et al., J. Med. Chem. 39 120-125, 1996; Schneider et al., Pharmacol.Biochem.Behav. 50 211-217, 1995; Banner and Page, Br. J. Pharmacol. 114 93-98, 1995; Barnette et al., J. Pharmacol.Exp. Ther. 273 674-679, 1995; Wright et al. "Differential in vivo and in vitro bronchorelaxant activies of CP-80633, a selective phosphodiesterase 4 inhibitor,"" Can. J. Physiol. Pharmacol. 75 1001-1008, 1997; Manabe et al." (Anti-inflammatory and bronchodilator properties of KF19514, KF19514, a phosphodiesterase 4 and 1 inhibitor. a phosphodiesterase 4 and 1 inhibitor), " Eur. J. Pharmacol. 332 97-107, 1997; and Ukita et al." A novel potent and selective phosphodiesterase-4 inhibitor that is an asthma agent: Novel, potent, and selective phosphodiesterase-4 inhibitor as antiasthmatic agents: synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives), " J. Med. Chem . 42 1088-1099, 1999). Thus, considerable interest continues in the art for the discovery of more selective inhibitors of PDE4.
[8] The present invention provides improved methods of treating a number of inflammatory, respiratory and allergic diseases and symptoms, in particular asthma; Chronic obstructive pulmonary disease (COPD), including chronic bronchitis, emphysema and bronchiectasis; Chronic rhinitis; And the use of selective PDE4 inhibitors for chronic sinusitis. However, to date, the primary therapies for the treatment of asthma and other obstructive airway diseases are not only the non-selective PDE inhibitors, theophylline, but also pentoxifylline and IBMX (these formulas (0.0.1) , (0.0.2) and (0.0.3) can be represented by)).
[9]
[10] Theophylline, in which PDE is one of the biochemical targets, affects the pulmonary system of the patient with increased pulmonary pressure in addition to the characteristic bronchodilator activity, inhibits inflammatory cell responses, and induces eosinophil apoptosis. Most commonly, the side effects of theophylline, the deep vein and nausea, are mediated by PDE inhibition, which has an improved side effect profile while at the same time being more selective to inhibit both in vitro immune cell function and in vivo allergic lung inflammation. Induce the development of PDE inhibitors. In the airways of patients with asthma and other obstructive airway diseases, PDE4 is the most important PDE isozyme as a target for drug development due to its distribution in airway smooth muscle and inflammatory cells. The various PDE4 inhibitors thus far introduced in the art have been designed to have improved therapeutic indices for the cardiovascular, gastrointestinal and central nervous system side effects of the non-selective xanthines mentioned above.
[11] Airflow obstruction and airway inflammation are characteristic of COPD as well as asthma. Bronchial asthma is characterized by eosinophilic inflammation, and neutrophils play a major role in the pathogenesis of COPD. Thus, PDEs involved in smooth muscle relaxation and found in neutrophils as well as neutrophils probably constitute an essential element in the course of both diseases. Participating PDEs include PDE4 as well as PDE4, and bronchodilator inhibitors have been developed that are selective PDE3 inhibitors and PDE3 / 4 biselective inhibitors. Examples of these include not only milrinone, which is a selective PDE3 inhibitor, but also zardaverine and benafentrine, both PDE3 / 4 dual-selective inhibitors, which are represented by the following formulas (0.0.4), (0.0 .5) and (0.0.6)):
[12]
[13] However, benafenthrin causes bronchial dilatation only when administered by inhalation, and zardaverin only causes mild and short-term bronchial dilatation. Miltonin, a cardiovascular agent, induces some protection against short-term bronchial dilatation and inducible bronchial contraction, but has significant side effects such as tachycardia and hypotension. Also unsatisfactory with the weakly selective PDE4 inhibitor tibenelast and the selective PDE5 inhibitor zaprinast, which can be represented by the following formulas (0.0.7) and (0.0.8) I got the result:
[14]
[15] The discovery and development of selective PDE4 inhibitors in the art has resulted in more appropriate success.
[16] In vivo, PDE4 inhibitors reduce the influx of eosinophils into the lungs of allergen-administered animals while reducing bronchial contraction and elevated bronchial reactivity that occur after allergen administration. PDE4 inhibitors also inhibit the activity of immune cells, including CD4 ⁺ T-lymphocytes, monocytes, mast cells and basophils, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), and inhibitory viarenaline Enhances inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduces airway smooth muscle mitogenesis, and induces bronchial dilatation. PDE4 inhibitors also inhibit the activity of many inflammatory cells associated with the pathophysiology of COPD, including monocytes / macrophages, CD8 ⁺ T-lymphocytes and neutrophils. PDE4 inhibitors also reduce venous smooth muscle likelihood and potentially prevent airway epidermal cells from producing pro-inflammatory mediators. Through the release of neutral proteases and acid hydrolases from these granules, and the generation of reactive oxygen species, neutrophils contribute to tissue destruction associated with chronic inflammation and are further involved in the pathogenesis of symptoms such as emphysema.
[17] Selective PDE4 inhibitors found so far that provide therapeutic benefit include SB-207,499 (Ariflo (ARIFLO®); can be represented by the following formula (0.1.9)):
[18]
[19] The twice daily (bid) 5, 10 and capacity as SB-207,499 oral administration of 15 mg is the lowest (trough) FEV _{1 (1-second} forced expiratory volume) compared to placebo in the second two weeks of study involving a large number of patients Increased significantly. Another potent selective PDE4 inhibitor, CDP840, has shown inhibition of late response to allergens inhaled 9.5 days after oral administration at doses of 15 and 30 mg in a group of patients with bronchial asthma. CDP840 can be represented by the following formula (0.0.9):
[20]
[21] PDE has also been studied as a potential treatment for obstructive pulmonary disease, including COPD. In a large study of SB-207,499 in patients with COPD, the group of patients receiving 15 mg twice daily experienced a gradual improvement at the lowest FEV ₁ and reached a maximum mean difference compared to placebo at 6 weeks. 11% improvement. Compton et al., "The efficacy of Ariflo (SB207499), a second generation, oral PDE4 inhibitor, in patients with COPD, '' Am. J. Respir. Crit. Care Med. 159 , 1999). Severe COPD patients are observed to suffer from pulmonary hypertension and obtain a decrease in mean pulmonary artery pressure under clinical conditions by oral administration of the selective PDE3 inhibitors milinon and enoximone. Enoxymone has also been shown to reduce airway tolerance in patients hospitalized with decompensated COPD. See Leeman et al., Chest 91 662-6, 1987. Using selective PDE3 inhibition by motapizone and selective PDE5 inhibition by zaprinast, the combined inhibition of PDE 3 and 5 corresponds widely to the pattern of PDE isozymes found in pulmonary smooth muscle. Causes relaxation of the pulmonary artery rings. See Rabe et al., Am. J. Physiol. 266 (LCMP 10): L536-L543, 1994. The structures of milnonone and japrinast are represented by formulas (0.0.4) and (0.0.8), respectively. The structures of Enoxymon and Motapizone can be represented by the formulas (0.0.10) and (0.0.11), respectively:
[22]
[23] The effect of PDE4 inhibitors on various inflammatory cell responses can be used as the basis for profiling and selection of inhibitors for further studies. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFα) release in eosinophils, neutrophils and monocytes. PDE4 inhibitors can induce side effects of vomiting, namely nausea and vomiting, as expected. When rolipram and denbufylline were used in clinical trials, vomiting side effects became apparent when PDE4 inhibitors were first studied for CNS signs such as depression. Rolipram and denbuphylline can be represented by the formulas (0.0.12) and (0.0.13), respectively:
[24]
[25] The mechanism by which PDE4 inhibitors potentially induce vomiting is uncertain, but studies of P-20 inhibitor, Ro-20-1724, suggest that nausea and vomiting are at least partially mediated by the brain's vomiting center. Gastrointestinal side effects can be attributed to local effects, for example, rolipram is a very potent stimulant of acid secretion from gastric wall cells, and excess acid obtained by producing local irritation can exacerbate gastrointestinal disorders. Ro-20-1724 can be represented by the following formula (0.0.14):
[26]
[27] Attempts to minimize or eliminate the above-mentioned side effects associated with PDE4 inhibitors sometimes include developing inhibitors that do not cross the central nervous system and administering PDE4 inhibitors by inhalation instead of oral.
[28] With respect to PDE4 subtypes A, B, C, and D, PDE4C is usually less sensitive to all inhibitors, while there is no clear evidence of inhibitor selectivity identified with a 10-fold difference in IC ₅₀ values for subtypes A, B, and D. Most inhibitors, especially RS-25,344, are more potent against PDE4D, while this is not equivalent to selectivity. RS-25,344 can be represented by the following formula (0.0.15):
[29]
[30] On the other hand, there is a stereoselective effect on the elevation of cAMP in a range of cell types, which is CDP840 and its less active enantiomer CT-1731 represented by the formula (0.0.9) above (which is represented by the formula (0.0. 16) has been demonstrated:
[31]
[32] It has been found for some time that rolipram has the ability to interact with the high affinity binding site of the brain membrane, after which a high affinity rolipram binding site (S _r ) that is distinct from the catalytic site (S _c ) is cleaved ( truncated) recombinant PDE4A and full length recombinant PDE4B. More recently, S _r has been identified for all four PDE4 subtypes. See, Hughes et al., Drug Disovery Today 2 (3) 89-101, 1997. The presence of S _r has been found to have a profound effect on the ability of certain inhibitors such as rolipram and RS-25,344 to inhibit the catalytic activity of PDE4 isozyme.
[33] The effect of residues on inhibitor binding is also significant. Single amino acid substitutions (substituting aspartate with alanine) in the catalytic region of PDE4B have been shown to be critical for inhibition by rolipram, and related inhibitors RP-73,401 and Ro-20-1724 also lose efficacy against mutant enzymes Therefore it appears to have a homogeneous effect. However, the role of the binding of the inhibitor to S _c or S _r is not currently fully understood in terms of elevation of cAMP and inhibition of cellular response.
[34] In guinea pig studies, RP-73,401 has been shown to be a selective force compared to other anti-asthmatic drugs for allergen-induced eosinophilia in guinea pig airways (Banner, KH, "Allergy-Induced Eosinophilia in Guinea Pig Airways." Effect of podiesterase inhibitors, " Pulm. Pharmacol. 8 37-42, 1995); (2) antigen-induced bronchial alveolar lavage (BAL) eosinophilia (Raeburn et al., "Anti-inflammatory and bronchial dilating properties of RP73401, a novel selective phosphodiesterase type IV inhibitor," Br. J. Pharmacol. 113 1423-1431, 1994); (3) antigen-induced airway eosinophilia and platelet activating factor (PAF)-and ozone-induced airway hyper-responsiveness (AHR) (Karlsson et al., "New Phosphodiesterase IV Inhibitor RP73401" Anti-inflammatory effect, " Int. Arch. Allergy Immunol. 107 425-428, 1995); And (4) active in inhibiting IL-5 induced pleural eosinophilia. The development of RP-73,401 piclamilast has been discontinued. Picclamilast can be represented by the following formula (0.0.17):
[35]
[36] Compounds of related fissures are represented by RPR-132294 and RPR-132703 which have been shown to have inhibitory activity of antigen-induced bronchial spasms in rat studies (Escott et al., "Drug Profile of Phosphodiesterase 4 (PDE4) Inhibitors). Ring, and Analysis of Treatment Rates in Rats and Dogs, " Br. J. Pharmacol. 123 (Proc. Suppl.) 40P, 1998; and Thurairatnam et al.," Biological Activities of New PDE4 Inhibitors RPR-132294 and RPR-132703 And side effect profiles, " XV ^th EFMC Int. Symp. Med. Chem. , 1998). The structure of RPR-132294 can be represented by the following formula (0.0.18):
[37]
[38] Another compound that has ceased development is WAY-PDA-641 filaminast, which has been shown to be active in the study of dogs in inhibiting seratonin-induced bronchial contraction. Pilaminast can be represented by the following formula (0.0.19):
[39]
[40] It has been suggested in the art that PDE4 inhibitors having a high affinity for S _r may be associated with increased vomiting and gastric acid secretion. RS-23,544, RP-73,401 and CP-80,633 induce vomiting and have a high affinity for S _r . CDP840 and SB-207,499 have a relatively low affinity for S _r , but CDP840 has a significantly higher potency at S _c than SB-207,499. CDP840 has been demonstrated to provide significant inhibition of late phase response in asthma treatment without any side effects of nausea or headache. Another PDE4 inhibitor that has been shown to have side effects of vomiting and vomiting is BRL-61,063, also referred to as cifamfilin, which is further described below. Development of CDP840 was discontinued, while CP-80,633 atizolam was advanced to clinical studies. CP-80,633 and BRL-61,063 can be represented by the following formulas (0.0.20) and (0.1.12), respectively:
[41]
[42] Another compound under development is LAS-31025 arophylline, which has been shown to be active in the inhibition of antigen-induced bronchial contraction in guinea pig studies (Beleta BJ "Characteristic of New Selective PDE IV Inhibitor LAS31025 Against Bronchial Asthma) , " Third Int. Conf. On Cyclic Nucleotide Phosphodiesterase: From Genes to Therapies , Glasgow, UK, 1996, Abstract 73). LAS-31025 arophylline can be represented by the following formula (0.0.21):
[43]
[44] Many PDE4 inhibitors are under development. For example, the effect of V-11294A on LPS-stimulated ex vivo TNF release and PHA-induced lymphocyte proliferation was measured in a randomized, double-blind placebo-controlled study where a 300 mg oral dose reduced TNF release and lymphocyte proliferation. (Landells et al., "Oral administration of phosphodiesterase (PDE) 4 inhibitor V11294A inhibits agonist-induced cell activation in vitro," Eur. Resp. J. 12 (Suppl 28) 362s, 1998; and Gale et al., "Pharmacodynamic-Pharmacokinetic (PD / PK) Profiles of Phosphodiesterase (PDE) 4 Inhibitor V11294A in Human Volunteers," Am. J. Respir. Crit. Care. Med. 159 A611, 1999).
[45] Compound D4418 was administered to healthy volunteers in a randomized, placebo-controlled Phase 1 study in a single escalating dose (Montana et al., “The activity of the new phosphodiesterase 4 (PDE4) inhibitor D4418 is a cell of asthma And animal models and early clinical studies, " Am. J. Respir. Crit. Care Med. 159 A108, 1999). D4418 is a moderately potent PDE4 inhibitor with an IC ₅₀ of 200 nM. It has good oral absorption and the 200 mg dose gives a plasma C _max of 1.4 μg / ml. D4418 was discontinued due to moderate efficacy and replaced by D4396, a pre-clinical development candidate.
[46] V-11294A and D4418 can be represented by the following formulas (0.0.22) and (0.0.23), respectively:
[47] _(0.0.23)
[48] Another compound CI-1018 was evaluated in 54 subjects, and no side effects were reported at doses below 400 mg (Pruniaux et al. "New phosphodiesterase inhibitor CI-1018 was applied to rolipram in sensitized brown Norwegian rats." Compared to antigen-induced pulmonary eosinophilia, " Inflammation S-04-6, 1999). CI-1018 has proven to have good oral bioavailability (57% in rats) and good oral efficacy with an ED ₅₀ of 5 mg / kg in the same species. CI-1018 is a relatively weak PDE4 inhibitor with an IC ₅₀ of 1.1 μM in U937 cells. CI-1018 has been identified or structurally closely related to PD-168787, which has been shown to be active in the inhibition of antigen-induced eosinophilia in rat studies (Pascal et al., "New PDE4 Inhibitor 4-oxo Synthesis and Structure-Activity Correlation of -1-phenyl-3,4,6,7-tetrahydro- [1,4] -diazepino [6,7,1-hi] indolin, "215 ^th ACS, Dallas, USA, MEDI 50, 1998). The putative structures of CI-1018 and PD-168787 belong to the nucleus diazepinone class which can be represented by the following formula (0.0.24):
[49]
[50] The aforementioned compounds were also evaluated in animal models, where PDE4 inhibitory activity was demonstrated. For example, V-11294A has been shown to be active in the inhibition of antigen-induced bronchial contraction in guinea pigs (Cavalla et al., "A novel phosphodiesterase 4 (PDE4) inhibitor in cellular and animal models of asthma). Activity of V11294A, " Amer. J. Respir. Crit. Care Med. 155 A660, 1997). D4418 has been shown to be active in guinea pig studies to inhibit antigen-induced early and late bronchial contraction and BAL eosinophilia (Montana, et al., Ibid ). CI-1018 has been shown to be active in the inhibition of antigen-induced eosinophilia in rat studies (Burnouf, et al., “Pharmacology of New Phosphodiesterase Type 4 Inhibitor CI-1018,” 215 ^th ACS Nat. Meeting, MEDI 008, 1998).
[51] Other compounds under development include CDC-3052, D-22888, YM-58997 and roflumilast (the following formulas (0.0.27), (0.0.28), (0.0.29) and (0.0) .30)):
[52]
[53] CDC-3052 was discontinued, but was inherited with a very potent PDE4 inhibitor, such as the compound represented by the following formula (0.0.31), and an anti-inflammatory compound CDC-801 represented by the following formula (0.0.32) :
[54]
[55] The compounds of formula (0.0.32) have been reported to have IC ₅₀ values of 42 pM and 130 nM as inhibitors of PDE4 and TNF production (Muller et al., "N-phthaloyl beta-aryl-beta-amino Derivatives: potent TNF-alpha and PDE4 inhibitors, "217 ^th American Chemical Society, Annheim , Germany, MEDI 200, 1999; and Muller et al.," Thalidomide homologues and PDE4 inhibitors, " Bioorg. Med. Chem Letts , 8 2669-2674, 1998).
[56] CDC-801 is derived from a series of compounds based on thalidomide and was primarily developed to improve the TNF-α inhibitory activity of thalidomide for the treatment of autoimmune diseases. Thalidomide can be represented by the following formula (0.0.33):
[57]
[58] CDC-801 has also been studied for the treatment of Crohn's disease, an unknown cause of chronic granulomatous inflammatory disease, usually accompanied by terminal ileum, with scarring and thickening of the intestinal wall, often causing intestinal obstruction and hemorrhoids and boil formation. Crohn's disease has a high recurrence rate after treatment.
[59] YM-58997 has an IC ₅₀ value of 1.2 nM for PDE4 (Takayama et al., “Synthesis Study for Selective Type 4 Phosphodiesterase (PDE IV) Inhibitors,” 214 ^th American Chemical Society , Las. Vegas, USA, MEDI 245, 1997). YM-58997 has a 1,8-naphthyridin-2-one structure like YM-976.
[60] Roflumilast has been studied for the treatment of both COPD and asthma, and asthma has an IC ₅₀ value of 3.5 nM in a standard in vitro guinea pig model. The use of roflumilast and surfactants for the treatment of adult respiratory distress syndrome (ARDS) has also been described.
[61] AWD-12,281, now referred to as loteprednol, has been shown to be active in a rat model of allergic rhinitis, as described further below in the section dealing with allergic rhinitis and the use of PDE4 inhibitors to treat it. AWD-12,281 can be represented by the following formula (0.0.34):
[62]
[63] Compounds structurally associated with CDP840 represented by the formula (0.0.9) include L-826,141, which has been reported to have activity in a rat model of bronchitis (Gordon et al., "Rat model of chronic bronchitis Anti-inflammatory effect of PDE4 inhibitors, " Am. J. Respir. Crit. Care Med . 159 A33, 1999). Other such compounds are structurally associated with those reported in Perrier et al., "Substituted furans that are inhibitors of the PDE4 enzyme," Bioorg. Med. Chem. Letts . 9 323-326, 1999. Is displayed as (0.0.35):
[64]
[65] Other compounds found to be very potent PDE4 inhibitors are those represented by the formulas (0.0.36), (0.0.37) and (0.0.38):
[66]
[67] Compounds that combine PDE4 and matrix metalloproteinase (MMP) inhibitory activity in a single molecule were made (Groneberg et al., "(Polydiesulfonyl) phosphodiesterase 4 and Matrix Metals by Hydroxamic Acid Template"). Double inhibition of proteases, " J. Med. Chem . 42 (4) 541-544, 1999). Two examples of such compounds are represented by the formulas (0.0.39) and (0.0.40):
[68]
[69] The individual IC ₅₀ values for the compounds of formulas (0.1.36) and (0.1.37) using the guinea-pig macrophage PDE4 assay were 1 nM and 30 nM.
[70] Compounds identified as KF19514 and KF17625 have been shown to have activity in the following inhibition in guinea-pig studies: histamine induction and antigen-induced bronchial contraction; PAF induced pulmonary eosinophilia and antigen induced BAL eosinophilia; Acetylcholine (ACh) -induced AHF; PAF induced BAL eosinophilia and neutropenia, and AHR; Antigen induced bronchial spasms; And anaphylaxis bronchial contraction (Fujimura et al., "Bronchoprotective Effects of KF-19514 and Ciloostazol in Guinea-Pig In Vivo," Eur. J. Pharmacol . 327 57-63, 1997; Manabe et al. , Ibid .; Manabe et al., "KF19514, a phosphodiesterase 4 and 1 inhibitor, inhibits PAF-induced pulmonary inflammatory response by inhaled administration in guinea-pigs," Int. Arch. Allergy Immunol . 114 389 -399, 1997; Suzuki et al., "New Bronchodilator 3. Imiazole [4,5-c] [1,8] naphthyridin-4- (5H) -one," J. Med. Chem . 35 4866 -4874, 1992; Matsuura et al., "Substituted 1,8-naphthyridin-2- (1H) -one as a selective phosphodiesterase IV inhibitor," Biol. Pharm. Bull . 17 (4) 498 -503, 1994; and Manabe et al., " Pharmacological properties of the new bronchodilator KF17625," Jpn. J. Pharmacol . 58 (Suppl. 1) 238P, 1992). KF19514 and KF17625 can be represented by the formulas (0.0.41) and (0.0.42):
[71]
[72] The absence of reported efficacy and vomiting for a series of indandiones suggests that the hypothesis that vomiting-related side effects are related to the affinity ratio of the PDE4 enzyme relative to the high affinity rolipram binding site (HARBS) is incorrect. Such indandione can be represented by the formulas (0.0.43) and (0.0.44):
[73]
[74] The PDE4 inhibitors thus far developed belong to a significant number of different classes in their chemical structure. This classification is as diverse as phenanthridine and naphthyridine. One class of PDE4 inhibitors is lignans such as T-440, which have been demonstrated to have the following inhibitory activity: antigen, histamine, LTD4, U-46619, Ach, neurokinin A and endothelin-1 Early phase bronchial contraction; Early and late phase bronchial contraction and BAL eosinophilia; And ozone-induced AHR and airway epithelial damage. Optimization of the PDE4 inhibitory efficacy of these compounds led to the discovery of T-2585, which is one of the most potent PDE4 inhibitors described to date with an IC ₅₀ value of 0.13 nM for guinea-pig lung PDE4. T-440 and T-2585 can be represented by the formulas (0.0.45) and (0.0.46):
[75]
[76] Another class of PDE4 inhibitors consists of benzofuran and benzothiophene. In particular, furan and croman rings have been used as a substitute for cyclopentyl ether by rolipram pharmacophore. One example of such a compound is one that is structurally clearly associated with BAY 19-8004 and can be represented by the following formula (0.0.47):
[77]
[78] Other benzofuran-type compounds have been reported to have IC ₅₀ values of 2.5 nM and can be represented by the following formula (0.0.48):
[79]
[80] Related structures, but not benzofuran compounds, have been reported to be characterized by fused deoxycin rings and cause near complete inhibition of tracheal PDE4 in dogs at 100 nM. This compound can be represented by the following formula (0.0.49):
[81]
[82] Quinolines and quinolones are another class of PDE4 inhibitor structures, which act as surrogates of the catechol residues of rolipram. This compound and two compounds of similar structure can be represented by the following formulas (0.0.50), (0.0.51) and (0.0.52):
[83]
[84]
[85] Purine, xanthine and pteridine represent another class of compounds to which the PDE4 inhibitors described so far are described in the art. Compound V-11294A further described above and represented by the formula (0.0.22) is purine. PDE4 inhibitors, xanthine compounds, which belong to theophylline are described in the art (Montana et al., "PDE4 inhibitors, novel xanthine homologs," Bioorg. Med. Chem. Letts . 8 2925-2930, 1998). The xanthine compound may be represented by the following formula (0.0.54):
[86]
[87] One potent PDE4 inhibitor belonging to the compound of the pteridine class has an IC ₅₀ value of 16 nM for PDE4 derived from tumor cells and has been found to inhibit tumor cell growth at micromolar concentrations (Merz et al., "Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potential for cAMP-specific phosphodiesterase and malignant tumor cell growth Inhibitors, " J. Med. Chem . 41 (24) 4733-4743, 1998). Pteridine PDE4 inhibitors can be represented by the following formula (0.0.55):
[88]
[89] Triazines represent another class of compounds to which the PDE4 inhibitors described so far belong. These two triazines exhibit bronchial dilatation activity and have been described as potent relaxants in the guinea-pig organ model. These compounds, which can be represented by the formulas (0.0.56) and (0.0.57), are moderately potent PDE4 inhibitors with IC ₅₀ values of 150 and 140 nM, respectively:
[90]
[91] Triazines with structures believed to be closely associated with the compounds of formulas (0.0.56) and (0.0.57) are UCB-29936, which has been demonstrated to have activity in a rat model of sepsis shock (Danhaive et al. "Selective phosphodiesterase type IV inhibitor UCB29936: the possibility of treatment in endotoxin shock," Am. J. Respir. Crit. Care. Med . 159 A611, 1999).
[92] There is also an effort in the art to improve the selectivity of PDE4 inhibitors for the above-described subtypes A to D. There are currently four known isoforms (subtypes) of PDE4 isozyme comprising the seven more splice variants described above. PDE4D isoform mRNA is expressed in inflammatory cells such as neutrophils and eosinophils, and the art has suggested that D-selective inhibitors of PDE4 can provide good clinical efficacy with reduced side effects. Nicotinamide derivatives that show selectivity for inhibition of PDE4D isoforms have been described (WO 98/45268) and naphthyridine derivatives have been reported to be PDE4D selective inhibitors (WO 98/18796). These compounds can be represented by the formulas (0.0.58) and (0.0.59), respectively:
[93]
[94] It has been described in the art that other nicotinamide compounds may be useful in the treatment of CNS diseases such as multiple sclerosis (GB-2327675), and rolipram derivatives are known in the art with equivalent affinity to both the catalytic and HARB sites for human PDE4B2B. It is described as a PDE4 inhibitor that is bound (Tian et al., "(R, R)-(+/-)-methyl-3-acetyl-4- [3- (cyclopentyloxy) -4-methoxyphenyl]- Double inhibition of human type 4 phosphodiesterase by 3-methyl-1-pyrrolidine carboxylate, " Biochemistry 37 (19) 6894-6904, 1998). Nicotinamide derivatives and rolipram derivatives can be represented by the formulas (0.0.60) and (0.0.61), respectively:
[95]
[96] Additional background information regarding optional PDE4 isozymes is available in the art, such as (Norman, "PDE4 inhibitor 1999," Exp. Opin. Ther. Patents 9 (8) 1101-1118, 1999 (Ashley Publications Ltd.). And Dyke and Montana, "Therapeutic Ability of PDE4 Inhibitors," Exp. Opin. Invest.Drugs 8 (9) 1301-1325, 1999 (Ashley Publication Ltd.).
[97] 3.0 Description of State of the Art
[98] WO 98/45268 (Marfar et al., Published October 15, 1998) discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme. These optional inhibitors are represented by the formula (0.1.1).
[99]
[100] US 4,861,891 (Saccomano et al., Published August 29, 1989) discloses nicotinamide compounds that act as calcium independent c-AMP phosphodiesterase inhibitors useful as antidepressants of formula (0.1.2).
[101]
[102] Typical compounds of the nicotinamide nucleus disclosed in this patent are 1-piperidyl, 1- (3-indolyl) ethyl, C ₁ -C ₄ alkyl, phenyl, 1- (1-phenylethyl), or methyl, methoxy Is directly bonded to the R ¹ group which is optionally monosubstituted benzyl by chloro or fluoro. R ² substituent is bicyclo [2.2.1] hept-2-yl or
[103] to be.
[104] Wherein Y is H, F or Cl; X is H, F, Cl, OCH ₃ , CF ₃ , CN, COOH, -C (= 0) (C ₁ -C ₄ ) alkoxy, NH (CH ₃ ) C (= 0)-(methylcarbamoyl) Or N (CH ₃ ) ₂ C (= 0)-(dimethylcarbamoyl).
[105] US 4,692,185 to Michaely et al. Discloses herbicides such as compounds of the formula (0.1.3).
[106]
[107] Wherein R is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl or halo.
[108] EP 550 900 (Jeschke et al.) Discloses herbicides and plant nematicides of the formula (0.1.4).
[109]
[110] Wherein n is 0 to 3; R ¹ is selected from various groups, but is typically H, 6-CH ₃ or 5-Cl; R ² is alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl; R ¹ and R ² are halo, CN, NO ₂ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy or arylthio; R ⁴ is alkyl.
[111] EP 500 989 (Mollner et al.) Discloses ACE inhibitors of the formula (0.1.5).
[112]
[113] Wherein n is 0 to 3; R is OH, SH, COOH, NH ₂ , halo, OR ₄ , SR ₄ , COOR ₄ , NHR ₄ or N (R ₄ ) ₂ , wherein R ₄ is lower alkyl, optionally substituted aryl, or acyl; R ₁ is OH, lower alkoxy, optionally substituted aryl lower alkoxy, aryloxy or disubstitutedamino; R ₂ is lower alkyl or amino lower alkyl; R1 and R2 are halo, NO ₂ , lower alkyl, halo lower alkyl, aryl lower alkyl or aryl. Specific embodiments disclosed include compounds such as the following formula (0.1.6).
[114]
[115] FR 2.140.772 (Aries) discloses compounds claimed to have utility as analgesics, neurostabilizers, antipyretics, anti-inflammatory agents and antirheumatic drugs of the formula (0.1.7).
[116]
[117] Wherein R is 1 or 2 substituents selected from lower alkyl, trihalomethyl, alkoxy and halo, R 'is H or alkyl and R "is hydrogen or alkyl.
[118] JP 07 304775 (Otsuka et al.) Discloses naphthyridine and pyridopyrazine having anti-inflammatory, immunomodulatory, analgesic, antipyretic, antiallergic and antidepressant actions. Also disclosed are intermediates of the formula (0.1.8).
[119]
[120] Wherein X may be CH and R and R 'are each lower alkyl.
[121] With respect to the above mentioned patents and published patent applications, it can be evident that only the disclosure of WO 98/45268 (Marfat et al.) Relates to the inhibition of PDE4 isozyme. The state of the art also includes information regarding compounds which differ in chemical structure from the compounds of formula (1.0.0) of the present invention but on the other hand have biological activities similar to those of formula (1.0.0). Representative patents and patent applications that disclose such information are further illustrated below.
[122] US 5,552,438, US 5,602,157 and US 5,614,540 (all Christensen, all of which have the same date of April 2, 1992) have the following formula (0.1.9) and are the compounds named below: Ariflo It relates to a therapeutic agent identified by (ARIFLO®).
[123]
[124] Compounds of formula (0.1.9) are in the range of US 5,552,438 which discloses species of compounds of formula (0.1.10).
[125]
[126] Wherein R ₁ =-(CR ₄ R ₅ ) _r R ₆ , where r = 0 and R ₆ = C _3-6 cycloalkyl; X = YR ₂ , where Y = 0 and R ₂ = —CH ₃ ; X ₂ = O; X ₃ = H; X ₄ = partial residue of formula (0.1.10.1).
[127]
[128] Wherein X ₅ = H; s = 0; R ₁ and R ₂ = CN; And Z = C (O) OR ₁₄ , where R ₁₄ = H. The disclosures of US 5,602,157 and US 5,614,540 differ from the disclosures of US 5,552,438 and are CN in the case of Ariflo® compounds, respectively, in the definition of the R ₃ group. A preferred salt form of the Ariflo® compound is disclosed as the tris (hydroxymethyl) ammonium methane salt.
[129] US 5,863,926 (Christstensen et al.) Discloses homologues of Ariflo® compounds, for example compounds of formula (0.1.11).
[130]
[131] WO 99/18793 (Webb et al.) Discloses a process for preparing ariflo® and related compounds. WO 95/00139 (Barnette, etc.) are high affinity roll leaf person and a combined PDE IV IC ₅₀ low affinity binding form of a roll leaf person and at least about 0.1 IC ₅₀ divided by the IC ₅₀ ratio for the compounds to form a catalyst for the However, the dependent claims limit the scope to compounds not known as PDE4 inhibitors before June 21, 1993.
[132] WO 99/20625 (Eggleston) discloses a crystalline polymorphic form of sifamphyline for the treatment of PDE4 and TNF mediated diseases of the formula (0.1.12).
[133]
[134] WO 99/20280 (Griswold et al.) Discloses a method of treating pruritus by administering an effective amount of a PDE4 inhibitor, for example a compound of formula (0.1.13).
[135]
[136] US 5,922,557 (Pon), in turn, is used to test potent PDE4 enzyme inhibitors and to compare the rank order of efficacy in elevated cAMP in whole cell preparations with the ability to inhibit phosphodiesterase activity in disrupted cell preparations. We disclose a CHO-K1 cell line which stably expresses full-length low-Km cAMP specific PDE4A enzyme at high levels. In addition, soluble enzyme inhibition assays described in the art were found not to reflect the inhibitory behavior in vivo. Improved soluble enzyme whole cell assays have been disclosed that reflect the inhibitor's in vivo behavioral behavior. It is further disclosed that there are at least four different PDE4 isoforms or subtypes, each subtype producing a number of splice variants that can exhibit different cell localizations and affinity for inhibitors. have.
[137] With regard to the disclosures of these patents and published patent applications, it may be apparent that related compounds have the same biological activity as the compounds of formula (1.0.0). At the same time, however, one skilled in the art will observe that the chemical structures of the compounds disclosed in the prior art are not only different but also different from the novel compounds of the invention. The state of the art includes further information regarding compounds which differ in chemical structure from compounds of formula (1.0.0) and which do not have similar PDE4 inhibitory activity as compounds of formula (1.0.0). Nevertheless, such compounds disclosed in the prior art often have therapeutic uses similar to those of compounds of formula (1.0.0) (ie, treatment of inflammation, respiratory and allergic diseases and symptoms). In particular, it is applicable to certain enzyme inhibitors and receptor antagonists of the so-called leukotriene pathway. This is especially the case for leukotriene LTB ₄ and LTD ₄ . Thus, representative patents and published patent applications that disclose additional information of this type are described below.
[138] Arachidonic acid is metabolized by cyclooxygenase-1 and 5-lipoxygenase. The 5-lipoxygenase pathway leads to the production of leukotriene (LT), which includes neutrophil aggregation, degranulation and chemotaxis; Vascular permeability; It contributes to the inflammatory response through its effects on smooth muscle contractility and lymphocytes. Cysteinyl leukotrienes LTC ₄ , LTD ₄ and LTE ₄ play an important role in the pathogenesis of asthma. The elements of the leukotriene pathway that provide a target for therapeutic intervention are shown in the diagram below.
[139]
[140] Thus, agents that can interfere with any stage of the 5-lipoxygenase pathway provide an opportunity for therapeutic treatment. One example of such a medicament is the 5-lipoxygenase inhibitor zileuton, which is a therapeutic agent identified by Zyflo (ZYFLO®) which can be represented by the following formula (0.1.14).
[141]
[142] Another such agent is the LTD ₄ receptor antagonist zafirlukast, a therapeutic agent identified by ACCOLATE® which can be represented by the following formula (0.1.15).
[143]
[144] Another such LTD ₄ receptor antagonist is montelukast, which is a therapeutic agent identified by SINGULAIR® which can be represented by the following formula (0.1.16).
[145]
[146] Another type of therapeutic target is the LTB ₄ receptor, and one example of an antagonist for the receptor is BIL-260, a therapeutic agent that can be represented by the following formula (0.1.17).
[147]
[148] Another example of a therapeutic agent that is an LTB ₄ receptor antagonist is CGS-25019c, which can be represented by the following formula (0.1.18).
[149]
[150] None of the above described conditions in the art discloses or implies a significant improvement in therapeutic uses and therapeutic indices in the treatment of novel compounds of the invention or their PDE4 inhibitory activity and the resulting inflammation, respiratory and allergic diseases and conditions. I never do that.
[151] 4.0 Summary of the Invention
[152] The present invention relates to novel compounds having biological activity as inhibitors of phosphodiesterases, the so-called "type IV" isoenzymes ("PDE4 isozyme"). Embodiments of the novel compounds of the invention are active as non-selective inhibitors of PDE4 isozyme. Other embodiments of the novel compounds particularly have PDE4 isozyme substrate specificity for the D subtype. Such novel compounds with non-selective or D-selective PDE4 inhibitor activity are generally useful for the treatment of various inflammatory, allergic and respiratory diseases and symptoms, in particular for the treatment of obstructive respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). Significantly improves.
[153] The present invention relates to a compound of formula (1.0.0) or a pharmaceutically acceptable salt thereof.
[154]
[155] In the above formula,
[156] -g is 0 or 1;
[157] -j is 0 or 1 except that n must be 2 when j is 0;
[158] -k is 0 or 1;
[159] -m is 0, 1 or 2;
[160] -n is 1 or 2;
[161] -W ¹ is -O-, -S (= O) _t- (where t is 0, 1 or 2), or -N (R ³ )-(where R ³ has the same meaning as defined below )ego;
[162] -W ² is -O-, -S (= O) _t- (where t is 0, 1 or 2), -N (R ³ )-(where R ³ has the same meaning as defined below) Or -CR ²⁹ R ^30- ;
[163] Wherein --R ²⁹ and R ³⁰ are each -H, -F, -CF ₃ ,-(C ₁ -C ₃ ) alkyl,-(C ₃ -C ₆ ) cycloalkyl, phenyl, benzyl and pyridyl, wherein , Alkyl, cycloalkyl, phenyl, benzyl and pyridyl residues are each independently selected from the group consisting of 0 to 3 substituents R ¹⁰ (wherein R ¹⁰ has the same meaning as defined below) Become;
[164] -Y is = C (R ¹ _a )-wherein R ¹ _a has the same meaning as defined below; Or-[N⇒ (O) _k ]-, where k is 0 or 1;
[165] Wherein --R ¹ _a is -H, -F, -Cl, -CN, -NO ₂ ,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkynyl, fluorinated- (C ₁ -C ₃ ) alkyl, fluorinated- (C ₁ -C ₃ ) alkoxy, -OR ¹⁶ and -C (= 0) NR ²² _a R ²² _b ;
[166] Here, --- R ²² _a and R ²² _b are each independently -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl or cyclopentyl;
[167] -R ^A and R ^B are each -H, -F, -CF ₃ ,-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl and benzyl, wherein the cycloalkyl, phenyl And benzyl residues are each independently selected from the group consisting of 0 to 3 substituents R ¹⁰ ;
[168] {Wherein --R ¹⁰ is phenyl, pyridyl, -F, -Cl, -CF ₃ , oxo (= O), -OR ¹⁶ , -NO ₂ , -CN, -C (= O) OR ¹⁶ ,- OC (= 0) R ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0) OR ¹⁷ , -NR ¹⁶ S (= 0) ₂ R ¹⁷ and -S (= 0) ₂ NR ¹⁶ R ¹⁷ , wherein the phenyl or pyridyl is substituted with 0-3 R ¹¹ It is selected from the group consisting of;
[169] Wherein --- R ¹¹ is -F, -Cl, -CF ₃ , -CN, -NO ₂ , -OH,-(C ₁ -C ₃ ) alkoxy,-(C ₁ -C ₃ ) alkyl or -NR ¹⁶ R ¹⁷ ;
[170] ---- R ¹⁶ and R ¹⁷ are -H,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkenyl,-(C ₃ -C ₆ ) cycloalkyl, phenyl, benzyl and Pyridyl, wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl or pyridyl is 0 selected from the group consisting of -F, -Cl, -CF ₃ , -CN and-(C ₁ -C ₃ ) alkyl To substituted with 3 substituents)
[171] Or -R ^A and R ^B together form only a spiro moiety of the formula (1.2.0) when m is 1;
[172]
[173] {here,
[174] --r and s are independently 0 to 4, provided that the sum of r + s is 1 or more and 5 or less;
[175] --X ^A is -CH _2- , -CH (R ¹¹ )-, C (R ¹¹ ) _2- (wherein R ¹¹ are each independently selected and each has the same meaning as defined above), -NR ¹⁵ −, wherein R ¹⁵ has the same meaning as defined below, —O—, or —S (═O) _t −, where t is 0, 1 or 2;
[176] The spiro moiety of the partial formula (1.2.0) is substituted with any one or more carbon atoms other than defining X ^A by 0 to 3 substituents R ¹⁴ , wherein R ¹⁴ has the same meaning as defined below Become; The nitrogen atom is substituted by zero or one substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined below; Sulfur atom is replaced by zero or two oxygen atoms}
[177] -R ^C and R ^D have the same meaning as defined above for R ^A and R ^B except that one of them should be -H, and they are selected independently of each other and R ^A and R ^B ;
[178] -R ¹ and R ² may appear individually or together in any ring (s) comprising the meaning of residue Q ² as defined below; R ¹ and R ² are each -H, -F, -Cl, -CN, -NO ₂ ,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkynyl, fluorinated- (C ₁ Independently from the group consisting of -C ₃ ) alkyl, -OR ¹⁶ and -C (= 0) NR ²² _a R ²² _b , wherein R ¹⁶ , R ²² _a and R ²² _b have the same meaning as defined above Selected;
[179] -R ³ is -H,-(C ₁ -C ₃ ) alkyl, phenyl, benzyl or -OR ¹⁶ , wherein R ¹⁶ has the same meaning as defined above;
[180] -R ⁴ , R ⁵ and R ⁶ may appear individually or together in any ring (s) comprising the meaning of residue Q ¹ as defined below, and R ⁴ , R ⁵ and R ⁶ may each be independently selected from the group consisting of a) to (d);
[181] -(a) -H, -F, -Cl,-(C ₂ -C ₄ ) alkynyl, -R ¹⁶ , -OR ¹⁶ , -S (= O) _p R ¹⁶ , -C (= O) R ¹⁶ , -C (= O) OR ¹⁶ , -OC (= O) R ¹⁶ , -CN, -NO ₂ , -C (= O) NR ¹⁶ R ¹⁷ , -OC (= O) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= 0) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= NR ¹² ) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= NCN) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= N- NO ₂ ) NR ¹⁶ R ¹⁷ , -C (= NR ²² _a ) NR ¹⁶ R ¹⁷ , -CH ₂ C (= NR ²² _a ) NR ¹⁶ R ¹⁷ , -OC (= NR ²² _a ) NR ¹⁶ R ¹⁷ ,- OC (= N-NO ₂ ) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -CH ₂ NR ¹⁶ R ¹⁷ , -NR ²² _a C (= O) R ¹⁶ , -NR ²² _a C (= O) OR ¹⁶ , = NOR ¹⁶ , -NR ²² _a S (= 0) _p R ¹⁷ , -S (= 0) _p NR ¹⁶ R ¹⁷ and -CH ₂ C (= NR ²² _a ) NR ¹⁶ R ¹⁷ ;
[182] {Where --p is 0, 1 or 2; R ²² _a , R ¹⁶ and R ¹⁷ have the same meaning as defined above}
[183] _{- (b) - (C 1} -C 4) alkyl, and R ^4, R ⁵ or R ⁶ has one or more of the meaning of -OR ¹⁶ in the above (a), R ¹⁶ is - (C ₁ -C ₄ )-(C ₁ -C ₄ ) alkoxy when defined as alkyl, wherein the alkyl and alkoxy are each independently 0 to 3 substituents -F or -Cl, or 0 or 1 substituent (C _1- C ₂ ) alkoxycarbonyl-, substituted with (C ₁ -C ₂ ) alkylcarbonyl- or (C ₁ -C ₂ ) alkylcarbonyloxy); And
[184] (c) phenyl, benzyl, furanyl, tetrahydrofuranyl, oxetanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl , Thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl , Pyridazinyl, piperidinyl, piperazinyl, triazolyl, triazinyl, tetrazolyl, pyranyl, azetidinyl, morpholinyl, parathiazinyl, indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, 2-H-chromenyl, chromanyl, benzothienyl, 1-H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinoli Aryl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and furinyl; Aryl or heterocyclyl moieties, wherein the aryl and heterocyclyl moieties are each independently substituted with 0 to 2 substituents R ¹⁴ ;
[185] Wherein: --R ¹⁴ is-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl, benzyl, pyridyl and quinolinyl, wherein said alkyl, cycloalkyl, phenyl, Benzyl, pyridyl or quinolinyl are substituted from the group consisting of 0, 1 or 2 substituents -F, -Cl, -CH ₃ , -OR ¹⁶ , -NO ₂ , -CN or -NR ¹⁶ R ¹⁷ And the R ¹⁴ group is also selected from -F, -Cl, -CF ₃ , oxo (= 0), -OR ¹⁶ , -NO ₂ , -CN, -C (= 0) OR ¹⁶ , -OC (= 0). R ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0) OR ¹⁷ , —NR ¹⁶ S (═O) ₂ R ¹⁷ or —S (═O) ₂ NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ have the same meaning as defined above;
[186] Furthermore, where -R ¹⁵ is -H, -NR ¹⁶ R ¹⁷ , -C (= O) R ¹⁶ , OR ¹⁶ ,-(C ₁ -C ₄ ) alkyl-OR ¹⁶ , -C (= O) OR ¹⁶ , (C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁶ , —C (═O) NR ¹⁶ R ¹⁷ ; -(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkenyl,-(CH ₂ ) _u- (C ₃ -C ₇ ) cycloalkyl, where u is 0, 1 or 2, Phenyl, benzyl, pyridyl and quinolinyl, wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl is substituted with 0 to 3 substituents R ¹² , and R ¹⁶ and R ¹⁷ has the same meaning as defined above);
[187] Where ---- R ¹² is -F, -Cl, -CO ₂ R ¹⁸ , -OR ¹⁶ , -CN, -C (= 0) NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , -NR ¹⁸ C ( = O) R ¹⁹ , -NR ¹⁸ C (= O) OR ¹⁹ , -NR ¹⁸ S (= O) _p R ¹⁹ , -S (= O) _p NR ¹⁸ R ¹⁹ , where p is 1 or 2 , - (C ₁ -C ₄₎ alkyl, and R ¹² has a meaning of the -OR ¹⁶ R ¹⁶ is - (C ₁ -C ₄₎ in a case defined with alkyl - (C ₁ -C ₄₎ alkoxy Independently selected from the group consisting of wherein alkyl and alkoxy are each independently -F, -Cl,-(C ₁ -C ₂ ) alkoxycarbonyl,-(C ₁ -C ₂ ) alkylcarbonyl and- Substituted with 0 to 3 substituents independently selected from (C ₁ -C ₂ ) alkylcarbonyloxy, R ¹⁶ has the same meaning as defined above);
[188] Wherein ----- R ¹⁸ and R ¹⁹ consist of -H,-(C ₁ -C ₄ ) alkyl and phenyl, wherein said alkyl or phenyl is substituted with 0-3 occurrences of -F or -Cl Independently selected from the group}
[189] Or when Q ¹ is phenyl,
[190] -(d) R ⁵ and R ⁶ together form a residue selected from the group consisting of the following partial formulas (1.3.1) to (1.3.15),
[191]
[192] {here,
[193] --R ²⁰ and R ²¹ are each _{-H, -F, -Cl, -CH 3} , -CH 2 F, -CHF 2, -CF 3, -OCH 3 , and are independently selected from the group consisting of -OCF ₃ ;
[194] --R ²³ and R ²⁴ are each independently -H, -CH ₃ , -OCH ₃ , -CH ₂ CH ₃ , -OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ or absent, where dotted line ---- Represents a double bond}
[195] -Q ¹ is a moiety comprising a saturated or unsaturated carbon ring system that is 3-7 membered monocyclic or 7-12 membered fused polycyclic, provided that Q ¹ is discontinuous or restricted as defined in Q ² hereinafter. Not a biaryl moiety, wherein optionally one carbon atom in the carbon ring system may be substituted by a heteroatom selected from N, O and S, and optionally a second carbon atom and more optionally a third carbon atom is replaced by N Can;
[196] Herein, the residues defining the Q ¹ is R ^4, R ⁵ and R ⁶ which is substituted in any ring (s) by (wherein, R ^4, R ⁵ and R ⁶ have the same significance as defined above);
[197] -Q ² is a discontinuous or restricted biaryl moiety consisting of a saturated or unsaturated carbon ring system that is 3-7 membered monocyclic, 7-12 membered fused polycyclic, wherein one carbon atom of the carbon ring system is N, O And optionally substituted by a heteroatom selected from S, optionally a second carbon atom and more optionally a third carbon atom may be substituted with N;
[198] -Z is independently selected from the group consisting of (a) and (b);
[199] -(a) the group consisting of the following partial formulas (1.1.1) to (1.1.15):
[200]
[201] Wherein R ¹⁶ and R ¹⁷ have the same meaning as defined above and R ⁹ has the same meaning as defined below;
[202] -"*" Indicates the point of attachment of the partial formulas (1.1.1) to (1.1.15) to the remaining portion of each formula (1.0.0);
[203] -q is 1, 2 or 3, provided that if q is 2 or 3 then R ⁹ has the meaning of -H in one or more cases or in each of two cases;
[204] --v is 0 or 1;
[205] --W ³ is -O-, -N (R ⁹ )-(wherein R ⁹ has the same meaning as defined below) or -OC (= O)-;
[206] --R ⁷ _A is independently selected from the group consisting of (1) to (4):
[207] -(1) -H;
[208] -(2)-(C ₁ -C ₆ ) alkyl,-(C ₂ -C ₆ ) alkenyl or-(C ₂ -C ₆ ) alkynyl, wherein the alkyl, alkenyl or alkynyl is 0 to Substituted with three substituents R ¹⁰ , wherein R ¹⁰ has the same meanings as defined above;
[209] -(3)-(CH ₂ ) _u- (C ₃ -C ₇ ) cycloalkyl, wherein u is 0, 1 or 2, and wherein (C ₃ -C ₇ ) cycloalkyl is 0 to 3 substituents substituted with R ¹⁰ (wherein, R ¹⁰ can have the same significance as defined above)); And
[210] -(4) phenyl or benzyl, wherein said phenyl or benzyl is independently substituted with 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined above;
[211] --R ⁷ _B is independently selected from the group consisting of (1) and (2):
[212] -(1) tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-one-5-yl, 1,2,3-triazole -5-yl, imidazol-2-yl, imidazol-4-yl, imidazolidin-2-one-4-yl, 1,3,4-oxadiazolyl, 1,3,4-oxadia Zol-2-one-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazole-5-one-3-yl, 1,2,4-oxadia Zol-5-yl, 1,2,4-oxadiazol-3-one-5-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, morpholinyl, parathia Genyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, succinimidyl, glutarimidyl, pyrrolidoneyl, 2-piperidonyl, 2-pyridonyl, 4- Pyridonyl, pyridazine-3-onyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; And
[213] -(2) indolyl, indolinyl, isoindolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2H-1-benzopyra Nil, 2-H-chromenyl, chromamanyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl; Benzothiazolyl, benzotriazolyl, benzotriazinyl, phthalazinyl, 1,8-naphthyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolo [3,4-d] Pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, imidazo [1,2-a] pyridinyl, pyridopyridinyl, putridinyl and 1H-purinyl;
[214] Wherein any residue of (1) or (2) is selected from (i) any one or more carbon atoms by substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above; (ii) any one or more nitrogen atoms and all tautomeric forms thereof that are not at the point of attachment of said residue by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined above; (iii) optionally substituted for any sulfur atom that is not the point of attachment of the residue by zero, one or two oxygen atoms;
[215] --R ⁹ is -H,-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl, benzyl, pyridyl, -C (= 0) OR ¹⁶ , -C (= 0 ) R ¹⁶ , -OR ¹⁶ ,-(C ₁ -C ₂ ) alkyl-OR ¹⁶ and-(C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁶ , wherein R ¹⁶ has the same meaning as defined above Having the same composition;
[216] -R ⁷ _c is independently selected from the group consisting of the meanings of R ⁷ _A and meanings of R ⁷ _B as defined above;
[217] Further here, Comprises saturated or unsaturated 4-8 membered monocyclic, or 5-10 membered fused or open bicyclic carbocyclic ring systems containing nitrogen heteroatoms as indicated in partial formula (1.1.15); Wherein, optionally one to three carbon atoms in the carbocyclic ring system may each be substituted with a nitrogen heteroatom, or optionally one carbon atom may be substituted with an oxygen heteroatom or a sulfur heteroatom, or optionally two carbon atoms may each be nitrogen Heteroatoms and oxygen heteroatoms, or nitrogen heteroatoms and sulfur heteroatoms, respectively;
[218] Wherein any moiety of the partial formula (1.1.15) may be selected from (1) any one or more carbon atoms by substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above; (2) any one or more nitrogen atoms, all tautomeric forms, and optionally their N-oxide forms, by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined above; (3) optionally substituted for any sulfur atom by zero, one or two oxygen atoms}
[219] Z is also
[220] -(b) -OP (= O) (OH) ₂ (phosphoric), -PH (= O) OH (phosphonic), -P (= O) (OH) ₂ (phosphonic),-[P ( = O) (OH) -O ( C 1 -C 4) alkyl] (phosphono alkyl), -P (= O) ( OH) -O (C 1 -C 4) alkyl (phosphinylmethyl alkyl), -P (= O) (OH) NH ₂ (phosphoramido), -P (= O) (OH) NH (C ₁ -C ₄ ) alkyl and -P (= O) (OH) NHR ²⁵ (substituted phosphor Amido), -OS (= O) ₂ OH (sulfuric), -S (= 0) ₂ 0H (sulphonic), -S (= O) ₂ NHR ²⁶ or -NHS (= O) ₂ R ²⁶ ( Sulfonamido), wherein R ²⁶ is -CH ₃ , -CF ₃ or o-toluyl, and -C (= 0) NHS (= 0) ₂ R ²⁵ , -C (-0) NHS (= 0) ) ₂ NH ₂ , -C (= O) NHS (= O) ₂ (C ₁ -C ₄ ) alkyl, -C (= O) NHS (= O) ₂ NH (C ₁ -C ₄ ) alkyl, -C (O) NHS (= O) 2 N [(C 1 -C 4) _{alkyl] 2, -S (= O)} 2 NHC (= O) (C 1 -C 4) alkyl, -S (= O) ₂ NHC (= O) NH ₂ , -S (= O) ₂ NHC (= O) NH (C ₁ -C ₄ ) alkyl, -S (= O) ₂ NHC (= O) N [(C ₁ -C ₄ ) Alkyl] ₂ , -S (= O) ₂ NHC (= O) R ²⁵ , -S (= O) ₂ NHCN, -S (= 0) ₂ NHC (= S) NH ₂ , -S (= O) ₂ NHC (= S) NH (C ₁ -C ₄ ) alkyl, -S (= O) ₂ NHC (= S) N [(C ₁ -C ₄ ) alkyl] ₂ and -S (= O) ₂ NHS ( = O) ₂ R ²⁵ {wherein, --R ²⁵ is _{-H, - (C 1 -C 4} ) alkyl, Fe Or -OR ¹⁸ is selected from a moiety selected from the group consisting of acyl sulfonamido road is selected from the group consisting of Im (wherein, R ¹⁸ can have the same significance as defined above)}.
[221] In particular, the present invention relates to compounds of formula (1.0.0) cited above, wherein the Q ² group comprises a group selected from the group consisting of the following moieties represented by the following partial formulas (1.2.1) to (1.2.32) .
[222]
[223]
[224]
[225] Here, "*" is a symbol indicating two points of attachment of said Q ² group to the remaining component of formula (1.0.0).
[226] In particular, the present invention provides that the terminal group Z has the partial formulas (1.1.1) to (1.1.3), (1.1.5), (1.1.6) and (1.1.10) to (1.1.14) (where R is Preferred meaning of ⁷ _A or R ⁷ _C consists of hydrogen, methyl, trifluoromethyl, iso-propyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) and the following partial formula (1.4.24) To a compound of formula (1.0.0) comprising a residue selected from the group represented by (1.4.28).
[227] The invention also relates to compounds of formula (1.0.0) wherein Z comprises partial formulas (1.1.4) and (1.1.10) to (1.1.14). Preferred meanings of R ⁷ _B in partial formula (1.1.4) or R ⁷ _C in partial formulas (1.1.10) to (1.1.14) in which v is 0 or 1 are as follows: partial formulas (1.4.1) to (1.4.28), meaning groups selected from the group consisting of all tautomeric forms and optionally their N-oxide forms.
[228]
[229]
[230] Here, "*" denotes the point of attachment to the remaining part of the formula (1.0.0), each carbon atom is optionally substituted with a substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ have the same meaning as defined above.
[231] In particular, the present invention provides that the terminal groups Z comprise the partial formulas (1.1.4) and (1.1.10) to (1.1.14), the partial formulas (1.1.4) and (1.1.10) to (1.1. The preferred meanings of R ⁷ _B and R ⁷ _C in 14) are each independently selected from the group consisting of the following partial formulas (1.5.1) to (1.5.29), all tautomers, and optionally their N-oxide forms To a compound of formula (1.0.0).
[232]
[233]
[234] Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted by substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ have the same meaning as defined above .
[235] In addition, the present invention provides that at least one terminal is represented by the number and position of the carbon atoms and their substitution by one or more heteroatoms, as well as by R ¹⁴ where R ¹⁴ is oxo (═O). Formula (1.0.0) wherein the substitution of the carbon atom means a moiety of the partial formula (1.5.15) wherein Z is selected from the group consisting of the following partial formulas (1.7.1) to (1.7.46) It relates to a compound of).
[236]
[237]
[238]
[239] Any moiety that is a member selected from the group consisting of the partial formulas (1.7.1) to (1.7.46) shown above includes (1) substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as described above Any one or more carbon atoms thereof; (2) any one or more nitrogen atoms, and all tautomeric forms thereof, and optionally their N-oxide forms, by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as described above; Or (3) any substitution thereof with respect to any sulfur atom thereof by zero, one or two oxygen atoms.
[240] The present invention also relates to a PDE4 isozyme that acts to modulate the activation and degranulation of human eosinophils, in particular comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1.0.0) A method of treating a subject having a disease or condition mediated by its D subtype. Similarly, the present invention also relates to a pharmaceutical composition for use in such a treatment comprising a compound of formula (1.0.0) described above together with a pharmaceutically acceptable carrier.
[241] The present invention relates to a PDE4 isozyme, in particular a D subtype inhibitor, comprising a compound of formula (1.0.0) as described above useful for treating or preventing one or more elements selected from the group of diseases, disorders and symptoms consisting of It is about:
[242] -Asthma of any type, cause or onset, or by atopic asthma, non-atopic asthma, allergic asthma, atopy, bronchial, IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Intrinsic asthma induced, exogenous asthma caused by environmental factors, intrinsic asthma of unknown or unknown cause, non-atopic asthma, bronchitis asthma, emphysema, asthma, exercise-induced asthma, occupational asthma, bacteria , Asthma selected from the group consisting of infectious asthma, non-allergic asthma, early asthma, whistle infant syndrome caused by fungal, protozoan or viral infection,
[243] -Chronic or acute bronchial constriction, chronic bronchitis, small airway obstruction and emphysema,
[244] Obstructive or inflammatory airway disease of any type, cause or onset, or COPD, irreversible progressive progression, including asthma, pneumoconiosis, chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or related dyspnea Obstructive or inflammatory airway disease selected from the group consisting of COPD, adult respiratory distress syndrome (ARDS) characterized by airway obstruction, and exacerbation of airway hyperresponsiveness by other pharmacotherapy,
[245] -Pneumoconiosis of any type, cause or onset, or disease of aluminosis or bauxite workers, asthma or asthma of miners, asbestos or steam mechanic's asthma, chalicosis or sputum, dust of ostrich hair Ptilosis caused by inhaling iron, siderosis caused by inhaling iron particles, silicosis or crushed pore disease, cotton fever or cotton-dust asthma, and talc pneumoconiosis Pneumoconiosis,
[246] -Bronchitis of any type, cause or onset, or acute bronchitis, bronchitis of acute laryngeal trachea, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, wet bronchitis ( productive bronchitis), Staphylococcus or Streptococcus bronchitis, and bronchiolitis bronchitis,
[247] From a group consisting of any type, cause or onset of bronchiectasis, or columnar bronchiectasis, pocket-shaped bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis Bronchiectasis chosen,
[248] Seasonal allergic rhinitis, or perennial allergic rhinitis, or sinusitis of any type, cause or onset, or sinusitis selected from the group consisting of purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoidal sinusitis,
[249] -Consisting of rheumatoid arthritis of any type, cause or onset, or acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, and spondyloarthritis Rheumatoid arthritis selected from the group,
[250] Gout, and fever and pain associated with inflammation,
[251] Eosinophil-related disorders of any type, cause, or onset, or eosinophilia, pulmonary infiltrating eosinophilia, Loffler syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchial pneumonia-type aspergillosis Eosinophil-related disorders selected from the group consisting of, aspergillosis, granulomas including eosinophils, allergic granulomatous vasculitis or Chuck-Straus syndrome, nodular arteritis (PAN), and systemic necrotic vasculitis,
[252] -Atopic dermatitis, or allergic dermatitis, or allergic or atopic eczema,
[253] Urticaria of any type, cause or onset, or immune-mediated urticaria, complement-mediated urticaria, urticaria-induced urticaria, physical drug-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, Hives selected from the group consisting of cholinergic urticaria, autosomal dominant or acquired forms, cold urticaria, contact urticaria, giant urticaria, and papular urticaria,
[254] Conjunctivitis of any type, cause or onset, or conjunctivitis selected from the group consisting of photoconjunctivitis, acute cataract conjunctivitis, acute infectious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic cataract conjunctivitis, purulent conjunctivitis, and spring conjunctivitis,
[255] -Uveitis of any type, cause or onset, or inflammation of all or part of the uvea, anterior uveitis, iris, cystitis, iris phloemitis, granulomatous uveitis, granulomatous uveitis, crystalline antigenic uveitis, posterior uveitis, portal vein Uveitis selected from the group consisting of meningitis, and chorioretinitis,
[256] -Psoriasis,
[257] Multiple sclerosis selected from the group consisting of multiple sclerosis of any type, cause or onset, or primary progressive multiple sclerosis, and relapsing-remitting multiple sclerosis,
[258] -Autoimmune / inflammatory diseases of any type, cause or onset, or autoimmune hematological disorders, hemolytic anemia, aplastic anemia, sore erythrocytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple chondritis, skin Sclerosis, Wegner granulomatosis, dermatitis, chronic active hepatitis, myasthenia gravis, Stevens-Jones syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Endocrine opthamopathy, Graves' disease, sarcoidosis, alveolitis, chronic irritable pneumonia, primary biliary cirrhosis, childhood diabetes or type I diabetes, anterior uveitis, granulomatosis or posterior uveitis, dry keratoconjunctivitis, Epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, dune with nephrotic syndrome Nephritis, glomerulonephritis without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory / hyperproliferative dermatosis, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial cystic ulcer, lupus erythematosus , Autoimmune / inflammatory diseases selected from the group consisting of, deciduous pemphigus, and vulgaris
[259] Prevention of allograft rejection following organ transplantation,
[260] Inflammatory bowel disease (IBD) of any type, cause or onset, or inflammatory bowel disease selected from the group consisting of ulcerative colitis (UC), collagen colitis, polyp colitis, pancreatitis colitis, and Crohn's disease (CD) ,
[261] Septic shock of any type, cause or onset, or renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremia cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancerous cachexia Pulmonary shock, selected from the group consisting of cachexia as a result of infection of human immunodeficiency virus (HIV),
[262] -Liver damage,
[263] Pulmonary hypertension, and hypoxia induced pulmonary hypertension,
[264] Bone loss, primary osteoporosis, and secondary osteoporosis,
[265] Central nervous system disorders of any type, cause or onset, or depression, Parkinson's disease, learning and memory disorders, delayed motor disorders, drug dependence, atherosclerosis dementia, and Huntington chorea, Wilson's disease, tremor and atrophy Central nervous system disorder selected from the group consisting of accompanying dementia,
[266] Infections, especially with the herpes virus, including HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and herpes zoster and Herpes simplex Infection with a virus that increases the production of TNF-α in a host, including a virus selected from the group consisting of, or that is sensitive to the upregulation of TNF-α in a host, negatively affecting replication and other viral activity ,
[267] In particular polymyxins (e.g. polymyxin B), imidazoles (e.g. clotrimazole, econazole, myconazole and ketoconazole), triazoles (e.g. fluconazole and itranazole), and amphotericin (e.g. amphoteric) Upregulation of TNF-α or TNF-α production in the host when administered with other drugs selected for the treatment of systemic yeast and fungal infections, including but not limited to erysine B and liposome amphotericin B) Yeast and fungal infections sensitive to induction (e.g. fungal meningitis),
[268] Ischemia-reperfusion injury, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteric diseases, genitourinary and gastrointestinal disorders, and prostate disease.
[269] In particular, the compounds of formula (1.0.0) include (1) inflammatory diseases including joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatosis, and Crohn's disease; Diseases, (2) respiratory diseases and symptoms, including asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease and silicosis, (3) sepsis, septic shock, endotoxin shock, gram negative sepsis , Infectious diseases and symptoms, including toxic shock syndrome, fever and myalgia from bacterial, viral or fungal infections, and influenza, (4) autoimmune diabetes, systemic lupus erythematosus, graft-to-host response, allograft rejection, Immune diseases and symptoms, including multiple sclerosis, psoriasis and allergic rhinitis, and (5) secondary cachexia of bone resorption disease, reperfusion injury, infection or cancer, human Useful for the treatment of secondary cachexia, scaroma formation, type 1 diabetes, and leukemia in acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related syndrome (ARC).
[270] Detailed description of the invention
[271] 5.0 Compound
[272] The present invention relates to novel compounds which can be represented by the following formula (1.0.0):
[273]
[274] The maximum range of compounds of the present invention is limited above under the summary of 4.0 invention . Further descriptions of such compounds are provided below with respect to embodiments characterizing and exemplifying compounds of formula (1.0.0), as well as the range of different types and groups of specific embodiments. While preferred and more preferred embodiments of such compounds are also described, it will be understood that the above description of these preferred embodiments does not imply, but limit, the scope of the present invention with respect to the compounds.
[275] Terminal residue Z, detailed in detail above, means a member independently selected from the group consisting of partial formulas (1.1.1) to (1.1.15):
[276]
[277] Substituents R ⁷ _A , R ⁷ _B and R ⁷ _C of the partial formulas enumerated above, as well as R ⁹ , R ¹⁶ and R ¹⁷ , as well as sub-substituents R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ and R ¹⁹ have been defined above and provide a clear description of the intended range of the compounds of the invention. Certain embodiments within this range include the substituents R ⁷ _A , R ⁷ _B , R ⁷ _C and R ⁹ , as well as the specific meanings of other substituents forming part of Formula (1.0.0). Such embodiments further include, but are not limited to, those described above in (i) to (vi) below.
[278] The specific terms and expressions used herein to define the scope of the present invention and the limits of the specification described below are defined below.
[279] As used herein, the expressions “-(C ₁ -C ₃ ) alkyl”, “-(C ₁ -C ₄ ) alkyl” and “-(C ₁ -C ₆ ) alkyl” include straight chains as well as branched chains of these aliphatic groups. Form is included. Thus, the expressions cited above include branched chain iso-propyl, iso-butyl, sec-butyl, tert-butyl, in addition to the straight chain methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, iso-pentane (2-methylbutane), 2-methylpentane, 3-methylpentane, 1-ethylpropane and 1-ethylbutane. In addition, the expressions recited above mean that they apply to such expressions whether or not they are substituted. Thus, the expression “fluorinated- (C ₁ -C ₃ ) alkyl” is intended to include various fluorinated species of n-propyl and iso-propyl aliphatic groups.
[280] Q ¹ and Q ² are both defined herein to include saturated or unsaturated carbon ring systems that are 3-7 membered monocyclic or 7-12 membered fused polycyclic, wherein any one of said carbon ring systems The carbon atom of may be substituted by a heteroatom selected from N, O and S, and any second carbon atom thereof and any additional third carbon atom thereof may be substituted by N. These definitions refer to carbon ring systems having at least two rings, in particular bicyclic and tricyclic, more particularly bicyclic ring systems, in which the rings are fused, ie having at least one pair of bridgehead present carbon atoms. These polycyclic ring systems can be saturated or unsaturated. Next, the definition recited above also refers to a carbon ring system having two or more rings in which the rings are discontinuous, ie bonded to each other by single or double covalent bonds, and without a bridgehead present carbon atom. These polycyclic ring systems can also be saturated or unsaturated.
[281] With regard to the situation where a discontinuous carbon ring system is selected as opposed to fused, it should be noted that residue Q ¹ is not recognized as such a discontinuous carbon ring system. On the other hand, residue Q ² is required discontinuously in this situation. It is further provided herein that the residue Q ² means either a discontinuous carbon ring system or should mean a "limited biaryl" carbon ring system. Thus, as used herein, under the expression “discontinuous or limited biaryl”, which means either a discontinuous ring system or a fused polycyclic ring system as defined above, the (1) bridgehead carbon atom is joined by a bond, ie the bridgehead There are no additional carbon atoms present between the carbon atoms; (2) When present, the heteroatoms essentially required these two requirements to be contained only in tricyclic or higher polycyclic fused ring systems.
[282] Thus, types of restricted biaryl and discontinuous ring systems, which may include the meaning of Q ² , but may not include the meaning of Q ¹ , are referred to herein by numbers following the designations referring to their partial formulas. In particular, the following are included: biphenyl (1.2.1); 3-phenyl-pyridine (1.2.2); Cyclohexyl-benzene (1.2.3); [2,2 '] bipyridinyl (1.2.4); Bicyclohexyl (1.2.5); 2-phenyl-thiophene (1.2.6); 2-phenyl-furan (1.2.7); Naphthalene (1.2.8); Diphenylmethane (1.2.9); 4,5-diphenyl-1H-imidazole (1.2.10); 3-benzyl-pyridine (1.2.11); 4,5-diphenyl-oxazole (1.2.12); Fluorene (1.2.13); 9H-carbazole (1.2.14); Phenyl ether (1.2.15); 1H-indole (1.2.16); Quinoline (1.2.17); Phenanthrene (1.2.18); Phenanthridine (1.2.19); [3,3 '] bipyridinyl (1.2.20); [4,4 '] bipyridinyl (1.2.21); 2-cyclohexyl-pyridine (1.2.22); Biphenylene (1.2.23); 3-benzhydryl-pyridine (1.2.24); 2-phenyl-thiazole (1.2.25); 2-phenyl-oxazole (1.2.26); 5-phenyl-pyrimidine (1.2.27); 10H-phenothiazine (1.2.28); 2-phenyl-benzooxazole (1.2.29); 2-phenyl-benzothiazole (1.2.30); 2-phenyl-1H-benzoimidazole (1.2.31); And 10,11-dihydro-5H-dibenzo [b, f] azepine (1.2.32).
[283] For further explanation, it will be understood, for example, that a naphthyl moiety is a limited biaryl moiety as defined above since the fused bicyclic is free of heteroatoms present with a bond between the bridgehead carbon atoms. On the other hand, the quinolinyl moiety is also a fused bicyclic group having a bond between the bridgehead carbon atoms, whereas the nitrogen is not a limited biaryl moiety as defined above because of the presence of a heteroatom, and the definition of a limited biaryl as used herein. It is required that the fused ring system be polycyclic or higher than tricyclic in which heteroatoms are present. Thus, a biphenyl moiety is an example of a discontinuous ring system that may mean Q ² but not Q ¹ .
[284] As used herein, the expression "... a fused or discontinuous polycyclic saturated or unsaturated carbon ring system of 7 to 12 members" refers to norbornane, bicyclo [2.2.2] octanyl, bicyclo [3.2.1] Saturated fused bicyclic and tricyclic carbon ring systems such as octanyl, bicyclo [3.3.0] octanyl, bicyclo [3.3.1] nonanyl, cyclodecanyl and adamantanyl. The expressions cited above also include mono-unsaturated bicyclic and tricyclic carbon ring systems such as norborneneyl, bicyclo [2.2.2] oct-5-enyl and bicyclo [2.2.2] oct-7-enyl; But also aromatic bicyclic and tricyclic carbon ring systems such as naphthylene and biphenylene. The expressions cited above further include aromatic discontinuous bicyclic carbon ring systems such as biphenylene.
[285] The carbon ring system encompassed within the scope of the above-cited expression and also mentioned above may also be substituted by any one carbon atom thereof by a heteroatom selected from N, O or S, and when N is selected, any second thereof Included are residues in which the carbon atom may be substituted by heteroatoms selected from N, O and S. The resulting residues include pyrrolyl; Pyrrolidinyl; Furanyl; Thienyl; Pyridyl; Pyrimidinyl; Piperidinyl; Piperazinyl; Imidazolyl; Imidazolidinyl; Oxazolyl; Isoxazolyl; Thiazolyl; Indolyl; Quinolinyl; Isoquinolinyl; Benzimidazolyl; Benzoxazolyl; Morpholinyl; Quinuclidinyl; And azabicyclo [3.3.0] octanyl.
[286] As used herein for compounds of formula (1.0.0) as well as other formulas and partial formulas associated therewith, wherein at least one nitrogen atom component (s) is represented by [N⇒ (O)], The compound includes any nitrogen oxide form of the nitrogen atom (s). If there are more than one of these nitrogen oxide forms, they are selected independently of each other. In addition, the nitrogen oxide form (s) may also be expressed as "[N⇒ (O) _u ]" where u is 0 or 1.
[287] (i) Embodiments of the present invention provide that Q ¹ is phenyl or pyridyl, ◇◇ Q ² is biphenyl, 3-phenylpyridine, cyclohexyl-benzene, [2,2 '] bipyridinyl, bicyclohexyl, Naphthalene or biphenylene, ◇◇ j is 1, ◇◇ m is 0 or 1, ◇◇ n is 1, ◇◇ Z is partial formulas (1.1.1) to (1.1.3), (1.1 .5), (1.1.6) and (1.1.10) to (1.1.14) is a residue selected from (wherein R ⁷ _A is (a) -H, -CH substituted with 0 to 3 R ¹⁰ ₃ where R ¹⁰ is -F, -CH ₃ substituted with 0 or 1 R ¹⁰ , wherein R ¹⁰ is -CN or -OR ¹⁶ , wherein R ¹⁶ is -CH ₃ or -CH ₂ CH ₃ ) or R ¹⁰ is —NR ¹⁶ R ¹⁷ or —NR ¹⁶ C (═O) R ¹⁷ , wherein R ¹⁶ and R ¹⁷ are —H or —CH ₃ ), (b) cyclopropyl, cyclo Butyl, cyclopentyl or cyclohexyl, or (c) phenyl or benzyl substituted with 0 to 2 R ¹⁰ , wherein R ¹⁰ is —F, —Cl, —CF ₃ , —CH ₃ , —CH ₂ OH, — SCH ₃ , -CN, -NO ₂ , -OR ¹⁶ or -NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ are -H, -CH ₃ or -CH ₂ CH ₃ ), ◇◇ R ⁹ is -H or -CH ₃ ◇◇ W ¹ is -O-, ◇◇ g is 1, W ² is -O- or -CR ²⁹ R ^30- (where R ²⁹ and R ³⁰ are both -H) or g is 0, W ² is therefore absent, ◇◇ Y is = C (R ¹ _a )-, ◇◇ R ¹ _a is -H or -F, and ◇◇ R ^A and R ^B are independently -H or -CH _3, or R ^a and R ^B together are - (C ₃ -C ₇₎ cycloalkyl-spiro moiety and one of the forming and, ◇◇ R ^C and R ^D is -H, the other is -H or CH ₃ , ◇◇ R ¹ and R ² are -H, -F or -OCH ₃ , ◇◇ R ³ is -H or -CH ₃ , ◇◇ R ⁴ , R ⁵ and R ⁶ is -H ( Provided that both R ⁵ and R ⁶ are not simultaneously -H, -F, -Cl, -OCH ₃ , -CN, -NO ₂ , -C (= O) R ³ or -C (= O) OR ³ Wherein R ³ is -CH ₃ or R ⁵ and R ⁶ together form partial formulas (1.3.1), (1.3.2), (1.3.3), (1.3.4), (1.3.11 ), (1.3.12) or (1.3. Compound of formula (1.0.0) forming a residue of 15).
[288] (ii) Preferred embodiments of the type described in the immediately preceding paragraph are those in which Z is a moiety of the partial formula (1.1.1), (1.1.3), (1.1.6) or (1.1.10), and R ⁹ is- H, R ^A and R ^B are both -H, R ^C and R ^D are both -H, R ³ is -H, R ⁴ is -H, and R ⁵ is -H, -F, -Cl , -CN, -OCH ₃ , -C (= O) CH ₃ or -NO ₂ , and R ⁶ is -H (R ⁵ and R ⁶ are not both -H at the same time), or -F or R ⁵ and R ⁶ together form a residue of partial formula (1.3.1), or partial formula (1.3.11), wherein neither R ²³ nor R ²⁴ is present.
[289] (iii) another embodiment of the invention wherein ◇◇ Q ¹ is phenyl or pyridyl, ◇◇ Q ² is biphenyl, 3-phenyl-pyridine, cyclohexyl-benzene, [2,2 '] bipyridinyl, Bicyclohexyl, naphthalene or biphenylene, ◇ ◇ j is 1, ◇ ◇ m is 0 or 1, ◇ ◇ n is 1, and ◇ ◇ Z are partial formulas (1.1.4) and (1.1.7 Is a residue selected from (wherein R ⁷ _B is tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-one-5-yl, Imidazol-2-yl, imidazol-4-yl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazole-5- 1, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, succinimidyl, pyrrolidoneyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl , Pyridyl, pyrazinyl, furanyl, tetrahydrofuranyl, thienyl, indolyl, 2,3-dihydrobenzofuranyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzo tree Azolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,6-naphthyridinyl or 1,8-naphthyridinyl, wherein these modes are independently 0 or 1 R ¹⁴ , wherein , R ¹⁴ is -CH ₃ , -OR ¹⁶ , where R ¹⁶ is -H or -CH ₃ , oxo (= 0) or -C (= 0) OR ¹⁶ , where R ¹⁶ is H or -CH ₃ ), ◇◇ R ⁹ is -H or -CH ₃ , ◇◇ W ¹ is -O-, ◇◇ g is 1, W is -O- or -CR ²⁹ R ^30- (where R ²⁹ and R ³⁰ are both -H) or g is 0, W ² is therefore absent, ◇◇ Y is = C (R ¹ _a )-, and ◇◇ R ¹ _a is -H or -F, ◇◇ R ^A and R ^B are independently -H or -CH _3, or R ^A and R ^B together form a-(C ₃ -C ₇ ) cycloalkyl-spiro moiety, One of R ^C and R ^D is -H, the other is -H or -CH ₃ , and R ¹ and R ² are -H, -F or -OCH ₃ , and ◇◇ R ³ is -H Or -CH ₃ , ◇◇ R ⁴ , R ⁵ and R ⁶ is -H (R ⁵ and R ⁶ are not both -H at the same time), -F, -Cl, -OCH ₃ , -CN, -NO ₂ , -C (= O) R ³ or -C (= O) OR ³ , where R ³ is -CH ₃ or R ⁵ and R ⁶ together form partial formulas (1.3.1), (1.3.2), (1.3.3), (1.3.4), (1.3. 11), (1.3.12) or (1.3.15), to include a compound of formula (1.0.0).
[290] (iv) Preferred embodiments of the type described in the immediately preceding paragraph are those in which R ⁹ is -H, both R ^A and R ^B are -H, both R ^C and R ^D are -H, and R ³ is -H R ⁴ is -H, R ⁵ is -H, -F, -Cl, -CN, -OCH ₃ , -C (= O) CH ₃ or -NO ₂ , and R ⁶ is -H (where R ⁵ and R ⁶ are not each -H at the same time or -F, or R ⁵ and R ⁶ together are partial formula (1.3.1) or partial formula (1.3.11) (where R ²³ and R ²⁴ are not present) Not formed).
[291] (v) Another embodiment of the invention is that Q ¹ is phenyl or pyridyl, ◇◇ Q ² is biphenyl, 3-phenyl-pyridine, cyclohexyl-benzene, [2,2 '] bipyridinyl, bicyclo Hexyl, naphthalene or biphenylene, ◇◇ j is 1, ◇◇ m is 0 or 1, ◇◇ n is 1, ◇◇ Z is phthalimide-1-yl, succinimide-1- 1, pyrrolid-2-one-1-yl, glutarimid-1-yl, piperid-2-one-1-yl, pyrid-2-one-1-yl, imidazolidine-2, 4-dione-1-yl, 4,5-dihydro-5-oxo-1H-tetrazol-1-yl, benzimidazolin-2-one-1-yl, norborn-5-ene-2, 3-dicarboximide-1-yl, imidazolidin-2-one-1-yl, thiazolidin-3-yl, 1H-1,2,3-triazol-1-yl, 1H-1 , 2,4-triazol-1-yl, pyrrolidin-1-yl, tetrazol-1-yl, piperidin-1-yl, piperazin-1-yl, 1H-pyrazolo [4,5 -e] pyridin-7-on-2-yl, 1H-indazol-3-on-2-yl, 1H-benzimidazol-2-one-3-yl or pyrrolo [3,4-b] pyridine Containing -5,7-dione-6-day Minutes, a residue of Formula (1.1.15), ◇◇ and W ¹ is -O-, and ◇◇ g is 1, W ² is -O- or -CR ²⁹ R ³⁰ - (wherein, R ²⁹ and R ³⁰ is All are -H) or g is 0, W ² is therefore absent, ◇◇ Y is = C (R ¹ _a )-, ◇◇ R ¹ _a is -H or -F, and ◇◇ R ^A And R ^B is independently —H or —CH _3, or R ^A and R ^B together form a — (C ₃ -C ₇ ) cycloalkyl-spiro moiety and one of ◇◇ R ^C and R ^D is -H The other is -H or -CH ₃ , ◇◇ R ¹ and R ² are -H, -F or -OCH ₃ , ◇◇ R ³ is -H or -CH ₃ , ◇◇ R ⁴ , R ⁵ and R ⁶ are -H (R ⁵ and R ⁶ are not both -H at the same time), -F, -Cl, -OCH ₃ , -CN, -NO ₂ , -C (= O) R ³ Or -C (= 0) OR ³ , wherein R ³ is -CH ₃ or R ⁵ and R ⁶ together form partial formulas (1.3.1), (1.3.2), (1.3.3), ( 1.3.4), (1.3.11), (1.3.12) or residues of (1.3.15), where R ²³ and R ²⁴ both for partial formulas (1.3.11) and (1.3.12) Is absent) compounds of formula (1.0.0).
[292] (vi) Preferred embodiments of the type described in the preceding paragraph are those in which R ⁹ is -H, both R ^A and R ^B are -H, both R ^C and R ^D are -H, and R ³ is -H And R ⁴ and R ⁵ are both —H and R ⁶ is —F or R ⁵ and R ⁶ together form a moiety of the partial formula (1.3.1) or (1.3.11).
[293] The central nuclear part of the compound of formula (1.0.0) is thiazolyl-, oxazolyl-, pyrrolyl- or imidazolyl-amide of formula (1.0.1) derived from nicotinic acid.
[294]
[295] The central nucleus portion represents the Y moiety as -S (= O) _t -or-[N⇒ (O) _k ] where k is 0 or 1 and the symbol ⇒ (O) is in the form of N-oxide when k is 1 It represents the nitrogen heteroatom in In the case of N-containing heterocyclyl moieties defining R ⁷ _B and R ⁷ _C , optionally one or more N-heteroatom containing heterocyclyl moieties may be in the N-oxide form of the N-heteroatom. . Thus, the above considerations regarding N-oxides also apply to these N-oxide containing residues that define R ⁷ _B and R ⁷ _C.
[296] When Y means-[N⇒ (O) _k ]-, the compound of the present invention is pyrimidine. The pyrimidine groups of the compounds of formula (1.0.0) are a significant part of the scope of the invention. Nevertheless, the compound of formula (1.0.0) does not contain a Y moiety defined by = C (R ¹ _a )-wherein substituent R ¹ _a is independently selected from other substituents forming a compound of formula (1.0.0). It is desirable to have.
[297] = C (R ¹ _a) - moiety of the R ¹ _a is -H addition, -F, -Cl, -CN, -NO 2, - (C 1 -C 4) alkyl, - (C ₂ -C ₄₎ alkynyl carbonyl fluoride, - (C ₁ -C ₃₎ alkyl, fluorinated - (C ₁ -C ₃₎ alkoxy, -OR ^16, and _{^{-C (= O) NR 12 a}} R 12 b ( where, R ¹² _a and R ¹² _b are each independently -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl or cyclopentyl).
[298] It is preferred that the R ¹ _a substituent of = C (R ¹ _a )-moiety means -H, -F, -Cl, -CH ₃ , -OCH ₃ or-(C ₂ -C ₄ ) alkynyl, R More preferably, ¹ _a is -F or -H.
[299] 5.1 Combination (W ^One ) And R ⁴ -, R ⁵ -And R ⁶ -Substituted residue Q ^One
[300] The nicotinamide central nucleus of formula (1.0.0) is characterized in that it forms a bond in the ring comprising the residue Q ¹ at the 2-position carbon atom of the pyridyl or pyrimidinyl ring. In a preferred embodiment, residue Q ¹ is para-substituted by residue R ⁶ , meta-substituted by residue R ⁵ or substituted at any remaining position by residue R ⁴ , giving the partial formula (1.0.3) It means a phenyl ring to form the residue of.
[301]
[302] Where W ¹ is -O-, -S (= O) _t- (where t is 0, 1 or 2) or -N (R ³ )-(where R ³ is -H,-(C ₁ -C ₃ ) alkyl, phenyl, benzyl or -OR ¹⁶ , wherein R ¹⁶ has the same meaning as defined above.
[303] In another embodiment of the present invention, W ¹ is -S (= 0) _t -where t is 0, 1 or 2, and -S- is preferred in which a thioether bond is formed. When the sulfur atom of the thioether bond is oxygenated, a sulfinyl or sulfonyl bond is obtained. In another embodiment, where W ¹ means -N (R ³ )-, an amino bond is formed, and -NH- is preferred. Nevertheless, the nitrogen atom may be substituted, in which case it is preferred that the substituent is -CH ₃ .
[304] R ⁴ , R ⁵ and R ⁶ substituents are selected from the same set of definitions, but it is understood that the above meanings are selected on independent criteria. R ⁵ and R ⁶ may be -H, provided that R ⁵ and R ⁶ are not both -H at the same time. Thus, when the residue Q ¹ means a phenyl ring, the para- (R ⁶ ), meta- (R ⁵ ) or ortho- (R ⁴ ) -position of the phenyl ring is substituted, or all three positions are substituted, Any combination of the above positions may be substituted. However, in the compounds of the formula (1.0.0), it is preferred that para- and / or meta-positions are substituted rather than ortho-positions.
[305] When residue Q ¹ has the preferred meaning of a phenyl ring, R ⁵ and R ⁶ may together form a residue selected from the group of partial formulas described in more detail below. Some of the meanings of R ⁵ and R ⁶ formed together also constitute a preferred embodiment of the compound of formula (1.0.0).
[306] R ⁵ and R ⁶ may be -H, provided that R ⁵ and R ⁶ are not both -H at the same time, and thus the substituents are always present at one or both of the positions bonded by R ⁵ and R ⁶ . R ⁵ and R ⁶ are in addition to -H, in particular, -F, -Cl, -CN, -NO ₂ , -C (= 0) R ¹⁶ , -OR ¹⁶ , -C (= 0) OR ¹⁶ or -NR ¹⁶ R ¹⁷ may be. Preferred embodiments of the invention are obtained when R ⁵ is -H and R ⁶ is -F. In a more preferred embodiment of the invention, R ⁵ and R ⁶ are also —OR ¹⁶ wherein R ¹⁶ is hydrogen, (C ₁ -C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, said alkyl and Cycloalkyl may be substituted with 0 to 3 substituents selected from the group consisting of -F and -Cl). Another preferred embodiment is a compound wherein R ¹⁶ is methyl, difluoromethyl, ethyl or cyclopentyl.
[307] Physicists will recognize that the choice of substituents among the substituents described above depends on the effect that these substituents have on the physico-chemical properties of the entire molecule obtained. The art provides the ability to quickly and easily synthesize a large number of chemically very similar compounds based on the substituent selection described above, thus providing the ability to quickly test the relative effectiveness of the resulting molecules by in vitro assays. Combination synthesis and test procedures currently available in the art have further expanded the number of substituent combinations that can be quickly evaluated. The information obtained using these techniques allows one to reasonably anticipate the specific choices that exist in the various embodiments of the invention. Such preferred embodiments have been described in detail herein.
[308] Preferred embodiments of the invention are those in which both R ⁵ and R ⁶ are -F, R ⁵ is -H, R ⁶ is -F, R ⁶ is -H and R ⁵ is -F, -OR ¹⁶ (e.g. , -OCH _3, -OCH further including ₂ F, -OCHF ₂ or _{-OCF 3), -CN, -COOH,} -COOCH 3, -CONH 2, -OCOCH 3 , or NH ₂ the compound. Most preferred embodiments are those in which R ⁵ is —H, R ⁶ is —F, R ⁵ is —CN, R ⁶ is —H, and R ⁵ is —NO ₂ , —CN, —OCH ₃ or —C (═O ) CH ₃ and R ⁶ is -H.
[309] In addition, R ⁵ and R ⁶ are-(C ₁ -C ₄ ) alkyl and-(C ₁ -C ₄ ) alkoxy, wherein said alkyl and alkoxy are substituted with 0 to 3 substituents -F or -Cl, or 0 Or substituents comprising one substituent (C ₁ -C ₂ ) alkoxycarbonyl-, (C ₁ -C ₂ ) alkylcarbonyl- or (C ₁ -C ₂ ) alkylcarbonyloxy-) Can be selected.
[310] 5.2.0 Q ^One Is phenyl and R ⁵ And R ⁶ Are formed together
[311] When residue Q ¹ has the preferred meaning of a phenyl ring, R ⁵ and R ⁶ may also together form a residue selected from the group consisting of the following partial formulas (1.3.1) to (1.3.15).
[312]
[313] Wherein, R ²⁰ and R ²¹ are each _{-H, -F, -Cl, -CH 3} , -CH 2 F, -CHF 2, -CF 3, -OCH 3 , and are independently selected from the group consisting of -OCF ₃ , R ²³ and R ²⁴ are each independently —H, —CH ₃ , —OCH ₃ , —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₂ CH ₂ CH ₃ , —CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ or absent, dotted line ---- is double Indicates binding. For moieties of partial formula (1.3.13), its nitrogen atom component is represented by-[N (⇒O)]-and therefore includes any nitrogen oxide form of said nitrogen atom selected independently of one another. It is evident that the nitrogen oxide form may be represented by -N (⇒O) _j ]-when j is 0 or 1 as in Formula (1.0.0).
[314] When residue Q ¹ has the preferred meaning of a phenyl ring, and R ⁵ and R ⁶ together form a residue of partial formula (1.3.1), and both R ²⁰ and R ²¹ are hydrogen, together with the attached phenyl group 1, Form 3-benzodioxol groups. Similarly, the structure of partial formula (1.3.2) forms a 1,4-benzodioxane group.
[315] When Q ¹ has the preferred meaning of a phenyl ring, R ⁵ and R ⁶ together form a moiety of the partial formulas (1.3.9) to (1.3.13), in particular when R ²³ and R ²⁴ are defined, Benzofurazane, benzothiofurazane, triazole and other similar groups, as well as substituted derivatives thereof, are formed comprising the following partial formulas (2.1.1) to (2.1.20).
[316]
[317] Here, in partial formulas (2.1.18), (2.1.19) and (2.1.20), the dashed lines ---- denote double bonds in which no oxygen atom is attached to the corresponding nitrogen atom, and the oxygen atom corresponds to the corresponding Represents a single bond attached to a nitrogen atom.
[318] Those skilled in the art of organic molecules manufacturing the partial formula wherein A together are R ⁵ and ^{R 6 (2.1.2), (2.1.3} ), (2.1.7), (2.1.8), (2.1.10), (2.1 .12) and compounds of formula (1.0.0), which form the residues of (2.1.14), exist in tautomeric forms and are provided in the partial formulas (2.1.2), (2.1.3), (2.1.7) It will be appreciated that each residue of, (2.1.8), (2.1.10), (2.1.12) and (2.1.14) will have tautomeric pairs. These tautomers are associated with the migration of hydrogen and one or more π-bonds, and one of ordinary skill in the art will readily be able to identify or determine which tautomeric form is present or most stable, as needed.
[319] Preferred embodiments of the present invention are R ⁵ and R ^{6 together} to form residues selected from the group consisting of the following partial formulas (1.3.1), (1.3.11), (1.3.12) and (1.3.15) Obtained directly from the definition.
[320]
[321] Thus, further residues of the following partial formulas (1.0.15) to (1.0.18) are obtained.
[322]
[323] Wherein R ²³ is -H or -CH ₃ , W ¹ is -O-, -S (= O) _t- (where t is 0, 1 or 2), or -N (R ³ )-( Wherein R ³ is as defined herein, -H or -CH ₃ is preferred). In a preferred compound of formula (1.0.0), W ¹ means —O— which produces an ether bond to attach a benzo-fused bicyclic heterocycle to the central nucleus described above.
[324] In a preferred embodiment of the compound of formula (1.0.0), R ²³ and with the exception of compounds of the type represented by partial formula (1.3.11) where only one of R ²³ or R ²⁴ may not be present R ²⁴ does not exist at all. If neither R ²³ nor R ²⁴ is present, and therefore the dashed line --- represents a double bond, the phenyl portion of the benzo-fused bicyclic heterocycle obtained because the pentavalent carbon atom at the phenyl position is prohibited is It will be appreciated that it may not have all of the double bonds shown in.
[325] Therefore, when neither R ²³ nor R ²⁴ is present, the obtained compound is characterized by the structures shown in the above partial formulas (1.0.16) and (1.0.17).
[326] In another embodiment of the compound of formula (1.0.0), substituents R ²⁰ and R ²¹ on the benzo-fused bicyclic heterocycle represented by the partial formula (1.3.1) are -H, -F, -Cl,- CH ₃ , -CH ₂ F, -CHF ₂ or -CF ₃ . Preferably, R ²⁰ and R ²¹ are both —H or —F, in which case the compound obtained is characterized by the structure represented by the partial formula (1.0.15) or its corresponding difluoro analog (not shown). It is done. Substituents R ²³ and R ²⁴ on the benzo-fused bicyclic heterocycle represented by the moieties of the partial formulas (1.3.9) to (1.3.13) are each independently —H, —CH ₃ , —OCH ₃ or a dotted line— It does not exist if --- represents a double bond. Of course, when R ²³ and R ²⁴ are absent, it will be understood that there are no pentavalent carbon atoms present in the phenyl portion of the benzo-fused bicyclic heterocycle. The resulting benzo-fused bicyclic heterocyclic structures are shown in partial formulas (1.0.15) to (1.0.18) above.
[327] 5.2.1 Q ^One Is not phenyl
[328] In addition to embodiments of the invention wherein Q ¹ has the preferred meaning of phenyl, the invention also relates to saturated or unsaturated carbon ring systems wherein Q ¹ is a 3-7 membered monocyclic or 7-12 membered fused polycyclic. A moiety defined in connection with a compound of formula (1.0.0) having the meaning as defined above as a residue comprising: wherein any one carbon atom of the carbon ring system is substituted with a heteroatom selected from N, O and S And optionally a second carbon atom and more optionally a third carbon atom may be substituted with N. The present invention also relates to the fact that Q ¹ is particularly pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, imidazolyl, imidazolidinyl, oxazolyl, Sazolyl, morpholinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinuclidinyl, azabicyclo [3.3.0] octanyl, monocyclic-( C ₃ -C ₇ ) cycloalkyl moieties, cyclopentenyl, cyclohexenyl and cycloheptenyl monocyclic-(C ₅ -C ₇ ) cycloalkenyl moieties selected from the group consisting of, and norbornanyl, norborn Nenyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.1] octanyl, bicyclo [3.3.0] octanyl, bicyclo [2.2.2] oct-5-enyl, bicyclo [2.2. 2] oct-7-enyl, bicyclo [3.3.1] nonanyl, cyclodecanyl and adamantyl; bicyclic-(C ₇ -C ₁₀ ) cycloalkyl or-(C ₇ -C ₁₀ ) cycloal A compound of formula (1.0.0) comprising a group selected from the group consisting of kenyl moieties.
[329] 5.2.2 Representative subfamily Q ^One Residue
[330] In addition, the present invention specifically selects such that Q ¹ and substituents R ⁴ , R ⁵ and R ⁶ are represented by the following partial formulas (2.0.1) to (2.0.72) at the left end of the compound of formula (1.0.0) It relates to a compound of formula (1.0.0).
[331]
[332]
[333]
[334] 5.3.0 Q ² Residue
[335] Residue Q ² is one of the key forms of the compound of formula (1.0.0) and is referred to as a biaryl moiety. As used herein, the term “biaryl” includes not only conventional biaryl groups such as biphenyl, but also fused, naphthyl- and heteroatom-containing variants, and benzhydryl variants thereof. Thus, the biaryl groups defining residues Q ² are biphenyl (1.2.1), 3-phenyl-pyridine (1.2.2), cyclohexyl-benzene (1.2.3), [2,2 '] bipyridinyl ( 1.2.4), bicyclohexyl (1.2.5), 2-phenylthiophene (1.2.6), 2-phenyl-furan (1.2.7), naphthalene (1.2.8), diphenylmethane (1.2.9 ), 4,5-diphenyl-1H-imidazole (1.2.10), 3-benzyl-pyridine (1.2.11), 4,5-diphenyl-oxazole (1.2.12), fluorene (1.2. 13), 9H-carbazole (1.2.14), phenyl ether (1.2.15); 1H-indole (1.2.16), quinoline (1.2.17), phenanthrene (1.2.18), phenanthridine (1.2.19), [3,3 '] bipyridinyl (1.2.20), [4 , 4 '] bipyridinyl (1.2.21), 2-cyclohexyl-pyridine (1.2.22), biphenylene (1.2.23), 3-benzhydrylpyridine (1.2.24), 2-phenyl- Thiazole (1.2.25), 2-phenyl-oxazole (1.2.26), 5-phenyl-pyrimidine (1.2.27), 10H-phenothiazine (1.2.28), 2-phenyl-benzooxazole (1.2.29), 2-phenylbenzothiazole (1.2.30), 2-phenyl-1H-benzoimidazole (1.2.31) and 10,11-dihydro-5H-dibenzo [b, f] ases Pin (1.2.32). The numbers in parentheses having the above cited meaning of residue Q ² correspond to the structural formulas which can be represented by the following partial formulas (1.2.1) to (1.2.32). It is to be appreciated that the point of attachment at both sides of the nonaryl moiety is depicted nonspecifically such that the partial formula may include modifications within each moiety contemplated by the scope of the present invention.
[336]
[337]
[338] The illustrated group of partial Formula (1.2.1) through (1.2.39) which define the moiety Q ² are optionally R ¹ and R ² (wherein, R ¹ and R ² is a partial formula (1.2 to define the Q ^2. And may appear individually or together in any ring (s) comprising the residues or components of 1) to (1.2.39). R ¹ and R ² are -H, -F, -Cl, -R ¹² , -OR ¹² , -S (= 0) _p R ¹² , -C (= 0) OR ¹² , -OC (= 0) R ¹² , ═O (oxo), —CN, —NO ₂ , —C (═O) NR ¹² R ¹³ , —OC (═O) NR ¹⁵ R ¹² , -NR ¹⁴ C (= 0) NR ¹⁵ R ¹² , -NR ¹⁴ C (= NR ¹⁴ ) NR ¹⁵ R ¹² , -NR ¹⁴ C (= NCN) NR ¹⁵ R ¹² , -NR ¹⁴ C (= N-NO ₂ ) NR ¹⁵ R ¹² , -C (= NR ¹⁴ ) NR ¹⁵ R ¹² , -OC (= NR ¹⁴ ) NR ¹⁵ R ¹² , -OC (= N-NO) ₂ NR ¹⁵ R ¹² , -NR ¹⁵ R ¹² , -CH ₂ NR ¹⁵ R ¹² , -NR ¹⁴ C ( = O) R ¹² , -NR ¹⁴ C (= O) OR ¹² , = NOR ¹² , -NR ¹⁴ S (= O) _p R ¹³ and -S (= O) _p NR ¹² R ¹³ , wherein R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ have the same meaning as defined above).
[339] 5.3.1 Q ² R ^One And R ² For biphenyl substituted by
[340] The left side of the compound of formula (1.0.0) has a nicotinamide nucleus having an ether, thioether or sulfonyl linkage to a substituted phenyl group, while the right side of the compound of formula (1.0.0) has a Q ² substituent R ¹ and Preferred embodiments are preferred, meaning biphenyls substituted with R ² . It is preferred that only one substituent, R ¹ or R ^2, is present in each ring and the biphenyl group is substituted with residues containing substituents R ^A , R ^B and Z at the 4-position. The preferred right side of the compound of formula (1.0.0) can be represented by the following formula (1.0.4).
[341]
[342] When R ¹ and / or R ² is —H, there is preferably no substituent at any position attached to the left part of the molecule of formula (1.0.0). Another preferred embodiment is a compound of the present invention having a substituent at the 2-position of one or both of the phenyl groups, particularly the biphenyl moiety. Thus, in some preferred embodiments of the compounds of the present invention, R ¹ and R ² means -H, -Cl, -F, chlorinated- and / or fluorinated- (C ₁ -C ₃ ) alkyl, chlorinated- And / or fluorinated- (C ₁ -C ₃ ) alkoxy or (C ₂ -C ₄ ) alkynyl.
[343] It is preferable to have a halogen group at the molecular point where the R ¹ and R ² substituents are bonded, because this usually improves the inhibitory activity. R ¹ or R ² comprises -Cl or -F, chlorinated- and / or fluorinated- (C ₁ -C ₃ ) alkyl or chlorinated- and / or fluorinated- (C ₁ -C ₃ ) alkoxy It is believed that small lipophilic groups are within the scope of the present invention.
[344] Accordingly, embodiments of the invention wherein residue Q ² is biphenyl substituted with R ¹ and optionally R ² include residues represented by the following partial formulas (2.6.1) to (2.6.12).
[345]
[346] 5.3.2 Q in Specific Embodiments ²
[347] In addition, the present invention further provides that in particular the Q ² and substituents R ¹ and R ² represent this moiety at the right end of the compound of the formula (1.0.0) with the following partial formulas (3.0.1) to (3.0.29) The compound of formula (1.0.0) is selected in such a way.
[348]
[349]
[350]
[351] 5.4.0 [W ² ] _g Residue
[352] The residue [W ² ] _g in the formula (1.0.0) offers the possibility of ethers, thioethers, amines and carbon-linked derivatives of the compounds of the invention. Thus, when g is 1, W ² is -O-; -S (= 0) _t -where t is 0, 1 or 2; -N (R ³ )-(wherein R ³ is as defined herein) or -CR ²⁹ R ^30- . When W ² has the meaning -N (R ³ )-, R ³ is preferably -H and a simple amino chain output. When W ² has the meaning -S (= O) _t- , t is preferably 0 and a simple thioether chain output. When g is 1, it is most preferable that W ² has the meaning of -O- in which a simple ether chain is produced. When g is 1, W ² represents that R ²⁹ and R ³⁰ are each -H, -F, -CF ₃ ,-(C ₁ -C ₃ ) alkyl,-(C ₃ -C ₆ ) cycloalkyl, phenyl, Benzyl and pyridyl, wherein said alkyl, cycloalkyl, phenyl, benzyl and pyridyl moieties are each independently substituted with 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined herein It also means a carbon residue -CR ²⁹ R ³⁰ -selected from the group consisting of). When W ² has the meaning of —CR ²⁹ R ³⁰ —, it is preferred that both R ²⁹ and R ³⁰ have the meaning of —H in which a simple ether chain is produced.
[353] 5.4.1 R ^A And R ^B Substituent
[354] The group of partial formula (1.0.4) is substituted at the 4-position by a moiety containing substituents Z, R ^A and R ^B which can be represented by the following partial formula (1.1.15).
[355]
[356] Where m is 0, 1, 2 or 3. In a more preferred embodiment of the compounds of the invention, m means 0 or 1. When m is 1, residues-[R ^A -CR ^B ] _m -are present and R ^A and R ^B are each independently selected from the group consisting of -H and (C ₁ -C ₄ ) alkyl. .
[357] In another preferred embodiment of the invention, R ^A and R ^B can form together, but only when m is 1, a spiro moiety of the formula (1.2.0).
[358]
[359] Here, r and s are independently 0 to 4, provided that the sum of r + s is 1 or more and 5 or less, and X ^A is -CH ₂ , -CHR ¹¹ , -C (R ¹¹ ) _2- (wherein Each R ¹¹ is independently selected from each other, each R ¹² has the same meaning as defined herein, -NR ^15- , wherein R ¹⁵ has the same meaning as defined herein, -O- or -S (= 0) _t where t is 0, 1 or 2, the spiro moiety being substituted by any one or more carbon atoms with 0 to 3 substituents R ¹⁴ and a nitrogen atom with 0 or 1 substituent Is substituted with R ¹⁵ and the sulfur atom is substituted with 0 or 2 oxygen atoms. Thus, in particular, residues represented by the partial formulas (1.5.1) to (1.5.12) below are obtained.
[360]
[361] Wherein t is 0, 1 or 2 and R ¹⁴ and R ¹⁵ have the same meaning as defined herein.
[362] Preferred meanings of the R ¹⁴ substituents are -F, -Cl, = O, -OH, -CH ₃ , -CH ₂ OH, -CH (CH ₃ ) OH, -C (CH ₃ ) ₂ 0H, -OCH ₃ ,- C (= O) OH, -C (= O) NH ₂ , -NH ₂ , -NHCH (CH ₃ ) ₂ , -NHC (= O) CH ₃ , -NHC (= O) OCH ₂ CH ₃ , -NHS (= O) ₂ CH ₃ and -S (= O) ₂ NH ₂ , residues such as partial formulas (3.1.1) to (3.1.34) are obtained.
[363]
[364]
[365] 5.4.2 R ^C And R ^D Substituent
[366] As noted above, R ^C and R ^D have the same meanings as defined above for R ^A and R ^B , except that one of them must be -H, and is independently selected from each other and R ^A and R ^B . Thus, all of the specific and preferred embodiments of the compounds of formula (1.0.0) described in detail above for the R ^A and R ^B substituents are also the majority of the compounds of formula (1.0.0) for the R ^C and R ^D substituents. Specific and preferred embodiments.
[367] 5.5 residues-[N (R ³ )] _j -
[368] The subscript j means 0 or 1. When j means 1 (preferably), the residue -N (R ³ )-is present and the compound of formula (1.0.0) is structurally nicotineamide in nature. The nitrogen atom substituent R ³ is preferably selected from -H,-(C ₁ -C ₃ ) alkyl and-(C ₁ -C ₃ ) alkoxy, more preferably -H, -CH ₃ or -OCH ₃ . In the most preferred embodiment of the compound of formula (1.0.0), R ³ means -H.
[369] When Q ¹ has the preferred meaning of phenyl, Q ² has the preferred meaning of biphenyl, and j means 0 (less preferred than when j is 1), residues —N (R ³ ) — are present Rather, the compounds of formula (1.0.0) are structurally essentially nicotinoyl residues, ie ketones. The ketone structure of the compound of formula (1.0.0) is represented by the following formula (1.0.7).
[370]
[371] Wherein all substituents and components, i.e., Z, W ¹ , W ² , Y, g, k, m, n, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A , R ^B , R ^C And the meaning of R ^D is in most cases the same as the specific and preferred meaning described herein in detail where j is 1 and the compound is structurally thiazolyl- and similar amides.
[372] 5.6.0 when Z is a moiety of the partial formulas (1.1.1) to (1.1.15)
[373] Z is selected from the group of residues defined by the partial formulas (1.1.1) to (1.1.15) above. The moieties of the partial formulas (1.1.1) to (1.1.5) defining the Z groups are typically, but not necessarily, heterocyclyl groups that act like acids, amides, and acid and amide mimetics, but of this type It is not limited to a functional group. The moieties of the partial formulas (1.1.6) to (1.1.9) defining the Z groups are usually, but not necessarily, tertiary alcohols and mimetics thereof, in particular similar acyl and nitrile residues, but limited to functional groups of this type It doesn't happen. The moieties of the partial formulas (1.1.10) to (1.1.15) that define the Z group are typically, but not necessarily, reverse amides and mimics thereof, but are not limited to functional groups of this type. Other residues described herein can be used to the right of the compound of formula (1.0.0). Bioisostereic such that compounds of formula (1.0.0) in which these residues contain such residues achieve PDE4 inhibition, in particular those equivalent to those achieved by other residues, especially acid, amide, alcohol and inverse amide residues. to be.
[374] Accordingly, Z is selected from the group of residues defined by partial formulas (1.1.1) to (1.1.15), which residues are R ⁸ , R ⁹ as well as substituents R ⁷ _A , R ⁷ _B and R ⁷ _C , R ¹⁶ and R ¹⁷ , in the case of partial formula (1.1.15) the residue consists of a nitrogen-containing heterocyclic ring system. Portions All residues of formulas (1.1.1) to (1.1.15) are attached to the remainder of formula (1.0.0).
[375] 5.6.1 when Z is a residue of the formula (1.1.1), (1.1.2) or (1.1.3)
[376] Embodiments of the present invention, in which the definition of group Z is shown by the following partial formulas (1.1.1), (1.1.2) and (1.1.3), are as follows.
[377]
[378] One of the preferred residues defining the Z group is the residue of partial formula (1.1.1), wherein R ⁷ _A means -H, which is the preferred meaning of this substituent. In the formula (1.0.0) when R ⁷ is hydrogen and m is 1, 2 or 3, a simple carboxylic acid -COOH is obtained and the group becomes lower alkanoic acid.
[379] R ¹⁰ is any substituent of the residue defining R ⁷ _A , and when present, up to three such substituents may be possible. R ¹⁰ substituents include phenyl or pyridyl, wherein the phenyl or pyridyl is again substituted with up to 3 substituents R ¹¹ (wherein R ¹¹ is —F, —Cl, —CN, —NO ₂ , —OH, — ( C ₁ -C ₃ ) alkoxy, — (C ₁ -C ₃ ) alkyl or —NR ¹⁶ R ¹⁷ ). In a preferred embodiment including such R ¹¹ _{substitution, -F, -Cl, -CH 3,} -OCH 3, -OH, -CN , or -N (CH ₃₎ R ¹¹ substituents, which means the _second one or two exist. 0 or 1 such R ¹¹ substituents are present and, where present, is preferably -F or -Cl. Substituents R ¹⁰ include —F, —Cl, —CF ₃ , oxo (═O), —OR ¹⁶ , —NO ₂ , —CN, —C (═O) OR ¹⁶ , and —OC (═O) R ¹⁶ , -C (= O) NR ¹⁶ R ¹⁷ , -OC (= O) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= O) R ¹⁷ , -NR ¹⁶ C (= O) OR ¹⁷ , -NR ¹⁶ S (= 0) ₂ R ¹⁷ or -S (= 0) ₂ NR ¹⁶ R ¹⁷ is further included.
[380] Sub-substituents R ¹⁶ and R ¹⁷ are -H,-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ ,-(C ₂ -C ₄ ) alkenyl,-(C ₃ -C ₆ ) cycloalkyl , Preferably cyclopropyl, phenyl, benzyl or pyridyl. The alkyl, alkenyl, cycloalkyl, phenyl, benzyl or pyridyl groups are in turn optionally substituted with up to three substituents -F, -Cl or -CN. Among the above additional meanings for R ¹⁰ , if present, the R ¹⁰ substituent is —F, —Cl, —OCH ₃ , —CN, —NO ₂ or —NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ are independently Pyridyl optionally substituted with -H or -CH ₃ , or when present, the R ¹⁰ substituent is -F, -Cl, -CF ₃ , -CN, -NO ₂ , -C (= 0) OR ¹⁶ or- It is preferred that NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ are independently —H or —CH ₃ .
[381] These and other preferred embodiments of compounds of formula (1.0.0) comprising residues of partial formula (1.1.1) based on the preferred meanings of R ⁷ _A and R ⁹ as described above, in particular, 3.5.1) to (3.5.15).
[382]
[383]
[384] Z is a nitrogen atom R ⁹ (wherein R ⁹ is —H, — (C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl, benzyl, -C (= 0) OR ¹⁸ , -C (= O) R ¹⁶ , -OR ¹⁶ ,-(C ₁ -C ₂ ) alkyl-OR ¹⁶ or-(C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁶ , wherein R ¹⁶ is —H or (Which means-(C ₁ -C ₄ ) alkyl)). R ¹⁶ is preferably -H or -CH ₃ .
[385] Accordingly, embodiments of the invention wherein the Z group is represented by the partial formula (1.1.2) can be represented by the following partial formulas (4.1.1) to (4.1.5).
[386]
[387] Said embodiment in which the definition of Z is an amide is represented by the following partial formula (1.1.3).
[388]
[389] These and other preferred embodiments of the compounds of formula (1.0.0) comprising the residues of partial formula (1.1.3) based on the definitions of R ⁷ _A and R ⁹ described above, in particular, the following partial formula (4.5.1) ) To (4.5.20).
[390]
[391] 5.6.2 When Z is a residue of partial formula (1.1.4)
[392] In addition, preferred embodiments of the invention include compounds of formula (1.0.0) wherein the terminal residue Z falls within the scope of the partial formula (1.1.4), ie embodiments of this type are those in which the Z residue is a partial formula If it has the meaning of (1.1.4) it is included in the category of Z residues.
[393]
[394] Wherein R ⁷ _B is tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-one-5-yl, 1,2,3-tria Zol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazolidin-2-one-4-yl, 1,2,4-oxadiazol-3-yl, 1,2 , 4-oxadiazol-5-one-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-one-5-yl, 1,3 , 4-oxadiazolyl, 1,3,4-oxadiazol-2-one-5-yl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, succinimidyl, glutarimidyl, pyrrolido Nyl, 2-piperidonyl, 2-pyridonyl, 4-pyridonyl, pyridazine-3-onyl, pyridazine-3-onyl, thiazolyl, isothiazolyl, thiadiazolyl, morpholinyl, para Thiazinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indolinyl, isoindolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, 1,3-di Hydroisobenzofuranyl, 2H-1-benzopyranyl, 2-H-chromenyl, chromamanyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzox Sazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, phthalazinyl, 1,8-naphthyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolo [3,4-d] pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, imidazo [1,2-a] pyridinyl, pyridopyridinyl, putridinyl and 1H-purinyl Monocyclic or bicyclic heterocyclyl selected from the group consisting of:
[395] The partial formulas (1.1.3) and (1.1.4) are similar, but differences between them should be recognized. The partial formulas (1.1.3) and (1.1.4) are as follows.
[396]
[397] When v is 0, R ⁷ _B is directly linked to the remainder of the compound of formula (1.0.0), so that R ⁷ _A is via the amide bridge residue -C (= 0) NR ^9- (1.0. Partially linked to the remaining portion of the compound of 0) is readily distinguishable from residues of formula (1.1.3). However, when v is 1, both R ⁷ _B and R ⁷ _A residues are linked to the remainder of the compound of formula (1.0.0) via the amide bridge residue -C (= 0) NR ^9- . In this case, the division between partial formula (1.1.3) and (1.1.4) residues includes the difference between the meanings of the R ⁷ _B and R ⁷ _A residues. This difference has already been described in detail above.
[398] To facilitate subsequent descriptions, the monocyclic heterocyclyl moiety and the bicyclic heterocyclyl are treated together first, and then discussed as respective groups.
[399] Any one or more carbon atoms in the phenyl, benzyl or heterocyclyl moiety may be selected from 0 to 3 substituents R ¹⁴ in which R ¹⁴ represents partial formulas (1.1.1), (1.1.2) and (1.1.3). Having the meanings and the preferred meanings described above. It is contemplated to appear only in the case of heterocyclyl moieties and any one or more nitrogen atoms which are not the point of attachment of said heterocyclyl moiety are optionally substituted by up to three substituents R ¹⁵ . Any sulfur atom that appears at the heterocyclyl moiety and is not the point of attachment of the heterocyclyl moiety is substituted with 0, 1 or 2 oxygen atoms.
[400] Optional nitrogen heterocyclyl substituent R ¹⁵ is -H, -NR ¹⁶ R ^17- , -C (= 0) R ¹⁶ , -OR ¹⁶ , preferably -OCH ₃ ,-(C ₁ -C ₄ ) alkyl- OR ¹⁶ , -C (= 0) OR ¹⁶ ,-(C ₁ -C ₂ ) alkyl-C (= 0) OR ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ ,-(C ₁ -C ₄ ) alkyl , Preferably -CH ₃ ,-(C ₂ -C ₄ ) alkenyl,-(CH ₂ ) _u- (C ₃ -C ₇ ) cycloalkyl, where u is 0, 1 or 2, preferably Includes cyclopropyl, phenyl, benzyl, pyridyl or quinolinyl. The alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, pyridyl and quinolinyl groups included are optionally substituted by up to two substituents R ¹² .
[401] Sub-substituents R ¹² are —F, —Cl, —CO ₂ R ¹⁸ , —OR ¹⁶ , —CN, —C (═O) NR ¹⁸ R ¹⁹ , —NR ¹⁸ R ¹⁹ , —NR ¹⁸ C (═O) R ¹⁹ , -NR ¹⁸ C (= 0) OR ¹⁹ , -NR ¹⁸ S (= 0) _p R ¹⁹ , -S (= 0) _p NR ¹⁸ R ¹⁹ , wherein p is 1 or 2, preferably 2),-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ , and-(C ₁ -C ₄ ) alkoxy, wherein R ¹² has the meaning of -OR ¹⁶ and R ¹⁶ Is defined as-(C ₁ -C ₄ ) alkyl, and R ¹² is preferably -OCH ₃ (wherein said alkyl and alkoxy again have up to three substituents -F, -Cl,-(C ₁ -C ₂₎ ) Alkoxycarbonyl,-(C ₁ -C ₂ ) alkylcarbonyl and-(C ₁ -C ₂ ) alkylcarbonyloxy). R ¹⁸ and R ¹⁹ substituents are independently selected from —H, — (C ₁ -C ₂ ) alkyl, preferably —CH ₃ or phenyl, optionally substituted with up to 3 —F or —Cl.
[402] As the general formula (1.4.1), part of the less well to (1.4.20), the R ⁹ substituent does not appear, this R ⁹ substituent is attached to the heterocyclic because only attached nitrogen atom that does not form the essential component of the click residue to be. R ⁹ substituents are optional in the symbols where “-H” is included in the definition of R ⁹ substituents, and in many embodiments of the compound of formula (1.0.0), -H is the preferred meaning of R ⁹ . Another preferred meaning of R ⁹ is -CH ₃ .
[403] The difference between the substituents R ⁹ and R ¹⁵ , all attached only to the nitrogen atom in any sense of the residue Z, is also pointed out. Substituent R ¹⁵ refers to the more specific heterocyclic moieties of the partial formulas (1.4.1) to (1.4.20) represented above and below, in particular through the R ⁷ _B substituents of partial formula (1.1.4) It is attached only to a nitrogen atom which is an essential component of any heterocyclic moiety which can be defined as. On the other hand, the substituent R ⁹ is attached only to nitrogen but only to nitrogen atoms which are not an essential component of any heterocyclic residues defined by partial formulas (1.1.2), (1.1.3) and (1.1.5). R ¹⁵ substituents may be attached to one or more nitrogen atoms, which nitrogen atoms fall within any of the categories of partial formula (1.1.4) which may be characterized as containing or comprising nitrogen-containing heterocyclic moieties. May be present at the residue.
[404] As examples of preferred subgroup embodiments of the invention in which the Z group has the meaning of residues falling within the scope of the partial formula (1.1.4), the groups of the partial formulas (1.4.1) to (1.4.28) are described below.
[405]
[406]
[407] To describe differently preferred embodiments of the compound of formula (1.0.0) with reference to the Z group which is a residue of partial formula (1.1.4), v is 0 or 1 and R ⁷ _B is a monocyclic heterocyclic group For this purpose, the group consisting of partial formulas (4.8.1) to (4.8.80) in which the Z moiety is selected in this preferred embodiment is described below.
[408]
[409]
[410]
[411]
[412] In addition, preferred embodiments of the invention wherein the Z group is a moiety of the partial formula (1.1.4) and v is 0 or 1 are preferred, the residues R ⁷ _B are indolyl, indolinyl, isoindolinyl, benzo [b] furanyl , 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2H-1-benzopyranyl, 2H-chromenyl, chromanyl, benzothienyl, 1H-indazolyl, benzimida Zolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, phthalazinyl, 1,8-naphthyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl , Pyrazolo [3,4-d] pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, imidazo [1,2-a] pyridinyl, pyridopyridinyl, pterridinyl and 1H- Compound containing a bicyclic heterocyclic group selected from the group consisting of furinyl.
[413] Particularly preferred embodiments of compounds of formula (1.0.0) are residues of formula (1.1.4), v is 0 or 1, R ⁷ _B is a bicyclic heterocyclic group and group Z is referenced To this end, the group consisting of partial formulas (5.0.1) to (5.0.28), all tautomeric forms and optionally their N-oxide forms, in which the Z moiety is selected in this preferred embodiment, is described below.
[414]
[415]
[416] Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted by substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ have the same meaning as defined above .
[417] 5.6.3 when Z is a residue of partial formula (1.1.5)
[418] There is another embodiment of a compound of Formula (1.0.0) wherein the Z moiety comprises a group falling within the scope of the partial formula (1.1.5) below.
[419]
[420] Wherein q is 1, 2 or 3, provided that when q is 2 or 3, R ⁹ means -H in at least one or two cases, respectively, and W ³ is -O-, -N (R ⁹ )-or -OC (= O)-, wherein R ⁹ has the same meaning as defined above and R ⁷ has the same meaning as defined above.
[421] In a preferred embodiment of the compound of partial formula (1.1.5), q is 1 or 2, R ⁹ is -H or -CH ₃ and W ³ is -O-, -O (C = 0)-or- NH-, and R ⁷ _A is one of the preferred residues described above.
[422] Exemplary embodiments of compounds of formula (1.0.0) in which the Z residues fall within the scope of partial formula (1.1.5) are represented by the following partial formulas (6.0.1) to (6.0.6).
[423]
[424] 5.6.4 When Z is not a carboxylic acid
[425] Embodiments of compounds of Formula (1.0.0) include those wherein the Z moiety is not a carboxylic acid, but instead is phosphorus or sulfuric acid or a derivative thereof. There are a number of such derivatives from which Z residues can be selected, for example: -OP (= 0) (OH) ₂ (phosphoric), -PH (= 0) OH (phosphonic), -P _{(= O) (OH) 2} ( phosphonic sulphonic), - [P (= O ) (OH) -O (C 1 -C 4) alkyl] (phosphono alkyl), -P (= O) ( OH) - O (C ₁ -C ₄ ) alkyl (alkylphosphinyl), -P (= O) (OH) NH ₂ (phosphoramido), -P (= O) (OH) NH (C ₁ -C ₄ ) Alkyl and -P (= 0) (OH) NHR ²⁵ (substituted phosphoramido), -OS (= 0) ₂ OH (sulfuric), -S (= 0) ₂ OH (sulphonic), -S ( = O) ₂ NHR ²⁶ or -NHS (= O) ₂ R ²⁶ (sulfonamido), wherein R ²⁶ is -CH ₃ , -CF ₃ or o-toluyl, and -C (= 0) NHS ( = O) ₂ R ²⁵ , -C (= O) NHS (= O) ₂ NH ₂ , -C (= O) NHS (= O) ₂ (C ₁ -C ₄ ) alkyl, -C (= O) NHS _{(= O) 2 NH (C} 1 -C 4) alkyl, -C (= O) NHS ( = O) 2 N [(C 1 -C 4) _{alkyl] 2, -S (= O)} 2 NHC (= O) (C ₁ -C _{4) alkyl, -S (= O) 2 NHC} (= O) NH 2, -S (= O) 2 NHC (= O) NH (C 1 -C 4) alkyl, -S _{(= O) 2 NHC (=} O) N [(C 1 -C 4) _{alkyl] 2, -S (= O)} 2 NHC (= O) R 25, -S (= O) 2 NHCN, -S ( = 0) ₂ NHC (= S) NH ₂ , -S (= O) ₂ NHC (= S) NH (C ₁ -C ₄ ) alkyl, -S (= O) ₂ NHC ( _{= S) N [(C 1} -C 4) _alkyl] and _{-S (= O) 2 NHS (} = O) 2 R 25 ( wherein, R ²⁵ is _{-H, - (C 1 -C 4} ) alkyl, Phenyl or -OR ¹⁶ , and R ¹⁶ has the same meaning as defined above.
[426] Preferred embodiments of compounds of formula (1.0.0) wherein Z is phosphoric acid or sulfuric acid or derivatives thereof, wherein Z is -P (= 0) (OH) NHR ²⁵ (substituted phosphoramido), -S (= 0) ₂ NHR ²⁶ or —NHS (═O) ₂ R ²⁶ (sulfonamido), or —C (═O) NHS (═O) ₂ R ²⁵ (acylsulfonamido), wherein R ²⁶ and R ²⁵ are defined above Having the same meaning as the above). Some of these preferred embodiments can be represented by the following partial formulas (6.5.1) to (6.5.9).
[427]
[428] 5.6.5 when Z is a moiety of the partial formulas (1.1.6) to (1.1.9)
[429] In another embodiment of the compound of Formula (1.0.0), the terminal group Z is a moiety selected from the group consisting of partial formulas (1.1.6), (1.1.7), (1.1.8) and (1.1.9) to be.
[430]
[431] Wherein "*" indicates the point of attachment of the residue of the partial formula (1.1.6), (1.1.7), (1.1.8) or (1.1.9) to the remaining portion of the compound of formula (1.0.0) Display; Both R ⁷ _A and R ⁷ _B have the same meaning as described above. R ¹⁶ and R ¹⁷ also have the same meaning as described above, ie each is —H, — (C ₁ -C ₄ ) alkyl, — (C ₂ -C ₄ ) alkenyl, — (C ₃ -C ₆ Cycloalkyl, phenyl, benzyl and pyridyl, wherein the alkyl, alkenyl, cycloalkyl, phenyl, benzyl or pyridyl is -F, -Cl, -CF ₃ , -CN and-(C ₁ -C ₃ ) Independently substituted from 0 to 3 substituents selected from the group consisting of alkyl).
[432] In order to further explain the meaning of Z in the categories of partial formulas (1.1.6), (1.1.7), (1.1.8) and (1.1.9), Residues of partial formulas (3.3.1) to (3.3.15) that represent meanings are shown below.
[433]
[434] Another meaning of Z is within the scope of partial formula (1.1.9) in which the hydroxyl group of the partial formula (1.1.8) has been replaced by the nitrile group -C≡N. Therefore, the residues of the partial formulas (3.8.1) to (3.8.10) showing different meanings falling within the scope of the partial formula (1.1.9) are shown below.
[435]
[436] To illustrate the additional meaning of Z falling within the categories of partial formulas (1.1.6), (1.1.7), (1.1.8) and (1.1.9), it is within the scope of partial formulas (1.1.6). Residues of partial formulas (3.9.1) to (3.9.9) with different meanings are indicated below.
[437]
[438] Wherein R ⁷ _A is —H substituted with 0 to 3 substituents R ¹⁰ ; - (C ₁ -C ₆₎ alkyl; -(C ₂ -C ₆ ) alkenyl; Or-(C ₂ -C ₆ ) alkynyl. Preferably, R ⁷ _A is -H. R ⁷ _A is 3 -F or 1 R ¹⁰ , wherein R ¹⁰ is preferably -F; -Cl; -CF ₃ ; -NO ₂ ; -CN; -C (= 0) NR ¹⁶ R ¹⁷ ; Or-(C ₁ -C ₄ ) alkyl unsubstituted or substituted with —NR ¹⁶ R ¹⁷ . R ⁷ _A is — (CH ₂ ) _u — (C ₃ -C ₇ ) cycloalkyl substituted with 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined above, wherein u is 0, 1 or 2). R ⁷ _A is further selected from phenyl or benzyl substituted with 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined above.
[439] Thus, preferred embodiments of Z falling within the range of partial formula (1.1.6) are shown in partial formulas (3.9.1) to (3.9.9).
[440]
[441] 5.6.6 When Z is a residue of partial formulas (1.1.10) to (1.1.15)
[442] Z is also selected from the group of residues defined by the partial formulas (1.1.10) to (1.1.15) above. The meaning of Z in the moieties of the partial formulas (1.1.10) to (1.1.14) means that the linking group comprising the remaining moieties of the partial formulas (1.1.10) to (1.1.14) can be terminated. 1.0.0) consisting of terminal R ⁷ _C groups attached to the remainder. The meaning of R ⁷ _C is in turn selected independently from the group consisting of the meanings of R ⁷ _A and meanings of R ⁷ _B as defined above.
[443] The linking group of the partial formula (1.1.10) includes an inverse amide structure, which may be represented by carbamoyl or the formula —N (R ⁹ ) —C (═O) — (read from left to right). In the sense of substituent R ⁹ , -H is the most abundant, and the reverse amide linkage can be represented by -NHC (= O)-(read from left to right). Thus, when Z means partial formula (1.1.10), the preferred embodiment of the compound of formula (1.0.0) has the right end as follows: —NHC (═O) —R ⁷ _C.
[444] Z may also be selected as the residue defined by partial formula (1.1.11). When the substituent R ⁹ appearing at all means preferably -H, the resulting embodiment of the compound of formula (1.0.0) has the right end as follows: NHC (= 0) NH-R ⁷ _C. Similarly, when Z is selected as the residue defined by partial formula (1.1.11) and the substituent R ⁹ means -H, the resulting embodiment of the compound of formula (1.0.0) Has: -NHC (= O) OR ⁷ _C.
[445] In addition, Z may be selected as the residue defined by partial formula (1.1.13) or (1.1.14), and when substituent R ⁹ has the preferred meaning of -H, the practice of obtaining a compound of formula (1.0.0) The embodiment has the right end as follows: —NHS (═O) ₂ —R ⁷ _C and —NH—R ⁷ _C. However, the meaning of Z as defined by partial formulas (1.1.13) and (1.1.14) is as significant as the meaning of Z as defined by partial formulas (1.1.10) and (1.1.11), and sometimes (1.1.12). Not preferred.
[446] Finally, Z may be selected as the residue defined by partial formula (1.1.6) in which the nitrogen atom of the heterocycle is attached by direct bond to the remainder of the compound of formula (1.0.0). In some preferred embodiments, the carbon atom of the nitrogen-containing heterocycle in α position relative to the nitrogen atom may be carbonylated, ie, oxo (═O) substituted. The most preferred meaning of Z in the compound of formula (1.0.0) is defined by the partial formulas (1.1.1), (1.1.10) and (1.1.15).
[447] 5.6.7 when Z is a residue of the formulas (1.1.10) to (1.1.14)
[448] Embodiments of the invention wherein the definition of the group Z are shown by the partial formulas (1.1.10), (1.1.11), (1.1.12), (1.1.13) and (1.1.14) are as follows.
[449]
[450] One of the many preferred residues defining the Z group is that R ⁷ _C is-(C ₁ -C ₄ ) alkyl, preferably methyl, ethyl, n-propyl, iso-propyl or tert-butyl, cyclo (C ₃ -C ₆ ) alkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl (all of which are attached directly or through a methylene bridge), phenyl, benzyl or heterocycle, preferably pyrrolyl, pyrrolidinyl, Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxdiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, indazolyl, indolyl, isoindoleyl, benzimidazolyl, A moiety of partial formula (1.1.10) meaning benzisoxazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl or quinazolinyl.
[451] R ⁹ is a substituent which appears at each of the Z residues represented by the partial formulas (1.1.10), (1.1.11), (1.1.12), (1.1.13) and (1.1.14). R ⁹ is —H, — (C ₁ -C ₄ ) alkyl, preferably methyl, — (C ₃ -C ₇ ) cycloalkyl, preferably cyclopropyl or cyclopentyl, phenyl, benzyl, pyridyl, -OR ¹⁸ ,-(C ₁ -C ₂ ) alkyl-OR ¹⁸ and-(C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁸ , wherein R ¹⁸ is —H or — (C ₁ -C ₄ ) alkyl Mean). R ¹⁸ is preferably -H or -CH ₃ .
[452] R ¹⁰ is any substituent of the above preferred moiety defining R ⁷ _C , and where present, up to three such substituents may be present. The meaning of the R ¹⁰ substituent includes phenyl or pyridyl, wherein the phenyl or pyridyl may again contain up to 3 substituents R ¹² (wherein R ¹² is —F, —Cl, —CN, —NO ₂ , —OH, - is optionally substituted with (C ₁ -C ₃₎ alkyl or -NR ¹⁶ R ¹⁷ Im) - (C ₁ -C ₃₎ alkoxy. In a preferred embodiment comprising such a R ¹² substituent, one or two substituents R ¹² , meaning —F, —Cl, —CH ₃ , —OCH ₃ , —OH, —CN or —N (CH ₃ ) ₂ , are exist. Substituents for R ¹⁰ substituents include: -F, -Cl, -CF ₃ , oxo (= O), -OR ¹⁶ , -NO ₂ , -CN, -C (= O) OR ¹⁶ , -0-C (= O ) R ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0 ) OR ¹⁷ , -NR ¹⁶ S (= 0) ₂ R ¹⁷ or -S (= 0) ₂ NR ¹⁶ R ¹⁷ is further included. The meaning of the R ¹⁰ substituents from -F, -Cl, -CF _3, oxo (= O), -OH, -OCH 3, -NO 2, -CN, -C (= O) OH, -C (= O Preference is given to) NH ₂ , -NH ₂ , -N (CH ₃ ) ₂ or -NHS (= 0) ₂ CH ₃ .
[453] Sub-substituents R ¹⁶ and R ¹⁷ are -H,-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ ,-(C ₂ -C ₄ ) alkenyl,-(C ₃ -C ₆ ) cycloalkyl , Preferably cyclopropyl, phenyl, benzyl or pyridyl. The alkyl, alkenyl, cycloalkyl, phenyl, benzyl or pyridyl groups are again optionally substituted with up to three -F, -Cl or -CN.
[454] As an example of a preferred bifamily embodiment of the invention wherein the Z group represents a moiety of the partial formulas (1.1.10) to (1.1.14), R ⁷ _C of the partial formulas (7.0.1) to (7.0.39) As defined, o-toluyl, cycloalkyl, phenyl, benzyl and monocyclic heterocyclic groups of the preferred meaning of R ⁷ _C in the sulfonamide residues of partial formula (1.1.12), all tautomeric forms or optionally The N-oxide form is described below.
[455]
[456]
[457]
[458] Where "*" indicates the point of attachment of the partial formulas (7.0.1) to (7.0.41) to the remainder of each formula (1.0.0), and the partial formulas (7.0.1) to (7.0.38) ) each of the carbon atoms are optionally substituted by the substituents R ^14, R ¹⁴ and R ¹⁵ the have the same meaning as defined above.
[459] R ⁹ substituents do not appear in the partial formulas (7.0.1) to (7.0.41) because they are attached only to a nitrogen atom which does not form an essential component of the heterocyclic moiety to which the R ⁹ substituent is attached. The R ⁹ substituents are optional to the symbols containing "-H" in the definition of R ⁹ substituents, and in many embodiments of the compound of formula (1.0.0) -H is the preferred meaning of R ⁹ . Another preferred meaning of R ⁹ is -CH ₃ .
[460] The difference between the substituents R ⁹ and R ¹⁵ , all attached only to the nitrogen atom in any sense of the residue Z, is also pointed out. Substituent R ¹⁵ is substituted via the R ⁷ _C substituents of partial formulas (1.1.10) to (1.1.14), in particular, more specific heteros of partial formulas (7.0.1) to (7.0.28) and (7.0.31) It is attached only to a nitrogen atom which is an essential component of any heterocyclic moiety that can be defined with reference to a cyclyl moiety. On the other hand, the substituent R ⁹ is attached to nitrogen but only to a nitrogen atom which is not an essential component of any heterocyclic moiety defined by partial formulas (1.1.10) to (1.1.14). R ¹⁵ substituents may be attached to one or more nitrogen atoms, wherein the nitrogen atoms contain partial formulas (1.1.10) to (1.1.14) which may be characterized as containing or comprising nitrogen-containing heterocyclic moieties. It may be present at any residue within the scope of.
[461] Preferred embodiments of the invention wherein the Z group is a moiety of the partial formulas (1.1.10) to (1.1.14) also include residues R ⁷ _C are indolyl, indolinyl, isoindolinyl, benzo [b] furanyl, 2 , 3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2H-1-benzopyranyl, chromanyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzi Soxazolyl, benzothiazolyl, benzotriazolyl, phthalazinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolo [3,4-d] pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, imidazo [1,2-a] pyridinyl, pyridopyridinyl, putridinyl and 1H-purinyl Compound comprising a bicyclic heterocyclic group selected from the group consisting of:
[462] To further describe a preferred embodiment of the compound of formula (1.0.0) with reference to the Z group, which is a moiety of the partial formulas (1.1.10) to (1.1.14), wherein R ⁷ _C is a bicyclic heterocyclic group, The group consisting of partial formulas (7.5.1) to (7.5.29), all tautomeric forms and optionally their N-oxide forms, wherein the Z moiety is selected in this preferred embodiment, is described below.
[463]
[464]
[465] Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted by substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ have the same meaning as defined above .
[466] 5.6.8 Z is a residue of partial formula (1.1.15)
[467] Preferred embodiments of the invention also include compounds of formula (1.0.0) in which the terminal residue Z falls within the scope of partial formula (1.1.15), ie embodiments of this type are described in partial formula (1.1.15) If included in the category of Z residues.
[468]
[469] When the terminal residue Z is defined by the partial formula (1.1.15), it is understood to include inherently nitrogen-containing heterocyclic groups. Any one or more carbon atoms of the heterocyclic group is substituted with 0 to 3 substituents R ¹⁴ . Accordingly, R ¹⁴ is any one or more of the carbon atoms of the moieties falling within the scope of the partial formula (1.1.6), up to three arbitrary substituents in total. The R ¹⁴ substituent is-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ ,-(C ₃ -C ₇ ) cycloalkyl, preferably cyclopropyl, phenyl, benzyl, pyridyl or quinolinyl Wherein said alkyl, cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl moiety is again substituted with one or two substituents -F, -Cl, -CH ₃ , -OCH ₃ , -OR ¹⁶ , -CN or- Substituted with NR ¹⁶ R ¹⁷ . In a preferred embodiment, R ¹⁶ and R ¹⁷ are independently -H or -CH ₃ . When R ¹⁴ is substituted, it is preferable that the substituent is -F or -Cl. R ¹⁴ substituents are -F, -Cl, -CF ₃ , oxo (= O), -OR ¹⁶ , -CN, -NO ₂ , -C (= O) OR ¹⁶ , -OC (= O) R ¹⁶ ,- C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0) OR ¹⁷ ,- NR ¹⁶ S (= 0) ₂ R ¹⁷ or -S (= 0) ₂ NR ¹⁶ R ¹⁷ . In addition to these preferred embodiments above, when R ¹⁴ is present it is also preferred to mean -F, -Cl, -CF ₃ , -OCH ₃ , -CN or -NO ₂ .
[470] Any one or more nitrogen atoms included in the nitrogen-containing heterocyclic group are included within the scope of the partial formula (1.1.15), provided that the nitrogen atom is not at the point of attachment of the heterocyclic group and is no more than three Optionally substituted by substituent R ¹⁵ . Any sulfur atom that is present in the heterocyclic group, provided that it is not the point of attachment of the heterocyclic group is substituted with 0, 1 or 2 oxygen atoms.
[471] Optional nitrogen heterocyclyl substituent R ¹⁵ is -H, -C (= 0) OR ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ ,-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ , -(C ₂ -C ₄ ) alkenyl,-(C ₁ -C ₂ ) alkoxy, preferably -OCH ₃ ,-(C ₃ -C ₇ ) cycloalkyl, preferably cyclopropyl, phenyl or benzyl Wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl or benzyl is optionally substituted with up to two substituents R ¹¹ .
[472] Sub-substituent R ¹¹ is —F, —Cl, —CO ₂ R ¹⁸ , —OR ¹⁶ , —CN, —C (═O) NR ¹⁸ R ¹⁹ , —NR ¹⁸ R ¹⁹ , —NR ¹⁸ C (═O) R ¹⁹ , -NR ¹⁸ C (= 0) OR ¹⁹ , -NR ¹⁸ S (= 0) _p R ¹⁹ , -S (= 0) _p NR ¹⁸ R ¹⁹ , wherein p is 1 or 2, preferably 2 ),-(C ₁ -C ₄ ) alkyl, preferably -CH ₃ and-(C ₁ -C ₄ ) alkoxy, wherein R ¹¹ has the meaning -OR ¹⁶ and R ¹⁶ is- (C ₁ -C ₄ ) alkyl, preferably -OCH ₃ , wherein alkyl and alkoxy are again up to 3 substituents -F, -Cl,-(C ₁ -C ₂ ) alkoxycarbonyl,-( Optionally substituted with C ₁ -C ₂ ) alkylcarbonyl and-(C ₁ -C ₂ ) alkoxycarbonyloxy. R ¹⁸ and R ¹⁹ substituents include -H, or-(C ₁ -C ₂ ) alkyl optionally substituted with up to 3 -F or -Cl, preferably -CH ₃ .
[473] In addition, the present invention provides that at least one terminal is represented by the number and position of the carbon atoms and their substitution by one or more heteroatoms, as well as by R ¹⁴ where R ¹⁴ is oxo (═O). Wherein the substitution of said carbon atom means a residue of partial formula (1.1.15) wherein Z is selected from the group consisting of the following partial formulas (1.7.1) to (1.7.46): It relates to a compound of 0).
[474]
[475]
[476]
[477] Any residue selected from the group consisting of the partial formulas (1.7.1) to (1.7.46) described above is optionally selected from (1) substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above. At least one carbon atom of; (2) any one or more nitrogen atoms, all tautomeric forms, and optionally their N-oxide forms, following the substituents R ¹⁵ , where R ¹⁵ has the same meaning as defined above; Or (3) any substitution thereof for any sulfur atom by zero, one or two oxygen atoms.
[478] The present invention provides a moiety wherein R ⁷ _C and R ⁹ of the partial formulas (1.1.10) to (1.1.15) are both moieties wherein Z is selected from the group consisting of Further preferred are described in terms of preferred subgroups comprising compounds of formula (1.0.0), which are selected to include.
[479]
[480]
[481]
[482]
[483]
[484]
[485]
[486] Any residue selected from the group consisting of the partial formulas (8.0.1) to (8.0.139) described above is optionally selected from (1) substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above. At least one carbon atom of; (2) any one or more nitrogen atoms, all tautomeric forms, and optionally N-oxides thereof, by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined above; Or (3) any substitution thereof for any sulfur atom by zero, one or two oxygen atoms.
[487] 5.7 Representative Species of Formula (1.0.0)
[488] In the above, various preferred aspects of the compounds of formula (1.0.0) have been described. For further explanation of the scope and spirit of the present invention, specific compounds are listed, including embodiments of compounds of Formula (1.0.0). Such species of formula (1.0.0) include, but are not limited to, compounds of formulas (8.5.1) to (8.5.28).
[489]
[490]
[491]
[492]
[493]
[494]
[495]
[496]
[497] Detailed description of the invention
[498] 6.0 Method of Preparation of Compound of Formula (1.0.0)
[499] A suitable method for preparing the right part of the compound of the formula (1.0.0) wherein the Q ² group is a biphenyl moiety of the partial formula (1.2.1) and the Z group is the carboxyl residue of the partial formula (1.1.1) is shown in the following scheme. (10.0.0).
[500]
[501] The left part of the compound of formula (1.0.0) is subjected to amide coupling of a suitably substituted phenoxy-, phenylthio- or phenylsulfonyl-nicotinic acid to the right moiety prepared as described above, followed by formula (10.0.5). Prepared by converting the intermediate of) into the corresponding amine. These steps are carried out according to the following scheme (10.1.0).
[502]
[503] If the compound of the formula (1.0.0) is prepared according to the schemes (1.0.0) and (10.1.0) described above, further embodiments of the compound of the formula (1.0.0) are suitable for the Z group when the Z group is a carboxyl group It can be prepared by the reaction.
[504] Detailed description of the invention
[505] 7.0 Pharmaceutical Salts and Other Forms
[506] The above-mentioned compounds of the present invention may be used in the form of acids, esters, or other chemical classes of compounds to which the described compounds belong. It is also within the scope of the present invention to use these compounds in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to methods known in the art.
[507] Pharmaceutically acceptable salt forms of the compounds of formula (1.0.0) are prepared by most conventional means. If the compound of formula (1.0.0) comprises a carboxylic acid group, suitable salts thereof can be formed by reacting the compound with the appropriate base to provide the corresponding base addition salt. Examples of such bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide, alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide, alkali metal alkoxides such as potassium ethanolate and sodium propanolate, and piperidine, diethanol Various organic bases such as amines and N-methylglutamine. Also included are aluminum salts of compounds of formula (1.0.0).
[508] For certain compounds of formula (1.0.0), acid addition salts can be used to form pharmaceutically acceptable organic and inorganic acids, for example hydrohalides such as hydrochloride, hydrobromide, hydroiodide, other minerals and alcohols. Their corresponding salts such as pate, nitrate, phosphate and the like, and alkyl- and mono-arylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and acetates, tartrates, maleates, It can be formed by treatment with their corresponding salts such as succinate, citrate, benzoate, salicylate ascorbate and the like.
[509] Thus, pharmaceutically acceptable acid addition salts of compounds of formula (1.0.0) include acetates, adipates, alginates, arginates, aspartates, benzoates, benzenesulfonates (vesylates), bisulfates, bisulfates Fight, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate Ethanesulfonate, fumarate, galactate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, Heptanoate, Hexanoate, Hyporate, Hydrochloride, Hydrobromide, Hydroiodide, 2-hydroxyethanesulfo Yate, iodide, isethionate, iso-butyrate, lactate, lactobionate, maleate, maleate, malonate, mandelate, metaphosphate methanesulfonate, methylbenzoate, monohydrogenphosphate, 2- Naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate Do not.
[510] Base salts of the compounds of the invention also include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium and zinc salts. It doesn't work. Preferred among the salts listed above are ammonium, alkali metal salts sodium and potassium, and alkaline earth metal salts calcium and magnesium. Salts of compounds of formula (1.0.0) derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ions. Exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzatin), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol , 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -Methylamine (trometamine) included However, it is not limited to this.
[511] Compounds of the invention comprising basic nitrogen containing groups include (C ₁ -C ₄ ) alkyl halides such as methyl, ethyl, iso-propyl and tert-butyl chloride, bromide and iodide; Di (C ₁ -C ₄ ) alkyl sulfates such as dimethyl, diethyl and diamyl sulfates, (C ₁₀ -C ₁₈ ) alkyl halides such as decyl, dodecyl, lauryl, myristyl and ste Aryl chlorides, bromide and iodide; And aryl- (C ₁ -C ₄ ) alkyl halides such as benzyl chloride and phenethyl bromide. Such salts allow the preparation of both water soluble and fat soluble compounds of the invention.
[512] Among the preferred pharmaceutical salts listed above are acetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hypofulate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate Ates, phosphonates, pivalates, sodium phosphates, stearates, sulfates, sulfosalicylates, tartrates, thiomalates, tosylate and trometamines.
[513] Acid addition salts of basic compounds of formula (1.0.0) are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base can be regenerated by contacting the salt form with the base and isolating the free base in a conventional manner. The free base forms differ somewhat in their respective salt forms and in certain physical properties such as solubility in polar solvents, but in other respects the salts are equivalent to their respective free base forms for the purposes of the present invention.
[514] As pointed out, pharmaceutically acceptable base addition salts of compounds of formula (1.0.0) are formed with metals or amines, for example alkali metals and alkaline earth metals, or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
[515] Base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid form in a conventional manner. The free acid forms differ somewhat in their respective salt forms and physical properties such as solubility in polar solvents, but in other respects the salts are equivalent to their respective free acid forms for the purposes of the present invention.
[516] When the compounds of the present invention include one or more groups capable of forming such pharmaceutically acceptable salts, the scope of the present invention includes complex salt forms. Examples of common complex salt forms include, but are not limited to, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride.
[517] In view of the foregoing, the expression “pharmaceutically acceptable salts” as used herein refers to an active ingredient comprising a compound of formula (1.0.0) used in its salt form, in particular wherein the salt form is active to the active ingredient. It is intended to mean an active ingredient comprising a compound of formula (1.0.0) which is used in the free form of a component or in the form of a salt which confers improved pharmacodynamic properties compared to some other salt forms of the active ingredient conventionally used. . Pharmaceutically acceptable salts of the active ingredient may initially impart the desired pharmacodynamic properties on the active ingredient which do not previously have, and more positively affect the pharmacokinetics of the active ingredient with respect to therapeutic activity in the human body. Can be crazy
[518] The pharmacodynamic properties of the active ingredient which can be advantageously influenced, for example, are such that the active ingredient is transported through the cell membrane and subsequently directly and positively affects the absorption, distribution, biotransformation and excretion of the active ingredient. Include how you can. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can critically affect bioavailability, the solubility of the active ingredient usually depends on the nature of the particular salt form thereof employed. In addition, as will be appreciated by those skilled in the art, an aqueous solution of the active ingredient allows the active ingredient to be absorbed most rapidly into the body of the patient being treated, while solid solution forms as well as fat solutions and suspensions absorb the active ingredient less quickly. Will be done.
[519] Oral intake of the active ingredient of formula (1.0.0) is the most preferred route of administration for reasons of safety, convenience and economy, but absorption of this oral dosage form is caused by vomiting and digestion of digestive enzymes caused by irritation of polar, gastrointestinal mucus. And low pH, irregular absorption or propulsion in the presence of food or other drugs, and metabolism by mucus, intestinal plexus or liver enzymes. Formulation of such active ingredients into different pharmaceutically acceptable salt forms may be effective in overcoming or alleviating one or more of the problems listed above encountered with the absorption of oral dosage forms.
[520] Compounds of formula (1.0.0) prepared according to the methods described herein can be separated from the reaction mixtures finally prepared by any conventional means known to chemists skilled in the art in the preparation of organic compounds. The compound, once separated, can be purified by known methods. Various methods and techniques can be used as separation and purification means and include, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, and solvent extraction. .
[521] 7.1 Stereoisomers
[522] Compounds within the scope of formula (1.0.0) may be those in which the constituent atoms may be arranged in two or more different ways in space despite the same connectivity. As a result, the compound is present in the form of stereoisomers. Cis-trans isomerization is only one type of stereoisomerization. If the stereoisomers are mirror images that do not overlap one another, they are enantiomers that have chirality or handedness only in one direction due to the presence of one or more asymmetric carbon atoms in the constituent structure. Enantiomers are optically active and are therefore distinguished from each other by rotating the plane of polarization in the same amount or in opposite directions.
[523] If two or more asymmetric carbon atoms are present in the compound of formula (1.0.0), there are two possible arrangements for each said carbon atom. If two or more asymmetric carbon atoms are present, for example there are four possible stereoisomers. In addition, these four possible stereoisomers may be arranged in six possible stereoisomeric pairs that are different from each other. If molecular pairs having one or more asymmetric carbons are enantiomers, they must have different arrangements on all asymmetric carbons. These pairs not associated with enantiomers have different stereochemical relationships called diastereomeric relationships. Stereoisomers that are not enantiomers are called diastereomers or more commonly diastereomers.
[524] All these known stereochemical aspects of the compounds of formula (1.0.0) are considered to be part of the present invention. Accordingly, within the scope of the present invention, stereoisomers and enantiomers, individual enantiomers, racemic mixtures of said enantiomers, and said enantiomers in a proportion different from the proportion of said enantiomers found in artifacts, ie racemic mixtures Included mixtures containing isomers are included. Where the compound of formula (1.0.0) comprises stereoisomers that are diastereomers, the scope of the compound includes not only individual diastereomers but also mixtures of any two or more of the diastereomers in all proportions.
[525] By way of example, where a single asymmetric carbon atom is present in a compound of formula (1.0.0) to obtain its (-) (R) and (+) (S) enantiomers, the scope of the compound includes diseases described further herein and All pharmaceutically acceptable salt forms, prodrugs and metabolites thereof that are therapeutically active and useful for treating or preventing a condition are included. When the compound of formula (1.0.0) is present in the form of (-) (R) and (+) (S) enantiomers, the scope of the compound also includes all, substantially all of the therapeutic activity or the superior portion of the therapeutic activity. Only (+) (S) enantiomers or (-) (R) enantiomers are included if there is only one such enantiomer and (or) unwanted side effects are present in only one of the enantiomers. do. If there is no substantial difference between the biological activities of both enantiomers, then the range of compounds of formula (1.0.0) includes (+) () together with racemic mixtures or non-racemic mixtures in all proportional amounts. S) Enantiomers and (-) (R) Enantiomers are present.
[526] For example, the specific biological activity and / or physical and chemical properties of a pair or set of compounds of formula (1.0.0), when so present, may suggest the use of the enantiomers in a constant ratio constituting the final therapeutic product. have. To illustrate, where there are pairs of enantiomers, they are 90% (R) -10% (S); 80% (R) -20% (S); 70% (R)-30% (S); 60% (R) -40% (S); 50% (R) -50% (S); 40% (R) -60% (S); 30% (R) -70% (S); 20% (R) -80% (S); And 10% (R) -90% (S). After evaluating the properties of the various enantiomers of the compound of formula (1.0.0) when present, the proportional amounts of one or more of the enantiomers having the specific desired properties constituting the final therapeutic product can be determined in a simple manner.
[527] 7.2 Isotopes
[528] It is also contemplated to include isotopically labeled forms thereof within the scope of the compound of formula (1.0.0). Isotope labeled forms of the compounds of formula (1.0.0) are identical to those of the compounds, but one or more atoms of the compounds have an atomic mass or number of atoms different from the atomic mass or number of atoms commonly found in nature Or replaced by atoms. Examples of isotopes that are readily commercially available and that can be introduced to the compound of formula (1.0.0) according to established processes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, eg For example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds of formula (1.0.0), their prodrugs or pharmaceutically acceptable salts, comprising one or more of the aforementioned isotopes and / or other isotopes of other atoms are contemplated as being within the scope of this invention.
[529] Isotopically labeled compounds of formula (1.0.0) can be used in a number of beneficial means. For example, the introduction of isotopically labeled compounds of formula (1.0.0), such as radioactive isotopes such as ³ H or ¹⁴ C, can be useful for drug and / or substrate tissue distribution analysis. These radioisotopes, ie tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred because of their simplicity and excellent detectability. Introducing heavy isotopes (eg deuterium ( ² H)) into a compound of formula (1.0.0) can provide therapeutic benefits based on the greater metabolic stability of the isotopically labeled compound. Greater metabolic stability translates directly into increased in vivo half-life or reduced dose requirements, which will constitute a preferred embodiment of the present invention under most circumstances. Isotope labeled compounds of formula (1.0.0) use readily available isotopically labeled reagents in place of corresponding non-isotopically labeled reagents, and include the synthetic schemes and related descriptions, examples, and preparations herein. It can be prepared conventionally by performing the method disclosed in.
[530] Deuterium ( ² H) may be introduced into the compound of formula (1.0.0) for the purpose of regulating the oxidative metabolism of the compound by primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of the chemical reaction caused by the substitution of the isotope nucleus and hence the ground state energy change required for covalent bond formation after said isotope substitution. Substitution of heavy isotopes typically lowers the ground state energy of chemical bonds, thereby reducing the rate of the rate limiting bond decomposition step. If bond decomposition takes place at or near the peak point, depending on the coordinates of the plural product reaction, the product distribution ratio can vary substantially. To illustrate, a speed difference of k _M / k _D = 2 to 7 is typical when deuterium is bonded to a carbon atom at an immutable site. This speed difference successfully applied to compounds of formula (1.0.0) that are susceptible to oxidation dramatically affects the in vivo profile of the compounds and results in improved pharmacodynamic properties.
[531] In finding and developing therapeutic agents, those skilled in the art attempt to optimize pharmacodynamic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacodynamic profiles are susceptible to oxidative metabolism. Currently available in vitro hepatic microsome analysis provides valuable information about this oxidative metabolic pathway, which indicates that the deuterated compounds of formula (1.0.0) have improved stability through resistance to such oxidative metabolism. Makes rational design possible. This results in a significant improvement in the pharmacodynamic profile of the compound of formula (1.0.0), which is in vivo half-life (t / 2), concentration at maximum therapeutic effect (C _max ), dose response curve area (AUC) , And increase in F and decrease in clearance, capacity and commodity price.
[532] To illustrate the above, a compound of formula (1.0.0) having a plurality of potential sites for oxidative metabolism (e.g., benzyl-based hydrogen atoms and hydrogen atoms α for nitrogen atoms) is a combination of various hydrogen atoms. Substituted by atoms, some, most or all of these hydrogen atoms are made up of a series of homologues in which deuterium atoms are replaced. Half-life measurements provide a simple and accurate measure of the degree of improvement in resistance to oxidative metabolism. In this way, it is determined that the half-life of the parent compound can be extended by 100% as a result of the substitution with deuterium for this hydrogen.
[533] Substitution of deuterium for hydrogen in the compound of formula (1.0.0) may also be used to obtain desirable changes in the metabolic profile of the parent compound in a way to reduce or eliminate unwanted toxic metabolites. For example, where toxic metabolites are produced through oxidative carbon-hydrogen (CH) bond cleavage, deuterated homologues will reasonably reduce or eliminate the formation of unwanted metabolites even if certain oxidation is not a speed determining step. Is predicted.
[534] Further information regarding the state of the art for substitution of deuterium for hydrogen is described, for example, in Hanzlik et al., J. Org. Chem. 55 3992-3997, 1990; Reider et al., J. Org. Chem. 52 3326-3334, 1987; Foster, Adv. Drug Res. 14 1-40, 1985; Gillette et al., Biochemistry 33 (10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16 (4) 683-688, 1993).
[535] Detailed description of the invention
[536] 8.0 Therapeutic Applications and Clinical Endpoints
[537] The following description relates to the therapeutic applications in which compounds of formula (1.0.0) can be placed, and where applicable, the clinical endpoints associated with such therapeutic applications. In addition, various in vitro assays and animal model experiments are disclosed that can provide sufficient data to define and demonstrate the therapeutic utility of a compound of Formula (1.0.0).
[538] The therapeutic utility of a compound of formula (1.0.0) is applicable to a patient or subject suffering from a disease or condition set forth herein and thus requiring such treatment. There are therapeutically beneficial results, whether administered to animals or humans. As used herein, the terms "animal" and "human" are used only for the purpose of referring to humans as opposed to other members of the animal group. Compounds of formula (1.0.0) have therapeutic utility in the treatment of mammals, especially humans. All major subdivisions of the mammalian class ( Mammalia ) are included within the scope of the present invention with respect to recipients of the therapeutic treatments described herein. Mammals are valuable as human pets and can therefore be treated. This applies in particular to the canine and feline families of mammals. Other mammals are valuable as domesticated animals and their treatment according to the invention is suitable in terms of the negative economic effect of not treating the diseases and symptoms described herein. This applies in particular to mammals of the horse, cow, pig and sheep families.
[539] Compounds of formula (1.0.0) inhibit PDE4 isozymes and therefore have a wide range of therapeutic uses as described herein below because of the essential role that isozymes with PDE4 play in the physiology of all mammals. . The enzymatic role played by PDE4 isozyme is intracellular hydrolysis of adenosine-3 ', 5'-monophosphate (cAMP) in pro-inflammatory leukocytes. cAMP mediates the effects of numerous hormones in the body, and as a result, PDE4 inhibition plays an important role in various physiological processes. In addition to cAMP elevations, considerable literature is available in the art describing the effects of PDE inhibition on various inflammatory cell responses, including superoxide production, degranulation, chemotaxis, and tumor necrosis factor (TNF) release in eosinophils, neutrophils, and monocytes. exist.
[540] PDE4 was first identified in 1985 (Nemoz et al., Biochem. Pharmacol . 34 2997-3000, 1985), and the PDE4 inhibitors rolipram and denbuphylline were initially studied in clinical trials for CNS signs such as depression. It was then established that PDE4 is the major phosphodiesterase in inflammatory leukocytes. The four subtypes of PDE4, PDE4A, PDE4B, PDE4C and PDE4D, are widely distributed in human tissues as confirmed by the presence of their mRNAs. PDE4D is expressed in kidney, thymus, small intestine and colon tissues and strongly expressed in brain, lung, skeletal muscle, prostate and peripheral blood leukocyte (PBL) tissues. It is only weakly expressed in the heart, placenta, liver, pancreas, spleen, testes and ovarian tissue. PDE4A and PDE4B are also strongly expressed in brain and skeletal muscle tissue and only weakly expressed in placenta, liver and ovarian tissue. PDE4C is not only strongly expressed in skeletal muscle tissue, but also only weakly expressed in ovarian tissue. PDE4C is typically not detected in most of the aforementioned cells.
[541] Isozyme with the PDE4 family is the predominant form of phosphodiesterase found in cell types involved in chronic inflammatory diseases, and among bone marrow derived cell types, only platelets do not express PDE. PDE4 is a major cAMP-metabolizing enzyme in immune and inflammatory cells and one of two major cAMP-metabolizing enzymes in airway smooth muscle. PDE4 is present alone in neutrophils, eosinophils, basophils and monocytes, but PDE3 and PDE1 activity in macrophages and PDE7 activity in T lymphocytes have also been shown. Beneficial anti-inflammatory effects of inhibition of PDE have been demonstrated to date using in vitro experiments, which compounds have been shown to produce superoxide in human monocytes, eosinophils and neutrophils, mediator release in basophils, macrophages and neutrophils, and monocytes and macrophages. Inhibits TNF-α release. PDE inhibitors also inhibit the mediator release of inflammatory cells such as monocytes and monocyte-derived macrophages, lung mast cells, T lymphocytes, B lymphocytes, alveolar macrophages and eosinophils.
[542] In addition, beneficial anti-inflammatory effects, including inhibition of microvascular leakage into the lungs of sensitized guinea pigs, and reduction of bronchial hyperresponsiveness and eosinophilia in cynomolgus monkeys after repeated antigen administration have so far been demonstrated in vivo. Was observed. It has also been found to date that PDE4 inhibitors strongly inhibit TNF-α release from monocyte phagocytes.
[543] 8.1 Asthma
[544] One of the most important respiratory diseases treatable with PDE4, in particular types of PDE4 inhibitors within the scope of the compound of formula (1.0.0), is chronic and increasing common disease worldwide, which is associated with intermittent reversible airway obstruction, airway hyperresponsiveness and inflammation. It is characterized by asthma. The cause of asthma is not yet known, but the most common pathological manifestation of asthma is inflammation of the respiratory tract, which may also be significant in the airways of mild asthmatic patients. Based on bronchial biopsy and washing, it has been clarified that asthma involves infiltration into the patient's airway by mast cells, eosinophils and T-lymphocytes. Bronchoalveolar lavage (BAL) of atopic asthma shows the activation of interleukin (IL) -3, IL-4, IL-5 and granulocyte / macrophage-collecting stimulating factor (GM-CSF), which are T-assisted ( The presence of Th-2) type T-cell individuals.
[545] Compounds of formula (1.0.0) inhibit PDE4 in human eosinophils and are therefore useful for the treatment of atopic and non-atopic asthma, the term "atopy" refers to type 1 (immediate) for common environmental antigens. ) Genetic predisposition to the development of hypersensitivity reactions. The most common clinical signs are allergic rhinitis, but bronchial asthma, atopic dermatitis, and food allergies are less common. Thus, the expression "atopic asthma" as used herein is synonymous with "allergic asthma" (ie, bronchial asthma, which is an allergic manifestation in sensitized persons). As used herein, the term “non-atopic asthma” refers to all other asthma, especially idiopathic or “true” asthma caused by various factors including strenuous exercise, stimulant particles, psychological stress, and the like.
[546] Uses of the compounds of formula (1.0.0) for the treatment of atopic or non-atopic asthma have been established and demonstrated by the PDE inhibition, inhibition of eosinophil activity and cell infiltration models described below.
[547] Pulmonary Inflammation in Allergic Cynomolgus Monkeys-The ability to inhibit the Ascaris antigen, which induces an increase in the inflammatory cell content of the bronchoalveolar lavage secretion from cynomolgus monkey subjects, is compared to the therapeutic combination of the present invention. Evaluate by method. Using crossover design, 8 to 10 Ascaris-sensitive cynomolgus monkeys are treated with vehicle or drug. At the appropriate pretreatment time, each monkey is anesthetized (ketamine 10 m / kg + xylazine 1 mg / kg, im) and the endotracheal tube is intubated. Bronchoalveolar lavage (BAL) is performed by washing once with 15 ml of phosphate buffered saline (PBS) delivered through a pediatric optical fiber bronchoscope inserted through an intrabronchial tube and pushed into a third to fifth developing bronchus. The wash secretion is gently drawn off with a syringe and collected. After completion of BAL, each animal is exposed for two minutes to a concentration of Ascaris suum aerosol that is twice the respiratory resistance measured by preliminary experiments. Each monkey is returned to its cage and after 24 hours a second wash is performed using 15 ml of PBS on the opposite side of the lung. After 1 week of the first experiment, the control and treatment group monkeys are reversed and the experiment is repeated. To determine the composition percentage of each leukocyte type, two slides from each monkey BAL sample are obtained by centrifuging 2 × 150 μL of wash secretion for 2 minutes at 500 rpm in a Cytospin centrifuge. . Slides are stained with Diff-Quick for cells identified by different cell controls and standard morphology criteria. The total leukocyte count per 1 ml of BAL solution is measured by diluting 20 μl of the sample in 20 ml of isotone, adding 3 drops of japoglobin to hemolyze red blood cells, and reading the sample using the Coulter Counter. . The ratio of increase in the alveolar lavage eosinophil, cytokine or mediator level of bronchus of pre-antigen administration with drug treatment vs. 24 hours post-antigen administration versus drug treatment versus antigen administration with 24 hours post-administration is compared.
[548] In this test model, the combination of therapeutic agents of the present invention exhibits anti-inflammatory activity at an intravenous dose of 0.001 to 0.1 mg / kg or an oral dose of 0.01 to 10.0 mg / kg or an intravenous dose of 0.001 to 0.1 mg / kg.
[549] Another useful assay, based on primate use, is described in Turner et al., "Characterization of a primate model of asthma using anti-allergy / anti-asthmaagents," Inflammation Research 45 239-245, 1996.
[550] Anti-Inflammatory Activity — Anti-inflammatory activity of the therapeutic combinations of the present invention is determined by inhibition of eosinophil activation measured by Sephadex Bead Stimulated LTE4 production in human whole blood. Sephadex beads are used as stimulants for whole blood analysis for LTE4. The day before analysis, glass tubes are siliconized with Sigmacote (Sigma, Cat # SL-2). Prior to blood collection, the compounds were diluted with DMSO 1000 ×, 1 μl of DMSO or compound was added to each individual tube, and the tube rack was placed in a 37 ° C. water bath. Blood is drawn in heparinized Vacutainer tube # 6480 (143 USP units sodium heparin, 10 ml, 10 tubes = 100 ml of blood). Combine the blood tubes into two 50 ml conical tubes. 1 ml of whole blood is added to each siliconized tube containing DMSO or compound VORTEX and then incubated at 37 ° C. for 15 minutes. To prepare a Sephadex G-15 Bead (Pharmacia, Cat #; 17-0020-01) suspension, 3.3 g of Sephadex G-15 are added, mixed with 20 ml of PBS in a 100 ml beaker, followed by a magnetic stir bar Mix with. After 15 minutes, 100 μl of Sephadex G-15 beads are added to each tube except the Sephadex tube, which will provide a reference for LTE4 release. Vortex and incubate at 37 ° C. for 90 minutes. At the end of incubation 90 minutes, 20 μl of 15% EDTA, VORTEX is added and centrifuged at 1000 rpm for 5 minutes. The plasma sample for analysis is then removed and stored. LTE4 levels are measured with Cayman's Cysteinyl-LT ELISA kit (Cat # 520501). Percent inhibition is calculated as 100 × 1 − (LTE4 concentration in dragged sample ÷ LTE4 concentration in untreated drug sample).
[551] Compounds of formula (1.0.0) are active at concentrations ranging from 0.0001 μM to 20.0 μM in the above test methods, and preferred embodiments are active at concentrations ranging from 0.5 nM to 1000 nM.
[552] From the above, it can be seen that the compound of formula (1.0.0) is useful for the treatment of inflammatory or obstructive airway disease or other symptoms including airway obstruction. In particular, they are useful for the treatment of bronchial asthma.
[553] In view of their anti-inflammatory activity, as regards their effects on airway hyperresponsiveness and profiles related to PDE isoenzyme inhibition, in particular selective PDE4 inhibitors, the compounds of formula (1.0.0) can be used in the treatment of obstructive or inflammatory It is useful for prophylactic treatment. Thus, by sustained and regular administration over an extended period of time, the compounds of formula (1.0.0) are useful for providing progressive protection against bronchial contraction or other symptomatic development caused by obstructive or inflammatory airway disease. Compounds of formula (1.0.0) are also useful for the control, amelioration or reversal of the underlying conditions of such diseases.
[554] With regard to the bronchodilator activity of the compounds of formula (1.0.0) they are useful as bronchodilators, for example in the treatment of chronic or acute bronchial contraction, and in the symptomatic treatment of obstructive or inflammatory airway disease.
[555] The terms "treatment" and "treating" as used throughout this specification and claims in connection with obstructive or inflammatory airway disease should be understood to encompass both prophylactic and symptomatic forms of treatment.
[556] With respect to the above description, the present invention also provides a method for treating airway hyperresponsiveness in a mammal, a method for achieving bronchodilation in a mammal, comprising administering to a subject mammal an effective amount of a compound of formula (1.0.0), and In mammals in need thereof it can be seen in particular to methods of treating obstructive or inflammatory airway disease, in particular asthma.
[557] Obstructive or inflammatory airway diseases to which the present invention is applied include asthma, pneumoconiosis, chronic eosinophilic pneumonia, chronic obstructive airway or pulmonary disease (COAD or COPD), and adult respiratory distress syndrome (ARDS) as well as other drug therapies such as aspirin or exacerbation of airway hyperresponsiveness as a result of β-agonist therapy).
[558] Compounds of formula (1.0.0) are of any type, etiology or pathogenesis, including endogenous asthma due to pathophysiological disorders, exogenous asthma caused by some factors in the environment, and essential asthma of unknown or unknown causes Useful for treating asthma Compounds of formula (1.0.0) are useful for the treatment of allergy (atopy / bronchi / IgE-mediated) asthma, which also include non-atopic asthma, including, for example, bronchitis, emphysema, exercise-induced and occupational asthma, Infectious asthma, which is sequel to microbial, in particular bacterial, fungal, protozoan or viral infections; And other non-allergic asthma, such as early asthma (shortness of breath syndrome in infants).
[559] Compounds of formula (1.0.0) include aluminumosis (a disease of bauxite workers); Abolition (asthma of miners); Asbestos (steam mechanic's asthma); Schizophrenia (sclerosis); Decongestion caused by inhaling dust from ostrich hair; Iron syndrome caused by inhaling iron particles; Silicosis (crushed scoliosis); It is useful for the treatment of pneumoconiosis of any type, etiology or onset, including cotton fever (cotton-dust asthma), and talc pneumoconiosis.
[560] 8.2 Chronic Obstructive Pulmonary Disease (COPD)
[561] Compounds of formula (1.0.0) are further useful for the treatment of COPD or COAD, including associated chronic bronchitis, emphysema or dyspnea. COPD is characterized by irreversible progressive airway obstruction. Chronic bronchitis is associated with the proliferation and enlargement of submucosal mucous glands in large cartilage airways. Goblet cell proliferation, mucosal and submucosal inflammatory cell infiltration, edema, fibrosis, mucus metastasis and increased smooth muscle are all found in terminal and respiratory bronchioles. Small airways are known to be a major part of airway obstruction. Emphysema is characterized by destruction of the alveolar walls and loss of lung elasticity. A number of risk factors have been found to be associated with an increase in COPD. The link between smoking and COPD is well established. Other risk factors include exposure to coal dust and other genetic factors. See Stanford et al., “Genetic risk factors for chronic obstructive pulmonary disease,” Eur. Respir. J. 10 1380-1391, 1997. The incidence of COPD is increasing, which represents a significant economic burden on the population of industrial countries. COPD also exhibits a clinically wide variation ranging from simple chronic bronchitis without disorders to patients with severe disability of chronic respiratory failure.
[562] COPD is characterized by inflammation of the airways as in the case of asthma, but inflammatory cells found in bronchoalveolar lavage secretions and sputum in patients are neutrophils rather than eosinophils. Elevated levels of inflammatory mediators, including IL-8, LTB ₄ and TNF-α, are also found in COPD patients, and the epidermis and sub-epidermis of these patients are infiltrated by T-lymphocytes and macrophages. Found. The use of β-agonists and anticholinergic bronchodilators can alleviate signs of COPD patients, but disease progression remains unchanged. COPD is treated with theophylline, but although it reduces the neutrophil count in the sputum of COPD patients, it is not very successful. Steroids are also not a satisfactory treatment for COPD.
[563] Thus, the use of the compounds of formula (1.0.0) to treat COPD and associated airway diseases associated with and included there represents a significant advance in the art. The present invention is not limited to any particular mode of action or hypothesis to the manner in which the desired therapeutic objective is obtained by using a compound of formula (1.0.0). However, it is recognized in the art that PDE4 is the dominant PDE in neutrophils and macrophages (Cheng et al., “Synthesis and In Vitro Profile of the New Line of Catechol Benzimidazoles. Severe for the [3H] rolipram binding site. Discovery of Strong and Selective Phosphodiesterase Type IV Inhibitors with Attenuated Affinity, " Bioorg. Med. Chem. Lett 5 1969-1972, 1995; Wright et al.," Differential Inhibition of Human Neutrophil Function: Cyclic Role of AMP-specific, cyclic GMP-insensitive phosphodiesterases, " Biochem. Pharmacol . 40 699-707, 1990; Schudt et al.," Selective for human neutrophil function and levels of cAMP and Cai Influence of phosphodiesterase inhibitors, " Naunyn Schmiedebergs Arch. Pharmacol . 344 682-690, 1991; and Tenor et al.," Cyclic nucleotide phosphodiesterase isoenzyme activity in human alveolar macrophages, " Clin Exp. Allergy 25 625-633, 1995).
[564] For a better understanding of the present invention, reference is made to the following references that compounds of formula (1.0.0) inhibit PDE4 in neutrophils, resulting in reduced chemotaxis, activation, adhesion and degranulation ( Schudt el al., Ibid .; Nelson et al., “Effect of Selective Phosphodiesterase Inhibitors on Polymorphonuclear Leukocyte Respiratory Release,” J. Allergy Clin. Immunol . 86 801-808, 1990; and Bloeman et. al., “Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human bronchial epithelial cells,” Am. J. Physiol . 272 L580-587, 1997).
[565] Compounds of formula (1.0.0) are also believed to reduce superoxide anion production mediated by PDE4 in peripheral blood neutrophils and to modulate leukotriene synthesis mediated by PDE4 (Wright et al., Schudt et al., Ibid .: Bloeman et al., Ibid .: Al Essa et al., “Heterogeneity of circulating and exudating polymorphonuclear leukocytes in superoxide generation reactions to cyclic AMPs and cyclic AMP-synergists,” Biochem. Pharmacol . 49 315-322, 1995; Ottonello et al., "Cyclic AMP- synergists down-regulate oxidative release induced by granulocyte-macrophage colony synergism factor (GM-CSF) in attached neutrophils," Clin. Exp. Immunol . 101 502-506, 1995; and Ottonello et al., “Tumor Necrosis Factor Alpha-Induced Oxidative Release in Neutrophils Attached to Fibronectin: Effect of Cyclic AMP-Uplifters,” Br. J. Haematol 91 566-570, 1995).
[566] In addition, compounds of formula (1.0.0) are believed to inhibit CD11b / CD18 expression (Berends et al., “PAF of CD11b in Human Neutrophils and Eosinophils by Rolipram, a Type IV Selective PDE Inhibitor -Inhibition of induced expression and exfoliation of L-selectin, "Eur. Respir. J. 10 1000-1007, 1997; and Derian et al.," Chaptogenic peptide-induced neutrophil adhesion to vascular endothelial cells by cAMP modulators. Inhibition, " J. Immunol . 154 308-317, 1995).
[567] Furthermore, the compound of formula (1.0.0) inhibits alveolar macrophage PDE4, thereby reducing the release of chemotactic factor and TNF-α, wherein the compound of formula (1.0.0) is an anti-inflammatory cytokine IL- 10 increases synthesis and promotes release from monocytes, which may reduce the production of TNF-α, IL-1β and GM-CSF by synovial monocytes, thereby reducing It is believed to increase the overall anti-inflammatory profile of PDE4 inhibitors (Schudt et al., “PDE isoenzymes as targets for anti-asthmatic drugs,” Eur. Respir. J. 8 1179-1183, 1995; and Kambayashi et al., "Cyclic nucleotide phosphodiesterase type IV is involved in the regulation of IL-10 and subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages," J. Immunol 155 4909-4916, 1995).
[568] The application of PDE4 inhibitors to the treatment of COPD in human patients has been demonstrated in clinical trials. Treatment with SB-207,499 of formula (0.1.9) at a dose of 15 mg twice daily for 6 weeks increased FEV ₁ and forced lung capacity (FVC) (Brown, MW “SB-207499,” Anti-inflamm. Immunomodulatory Invest.Drugs 1 39-47, 1999). The clinical efficacy of SB-207,499 is also demonstrated in a four week trial providing evidence of improved FEV ₁ , and a six week trial in COPD patients receiving 15 mg twice daily for providing evidence of improved FEV ₁ . (Brown, Ibid .) SB-207,499 has already been described above and is represented by the formula (0.1.9).
[569]
[570] 8.3 Bronchitis and bronchiectasis
[571] Depending on the specific various inhibitory activities described above possessed by the compounds of the formula (1.0.0), they are, for example, short but have a severe course, acute bronchitis caused by exposure to cold, inhalation of irritants, or acute infection; Acute laryngeal bronchitis in the form of non-diphtheria croup; Arachidic bronchitis caused by the presence of a nucleus in the bronchus; Catarrhal bronchitis in the form of acute bronchitis with excessive mucolytic release; Acute bronchitis, which is a long-term form of bronchitis, with increased or decreased tendency to relapse after the stop phase due to the invention of acute bronchitis or chronic general disease, characterized by a sparing or sparing of sputum, and a cough attack caused by secondary changes in lung tissue. ; Croupous bronchitis, characterized by a violent cough and dyspnea; Dry bronchitis, characterized by a poor release of chewy sputum; Infectious asthmatic bronchitis, a syndrome characterized by the development of symptoms of bronchial spasms after respiratory tract infection in asthmatic patients; Wet bronchitis, which is bronchitis associated with wet cough; Staphylococcus or Streptococcus bronchitis caused by Staphylococcus or Streptococcus; And vesicular bronchitis of any type, etiology or pathogenesis, including bullous bronchitis, in which inflammation extends from the pleura into the visible lungs, sometimes under the pleura, such as granule seeds.
[572] Bronchiectasis is a chronic dilatation of the bronchus, characterized by odorous breathing and paroxysmal cough with the release of mucolytic substances. This may affect the tube uniformly, in which case it may be referred to as cylindrical bronchiectasis, or it may occur in irregular pockets, in which case it is called pouch bronchiectasis. An enlarged bronchial tube has a terminal spherical bulge and the term spindle bronchiectasis is used. When the dilated state expands into the bronchioles, it is referred to as capillary bronchiectasis. If bronchiectasis are spherical, this condition is called cystic bronchiectasis. Dry bronchiectasis occurs when the infection involved is transient, which may involve the sputation of hemoptysis, blood or blood contaminated sputum. During the stop phase of dry bronchiectasis, the cough that develops is unproductive. Follicular bronchiectasis is a significant swelling of lymphoid tissue in the diseased area and can be severely distorted and partially obstructed by projection to the bronchial lumen. Thus, compounds of formula (1.0.0) are useful for the beneficial treatment of various aforementioned types of bronchiectasis as a direct result of inhibition of PDE4 isozyme.
[573] The usefulness of the compounds of formula (1.0.0) as bronchodilators or bronchial economies for treating bronchial asthma, chronic bronchitis and related diseases and disorders described herein includes many known in the art, including those described in the following paragraphs. Is identifiable through the use of different in vivo animal models.
[574] In Vitro Bronchoscope Activity —The ability to induce relaxation of guinea-pig organ smooth muscle of a compound of formula (1.0.0) is demonstrated in the following test methods. Guinea-pig (350-500 g) dies with sodium pentotal (100 mg / kg ip). The trachea is excised and a section of 2-3 cm length is excised. In a cartridge plate that alternates the trachea, a transverse incision is made in the transverse plate to obtain a tissue ring of 3-5 mm depth. Remove proximity and remote rings. One of the individual rings is secured to the bottom of the tracheal bath and the other is attached to an isometric transducer to place the individual rings perpendicular to the stainless steel support. Dip the ring in Krebs solution (composition μM: NaHCO ₃ 25; NaCl 113; KCl 4.7; MgSO ₄ .7H ₂ O 1.2; KH ₂ PO ₄ 1.2; CaCl ₂ 2.5; glucose 11.7) at 37 ° C., O ₂ Gas with / CO ₂ (95: 5, v / v). Prepared in this way and 1 g of pre-loaded rings give rise to spontaneous tension and are consistently relaxed upon addition of antispasmodic drug after equilibrium (45-60 minutes). To confirm the true activity, the test compound of formula (1.0.0) is dissolved in physiological saline and added to the trachea bath at intervals of 5 minutes to obtain a cumulative concentration-effect curve.
[575] In this test model, the compound of formula (1.0.0) causes concentration-related relaxation of the guinea-pig organ ring preparation at a concentration in the range of 0.001 to 1.0 μM.
[576] Anti-inflammatory activity of the therapeutic combinations of the invention is evidenced by inhibition of TNFα production in human whole blood stimulated with lipopolysaccharide (LPS). Compounds are analyzed in the presence of beta agonists (10 ng / ml) and indomethacin (1 μM). 250 ml of 200 mM HEPES Assay Buffer in filtered RPMI 1640 is prepared. The following is carried out on a bench at room temperature. Add 0.4 ml of indomethacin (4 mM stock) and 0.4 ml of beta agonist (0.04 mg / ml stock) to make an "IP" cocktail in a 50 ml polypropylene tube with 40 ml final volume with assay buffer. Powder stocks are added to DMSO to prepare 200 or 60 mM compound compound stock solutions. Dilute 8-point halflog serial in glass vials or microtubes. 0.01 ml of each compound dilution is added to a 5 ml polypropylene tube to which 0.490 ml of assay buffer and 0.50 ml of “IP” cocktail are added and the final volume is 1.0 ml. (Compact Assay Final Concentration 100 to 0.1 μM) Add 0.08 ml of LPS (stock solution 1 mg / ml) to 40 ml of assay buffer and prepare an LPS solution to a final concentration of 2 μg / ml. 6. Add 200 μl of DMSO to 9.8 ml of assay buffer to prepare a 2% DMSO solution. 10 ml of IP cocktail is added to a 2% DMSO solution. This cocktail is used to adjust the indomethacin assay final concentration to 1 μM and the beta agonist final concentration to 10 ng / ml. The following is carried out under a tissue culture hood. To the U-bottom sterile Costar 96-well plate # 3790 add 0.0125 ml of the appropriately diluted compound. 0.0125 ml of LPS is added to all wells (final concentration 0.1 μg / ml) except the opposite control wells. Fresh human whole blood (approximately 22 ml per 96-well plate) is drawn into sterile heparin tubes maintained at 37 ° C., generally at 4 green tops per donor. 0.225 ml of whole blood is added to the plate. Covered, incubated at 37 ° C. and shaken for 4 hours. The plate is centrifuged at 2000 rpm for 10 minutes. Prepare an ELISA standard. Lift 100 μl of serum into a flat bottom plate. Lift 15 μl and dilute 1:20 by adding 285 μl of RD6 diluent. Freeze at -20 ° C. For analysis, thaw and add 200 μl to the R & D Systems TNFα ELISA. Plates are processed according to the R & D Systems protocol. Softmax Pro. Plates are read at 450 nm using annealize (SoftMax Pro. Analyze) and interpreted with a Java Fitter to determine IC50 values. Dose response curves of data presented as percentage controls are shown. At least six triple points are drawn for each compound. The IC50 value is calculated using a Java filter curve-fit program under the "IC50 fix both" parameter.
[577] In this test model, the therapeutic combinations of the present invention obtain inhibition of concentration-related TNFα production in a concentration range of 0.001 to 0.1 μM.
[578] 8.4 allergic and other types of rhinitis; Sinusitis
[579] Allergic rhinitis is characterized by stuffy nose, itching, watery nasal passages, sneezing and temporary loss of smell. Allergic rhinitis is divided into two disease categories, seasonal and perennial, the former being due to pollen or outdoor fungal spores, while the latter is due to common allergens such as house dust mites, animal dander and fungal spores. Allergic rhinitis generally exhibits early and late phase reactions. Early phase responses are associated with mast cell degranulation, while late phase responses are characterized by infiltration of eosinophils, basophils, monocytes and T-lymphocytes. Various inflammatory mediators are also released by these cells, all of which may contribute to the inflammation present in later phase reactions.
[580] Particularly predominant forms of seasonal allergic rhinitis are fever, which is characterized by acute conjunctivitis with oily and itching, swelling of the nasal mucosa, non-cataract, sudden sneezing, and asthma symptoms. Compounds of formula (1.0.0) are particularly useful for the beneficial treatment of hyperthermia.
[581] Another type of rhinitis, in which the compound of formula (1.0.0) can be used as a therapeutic agent, is characterized by acute hyperemia of the nasal mucosa, characterized by drying and subsequent increase in the secretion of mucus from the membrane, respiratory disorders through the nose , And cold head acute catarrhal rhinitis with some pain; Atopic rhinitis, a chronic form characterized by a deterioration of the mucous membranes and glands; Purulent rhinitis, a chronic rhinitis in which pus is formed; And vasomotor rhinitis, which is a non-allergic rhinitis caused by stimuli such as cold, fatigue, anger and anxiety, with temporary changes in permeability with the same symptoms as vascular strain and allergic rhinitis.
[582] There is a recognized link between allergic rhinitis and asthma. Allergic rhinitis often involves asthma, and treating allergic rhinitis has proven to improve asthma. Epidemiological data are also used to indicate the link between severe rhinitis and more severe asthma. For example, compound D-22888 has shown a potent anti-allergic effect under preclinical development for the treatment of allergic rhinitis and has been shown to inhibit nasal in antigen-induced pigs. See Marx et 30 al “New PDE4 Inhibitors for the Treatment of D-22888-Allergic Rhinitis and Other Allergic Diseases,” J. Allergy Clin. Immunol . 99 S444, 1997. Another experimental compound AWD-12,281 has been shown to be active in a rat model of allergic rhinitis. "Poppe et al" Effects of AWD 12-281, Loteprednol and Beclomethasone, a Novel Selective PDE-4 Inhibitor in a Model of Allergic Rhinitis and Airway Inflammation in Brown Norwegian Rats, " Am. J. Respir. Crit Care Med . A95, 1999). Compounds D-22888 and AWD-12,281 have already been described above and are represented by the following formulas (0.0.28) and (0.0.34), respectively.
[583]
[584] Sinusitis is associated with rhinitis in that it is not only anatomic proximity but also in some cases a shared etiology and pathogenesis. Sinusitis is an inflammation of the paranasal sinuses, and the symptoms are purulent or non-purulent, and can be acute or chronic. Depending on the sinuses where the inflammation is located, the symptoms are known as esophagitis, frontal sinusitis, maxillary sinusitis or acute sinusitis. The ethmoid sinus is a type of sinus located in the ethmoid sinus. The frontal sinus is one of the paired sinuses located in the frontal bone. The maxillary sinus is one of the paired sinuses located in the maxillary body. Thus, the compounds of formula (1.0.0) are useful for the beneficial treatment of acute or chronic sinusitis, specifically chronic sinusitis.
[585] 8.5 rheumatoid arthritis, osteoarthritis, pain, fever and gout
[586] Arthritis is defined as inflammation of the joints, and rheumatoid arthritis is a chronic systemic disease of the joints, usually polyarthritis, primarily characterized by inflammation of the synovial and joint structures, and muscle atrophy and thinning of the bone. The late phase of rheumatoid arthritis is characterized by ankle joints and deformations. Rheumatoid arthritis is a disordered autoimmune disease of unknown etiology that affects more than 1% of the population.
[587] As used herein, the term "rheumatic arthritis" is also intended to include within its scope relevant and associated arthritis types as applicable in the art that can be treated with a compound of formula (1.0.0). Thus, the term "rheumatic arthritis" refers to acute arthritis, which is arthritis characterized by pain, fever, flushing, and swelling due to inflammation, infection, or trauma; Acute arthritis associated with gout includes acute gouty arthritis; Chronic inflammatory arthritis, which is inflammation of the joints in chronic diseases such as rheumatoid arthritis; Degenerative arthritis, osteoarthritis; Infectious arthritis, which is arthritis caused by bacteria, rickettsia, mycoplasma, viruses, fungi or parasites; Lyme arthritis, a large joint arthritis associated with Lyme 20 disease; Proliferative arthritis, which is an inflammation of the joints accompanied by the proliferation of the synovial membrane seen in rheumatoid arthritis; Psoriatic arthritis, which is a syndrome in which psoriasis develops in association with inflammatory arthritis, and vertebral arthritis, which is inflammation such as intervertebral discs.
[588] Three major pathological characteristics of rheumatoid arthritis, which are responsible for progressive joint destruction, are inflammation, abnormal cellular and hormonal responses, and synovial proliferation. Specific cellular conditions of rheumatoid arthritis include the presence of T-cells and monocytes. T-cells, primarily memory T-cells, constitute 50% or less of the cells recovered from the synovial tissue of patients with rheumatoid arthritis, and 30-50% of the monocytes found in the same tissue are antigen presenting cells, It shows autoimmune characteristics. Pro-inflammatory cytokines such as IL-1, IL-4, IL-5, IL-6, IL-9, IL-13 and TNF-α may cause joint tissue damage, inflammation, proliferation, pannus formation And bone resorption. See Firestein, GS and Zvaifier, WJ "How important are T-cells in chronic rheumatoid synovitis " Arth. Rheum . 33 768-773 (1990). This has been demonstrated, for example, by the fact that monoclonal antibodies against TNF-α (Mab) show promise in RA clinical trials (Maini et al., “The Beneficial Effect of Tumor Necrosis Factor-alpha (Rheumatoid Arthritis) TNF-α blockade in (RA)), " Clin. Exp. Immunol . 101 207-212, 1995).
[589] PDE4 inhibitors of formula (1.0.0) are useful for the treatment of rheumatoid arthritis due to their ability to inhibit the activity of various inflammatory cells, including basophils, eosinophils and mast cells. This inhibitory activity of the compounds of formula (1.0.0) has already been described above and is broad through the release of reactive oxygen species, prostaglandins and inflammatory cytokines such as IL-5, IFN-γ and TNF-α. It has a range of in vitro anti-inflammatory effects. Cohan et al., "In Vitro Pharmacology of CP-80,633, a New Phosphodiesterase Type IV Inhibitor," J. Pharm.Exp . Ther . 278 1356-1361, 1996; and Barnette et al., "SB207499 (Ariflo), potent and selective second generation phosphodiesterase 4 inhibitors: in vitro anti-inflammatory action, " J. Pharm. Exp. Ther . 284 420-426, 1998). PDE4 inhibitors of formula (1.0.0) are useful in the treatment of rheumatoid arthritis due to their effectiveness in inhibiting T-cell proliferation mediated through a variety of different substances, including antigens such as house dust mites, which have been demonstrated in the art. (Barnetta et al., Ibid ). The ability of compounds of formula (1.0.0) to promote the release of cytokine IL-10 from monocytes further extends to TNF-α, IL-1, IL-4, IL-5, IL-6, IL by synovial monocytes. -9, IL-13 and GM-CSF can be reduced, and further demonstration of the overall anti-inflammatory profile of the PDE4 inhibitor of formula (1.0.0) (Kambayashi et al., Ibid ). In addition, the ability of compounds of formula (1.0.0) to inhibit TNF-α release from stimulated monocytes may be correlated with animal models of inflammation, where the anti-inflammatory effect corresponds to the inhibition of TNF-α accumulation. May appear. One such animal model includes the inhibition of LPS-induced TNF-α release in mice by oral administration of PDE4 inhibitors (Cheng et al., “Phosphodiesterase Type 4 (PDE4) Inhibitor CP-80,633 in Mice Raises cyclic AMP levels and reduces TNF-α production: effect of adrenal extraction, " J. Pharm. Exp. Ther . 280 621-626, 1997). Another such animal model includes the inhibition of edema of rat paws induced by carageenan by oral administration of rolipram (Singh et al., "Synovial Levels of Tumor Necrosis Factor a in Congested Rat Knees: Regulation of dexamethasone and matrix metalloproteinases with inhibitors and phosphodiesterases, ” Inflamm. Res . 46 (Suppl. 2) S153-S154, 1997).
[590] Gout refers to a group of disorders of purine metabolism, and fully developed gout is a recurrent characteristic acute inflammatory arthritis caused by the determination of hyperuricemia, monosodium urate monohydrate, joint destruction and limbs that can lead to severe disorders Nodular precipitation of the crystals in and around, and various combinations of uric acid urolithiasis. Rheumatoid gout is another name for rheumatoid arthritis. Nodular gout is a gout with nodular or chalky precipitation of sodium ureate. While some therapeutic agents, such as phenylbutazone and colchicine, are useful for treating both gout and accompanying inflammation, other therapeutic agents, such as sulfinpyrazone and benzbromarone, have only uric acid excretion promoting properties.
[591] Fever or fever may be the result of any one of a large number of different factors, but in the context of the present invention, this fever is manifested as pharyngeal conjunctival fever or rheumatic fever, or during inflammation. Concomitant with inflammation is pain, in particular pain in the joints and connective tissue of patients with rheumatoid arthritis and gout.
[592] Thus, compounds of formula (1.0.0) provide beneficial results in the treatment of gout and fever and pain associated with inflammation.
[593] Animal models of rheumatoid arthritis have also been used for the purpose of demonstrating the correlation between in vitro regulation of TNF-α by PDE-4 inhibitors and their utility in the treatment of rheumatoid arthritis. The activity of rolipram in animal models of acute inflammation, such as the mouse adjuvant arthritis model, has been demonstrated in the art (Sekut et al., "Phosphodiesterase (PDE) in acute and chronic models of inflammation). Anti-inflammatory activity of IV inhibitors, " Olin. Exp. Immunol . 100 (1) 126-132, 1995). The ability of rolipram to reduce disease severity in collagen II induced arthritis (CIA) models following subcutaneous or intraperitoneal injection has been demonstrated in the art (Nyman et al.m., “Type IV phosphodiesterase inhibitors Improvement of Collagen II Induced Arthritis in Rats by Rolipram, " Olin. Exp. Immunol . 108 415-419, 1997). In this study, the dose plan of rolipram was twice daily at 2 mg / kg for 5 days prior to the onset of arthritis, which significantly delayed the onset of symptoms of arthritis. After discontinuation of treatment the test animals developed arthritis and reached an arthritis highest score equivalent to the control. In the same study, rolipram was also administered twice daily at 3 mg / kg when arthritis appeared. Treatment dramatically changed the development of the disease to prevent exacerbation after discontinuation of treatment, and the arthritis score did not reach levels observed in untreated animals. The researchers also demonstrated strong downregulation of TNF-α and IFN-γ mRNA in regional lymph nodes, suggesting that the major effects of rolipram are exerted on the effector of the inflammatory process (Nyman et al., Ibid ).
[594] In Vitro Inhibition of TNF-α Production by Human Monocytes—Inhibitory effects of compounds of formula (1.0.0) on in vitro TNF-α production by human monocytes are described in EP 411 754 (Badger et al.) And WO 90/15534 ( Can be measured according to the protocol described in Hanna). Reference publications also describe two models of endotoxin shock that can be used to determine the in vivo inhibitory activity of a compound of formula (1.0.0). The protocol used in this model is detailed and test compounds show positive results by reducing the serum levels of TNF-α induced by injection of endotoxin.
[595] Selective PDE4 inhibitors such as RP73401 show significant improvement in disease, specifically joint destruction, synovitis and fibrosis, in animal models such as including Streptococcus cell wall (SCW) -induced arthritis (Souness et al., "The potential of phosphodiesterase type IV inhibitors in the treatment of rheumatoid arthritis," Drugs 1 541-553,1998).
[596] Of particular interest for the treatment of rheumatoid arthritis is the observation that PDE4 inhibitors have a positive effect at the site of action of the disease. For example, RP73401 has been shown to reduce TNF-α mRNA expression at the Pannus / Cartilage interface of the foot joints of collagen II treated mice (Souness et al., Ibid ). RP73401 has also been clinically studied in patients with rheumatoid arthritis in a placebo-controlled double-blind phase II study in which 400 pg of compound is administered three times a day to 35 patients with rheumatoid arthritis. The compound could induce a positive trend for clinical improvement associated with a decrease in C-reactive protein and IL-6 serum levels. Chikanza et al., “Clinical Effects of RP73401 Phosphodiesterase Type 4 Inhibitors in Patients with Rheumatoid Arthritis,” Br. J. RheumatoL 36: Abstr. Suppl. I, 186, 1997.
[597] Increased cAMP Accumulation Assay in Complete Tissue Using U-937 Cells— Another suitable assay to explain the PDE4 inhibitory activity of a compound of Formula (1.0.0) is U-derived from human monocyte cell lines that have been shown to contain large amounts of PDE4. 937 cells. To assess the inhibition of PDE4 activity in intact cells, undifferentiated U-937 cells at a density of about 10 ⁵ cells per reaction tube were tested for 0.01 to 1000 pM for 1 minute, and 1 μM of prostaglandin E2 for an additional 4 minutes. Incubate with. Five minutes after the start of the reaction, the cells were lysed by the addition of 17.5% perchloric acid, and then the pH was neutralized by adding 1 M potassium carbonate. The cAMP content of the reaction tube is measured using the RIA technique. Detailed protocols for performing this assay are described in Brooker et al., “ Radioimmunoassay of Cyclic AMP and Cyclic GMP,” Adv. Cyclic Nucleotide Res . 10 1-33, 1979.
[598] 8.6 eosinophil-related disorders
[599] The ability to inhibit eosinophil activation as part of its overall anti-inflammatory activity of the PDE4 inhibitor of Formula (1.0.0) is as described above. Thus, compounds of formula (1.0.0) are useful for the therapeutic treatment of eosinophil-related diseases. Such diseases include eosinophilia, in which an abnormally high number of eosinophils is formed and accumulated in the blood. The name of the disease is derived from "eosin", a rosy colorant or dye comprising a bromine derivative of fluorescein, which is easily identified by easily coloring "eosinophilic leukocytes" in the blood of a patient. A specific eosinophilic disease that can be treated according to the present invention is pulmonary infiltrating eosinophilia. The disease includes, in particular, Loupler syndrome, a symptom characterized by transient infiltration of the lung accompanied by coughing, fever, dyspnea and eosinophilia.
[600] Other eosinophilic disorders include chronic eosinophilic pneumonia characterized by cough, dyspnea, malaise, fever, night sweats, weight loss, eosinophilia, and chest film exposure non-segmented, non-mobile infiltration at the lung end; It is a subacute or chronic form of hidden filamentous disease, usually involving tropical animals, including Brugia malayi, Wuchereria bancrofti, or filamentous insects, which occur in the tropics, and illustrated nighttime sneezing and coughing Tropical pulmonary eosinophilia characterized by a sudden increase in eosinophils and reticulated infiltration of diffused lungs; Causes disease states characterized by inflammatory granulomatous necrosis of the nasal sinuses and lungs, as well as the skin, ears, eyes and sometimes bones and meninges, and is formed by colony formation of Aspergillus in the bronchus or lung cavity Bronchiopulmonary aspergillosis, which is an infection of the bronchus and lungs, caused by Aspergillus fungus, which causes Aspergillosis, the most common form of fungal ball.
[601] The term "granulomatous" is meant to include granulomas, and the term "granulomatous" is usually surrounded by the edges of lymphocytes with small nodular marginal aggregation of any small mononuclear inflammatory cells or fibrosis commonly seen around the lesion. It refers to this population of epithelial cells resembling modified macrophages. Some granulomas include eosinophils. Granulomatous formation represents a chronic inflammatory response initiated by various infectious and non-infectious agents. Many such granulomatous symptoms are treatable using compounds of formula (1.0.0), for example allergic granulomatous vasculitis (also called Chuck-Strauss syndrome, generally eosinophilia, granulomatous reactions and usually severe In the form of systemic necrotic vasculitis with a significant pulmonary relationship manifested by asthma). Related diseases are characterized by multiple inflammatory destructive arterial lesions and nodular polyarteritis (PAN), which is a form of systemic necrotic vasculitis involving the arterial and middle arteries with symptoms and signs arising from the involvement of the organ system, especially the lung infarction and scars. to be. Other eosinophil-related diseases that can be treated in accordance with the present invention are those that affect the airways induced or caused by a response to a therapeutic agent that is not associated with any compound of formula (1.0.0).
[602] 8.7 Atopic Dermatitis, Urticaria, Conjunctivitis and Uveitis
[603] Atopic dermatitis is a chronic inflammatory skin disease that often occurs in individuals with genetic predisposition to lowered transdermal thresholds for pruritus, which are accompanied by allergic rhinitis, high fever and asthma, and are often characterized by excessive itching. Atopic dermatitis is also called allergic dermatitis, and allergy or atopic eczema.
[604] Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in children, which affects 10% to 15% of the infant population. Atopic dermatitis often accompanies asthma and allergies and therefore has become known as a component of the so-called "atopic dermatitis" because they occur mainly in individuals with asthma and / or allergic rhinitis. See Leung Dym. Atopic Dermatitis: From Pathogenesis To Treatment , RG Landes Co., Austin, Texas, 1-226,1996. Thus, immune dysfunction associated with atopic dermatitis can be treated with a therapeutic agent that is a PDE4 inhibitor. For example, rolipram (Ro-201724) and denbuphylline have been reported to cause concentration-related inhibition of proliferation of human peripheral blood mononuclear cells (HPBM) from normal patients as well as subjects with atopic dermatitis. See Torphy et al., Drugs and the Lung , Eds. Page and Metzger, Raven Press, New York 1994; and O'Brien, Mol. Medicine Today , 369, 1997, respectively. These studies also confirmed that the proliferative response of HPBM in patients with atopic dermatitis is more sensitive to PDE4 inhibitors than the proliferation observed in HPBM from normal subjects.
[605] Th2 type cytokine secreting T-cells expressing cutaneous lymphocyte associated antigens play a central role in the induction of local IgE responses and recruitment of eosinophils in this disease. Chronic inflammation seen in atopic dermatitis is believed to be the result of several interdependent factors, such as repeated or persistent allergen exposure that can lead to Th2 cell expansion. It has been found that allergen specific T-cells have an increased tendency to increase IL-4, IL-5 and IL-3 levels in the blood of atopic dermatitis patients. See Leung Dym et al., “Allergic and Immunological Skin Disorders,” JAMA 278 (22) 1914-1923, 1997. This is important because IL-4 and IL-3 induce adhesion molecules involved in the expression of vascular adhesion molecule-1 (VCAM-1) and migration of monocyte cells and eosinophils to tissue inflammation sites. IL-5 is also a major mediator of eosinophil activation, a common property of atopic diseases.
[606] Increasing concentrations of cAMP in lymphocytes and basophils have long been associated with decreased mediator release from these cells, and more recently histamine action on H2 receptors increases cAMP levels and IL-4 production in rat Th2 cells. Suppression has been reported. Thus, it is summarized that atopic diseases such as atopic dermatitis, impaired β-adrenergic response or increased PDE activity of leukocyte inflammatory response are present. Reduced cAMP response may be due to increased PDE4 activity, which is either genetic based or obtained conditions.
[607] A study was conducted comparing different cell types obtained from atopic patients to those of healthy volunteers, and the results showed that increased cAMP-PDE activity in atopic cells correlated with abnormal inflammation and immune cell function in atopic dermatitis. In addition, PDE4 enzymes from atopic leukocytes were more sensitive to PDE4 inhibitors than PDE4 enzymes from normal leukocytes, and up to 14-fold differences were identified. Chan and Hanifin, "Differential Inhibitory Effects of the cAMP Phosphodiesterase Isomorphism in Atopy and Normal Leukocytes," J. Lab. Clin. Med ., 121 (1) 44-51, 1993). Increased sensitivity can also be seen in the inhibition of proliferation of peripheral blood mononuclear cells obtained from atopic donors for treatment with PDE4 inhibitors. For example, rolipram is IC ₅₀ = 280 nM compared to IC ₅₀ = 2600 nM, respectively, and it was found that it was more effective to inhibit PHA stimulated atopic dermatitis PBMC proliferation than to inhibit PHA stimulated normal PBMC proliferation. .
[608] In addition, structurally diverse ranges of selective PDE4 inhibitors have been shown to be effective in reducing skin eosinophilia in guinea pigs mediated through a range of substances such as PAF, arachidonic acid zymosan activated plasma, and anaphylaxis proteins in the skin. See Beesley et al., “Synthesis and Evaluation of New Class of Phosphodiesterase 4 Inhibitors. Possible Therapies for Asthma,” Bioorg. Med. Chem. Letts . 8 2629-2634, 1998. These data show the utility of PDE4 inhibitors in treating skin diseases caused by eosinophils. This treatment is by topical method of administration, for example, in clinical trials, the application of topical artozram to both patients over 8 days has been shown to be effective in suppressing all inflammatory parameters tested, qualitatively and without side effects. It was found to be quantitatively improved. See Hanifin et al., "Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis," J. Invest. Dermatol. 107 51-56, 1996.
[609] Thus, PDE4 inhibitors of formula (1.0.0) are useful for the beneficial treatment of atopic dermatitis as described above. A related field of therapeutic application in which compounds of formula (1.0.0) also produce useful results is in the treatment of urticaria. Urticaria is a typically transient vascular response involving the upper dermis that exhibits local edema caused by relaxation of the capillaries and increased permeability, and is characterized by the development of swells or rashes. Many different stimuli can induce urtic response and can be classified by cause as follows: immune mediated, complement mediated (which may include immunological or non-immune mechanisms), urticaria induced, physical induced , Stress induction or idiopathic. Symptoms may also be manifested as acute or chronic depending on the duration of the onset. Vascular edema is the same response in dermis or subcutaneous or submucosal tissue.
[610] The most common type of urticaria that is treatable with a compound of formula (1.0.0) is that acetylcholine released from parasympathetic or motor nerve endings induces the release of mediators from mast cells and is ventilated by symptoms of force, stress or increased ambient heat. Cholinergic urticaria, characterized by the presence of unusual punctuated boils surrounded by erythema regions that are thought to be or are non-immune hypersensitive; In two forms (in autosomal dominant forms associated with fever, arthralgia and leukocytosis, the lesions are present as erythematous, plastic papules and macules, and more commonly are idiopathic and self-limiting acquired). Cold urticaria, which is hives that are precipitated by cold air, water, or objects that become wet; Contact urticaria, which is a local or general transient swelling and flare reaction caused by exposure to rapidly absorbable urticaria agents; Giant urticaria that is angioedema; And papular urticaria, a persistent skin rash that shows hypersensitivity to insect bites.
[611] Thus, compounds of formula (1.0.0) are useful for the beneficial treatment of various types of urticaria as described above. A related field of therapeutic application in which the compounds of formula (1.0.0) also produce beneficial results is the treatment of various ophthalmic uses, especially conjunctivitis and uveitis.
[612] Conjunctivitis is a delicate film that lines the eyelids and covers the exposed surface of the sclera. Conjunctivitis is an inflammation of the conjunctiva that is usually made of conjunctival hyperemia with discharge. The most common types of conjunctivitis treatable with a compound of formula (1.0.0) include photoconjunctivitis caused by ultraviolet light; Acute catarrhal conjunctivitis, acute, infectious conjunctivitis associated with cold or catarrh, characterized by clear hyperemia, edema, loss of translucent, and mucus or mucus discharge; Acute infectious conjunctivitis, a mucinous epidemic conjunctivitis that has the same symptoms as acute catarrhal conjunctivitis and is also caused by Haemophilus aegyptius , also called "pinkeye"; Allergic conjunctivitis, an element of high fever; Atopic conjunctivitis, an immediate type of allergic conjunctivitis caused by airborne allergens (eg pollen, dust, spores and animal dander); Chronic catarrhal conjunctivitis, a mild chronic conjunctivitis with only mild hyperemia and mucus release; Mucolytic conjunctivitis which is acute conjunctivitis caused by bacteria or viruses, in particular gonococcus, meningococcus, pneumococcus and streptococcus, characterized by severe conjunctival inflammation and massive pus release; And bilateral conjunctivitis of seasonal occurrence of unknown cause in children, especially boys, and spring conjunctivitis characterized by flat papules and thick, gelatinous exudate. Thus, PDE4 inhibitors of formula (1.0.0) are useful for the beneficial treatment of various types of conjunctivitis as described above. A related field of therapeutic application in which compounds of formula (1.0.0) also produce beneficial results is uveitis.
[613] The uvea is the vascular intermediate coat or coat of the eye, including the iris, ciliary body and choroid. Uveitis is inflammation of all or part of the uvea and typically includes other coatings of the eye, namely the sclera and cornea, and the retina. The most common types of uveitis treatable with a compound of formula (1.0.0) include anterior uveitis, an uveitis that includes iris and / or ciliary structures, including iris, ciliary and iris-shaped salts; Granulomatous uveitis, which is all parts of the uvea, especially the late uveitis, characterized by a nodular collection of giant cells surrounded by epithelial cells and lymphocytes; Granulomatous uveitis, an inflammation of the anterior part of the uve, ie the iris and ciliary body; Phacoantigenic uveitis, one of lens-induced uveitis, which is a severe anterior uveitis similar to sympathetic ophthalmopathy observed weeks or months after extracapsular lens surgery or other trauma to the capsule; And posterior uveitis, which is uveitis including the posterior compartment of the eye, including choroiditis and chorioretinitis. Thus, PDE4 inhibitors of formula (1.0.0) are useful for the beneficial treatment of various types of uveitis as described above.
[614] 8.8 Psoriasis
[615] Psoriasis is a common chronic, squamous skin disease of multifactorial heredity and variation characterized by small tumors and spongy pustules, as well as erythema, dry, and scaling patches of various sizes. Psoriasis is a common skin disease that affects about 2% of the population, and more than 1.5 million people in the United States who discuss treatment with their doctors annually. Psoriasis usually recurs and in some cases is very debilitating. The pathogenesis of psoriasis is unknown, but it has been shown to be an autoimmune disease with a genetic tendency.
[616] Psoriasis involves many T-cell infiltration in the affected areas of the skin and has CD4 + lymphocytes in the dermis and CD8 + lymphocytes in the epithelium. These lymphocytes secrete IL-2, IFN-γ and TNF-α, which alter keratinocyte proliferation and differentiation. In addition, 5% to 10% of psoriasis patients develop psoriatic arthritis, whose symptoms are very similar to rheumatoid arthritis. The wide range of anti-inflammatory activity exhibited by the PDE4 inhibitors already discussed above allows these inhibitors to be beneficially used in the treatment of psoriasis.
[617] Treatment of epithelial basal cells in primary culture with PDE4 inhibitor Ro 20-1724 proved to cause a threefold increase in cAMP concentration. In addition, treatment of psoriatic epithelial slices and keratinous psoriatic epithelial slices with Ro 20-1724 has been shown to result in very large rises in cAMP concentrations as compared to controls. Specifically, a 1395% increase in cAMP concentration in keratinized psoriasis epithelium was observed. PDE4 inhibitors have also been shown to inhibit inflammatory responses of various mediators via local or systemic administration. For example, rolipram has been shown to inhibit ear papilla-induced ear inflammation in mice at topical doses as low as 0.03 mg per ear. The selective PDE4 inhibitor Ro 20-1724 was also studied in two double blind studies compared to efficacy on vehicles, where it has been shown to improve psoriasis damage without negative systemic or skin effects.
[618] 8.9 Multiple Sclerosis and Other Inflammatory Autoimmune Diseases
[619] Sclerosis refers to hardening or hardening, in particular referring to hardening from inflammation, and from increased formation of connective tissue, and from some of the diseases of the interstitial material. The term "sclerosis" is used mainly for the hardening of the nervous system due to precipitation of connective tissue or tightness of distinguishable blood vessels. Multiple sclerosis (MS) extends through the central nervous system, sometimes to gray matter, with dehydration lesions of various sizes, causing weakness, ataxia, perception, speech disorders and visual dissatisfaction. Multiple sclerosis is a disease of unknown etiology with an extended course that involve multiple recovery and recurrence.
[620] Multiple sclerosis is an autoimmune disease that causes gliosis in the central nervous system in addition to chronic inflammation and dehydration. There are several subtypes of disease, including primary progressive multiple sclerosis, and recurrent recurrent multiple sclerosis. These disease subtypes can be distinguished from each other based on the course of the disease, the type of inflammation involved, and through the use of magnetic resonance imaging (MRI). It is also possible that the underlying disease mechanism, during which the inflammation-based process is later replaced by including dehydration and axon damage, is altered during multiple sclerosis. See Weilbach and Gold, “Treatment of Disease Change in Multiple Sclerosis. What Are the Limits ” CNS Drugs 11 133-157, 1999.
[621] In multiple sclerosis, hardening fragments characterized by dehydration are characteristic of the disease, but inflammatory lesions are local, but predominantly via white matter in the central nervous system. The development of dehydration is caused by necrosis of oligodendrocytes, which, together with local cells such as astrocytes, microglia and small-vascular brain epithelial cells, lead to major histocompatibility complexes ( MHC) involves infiltrates consisting mainly of T-cells and macrophages expressing Group II. Thus, these cells affect antigen presentation and inflammatory responses, and various pro-inflammatory cytokines, including TNF-α, TNF-β, IL-1, IL-6, and IFN-γ, have brain tissue in patients with multiple sclerosis. And their presence is generally associated with active lesions. In particular, TNF-α is of interest because it mediates in vitro damage of medullary and oligodendrocytes, induces astrosite to express surface adhesion molecules, and is associated with disruption of the blood-brain barrier.
[622] Animal models were used to elucidate the role of TNF-α in multiple sclerosis, and administration of anti-TNF antibodies or water soluble TNF receptors, for example in experimental allergic encephalomyelitis (EAE), has been shown to provide a protective effect. See Selmaj et al., "Prevention of Chronic Recurrent Experimental Autoimmune Encephalomyelitis by Water-soluble Tumor Necrosis Factor," J. Neuroimmunol . 56 135-141, 1995. A direct correlation between the level of TNF-α mRNA and the progression of EAE was also reported. Reeno et al., “TNF-alpha expressed by endogenous microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis: regulation by Th1 cytokines,” J. Immunol . 154 944-953 , 1995). Further evidence proving that TNF-α is a mediator of multiple sclerosis is an increased concentration of TNF-α in the cerebrospinal fluid of patients with multiple sclerosis during disease progression. In addition, transgenic mice overexpressing TNF-α in the central nervous system show signs of spontaneous dehydration, whereas transgenic TNF-α knockout mice show a protective effect. Probert et al., "Spontaneous Inflammatory Dehydrogenation Disease in Transgenic Mice Showing Central Nervous System Specific Expression of Tumor Necrosis Factor Alpha," Proc. Natl. Acad. Sci . USA 92 11294-11298, 1995; and Liu et al., "TNF is a potent anti-inflammatory cytokine in autoimmune mediated dehydration," Nature Med . 4 78-83, 1998).
[623] Since PDE4 inhibitors also inhibit TNF-α, they are beneficial in the treatment of multiple sclerosis because TNF-α plays a key role in mediating multiple sclerosis as discussed above. For example, in the mamoset model of experimental allergic encephalomyelitis, rolipram has been shown to suppress clinical signs and eliminate abnormalities in MRI imaging. In another study of the effect of rolipram on chronic recurrent experimental allergic encephalomyelitis in SJL mice, rolipram improves clinical signs and pathological changes in this model. Genain et al., “Ebang of Autoimmune Dehydration in Nonhuman Extensions with cAMP-Specific Phosphodiesterases,” Proc. Natl. Acad. Sci . USA 92 3601-3605, 1995; and Sommer et. al., “Therapeutic Capacity of Phosphodiesterase Type 4 Inhibitors in Chronic Autoimmune Dehydration Diseases,” J. Neuroimmunol . 79 54-61, 1997).
[624] In addition to inhibiting PDE4 activity and production of TNF-α, the compounds of formula (1.0.0) also have activity as immunosuppressive agents, especially where inflammation is part of an autoimmune disease, or inflammation is the pathogenesis of an autoimmune disease. It is useful for treating autoimmune diseases, some of which are inflammation or otherwise involved in autoimmune diseases. Alternatively, the compound of formula (1.0.0) may be an inflammatory disease wherein the autoimmune response is part of an inflammatory disease, the autoimmune response is part of the pathogenesis of an inflammatory disease, or the autoimmune response is otherwise involved in an inflammatory disease. It is an anti-inflammatory agent useful in the treatment of. Thus, the compounds of formula (1.0.0) are useful for the treatment of multiple sclerosis as discussed in detail above.
[625] Other autoimmune / inflammatory diseases that can be treated with a therapeutic agent comprising a compound of formula (1.0.0) include hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thromboembolic purpura, systemic lupus erythematosus, multiple chondritis, Scleroderma, Wegener's granulomas, dermatitis, chronic active hepatitis, myasthenia gravis, Stevens-Jones syndrome, idiopathic sprue, ulcerative colitis and Crohn's disease, autoimmune inflammatory bowel disease, endocrine eye disease, Graves disease, Sarcoid Syndrome, alveolitis, chronic hypersensitivity pneumonia, primary biliary cirrhosis, childhood diabetes (type 1 diabetes), anterior uveitis and granulomatous (rear) uveitis, dry keratoconjunctivitis and epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis (interstitial pulmonary fibrosis) ), Including idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, acute glomerulonephritis, idiopathic nephrotic syndrome, and minimal change nephropathy Glomerulonephritis with nephrotic syndrome and glomerulonephritis without nephrotic syndrome, psoriasis and atopic dermatitis as discussed in detail above, contact dermatitis, allergic contact dermatitis, benign familial cystic lanceolate, erythematous cystic lanceolate, deciduous celestial acne and vulgaris Inflammatory / hyperproliferative skin diseases including, but not limited to, mucosa.
[626] In addition, compounds of formula (1.0.0) may be used to prevent allogeneic graft rejection following organ transplantation, where the organs typically include bone marrow, colon, heart, kidney, liver, lung, pancreas, skin and cornea. It can be used as an immunosuppressant against.
[627] 8.10 Inflammatory Bowel Disease
[628] Ulcerative colitis (UC) is a chronic, recurrent ulcer of the large intestine, predominantly mucosa and submucosa, which is an unknown cause, clinically abnormal convulsive pain, rectal bleeding, and dilute release of blood, juice and poor feces Appears as mucus with particles. Related diseases of the colon are characterized by the precipitation of collagen substances under the epithelium of the colon and are a type of unknown cause of colitis that is manifested by abnormal convulsive pain accompanied by a pronounced decrease in fluid and electrolyte absorption leading to watery diarrhea. Collagen colitis; Polypitis colitis, an ulcerative colitis that involves the formation of a gaplip (ie, an edematous congested site of the mucosa between ulcer sites); And clinically resembling ulcerative colitis, but with ulcers often long-term or deep, disease often partial, common stenosis, often with the formation of non-casey degenerative granulomas, often accompanied by pores (especially in the perineum) Pulmonary colitis, which is an inflammation of the entire thickness of the large intestine rather than mucosal and submucosal diseases, is included.
[629] Crohn's disease (CD) includes all parts of the gastrointestinal tract, but is a chronic granulomatous inflammatory disease of unknown etiology that typically includes terminal ileum with scarring and thickening of the large intestinal wall, often intestinal obstruction, and fistula and Boil formation, high recurrence rate after treatment. Ulcerative colitis, Crohn's disease and related diseases discussed above are collectively referred to as inflammatory bowel disease (IBD). These diseases are immunologically mediated and their onset is a chronic, spontaneous recurrent disease of unknown cause, established through the use of animal models and advanced immunological techniques. (Bickston and Caminelli, "Recent Developments in Medical Therapies of IBD," Curr. Opin. Gastroenterol . 14 6-10, 1998; and Murthy et al., "Inflammatory Bowel Disease: A New Wave of Treatment," Exp. Opin See Ther. Patents 8 (7) 785-818, 1998). Although the incidence of ulcerative colitis remains relatively stable, the incidence of Crohn's disease has increased significantly.
[630] Current treatments for inflammatory bowel disease include 5-aminosalicylic acid, corticosteroids, and immunomodulators such as azathioprine, 6-mercaptopurine and methotrexate. These substances have a wide range of side effects and do not alter the disease itself, so there is a continuing need for more effective therapeutics. Compounds of formula (1.0.0) can advantageously treat inflammatory bowel disease as a result of its ability to inhibit the production of TNF-α since TNF-α causes immune cell activation, proliferation and mediator release in inflammatory bowel disease. See Radford-Smith and Jewell, “Cytokines and Inflammatory Bowel Disease,” Baillieres Clin. Gasteroenterol . 10 151-164, 1996. In addition, TNF-α was detected in the feces and intestinal mucosa of patients with inflammatory bowel disease. In addition, early clinical studies of Crohn's disease with TNF monoclonal antibodies have shown considerable promise.
[631] As already detailed above, selective PDE4 inhibitors have a significant effect on the inhibition of the release of TNF-α from peripheral blood mononuclear cells after stimulating the cells with a wide range of mediators both in vitro and in vivo. The selective PDE4 inhibitor arophylline has been shown to provide a beneficial effect when tested in a rat colitis model. In addition, in rat dextran sulfate-induced colitis model, rolipram and the selective PDE4 inhibitor LAS31025 showed a beneficial effect comparable to prednisolone. Both test compounds have been shown to improve bleeding and inflammatory markers. See Puig et al., “Therapeutic Effect of Phosphodiethese 4 Inhibitors in Dextran Sulfate Sodium Induced Colitis in Rats,” Gastroenterology 114 (4) A1064, 1998. Other researchers used additional models to demonstrate the ability of selective PDE4 inhibitors to provide gastrointestinal protection. For example, it has been shown that lipopolysaccharide-induced erythrocyte ejection in rats and intestinal hypoperfusion in dogs can be attenuated by the selective PDE4 inhibitors rolipram and denbuphylin. Cardelus et al., “LPS-induced colonic red blood cell ejection in rats by phosphodiesterase inhibitors, and inhibition of hepatic hepatic perfusion in dogs,” Eur. J. Pharmacol . 299 153-159, 1996; and Cardelus et. al., “The Protective Effect of Denbuphylline on Endotoxin Induced Colon Hyperplasia,” Met. Find. Exp. Clin. Pharmacol . 17 (Suppl. A) 142, 1995).
[632] 8.11 Septic Shock, Renal Failure, Cachexia, and Infection
[633] Septic shock is a shock associated with an irresistible infection, most commonly associated with infection by Gram-negative bacteria, although this may be caused by other bacteria, viruses, fungi and protists. Septic shock arises from the action of endotoxins or other products of infectious substances on the vascular system, causing large amounts of blood to be sequestered in capillaries and veins. Activation of the complement and kinin systems and release of histamine, cytokines, prostaglandins and other mediators are also involved.
[634] Ro-201724, a selective PDE4 inhibitor given at 10 μg / kg / min post-treatment in a model of endotoxin-induced acute renal failure in rats, significantly increased urinary cAMP excretion and significantly increased endotoxin-induced increase in renal resistance. Weakens and reduces renal blood flow and glomerular filtration rate. Ro-201724 has also been shown to improve survival of endotoxin treated rats. See Carcillo et al., Pharmacol. Exp. Ther . 279 1197, 1996. Pentoxifylline has also been studied in patients with sepsis. In this study, 24 individuals in the sepsis shock category were selected, 12 of whom received 1 mg / kg / hr of pentoxifylline over 24 hours, while the other 12 were controls. After 24 hours, TNF-α levels were significantly reduced in the treatment group, but IL-6 levels were found to be significantly increased.
[635] In another study, three to five to 50 mg / kg intraperitoneal administration of pentoxifyl, or three to ten to 30 mg / kg intraperitoneal administration of the selective PDE4 inhibitor rolifram and 0.1 to 3 mg of denbuphylline Pretreatment with / kg intraperitoneal administration reduced lipopolysaccharide-induced colonic red blood cell ejection in rats, and denbuphylline decreased lipopolysaccharide-induced mesenteric blood flow drop without effect on renal blood flow or cardiac output coefficient than pentoxifylline. It was found that the decline was 100 times stronger. See Cardelus et al., Ibid ., Eur. J. Pharmacol .
[636] Renal failure is the inability of the metabolites to excrete to normal plasma levels under conditions of normal load, or of electrolyte maintenance under conditions of normal influx. In the acute form, it manifests as uremia, with hyperkalemia and pulmonary edema, usually diabetic or urinary. Based on the activity of the selective PDE4 inhibitors described above, selective PDE4 inhibitors have proven useful for the treatment of renal failure, especially acute renal failure. Begany et al., “Inhibition of type IV phosphodiesterase by Ro-20-1724 attenuates endotoxin induced acute renal failure,” J. Pharmacol. Exp. Thera . 278 37-41, 1996 ) Reference. See also WO 98/00135, assigned to the University of Pittsburgh. Thus, the compounds of formula (1.0.0) are useful for the treatment of renal failure, in particular acute renal failure.
[637] Cachexia is a deep, prominent condition of disorders of the constitutional disorder characterized by general illness, health and malnutrition. Cachexia may be the end result of various causative factors, for example, it may be caused by infection by any one of a variety of different single cell organisms or microorganisms, including bacteria, viruses, fungi and protozoa. Malaria cachexia is representative and includes the main signs of a group of chronic natures resulting from a prior onset of severe malaria, anemia, yellowish skin, yellow sclera, dyspnea and hepatomegaly. Another cause of cachexia is the loss or degradation of hormones or other organic functions, for example pituitary cachexia is the complete development of pituitary function, including pulmonary tuberculosis, loss of sexual function, atrophy of the pituitary target, bradycardia, hypothermia, anesthesia and coma Includes a series of symptoms due to loss. Urotoxic cachexia is cachexia accompanied by other systemic symptoms of advanced renal failure. Psychogenic cachexia includes weakness caused by heart disease. Adrenal cachexia or Addison's disease is a disease characterized by hypotension, weight loss, loss of appetite and weakness due to corticosteroid deficiency. This is due to the destruction of tuberculosis or autoimmune induced adrenal cortex causing deficiency of aldosterone and cortisol.
[638] Cachexia may also be the result of various types of disease states. Cancer cachexia includes weak and debilitating symptoms in the case of malignant tumors. Cachexia may also be the result of infection with human immunodeficiency virus (HIV) and includes symptoms commonly referred to as AIDS. Compounds of formula (1.0.0) are useful for treating the different types of cachexia described above as a result of their ability to provide downregulation or inhibition of TNF-α release. Selective PDE4 inhibitors of the invention have a pronounced effect on inhibiting TNF-α release from peripheral blood mononuclear cells after stimulating the cells with a wide range of mediators. TNF-α release comprises or plays a mediating role in a disease or condition in which the etiology involves or involves pathological, ie unhealthy, excessive or unregulated TNF-α release.
[639] PDE4 inhibitory compounds of formula (1.0.0) are furthermore viruses that increase the production of TNF-α in infections, in particular in the host, or are sensitive to upregulation of TNF-α in the host, thereby negatively affecting replication or other vital activity. It is useful for the treatment of infection by. Such viruses include, for example, HIV-1, HIV-2 and HIV-3; Cytomegalovirus, CMV; influenza; Adenovirus; And herpes viruses, especially herpes zoster and herpes simplex.
[640] PDE4 inhibitory compounds of formula (1.0.0) are further useful for the treatment of yeast and fungal infections that are sensitive to upregulation by TNF-α or cause TNF-α production in the host. A particular disease treatable in this way is fungal meningitis. Compounds of formula (1.0.0) also provide a beneficial effect when used in combination, ie when administered together, for example, for the treatment of systemic yeast and fungal infections. Such optional drugs include polymyxins (such as polymyxin B), imidazoles (such as clotrimazole, econazole, myconazole and ketoconazole), triazoles (such as fluconazole and itranazole), and amphotericin (such as : Amphotericin B and liposome amphotericin B), but are not limited thereto. As used herein for the compound of Formula (1.0.0) and a drug selected for the treatment of systemic yeast and fungal infections, the term "co-administration" refers to such compounds (a) when formulated together in a single dosage form. Simultaneous administration of the compound (s) and drug (s), (b) substantially simultaneous administration of such compound (s) or drug (s) to a subject when formulated in separate dosage forms from each other, and (c) separately formulated from each other In other words, it is intended to mean and include sequential administration of such compound (s) and drug (s) when administered to a subject at a constant time interval.
[641] 8.12 Liver damage
[642] In addition to the negative effects of TNF-α described above, it also causes liver failure in humans, a phenomenon seen in various animal models. For example, in an acute model of T-cell mediated liver failure, rolipram administered 0.1 to 10 mg / kg intraperitoneally 30 minutes prior to the administration of concanavalin A or Staphylococcus endotoxin B is associated with plasma TNF- While it has been shown to significantly reduce α and INF-γ concentrations, it also significantly increases IL-10 levels. See Gantner et al., J. Pharmacol. Exp. Ther . 280 53 1997. In the same study, rolipram has also been shown to inhibit concanavalin A-induced IL-4 release. In addition, the plasma activity of the liver specific enzymes ALT, AST and SDH was evaluated in this study because any of their elevated levels could indicate massive hepatocellular destruction. In the intraperitoneal administration pretreatment of rolipram 0.1-10 mg / kg in natural mice administered concanavalin A, or galactosamine-sensitized mice administered galactosamine / staphylococcus endotoxin B Was found to dose-dependently inhibit the above-mentioned plasma enzyme activity. Thus, compounds of formula (1.0.0) are useful for the treatment of T-cell disorders such as liver failure.
[643] 8.13 Pulmonary Hypertension
[644] It is known that the activity of phosphodiesterases that hydrolyze the vasodilatory secondary messengers cAMP and cGMP can be increased by hypoxia-induced pulmonary hypertension (HPH). Hypoxia is the reduction of oxygen supply to tissues below physiological levels despite the proper perfusion of tissues by the blood. The resulting pulmonary hypertension is characterized by increased pressure in the pulmonary artery circulation, ie, above 30 mm Hg systolic pressure and above 12 mm Hg diastolic pressure. Using a model using pulmonary artery rings isolated from normal rats and rats with hypoxia-induced pulmonary hypertension, the selective PDE4 inhibitor rolifram was found to enhance the relaxation activity of isoproterenol and forskolin. lost. The same effect was observed by supporting the inhibition of both PDE3 and PDE4 to significantly improve pulmonary artery relaxation in hypoxia-induced pulmonary hypertension when using the selective PDE3 inhibitor milinon. See Wagner et al., J. Pharmacol. Exp. Ther . 282 1650, 1997. Thus, the compounds of formula (1.0.0) are useful for the treatment of pulmonary hypertension, especially hypoxia-induced pulmonary hypertension.
[645] 8.14 Bone Loss Disease
[646] Bone loss disease, more commonly referred to as osteoporosis, is a condition of low bone mass and microstructural disruption that causes fractures with minimal trauma. Secondary osteoporosis is due to a systemic disease or mediation such as glucocorticoids. It is argued that primary osteoporosis should be seen to include two symptoms: Type 1 osteoporosis, a loss of striatal bone due to estrogen deficiency during menopause, and prolonged remodeling inefficiency, inadequate diet and age-dependent parathyroid axis activation Type 2 osteoporosis due to loss of cortical and striatal bone. Primary regulation of adult bone mass includes physical activity, reproductive endocrine status, and calcium influx, and optimal maintenance of bone requires that all three of these areas be sufficient.
[647] Selective PDE4 inhibitors have been found to be useful for the beneficial treatment of bone loss diseases, especially osteoporosis. The effects of denbuphylline walker 256 / S-born rats on bone loss and mineralized nodule formation and osteoclast-like cell formation were studied in a bone marrow culture system. A series of oral administrations of denbuphylline inhibit the reduction of bone mineral density in the femur obtained from Walker 256 / S-born rats and maintain the number of osteoclasts and osteoblasts per striae of the femoral metaphyseal stem. Found. Administration of denbuphylline also increases the number of mineralized nodules and reduces the number of osteoclast-like cells in a bone marrow culture system in vivo. This beneficial effect is specific to PDE4 inhibitors and is mimicked by dibutyryl cAMP, demonstrating that PDE4 isozyme plays an important role in bone turnover through cAMP. Miyamoto et al., Biochem. Pharmacol . 54 613, 1997; Waki et al., “Effects of XT-44, a phosphodiesterase 4 inhibitor on osteoblastogenesis and osteoclastogenesis in culture, and rat osteopenia model Its therapeutic effect, " Jpn. J. Pharmacol . 79 477-483, 1999; and JP 9169665 (1997), assigned to Miyamoto). As a result, selective PDE4 inhibitors of formula (1.0.0) are useful for the treatment of diseases involving bone loss, in particular osteoporosis.
[648] 8.15 CNS Disorders
[649] The PDE4 selective inhibitor rolipram was initially developed as an antidepressant and ongoing research in clinical trials on this indication. In addition, selective PDE4 inhibitors include Parkinson's disease (Hulley et al., "Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in melanocyte neurons in vivo," Eur. J. Neurosci . 7 2431-2440; 1995) as well as learning and memory impairment (Egawa et al., “Phosphodiesterase 4 inhibitor rolifram and its optical isomers attenuate scopolamine-induced learning and memory impairment in rats,” Jpn. J. Pharmacol . 75 275-281, 1997; Imanish et al., “Attenuated Effect of Rolipram on Experimentally Induced Learning and Memory Impairment in Rodents,” Eur. J. Pharmacol . 321 273-278, 1997; and Barad et al., "Rolipram, a type IV-specific phosphodiesterase inhibitor, promotes the establishment of sustained long-term awareness and improves memory," Proc. Natl. Acad. Sci . USA 95 15020-15025, 1998). Provides a beneficial effect on other central nervous system disorders, including.
[650] The use of PDE4 inhibitors to treat tardive dyskinesia and drug dependence is also disclosed in the art (WO 95/28177 and JP 92221423 (1997) all assigned to Meiji Seika Kaisha Ltd.) . PDE4 isozyme has been shown to play a pivotal role in regulating dopamine biosynthesis in midbrain neurons, and therefore PDE4 inhibitors are useful for the treatment of diseases and conditions associated or mediated with dopamine in and around midbrain neurons (Yamashita et al. "Rolipram, an optional inhibitor of phosphodiesterase type 4, significantly enhances the forskolin-induced promotion of dopamine biosynthesis in primary cultured rat midbrain neurons," Jpn. J. Pharmacol . 75 91-95 , 1997).
[651] PDE4 inhibitory compounds of formula (1.0.0) are further useful for the treatment of atherosclerotic dementia and subcortical dementia. Atherosclerotic dementia, also referred to as vascular dementia and multiple-infarction dementia, is a dementia with a series of minor strokes and an irregular distribution of neurological damage caused by cerebrovascular disease. Subcortical dementia is caused by lesions that affect the subcortical brain structure and are characterized by memory loss that slows down the processing of information or intellectual responses. Dementia with Huntington's chorea, Wilson's disease, paralysis and thalamic atrophy.
[652] 8.16 Other Therapeutic Applications
[653] PDE4 inhibitors treat ischemia-reperfusion injury (Block et al., “Delayed treatment with rolipram protects against neuronal damage after extensive ischemia in rats,” NeuroReport 8 3829-3832, 1997 and Belayev et al., "Protection of blood-brain barrier destruction in regional cerebral ischemia by type IV phosphodiesterase inhibitor BBB022: a quantitative study," Brain Res . 787 277-285, 1998), Treatment of Autoimmune Diabetes (Liang et al. "Phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice," Diabetes 47 570-575, 1998), Treatment of Retinal Autoimmunosis (Xu et al., "In EAU Protective Effect of Type IV Phosphodiesterase Inhibitor Rolipram: Protection is Independent of IL-10 Inducing Effect, " Invest. Opthalmol. Visual Sci . 40 942-950, 1999), Treatment of Chronic Lymphocytic Leukemia (Kim and Lerner, “Type 4 Cyclic as a Treatment for Chronic Lymphocytic Leukemia To didanosine monophosphate phosphodiesterase, "Blood 92 2482-2494, 1998) , treatment of HIV infection (Angel et al.," Selective type IV phosphodiesterase inhibitor, leaf roll person is HIV-1 replication Is a potent inhibitor of AIDS 9 1137-1144, 1995 and Navarro et al., "Inhibitors of phosphodiesterase type IV inhibit human immunodeficiency virus type 1 replication and cytokine production in primary T cells: Involvement of NF-kappa B and NFAT, " J. Viol . 72 4712-4720, 1998), treatment of lupus erythematosus (JP 10067682 (1998) assigned to Fujisawa Pharm. Co. Ltd.) ), Treatment of renal and urological diseases (DE 4230755 (1994), assigned to Schering AG), treatment of urogenital and gastrointestinal disorders (WO 94/06423, assigned to Schering AG), and prostate Treatment of diseases (WO 99/02161 assigned to Porssmann and WO 99/02161 assigned to Stief). useful.
[654] In accordance with the above description, it is to be understood that the compounds of formula (1.0.0) are useful for any one or more beneficial treatments selected from the group consisting of the following diseases, disorders or symptoms:
[655] -Asthma of any type, cause or onset, or by atopic asthma, non-atopic asthma, allergic asthma, atopy, bronchial, IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Intrinsic asthma induced, exogenous asthma caused by environmental factors, intrinsic asthma of unknown or unknown cause, non-atopic asthma, bronchitis asthma, emphysema, asthma, exercise-induced asthma, occupational asthma, bacteria , Asthma selected from the group consisting of infectious asthma, non-allergic asthma, early asthma, shortness of breath syndrome in infants caused by fungal, protozoan or viral infections,
[656] -Chronic or acute bronchial constriction, chronic bronchitis, small airway obstruction and emphysema,
[657] Obstructive or inflammatory airway disease of any type, cause or onset, or COPD, irreversible progressive progression, including asthma, pneumoconiosis, chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or related dyspnea Obstructive or inflammatory airway disease selected from the group consisting of COPD, adult respiratory distress syndrome (ARDS) characterized by airway obstruction, and exacerbation of airway hyperresponsiveness by other pharmacotherapy,
[658] Pneumoconiosis of any type, cause or onset, or disease of aluminosis or bauxite workers, asthma or miners' asthma, asbestos or steam mechanic's asthma, pulmonary or septic pulmonary, or dust from ostrich hair Pneumoconiosis caused by inhalation, iron syndrome caused by inhaling iron particles, silicosis or crushed pore disease, cotton mill fever or cotton-dust asthma, and pneumoconiosis selected from the group consisting of talc pneumoconiosis,
[659] -Bronchitis of any type, cause or onset, or acute bronchitis, bronchitis of acute laryngeal trachea, arachid bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthmatic bronchitis, wet bronchitis, staphylococcus or Streptococcus Bronchitis, and bronchitis selected from the group consisting of endoplasmic reticulum bronchitis,
[660] From a group consisting of any type, cause or onset of bronchiectasis, or columnar bronchiectasis, pocket-shaped bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis Bronchiectasis chosen,
[661] Seasonal allergic rhinitis, or perennial allergic rhinitis, or sinusitis of any type, cause or onset, or sinusitis selected from the group consisting of purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoidal sinusitis,
[662] -Selected from the group consisting of rheumatoid arthritis of any type, cause or onset, or acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, and spinal arthritis Rheumatoid arthritis,
[663] Gout, and fever and pain associated with inflammation,
[664] Eosinophil-related disorders of any type, cause, or onset, or eosinophilia, pulmonary infiltrating eosinophilia, loupler syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchial pneumococcal aspergillosis, aspergillosis Eosinophil-related disorders selected from the group consisting of granulomas including eosinophils, allergic granulomatous vasculitis or Chuck-Strauss syndrome, nodular polyarteritis (PAN), and systemic necrotic vasculitis,
[665] -Atopic dermatitis, or allergic dermatitis, or allergic or atopic eczema,
[666] Urticaria of any type, cause or onset, or immune-mediated urticaria, complement-mediated urticaria, urticaria-induced urticaria, physical drug-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, Hives selected from the group consisting of cholinergic urticaria, autosomal dominant or acquired forms, cold urticaria, contact urticaria, giant urticaria, and papular urticaria,
[667] Conjunctivitis of any type, cause or onset, or conjunctivitis selected from the group consisting of photoconjunctivitis, acute cataract conjunctivitis, acute infectious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic cataract conjunctivitis, purulent conjunctivitis, and spring conjunctivitis,
[668] -Uveitis of any type, cause or onset, or inflammation of all or part of the uvea, anterior uveitis, iris, cystitis, iris phloemitis, granulomatous uveitis, granulomatous uveitis, crystalline antigenic uveitis, posterior uveitis, portal vein Uveitis selected from the group consisting of meningitis, and chorioretinitis,
[669] -Psoriasis,
[670] Multiple sclerosis selected from the group consisting of multiple sclerosis of any type, cause or onset, or primary progressive multiple sclerosis, and relapsing-remitting multiple sclerosis,
[671] -Autoimmune / inflammatory diseases of any type, cause or onset, or autoimmune hematological disorders, hemolytic anemia, aplastic anemia, sore erythrocytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple chondritis, skin Sclerosis, Wagner's granulomatosis, dermatitis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, endocrine ophthalmopathy, Graves disease, sarcoidosis , Alveolitis, chronic irritable pneumonia, primary biliary cirrhosis, childhood diabetes or type I diabetes, anterior uveitis, granulomatosis or posterior uveitis, dry keratoconjunctivitis, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, Idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, acute With glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory / hyperproliferative dermatosis, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial cystic swelling, lupus erythematosus, deciduous cystic spear, and vulgaris Autoimmune / inflammatory diseases selected from the group consisting of:
[672] Prevention of allograft rejection following organ transplantation,
[673] Inflammatory bowel disease (IBD) of any type, cause or onset, or inflammatory bowel disease selected from the group consisting of ulcerative colitis (UC), collagen colitis, polyp colitis, pancreatitis colitis, and Crohn's disease (CD) ,
[674] -Septic shock of any type, cause or onset, or renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremia cachexia, cardiac cachexia, adrenal cachexia or Addison disease, cancer cachexia, and human immunodeficiency virus ( Pulmonary shock, selected from the group consisting of cachexia as a result of infection with HIV),
[675] -Liver damage,
[676] Pulmonary hypertension, and hypoxia induced pulmonary hypertension,
[677] Bone loss, primary osteoporosis, and secondary osteoporosis,
[678] Central nervous system disorders of any type, cause or onset, or depression, Parkinson's disease, learning and memory disorders, delayed motor disorders, drug dependence, atherosclerosis dementia, and Huntington chorea, Wilson's disease, tremor and atrophy Central nervous system disorder selected from the group consisting of accompanying dementia,
[679] Infections, in particular viruses selected from the group consisting of HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and herpes viruses, including herpes zoster and herpes simplex Infection by a virus that increases the production of TNF-α in the host, or which is sensitive to the upregulation of TNF-α in the host, negatively affecting replication and other viral activity,
[680] In particular polymyxins (e.g. polymyxin B), imidazoles (e.g. clotrimazole, econazole, myconazole and ketoconazole), triazoles (e.g. fluconazole and itranazole), and amphotericin (e.g. amphoteric) Upregulation of TNF-α or TNF-α production in the host when administered with other drugs selected for the treatment of systemic yeast and fungal infections, including but not limited to erysine B and liposome amphotericin B) Yeast and fungal infections sensitive to induction (e.g. fungal meningitis),
[681] Ischemia-reperfusion injury, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteric diseases, genitourinary and gastrointestinal disorders, and prostate disease.
[682] Detailed description of the invention
[683] 9.0 Combination with other drugs or therapies
[684] The present invention provides that the compound of formula (1.0.0) is the only therapeutic agent used alone or more commonly in combination with a pharmaceutically acceptable carrier to prepare a dosage form suitable for administration to a patient as described above. Consider the aspect. Other embodiments of the present invention contemplate combinations of some of the compounds of formula (1.0.0) with one or more additional therapeutic agents that are co-administered to the patient to obtain in particular the desired therapeutic end result. The second therapeutic agent may also be one or more compounds of formula (1.0.0) or one or more PDE4 inhibitors known in the art and described in detail herein. More typically, the second such therapeutic agent may be selected from different kinds of therapeutic agents. These choices are described in detail below.
[685] The terms "co-administered" "co-administered" and "in combination with" as used herein referring to a compound of formula (1.0.0) and one or more other therapeutic agents, are intended to mean (A) simultaneous administration of a combination of compound (s) and drug (s) to a patient when formulated together in a single dose form that substantially releases the ingredients to a patient in need thereof, (b) Compound (s) to a patient in need of treatment when the components are digested substantially simultaneously by the patient in need of treatment, whereby the ingredients are formulated separately from each other in separate dosage forms where the ingredients are released to the patient substantially simultaneously. And substantially simultaneous administration of the combination of drug (s), (c) the components are continuously digested with significant time intervals between each digestion by the patient in need of treatment, thereby Sequential administration of a combination of compound (s) and drug (s) to the patient when formulated separately from each other in separate dosage forms that are released to the patient at substantially different times, (d) controlled modality To the patient when formulated together in a single dosage form that is released into the body and thereby is digested simultaneously, continuously and / or redundantly simultaneously and / or at different times by the patient in need thereof. ) And the combination of drug (s).
[686] 9.1 Leukotriene Biosynthesis Inhibitors: with 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenase activating protein (FLAP) antagonists
[687] At least one compound of formula (1.0.0) is used in combination with a leukotriene biosynthesis inhibitor, ie a 5-lipoxygenase inhibitor and / or a 5-lipoxygenase activating protein antagonist, to form an embodiment of the invention. As already mentioned above, 5-lipoxygenase is one of two groups of enzymes that metabolize arachidonic acid, and the other group is cyclooxygenase COX-1 and COX-2. The 5-lipoxygenase activating protein is an 18 kDa membrane-bound arachidonate-binding protein that stimulates the conversion of cellular arachidonic acid by 5-lipoxygenase. Arachidonic acid is converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which leads to the production of inflammatory leukotrienes, which then leads to the 5-lipoxygenase activating protein or the 5-lipoxygenase enzyme itself. Blockade provides a desirable target that advantageously interferes with that pathway. One such 5-lipoxygenase inhibitor is zileuton represented by the formula (0.1.14) as seen above and below. Among the classes of leukotriene synthesis inhibitors useful for forming therapeutic combinations with compounds of formula (1.0.0) are:
[688] (a) Redox activators comprising N-hydroxyurea, N-alkylhydroxysamic acid, selenite, hydroxybenzofuran, hydroxylamine and catechol. Ford-Hutchinson et al., “5-lipoxygenase,” Ann. Rev. Biochem . 63 383-417, 1994; Weitzel and Wendel, “Selenoenzyme is a leukocyte 5-lipoxygenase via a peroxide state. " J. Biol. Chem . 268 6288-92, 1993; Bjoernstedt et al.," Selenite incubated with NADPH and mammalian thioredoxin reductase inhibits lipoxygenase and active site iron. Produces selenides that change the electron spin resonance spectra of, " Biochemistry 35 8511-6, 1996; and Stewart et al.," Structure-activity Correlation of N-hydroxyurea 5-lipoxygenase Inhibitors, " J Med. Chem . 40 1955-68, 1997).
[689] (b) It has been found that compounds reacting with alkylating agents and SH groups inhibit leukotriene synthesis in vitro (Larsson et al., "5-lipoxygenase activity of 1-chloro-2,4,6-trinitrobenzene and cells Effect on leukotriene synthesis, " Biochem. Pharmacol . 55 863-71, 1998).
[690] (c) Competitive inhibitors of 5-lipoxygenase based on thiopyranoindole and methoxyalkyl thiazole structures that can act as non-redox inhibitors of 5-lipoxygenase (Ford-Hutchinson et al., Ibid .; And Hamel et al., "Synthesis, biological profile and pharmacodynamics of substituted (pyridylmethoxy) naphthalene-L-739,010, a potent and orally active 5-lipoxygenase inhibitor," J. Med. Chem . 40 2866-75 , 1997).
[691] The observation that arachidonoyl hydroxyxamate inhibits 5-lipoxygenase has been clinically observed, such as N-hydroxyurea derivatives zileuton and ABT-761 represented by the formulas (0.1.14) and (5.2.1), respectively. This led to the development of useful selective 5-lipoxygenase inhibitors:
[692]
[693] Another N-hydroxyurea compound is fenleutone (Abbott-76745) represented by the formula (5.2.2).
[694]
[695] Zirtonone is assigned U.S. Pat. No. 4,873,259 to Abbott Laboratories, which discloses indole, benzofuran and benzothiophene comprising a lipoxygenase inhibiting compound which can be represented by the following formula (5.2.3): Protected by Summers et al.
[696]
[697] Wherein R ₁ is H, (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl or NR ₂ R ₃ , wherein R ₂ and R ₃ are H, (C ₁ -C ₄ ) alkyl , Or OH, and X is O, S, SO ₂ or NR ₄ , wherein R ₄ is H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, aroyl or alkylsulfo Ni), A is (C ₁ -C ₆ ) alkylene or (C ₂ -C ₆ ) alkenylene, n is 1-5, Y is H, halo, OH, CN, halo substituted alkyl, ( C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₁ -C ₁₂ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₈ ) thioalkyl, aryl, aryl Substitution of oxy, aroyl, (C ₁ -C ₁₂ ) arylalkyl, (C ₂ -C ₁₂ ) arylalkenyl, (C ₁ -C ₁₂ ) arylalkoxy, (C ₁ -C ₁₂ ) arylthioalkoxy or aryl Derivatives, aryloxy, aryloil, (C ₁ -C ₁₂ ) arylalkyl, (C ₂ -C ₁₂ ) arylalkenyl, (C ₁ -C ₁₂ ) arylalkoxy, (C ₁ -C ₁₂ ) arylthioalkoxy , wherein the substituents are halo, NO _2, CN or (C ₁ -C ₁₂₎ - alkyl, - alkoxy, - halo-substituted alkyl, Z is O Is S, M is H, a pharmaceutically acceptable cation, aroyl or (C ₁ -C ₁₂₎ alkanoyl.
[698] Related compounds are described in U.S. Patents 4,769,387 (Summers et al.), U.S. Patent 4,822,811 (Summers), U.S. Patent 4,822,809 (Summers and Steward), U.S. Patent 4,897,422 (Summers), U.S. Patent 4,992,464 ( Summers et al. And US Pat. No. 5,250,565 to Brooks and Summers, each of which is hereby incorporated by reference in its entirety, although fully shown herein.
[699] Zirtonone or any of the derivatives described above is used in combination with a compound of formula (1.0.0) to form an embodiment of the invention.
[700] Penleuton is U.S. Patent 5,432,194, U.S. Patent 5,446,062, U.S. Patent 5,484,786, U.S. Patent 5,559,144, U.S. Patent 5,616,596, U.S. Patent 5,668,146, U.S. Patent 5,668,150, U.S. Patent 5,843,968 , U.S. Patent 5,407,959, U.S. Patent 5,426,111, U.S. Patent 5,446,055, U.S. Patent 5,475,009, U.S. Patent 5,512,581, U.S. Patent 5,516,795, U.S. Patent 5,476,873, U.S. Patent 5,714,488, U.S. Patents 5,783,586, U.S. Patent 5,399,699, U.S. Patent 5,420,282, U.S. Patent 5,459,150, and U.S. Patent 5,506,261, each of which is hereby incorporated by reference in its entirety, although fully shown herein. Further explanation of such N-hydroxyurea and 5-lipoxygenase and related inhibitors of the synthesis of inflammatory leukotrienes is described in WO 96/30671, WO 96/02507, WO 97/12865, WO 97/12866, WO 97/12867, It can be found in WO 98/04555 and WO 98/14429.
[701] Tepoxalin is a dual COS / 5-LO inhibitor with short-term in vivo activity that led to the development of a series of hybrid compounds of the N-hydroxyurea and hydroxamic acids of formulas (5.2.4) and (5.2.5), respectively. .
[702]
[703] Wherein R ¹ to R ⁴ are H, Cl, CH ₃ , ethyl, iso-propyl or n-propyl, or R ³ and R ⁴ together are (CH ₂ ) ₅ or (CH ₂ ) ₂ O (CH ₂₎ ;) _2, R ⁵ is methyl, ethyl, iso- propyl, methoxy, trifluoromethyl, chloro, methyl, ethyl propionate, phenyl, 2-furyl, 3-pyridyl or 4-pyridyl. See Connolly et al., "N-hydroxyurea and hydroxyxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase," Bioorganic & Medicinal Chemistry Letters 9 979-984, 1999.
[704] Another N-hydroxyurea compound is Abbott-79175 represented by the following formula (5.2.6).
[705]
[706] Abbott-79175 has a longer duration of action than zileuton (Brooks et al., J. Pharm. Exp. Therapeut . 272 724, 1995).
[707] Another N-hydroxyurea compound is Abbott-85761 represented by the following formula (5.2.7).
[708]
[709] Abbott-85761 is delivered to the lungs by aerosol administration of a uniform, physically stable and nearly monodisperse formulation (Grupta et al., "Pulmonary Delivery of Abbott-85761, a 5-lipoxygenase inhibitor in non-eagle dogs," International Journal of Pharmaceutics 147 207-218, 1997).
[710] Penleuton, Abbott-79175, Abbott-85761 or any of its derivatives described above or derivatives of tepoxalin are combined with a compound of formula (1.0.0) to form an embodiment of the invention.
[711] Because of the description of the 5-LO biosynthetic pathway, discussion is underway whether it is more advantageous to inhibit the 5-lipoxygenase enzyme or to antagonize the peptide- or non-peptido leukotriene receptor. 5-lipoxygenase inhibitors block the action of the entire spectrum of 5-LO products, whereas LT-antagonists have a narrower effect, so it is thought that inhibition of 5-epoxygenase is better than LT-receptor antagonists . Nevertheless, embodiments of the invention include combinations of compounds of formula (1.0.0) with LT-antagonists as well as 5-LO inhibitors, as described below. Inhibitors of 5-lipoxygenase having a chemical structure different from the classification of N-hydroxyurea and hydroxamic acid described above are also used in combination with a compound of formula (1.0.0) to form a further embodiment of the invention. . An example of such a different classification is N- (5-substituted) -thiophene-2-alkylsulfonamides of the formula (5.2.8).
[712]
[713] Wherein X is O or S, R 'is methyl iso-propyl, n-butyl, n-octyl or phenyl, R is n-pentyl, cyclohexyl, phenyl, tetrahydro-1-naphthyl, 1- Or 2-naphthyl, or phenyl mono- or di-substituted by Cl, F, Br, CH ₃ , OCH ₃ , SCH ₃ , SO ₂ CH ₃ , CF ₃ or iso-propyl. Preferred compounds are of the formula (5.2.9).
[714]
[715] Further descriptions of these compounds are described in Beers et al., “N- (5-substituted) -thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase,” Bioorganic & Medicianl Chemistry 5 (4) 779- 786, 1997).
[716] Other different classes of 5-lipoxygenase inhibitors are described in Cudroro et al., "Synthesis and Biological Evaluation of 2,6-di-tert-butylphenol Hydrazone as 5-lipoxygenase Inhibitor," Bioorganic & Medicinal Chemistry 7 173-180, 1998). 2,6-di-tert-butylphenol hydrazone. Compounds of this type are represented by the following formula (5.2.10).
[717]
[718] Wherein "Het" is benzoxazol-2-yl, benzothiazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, 4-phenylpyrimidin-2- 1,4,6-diphenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-butylpyrimidin-2-yl, 4,6 Dibutylpyrimidin-2-yl and 4-methyl-6-phenylpyrimidin-2-yl.
[719] N- (5-substituted) -thiophene-2-alkylsulfonamides of formula (5.2.8) or 2,6-di-tert-butylphenol hydrazones of formula (5.2.10) or any derivatives thereof described above Is combined with a compound of formula (1.0.0) to form an embodiment of the invention.
[720] Another different class of 5-lipoxygenase inhibitors is methoxytetrahydropyran to which Geneca ZD-2138 belongs. ZD-2138 is represented by the formula (5.2.11).
[721]
[722] ZD-2138 is highly selective among various species, highly orally active and evaluated in the treatment of asthma and rheumatoid arthritis by oral administration. Further description of ZD-2138 and its derivatives is disclosed in Crawley et al., J. Med. Chem . 35 2600, 19992; and Crawley et al., J. med. Chem . 36 295, 1993. .
[723] Another different class of 5-lipoxygenase inhibitors belongs to the Smithcline Misery Compound SB-21066. SB-210661 is represented by the formula (5.2.12).
[724]
[725] Two further different and related classes of 5-lipoxygenase inhibitors include a series of pyridyl-substituted 2-cyanophthalene compounds and a series of 2-cyanoquinoline compounds found by Merck Frosst. . These two classes of 5-lipoxygenase inhibitors are, for example, L-739,010 and L-746,530 represented by the following formulas (5.2.13) and (5.2.14), respectively.
[726]
[727] A description of L-739,010 and L-746,530 can be found in Dube et al., "Quinoline as a potent 5-lipoxygenase inhibitor: Synthesis and Biological Profile of L-746,530," Bioorganic & Medicinal Chemistry 8 1255-1260, 1998) And WO 95/03309 (Friesen et al).
[728] Methoxytetrazolehydropyranes comprising Geneca ZD-2138 of formula (5.2.11) or leading compound SB-210661 of formula (5.2.12) and the class to which this compound belongs, or pyridinyl to which L-739,010 belongs; Substituted 2-cyanophthalene compounds, or 2-cyanoquinoline compounds to which L-746,530 belongs, or all of the aforementioned derivatives of all the above-mentioned classes are used in combination with a compound of formula (1.0.0) Forms an embodiment.
[729] In addition to the 5-lipoxygenase enzyme, another endogenous substance that plays an important role in the biosynthesis of leukotriene is 5-lipoxygenase activating protein (FLAP). This role is indirect to the opposite of the direct role of the 5-lipoxygenase enzyme. Nevertheless, antagonists of 5-lipoxygenase activating protein are used to inhibit the cell synthesis of leukotriene, and thus also in combination with a compound of formula (1.0.0) to form an embodiment of the invention.
[730] Compounds that bind to 5-lipoxygenase activating proteins and thereby block the use of arachidonic acid in the endogenous pool present are synthesized from indole and quinoline structures. Ford-Hutchinson et al., Ibid .; Rouzer et al., “Mk-886, a potent and selective inhibitor of leukotriene biosynthesis, blocks and reverses membrane association of 5-lipoxygenase in ionophore-induced leukotrienes. , " J. Biol. Chem . 265 1436-42, 1990; and Gorenne et al.," Strong leukotriene synthesis inhibitor {(R) -2-quinolin-2-yl-methoxy) phenyl) -2-cyclopentyl acetic acid } (BAY x1005): effect on anti-IgE induction in human airways, ” J. Pharmacol. Exp. Ther . 268 868-72, 1994).
[731] MK-591, referred to as cupripon sodium, is represented by the formula (5.2.15).
[732]
[733] The above-mentioned indole and quinoline compounds to which specific compounds MK-591, MK-886 and BAY x1005 belong, or all the above-mentioned derivatives of all the above-mentioned classes, can be used in combination with a compound of the formula (1.0.0) Form an embodiment.
[734] 9.2 Leukotriene LTB ₄ , LTC ₄ , LTD ₄ And LTE ₄ With receptor antagonists for
[735] One or more compounds of formula (1.0.0) are used in combination with receptor antagonists for leukotriene LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ . The most important leukotrienes in mediating the inflammatory response are LTB ₄ and LTD ₄ . Antagonist classification for these leukotriene receptors is described in the following paragraphs.
[736] 4-bromo-2,7-dimethoxy-3H-phenothiazine, including L-651,392 described in US Pat. No. 4,939,145 (Guindon et al.) And US Pat. No. 4,845,083 (Lau et al.) 3-one is a potent receptor antagonist for LTB ₄ . L-651,392 is represented by the following formula (5.2.16).
[737]
[738] Amidino compounds including CGS-25019c are described in US Pat. No. 5,451,700 (Morrissey and Suh), US Pat. No. 5,488,160 (Morrissey) and US Pat. No. 5,639,768 (Morrissey and Suh). These receptor antagonists for LTB ₄ are represented by CGS-25019c represented by the following formula (5.2.17).
[739]
[740] Ontazolast, a member of benzoxaolamines, a receptor antagonist for LTB ₄ , is described in EP 535 521 (Anderskewitz et al.), Which is represented by the following formula (5.2.18).
[741]
[742] Researchers in the same group are described in WO 97/21670 (Anderskewitz et al.), And WO 98/11119 (Anderskewitz et al.) And in LTB ₄ represented by BIIL 284/260 of formula (5.2.19) A classification of benzenecarboximidamide, a receptor antagonist, was developed.
[743]
[744] Zafirlukast is a receptor antagonist for LTC ₄ , LTD ₄ and LTE ₄ sold under the trade name Accolate®. This is described in US Pat. No. 4,859,692 (Bernstein et al.), US Pat. No. 5,319,097 (Holohan and Edwards), US Pat. No. 5,294,636 (Edwards and Sherwood), US Pat. No. 5,482,963, US Pat. No. 5,583,152 (Bernstein et al. .), And the heterocyclic amide derivatives described in US Pat. No. 5,612,367 (Timko et al.). Zafirlukast is represented by the following formula (5.2.20).
[745]
[746] Abluecast is a receptor antagonist for LTD ₄ , referred to as Ro 23-3544 / 001 and is represented by the formula (5.2.21).
[747]
[748] Montelukast is a receptor antagonist for LTD ₄ sold under the name Singulair® and described in US Pat. No. 5,565,473. Montelukast is represented by the following formula (5.2.22).
[749]
[750] Other receptor antagonists for LTD ₄ include Franlukast, Berlucast (MK-679), RG-12525, Ro-245913, Irallukast (CGP 45715A) and BAY x7195.
[751] The above-mentioned phenothiazine-3-one compounds comprising L-651,392, amidino compounds comprising CGS-25019c, benzoxaolamines containing ontazolast, benzenecar represented by BIIL284 / 260 Voximidamides, heterocyclic amide derivatives including zafirlukast, ablucast and montelukast and the compounds to which they belong, or all of the aforementioned derivatives of all the above-mentioned classes are represented by the formula (1.0.0) Used in combination with a compound of to form an embodiment of the present invention.
[752] 9.3 with other therapeutic agents forming additional combinations
[753] At least one compound of formula (1.0.0) is a further embodiment of the invention and is used in combination with other therapeutic and non-therapeutic agents useful for the treatment of a great many different diseases, disorders and conditions described herein. Said embodiment comprises at least one compound of formula (1.0.0) with at least one of the following:
[754] (a) a PDE4 inhibitor comprising an inhibitor of isoform PDED4,
[755] (b) a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein (FLAP) antagonist,
[756] (c) dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF),
[757] (d) leukotriene antagonists (LTRA), including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ,
[758] (e) antihistamine H ₁ receptor antagonists, including cetirizine, loratadine, desloratadine, fexofenadine, astemizol, azelastine and chlorpheniramine,
[759] (f) gastroprotective H ₂ receptor antagonist,
[760] (g) congestion comprising propylhexerine, phenylephrine, phenylpropanolamine, pseudoephedrine, napazoline hydrochloride, oxymethazolin hydrochloride, tetrahydrozoline hydrochloride, xylomethazolin hydrochloride and ethylnorpinephrine hydrochloride Α ₁ -and α ₂ -adrenergic agonists vasoconstrictive sympathomimetic drugs administered orally or topically for palliative use,
[761] (h) α ₁ -and α ₂ -adrenergic agonists in combination with 5-lipoxygenase (5-LO) inhibitors,
[762] (i) an anticholinergic agent comprising ipratropium bromide,
[763] (j) β ₁ -to β ₄ -arre including isoprelinin, albuterol, salbutamol, formoterol, salmeterol, terbutalin, orciprelinin, bitolterol mesylate and pirbuterol Blown Receptor Agonist,
[764] (k) theophylline and aminophylline,
[765] (l) sodium chromoglycate,
[766] (m) muscarinic receptors (M1, M2 and M3) antagonists,
[767] (n) COX-1 inhibitors (NSAIDs), COX-2 selective inhibitors including rofecoxib, and nitric oxide NSAIDs,
[768] (o) insulin-like growth factor type 1 (IGF-1) mimetics,
[769] (p) ciclesonide,
[770] (q) inhaled glucocorticoids with reduced systemic side effects including flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate,
[771] (r) tryptase inhibitors,
[772] (s) platelet activating factor (PAF) antagonists,
[773] (t) monoclonal antibodies against endogenous inflammatory entities,
[774] (u) IPL 576,
[775] (v) anti-tumor necrosis factor (TNFα) substances, including etanercept, infliximab, and D2E7,
[776] (w) DMARDs comprising leflunomide,
[777] (x) TCR peptides,
[778] (y) interleukin converting enzyme (ICE) inhibitors,
[779] (z) IMPDH inhibitors,
[780] (aa) adhesion molecule inhibitors, including VLA-4 antagonists,
[781] (bb) cathepsin,
[782] (cc) MAP kinase inhibitors,
[783] (dd) glucose-6 phosphate dehydrogenase inhibitors,
[784] (ee) kinin-B ₁ -and B ₂ -receptor antagonists,
[785] (ff) gold in the form of an aurothio group with various hydrophilic groups,
[786] (gg) immunosuppressive agents such as cyclosporin, azathioprine and methotrexate,
[787] (hh) antigout agents, such as colchicine,
[788] (ii) xanthine oxidase inhibitors, such as allopurinol,
[789] (jj) urinary urinary excretion accelerators such as probeneside, sulfinpyrazone and benzbromarone,
[790] (kk) anti-neoplastic agents, in particular mitotic drugs, including vinca alkaloids such as vinblastine and vincristine,
[791] (ll) growth hormone secretagogue,
[792] (mm) stromelysin, collagenase, gelatinase as well as aggrecanase, in particular collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 ( Inhibitors of matrix metalloproteinases (MMP) which are MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11),
[793] (nn) transforming growth factor (TGFβ),
[794] (oo) platelet derived growth factor (PDGF),
[795] (pp) fibroblast growth factor, such as basic fibroblast growth factor (bFGF),
[796] (qq) granulocyte-macrophage colony stimulating factor (GM-CSF),
[797] (rr) capsaicin cream,
[798] (ss) anti-emetic agents, including NK-1 receptor antagonists and D-4418,
[799] (tt) anti-depressants.
[800] Detailed description of the invention
[801] 10.0 Pharmaceutical Compositions and Formulations
[802] The following description is intended for use in all given patients in combination with most conventional pharmaceutically acceptable carriers in combination with other therapeutic or non-therapeutic agents, where the compound of formula (1.0.0) is preferred, as well as diseases, disorders for all given patients to be treated. Or to form dosage forms suitable for different routes of administration appropriate to the condition.
[803] Preferred routes of administration for compounds of formula (1.0.0) are for oral and aerosol formulations which are prepared and delivered in conventional manner. Detailed information regarding the preparation and manner of such formulations to be administered to patients in need of treatment is discussed further below.
[804] The pharmaceutical compositions of the present invention may be prepared by any one or more of the above-described inhibitory compounds of the present invention, or pharmaceutically acceptable salts thereof, also described above, depending on the nature and expected practice of such carriers known in the art. Include with.
[805] The amount of active material that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. However, specific dosages and treatment regimens for any particular patient may be determined by the activity, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and treatment of the specific compound used, and the particular treatment being treated. It should be understood that this will vary depending on the severity of the disease. The amount of active substance, if present, may also vary depending on the therapeutic or prophylactic agent to which the component is coadministered.
[806] The compounds of the invention described above can be used in the form of acids, esters, or other chemical classes of compounds to which the compounds described belong. It is also within the scope of the present invention to use such compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to the processes described above and known in the art. Active ingredients comprising compounds of formula (1.0.0) often contain active ingredients with improved pharmacodynamic properties, in particular compared to the free form of the active ingredient or other salt forms of the active ingredient conventionally used. If used, it is used in its salt form. The pharmaceutically acceptable salt form of the active ingredient has not been conventionally present and may impart desirable active pharmacodynamic properties to the active ingredient which may positively affect the pharmacokinetics of the active ingredient for therapeutic activity in the human body.
[807] The pharmacodynamic properties of the active ingredient which can be advantageously affected are, for example, a form in which the active ingredient is transported through the cell membrane, which can directly and positively affect the absorption, distribution, bioconversion and excretion of the active ingredient. It includes. Although the route of administration of the pharmaceutical composition is important, various anatomical, physiological and pathological factors can have an extreme impact on bioavailability, and the solubility of the active ingredient depends on the characteristics of the particular salt form commonly employed. In addition, as will be appreciated by those skilled in the art, an aqueous solution of the active ingredient provides the fastest absorption of the active ingredient into the human body of the treated patient, while fat solutions and suspensions as well as solid dosage forms provide less amount of the active ingredient. Will cause rapid absorption. Oral ingestion of the active ingredient is the most preferred route of administration for reasons of stability, convenience and economy, but absorption of this oral dosage form is dependent upon physical properties such as polarity, vomiting caused by stimulation of the gastrointestinal mucosa, digestive enzymes and low pH. May be negatively affected by degradation, by prolonged absorption or propulsion in the presence of food or other drugs, and by metabolism by mucosal, intestinal plexus or liver enzymes. Formulation of such active ingredients into different pharmaceutically acceptable salts may be effective to overcome or alleviate one or more of the above mentioned problems encountered upon absorption of oral dosage forms.
[808] Among the pharmaceutical salts mentioned above, preferred ones include acetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hypofurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate Laterate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate or trometamine.
[809] Complex salt forms in which the compounds of the present invention comprise one or more groups capable of forming such pharmaceutically acceptable salts are included within the scope of the present invention. Examples of typical complex salt forms include, but are not limited to, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride.
[810] Pharmaceutical compositions of the present invention comprise at least one of the aforementioned inhibitory compounds of the present invention or also the aforementioned pharmaceutically acceptable salts, together with the pharmaceutically acceptable carriers according to the nature and anticipated performance of the carriers known in the art. .
[811] As used herein, the term “carrier” includes acceptable diluents, excipients, adjuvant, vehicles, dissolution aids, viscosity modifiers, preservatives and other materials known in the art to provide suitable properties for the final pharmaceutical composition. To illustrate such carriers, a brief overview of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention, followed by a more detailed description of the various types of components. Typical carriers include ion exchange compositions, alumina, aluminum stearate, lecithin, plasma proteins (e.g. human plasma albumin), phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, hydrogenated palm oil, water, salts Or electrolytes such as prolamin sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based components such as sodium carboxy Methylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers and wool fats, but are not limited to these.
[812] More specifically, the carriers used in the pharmaceutical compositions of the present invention include additives of various classes and species which are members independently selected from the group consisting mainly of those listed in the following paragraphs.
[813] Acidifying and alkalizing agents are added to obtain the desired or predetermined pH and include acidifying agents such as acetic acid, glacial acetic acid, malic acid and propionic acid. Strong acids such as hydrochloric acid, nitric acid and sulfuric acid may be used but are less preferred. Alkylating agents include, for example, edetol, potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate, and sodium hydroxide. Alkaliating agents comprising active amine groups such as diethanolamine and trolamine may also be used.
[814] Aerosol propellants are preferred when the pharmaceutical composition is to be delivered as an aerosol under significant pressure. Such propellants include, for example, acceptable fluorochlorohydrocarbons such as dichlorodifluoromethane, dichlorotetrafluoroethane and trichloromonofluoromethane; nitrogen; Or volatile hydrocarbons such as butane, propane, isobutane or mixtures thereof.
[815] Including antimicrobial, antifungal and antigenic probiotics when the pharmaceutical composition is topically applied to areas of the skin where the skin is exposed to infections caused by bacteria, fungi or protozoa, or where there may be a negative or persistent abrasion or scratch Antimicrobial agent is added. Antimicrobial agents include compounds such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, potassium sorbate and sorbic acid. Antifungal agents include compounds such as benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben and sodium benzoate.
[816] Antimicrobial preservatives are added to the pharmaceutical compositions of the present invention to protect against the potent and harmful microorganisms that typically invade the aqueous phase but often also grow in the oil phase of the composition. Therefore, preservatives having both water solubility and fat solubility are preferred. Suitable antimicrobial preservatives are, for example, alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, methylparaben sodium, propylparaben sodium, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride, Benzyl alcohol, hydantoin derivatives, quaternary ammonium compounds and cationic polymers, imidazolidinyl urea, diazolidinyl urea and trisodium ethylenediamine tetraacetate (EDTA). Preservatives are preferably used in amounts of about 0.01% to about 2.0% of the total composition weight.
[817] Antioxidants are added to protect all components of the pharmaceutical composition from damage or degradation by oxidants present in the composition itself or in the environment of use, such as enoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxide Oxytoluene, hypophosphoric acid, potassium metabisulfite, propyl octyl and dodecyl gallate, sodium metabisulfite, sulfur dioxide and tocopherol.
[818] The buffering agent compound is used to maintain the desired pH of the composition once set from the effects of foreign substances and the equilibrium shift of the components of the composition. Buffering agents may be selected from those familiar to those skilled in the art of preparing pharmaceutical compositions, for example calcium acetate, potassium metaphosphate, potassium phosphate monobasic and tartaric acid.
[819] Chelating agents are used to help maintain the ionic strength of pharmaceutical compositions and to effectively bind and remove destructive compounds and metals and include, for example, edetate dipotassium, edetate disodium and edemic acid.
[820] Dermatologically active substances are added to the pharmaceutical compositions of the present invention when applied topically and include, for example, peptide derivatives, yeast, panthenol, hexylesorcinol, phenol, tetracycline hydrochloride, lamin and chitenin Wound healing agents; Retinoids for treating skin cancer, such as retinol, tretinoin, isotretinoin, etretinate, acitretin and arotinoids; Weak antibacterial agents for treating skin infections such as resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin and clindamycin; Antifungal agents for the treatment of ringworm, tinea ringworm, candidiasis and nausea, for example azoles such as griseofulvin, myconazole, echoazole, itraconazole, fluconazole and ketoconazole, and allylamine such as naphthypine and terpinafine; Antiviral agents for treating cutaneous herpes simplex, herpes zoster and chickenpox, such as acyclovir, famcyclovir and valacyclovir, pruritus, atopic and contact dermatitis, for example diphen Hydramine, terpenadine, astemizole, loratadine, cetirizine, acribastine and temelastin; Local anesthetics to relieve pain, irritation and itching, such as benzocaine, lidocaine, dibucaine and pramoxin hydrochloride; Topical analgesics for alleviating pain and inflammation, such as methyl salicylate, camphor, menthol and resorcinol; Topical preservatives to prevent infections such as benzalkonium chloride and povidone-iodine; And vitamins and derivatives thereof such as tocopherol, tocopherol acetate, retinoic acid and retinol.
[821] Dispersing and suspending agents are used as adjuvants for preparing stabilizing agents and include, for example, polyginane, povidone and silicon dioxide.
[822] Emollients are materials that soften and smoothen the skin, especially those that dry out due to excess water loss, preferably non-oil soluble materials. Such materials are used in conjunction with the pharmaceutical compositions of the invention for topical application, for example hydrocarbon oils and waxes, triglyceride esters, acetylated monoglycerides, methyl and other alkyl esters of C ₁₀ -C ₂₀ fatty acids, C ₁₀ -C ₂₀ Fatty acids, C ₁₀ -C ₂₀ fatty alcohols, lanolin and derivatives, polyhydric alcohol esters such as polyethylene glycol (200-600), polyoxyethylene sorbitan fatty acid esters, wax esters, phospholipids and steroids; Emulsifiers used to prepare oil-in-water emulsions; Excipients such as laurocapram and polyethylene glycol monomethyl ether; Wetting agents such as sorbitol, glycerin and hyaluronic acid; Ointment bases such as petrolatum, polyethylene glycol, lanolin, and poloxamers; Penetration enhancers such as dimethyl isosorbide, diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one and dimethylsulfoxide (DMSO); Preservatives such as benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propylparaben, potassium benzoate and thimerosal; Sequestrants including cyclodextrins; Solvents such as acetone, alcohols, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil Phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil, and purified water; Stabilizers such as calcium saccharide and thymol; Surfactants such as rapylium chloride; Laureth 4, ie α-dodecyl-ω-hydroxy-poly (oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether.
[823] Emulsifiers, including emulsifying and reinforcing and tanning agents, are used to prepare oil-in-water emulsions when forming the basis of a pharmaceutical composition of the present invention. Such emulsifiers are, for example, nonionic emulsifiers such as C ₁₀ -C ₂₀ fatty alcohols and condensed with 2 to 20 moles of ethylene oxide or propylene oxide condensed with 2 to 20 moles of ethylene oxide (C ₆ -C ₁₂ ) alkyl phenol, mono- and di-C ₁₀ -C ₂₀ fatty acid esters of ethylene glycol, C ₁₀ -C ₂₀ fatty acid monoglycerides, diethylene glycol, polyethylene glycol of MW 200-6000, poly of MW 200-3000 Propylene glycol, and in particular sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan, hydrophilic wax esters, cetostearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, mono- and di-glycerides, glyceryl monostea Mixed mono- and distearic acid esters, propylene glycol of polyethylene glycol monostearate, ethylene glycol and polyoxyethylene glycol Monostearate and hydroxypropyl cellulose. Emulsifiers containing active amine groups can also be used, typically fatty acid soaps such as sodium, potassium and triethanolamine soaps of C ₁₀ -C ₂₀ fatty acids; Anionic emulsifiers such as alkali metals, ammonium or substituted ammonium (C ₁₀ -C ₃₀ ) alkyl sulfates, (C ₁₀ -C ₃₀ ) alkyl sulfonates, and (C ₁₀ -C ₅₀ ) alkyl ethoxy ether sulfonates Included. Other suitable emulsifiers include castor oil and hydrogenated castor oil; lecithin; And polymers of acrylic acid, crosslinked with allyl ethers of sucrose and / or pentaerythritol, all of which have various viscosities and have the product names carbomer 910, 934, 934P, 940, 941 and 1342. Polymers of phenoic acid. Cationic emulsifiers with active amine groups can also be used, including those based on quaternary ammonium, morpholinium and pyridinium compounds. Similarly, amphoteric emulsifiers with active amine groups such as cocobetaine, lauryl dimethylamine oxide and cocoylimidazoline can be used. Useful emulsifying and reinforcing agents also include cetyl alcohol and sodium stearate; And emulsion adjuvant such as oleic acid, stearic acid and stearyl alcohol.
[824] Excipients include, for example, laurocapram and polyethylene glycol monomethyl ether.
[825] When the pharmaceutical composition of the invention is applied topically, penetration enhancers can be used, for example dimethyl isosorbide, diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one and Dimethyl sulfoxide (DMSO). Such compositions also typically include ointment bases such as petrolatum, polyethylene glycol, lanolin and poloxamers (block copolymers of polyoxyethylene and polyoxypropylene, which may also act as surfactants or emulsifiers).
[826] Preservatives are used to protect the pharmaceutical compositions of the present invention from degradation attacks by atmospheric microorganisms, for example benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, derivatives of idatone, cetylpyridinium Chloride, monothioglycerol, phenol, phenoxyethanol, methylparagen, imidazolidinyl urea, sodium dehydroacetate, propylparaben, quaternary ammonium compounds, especially polymers such as polycetoninium chloride, potassium benzoate, sodium form Aldehyde sulfoxylates, sodium propionate and thimerosal.
[827] Sequestrants are used to improve the stability of the pharmaceutical compositions of the present invention and are, for example, natural cyclic oligosaccharide families that can form inclusion complexes with various substances, typically α-cyclodextrins, β-cyclodextrins, and cyclodextrins of various ring sizes with 6-, 7- and 8-glucose residues in the ring called γ-cyclodextrin. Suitable cyclodextrins include, for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin and cationized cyclodextrins.
[828] Solvents that may be used to prepare the pharmaceutical compositions of the present invention include, for example, acetone, alcohols, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostear Aryl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil and purified water.
[829] Suitable stabilizers for use include, for example, calcium saccharides and thymol.
[830] Reinforcing agents are commonly used in topical formulations to provide the desired viscosity and handling properties and include, for example, cetyl ester waxes, myristyl alcohols, paraffins, synthetic paraffins, emulsifying waxes, microcrystalline waxes, white waxes and yellow waxes. Include.
[831] Sugars are often used to impart various desirable properties of the pharmaceutical compositions of the present invention and to improve the results obtained, for example, glucose, xylose, fructose, leoth, ribose, pentose, arabinose, allose, talos, Monosaccharides, disaccharides and polysaccharides such as altrose, mannose, galactose, lactose, sucrose, erythrose, glyceraldehyde or any combination thereof.
[832] Surfactants are used to provide stability to the multi-component pharmaceutical compositions of the present invention, to increase the existing properties of these compositions, and to impart desirable novel properties to the compositions. Surfactants are used as wetting agents, antifoams, and emulsifiers, dispersants, and penetrants to reduce the surface tension of water and include, for example, rapylium chloride; Laureth 4, ie α-dodecyl-ω-hydroxy-poly (oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether; Laureth 9, a mixture of polyethylene glycol monododecyl ethers with an average of about 9 ethylene oxide groups per molecule; Monoethanolamine, nonoxinol 4, 9 and 10, ie polyethylene glycol mono (p-nonylphenyl) ethers; Nonoxynol 15, ie α- (p-nonylphenyl) -ω-hydroxypenta-deca (oxyethylene); Nonoxynol 30, ie α- (p-nonylphenyl) -ω-hydroxytriconta (oxyethylene); Poloxylene, ie a nonionic polymer of the polyethylene-polypropylene glycol type, MW = about 3000; Poloxamers further discussed and referred to in the ointment base; Polyoxyl 8, 40 and 50 stearate, ie poly (oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-; Octadecanoate; Polyoxyl 10 oleyl ether, ie poly (oxy-1,2-ethanediyl), α-[(Z) -9-octadecenyl-ω-hydroxy-; Polysorbate 20, ie sorbitan, monododecanoate, poly (oxy-1,2-ethanediyl); Polysorbate, 40, ie sorbitan monohexadecanoate, poly (oxy-1,2-ethanediyl); Polysorbate 60, ie sorbitan, monooctadecanoate, poly (oxy-1,2-ethanediyl); Polysorbate 65, ie sorbitan, trioctadecanoate, poly (oxy-1,2-ethanediyl); Polysorbate 80, ie sorbitan, mono-9-monodecanoate, poly (oxy-1,2-ethanediyl); Polysorbate 80, ie sorbitan, mono-9-monodecenoate, poly (oxy-1,2-ethanediyl); Polysorbate 85, ie sorbitan, tri-9-octadecenoate, poly (oxy-1,2-ethanediyl); Sodium lauryl sulfate; Sorbitan monolaurate; Sorbitan monooleate; Sorbitan monopalmitate; Sorbitan monostearate; Sorbitan sesquioleate; Sorbitan trioleate; And sorbitan tristearate.
[833] Pharmaceutical compositions of the invention can be prepared using very easy methods well understood by those skilled in the art. When the pharmaceutical composition of the present invention is a simple aqueous and / or other solvent solution, the various components of the total composition are given any working order, indicated primarily in view of convenience. Although the water solubility is reduced, all of these components having sufficient solubility in the same cosolvent with water can be dissolved in the cosolvent, and then the cosolvent solution is added to the water portion of the carrier, thereby allowing the solvent to be dissolved in water. Will be. Surfactants may be used to assist in the dispersion / solution process.
[834] When the pharmaceutical composition of the present invention is in the form of an emulsion, the components of the pharmaceutical composition will be obtained according to the following general procedure. The continuous aqueous phase is first heated to a temperature of about 60 ° C. to about 95 ° C., preferably about 70 ° C. to about 85 ° C., and the choice of temperature used depends on the physical and chemical properties of the components that make up the oil-in-water emulsion. . When the continuous water phase reaches the selected temperature, the components of the final composition added in this step are mixed with water and dispersed in it by high speed stirring. Next, the temperature of the water is returned to the almost initial level, after which the components of the composition comprising the next step are added to the composition mixture under light agitation, depending on the components of the first two steps, preferably from about 5 to about 60 minutes, preferably about Mixing is continued for 10 to about 30 minutes. Thereafter, the composition mixture is passively or actively cooled to about 20 ° C. to about 55 ° C. for the addition of any component of the next step, and then a sufficient amount of water is added to reach an initial predetermined concentration in the total composition.
[835] According to the invention, the pharmaceutical composition may be in the form of sterile injectable preparations, for example sterile injectable aqueous or oily suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example in solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Particularly useful for the preparation of injectables are fatty acids such as oleic acid and their glyceride derivatives, such as natural pharmaceutically acceptable oils such as olive oil or castor oil in the polyoxyethylated type. These oil solutions or suspensions may also contain long chain alcohol diluents or dispersants such as Rh , HCIX or similar alcohols.
[836] The pharmaceutical composition of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, carriers that are commonly used include lactose and corn starch. Glidants, such as magnesium stearate, are typically added. Diluents useful for oral administration in capsule form include lactose and anhydrous corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal administration. It can be prepared by mixing the material with a suitable non-irritating excipient which is solid at room temperature or liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[837] Pharmaceutical compositions of the invention may also be administered topically when the therapeutic target comprises a region or organ that is readily applicable by topical application, particularly including diseases of the eye, skin or lower intestine. Suitable topical formulations are readily prepared for each of these areas or organs.
[838] Topical application for the lower intestine may be accomplished with rectal suppository formulations, or suitable enema formulations as described above. Topically active transdermal patches can also be used.
[839] For topical application, the pharmaceutical composition may be formulated in a suitable ointment containing the active substance suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[840] Pharmaceutical compositions within the scope of the present invention comprise a systemically effective amount of the active ingredient comprising a compound of the present invention that is required for treating or preventing diseases or disorders and conditions mediated or associated by modulating PDE4, in particular PDE4D activity, as described herein. Provided in a dosage form suitable for administration. Such pharmaceutical compositions will contain the active ingredient in liquid form suitable for delivery by: (1) injection or infusion in intraarterial, intradermal or transdermal, subcutaneous, intramuscular, intramedullary, intradural or intravenous Wherein the active ingredient is (a) dissolved in the solution as a solution, (b) in the discontinuous phase of the emulsion, or in a continuous phase of the reversed phase emulsion which is reversed by injection or injection, the emulsion containing a suitable emulsifier or Or (c) in suspension in solid form in the form of a colloidal or microparticle, which suspension contains a suitable suspending agent, (2) injection or infusion into a body tissue or lumen suitable as a depot, Wherein said composition provides a reservoir of said active ingredient and thus provides a delayed, sustained and / or controlled release of said active ingredient for systemic distribution, (3) suitable Dropping, inhaling or insufflation of the pharmaceutical composition into a suitable body tissue or lumen in solid form, wherein the active ingredient is (a) a solid that provides delayed, sustained and / or controlled release of the active ingredient Contained in a graft composition, (b) in a particle composition that is inhaled into the lung, or (c) in a particle composition that is blown into suitable body tissue or lumen, wherein the composition is a delayed, sustained and (Or) provide controlled release, or (4) ingestion of the pharmaceutical composition in solid or liquid form suitable for oral delivery of the active ingredient, wherein the active ingredient is contained in (a) solid dosage form, or (b A) in liquid dosage form.
[841] Certain dosage forms of the pharmaceutical compositions described above (1) contain a base that is solid at room temperature or melts at body temperature, and is incorporated into the surrounding tissues of the human body where the active ingredient is absorbed and transported to effect systemic administration, thereby slowly Suppository, which is a special type of implant that releases, (2) a solid oral dosage form selected from the group consisting of (a) delayed release oral tablets, capsules, caplets ), Lozenges, troches, and multiparticulates; (b) enteric skin tablets and capsules that prevent delivery and absorption in the stomach to promote delivery to the distant stomach of the patient being treated; (c) sustained release oral tablets, capsules and particulates that provide systemic delivery of the active ingredient in a controlled fashion up to 24 hours; (d) rapidly dissolving tablets; (e) encapsulated tablets; (f) oral pastes; (g) granules incorporated into or incorporated into the food of the patient to be treated; And (h) liquid oral dosage forms selected from the group consisting of solutions, suspensions, emulsions, reversed phase emulsions, elixirs, extracts, tinctures and concentrates.
[842] Pharmaceutical compositions within the scope of the present invention are treated with a therapeutically effective amount of an active ingredient comprising a compound of the present invention that is required to treat or prevent diseases or disorders and conditions mediated or associated by modulating PDE4, in particular PDE4D activity, as described herein. Provided in a dosage form suitable for topical administration to a patient in need thereof, wherein the pharmaceutical composition may contain the active ingredient in a suitable liquid form delivered by: (1) intraarterial, intraarticular, Intracorporeal, Intracostal, Intracystic, Intradermal or transdermal, Intramuscular, Intra ligament, Intramedullary, Intramuscular, Intranasal, Intraneuronal, Intraocular, or ophthalmic administration, Intraosseous, Intrapelvic, Intracardia, Intraspinal Injection or infusion into a topical site that is intrasternal, intrasynovial, intramuscular, or intrafoveal, where they prevent delayed-release, controlled-release, and / or sustained-release of the active ingredient into the topical site. A concomitant component, wherein the active ingredient is (a) included in solution as a dissolution, (b) a discontinuous phase of the emulsion, or in a discontinuous phase of a reverse phase emulsion reversed by injection or injection, wherein the emulsion Comprises a suitable emulsifier, or (c) is contained in the suspension in solid suspension in colloidal or particulate form, the suspension comprising a suitable suspending agent, or (2) delivering the active ingredient to the topical site. Injection or infusion as a reservoir for the composition, wherein the composition provides a delayed-, sustained- and / or controlled release of the active ingredient and subsequently to the topical site of the active ingredient, wherein the composition also Or comprises the ingredient which ensures that the active ingredient has predominantly local activity with little systemic carryover activity, or wherein said pharmaceutical The composition contains the active ingredient in a solid form suitable for delivering the inhibitor, and (3) dropping, inhaling or blowing into the topical site, wherein the active ingredient is (a) in a solid graft composition installed at the topical site And wherein the composition is optionally contained in a particle composition that provides delayed-, sustained- and / or controlled-release of the active ingredient to the topical site, or (b) is inhaled into a topical site comprising the lungs. Or (c) in a particle composition that is blown into the topical site, wherein the composition comprises an ingredient which ensures that the active ingredient has predominantly local activity with systemic carryover activity, and optionally the topical agent of the active ingredient Delayed-, sustained- and / or controlled release to the site. For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH adjusted sterile saline, or preferably as isotonic, pH adjusted sterile saline, with or without preservatives such as benzylalkonium chloride. have. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.
[843] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation using nebulizers, dry spray inhalers or metered dose inhalers. Such compositions are prepared according to techniques known in the art of pharmaceutical formulations, and are solutions in saline, benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, hydrofluorocarbons and / or other conventional dissolution or dispersing agents. It can be prepared using.
[844] As mentioned above, the active ingredient of formula (1.0.0) of the present invention may be administered systemically to a patient treated with a pharmaceutical composition in a suitable liquid form by injection or infusion. There are a variety of site and organ systems of the patient's body that, when injected or infused, allow the appropriately formulated pharmaceutical composition to be disseminated to all or all organ systems of the patient's body to be treated. Injection is a single dose of the pharmaceutical composition, usually by syringe, into the relevant tissue. The most common types of injections are intramuscular, intradermal and subcutaneous. In contrast, infusion is a gradual introduction of the pharmaceutical composition into the relevant tissue. The most common type of infusion is intravenous. Other types of injections or infusions are intraarterial, intradermal or transdermal (including subcutaneous) or spinal cord, especially intradural. In these liquid pharmaceutical compositions, the active ingredient may be contained in solution as a lysate. This is the most common and most preferred type of composition, but requires the active ingredient in salt form with a fairly good water solubility. Water (or saline) is by far the most preferred solvent for such compositions. Supersaturated solutions can sometimes be used, but there is a problem of stability that is not practical in daily use.
[845] If it is not possible to obtain the form of some of the compounds of the formula (1.0.0) with the required degree of water solubility as may occur sometimes, a continuous or second phase that is miscible with the discontinuous or internal phase of one liquid of a small sphere It is within the skill of one of ordinary skill in the art to prepare emulsions that are dispersion through trauma. The two liquids are kept in an emulsified state by the use of a pharmaceutically acceptable emulsifier. Thus, if the active ingredient is a water-insoluble oil, it can be administered in an emulsion in which it is present in a discontinuous phase. In addition, emulsions can be used when the active ingredient can be dissolved in a solvent that is water-insoluble or miscible with water. The active ingredient may be conventionally used as a discontinuous or internal phase of what is referred to as an oil-in-water emulsion, but it may also be used as a discontinuous or internal phase of a reversed phase emulsion commonly referred to as a water-in-oil emulsion. The active ingredient is soluble in water, It can be administered in a simple aqueous solution. However, reversed phase emulsions have the advantage of reversing into an aqueous medium such as blood upon injection or infusion and providing a more rapid and effective dispersion of the active ingredient into the aqueous medium obtainable using an aqueous solution. Reversed phase emulsions are prepared using suitable, pharmaceutically acceptable emulsifiers known in the art. If the active ingredient has limited water solubility, it may also be administered as a solid suspended in colloidal or particulate form in a suspension prepared using a suitable, pharmaceutically acceptable suspending agent. Suspended solids containing the active ingredient can also be formulated in delayed-, sustained- and / or controlled-release compositions.
[846] Although systemic administration can most often be performed by injection or infusion of liquid, there are many situations where it may be advantageous or more necessary to deliver the active ingredient as a solid. Systemic administration of a solid is carried out by dropping, inhaling or blowing the pharmaceutical composition in a suitable solid form containing the active ingredient. Dropping of the active ingredient may involve installing the solid implant composition into a suitable body tissue or lumen. The implant may comprise a matrix of bio-compatible and bio-erodible materials in which particles of the solid active ingredient are dispersed or, where possible, spheres of the liquid active ingredient or trapped cells. Preferably, the matrix can be destroyed by the body and completely absorbed. The composition of the matrix is also preferably selected to provide controlled-, sustained- and / or delayed release of the active ingredient over an extended period of time, even months.
[847] The term "graft" most often refers to a solid pharmaceutical composition containing the active ingredient, while the term "reservoir" is typically stored in any suitable body tissue or lumen to slowly move to surrounding tissues and organs and eventually systemically By liquid pharmaceutical composition containing the active ingredient, which forms the scale or pool that becomes to be distributed. However, this distinction is not always strictly adhered to in the art, and therefore, it is contemplated to include liquid implants and solid reservoirs within the scope of the present invention and further encompass each mixed solid and liquid form. Suppositories are a type of implant because they contain a solid at room temperature or a base that melts at the patient's body temperature, and slowly release the active ingredient into the tissues around the body of the patient being injected, where the active ingredient is absorbed and transported to obtain systemic effects. Can be considered.
[848] Systemic administration can also be carried out by inhalation or insufflation of a powder, ie, a particle composition containing the active ingredient. For example, the active ingredient in powder form can be inhaled into the lungs using conventional apparatus for aerosolizing the particle formulation. The active ingredient, which is a particle preparation, can also be administered by using a conventional apparatus for blowing, ie aerosolizing the particle preparation, or by blowing or otherwise dispersing into suitable body tissues or tourism by simple spraying. These particle compositions can also provide delayed-, sustained- and / or controlled-release of the active moiety according to formulated and understood principles and known materials.
[849] Other systemic means of administration that can use the active ingredients of the invention in liquid or solid form include the transdermal, intranasal and ophthalmic routes. In particular, transdermal patches prepared according to known drug delivery techniques are prepared, applied to the skin of a patient to be treated, and for the post-formulated solubility properties, the active ingredient passes through the epidermis and as part of the general circulation of the patient. Migrates to the dermal layer of the patient's skin and finally provides a systemic distribution over the desired extended period of time for the active ingredient. Also included are implants located beneath the epidermal layer of the skin, ie between the epidermis and the dermis of the patient's skin to be treated. Such implants may be formulated according to principles known in the delivery art and materials commonly used and in a manner that provides controlled, sustained, and / or delayed release of the active ingredient into the systemic circulation of the patient. Can be prepared. Such subcutaneous (subcutaneous) implants provide the same usability of installation and delivery as a transdermal patch, but are not limited to degradation, damage or accidental removal of the subject as a result of exposure on the upper layer of the patient's skin.
[850] In the above description of pharmaceutical compositions containing the active ingredient of formula (1.0.0), the equivalent expressions "administration" "administration of" "administering" and "administering" have been used with respect to the pharmaceutical composition. As used, these expressions are intended to mean that a pharmaceutical composition of the present invention is provided to a patient in need thereof by any route of administration described herein, wherein the active ingredient is PDE4, in particular PDE4D, in the patient. A compound of formula (1.0.0), or a prodrug, derivative or metabolite thereof, useful for treating a disease, disorder or condition mediated by or accompanied by modulation of activity. Thus, within the scope of the present invention are included all other compounds that can provide, directly or indirectly, a compound of formula (1.0.0) upon administration to a patient. Such compounds are recognized as prodrugs and various established processes are available for preparing such prodrug forms of compounds of formula (1.0.0).
[851] The dose and rate of administration of a compound of formula (1.0.0) effective for treating or preventing a PDE4, in particular a disease, disorder or condition accompanying, or accompanied by the modulation of PDE4D activity, depends on the nature of the inhibitor, the size of the patient, It will depend on various factors such as the therapeutic purpose, the conditional nature to be treated, the particular pharmaceutical composition used, and the findings and conclusions of the therapist.
[852] For example, when the dosage form is oral, such as a tablet or capsule, a suitable dosage level of the compound of formula (1.0.0) may be from about 0.1 μg / kg to about 50.0 mg / kg of body weight per day, Preferably from about 5.0 μg / kg to about 5.0 mg / kg of body weight per day, more preferably from about 10.0 μg / kg to about 1.0 mg / kg of body weight per day, most preferably about 20.0 μg of body weight per day / kg to about 0.5 mg / kg.
[853] When the dosage form is administered topically to the bronchus and lungs, for example by a powder inhaler or nebulizer, a suitable dosage level of the compound of formula (1.0.0) is such that the active ingredient is about 0.001 μg / kg of body weight per day. To about 10.0 mg / kg, preferably about 0.5 μg / kg of body weight per day to about 0.5 mg / kg, more preferably about 1.0 μg / kg to about 0.1 mg / kg of body weight per day, most preferably From about 2.0 μg / kg to about 0.05 mg / kg of body weight per day.
[854] Using representative weights of 10 kg and 100 kg to illustrate the range of daily aerosolized topical doses that can be used as described above, a suitable dose level of a compound of formula (1.0.0) is determined by formula (1.0.0). Active ingredient comprising a compound of) is about 1.0 to 10.0 μg and 500.0 to 5000.0 mg per day, preferably about 5.0 to 50.0 μg and 5.0 to 50.0 mg per day, more preferably about 100.0 to 1000.0 μg and 10.0 per day To 100.0 mg, most preferably about 200.0 to 2000.0 μg and about 5.0 to 50.0 mg per day. These dose ranges represent the total dose of active ingredient per day for a given patient. The number of times per day administered depends on the pharmacological and pharmacodynamic factors, such as the half-life of the active ingredient, which reflects the rate and clearance of catabolism, as well as the minimum and optimal plasma or other body fluid levels of the active ingredient maintained in the patient for therapeutic effect. Will depend.
[855] Various other factors should also be considered in determining the number of doses per day and the amount of active ingredient per dose that can be administered. The most important of these other factors is the individual response of the patient being treated. Thus, for example, if the active ingredient is used to treat or prevent asthma and is administered topically via aerosol inhalation into the lungs from one of four doses that make up the dispensing device, ie the "puff" of the inhaler, daily And each dose will contain about 50.0 μg to about 10.0 mg of active ingredient.
[856] Detailed description of the invention
[857] 11.0 Preparation Methods and Examples
[858] Various methods of preparation in which the intermediate is used to prepare the specific compound of formula (1.0.0) are described below. In addition, various examples illustrating the preparation of certain compounds of formula (1.0.0) are described below. These preparation methods and examples are thereby intended to further illustrate the compounds and processes of the present invention that can be readily prepared by those skilled in the art. Those skilled in the art will also know many other suitable processes available as well as acceptable variations of the processes described below.
[859] The following description is for the purpose of illustrating the invention and is not intended to be limiting, expressed or implied in any way to the scope of the invention. The following claims appended hereto are for the purpose of referring to the invention, expressing their anticipated scope, and pointing out the details.
[860] Analytical properties of the compounds prepared in the following preparation methods were determined by mass spectrometry confirmed by GCMS, AMPI, APCI or thermal spraying. All ¹ H NMR spectra were examined on a 400 MHz device.
[861] Preparation Example 1
[862] 4'-formyl-biphenyl-3-carboxylic acid methyl ester of formula (9.0.1):
[863] (9.0.1)
[864] 14 g (27.9 mmol) of 2M Na ₂ CO ₃ and 2.0 g (9.3 mmol) of methyl-3-bromobenzoate in 15 mL of dimethoxyethane, 1.5 g (10.2 mmol) of 4-formylbenzeneboronic acid and tetrakis ( A mixture of 537 mg (0.47 mmol) of triphenylphosphine) -palladium was heated at 80 ° C. for 4 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined and subsequently washed successively with 1N NaOH, 1N HCl, water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with ethyl acetate / hexanes (1: 5) gave 1.6 g of 4-formyl-biphenyl-3-carboxylic acid methyl ester as an oil.
[865] MS (m / z): 240 (M ⁺ , 100).
[866] Preparation Example 2
[867] 3'-Fluoro-4'-formyl-biphenyl-3-carboxylic acid methyl ester of formula (9.0.2):
[868] (9.0.2)
[869] 2.0 g (9.85 mmol) of 4-bromo-2-fluorobenzaldehyde, 2.8 g (10.8 mmol) of bis (pinacolato) diboron, 2.9 g (29.6 mmol) of potassium acetate and bis (di) in 60 ml of dimethylformamide A mixture of 216 mg (0.3 mmol) of phenylphosphino) ferrocene palladium dichloride was heated at 80 ° C. for 4 hours. The mixture was cooled, 4.2 g (19.7 mmol) of methyl 3-bromobenzoate and 216 mg (0.3 mmol) of bis (diphenylphosphino) ferrocene palladium dichloride were added and the mixture was heated at 80 ° C. for 18 hours. . The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined and then washed successively with 1 N NaOH, 1 N HCl, water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with ethyl acetate / hexanes (1: 5) gave 1.4 g of 3'-fluoro-4'-formyl-biphenyl-3-carboxylic acid methyl ester as an oil.
[870] MS (m / z): 258 (M ⁺ , 100).
[871] Preparation Example 3
[872] 4'hydroxymethyl-biphenyl-3-carboxylic acid methyl ester of formula (9.0.3):
[873] (9.0.3)
[874] To a stirred mixture of 1.56 g (6.5 mmol) of 4-formyl-biphenyl-3-carboxylic acid methyl ester in 30 ml of methanol at 0 ° C. was added 307 mg (8.1 mmol) of sodium borohydride. The mixture was stirred at 0 ° C. for 1 h and then quenched with saturated ammonium chloride solution. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with ethyl acetate / hexanes (1: 5) gave 1.5 g of 4'-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester as an oil.
[875]
[876] Preparation Example 4
[877] 3'-fluoro-4'-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester of formula (9.0.4):
[878] (9.0.4)
[879] This compound was prepared from 3'-fluoro-4'-formyl-biphenyl-3-carboxylic acid methyl ester in a similar manner to Preparation Example 3.
[880] Preparation Example 5
[881] 4 '-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl] -biphenyl-3-carboxylic acid methyl ester of formula (9.0.5):
[882] (9.0.5)
[883] 1.4 g (5.8 mmol) of 4'-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester, 25 g of phthalimide and 1.8 g of triphenylphosphine in 25 ml of tetrahydrofuran at 0 ° C. 6.9 mmol) was added 1.2 mL (7.5 mmol) of diethylazodicarboxylate. The mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined and subsequently washed successively with 1 N NaOH, 1 N HCl, water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford a solid. Trituration with diethyl ether gives 3.0 g of 4 '-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl] -biphenyl-3-carboxylic acid methyl ester as a solid. It was.
[884] MS (m / z): 371 (M ⁺ , 100).
[885] Preparation Example 6
[886] 4 '-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl] -3'-fluoro-biphenyl-3-carboxylic acid methyl ester of formula (9.0.6) :
[887] (9.0.6)
[888] This compound was prepared from 3'-fluoro-4'-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester in a similar manner to Preparation Example 5.
[889] MS (m / z): 389 (M ⁺ , 100).
[890] Preparation Example 7
[891] 4'-Aminomethyl-3'-fluoro-biphenyl-3-carboxylic acid methyl ester of formula (9.0.7):
[892] (9.0.7)
[893] 4 '-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl] -3'-fluoro-biphenyl-3 in 20 ml of ambient temperature methanol and 10 ml of tetrahydrofuran To 832 mg (2.14 mmol) of the carboxylic acid methyl ester was added 0.2 ml (6.42 mmol) of hydrazine hydrate. The mixture was stirred for 18 hours and the resulting precipitate was filtered off. The filtrate volume was reduced in vacuo, poured into 0.5 N HCl and washed with diethyl ether. The aqueous extract was basified with 6N NaOH to pH 10 and then extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to 4'-aminomethyl-3'-fluoro-biphenyl-3-carboxylic acid methyl ester 400 mg was obtained as an oil.
[894] MS (m / z): 258 (M ⁺ , 100).
[895] Preparation Example 8
[896] 4'-Aminomethyl-biphenyl-3-carboxylic acid methyl ester of formula (9.0.8):
[897] (9.0.8)
[898] This compound was prepared from 4 '-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl] -biphenyl-3-carboxylic acid methyl ester in a similar manner to Preparation Example 7. .
[899] MS (m / z): 241 (M ⁺ , 60), 240 (100).
[900] Preparation Example 9
[901] 4 '[[[2- [4-fluorophenoxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-carboxylic acid methyl ester of the formula (9.0.9):
[902] (9.0.9)
[903] 290 mg (1.24 mmol) of 2- [4-fluoro-phenoxy] -nicotinic acid in 10 ml of dimethylformamide at ambient temperature, 300 mg (1.24 mmol) of 4'-aminomethyl-biphenyl-3-carboxylic acid methyl ester And 285 mg (1.49 mmol) of 1- [3- [dimethylamino] propyl] -3-ethylcarbodiimide hydrochloride were added to 184 mg (1.36 mmol) of 1-hydroxybenzotriazole hydrate. The mixture was stirred at ambient temperature for 18 hours, then poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with 1N NaOH, water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford an oil. 4 '-[[[2- [4-fluorophenoxy] -pyridine-3-carbonyl] -amino] -methyl] -r eluted with ethyl acetate / hexanes (1: 1) and chromatographed on silica gel 310 mg of phenyl-3-carboxylic acid methyl ester were obtained as an oil.
[904]
[905] Preparation Example 10
[906] 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-cara of formula (9.0.10) Acid Methyl Ester:
[907] (9.0.10)
[908] This compound was prepared from 2- [benzo [1,3] dioxol-5-yloxy] -nicotinic acid and 4'-aminomethyl-biphenyl-3-carboxylic acid methyl ester in a similar manner to Preparation Example 9.
[909] MS (m / z): 483 (M ⁺ , 100).
[910] Preparation Example 11
[911] 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro- of formula (9.0.11) Biphenyl-3-carboxylic acid methyl ester:
[912] (9.0.11)
[913] This compound was prepared in a similar manner to Preparation Example 9 using 2- [benzo [1,3] dioxol-5-yloxy] nicotinic acid and 4'-aminomethyl-3'-fluoro-biphenyl-3-carboxylic acid methyl Prepared from esters.
[914] MS (m / z): 501 (M ⁺ , 100).
[915] Preparation Example 12
[916] 4 '-[[[2- [3-cyano-phenoxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro-biphenyl-3- of formula (9.0.12) Carboxylic Acid Methyl Ester:
[917] (9.0.12)
[918] This compound was prepared from 2- [3-cyano-phenoxy] -nicotinic acid and 4'-aminomethyl-3'-fluoro-biphenyl-3-carboxylic acid methyl ester in a similar manner to Preparation Example 9.
[919] MS (m / z): 482 (M ⁺ , 100).
[920] Example 1
[921] 4 ′-[[[2- [4-fluorophenoxyl] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-carboxylic acid of formula (8.5.1):
[922] (8.5.1)
[923] 4 '-[[[2- [4-fluorophenoxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-carboxylic acid methyl in 10 ml of t-butanol and 3 ml of water A mixture of 300 mg (0.66 mmol) of ester and 1.6 mL of 1.0 N NaOH was refluxed for 4 hours. The mixture was poured into water, acidified to pH 1 with 2N HCl and then extracted with ethyl acetate. The extracted ethyl acetate was combined, washed successively with water, brine, then dried (MgSO ₄ ) and concentrated to give an oil. Chromatography on silica gel eluting with methanol / dichloromethane (1:40) gave a foam. Recrystallization from ethyl acetate / hexanes gave 151 mg of 4 '-[[[2- [4-fluorophenoxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-carboxylic acid. Obtained as a solid (melting point 184 to 186 ° C.).
[924] Assay for C ₂₆ H ₁₉ N ₂ 0 ₄ F-Theoretic: C, 70.58; H, 4.33; N, 6.33.
[925] Found: C, 70.06; H, 4. 25; N, 6.25.
[926] Example 2
[927] 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-car of formula (8.5.2) Acid:
[928] (8.5.2)
[929] This compound was prepared in a similar manner to Example 1 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] amino] -methyl] -biphenyl-3 Prepared from carboxylic acid methyl ester (melting point 175-177 ° C).
[930] Analytical-Theoretical for C ₂₇ H ₂₀ N ₂ 0 ₆ : C, 69.23; H, 4. 30; N, 5.98.
[931] Found: C, 69.60; H, 4.59; N, 5.99.
[932] Example 3
[933] 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro- of formula (8.5.3) Biphenyl-3-carboxylic acid:
[934] (8.5.3)
[935] This compound was prepared in a similar manner to Example 1, 4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -3'- Prepared from fluoro-biphenyl-3-carboxylic acid methyl ester (melting point 190-192 ° C.).
[936] Assay for C ₂₇ H ₁₉ N ₂ 0 ₆ F—Theoretic: C, 66.67; H, 3.94; N, 5.76.
[937] Found: C, 66.68; H, 4.02; N, 5.95.
[938] Example 4
[939] 4 '-[[[2- [3-cyano-phenoxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3'-fluoro-biphenyl of formula (8.5.4) 3-carboxylic acid:
[940] (8.5.4)
[941] 4 '-[[[2- [3-cyano-phenoxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro-biphenyl in 20 ml of tetrahydrofuran and 2 ml of water A mixture of 336 mg (0.7 mmol) of 3-carboxylic acid methyl ester and 0.8 mL (0.8 mmol) of 1.0 N LiOH was stirred at ambient temperature for 18 hours. The mixture was poured into water, acidified to pH 1 with 1N HCl and then extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford a solid. Chromatography on silica gel eluting with methanol / dichloromethane (1:20) gave a solid. Recrystallize from ethyl acetate / hexanes to give 4 '-[[[2- [3-cyano-phenoxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro-biphenyl-3 280 mg of carboxylic acid were obtained as a solid (melting point 200-202 ° C.).
[942] Assay for C ₂₇ H ₁₈ N ₃ O ₄ F-Theoretic: C, 69.38; H, 3.88; N, 8.99.
[943] Found: C, 68.44; H, 3.97; N, 8.91.

权利要求:
Claims (10)
[1" claim-type="Currently amended] A compound of formula (1.0.0) or a pharmaceutically acceptable salt thereof.

In the above formula,
-g is 0 or 1;
-j is 0 or 1 except that n must be 2 when j is 0;
-k is 0 or 1;
-m is 0, 1 or 2;
-n is 1 or 2;
-W ¹ is -O-, -S (= O) _t- (where t is 0, 1 or 2), or -N (R ³ )-(where R ³ has the same meaning as defined below )ego;
-W ² is -O-, -S (= O) _t- (where t is 0, 1 or 2), -N (R ³ )-(where R ³ has the same meaning as defined below) Or -CR ²⁹ R ^30- ;
Wherein --R ²⁹ and R ³⁰ are each -H, -F, -CF ₃ ,-(C ₁ -C ₃ ) alkyl,-(C ₃ -C ₆ ) cycloalkyl, phenyl, benzyl and pyridyl, wherein , Wherein the alkyl, cycloalkyl, phenyl, benzyl and pyridyl moieties are each independently selected from the group consisting of 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined below Become;
-Y is = C (R ¹ _a )-wherein R ¹ _a has the same meaning as defined below; Or-[N⇒ (O) _k ]-, where k is 0 or 1;
Wherein --R ¹ _a is -H, -F, -Cl, -CN, -NO ₂ ,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkynyl, fluorinated- (C ₁ -C ₃ ) alkyl, fluorinated- (C ₁ -C ₃ ) alkoxy, -OR ¹⁶ and -C (= 0) NR ²² _a R ²² _b ;
Here, --- R ²² _a and R ²² _b are each independently -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl or cyclopentyl;
-R ^A and R ^B are each -H, -F, -CF ₃ ,-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl and benzyl, wherein the cycloalkyl, phenyl And benzyl residues are each independently selected from the group consisting of 0 to 3 substituents R ¹⁰ ;
{Wherein --R ¹⁰ is phenyl, pyridyl, -F, -Cl, -CF ₃ , oxo (= O), -OR ¹⁶ , -NO ₂ , -CN, -C (= O) OR ¹⁶ ,- OC (= 0) R ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0) OR ¹⁷ , -NR ¹⁶ S (= 0) ₂ R ¹⁷ and -S (= 0) ₂ NR ¹⁶ R ¹⁷ , wherein the phenyl or pyridyl is substituted with 0-3 R ¹¹ It is selected from the group consisting of;
Wherein --- R ¹¹ is -F, -Cl, -CF ₃ , -CN, -NO ₂ , -OH,-(C ₁ -C ₃ ) alkoxy,-(C ₁ -C ₃ ) alkyl or -NR ¹⁶ R ¹⁷ ;
---- R ¹⁶ and R ¹⁷ are -H,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkenyl,-(C ₃ -C ₆ ) cycloalkyl, phenyl, benzyl and Pyridyl, wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl or pyridyl is 0 selected from the group consisting of -F, -Cl, -CF ₃ , -CN and-(C ₁ -C ₃ ) alkyl To substituted with 3 substituents)
Or -R ^A and R ^B together form only a spiro moiety of the formula (1.2.0) when m is 1;

{here,
--r and s are independently 0 to 4, provided that the sum of r + s is 1 or more and 5 or less;
--X ^A is -CH _2- , -CH (R ¹¹ )-, C (R ¹¹ ) _2- (wherein R ¹¹ are each independently selected and each has the same meaning as defined above), -NR ¹⁵ −, wherein R ¹⁵ has the same meaning as defined below, —O—, or —S (═O) _t −, where t is 0, 1 or 2;
The spiro moiety of the partial formula (1.2.0) is substituted with any one or more carbon atoms other than defining X ^A by 0 to 3 substituents R ¹⁴ , wherein R ¹⁴ has the same meaning as defined below Become; The nitrogen atom is substituted by zero or one substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined below; Sulfur atom is replaced by zero or two oxygen atoms}
-R ^C and R ^D have the same meaning as defined above for R ^A and R ^B except that one of them should be -H, and they are selected independently of each other and R ^A and R ^B ;
-R ¹ and R ² may appear individually or together in any ring (s) comprising the meaning of residue Q ² as defined below; R ¹ and R ² are each -H, -F, -Cl, -CN, -NO ₂ ,-(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkynyl, fluorinated- (C ₁ Independently from the group consisting of -C ₃ ) alkyl, -OR ¹⁶ and -C (= 0) NR ²² _a R ²² _b , wherein R ¹⁶ , R ²² _a and R ²² _b have the same meaning as defined above Selected;
-R ³ is -H,-(C ₁ -C ₃ ) alkyl, phenyl, benzyl or -OR ¹⁶ , wherein R ¹⁶ has the same meaning as defined above;
-R ⁴ , R ⁵ and R ⁶ may appear individually or together in any ring (s) comprising the meaning of residue Q ¹ as defined below, and R ⁴ , R ⁵ and R ⁶ may each be independently selected from the group consisting of a) to (d);
-(a) -H, -F, -Cl,-(C ₂ -C ₄ ) alkynyl, -R ¹⁶ , -OR ¹⁶ , -S (= O) _p R ¹⁶ , -C (= O) R ¹⁶ , -C (= O) OR ¹⁶ , -OC (= O) R ¹⁶ , -CN, -NO ₂ , -C (= O) NR ¹⁶ R ¹⁷ , -OC (= O) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= 0) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= NR ¹² ) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= NCN) NR ¹⁶ R ¹⁷ , -NR ²² _a C (= N- NO ₂ ) NR ¹⁶ R ¹⁷ , -C (= NR ²² _a ) NR ¹⁶ R ¹⁷ , -CH ₂ C (= NR ²² _a ) NR ¹⁶ R ¹⁷ , -OC (= NR ²² _a ) NR ¹⁶ R ¹⁷ ,- OC (= N-NO ₂ ) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -CH ₂ NR ¹⁶ R ¹⁷ , -NR ²² _a C (= O) R ¹⁶ , -NR ²² _a C (= O) OR ¹⁶ , = NOR ¹⁶ , -NR ²² _a S (= 0) _p R ¹⁷ , -S (= 0) _p NR ¹⁶ R ¹⁷ and -CH ₂ C (= NR ²² _a ) NR ¹⁶ R ¹⁷ ;
{Where --p is 0, 1 or 2; R ²² _a , R ¹⁶ and R ¹⁷ have the same meaning as defined above}
_{- (b) - (C 1} -C 4) alkyl, and R ^4, R ⁵ or R ⁶ has one or more of the meaning of -OR ¹⁶ in the above (a), R ¹⁶ is - (C ₁ -C ₄ )-(C ₁ -C ₄ ) alkoxy when defined as alkyl, wherein the alkyl and alkoxy are each independently 0 to 3 substituents -F or -Cl, or 0 or 1 substituent (C _1- C ₂ ) alkoxycarbonyl-, substituted with (C ₁ -C ₂ ) alkylcarbonyl- or (C ₁ -C ₂ ) alkylcarbonyloxy); And
(c) phenyl, benzyl, furanyl, tetrahydrofuranyl, oxetanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl , Thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl , Pyridazinyl, piperidinyl, piperazinyl, triazolyl, triazinyl, tetrazolyl, pyranyl, azetidinyl, morpholinyl, parathiazinyl, indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, 2-H-chromenyl, chromanyl, benzothienyl, 1-H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinoli Aryl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and furinyl; Aryl or heterocyclyl moieties, wherein the aryl and heterocyclyl moieties are each independently substituted with 0 to 2 substituents R ¹⁴ ;
Wherein: --R ¹⁴ is-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl, benzyl, pyridyl and quinolinyl, wherein said alkyl, cycloalkyl, phenyl, Benzyl, pyridyl or quinolinyl are substituted from the group consisting of 0, 1 or 2 substituents -F, -Cl, -CH ₃ , -OR ¹⁶ , -NO ₂ , -CN or -NR ¹⁶ R ¹⁷ And the R ¹⁴ group is also selected from -F, -Cl, -CF ₃ , oxo (= 0), -OR ¹⁶ , -NO ₂ , -CN, -C (= 0) OR ¹⁶ , -OC (= 0). R ¹⁶ , -C (= 0) NR ¹⁶ R ¹⁷ , -OC (= 0) NR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= 0) R ¹⁷ , -NR ¹⁶ C (= 0) OR ¹⁷ , —NR ¹⁶ S (═O) ₂ R ¹⁷ or —S (═O) ₂ NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ have the same meaning as defined above;
Furthermore, where -R ¹⁵ is -H, -NR ¹⁶ R ¹⁷ , -C (= O) R ¹⁶ , OR ¹⁶ ,-(C ₁ -C ₄ ) alkyl-OR ¹⁶ , -C (= O) OR ¹⁶ , (C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁶ , —C (═O) NR ¹⁶ R ¹⁷ ; -(C ₁ -C ₄ ) alkyl,-(C ₂ -C ₄ ) alkenyl,-(CH ₂ ) _u- (C ₃ -C ₇ ) cycloalkyl, where u is 0, 1 or 2, Phenyl, benzyl, pyridyl and quinolinyl, wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl is substituted with 0 to 3 substituents R ¹² , and R ¹⁶ and R ¹⁷ is independently selected from the group consisting of the same meanings as defined above;
Where ---- R ¹² is -F, -Cl, -CO ₂ R ¹⁸ , -OR ¹⁶ , -CN, -C (= 0) NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , -NR ¹⁸ C ( = O) R ¹⁹ , -NR ¹⁸ C (= O) OR ¹⁹ , -NR ¹⁸ S (= O) _p R ¹⁹ , -S (= O) _p NR ¹⁸ R ¹⁹ , where p is 1 or 2 , - (C ₁ -C ₄₎ alkyl, and R ¹² has a meaning of the -OR ¹⁶ R ¹⁶ is - (C ₁ -C ₄₎ in a case defined with alkyl - (C ₁ -C ₄₎ alkoxy Independently selected from the group consisting of wherein alkyl and alkoxy are each independently -F, -Cl,-(C ₁ -C ₂ ) alkoxycarbonyl,-(C ₁ -C ₂ ) alkylcarbonyl and- Substituted with 0 to 3 substituents independently selected from (C ₁ -C ₂ ) alkylcarbonyloxy, R ¹⁶ has the same meaning as defined above);
Wherein ----- R ¹⁸ and R ¹⁹ consist of -H,-(C ₁ -C ₄ ) alkyl and phenyl, wherein said alkyl or phenyl is substituted with 0-3 occurrences of -F or -Cl Independently selected from the group}
Or when Q ¹ is phenyl,
-(d) R ⁵ and R ⁶ together form a residue selected from the group consisting of the following partial formulas (1.3.1) to (1.3.15),

{here,
--R ²⁰ and R ²¹ are each _{-H, -F, -Cl, -CH 3} , -CH 2 F, -CHF 2, -CF 3, -OCH 3 , and are independently selected from the group consisting of -OCF ₃ ;
--R ²³ and R ²⁴ are each independently -H, -CH ₃ , -OCH ₃ , -CH ₂ CH ₃ , -OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ or absent, where dotted line ---- Represents a double bond}
-Q ¹ is a moiety comprising a saturated or unsaturated carbon ring system that is 3-7 membered monocyclic or 7-12 membered fused polycyclic, provided that Q ¹ is discontinuous or restricted as defined in Q ² hereinafter. Not a biaryl moiety, wherein optionally one carbon atom in the carbon ring system may be substituted by a heteroatom selected from N, O and S, and optionally a second carbon atom and more optionally a third carbon atom is replaced by N Can;
Herein, the residues defining the Q ¹ is R ^4, R ⁵ and R ⁶ which is substituted in any ring (s) by (wherein, R ^4, R ⁵ and R ⁶ have the same significance as defined above);
-Q ² is a discontinuous or restricted biaryl moiety consisting of a saturated or unsaturated carbon ring system that is 3-7 membered monocyclic, 7-12 membered fused polycyclic, wherein one carbon atom of the carbon ring system is N, O And optionally substituted by a heteroatom selected from S, optionally a second carbon atom and more optionally a third carbon atom may be substituted with N;
-Z is independently selected from the group consisting of (a) and (b);
-(a) the group consisting of the following partial formulas (1.1.1) to (1.1.15):

Wherein R ¹⁶ and R ¹⁷ have the same meaning as defined above and R ⁹ has the same meaning as defined below;
-"*" Indicates the point of attachment of the partial formulas (1.1.1) to (1.1.15) to the remainder of each formula (1.0.0);
-q is 1, 2 or 3, provided that if q is 2 or 3 then R ⁹ has the meaning of -H in one or more cases or in each of two cases;
--v is 0 or 1;
--W ³ is -O-, -N (R ⁹ )-(wherein R ⁹ has the same meaning as defined below) or -OC (= O)-;
--R ⁷ _A is independently selected from the group consisting of (1) to (4):
-(1) -H;
-(2)-(C ₁ -C ₆ ) alkyl,-(C ₂ -C ₆ ) alkenyl or-(C ₂ -C ₆ ) alkynyl, wherein the alkyl, alkenyl or alkynyl is 0 to Substituted with three substituents R ¹⁰ , wherein R ¹⁰ has the same meanings as defined above;
-(3)-(CH ₂ ) _u- (C ₃ -C ₇ ) cycloalkyl, wherein u is 0, 1 or 2, and wherein (C ₃ -C ₇ ) cycloalkyl is 0 to 3 substituents substituted with R ¹⁰ (wherein, R ¹⁰ can have the same significance as defined above)); And
-(4) phenyl or benzyl, wherein said phenyl or benzyl is independently substituted with 0 to 3 substituents R ¹⁰ , wherein R ¹⁰ has the same meaning as defined above;
--R ⁷ _B is independently selected from the group consisting of (1) and (2):
-(1) tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-one-5-yl, 1,2,3-triazole -5-yl, imidazol-2-yl, imidazol-4-yl, imidazolidin-2-one-4-yl, 1,3,4-oxadiazolyl, 1,3,4-oxadia Zol-2-one-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazole-5-one-3-yl, 1,2,4-oxadia Zol-5-yl, 1,2,4-oxadiazol-3-one-5-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, morpholinyl, parathia Genyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, succinimidyl, glutarimidyl, pyrrolidoneyl, 2-piperidonyl, 2-pyridonyl, 4- Pyridonyl, pyridazine-3-onyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; And
-(2) indolyl, indolinyl, isoindolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2H-1-benzopyra Nil, 2-H-chromenyl, chromamanyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl; Benzothiazolyl, benzotriazolyl, benzotriazinyl, phthalazinyl, 1,8-naphthyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolo [3,4-d] Pyrimidinyl, pyrimido [4,5-d] pyrimidinyl, imidazo [1,2-a] pyridinyl, pyridopyridinyl, putridinyl and 1H-purinyl;
Wherein any residue of (1) or (2) is selected from (i) any one or more carbon atoms by substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above; (ii) any one or more nitrogen atoms and all tautomeric forms thereof that are not at the point of attachment of said residue by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined above; (iii) optionally substituted for any sulfur atom that is not the point of attachment of the residue by zero, one or two oxygen atoms;
--R ⁹ is -H,-(C ₁ -C ₄ ) alkyl,-(C ₃ -C ₇ ) cycloalkyl, phenyl, benzyl, pyridyl, -C (= 0) OR ¹⁶ , -C (= 0 ) R ¹⁶ , -OR ¹⁶ ,-(C ₁ -C ₂ ) alkyl-OR ¹⁶ and-(C ₁ -C ₂ ) alkyl-C (═O) OR ¹⁶ , wherein R ¹⁶ has the same meaning as defined above Having the same composition;
-R ⁷ _c is independently selected from the group consisting of the meanings of R ⁷ _A and meanings of R ⁷ _B as defined above;
Further here, Includes saturated or unsaturated 4-8 membered monocyclic, or 5-10 membered fused or open bicyclic carbocyclic ring systems containing nitrogen heteroatoms as shown in partial formula (1.1.15) Wherein optionally one to three carbon atoms in the carbocyclic ring system may each be substituted with a nitrogen heteroatom, optionally one carbon atom may be substituted with an oxygen heteroatom or a sulfur heteroatom, or optionally two carbon atoms each Nitrogen heteroatoms and oxygen heteroatoms, or nitrogen heteroatoms and sulfur heteroatoms, respectively;
Wherein any moiety of the partial formula (1.1.15) may be selected from (1) any one or more carbon atoms by substituent R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above; (2) any one or more nitrogen atoms, all tautomeric forms, and optionally their N-oxide forms, by substituent R ¹⁵ , wherein R ¹⁵ has the same meaning as defined above; (3) optionally substituted for any sulfur atom by zero, one or two oxygen atoms}
Z is also
-(b) -OP (= O) (OH) ₂ (phosphoric), -PH (= O) OH (phosphonic), -P (= O) (OH) ₂ (phosphonic),-[P ( = O) (OH) -O ( C 1 -C 4) alkyl] (phosphono alkyl), -P (= O) ( OH) -O (C 1 -C 4) alkyl (phosphinylmethyl alkyl), -P (= O) (OH) NH ₂ (phosphoramido), -P (= O) (OH) NH (C ₁ -C ₄ ) alkyl and -P (= O) (OH) NHR ²⁵ (substituted phosphor Amido), -OS (= O) ₂ OH (sulfuric), -S (= 0) ₂ 0H (sulphonic), -S (= O) ₂ NHR ²⁶ or -NHS (= O) ₂ R ²⁶ ( Sulfonamido), wherein R ²⁶ is -CH ₃ , -CF ₃ or o-toluyl, and -C (= 0) NHS (= 0) ₂ R ²⁵ , -C (-0) NHS (= 0) ) ₂ NH ₂ , -C (= O) NHS (= O) ₂ (C ₁ -C ₄ ) alkyl, -C (= O) NHS (= O) ₂ NH (C ₁ -C ₄ ) alkyl, -C (O) NHS (= O) 2 N [(C 1 -C 4) _{alkyl] 2, -S (= O)} 2 NHC (= O) (C 1 -C 4) alkyl, -S (= O) ₂ NHC (= O) NH ₂ , -S (= O) ₂ NHC (= O) NH (C ₁ -C ₄ ) alkyl, -S (= O) ₂ NHC (= O) N [(C ₁ -C ₄ ) Alkyl] ₂ , -S (= O) ₂ NHC (= O) R ²⁵ , -S (= O) ₂ NHCN, -S (= 0) ₂ NHC (= S) NH ₂ , -S (= O) ₂ NHC (= S) NH (C ₁ -C ₄ ) alkyl, -S (= O) ₂ NHC (= S) N [(C ₁ -C ₄ ) alkyl] ₂ and -S (= O) ₂ NHS ( = O) ₂ R ²⁵ {wherein, --R ²⁵ is _{-H, - (C 1 -C 4} ) alkyl, Fe Or -OR ¹⁸ is selected from a moiety selected from the group consisting of acyl sulfonamido road is selected from the group consisting of Im (wherein, R ¹⁸ can have the same significance as defined above)}.
[2" claim-type="Currently amended] The compound according to claim 1, wherein the Q ² group comprises a group selected from the group consisting of the following residues represented by the following partial formulas (1.2.1) to (1.2.32).



Here, "*" is a symbol indicating two points of attachment of said Q ² group to the remaining component of formula (1.0.0).
[3" claim-type="Currently amended] The compound of R ⁷ _B in partial formula (1.1.4) according to claim 1, wherein Z comprises partial formulas (1.1.4) and (1.1.10) to (1.1.14) and v is 0 or 1 Meaning or meaning of R ⁷ _C in partial formulas (1.1.10) to (1.1.14) is the following partial formulas (1.4.1) to (1.4.28), all tautomers, and optionally their N-oxides A compound meaning a group selected from the group consisting of forms.


Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted with a substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ have the same meaning as defined in claim 1 Has
[4" claim-type="Currently amended] The compound of claim 1, wherein Z comprises partial formulas (1.1.4) and (1.1.10) to (1.1.14), wherein the meanings of R ⁷ _B and R ⁷ _C in the partial formula are each independently Compounds selected from the group consisting of formulas (1.5.1) to (1.5.29), all tautomers, and optionally their N-oxide forms.


Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted by substituent R ¹⁴ , and R ¹⁴ and R ¹⁵ are the same as defined in claim 1 Has meaning.
[5" claim-type="Currently amended] The compound of claim 1, wherein Z comprises a group selected from the group consisting of the following partial formulas (1.7.1) to (1.7.46), all tautomers, and optionally their N-oxide forms.



Where "*" denotes the point of attachment to the remainder of formula (1.0.0), each carbon atom is optionally substituted with substituent R ¹⁴ , each nitrogen atom is optionally substituted with substituent R ¹⁵ , and R ¹⁴ and R ¹⁵ has the same meaning as defined in claim 1.
[6" claim-type="Currently amended] The compound of claim 1 wherein said compound is
4 '-[[[2- [4-fluorophenoxy] pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-carboxylic acid of formula (8.5.1);
4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3-car of formula (8.5.2) Acid;
4 '-[[[2-benzo [1,3] dioxol-5-yloxy] -pyridine-3-carbonyl] -amino] -methyl] -3'-fluoro- of formula (8.5.3) Biphenyl-3-carboxylic acid;
4 '-[[[2- [3-cyano-phenoxy] -pyridine-3-carbonyl] -amino] -methyl] -biphenyl-3'-fluoro-biphenyl of formula (8.5.4) 3-carboxylic acid;
[4 '-({[2- (benzo [2,1,3] thiadiazol-5-yloxy) -pyridine-3-carbonyl] -amino} -methyl) -ratio of formula (8.5.5) Phenyl-4-yloxy] -acetic acid;
[4 '-({[2- (benzo [2,1,3] oxadiazol-5-yloxy) -pyridine-3-carbonyl] -amino} -methyl) -ratio of formula (8.5.6) Phenyl-4-yloxy] -acetic acid;
[4 '-({[2- (benzo [1,3] dioxol-5-yloxy) -pyridine-3-carbonyl] -amino} -methyl) -biphenyl-4 of formula (8.5.7) -Yloxy] -acetic acid;
(±) -2- [4 '-({[2- (benzo [1,3] dioxol-5-yloxy) -pyridine-3-carbonyl] -amino} -methyl of formula (8.5.8) ) -2-fluoro-biphenyl-4-yloxy] -propionic acid;
(±) -2- (benzo [1,3] dioxol-5-yloxy) -N- (2'-fluoro-4 '[1- (1H-tetrazol-5) of formula (8.5.9) -Yl) -ethoxy] -biphenyl-4-ylmethyl} -nicotinamide;
(±) -2- [4 '-({[2- (benzo [1,3] dioxol-5-yloxy) -pyridine-3-carbonyl] -amino} -methyl of formula (8.5.10) ) -3'-fluoro-biphenyl-2-yloxy] -propionic acid;
(±) -2- (benzo [1,3] dioxol-5-yloxy) -N- (2'-fluoro-4 '[1- (5-methyl-4H-) of the formula (8.5.11) [1,2,4] triazol-3-yl) -ethoxy] -biphenyl-4-ylmethyl} -nicotinamide;
(±) -N- [4 '-(1-carbamoyl-ethoxy) -2'-fluoro-biphenyl-4-ylmethyl] -2- (3-cyano of formula (8.5.12) -Phenoxy) -nicotinamide;
(±) -2- [2,3'-difluoro-4 '-({[2- (3-methoxy-phenoxy) -pyridine-3-carbonyl] -amino of the formula (8.5.13) } -Methyl) -biphenyl-4-yloxy] -propionic acid;
2- (Benzo [1,3] dioxol-5-yloxy) -N- (4'-carbamoylmethyl-3-fluoro-biphenyl-4-ylmethyl)-of formula (8.5.14)- Nicotinamide;
[4 '-({[2- (3-cyano-phenoxy) -3-carbonyl] -amino} -methyl) -3'-fluoro-biphenyl-4-yl of formula (8.5.15) ] -Acetic acid;
2- (benzo [1,3] dioxol-5-yloxy) -N- {4 '-[(2-cyano-benzoylamino) -methyl] -2'-fluoro of formula (8.5.16) -Biphenyl-4-ylmethyl) -5-fluoro-nicotinamide;
Pyridine-2-carboxylic acid (3'-fluoro-4 '-{[2- (4-fluoro-phenoxy) -nicotinamide] -methyl} -biphenyl-4- of formula (8.5.17) Monomethyl) -amide;
2- (benzo [1,3] dioxol-5-yloxy) -N- {2'-fluoro-4 '-[1-methyl-1- (1H-tetrazol-) of formula (8.5.18) 5-yl) -ethyl] -biphenyl-4-ylmethyl} -nicotinamide;
5-Fluoro-N- (3-fluoro-4 '-{[(5-methyl-4H- [1,2,4] triazole-3-carbonyl) -amino] of formula (8.5.19) -Methyl} biphenyl-4-ylmethyl) -2- (3-methoxy-phenoxy) -nicotinamide;
2- (benzo [1,3] dioxol-5-yloxy) -N- {2'-fluoro-4 '-[(2-methoxy-benzoylamino) -methyl] of the formula (8.5.20) -Biphenyl-4-ylmethyl} -nicotinamide;
N- [4 '-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2'-fluoro-biphenyl-4-ylmethyl of formula (8.5.21) ] -2- (4-fluoro-phenoxy) -nicotinamide;
N- (2'-fluoro-4 '-{[(3H-imidazol-4-carbonyl) -amino] -methyl} -biphenyl-4-ylmethyl) -2- of formula (8.5.22) (3-nitro-phenoxy) -nicotinamide;
(±) -3- [4 '-({[2- (3-chloro-4-fluoro-phenoxy) -pyridine-3-carbonyl] -amino) -methyl) of formula (8.5.23)- 2-fluoro-biphenyl-4-yloxy] -butyric acid;
2- [4 '-({[2-benzo [2,1,3] thiadiazol-5-yloxy) -pyridine3-carbonyl] -amino} -methyl) -2 of formula (8.5.24) -2 -Fluoro-biphenyl-4-yl] -2-methyl-propionic acid;
(±) -2- [4 '-({[2- (benzo [2,1,3] oxadiazol-5-yloxy) -pyridine-3-carbonyl] -amino of the formula (8.5.25) } -Methyl) -2-fluoro-biphenyl-4-yloxy) -propionic acid;
(±) -2- [3'-fluoro-4 '-({[2- (2-methyl-2H-benzotriazol-5-yloxy) -pyridine-3-carr of formula (8.5.26) Carbonyl] -amino} -methyl) -biphenyl-4-yloxy] -propionic acid;
2- (3-Cyano-phenoxy) -N- {2'-fluoro-4 '[(pyridin-2-ylmethyl) -carbamoyl] -biphenyl-4- of formula (8.5.27) Monomethyl} -nicotinamide;
2- (benzo [1,3] dioxol-5-yloxy) -N- {2'-fluoro-4 '-[(quinolin-2-ylmethyl) -carbamoyl of formula (8.5.28) ] -Biphenyl-4-ylmethyl} -nicotinamide;
5-Fluoro-2- (4-fluoro-phenoxy) N- [3-fluoro-3 '-(1H-tetrazol-5-yl) -biphenyl-4- of formula (8.5.29) Ylmethyl] -nicotinamide;
N- {3-Fluoro-4 '-[(1-hydroxy-pyridin-2-ylmethyl) -carbamoyl] -biphenyl-4-ylmethyl} -2- (of formula (8.5.30) 3-methoxy-phenoxy) -nicotinamide;
(±) -N- [3-fluoro-4 '-(2-hydroxy-1,2-dimethyl-propoxy) -biphenyl-4-ylmethyl] -2- (of formula (8.5.31) 4-fluoro-phenoxy) -nicotinamide;
N- [2'-Fluoro-4 '-(1-hydroxy-1-methyl-ethyl) -biphenyl-4-ylmethyl] -2- (4-fluoro-phenoxy of formula (8.5.32) C) -nicotinamide; And
2- (3-Chloro-4-fluoro-phenoxy) -N- [4 '-(pyridin-2-ylmethoxy) -biphenyl-4-ylmethyl] -nicotinamide of formula (8.5.33) A compound selected from the group consisting of.
[7" claim-type="Currently amended] Administering a therapeutically effective amount of a compound of formula (1.0.0) as defined in claim 1 to a subject suffering from a disease, disorder or condition mediated by PDE4 isozyme, including the D subtype that regulates activation and degranulation of eosinophils. A method of treating a subject suffering from a disease, disorder, or condition mediated by PDE4 isozyme, including the D subtype, which regulates activation and degranulation of eosinophils.
[8" claim-type="Currently amended] Diseases, disorders mediated by PDE4 isozymes, including D subtypes, which regulate the activation and degranulation of eosinophils, comprising a therapeutically effective amount of a compound of formula (1.0.0) as defined in claim 1 together with a pharmaceutically acceptable carrier Or a pharmaceutical composition for treating a subject suffering from symptoms.
[9" claim-type="Currently amended] The method of claim 8, wherein the disease, disorder or condition is
-Asthma of any type, cause or onset, or by atopic asthma, non-atopic asthma, allergic asthma, atopy, bronchial, IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Intrinsic asthma induced, exogenous asthma caused by environmental factors, intrinsic asthma of unknown or unknown cause, non-atopic asthma, bronchitis asthma, emphysema, asthma, exercise-induced asthma, occupational asthma, bacteria , Asthma selected from the group consisting of infectious asthma, non-allergic asthma, early asthma, whistle infant syndrome caused by fungal, protozoan or viral infection,
-Chronic or acute bronchial constriction, chronic bronchitis, small airway obstruction and emphysema,
Obstructive or inflammatory airway disease of any type, cause or onset, or COPD, irreversible progressive progression, including asthma, pneumoconiosis, chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or related dyspnea Obstructive or inflammatory airway disease selected from the group consisting of COPD, adult respiratory distress syndrome (ARDS) characterized by airway obstruction, and exacerbation of airway hyperresponsiveness by other pharmacotherapy,
-Pneumoconiosis of any type, cause or onset, or disease of aluminosis or bauxite workers, asthma or asthma of miners, asbestos or steam mechanic's asthma, chalicosis or sputum, dust of ostrich hair Ptilosis caused by inhaling iron, siderosis caused by inhaling iron particles, silicosis or crushed pore disease, cotton fever or cotton-dust asthma, and talc pneumoconiosis Pneumoconiosis,
-Bronchitis of any type, cause or onset, or acute bronchitis, bronchitis of acute laryngeal trachea, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, wet bronchitis ( productive bronchitis), Staphylococcus or Streptococcus bronchitis, and bronchiolitis bronchitis,
From a group consisting of any type, cause or onset of bronchiectasis, or columnar bronchiectasis, pocket-shaped bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis Bronchiectasis chosen,
Seasonal allergic rhinitis, or perennial allergic rhinitis, or sinusitis of any type, cause or onset, or sinusitis selected from the group consisting of purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoidal sinusitis,
-Consisting of rheumatoid arthritis of any type, cause or onset, or acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, and spondyloarthritis Rheumatoid arthritis selected from the group,
Gout, and fever and pain associated with inflammation,
Eosinophil-related disorders of any type, cause, or onset, or eosinophilia, pulmonary infiltrating eosinophilia, Loffler syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchial pneumonia-type aspergillosis Eosinophil-related disorders selected from the group consisting of, aspergillosis, granulomas including eosinophils, allergic granulomatous vasculitis or Chuck-Straus syndrome, nodular arteritis (PAN), and systemic necrotic vasculitis,
-Atopic dermatitis, or allergic dermatitis, or allergic or atopic eczema,
Urticaria of any type, cause or onset, or immune-mediated urticaria, complement-mediated urticaria, urticaria-induced urticaria, physical drug-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, Hives selected from the group consisting of cholinergic urticaria, autosomal dominant or acquired forms, cold urticaria, contact urticaria, giant urticaria, and papular urticaria,
Conjunctivitis of any type, cause or onset, or conjunctivitis selected from the group consisting of photoconjunctivitis, acute cataract conjunctivitis, acute infectious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic cataract conjunctivitis, purulent conjunctivitis, and spring conjunctivitis,
-Uveitis of any type, cause or onset, or inflammation of all or part of the uvea, anterior uveitis, iris, cystitis, iris phloemitis, granulomatous uveitis, granulomatous uveitis, crystalline antigenic uveitis, posterior uveitis, portal vein Uveitis selected from the group consisting of meningitis, and chorioretinitis,
-Psoriasis,
Multiple sclerosis selected from the group consisting of multiple sclerosis of any type, cause or onset, or primary progressive multiple sclerosis, and relapsing-remitting multiple sclerosis,
-Autoimmune / inflammatory diseases of any type, cause or onset, or autoimmune hematological disorders, hemolytic anemia, aplastic anemia, sore erythrocytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple chondritis, skin Sclerosis, Wegner granulomatosis, dermatitis, chronic active hepatitis, myasthenia gravis, Stevens-Jones syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Endocrine opthamopathy, Graves' disease, sarcoidosis, alveolitis, chronic irritable pneumonia, primary biliary cirrhosis, childhood diabetes or type I diabetes, anterior uveitis, granulomatosis or posterior uveitis, dry keratoconjunctivitis, Epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, dune with nephrotic syndrome Nephritis, glomerulonephritis without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory / hyperproliferative dermatosis, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial cystic ulcer, lupus erythematosus , Autoimmune / inflammatory diseases selected from the group consisting of, deciduous pemphigus, and vulgaris
Prevention of allograft rejection following organ transplantation,
Inflammatory bowel disease (IBD) of any type, cause or onset, or inflammatory bowel disease selected from the group consisting of ulcerative colitis (UC), collagen colitis, polyp colitis, pancreatitis colitis, and Crohn's disease (CD) ,
Septic shock of any type, cause or onset, or renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremia cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancerous cachexia Pulmonary shock, selected from the group consisting of cachexia as a result of infection of human immunodeficiency virus (HIV),
-Liver damage,
Pulmonary hypertension, and hypoxia induced pulmonary hypertension,
Bone loss, primary osteoporosis, and secondary osteoporosis,
Central nervous system disorders of any type, cause or onset, or depression, Parkinson's disease, learning and memory disorders, delayed motor disorders, drug dependence, atherosclerosis dementia, and Huntington chorea, Wilson's disease, tremor and atrophy Central nervous system disorder selected from the group consisting of accompanying dementia,
Infections, especially with the herpes virus, including HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and herpes zoster and Herpes simplex Infection with a virus that increases the production of TNF-α in the host, or that is sensitive to the upregulation of TNF-α in the host, negatively affecting replication and other viral activity, including a virus selected from the group consisting of: ,
In particular polymyxin, polymyxin B; Imidazole, clotrimazole, econazole, myconazole and ketoconazole; Triazoles, fluconazoles and itranazoles; And upregulation by TNF-α in the host when administered with other drugs selected for the treatment of systemic yeast and fungal infections, including but not limited to amphotericin, amphotericin B and liposome amphotericin B Yeast and fungal infections sensitive to the induction of TNF-α production,
Ischemia-reperfusion injury, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteric diseases, genitourinary and gastrointestinal disorders, and prostate disease
It comprises one or more selected from the group consisting of.
[10" claim-type="Currently amended] A combination of a compound of formula (1.0.0) as defined in claim 1 with at least one selected from the group consisting of (a) to (vv).
(a) zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, N- (5-substituted) of formula (5.2.8) Methoxytetrahydro, including -thiophene-2-alkylsulfonamide, 2,6-di-tert-butylphenol hydrazone of formula (5.2.10), Zenca ZD-2138 of formula (5.2.11) Pyranes, compound SB-210661 of formula (5.2.12) and class to which this compound belongs, pyridinyl-substituted 2-cyanonaphthalene compounds to which L-739,010 belongs, 2-cyanoquinoline compound to which L-746,530 belongs Logistics, 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenase activating proteins, leukotriene biosynthesis inhibitors, selected from the group consisting of indole and quinoline compounds belonging to MK-591, MK-866 and BAY x 1005 (FLA) antagonists;
(b) Phenothiazine-3-one compounds belonging to L-651,392, amidino compounds belonging to CGS-25019c, benzoxazolamine compounds belonging to ontazolast, benzene to BIIL 284/260 Carboximidamide compounds, and compounds zafirlukast, alukast, montelukast, franlukast, verlukast (MK-679) ), Antagonists of leukotriene LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ selected from the group consisting of RG-12525, Ro-245913, iralukast (CGP 45715A) and compounds belonging to BAY x 7195;
(c) PDE4 inhibitors, including inhibitors of isoform PDE4D;
(d) 5-lipoxygenase (5-LO) inhibitors, or 5-lipoxygenase activating protein (FLAP) antagonists;
(e) dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF);
(f) leukotriene antagonists (LTRAs) including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ;
(g) antihistamine H ₁ receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizol, azelastine and chlorpheniramine;
(h) gastric protective H ₂ receptor antagonists;
(i) comprising propylhexerine, phenylephrine, phenylpropanolamine, pseudoephedrine, napazoline hydrochloride, oxymethazolin hydrochloride, tetrahydrozoline hydrochloride, xylomethazolin hydrochloride and ethylnorpinephrine hydrochloride, Α ₁ -and α ₂ -adrenoreceptor agonists vasoconstrictive sympathomimetic drugs administered orally or topically for decongestion use;
(j) α ₁ -and α ₂ -adrenergic agonists in combination with 5-lipoxygenase (5-LO) inhibitors;
(k) anticholinergic agents, including ipratropium bromide;
(l) β ₁ -to β ₄ -arre including isoprenalin, albuterol, salbutamol, formoterol, salmeterol, terbutalin, orciprelinin, bitolterol mesylate and pirbuterol Blown receptor agonist;
(m) theophylline and aminophylline;
(n) sodium chromoglycate;
(o) muscarinic receptors (M1, M2 and M3) antagonists;
(p) COX-1 inhibitors (NSAIDs), COX-2 selective inhibitors including rofecoxib and nitric oxide NSAIDs;
(q) insulin-like growth factor type 1 (IGF-1) mimetics;
(r) ciclesonide,
(s) inhaled glucocorticoids with reduced systemic side effects, including flunisolid, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate;
(t) tryptase inhibitors;
(u) platelet activating factor (PAF) antagonists;
(v) monoclonal antibodies against endogenous inflammatory entities;
(w) IPL 576;
(x) anti-tumor necrosis factor (TNFα) substances, including etanercept, infliximab, and D2E7;
(y) DMARDs comprising leflunomide,
(z) TCR peptides;
(aa) interleukin converting enzyme (ICE) inhibitors;
(bb) IMPDH inhibitors;
(cc) adhesion molecule inhibitors including VLA-4 antagonists;
(dd) cathepsin;
(ee) MAP kinase inhibitors;
(ff) glucose-6 phosphate dehydrogenase inhibitors;
(gg) kinin-B ₁ -and B ₂ -receptor antagonists;
(hh) gold in the form of aurothio groups bonded to various hydrophilic groups;
(ii) immunosuppressive agents such as cyclosporin, azathioprine and methotrexate;
(jj) antigout agents such as colchicine;
(kk) xanthine oxidase inhibitors such as allopurinol;
(ll) uric acid excretion accelerators such as probenside, sulfinpyrazone and benzbromarone;
(mm) anti-neoplastic agents, in particular, mitotic drugs including vinca alkaloids such as vinblastine and vincristine;
(nn) growth hormone secretagogue;
(oo) inhibitors of matrix metalloproteinases (MMP), for example stromelysin, collagenase, gelatinase, aggrecanase, in particular collagenase-1 (MMP-1), collagenase- 2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) );
(pp) transforming growth factor (TGFβ);
(qq) platelet derived growth factor (PDGF);
(rr) fibroblast growth factors such as basic fibroblast growth factor (bFGF);
(ss) granulocyte-macrophage colony stimulating factor (GM-CSF);
(tt) capsaicin cream;
(uu) anti-emetic agents, including NK-1 receptor antagonists and D-4418; And
(vv) anti-depressants.

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同族专利:

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公开号 | 公开日

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HU0400637A2|2004-06-28|

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ZA200304894B|2004-06-24|

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EP1355884A1|2003-10-29|

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CN1518542A|2004-08-04|

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OA12540A|2006-06-05|

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BG108038A|2004-07-30|

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BR0116852A|2004-02-25|

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ECSP034709A|2003-09-24|

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ECSP034710A|2003-09-24|

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PL364135A1|2004-12-13|

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JP2004520386A|2004-07-08|

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EE200300360A|2003-12-15|

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MA26983A1|2004-12-20|

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MXPA03006887A|2003-11-13|

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CA2436535A1|2002-08-08|

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US20040048903A1|2004-03-11|

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US20020193612A1|2002-12-19|

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NZ526453A|2005-01-28|

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IL156413D0|2004-01-04|

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WO2002060875A1|2002-08-08|

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US6649633B2|2003-11-18|

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SK8792003A3|2004-09-08|

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WO2002060875A8|2003-07-31|

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CR7025A|2003-11-25|

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CZ20031895A3|2004-08-18|

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NO20033397L|2003-09-19|

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IS6846A|2003-06-16|

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EA200300621A1|2003-12-25|

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NO20033397D0|2003-07-30|

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US6953810B2|2005-10-11|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-01-31|Priority to US26549201P

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2001-01-31|Priority to US60/265,492

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2001-12-06|Application filed by 화이자 프로덕츠 인크.

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2001-12-06|Priority to PCT/IB2001/002341

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2003-09-19|Publication of KR20030074761A

优先权:

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申请号 | 申请日 | 专利标题

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US26549201P| true| 2001-01-31|2001-01-31|

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US60/265,492|2001-01-31|

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PCT/IB2001/002341|WO2002060875A1|2001-01-31|2001-12-06|Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes|