Halogentated 2-amino-5,6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors

专利摘要:
The present invention discloses halogenated 2-amino-5,6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors.
公开号:KR20030040202A
申请号:KR1020027013747
申请日:2001-04-13
公开日:2003-05-22
发明作者:그라퍼라우스마가렛엘.；시코르스키제임스에이.；아와스티알록케이.；왕리주안제이.；피츨르바넷에스.；한슨도날드더블유.주니어.；메닝파멜라티.
申请人:파마시아 코포레이션；
IPC主号:

专利说明:

HALOGENTATED 2-AMINO-5,6 HEPTENOIC ACID DERIVATIVES USEFUL AS NITRIC OXIDE SYNTHASE INHIBITORS
[2] Since the early 1980s, vascular relaxation by acetylcholine has been known to depend on the vascular endothelium. It is produced in the vascular endothelium by endothelial induced relaxation factor (EDRF), also known as nitric oxide (NO), and nitric oxide synthase (NOS). The activity of NO as an vasodilator has been well known for over 100 years. In addition, NO is an active species derived from amynitrite, glyceryltrinitrate and other nitrovascular dilators. The identification of EDRF as NO was consistent with the discovery of a biochemical pathway in which NO is synthesized from amino acid L-arginine by the enzyme NO synthase.
[3] Nitric oxide is an endogenous stimulant of soluble guanylate cyclase. In addition to endothelial dependent relaxation, NO is involved in a number of biological activities, including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system.
[4] There are three or more types of NO synthase:
[5] (i) The constitutive, endothelial Ca ⁺⁺ / calmodulin dependent enzyme releases NO in response to receptors or physical stimuli.
[6] (ii) Constitutive, brain-located Ca ⁺⁺ / calmodulin dependent enzymes release NO in response to receptors or physical stimuli.
[7] (iii) Ca ⁺⁺ dependent enzymes induced after activation of vascular smooth muscle, macrophages, endothelial cells and many other cells by endotoxins and cytokines. Once expressed, this inducible nitric oxide synthase (hereinafter “iNOS”) produces NO continuously for a long time.
[8] NO released by each of the two constitutive enzymes acts as a conversion mechanism inherent in some physiological responses. NO produced by inducible enzymes is a cytotoxic molecule against tumor cells and invading microorganisms. It is also possible that the adverse effects of excessive NO production, particularly pathological vasodilation and tissue damage, can arise largely from NO synthesized by iNOS.
[9] There is increasing evidence that NO may be involved in the degeneration of cartilage that occurs as a result of certain conditions, such as arthritis, and it is also known that NO synthase is increased in rheumatoid arthritis and osteoarthritis.
[10] Some of the NO synthases proposed for therapeutic use are non-selective; They inhibit both constitutive NO synthase and inducible NO synthase. The use of such non-selective NO synthase inhibitors requires great care to avoid the potentially serious consequences of over-inhibition of constitutive NO synthase, which results include hypertension and possible thrombosis and tissue damage. In particular, for the therapeutic use of L-NMMA for the treatment of toxic shock (non-selective NO synthase inhibitors), it has been recommended that patients undergo continuous blood pressure monitoring after treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility under the condition that appropriate precautions are taken, selective NO in the sense that they inhibit inducible NO synthase to a significantly greater extent than the constitutive isoforms of NO synthase. Synthase inhibitors will be more therapeutically beneficial and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
[11] The following individual publications disclose compounds that have been described as useful for inhibiting nitric oxide synthesis, preferably for inhibiting the inducible isoforms of nitric oxide synthase:
[12] International Publication No. WO 96/35677
[13] International Publication No. WO 96/33175
[14] International Publication No. WO 96/15120
[15] International Publication No. WO 95/11014
[16] International Publication No. WO 95/11231
[17] International Publication No. WO 95/25717
[18] International Publication No. WO 95/24382
[19] International Publication No. W094 / 12165
[20] International Publication No. W094 / 14780
[21] International Publication No. W093 / 13055
[22] European Patent Application No. EP0446699A1
[23] U.S. Patent No. 5, 132, 453
[24] U.S. Patent No 5,684,008
[25] U.S. Patent No. 5, 830, 917
[26] U.S. Patent No. 5, 854, 251
[27] U.S. Patent No. 5, 863, 931
[28] U.S. Patent No. 5, 919, 787
[29] U.S. Patent No. 5, 945, 408
[30] U.S. Patent No. 5, 981, 511
[31] International Publication No. WO 95/25717 discloses certain amidino derivatives useful for inhibiting inducible nitric oxide synthase.
[32] International Publication No. WO 99/62875 further discloses amidino compounds useful for inhibiting inducible nitric oxide synthase.
[33] In particular, International Publication No. WO 99/46240 discloses compounds which are said to be useful for inhibiting inducible nitric oxide synthase. Furthermore, International Publication No. WO 96/15120 discloses aminotetrazole derivative compounds described as useful for inhibiting inducible nitric oxide synthase.
[34] Various attempts have been made to improve the efficacy and selectivity of NOS by adding one or more cure elements to the inhibitor's tissue. The publication by Y. Lee et al ( Bioorg. Med. Chem. 7, 1097 (1999)) teaches that imposing structural stiffness with one or more carbon-carbon double bonds is not a desirable approach to selectivity for NOS inhibitors. do. This teaching is repeated in RJ Young et al ( Bioorg. Med. Chem. Lett. 10, 597 (2000)).
[1] The present invention relates to halogenated amidino compounds and their use in therapy. In particular it relates to their use as nitric oxide synthase inhibitors.
[35] Summary of the Invention
[36] Compounds are now disclosed that have the benefit of being very effective as iNOS inhibitors in human cartilage transplantation assays, in vitro models for osteoarthritis.
[37] The present invention demonstrates that halogenated carbon-carbon double bonds can be used and that carbon-carbon double bonds can be used as curing elements, with the resulting compounds having unexpected potency and selectivity for the inhibition of inducible NOS. .
[38] The compounds of the present invention are unexpectedly potent and highly selective inhibitors of inducible nitric oxide synthase and exhibit relatively long half-lives in vivo. The compounds of the present invention may thus be optionally administered in an effectively divided dose, such as once every two days or twice a week.
[39] In a broad embodiment, the present invention provides for such inhibition or regulation by administering a novel compound, a pharmaceutical composition and a compound that inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoform of the nitric oxide synthase. Instructions are provided for using the compounds and compositions for inhibiting nitric oxide synthesis in a subject in need thereof. Yet another object of the present invention is to lower nitric oxide levels in subjects in need of such a drop. The compounds of the present invention have useful nitric oxide synthase inhibitory activity and are expected to be useful for the treatment or prevention of diseases or conditions in which the synthesis or over-synthesis of nitric oxide forms attracted moieties.
[40] In one embodiment of the invention, there is provided a compound having Formula I or a pharmaceutically acceptable salt thereof:
[41]
[42] (here:
[43] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[44] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[45] Provided that at least one of R ¹ or R ² contains halo;
[46] R ⁷ is selected from the group consisting of H and hydroxy;
[47] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[48] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
[49] R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, wherein the heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl , Dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroaryl Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, Arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dish Nocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, Diaalkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaalkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxy And optionally substituted with phosphonoalkyl, dialcoxylphosphonoalkyl, guanidino, amidino and acylamino.)
[50] Another embodiment of the present invention provides a compound having Formula II or a pharmaceutically acceptable salt thereof:
[51]
[52] Wherein R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[53] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[54] Provided that at least one of R ¹ or R ² contains halo;
[55] R ⁷ is selected from the group consisting of H and hydroxy;
[56] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[57] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl; R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul Ponyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroa Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono And optionally substituted with alkyl, dialcoxylphosphonoalkyl, guanidino, amidino, and acylamino.)
[58] Yet another embodiment of the present invention provides a compound having Formula III or a pharmaceutically acceptable salt thereof:
[59]
[60] Wherein R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[61] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[62] Provided that at least one of R ¹ or R ² contains halo;
[63] R ⁷ is selected from the group consisting of H and hydroxy;
[64] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[65] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
[66] R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, aiylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl ami Dosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroaryl Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono And optionally substituted with alkyl, dialcoxylphosphonoalkyl, guanidino, amidino and acylamino.)
[67] Particularly preferred embodiments of the present invention provide a compound having Formula IV or a pharmaceutically acceptable salt thereof:
[68]
[69] Wherein R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[70] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[71] Provided that at least one of R ¹ or R ² contains halo.)
[72] Another particularly preferred embodiment of the present invention provides a compound having Formula V or a pharmaceutically acceptable salt thereof:
[73]
[74] (here
[75] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[76] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[77] Provided that at least one of R ¹ or R ² contains halo.)
[78] Another very preferred embodiment of the present invention provides a compound having Formula VI or a pharmaceutically acceptable salt thereof:
[79]
[80] (here
[81] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[82] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[83] Provided that at least one of R ¹ or R ² contains halo.)
[84] The present invention also encompasses pharmaceutical compositions comprising a compound of formula (I), (II), (III), (IV), (V) or (VI).
[85] Another aspect of the invention is a novel intermediate used in the preparation of the therapeutic compounds of the invention, represented by formula VII.
[86]
[87] (here
[88] R ⁵ is selected from the group consisting of H, F and methyl;
[89] R ⁶ is selected from the group consisting of H, F and methyl;
[90] Provided that either R ⁵ or R ⁶ is F.
[91] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ ; Wherein R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl; R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul Ponyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroa Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono And optionally substituted with alkyl, dialcoxylphosphonoalkyl, guanidino, amidino, and acylamino.
[92] Q is H, or for example t-butoxycarbonyl, 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-nitro-phenylsulphenyl (Nps) or dithia- It is an appropriate nitrogen protecting moiety such as succinyl.)
[93] Best Mode for Carrying Out the Invention
[94] The present invention provides compounds with halogenated carbon-carbon double bonds, which have unexpectedly greater efficacy and selectivity for the inhibition of inducible NOS.
[95] The compounds of the present invention are unexpectedly potent and highly selective inhibitors of inducible nitric oxide synthase and exhibit a relatively long half-life in vivo when compared to known nitric oxide synthase inhibitors.
[96] Compounds of Formulas (I), (II), (III), (IV), (V) and (VI) can be used to treat inflammation in a subject, or for treating other nitric oxide synthase-mediated disorders, among others, such as painkillers in the treatment of pain and headache, for example. Will be useful. The compounds of the present invention will be useful in the treatment of pain, including both acute and chronic, somatic cell origin (invasive or neuropathic of the sense organs), and neuropathic, in which conventional NSAIDs or opioid analgesics are traditionally administered It can be used in situations involving pain.
[97] Conditions under which the compounds of the present invention will provide the advantage of inhibiting NO production from L-arginine include arthritis conditions. For example, the compounds of the present invention are not limited to arthritis, of course, but not limited to rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatoid arthritis, enteroarthritis, neuropathy It will be useful for treating sex arthritis, psoriatic arthritis and purulent arthritis.
[98] The compounds of the present invention may be used for asthma, bronchitis, menstrual cramps (e.g., dysmenorrhea), premature birth, tendonitis, bursitis, sunburn, sunburn, skin-related conditions such as dermatitis, pancreatitis, hepatitis, And inflammation from ophthalmic surgery such as cataract surgery and refractive surgery. The compounds of the present invention may also be useful for treating gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
[99] Compounds of the invention include vascular disease, migraine, nodular periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular disease, including myasthenia gravis, multiple sclerosis It may be useful for treating inflammation and tissue damage in diseases such as white matter disease, sarcoidosis, kidney syndrome, Behcet syndrome, polymyositis, gingivitis, nephritis, allergies, postoperative nodules, myocardial ischemia, and the like. The compounds will also be useful for the treatment of ocular diseases such as glaucoma, retinitis, retinopathy, uveitis, ocular photophobia, and inflammation and pain associated with acute surgery on ocular tissues. Of particular interest in the use of the compounds of the present invention is the treatment of glaucoma, especially glaucoma in which the symptoms of glaucoma are caused by the production of nitric oxide, such as in nitric oxide-mediated nerve damage. The compounds of the present invention may also be useful for the treatment of pulmonary inflammation, such as those associated with viral infections and cystic fibrosis. The compounds of the present invention may also be useful for the treatment of certain central nervous system disorders such as cerebral cortical dementia and central nervous system damage, including Alzheimer's disease resulting from stroke, anemia and mental shock. These compounds will also be useful in the treatment of allergic rhinitis, respiratory disorder syndrome, endotoxin shock syndrome and atherosclerosis. The compounds will also be useful for the treatment of pain, including but not limited to post-surgical pain, toothache, myalgia, pain caused by subtemporal joint syndrome, and pain resulting from cancer. The compound will be useful for the prevention of dementia, such as Alzheimer's disease.
[100] In addition to being useful for human treatment, it is also useful for the veterinary treatment of pets, foreign animals and farm animals, including stray and other vertebrates. More preferred animals include horses, dogs, and cats.
[101] The compounds of the present invention may also partially or wholly replace steroids, NSAIDs, COX-2 selective inhibitors, matrix metalloproteinase inhibitors, 5-lipoxygenase inhibitors, LTB ₄ antagonists and LTA ₄ valences in place of other conventional anti-inflammatory therapies. As with the degrading enzyme inhibitor, it may be used in co-therapy.
[102] Other conditions in which the compounds of the present invention may provide the benefits of inhibiting NO inhibition include cardiovascular anemia, diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm , Reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (lesion ischemia, thrombotic stroke and global ischemia (eg, are associated with cardiac arrest) ), Multiple sclerosis, and other NO-mediated central nervous system disorders, such as Parkinson's disease, and neurodegenerative disorders that may be more beneficial to NO inhibition include disorders such as hypoxia, hypoglycemia, epilepsy and the central nervous system (CNS). Trauma (such as spinal cord and head injury), hyperbaric oxygen spasms and poisoning, for example dementia, premature dementia, and AIDS-related dementia, cachexia, Sydenham chorea, Huntington's disease, muscular atrophy Includes lateral sclerosis, Korsakoff disease, cerebrovascular disorders, sleep disorders, schizophrenia, depression associated with depression, depression or premenstrual syndrome (PMS), anxiety and other symptoms associated with septic shock. .
[103] Still other disorders or conditions that can be conveniently treated by the compounds of the present invention include sedation resistance in patients in need of prolonged sedative analgesics, benzodiazepine resistance in patients taking benzodiazepines, and rapid addictive behaviors, for example, Treatment or prevention of nicotine addiction, alcohol detention, and eating disorders. The compounds and methods of the present invention will also be useful for the treatment or prevention of drug withdrawal symptoms, eg, for the treatment or prevention of withdrawal symptoms from opiate, alcohol or tobacco poisoning. The compounds of the present invention may also be useful for preventing tissue damage when therapeutically combined with antibacterial or antiviral agents.
[104] The compounds of the present invention also inhibit NO production from L-arginine, including systemic hypotension associated with septic and / or toxic hemorrhagic shock caused by a wide variety of agents; Treatment with cytokines such as TNF, IL-1 and IL-2; And as adjuvant for short term immunosuppression in transplantation therapy regimens.
[105] The compounds of the present invention are useful for the prevention or treatment of colorectal cancer and cancers such as breast cancer, lung cancer, prostate cancer, bladder cancer, cervical cancer and skin cancer. The present invention further suggests the use of the compounds of the present invention for the treatment and prevention of tumors. Tumors treatable or preventable by the compounds and methods of the invention include brain cancers, bone cancers, for example, chronic lymphoid cell leukemia, leukemias such as lymphomas, epithelial cell induced tumors such as basal cell carcinoma (epithelial carcinoma), adenocarcinoma, lip cancer Gastrointestinal cancers such as oral cancer, esophageal cancer, small intestine cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, uterine cancer, genitourinary cancers such as vulvar cancer, and lung cancer, breast cancer and squamous cell, melanoma, and basal cell cancer Skin cancers such as skin cancer, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body. The compounds of the present invention will of course also be useful in the treatment of mesenchymal induced tumors. Preferably, the tumor that can be treated is selected from skin cancers such as gastrointestinal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, vulvar cancer, lung cancer, breast cancer and squamous cell and basal cell cancer. The compounds and methods of the present invention can also be used to treat subjects with adenomatous polyps, including those with familial adenomatous polyposis (FAP). In addition, the compounds and methods of the present invention can be used to prevent polyp formation in patients at risk of FAP.
[106] Concomitant treatment of a compound of the present invention with another tumor growth inhibitor may create a synergistic effect or alternatively directly reduce the amount of treatment causing the side effect that requires the efficacy of the agent or directly ameliorate the symptoms of toxic side effects caused by the agent causing the side effect. Reducing it will reduce the toxic side effects associated with chemotherapy. The compounds of the present invention will be more useful as an adjuvant of radiation therapy to reduce side effects or enhance efficacy. In the present invention, another agent that can be therapeutically combined with a compound of the present invention includes any therapeutic agent capable of inhibiting the enzyme cyclooxygenase-2 ("COX-2"). Preferably such COX-2 inhibitors selectively inhibit COX-2 as compared to the enzyme cyclooxygenase-1 (“COX-1”). Such COX-2 inhibitors are known as "COX-2 selective inhibitors." More preferably, the compounds of the invention have a ratio of at least 10: 1, more preferably at least 30: 1 and still more preferably at least 50: 1, in the in vitro test of the COX-2 selective inhibitor compared to the inhibition of COX-1. In combination with a COX-2 selective inhibitor that selectively inhibits COX-2. COX-2 selective inhibitors useful in therapeutic combinations with compounds of the invention include celecoxib, valdecoxib, deracoxib, etoricoxib, rofecoxib, ABT-963 (2- (3,4-difluoro) Rophenyl) -4- (3-hydroxy-3-methyl-1 -butoxy) -5- [4- (methylsulfonyl) phenyl-3 (2H) -pyridazinone; PCT patent application No. WO 00 / 24719), or meloxycam. The compounds of the present invention can also be advantageously used in prodrugs of COX-2 selective inhibitors with, for example, therapeutic combinations with parecoxib.
[107] Another chemotherapeutic agent that will be useful in combination with the compounds of the present invention can be selected from the following list, for example, without being extensive and limiting:
[108] Alpha-difluoromethylornithine (DFMO), 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate Stearate, Cytarabine conjugate, Lilly DATHF, Merrel Dow DDFC, Dezaguanine, Dideoxycytidine, Dideoxyguanosine, Didox, Yoshitomi DMDC, Doxyfluidine, Wellcome EHNA, Merck & Co. EX015, pazarabine, phloxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropyldidoxine, Lilly LY-188011, Lilly LY-264618, methopenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, pyri Trexim, Plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, Thioguanine, Tiazopurin, Erbamont TIF, Trimetrexate, Tyrosine Kinase Inhibitors, Tyrosine Protein Kinase Inhibitors, Taiho UFT, Uricytin, Shionogi 254-S, Aldo-phosphamide analogue, Altretamine, Anaxylone, Boehringer Mannheim BBR-2207, Vestarabucil, Budotitanium, Wakunaga CA-102, Carboplatin, Carmustine, Chinoin-139, Chinoin 153 , Chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL286558; Sanofi CY-233, Ciflatate, Degussa D-19-384, Sumimoto DACHP (Myr) 2, Diphenylspiromustine, Diplatinum Cytosteatic, Erba Distamycin Derivatives, Chugai DWA-2114R, ITI E09, Elmustine, Erbamont FCE-24517, Estramustine Phosphate Sodium, Potemustine, Unimed G-6-M, Chinoin GYKI 17230, Hepsul-Farm, Iphosphamide, Iproplatin, Lomustine, Maposphamide, Mitolactol , Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, Oxaliplatin, Upjohn PCNU, Prednismustine, Proter PTT-119, Lanimustine, Semusstin, SmithKline SK & F-101772, Yakult Honsha SN-22 , Spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, theeroxylone, tetraplatin, trimelamol, Taiho 4181-A, aklarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, Aeroplycinin Derivatives, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda Anisomycin, Anthracycline, Ajino-Ma Sin-A, Nonsukaberine, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, Bleomycin Sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromocycin, dacactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, Dietrisrubicin B, Shionogi DOB-41, Doxorubicin, Doxorubicin Fibrinogen, Elsamicin-A, Epirubicin, Erbstatin, Esorubicin, Esperamicin-Al, S Feramicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, Postlysine, Fujisawa FR-900482, Glydobactin, Gregatin-A, Greencarmycin, Herbimycin, Idarubicin, Illudins, Car Zapycin, Kessarirodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Haldco KT-5432, Kyowa Hallo KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaryl, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalicin, oxauomycin, peplomycin, Pilates, Pyrurubicin, Portramycin, Pyridamycin A, Tobishi RA-I, Paramycin, Liqin, Rhodorubicin, Shivanomycin, Swenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, Sorangicin-A, Sparzomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, Stepymycin B, Taiho 4181-2, Deisomycin, Takeda TAN-868A , Terpenthecin, trazin, trichzarine A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 Zorubicin, alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, Alstonine, Amonafide, Amfetinyl, Amsacrine, Angiostat, Ankinomycin, Anti-neoplasm A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, apidicholine glycinate, asparaginase, Avarol, baccarin, batracillin , Benfluron, Benzotript, Ipsen- Beaufour BIM-23015, Bisantrene, Bristo-Myers BMY-40481, Vestar Boron-10, Bromophosphanide, Wellcome BW-502, Wellcome BW-773, Carracemide, Carmetizol Hydrochloride, Ajinomoto CDAF, Chlorsulfaquinoxalone, Chemex CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI- 937, Warner-Lambert CI-941, Warner-Lambert CI- 958, Clanfenur, Claviridinone, ICN Compound 1259, ICN Compound 4711, Contracan, Yakult Honsha CPT-11, Crisnatol, Kuradum, Cytokalacin B, Cytarabine, Cytocithin, Merz D-609, DABIS Maleate, decarbazine, datriptinium, didemnin-B, dihaematoporphyrin ether, dihydrorenferon, dynaline, distamycin, Toy o Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, Ellipabine, Elliptinium Acetate, Tsumura EPMTC, Ergotamine, Etoposide, Etretinate, Penretinide, Fujisawa FR-57704, Gallium Nir Latex, Gengadafamine, Chugai GLA43, Glaxo GR-63178, Gripolan NMF-5N, Hexadecylphosphocholine, Green Cross HO-221, Homoharingtorin, Hydroxyfree BTG ICRF-187, Ilfofosin, Iso Glutamine, Isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, Leukoregulin, Rodinamine, Lundbeck LU-23 -112, Lilly LY-186641, NCI (US) MAP, Maricin, Merrel Dow MDL-27048, Medco MEDR-340, Merbaron, Merocyanine Derivatives, Methylanilinoacridine, Molecular Genetics MGI-136, Minatibine , Nitonafide, mitoquidone, furdamol, motretinide, Zenyaku Kogyo MST-16, N- (retinoyl) amino acids, Nisshin Flour Milling N-021, N-acylated dehydro Alanis, Napazathrom, Taisho NCU-190, Nocodazole Derivatives, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, Octreotide, Ono ONO-112, Oquiza Nosin, AkzoOrg-10172, Pankrastatatin, Pazelliptin, Warner-Lambert PD-111707, Warner-Lambert PD 115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT Peptide D, Pyroxanthrone, Poly Matoporphyrin, Polypresan, Efamol Porphyrin, Proviman, Procarbazine, Proglumid, Invitron Protease Nexin I, Tobishi RA700, Lakaic Acid, Sapporo Breweries RBS, Lestritin-P, Letelliptine, Retinoic Acid, Rhone- Poulenc RP-49532, Rhone-Poulenc RP-56976, SmitliKline SK & F104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, Spartol, Spirocyclopropane Derivatives, Spirogermanium, Unimed, SS Pharmaceutical SS-554, Styrene Foldinone, Stipoldion, Suntory SUN 0237, Suntory SUN 2071, Superoxide Dismutase, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-0303, Teniposide, Tallyblastine, Eastman Kodak TJB-29, Tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, Ukrain, Eastman Kodak USB-006 Vinblastine sulphate, vincristine, vindesine, vinestramide, vinorelbine, vintrytol, vinzolidine, witanolide, Yamanouchi YM-534, euroguaniline, combretastatin, dolastatin, it is Rubicin, epirubicin, esturamustine, cyclophosphamide, 9-amino-2- (S) -camptothecin, topotecan, irinotecan (Camptosar), exemestane, decapeptyl (tryptorelin), Or omega-3 fatty acids.
[109] Examples of radioprotective agents that can be used in combination therapy with the compounds of the invention include AD-5, adjnon, amifostine analogues, detox, dimetha, 1-102, MM-159, N-acylateddehydro Includes Alanis, TGF-Genentech, Tiprotimod, Amifostine, WR-151327, FUT187, Cactopropene Transmal, Nabumetone, Superoxide Dismutase (Chiron) and Superoxide Dismutase Enzon do.
[110] The compounds of the present invention will also be useful for the treatment or prevention of angiogenesis-related disorders or conditions such as, for example, tumor growth, metastasis, cutaneous degeneration, and atherosclerosis.
[111] In another embodiment, the present invention also provides a therapeutic combination for the treatment or prevention of an ocular disorder or condition such as glaucoma. For example, the compounds of the present invention will be advantageously used in therapeutic combinations with agents that lower intraocular pressure in patients suffering from glaucoma. Such intraocular pressure-lowering agents include, but are not limited to: latanoprost, travoprost, bimatoprost or unoprostol. Therapeutic combinations of compounds of the invention with intraocular pressure lowering agents will be useful because each is believed to achieve its effect by acting on a different mechanism.
[112] In another combination of the invention, the compounds of the invention can be used in therapeutic combinations with antihyperlipidemic or cholesterol-lowering agents such as benzothiepine or benzothiazepine antihyperlipidemic drugs. Examples of benzothiazepine antihyperlipidemic agents useful in the therapeutic combinations of the present invention can be found in US Pat. No. 5,994,391, incorporated herein by reference. Some benzothiazepine antihyperlipidemic drugs are described in WO 93/16055. As an alternative, antihyperlipidemic or cholesterol-lowering agents useful in combination with the compounds of the present invention may be HMG Co-A reductase inhibitors. Examples of HMG Co-A reductase inhibitors useful in the therapeutic combinations of the invention are individually benfluorex, fluvastatin, lovastatin, provastatin, simvastatin, atorvastatin, cerivastatin, vervastatin, ZD-9720 (PCT patent Application No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for calcium salts; CAS No. 147098-18-8 for sodium salts; described in European Patent No. EP 521471) ), BMS 180431 (CAS No. 12982903-4), or NK-104 (CAS No. 141750-63-2). Therapeutic combinations of compounds of the invention with antihyperlipidemic or cholesterol lowering agents will be useful, for example, in lowering the risk of the formation of atherosclerotic lesions in blood vessels. Atherosclerotic lesions, for example, often begin at the site of inflammation in the blood vessels. Antihyperlipidemic or cholesterol lowering agents are proven to lower the risk of atherosclerotic lesions by lowering lipid levels in the blood. Without limiting the invention to a single mechanism of activity, the compounds of the combination of the present invention act in concert, in one way, for example, by lowering blood lipid levels and lowering inflammation of blood vessels, thereby providing enhanced control of atherosclerotic lesions. It is believed that
[113] In another embodiment of the invention, the compounds of the present invention may be used in combination with other compounds or therapies for the treatment of central nervous conditions or disorders such as migraine. For example, the compounds of the present invention may be used in combination with caffeine, 5HT-1B / 1D promoters (e.g., tripartan such as sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, or probatriptan), Dopamine D4 antagonist (e.g. sonepyprazole), aspirin, acetaminophen, ibuprofen, indomethacin, naproxen sodium, isomeptene, dichloralfenazone, butalbital, ergot alkaloids (e.g. ergotamine , Dihydroergotamine, bromocriptine, ergonobin, or methyl ergonobin), tricyclic antidepressants (eg, amitriptyline or nortriptyline), serotonergic antagonists (eg, methiserzid or sift Roheptadine), beta-adrenergic antagonists (e.g. propranolsol, timolol, athenol, nadolol or metprool), or monoamine oxidase inhibitors (e.g. fenelzin or isocarbox Aji ) It can be used for the treatment in combination with. Further embodiments provide therapeutic combinations of opioid compounds and compounds of the invention. Useful opioid compounds for this combination include, but are not limited to, morphine, methadone, hydromorphone, oxymorphone, levorphanol, revalorphan, codeine, dihydrocodeine, dihydrohydroxycodeinone, pentazosin, hydrocodone , Oxycodone, nalmefene, etopin, levorpanol, fentanyl, sufentanil, DAMGO, butorpanol, buprenorphine, naloxone, naltrexone, CTOP, diprenorphine, betafunaltrexamine, naloxonazin , Nalmorphine, pentazosin, nalbuphine, naloxone benzoylhydrazone, bremazosin, ethyl ketocyclazosin, U50,488, U69,593, spiradoline, nor-vinaltorphine, naltrindol, DPDPE, [ D-la ² , glu ⁴ ] deltorphine, DSLET, met-ekephalin, leu-enkaphalin, beta-endorphin, dinonorphine A, dinonorphine B, and alpha-neoendodolphin. An advantage of the combination of the opioid compound and the present invention is that the compound of the invention will enable a reduction in the dosage of the opioid compound, thereby lowering the risk or severity of opioid side effects.
[114] The term "alkyl", alone or in combination, preferably contains about 1 to about 10 carbon atoms, more preferably 1 to about 6 carbon atoms, and still more preferably about 1 to 3 carbon atoms. By acyclic alkyl radical, linear or branched. "Alkyl" also includes ring alkyl radicals containing about 3 to about 7 carbon atoms, preferably about 3 to 5 carbon atoms. Examples of such radicals are methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, cyanobutyl , isobutyl, sec -butyl, tert -butyl, pentyl, aminopentyl, iso-amyl , Hexyl, octyl and the like.
[115] The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched to the extent that it contains one or more double bonds. Such radicals contain 2 to about 6 carbon atoms, preferably 2 to about 4 carbon atoms, more preferably about 2 to about 3 carbon atoms. The alkenyl radicals may optionally be substituted with groups as defined below. Examples of suitable alkenyl radicals are propenyl, 2-chloropropyleneyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexene -1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl and the like.
[116] The term "alkynyl" refers to unsaturated, acyclic hydrocarbon radicals, linear or branched phases and, to the extent that they contain one or more triple bonds, such radicals are from 2 to about 6 carbon atoms, preferably 2 to about 4 carbons Atoms, more preferably 2 to about 3 carbon atoms. The alkynyl radicals may optionally be substituted with groups as defined below. Examples of suitable alkynyl radicals are ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentin-1-yl, pentyn-2-yl, 4-methoxypentin-2- 1, 3methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3, 3-dimethylbutyn-1-yl radicals and the like.
[117] The term "alkoxy" includes linear or branched oxy-containing radicals each having an alkyl moiety of 1 to about 6, preferably 1 to about 3 carbon atoms, such as a methoxy radical. The term “alkoxyalkyl” also includes alkyl radicals having one or more alkoxy radicals attached to the alkyl radicals, ie, forming monoalkoxyalkyl and dialkoxyalkyl radicals. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert -butoxy alkyl. “Alkoxy” radicals may be further substituted with one or more halo atoms such as fluoro, chloro or bromo to provide a “haloalkoxy” radical. Examples of such radicals are fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropro Contains Foxy.
[118] The term "alkylthio" includes radicals containing 1 to about 6 carbon atoms, linear or branched alkyl radicals attached to sulfur atoms. An example of "lower alkylthio" is methylthio (CH ₃ -S-).
[119] The term "alkylthioalkyl" includes alkylthio radicals attached to an alkyl group. Examples of such radicals include methylthiomethyl.
[120] The term "halo" means a halogen such as a fluorine, chlorine, bromine or iodine atom.
[121] The term “heterocyclyl” means a saturated or unsaturated mono- or polycyclic carbocycle in which one or more carbon atoms are replaced with N, S, P, or O. This includes, for example, the following structure:
[122]
[123] Wherein Z, Z ¹ , Z ² or Z ³ is C, S, P, O, or N, provided that one of Z, Z ¹ , Z ² or Z ³ is not carbon, but is another X atom by a double bond It is not O or S when attached to or attached to another O or S. Moreover, it is understood that the optional substituents are only attached to Z, Z ¹ , Z ² or Z ³ when each is C. The term “heterocyclyl” also refers to fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl Include. The term "heterocyclyl" also includes partially unsaturated ring structures, such as dihydrofuranyl, pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothiophenyl and others.
[124] The term "heteroaryl" means a fully unsaturated heterocycle.
[125] In either "heterocycle" or "heteroaryl", the point of attachment to the molecule of interest can be a heteroatom or elsewhere in the ring.
[126] The term "cycloalkyl" is a mono- or poly-cyclic carbocycle wherein each ring contains 3 to about 7 carbon atoms, preferably 3 to about 5 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" further includes a helical system.
[127] The term "oxo" refers to double bonded oxygen.
[128] The term "alkoxy" means a radical comprising an alkyl radical bonded to an oxygen atom, such as a methoxy radical. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to about 10 carbon atoms. Still more preferred alkoxy radicals have 1 to about 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert -butoxy.
[129] The term "aryl" means, but is not limited to, fully unsaturated mono or polycyclic carbon rings including substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
[130] The term “combination therapy” refers to the use of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure, such as atherosclerosis, pain, inflammation, migraine, tumor, angiogenesis related condition or disorder or others. Means administration. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, for example in a single capsule with a fixed proportion of active ingredient or in multiple individual capsules for each active ingredient. In addition, such administration also includes the use of each type in a sequential manner. In either case, the treatment regimen will provide the beneficial effect of the combination of agents in treating the condition or disorder described herein.
[131] The phrase “effective for treatment” is intended to include and suitably comprise the amounts of active ingredients combined in combination therapy. This combination will achieve the goal of improving symptoms, reducing or eliminating target conditions.
[132] In one embodiment, the present invention provides a compound or a salt thereof, wherein the compound having a structure corresponding to formula (I) or a pharmaceutically acceptable salt thereof
[133] Formula I
[134]
[135] (here:
[136] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[137] R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[138] Provided that at least one of R ¹ or R ² contains halo;
[139] R ⁷ is selected from the group consisting of H and hydroxy;
[140] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[141] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
[142] R ⁴ is selected from the group consisting of H, and a heterocyclic ring wherein at least one member of the ring is carbon and 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen, and sulfur; The heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, Hydroxy, amino, thio, nitro, alkylamino, dialkyamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl , Aminosulfonyl, monoalkyl aminosulfonyl, dialkyl aminosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, Heteroarylthio, Heteroarylsulfinyl, Heteroarylsulfonyl, Alkanoyl, Alkenoyl, Aroyl, Heteroaroyl, Aralkanoyl, Heteroarkanoyl, Haloalkanoyl, Alkyl, Alkenyl, Alkynyl, Alkylenedi Oxy, haloal Rendioxy, carboxyl, alkoxycarboxyl, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl , Hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, Arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboxyalkoxyalkyl, dicarboxyalkoxy Alkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarbo Cooxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkyl Optionally substituted with a moiety selected from the group consisting of amino, dialcoxylphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, dialcoxoxyphosphonoalkyl, guanidino, amidino, and acylamino do. )
[143] Formula I also
[144] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl which may be optionally substituted with one or more halo,
[145] R ² may be represented as fluorine.
[146] Moreover, formula (I)
[147] R ¹ is H;
[148] R ² may be represented as fluorine.
[149] Formula I is also wherein R ¹ is halo; R ² can be represented by a haloin compound.
[150] In addition, formula (I)
[151] R ¹ is fluorine; R ² may be selected from the group consisting of H and C ₁ -C ₃ alkyl which may be optionally substituted by one or more halo.
[152] Formula I also
[153] R ¹ is fluorine;
[154] R ¹ may be represented by a compound which is H.
[155] Moreover, formula (I)
[156] R ¹ is fluorine;
[157] R ² can be represented by a compound which is fluorine.
[158] Formula I can be represented by compounds wherein the compound is the E isomer.
[159] In another embodiment of the invention, it is represented by the compound represented by the formula (II), or a pharmaceutically acceptable salt thereof.
[160] Formula II
[161]
[162] Wherein R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[163] R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[164] Provided that at least one of R ¹ or R ² contains halo;
[165] R ⁷ is selected from the group consisting of H and hydroxy;
[166] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[167] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl; R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, wherein the heterocycle is heteroaryl Amino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, Thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl ami Dosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, hetero Arylsulfinyl, heteroarylsulfonyl, alkane oil, alkene oil, aroyl, hetero aroyl, arkanyl oil, hetero arkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano city Chloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dia Ralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralcoxiphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialralcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosph And optionally substituted with phonoalkyl, dialcoxylphosphonoalkyl, guanidino, amidino, and acylamino.
[168] Formula II is also
[169] R ¹ is fluorine; R ² may be selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[170] Another embodiment of the invention is that R ¹ is H; R ² is fluorine.
[171] Compounds of Formula II also
[172] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo; R ² may be represented as halo.
[173] Another embodiment of the invention
[174] R ¹ is selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted by one or more halo; R ² is formula II, which is halo.
[175] Formula II is also
[176] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo; R ² may be represented as fluorine.
[177] Furthermore, Formula II
[178] R ¹ is H; R ² may be represented as fluorine.
[179] Formula II is also
[180] R ¹ is halo; R ² may be represented as halo.
[181] Formula II is also
[182] R ¹ is fluorine;
[183] R ² may be represented as H.
[184] Furthermore, in formula II, R ¹ is fluorine; R ² can be represented as a compound.
[185] Formula II may represent that the compound is the E isomer.
[186] In yet another embodiment of the invention, the compound represented by formula III or a pharmaceutically acceptable salt thereof,
[187] Formula III
[188]
[189] here:
[190] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[191] R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
[192] Provided that at least one of R ¹ or R ² contains halo;
[193] R ⁷ is selected from the group consisting of H and hydroxy;
[194] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
[195] R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
[196] R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, wherein the heterocycle is heteroaryl Amino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, Thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl ami Dosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, hetero Arylsulfinyl, heteroarylsulfonyl, alkane oil, alkene oil, aroyl, hetero aroyl, arkanyl oil, hetero arkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano city Chloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dia Ralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralcoxiphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialralcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosph And optionally substituted with phonoalkyl, dialcoxylphosphonoalkyl, guanidino, amidino, and acylamino.
[197] In another embodiment of Formula III, the compound is:
[198] R ¹ is halo; R ² is selected from the group consisting of H, halo and alkyl, optionally substituted with one or more halo.
[199] In another embodiment, the compound is
[200] R ¹ is halo; R ² is represented by Formula III selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[201] Formula III is also:
[202] R ¹ is fluorine; R ² is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[203] Another embodiment of the invention
[204] R ¹ is fluorine;
[205] R ² is H in formula III.
[206] Formula III is also
[207] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted with one or more halo; R ² may be represented as halo.
[208] Another embodiment of the invention is:
[209] R ¹ is selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted with one or more halo; R ² is formula III, which is halo.
[210] Formula III is also
[211] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo; R ² is represented as fluorine.
[212] Moreover, the compounds of the present invention
[213] R ¹ is H; R ² may be represented by formula III, which is fluorine.
[214] Formula III is also
[215] R ¹ is halo; R ² can be represented by a haloin compound.
[216] Furthermore, Formula III
[217] R ¹ is fluorine; R ² may be represented by a compound selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[218] Moreover, Formula III
[219] R ¹ is fluorine; R ² may be represented as fluorine.
[220] Formula III may represent that the compound is the E isomer.
[221] In a particularly preferred embodiment of the invention, the compound is represented by formula IV:
[222] Formula IV
[223]
[224] Or a pharmaceutically acceptable salt thereof,
[225] (here:
[226] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[227] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[228] Provided that at least one of R ¹ or R ² contains halo.)
[229] In another embodiment of Formula (IV), the compound is
[230] R ¹ is halo; R ² is represented by Formula IV selected from the group consisting of H, halo and alkyl substituted by one or more halo.
[231] In another embodiment the compound is
[232] R ¹ is halo; R ² is represented by formula IV selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[233] Formula IV is also
[234] R ¹ is fluorine;
[235] R ² is shown to be selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[236] Another embodiment of the invention
[237] R ¹ is fluorine;
[238] R ² is H, Formula IV.
[239] The compound of formula IV is also
[240] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo and
[241] R ² is shown to be halo.
[242] Another embodiment of the invention
[243] R ¹ is selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted by one or more halo;
[244] R ² is formula IV, which is halo.
[245] Formula IV is also
[246] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo;
[247] R ² is shown to be fluorine.
[248] In addition, Formula IV
[249] R ¹ is H;
[250] R ² may be represented as fluorine.
[251] Formula IV is also
[252] R ¹ is halo;
[253] R ² can be represented by a haloin compound.
[254] In addition, Formula IV
[255] R ¹ is fluorine;
[256] R ² can be represented by a compound which is fluorine.
[257] Formula IV may represent that the compound is the E isomer.
[258] In another particularly preferred embodiment of the invention, the compound is represented by Formula V: or a pharmaceutically acceptable salt thereof
[259] Formula V
[260]
[261] here:
[262] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted with one or more halo;
[263] R ² is selected from the group consisting of H, halo and alkyl optionally substituted with one or more halo and
[264] Provided that at least one of R ¹ or R ² contains halo.
[265] In another embodiment of Formula (V), the compound is
[266] R ¹ is halo;
[267] R ² is shown to be selected from the group consisting of H, halo and alkyl optionally substituted with one or more halo.
[268] In another embodiment, the compound is
[269] R ¹ is halo;
[270] R ² is represented by the formula V selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[271] Formula V also
[272] R ¹ is fluorine;
[273] R ² may be selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[274] Another embodiment of the invention
[275] R ¹ is fluorine;
[276] R ² is H.
[277] Compounds of formula V also
[278] R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted with one or more halo;
[279] R ² may be represented as halo.
[280] Another embodiment of the invention
[281] R ¹ is selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl optionally substituted with one or more halo;
[282] R ² is the formula (V) which is halo.
[283] Formula V also
[284] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo;
[285] R ² may be represented as fluorine.
[286] In addition, Formula V is
[287] R ¹ is H;
[288] R ² may be represented as fluorine.
[289] Formula V also
[290] R ¹ is halo;
[291] R ² can be represented by a haloin compound.
[292] In addition, Formula V is
[293] R ¹ is fluorine;
[294] R ² can be represented by a compound which is fluorine.
[295] Formula V may represent that the compound is the E isomer.
[296] In another highly preferred embodiment of the invention, the compound is represented by Formula VI. Or a pharmaceutically acceptable salt thereof,
[297] Formula VI
[298]
[299] here:
[300] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[301] R ² is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[302] Provided that at least one of R ¹ or R ² contains halo.
[303] In another embodiment of Formula (VI), the compound is
[304] R ¹ is halo;
[305] R ² is shown to be selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo.
[306] In another embodiment, the compound is
[307] R ¹ is halo;
[308] R ² is represented by the formula VI selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl which may be optionally substituted by one or more halo.
[309] Formula VI also
[310] R ¹ is fluorine;
[311] R ² may be represented as being selected from the group consisting of H and C ₁ -C ₃ alkyl which may be optionally substituted by one or more halo.
[312] Another embodiment of the invention
[313] R ¹ is fluorine;
[314] R ² is H.
[315] Compounds of formula VI also
[316] R ¹ is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
[317] R ² may be represented as halo.
[318] Another embodiment of the invention
[319] R ¹ is selected from the group consisting of H, fluorine and C ₁ -C ₃ alkyl which may be optionally substituted by one or more halo;
[320] R ² is formula VI, which is halo.
[321] Formula VI also
[322] R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl which may be optionally substituted by one or more halo;
[323] R ² may be represented as fluorine.
[324] In addition, Formula VI
[325] R ¹ is H;
[326] R ² may be represented as fluorine.
[327] Formula VI also
[328] R ¹ is halo;
[329] R ² can be represented by a haloin compound.
[330] In addition, Formula VI
[331] R ¹ is fluorine;
[332] R ² can be represented by a compound which is fluorine.
[333] Formula VI may represent that the compound is the E isomer.
[334] When both R ¹ and R ² are represented by halogen in formula (I), (II), (III), (IV), (V) or (VI), the compound may be one of the E or Z isomers but is preferably the Z isomer.
[335] The invention also includes pharmaceutical compositions comprising a compound of Formula (I), (II), (III), (IV), (V) or (VI).
[336] The term “pharmaceutically acceptable salts” typically includes salts used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Pharmaceutically acceptable salts are particularly useful as products of the process of the invention because of their greater aqueous solubility compared to the corresponding parent or neutral compound. Such salts should have a pharmaceutically acceptable anion or cation. Pharmaceutically acceptable suitable acid addition salts of the compounds of the present invention can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids are aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxyl and sulfonic acid of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid. Citric acid, ascorbic acid, gluconone, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (famoic acid), methane Sulfonic acid, ateliylsulfonic acid, benzenesulfonic acid, sulfanilic acid, stearic acid, cyclohexylaminosulfonic acid, algenic acid, galacturonic acid. Suitable base addition salts of the compounds of the present invention are metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or N, N'-dibenzylethylenediamine, choline, chloroprocaine, di Organic salts made from ethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Pharmaceutically acceptable suitable acid addition salts of the compounds of this invention are, when possible, hydrochloric acid, hydrobromic acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid (including carbonate and hydrogencarbonate anion) Inorganic acids such as sulfonic acid and sulfuric acid, and acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothione, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfone, trifluoromethanesulfone And those derived from organic acids such as succinic acid, toluenesulfone, tartaric acid and trifluoroacetic acid. Suitable base salts that are pharmaceutically acceptable include alkali metal salts such as ammonium salts, sodium and potassium salts and alkaline earth salts such as magnesium and calcium salts. All of these salts can be prepared by conventional means from the corresponding base or conjugate acid of the compound of the invention, respectively, by reacting the appropriate acid or base with the base or conjugate acid of the compound. Another pharmaceutically acceptable salt is a resin-linked salt.
[337] It is possible to administer the compounds of the invention as crude chemicals, but it is preferred to give them in pharmaceutical compositions. According to a further aspect, the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof or solvate thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. It provides a pharmaceutical composition. The carrier (s) should be acceptable in the sense of being compatible with the other ingredients of the formulation and should not be harmful to the recipient.
[338] The most appropriate route may depend, for example, on the condition and disorder of the beneficiary, but the formulation may be oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (skin, buccal) Including sublingual, sublingual, and intraocular). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of the present invention or a pharmaceutically acceptable salt thereof or solvate thereof with a carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately combining the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
[339] Formulations of the invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient; As a powder or granules; As a solution or suspension in an aqueous liquid or a non-aqueous liquid; Or as a lactation liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a cyclic, soft or paste.
[340] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubrication, surface active or dispersant. Molded tablets can be made by molding a mixture of wet powder compounds with an inert liquid diluent in a suitable machine. Tablets may be optionally coated or nicked and formulated therein to provide slow or controlled release of the active ingredient.
[341] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, fungicides and solutes that make the formulation isotonic with the blood of the intended recipient; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be placed in unit dose or multi-dose containers, for example sealed ampoules and vials, and immediately prior to use, with only the addition of sterile liquid carriers, for example salt-containing, water for injection. Can be stored in a freeze-dried (freeze-dried) state. Instant injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
[342] Formulations for rectal administration may be prepared as suppositories with conventional carriers such as cocoa butter or polyethylene glycol.
[343] For example, orally or sublingually, preparations for topical administration in the oral cavity may be prepared by the use of the active ingredient in flavored medicinal preparations such as sucrose and acacia or tragacanth, and gelatin and glycerin or sucrose and acacia. As well as pastilles containing the active ingredient in the main medicine.
[344] Preferred unit dosage formulations are those which contain an effective dosage of the active ingredient, or an appropriate portion thereof, as cited below.
[345] In particular, in addition to the components mentioned above, it should be understood that the formulations of the present invention may comprise other liquid formulations of the prior art which pay attention to the type of formulation in question, and that those suitable for oral administration may include, for example, flavors. do.
[346] The compound of the present invention may be administered orally or by injection at a dosage of 0.01 to 20 mg / kg per day. Dosage ranges for adults are generally from 0.005 mg to 1 g / day. Tablets or other forms of the disclosure provided in discrete units conveniently contain units containing an amount of a compound of the invention effective in such a dosage or multiples thereof, for example 5 mg to 50 mg, typically about 1 mg to 20 mg. It may contain.
[347] The compounds of the formulas (I), (II), (III), (IV), (V) and (VI) are preferably administered orally or by injection (intravenously or subcutaneously). The exact amount of compound administered to the patient will be the responsibility of the attending physician. However, the dosage used will depend on a number of factors, including the age and sex of the patient, the exact disorder being treated and its severity. In addition, the route of administration may vary depending on the condition and its severity.
[348] The compounds of the present invention may exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates cis- and trans-geometric isomers, E- and Z-geometric isomers, R-enantiomers and S-enantiomers, diastereomers, d-isomers, l-isomers, within the scope of the present invention All such compounds are anticipated, including racemic mixtures and other mixtures thereof. Pharmaceutically acceptable salts in such tautomeric, geometric or stereoisomeric forms are also included within the scope of the present invention.
[349] The terms "cis" and "trans" refer to the form of geometric reason. Two carbon atoms connected by a double bond will each have two highest parent groups on the same side of the double bond ("cis") or on the opposite side of the double bond ("trans"). Some of the compounds described are meant to contain alkenyl groups and include both cis and trans or "E" and "Z" geometry.
[350] Some of the compounds described are meant to contain one or more stereocenters (stereocenters) and to include R, S and mixtures of R and S forms for each stereocenter present.
[351] The following schematic is useful for constructing the present invention. As used in the preceding schematics, the following terms and abbreviations apply:
[352] "Boc" means t-butoxycarbonyl;
[353] "p-TsOH" means p-toluenesulfonic acid.
[354]
[355] a) di-tert-butyldicarbonate, 4-dimethylaminopyridine, acetonitrile
[356] b) DIBAL, hexanes and diethyl ether
[357] c) triethyl 2-fluorophosphonoacetate, n-butyllithium, THF and hexane
[358] d) NaBH ₄ , methanol
[359] e) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[360] f) zinc dust, methanol, acetic acid, water, sonication
[361] g) aqueous HCl, heating
[362] h) HCl, dioxane, HOAc, room temperature
[363]
[364] a) NaBH ₄ , methanol
[365] b) carbon tribromide, THF, polymer-supported triphenylphosphine,
[366] c) sodium hydride, DMF, ethyl fluoro [(4-methoxyphenyl) sulfinyl] acetate; heating
[367] d) NaBH ₄ , methanol
[368] e) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[369] f) zinc dust, methanol, acetic acid, water, sonication
[370] g) aqueous HCl, heating
[371]
[372] a) di-tert-butyldicarbonate, 4-dimethylaminopyridine, acetonitrile
[373] b) DIBAL, hexanes and diethyl ether
[374] c) triethyl 2-fluorophosphonoacetate, n-butyllithium, THF and hexane
[375] d) NaBH ₄ , methanol
[376] e) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[377] f) zinc dust, methanol, acetic acid, water, sonication
[378] g) aqueous HCl, heating
[379]
[380] a) ethyl diazoacetate, tin (II) chloride, methylene chloride
[381] b) DAST, N-methyl-2-pyrrolidinone c) NaBH ₄ , methanol
[382] d) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[383] e) zinc dust, methanol, acetic acid, water, sonication
[384] f) aqueous HCl, heating
[385]
[386] a) (EtO) ₂ POSiMe ₃ , heating; p-TsOH
[387] b) DAST
[388] c) n-butyllithium, THF and hexanes; Ethyl glyoxalate
[389] d) NaBH ₄ , methanol
[390] e) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[391] f) zinc dust, methanol, acetic acid, water, sonication
[392] g) aqueous HCl
[393]
[394] a) methyl greenard, THF
[395] b) N-methylmorpholine-N-oxide, tetra-n-propylammonium perruthenate, methylene chloride
[396] c) triethyl 2-fluorophosphonoacetate, n-butyllithium, THF and hexane
[397] d) NaBH ₄ , methanol
[398] e) polymer-supported triphenylphosphine, 3-methyl-1,2,4-oxadiazolin-5-one, dimethylazodicarboxylate, THF
[399] f) zinc dust, methanol, acetic acid, water, sonication
[400] g) aqueous HCl, heating
[401]
[402] a) di-tert-butyldicarbonate, 4-dimethylaminopyridine, acetonitrile
[403] b) DIBAL, hexanes and diethyl ether
[404] c) triethyl 2-fluorophosphonoacetate, n-butyllithium, THF and hexane
[405] d) red-Al, THF
[406] e) methanesulfonyl chloride, triethylamine, methylene chloride f) potassium 3-methyl-1,2,4-oxadiazolin-5-onate, dimethyl formamide
[407] g) zinc dust, methanol, acetic acid, water, heating
[408] h) aqueous HCl, heating
[409]
[410] a) di-tert-butyldicarbonate, 4-dimethylaminopyridine, acetonitrile
[411] b) DIBAL, hexanes and diethyl ether
[412] c) triethyl 2-fluorophosphonoacetate, n-butyllithium, THF and hexane
[413] d) NaBH ₄ , methanol
[414] e) methanesulfonyl chloride, triethylamine, methylene chloride
[415] f) potassium 3-methyl-1,2,4-oxadiazolin-5-onate, DMF
[416] f) gaseous HCl, methanol
[417] ha) aqueous NaOH, room temperature hb) aqueous HCl
[418]
[419] a) aqueous HCl, methanol, heating
[420] b) di-tert-butyldicarbonate, triethylamine, dioxane, water
[421] c) 5-aminotetrazol monohydrate, 1,3-diisopropylcarbodiimide, THF
[422] d) zinc dust, methanol, acetic acid, water, heating
[423] e) HCl, HOAc in dioxane
[424] The novel intermediate compound in the preparation of the therapeutic compound of the present invention is represented by the formula (VII).
[425] Formula VII
[426]
[427] In which R ⁵ is selected from the group consisting of H, F and methyl;
[428] R ⁶ is selected from the group consisting of H, F and methyl;
[429] Provided that either R ⁵ or R ⁶ is F.
[430] J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl; R ⁴ is selected from the group consisting of H and a hetero ring, wherein at least one member of the ring is carbon and from 1 to about 4 hetero atoms are independently selected from oxygen, nitrogen and sulfur, said hetero ring optionally Heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, Amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, mono Alkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl Thio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralcanoyl, heteroaralcanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, Haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaral Kyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroaryl Alkyl, aryl alkenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanosi Roalkyl, Dicyanocycloalkyl, Carboxamidocycloalkyl, Dicarboxamidocycloalkyl, Carboalkoxycyanocycloalkyl, Carboalkoxycycloalkyl, Dicarboalkoxycycloalkyl, Formylalkyl, Acylalkyl, Dialkoxy Phosphonoalkyl, Diaalkoxyphosphonoalkyl, Phosphonoalkyl, Dialkoxyphosphonoalkoxy, Dialcoxoxyphosphonoalkoxy, Phosphonoalkoxy, Dialkoxyphosphonoalkylamino, Dialcoxylphosphonoalkylamino, Phosphonoalkyl It may be substituted with amino, dialkoxyphosphonoalkyl, dialralcoxiphosphonoalkyl, guanidino, amidino, and acylamino.
[431] Q is H or a suitable nitrogen protecting moiety such as t-butoxycarbonyl, 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-nitro-phenylsulphenyl (Nps) or Dithia-succionyl. Numerous protected amino groups useful in the present invention are described in Theodora W. Greene and Peter G. M. Wuts (Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, pp. 494-653). For example, NZ can be a 4-chlorobenzylimino group. In one embodiment of the invention, the protected amino group is any such group resulting from the reaction of an aldehyde with a corresponding amino group to form a Schiff base. A large number of deprotection reagents can be used advantageously in the present invention to convert intermediates to the desired compounds. Many such deprotection reagents are described by Greene and Wuts (homologous). For example, when the protected amino group is a 4-chlorobenzylimino group or a t-butoxycarbonylamino group, the preferred deprotection reagent is an acid. Some useful acid deprotectants include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, phosphoric acid, phosphoric acid, and acetic acid.
[432] The following examples are provided to illustrate the invention and are not intended to limit its scope. Those skilled in the art will readily appreciate that known compounds of the conditions and processes of the following preparation methods may be used to prepare these compounds.
[433] Example 1
[434]
[435] (2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate
[436]
[437] EX-1A) Trimethylsilyl chloride (107.8 g, 1.00 mol) was added dropwise to a cooled solution of L-glutamic acid (30.00 g, 0.20 mol) dissolved in 300 mL of methanol at 0 ° C. The resulting clear colorless solution was stirred at room temperature. Thin layer chromatography (30% ethyl acetate hexane solution) analysis after 18 hours showed no starting material remaining. The reaction was then cooled to 0 ° C. and triethylamine (134 g, 1.33 mol) was added to form a white precipitate. Di-tert-butyldicarbonate (49 g, 0.23 mol) was added and the mixture was allowed to warm to room temperature. After 3 hours the solvent was removed and 700 mL of diethyl ether was added. The solution was filtered and the filter cake was rinsed with 500 mL of additional diethyl ether. The filtrate was concentrated to give 60.8 g (> 95%) of tan oil which was used for next step without further purification.
[438] LCMS: m / z = 298.1 [M + Na] ⁺ . HRMS of C ₁₂ H ₂₁ NO ₆ : requires 276.1447 [M + H] ⁺ , found 276.1462. ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 1.95 (m, 1H), 2.50 (m, 1H), 2.40 (m, 2H), 3.69 (s, 3H), 3.75 (s, 3H), 4.32 (m, 1 H), 5.15 (m, 1 H).
[439]
[440] EX-1B) 4-dimethylaminopyridine (5.3 g, 0.44 mol) and di-tert-butyldicarbo at room temperature in a solution of the crude product (60 g, 0.22 mol) of Example EX-1A dissolved in 300 mL of acetonitrile. Nate (79.2 g, 0.36 mol) was added. The resulting mixture was stirred for 2 days at room temperature, and on day 2 thin layer chromatography (25% ethyl acetate hexane solution) analysis showed that most of the starting material was consumed. The solvent was removed in vacuo to give 85 g of red oil. This crude material was purified by flash column chromatography on silica gel eluting with 1:10 ethyl acetate: hexanes to give 66.4 g (81%) of the desired di-Boc product as a pale yellow solid.
[441] LCMS: m / z = 398.2 [M + Na] ⁺ . HRMS of C ₁₇ H ₂₉ NO ₈ : requires 398.1791 [M + Na] ⁺ , found 398.1790. ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.19 (m, 1H), 2.41 (m, 2H), 2.46 (m, 1H), 3. 66 (s, 3H), 3.70 (s, 3H ), 4.91 (dd, 1 H).
[442]
[443] EX-1C) DIBAL solution (64 mL of 1.0 M hexane solution, 63.9 mmol) was added dropwise over 30 minutes to a cooled solution of EX-1B (20 g, 53.3 mmol) dissolved in 400 mL of anhydrous diethyl ether at -78 ° C. After 30 minutes at −78 ° C. the solution was quenched with water (12 mL, 666 mmol) and allowed to warm to room temperature. The cloudy mixture was diluted with 350 mL of ethyl acetate, dried over MgSO ₄ and filtered through a pad of celite. The filtrate was concentrated to give a yellow oil. 18.9 g of the crude yellow oil was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to give 13.8 g (75%) of the desired aldehyde product as a clear oil.
[444] LCMS: m / z = 368.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.19 (m, 1H), 2.41 (m, 2H), 2.46 (m, 1H), 3.70 (s, 3H), 4.91 (dd, 1H), 9.8 (s, 1 H).
[445]
[446] EX-1D) n-butyllithium (10.9 mL, 17.5 mmol, 1.6 M hexane solution) was added to a cooled (-78 ° C) solution of triethyl 2-fluorophosphonoacetate (4.67 g, 19.3 mmol) dissolved in 20 mL of THF. Added. The mixture was stirred for 20 min at -78 ° C to give a light yellow solution. Next, a solution of the product of EX-1C (6.0 g, 17.5 mmol) dissolved in 5 ml of THF was added by syringe, and the resulting mixture was stirred at −78 ° C. for 2 hours, and at 2 hours thin layer chromatography ( 30% ethyl acetate hexane solution) analysis showed no starting material remained. The reaction was quenched with saturated aqueous NH ₄ Cl (30 mL) at −78 ° C. The organic layer was collected and the aqueous layer was extracted with diethyl ether (2x50 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over MgSO ₄ , filtered and concentrated. 8.6 g of the crude product, yellow oil, was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to give 6.05 g (79%) of the desired fluoro olefin product as a clear oil. ¹ H NMR and ¹⁹ F NMR showed that the isolated product had an E: Z ratio of approximately 95: 5.
[447] LCMS: m / z = 456.2 [M + Na] ⁺ . HRMS of C ₂₀ H ₃₂ NOSF: est. 456.2010 [M + Na] ⁺ , found 456.2094. ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.0 (m, 1H), 2.25 (m, 1H), 2.6 (m, 2H), 3.7 (s, 3H), 4.25 (m, 2H), 4.9 (m, 1H), 5.9 (dt, vinyl, 1H, J = 20 Hz), 6.2 (dt, vinyl, 1H, J = 30 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −129.12 (d, 0.09 F, J = 31 Hz, 9% Z-isomer), −121.6 (d, 0.91 F, J = 20 Hz, 91% E-isomer).
[448]
[449] EX-1E) To a solution of EX-1D (805 mg, 1.86 mmol) dissolved in 20 mL of methanol was added 200 mg of solid NaBH ₄ (844 mg, 22.3 mmol) at room temperature. The reaction was stirred at room temperature for 18 hours, and at 18 hours thin layer chromatography (30% ethyl acetate hexane solution) analysis showed that most of the starting material was consumed. The reaction was quenched with 20 mL saturated aqueous NH ₄ Cl and extracted with ethyl acetate (2 × 35 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. 700 mg of crude oil, a crude oil, was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to afford 353 mg (48%) of the desired allyl alcohol product as a clear oil. ^{According to 19} F NMR it contained mainly the desired E-isomer.
[450] LCMS: m / z = 414.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 1.95 (m, 1H), 2.1 (m, 1H), 2.2 (m, 1H), 2.35 (t, 1H), 3.7 (s, 3H), 4.25 (m, 2H), 4.8 (m, 1H), 5.15 (dt, 1H, J = 20 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −119.1 (d, 0.02F, J = 37 Hz, 2% Z-isomer), −111.8 (d, 0.98F, J = 24 Hz, 98% E-isomer).
[451]
[452] EX-1F) EX-1E (137 g, 3.5 mmol), polymer-supported triphenylphosphine (3 mmol / g, 1.86 g, 5.6 mmol) and 3-methyl-1,2,4-oxadiazoline in 50 mL THF) To a 5-one (450 mg, 4.55 mmol) mixture was added dropwise dimethylazodicarboxylate (820 mg, 5.6 mmol). The reaction was stirred at room temperature for 1 hour, and thin layer chromatography (40% ethyl acetate hexane solution) analysis at 1 hour showed no starting material remaining. The mixture was filtered through celite and the filtrate was concentrated. The resulting yellow oil was partitioned between 30 mL of methylene chloride and 30 mL of water. The organic layer was separated, washed with water (1 × 30 mL) and brine (1 × 30 mL), dried over MgSO ₄ , filtered and concentrated. 1.8 g of crude yellow oil was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to give 670 mg (40%) of the desired protected E-allyl amidine product as a clear oil. ^{According to 19} F NMR it contained only the desired E-isomer.
[453] LCMS: m / z = 496.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 1.85 (m, 1H), 2.2 (m, 3H), 2.25 (s, 3H), 3.64 (s, 3H), 4.25 (m, 2H), 4.8 (m, 1 H), 5.3 (dt, 1 H, J = 20 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −110.8 (q, 1F, J = 20 Hz).
[454]
[455] EX-1G) The product of EX-1F (670 mg, 1.4 mmol) was dissolved in 25 mL of methanol and 25 mL of 25% acetic acid aqueous solution. Zinc dust (830 mg, 12.7 mmol) was added and the mixture was agitated for 8 hours by sonication, and at 8 hours HPLC analysis showed 20% of the starting material remaining. Zn dust was filtered from the reaction mixture and the filtrate was stored at -20 ° C for 12 hours. The filtrate was allowed to warm up to room temperature and further cold acetic acid (7 mL) and zinc dust (400 mg, 6.1 mmol) were added and the mixture was sonicated for 1 hour at room temperature with HPLC analysis showing 96% product. The mixture was filtered through celite and the filtrate was concentrated. This crude material was added in 8 minutes using A (A: 100% acetonitrile with 0.01% trifluoroacetic acid, B: 100% H ₂ O with 0.01% trifluoroacetic acid) in a 20-95% gradient. Purification by reverse phase HPLC column chromatography on a YMC Combipre column eluting over. The portions containing the product were combined and concentrated to give 344 mg (45%) of the desired acetamide product as trifluoroacetate salt. ^{According to 19} F NMR it contained only the desired E-isomer.
[456] LCMS: m / z = 432.3 [M + H] ⁺ . ¹ H NMR (CD ₃ 0D) δ 1.52 (s, 18H), 2.9 (m, 1H), 2.2 (m, 3H), 2.27 (s, 3H), 4.2 (d, 1H), 5.4 (dt, vinyl, 1H, J = 20 Hz). ¹⁹ F NMR (CD ₃ 0D) δ −110. 83 (m, 1F, J = 20 Hz).
[457]
[458] EX-1H) A sample of the product of EX-1G was dissolved in cold acetic acid. To this stirred solution was added 10 equivalents of 1N HCl in dioxane. The solution was stirred at room temperature for 10 minutes and then all solvents were removed in vacuo to produce the illustrated methyl ester dihydrochloride.
[459] Example 1) A solution of EX-1G (344 mg, 1.4 mmol) dissolved in 6 mL of 6.0N HCl was refluxed for 1 hour. The solvent was removed in vacuo. The resulting solid was dissolved in water three more times and concentrated, then dissolved five times in 1.0 N HCl and concentrated to remove all remaining TFA salt. On completion, 160 mg (37%) of desired (2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride product was obtained as a white solid. Its melting point is 51.5-56.3 ° C. and contains only the desired E-isomer according to ¹⁹ F NMR.
[460] LCMS: m / z = 218.1 [M + H] ⁺ . HRMS of C ₉ H ₁₆ FN ₃ 0 ₂ : requires 218.1305 [M + H] ⁺ , found 218.1325. ¹ H NMR (D ₂ O) δ 1.8 (m, 2H), 2.05 (m, 2H), 2.1 (s, 3H), 3.7 (t, 1H), 4.00 (d, 2H), 5.3 (dt, vinyl, 1H, J = 21 Hz). ¹⁹ F NMR (D ₂ O) δ −109.9 (m, 1F, J = 20 Hz).
[461] Example 2
[462]
[463] (2S, 5E / Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride
[464]
[465] EX-2A) Triethylamine (38.35 g, 0.38 mol) was added to a cooled (0 ° C.) solution of L-glutamic acid 5-methyl ester (50.00 g, 0.31 mol) dissolved in 400 mL of 1: 1 H ₂ O in dioxane. After addition, di-tert-butyldicarbonate (80.00 g, 0.37 mol) was added. The resulting clear colorless solution was stirred at room temperature. Thin layer chromatography (30% ethyl acetate hexane solution) analysis after 18 hours showed no starting material remaining. The reaction mixture was quenched with 200 mL of 1.0N aqueous KHSO ₄ . The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3x100 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to give 72.00 g (89%) of the desired product as pale yellow oil.
[466] LCMS: m / z = 284.1 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.50 (s, 9H), 2.00 (m, 1H), 2.20 (m, 1H), 2.42 (m, 2H), 3.66 (s, 3H), 4.34 (d, 1H), 5.24 (d, 1 H).
[467]
[468] EX-2B) 4-methylmorpholine (28.11g, 0.28mol) and isobutylchloroformate (37.95g, 0.28mol) were added to a solution of the product of EX-2A (72.60g, 0.28mol) dissolved in 300mL of THF. Add quickly at -10 ° C. The clear yellow solution immediately formed a white precipitate. After 4 minutes the resulting hazy yellow mixture was filtered and the filtrate was cooled to −10 ° C., then a solution of NaBH ₄ (15.77 g, 0.42 mol) dissolved in 200 mL of H ₂ O was added dropwise while maintaining the temperature below 0 ° C. did. After NaBH ₄ was added all at once and the ice bath was removed, the reaction was stirred for 1.5 hours at room temperature. The reaction mixture was quenched with 200 mL of H ₂ O. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x100 mL). The organic layers were combined, washed with brine, dried over MgSO ₄ , filtered and concentrated to give 58 g (85%) of desired product as a yellow oil.
[469] LCMS: m / z = 270.1 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 9H), 1.65 (m, 1H), 1.85 (m, 2H), 2.42 (t, 2H), 3.66 (s, 3H), 4.8 (d, 1H).
[470]
[471] EX-2C) To a solution of EX-2B (30.95 g, 0.13 mol) dissolved in 100 mL of benzene, 2,2-dimethoxy propane (65.00 g, 0.63 mol) was added, followed by p-toluene sulfonic acid (2.40 g, 12.5 mmol) and 5 g of 3 'molecular sieves were added. The resulting mixture was refluxed for 2 hours, and at 2 hours thin layer chromatography (30% ethyl acetate hexane solution) analysis indicated the reaction was complete. The mixture was cooled to rt, diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO ₃ (100 mL) followed by brine (100 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. 30.5 g of crude yellow oil was purified by flash column chromatography on silica gel eluting with 1:10 ethyl acetate: hexanes to give 15.40 g (42%) of the desired product as pale yellow oil.
[472] LCMS: m / z = 310.1 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 12H), 1.56 (d, 3H), 1.85 (m, 2H), 2.38 (m, 2H), 3.66 (s, 3H), 3.7 (d, 1H), 3.95 (m, 2 H).
[473]
[474] EX-2D) DIBAL (6.0 mL of 1.0M solution dissolved in toluene) was added dropwise to a cooled (-78 ° C) solution of EX-2C (1.00 g, 3.00 mmol) dissolved in 10 mL of methylene chloride. After 30 minutes the reaction was quenched with 5 mL saturated potassium sodium tartrate (rosel salt) and then allowed to warm to room temperature. The mixture was then filtered through a pad of celite, dried over MgSO ₄ , refiltered and concentrated to give a yellow oil. 610 mg of crude yellow oil was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to give 550 mg (71%) of the desired product as a clear oil.
[475] ¹ H NMR (CDCl ₃ ) δ 1.50 (s, 12H), 1.58 (d, 3H), 2.00 (m, 2H), 2.5 (m, 2H), 3.7 (d, 1H), 3.95 (m, 2H), 9.8 (s, 1 H).
[476]
[477] EX-2E) 1,8-diazabicyclo [5.4.0] undec in an ice-cold (0 ° C) solution of triethyl 2-fluoro-phosphonoacetate (6.70 g, 27.6 mmol) dissolved in 100 mL of methylene chloride -7-ene (4.70 g, 31.0 mmol) was added. The mixture was stirred at 0 ° C. for 1 hour to make an organic solution. Next, an ice-cooled (0 ° C.) solution of EX-2D's product (5.71 g, 22.2 mmol) dissolved in 15 mL of methylene chloride was added by syringe, and the resulting mixture was stirred at ambient temperature for 18 hours and 18 hours. Thin layer chromatography (30% ethyl acetate hexane solution) analysis showed that no starting material remained. The solvent was removed in vacuo and the resulting mixture partitioned between 200 mL of ethyl acetate and 100 mL of water. The organic layer was collected and the aqueous layer extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with 1.0 M aqueous KHSO ₄ (100 mL), water (100 mL) and brine (100 mL), dried over MgSO ₄ , filtered and concentrated to afford the desired fluoro olefin product (8.0 g) as a yellow oil. ¹ H NMR and ¹⁹ F NMR showed that the isolated product had a Z: E ratio of approximately 70:30.
[478] LCMS: m / z = 368.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 5.9-6.0 (dt, 1H, J = 20 Hz), 6.05-6.20 (dt, 1H, J = 33 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −129.89 (d, 0.7F, J = 38 Hz, 70% Z-isomer), −122.05 (d, 0.3 F, J = 20 Hz, 30% E-isomer). This mixture was used without further purification.
[479]
[480] EX-2F) LiBH ₄ (2.0 M THF solution 12.7) was added to an ice-cooled (0 ° C.) solution of the product of EX-2E (8.0 g, 23.0 mmol) dissolved in 70 mL THF. The reaction mixture was stirred at ambient temperature for 18 hours and at 18 hours thin layer chromatography (30% ethyl acetate hexane solution) analysis showed no starting material remaining. THF was removed and the resulting mixture was dissolved in methylene chloride. After cooling to 0 ° C., the reaction was quenched by the slow addition of 1.0 M aqueous KHSO ₄ . Next, the mixture was extracted with ethyl acetate (3x50 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. 8.0 g of crude oil, a clear oil, was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to afford 900 mg (13%) of the desired product as a clear oil.
[481] LCMS: m / z = 326.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 4.79-4.94 (dm, 1 H), 5.10-5.25 (dt, 1 H). ¹⁹ F NMR (CDCl ₃ ) δ −119.82 (dt, 0.7F, J = 38 Hz, 70% Z-isomer), −111.09 (dt, 0.3 F, J = 27 Hz, 30% E-isomer).
[482]
[483] EX-2G) Methanesulfonyl chloride (390 mg, 3.4 mmol) was added to an ice-cold (0 ° C) solution of the product of EX-2F (950 mg, 3.1 mmol) dissolved in 5 mL of pyridine. The reaction was stirred at 0 ° C. for 5 minutes and then warmed to room temperature and stirred for 3 hours, at 3 hours thin layer chromatography (30% ethyl acetate hexane solution) analysis showed no starting material remaining. The reaction was diluted with diethyl ether (10 mL) and washed with saturated aqueous NaHCO ₃ (20 mL) followed by 1.0 M citric acid (20 mL). The organic layer was dried over MgSO ₄ and filtered to give 500 mg (51%) of the desired allyl chloride product as a white solid. This product was used next without further purification. LCMS: m / z = 344.1 [M + Na] ⁺ .
[484]
[485] EX-2H) Potassium phthalimide (290 mg, 1.57 mmol) was added to the stirring solution of the product of EX-2G (440 mg, 1.37 mmol) dissolved in 10 mL of DMF. The resulting mixture was heated to reflux for 18 hours, and at 18 hours thin layer chromatography (30% ethyl acetate hexane solution) analysis showed no starting material remaining. The cooled mixture was diluted with 30 mL of water, extracted with ethyl acetate (30 mL), dried over MgSO ₄ , filtered and concentrated to give 540 mg (91%) of the desired product as a yellow oil.
[486] LCMS: m / z = 455.2 [M + Na] ⁺ . HRMS: Theoretical 433.2139 [M + H] ⁺ , found 433.2144. ¹ H NMR (CDCl ₃ ) δ 1.4 (s, 18H), 1.6 (m, 6H), 2.05 (m, 2H), 3.6-4.42 (m, 4H), 4.9 (dt, vinyl, 1H), 5.2 (m , Vinyl, 1H), 7.7 (m, 2H), 7.9 (m, 2H). ¹⁹ F NMR (CDCl ₃ ) δ −117.09 (m, 0.7F, J = 38 Hz, 70% Z-isomer), −111.61 (m, 0.3 F, J = 22 Hz, 30% E-isomer).
[487]
[488] EX-2I) The product of EX-2H (600 mg, 1.38 mmol) was dissolved in 8 mL of acetic acid and 2 mL of water. The mixture was stirred overnight at room temperature and the next day thin layer chromatography (30% ethyl acetate hexane solution) analysis showed no starting material remaining. The solution was concentrated under nitrogen flow and the crude product was purified by flash column chromatography on silica gel eluting with 1: 2 ethyl acetate: hexanes to give 248 mg (63%) of the desired product as a white solid.
[489] LCMS: m / z = 415.1 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H), 1.56 (m, 2H), 2.15 (m, 1H), 3.64 (m, 2H), 4.35 (d, 2H), 4.9 (dt, vinyl, 1H , J = 37 Hz), 7.73 (m, 2H), 7.86 (m, 2H). ¹⁹ F NMR (CDCl ₃ ) δ −116.96 (dt, 0.8 F, J = 37 Hz, 80% Z-isomer), −111.09 (dt, 0.2 F, J = 22 Hz, 20% E-isomer).
[490]
[491] EX-2J) Pyridinium dichromate (1.14 g, 3.03 mmol) was added to a solution of the product of EX-2I (237 mg, 0.605 mmol) dissolved in 6 mL of DMF. The solution turned dark orange, which was stirred for 18 hours at room temperature, and at 18 hours the solution was poured into 20 mL of H ₂ O. The mixture was extracted with ethyl acetate (4x25 mL). The combined organic layers were washed with 5% aqueous KHCO ₃ ( ₃ × 25 mL). The aqueous layer was acidified to pH = 3 with 1.0 M KHSO ₄ and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated to give 235 mg (95%) of the desired amino acid product. The resulting white solid was used without further purification.
[492] LCMS: m / z = 429.1 [M + Na] ⁺ .
[493]
[494] EX-2K) To a solution of the product of EX-2J (230 mg, 0.56 mmol) dissolved in 7 mL of ethanol was added hydrazine hydrate (70 mg, 1.13 mmol) and the resulting solution was refluxed for 2 hours to form a white precipitate. The solvent was removed in vacuo. The resulting white solid was dissolved in 8 mL of water and acidified with cold acetic acid to pH = 4. Next, it was cooled in an ice bath and filtered. The filtrate was concentrated to give 136 mg (87%) of the desired allyl amine product as yellow crystals. This was used for next step without purification.
[495] LCMS: m / z = 277.1 [M + H] ⁺ .
[496]
[497] EX-2L) To a stirring solution of the product of EX-2K (136 mg, 0.50 mmol) dissolved in 6 mL of DMF was added ethyl acetimidate (252 mg, 2.04 mmol) in three portions and at 1.5 hour intervals. After the addition was complete the mixture was stirred at rt overnight. The pink solution was filtered off and the filter cake was washed with water. The solvent was removed in vacuo and the resulting yellow oil was washed over 7 minutes using A (A: 100% acetonitrile with 0.05% TFA, B: 100% water with 0.05% TFA) in a 1-50% gradient. Purified by reverse phase HPLC using an eluting YMC Combipre ODS-A semi-prep column. The portions containing the product were combined and concentrated to give 50 mg of the desired acetamidine product as the trifluoroacetate salt, which was used for the next step. LCMS: m / z = 318.2 [M + H] < + >.
[498] Example 2) The product of EX-2L was dissolved in 6 mL of 6.0N HCl and stirred at room temperature for 1 hour. The solvent was removed in vacuo. The resulting solid was dissolved three more times in water and concentrated to remove the TFA salt. ^{When 19} F NMR showed that all TFAs had been removed, the product was dried in vacuo to give the desired solid (2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) as a bubbling transparent solid. E] containing amino] -5-heptenic acid, dihydrochloride and (2S, 5Z) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride 30 mg (20%, combined yields of two steps) were obtained.
[499] HRMS of C ₉ H ₁₆ FN ₃ 0 ₂ : requires 218.1305 [M + H] ⁺ , found 218.1309. ¹ H NMR (D ₂ O) δ 2.01 (m, 2H), 2.21 (s, 3H), 2.24 (m, 2H), 3.96 (t, 1H), 4.00 (d, 2H), 5.07 (dt, vinyl, 1H, J = 37 Hz), 5.4 (dt, vinyl, 1H, J = 37 Hz). ¹⁹ F NMR (D ₂ 0) δ −116.8 (m, 0.8F, J = 37 Hz, 80% Z-isomer), −109.6 (m, 0.2F, J = 21 Hz, 20% E-isomer).
[500] Example 3
[501]
[502] (2S, 5Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride
[503]
[504] EX-3A) Triethyl 2-fluoro-phosphonoacetate (3.54 g, 14.6 mmol) was dissolved in 20 mL of CH ₂ Cl ₂ at 0 ° C. and 1,8-diazabicyclo [5.4.0] undec-7 -Ene (2.4 mL, 16.4 mmol) was added. The mixture was stirred at 0 ° C. for 20 minutes to make an orange solution. Next, the aldehyde product of EX-1C (4.04 g, 11.7 mmol) was added at 0 ° C. and the resulting brown mixture was stirred overnight at room temperature and the next day LCMS showed no starting material remaining. Solvent was removed and the residue partitioned between water (60 mL) and ethyl acetate (120 mL). The organic layer was collected and the aqueous layer extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water (60 mL) and 10% aqueous KHSO ₄ (60 mL), dried over MgSO ₄ , filtered and concentrated. 5.7 g of crude oil, crude, was purified by flash column chromatography on silica gel eluting with a 10% ethyl acetate hexane solution to afford 3.5 g (69%) of the desired fluoro olefin product as a clear oil. ¹ H NMR and ¹⁹ F NMR indicated that the isolated product had a Z / E ratio of 70:30.
[505] HRMS of C ₂₀ H ₃₂ 0 ₈ FN: est. 456.2010 [M + Na] ⁺ , found 456.2017. ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.0 (m, 1H), 2.25 (m, 1H), 2.6 (m, 2H), 3.7 (s, 3H), 4.25 (m, 2H), 4.9 (m, 1H), 5.9 (dt, vinyl, 1H, J = 21.2 Hz), 6.1 (dt, vinyl, 1H, J = 32.4 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −129.4 (d, 0.7F, J = 34 Hz, 70% Z-isomer), −121.6 (d, 0.3 F, J = 22 Hz, 30% E-isomer).
[506]
[507] EX-3B) The ester product of EX-3A (3.5 g, 8.1 mmol) was dissolved in 80 mL of methanol at room temperature and then solid NaBH ₄ (3 g, 80 mmol) was added in one portion. The mixture was stirred at rt for 18 h and at 18 h HPLC analysis showed that the reaction was at least 90% complete. The reaction was quenched with saturated NH ₄ Cl. The product was extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic layer was evaporated to afford 3.2 g of crude product as colorless oil, which was purified by Biotage flash column chromatography eluting with 20% to 30% ethyl acetate hexane solution to give the desired pure (Z: E = 97: clear oil). 3, ¹⁹ F NMR) 2.11 g (67%) of a Z / E mixture of the fluoro olefin product, a clear oil, with Z-isomer product.
[508] HRMS of C ₁₈ H ₃ 0NO ₇ F: Theorem 414.1904 [M + Na] ⁺ , found 414.1911. ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.0 (m, 1H), 2.2 (m, 3H), 3.7 (s, 3H), 4.1 (dd, 2H, J = 17 Hz), 4.8 (dt , 1H, J = 39 Hz), 4.9 (m, 1H). ¹⁹ F NMR (CDCl ₃ ) δ −119.1 (dt, 1F, J = 39 Hz, J = 17 Hz).
[509]
[510] EX-3C) The Z-alcohol product (390 mg, 1 mmol) and 3-methyl-1,2,4-oxadiazolin-5-one (130 mg, 1.3 mmol) of EX-3B were dissolved in 20 mL of THF. Next, Polymer Support-PPh ₃ was added to the solution and the mixture was stirred gently for 10 minutes. Next, diethyl azodicarboxylate was added dropwise and the mixture was stirred at room temperature for 1 hour, at 1 hour LCMS analysis showed that a product formed and no starting material was present. The polymer was removed by filtration through a pad of celite and the pad was washed with THF. The filtrate was evaporated to afford 1.0 g of crude product, which was purified by Biotage flash column chromatography eluting with 20% to 30% ethyl acetate hexane solution to give 500 mg of product contaminated with any hydrazide byproduct. This material was further purified by Biotage flash column chromatography eluting with 98: 2: 0.01 methylene chloride: methanol: ammonium hydroxide to afford 180 mg (38%) of the desired protected amidine as a clear oil. It contained only the desired Z-isomers by ¹⁹ F NMR.
[511] HRMS of C ₂₁ H ₃₂ N ₃ 0 ₈ F: requires 491.2517 [M + NH ₄ ] ⁺ , found 491.2523. ¹ H NMR (CDCl ₃ ) δ 1.5 (s, 18H), 1.9 (m, 1H), 2.1 (m, 3H), 2.3 (s, 3H), 3.7 (s, 3H), 4.2 (d, 2H), 4.8 (m, 1 H), 5.0 (dt, 1 H, J = 36 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −116.5 (dt, 1F, J = 38 Hz).
[512]
[513] EX-3D) The product of EX-3C (88 mg, 0.19 mmol) was dissolved in 4 mL of a 25% acetic acid aqueous solution containing several drops of methanol, and then Zn dust (109 mg, 1.67 mmol) was added. The mixture was stirred with sonication for 3 hours. Zn was filtered through a pad of celite and the pad was washed with water. The filtrate was evaporated to dryness to afford the crude product, which was obtained using A (A: 100% ACN with 0.01% TFA, B: 100% H ₂ O with 0.01% TFA) in a 20-80% gradient. Purification by reverse phase HPLC column chromatography on YMC Combipre column eluting over 8 minutes. The desired product was collected in two portions and the combined portions were concentrated. The product was obtained as a colorless oil as a mixture of trifluoroacetate salts, which according to ¹⁹ F NMR contained only the desired Z-isomer.
[514] 30% is mono-Boc-protected product: HRMS of C ₁₅ H ₂₆ N ₃ O ₄ F: found 332.1986 [M + H] ⁺ , found 332.2001, 70% is di-Boc-protected product: C ₂₀ H ₃₄ HRMS of N ₃ 0 ₆ F: found 432.2510 [M + H] ⁺ , found 432.2503. ¹ H NMR (D ₂ O) of di-Boc product δ 1.3 (s, 18H), 1.8 (m, 1H), 2.1 (m, 3H), 2.1 (s, 3H), 3.6 (s, 3H), 3.9 (d, 2H), 4.9 (dt, vinyl, 1H, J = 37 Hz). ¹⁹ F NMR (D ₂ O) δ −117.3 (dt, 1F, J = 37 Hz).
[515] Example 3) The combined mono- and di-Boc products of EX-3D were dissolved in 30 mL of 6N HCl, the solution was refluxed for 4 hours, and at 4 hours LCMS analysis indicated the reaction was complete. Excess HCl and water were removed in vacuo. 9 mg (40%) of desired (2S, 5Z) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride product as pale yellow, very hygroscopic foam upon completion , Yields of two steps combined) were obtained. ¹⁹ F NMR contained only the desired Z-isomer.
[516] HRMS of C ₉ H ₁₆ N ₃ 0 ₂ F: requires 218.1305 [M + H] ⁺ , found 218.1320. ¹ H NMR (D ₂ O) δ 1.3 (s, 18H), 1.9 (m, 2H), 2.1 (m, 2H), 2.1 (s, 3H), 3.8 (t, 1H), 3.9 (d, 2H) , 4.9 (dt, vinyl, 1H, J = 37 Hz). ¹⁹ F NMR (D ₂ O) δ −117.3 (dt, 1F, J = 37 Hz).
[517] Example 4
[518]
[519] (2S, 5Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, trihydrochloride, dihydrate
[520]
[521] EX-4A) The product of EX-1B (3.75 g, 10 mmol) was dissolved in 60 mL of methanol and solid NaBH ₄ (4 g, 106 mmol) was added in small portions over 10 hours at room temperature, at which time HPLC analysis was approximately 84 A reduction of% was shown. The reaction mixture was quenched with saturated NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to afford 3.2 g of crude product as yellow oil.
[522] HRMS of C ₁₆ H ₂₉ NO ₇ : Theoretical 348.2022 [M + H] ⁺ , found 348.2034. ¹ H NMR (CD ₃ 0D) δ 4.9 (q, 1H), 3.7 (s, 3H), 3.5 (t, 2H), 3.2 (m, 1H), 2.1 (m, 1H), 1.9 (m, 2H) , 1.5 (s, 18 H).
[523]
[524] EX-4B) The alcohol product of EX-4A (3.2 g, 9.0 mmol) was dissolved in 100 mL of THF and cooled in an ice bath. After addition of carbon tribromide (4.27 g, 12.9 mmol), the resulting solution was stirred for 30 minutes under 0 ° C. nitrogen. Polymer-supported PPh ₃ was added and the mixture was stirred gently at 0 ° C. for 1 hour and then at room temperature overnight. The polymer was removed by filtration through celite and the pad of celite was washed with THF. The filtrate was evaporated to afford crude product, which was purified by Biotage flash column chromatography eluting with 1: 3 ethyl acetate: hexanes to give 2.0 g (54%, yield of 2 steps) of the desired bromo product as colorless oil. )
[525] HRMS of C ₁₆ H ₂₈ NO ₆ Br: Theoretical 410.1178 [M + H] ⁺ , found 410.1137. ¹ H NMR (CDCl ₃ ) δ 4.9 (q, 1H), 3.7 (s, 3H), 3.4 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H), 1.5 (s, 18H).
[526]
[527] EX-4C) A solution of NaOEt (21% EtOH solution, 41.1 mL, 0.11 mol) dissolved in 60 mL ethanol was treated with p-methoxy benzenethiol (14.0 g, 0.1 mol), followed by ethyl chlorofluoroacetate (18.3). g, 0.13 mol). The mixture was stirred at rt for 2 h and diluted with 250 mL of 1: 1 hexane ethyl acetate solution. The organic layer was washed three times with water and dried over Na ₂ SO ₄ . The dried organic layer was evaporated to afford 25 g of crude product which was used next without further purification.
[528] LCMS of C ₁₁ H ₁₃ O ₃ SF: m / z = 267.10 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 7.5 (d, 2H), 6.9 (d, 2H), 6.0 (d, 1H, J = 51.9Hz), 4.2 (q, 2H), 3.8 (s, 3H), 1.2 ( t, 3H). ¹⁹ F NMR (CDCl ₃ ) δ −146.2 (d, 1F, J = 53.6 Hz).
[529]
[530] EX-4D) The crude product (24 g, 0.1 mol) of EX-4C dissolved in 200 mL of methylene chloride was cooled to -78 ° C and treated with 3-chloroperbenzoic acid (27 g, 0.12 mol) dissolved in 200 mL of methylene chloride. did. The reaction mixture was slowly warmed to room temperature and stirred overnight, and the next day LCMS analysis showed that a product formed and no starting material remained. The solid was filtered off and the filtrate was washed with saturated NaHCO ₃ and NH ₄ Cl. The organic layer was dried over MgSO ₄ and evaporated to give 30 g of orange oil, which was purified by Biotage flash column chromatography eluting with 2: 1 hexanes: ethyl acetate to give 17.5 g of desired sulfoxide product as a grayish white oil. %) Was obtained.
[531] HRMS of C ₁₁ H ₁₃ 0 ₄ FS: Theoretical 261.0597 [M + H] ⁺ , Found: 261.0598. ¹ H NMR (CDCl ₃ ) δ 7.6 (m, 2H), 7.0 (m, 2H), 5.6 (d, 1H, J = 50Hz major enantiomer), 5.4 (d, 1H, J = 49Hz minor enantiomer ), 4.2 (q, 2H), 3.8 (s, 3H), 1.2 (t, 3H). ¹⁹ F NMR (CDCl ₃ ) δ −194.3 (d, 1F, J = 53.6 Hz major enantiomer), −191.7 (d, 1F, J = 50.4 Hz minor enantiomer).
[532]
[533] EX-4E) A suspension of NaH (60% in mineral oil, 212 mg, 5.3 mmol) dissolved in 6 mL dry DMF was cooled to 0 ° C. under nitrogen and the sulfoxide product of EX-4D dissolved in 2 mL DMF (1.25 g, 4.8 mmol) solution. After stirring for 20 min at room temperature the mixture was cooled to 5 ° C. and the bromo product (2.17 g, 5.3 mmol) of EX-4B was added in one portion. The reaction was stirred at room temperature for 3 hours and then heated to reflux at 95 ° C. for 1 hour, at which time LCMS analysis indicated the formation of raw Seoul. The mixture was poured into an ice / aqueous NH ₄ Cl mixture. The product was extracted with 1: 1 hexanes: ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and evaporated to afford 3.17 g of crude yellow oil, which was purified by Biotage flash column chromatography eluting with a 10% ethyl acetate hexane solution to give the desired fluoro olefin ester product as a colorless oil, 1.05 g. (50%) was obtained. ¹⁹ F NMR showed that the isolated product contained the desired Z-isomer at 95: 5.
[534] HRMS of C ₂₀ H ₃₂ 0 ₈ FN: 456.2010 [M + Na] ⁺ , found: 456.2017.
[535] ¹ H NMR (CDCl ₃ ) δ 1.5 (s, 18H), 2.0 (m, 1H), 2.3 (m, 4H), 3.7 (s, 3H), 4.3 (m, 2H), 4.9 (m, 1H), 6.1 (dt, vinyl, 1H, J = 32.4 Hz, Z-isomer). ¹⁹ F NMR (CDCl ₃ ) δ −129.4 (d, 0.95F, J = 34.8 Hz, 95% Z-isomer), −121.6 (d, 0.05F, J = 21.6 Hz, 5% E-isomer).
[536]
[537] EX-4F) The ester product of EX-4E (1.05 g, 2.4 mmol) was dissolved in methanol at room temperature, and solid NaBH ₄ was added little by little. The mixture was stirred at rt for 18 h, then 2 mL of water was added, the mixture was stirred for 3 h further, and at 3 h HPLC analysis showed that the reaction was at least 95% complete. The reaction was quenched with saturated NH ₄ Cl. The product was extracted with ethyl acetate and the organic layer was dried over Na ₂ S0 ₄ and evaporated to give 0.95 g of crude product as colorless oil. ¹⁹ F NMR showed that the isolated crude product contained only the desired Z-isomer.
[538] HRMS of C ₁₈ H ₃₀ NO ₇ F: Theoretical 414.1904 [M + Na] ⁺ , found: 414.1949. ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.0 (m, 1H), 2.2 (m, 3H), 3.7 (s, 3H), 4.1 (dd, 2H, J = 17 Hz), 4.8 (dt , 1H, J = 36 Hz), 4.9 (m, 1H). ¹⁹ F NMR (CDCl ₃ ) δ −119.1 (dt, 1F, J = 38 Hz, J = 17 Hz).
[539]
[540] EX-4G) The alcohol product of EX-4F (0.95 g, 2.4 mmol) and 3-methyl-1,2,4-oxadiazolin-5-one (290 mg, 2.9 mmol) were dissolved in 60 mL THF. Polymer-bound triphenyl phosphine was added and the mixture was gently stirred for 10 minutes. Dimethyl azodicarboxylate was added dropwise and the mixture was stirred for 1 hour at room temperature, at 1 hour LCMS analysis showed that a product formed and no starting material remained. The polymer was removed by filtration through a pad of celite and the pad was washed with THF. The filtrate was evaporated to give a residue, which was partitioned with methylene chloride and water. The organic layer was washed twice with water, dried over MgSO ₄ and evaporated to afford 1.3 g of crude product, which was purified by Biotage flash column chromatography eluting with 20% to 30% ethyl acetate hexane solution to give the desired protected as colorless oil. 390 mg (34%, combined yields of two steps) of amidine product were obtained. ¹⁹ F NMR showed that the isolated product contained only the desired Z-isomer.
[541] HRMS of C ₂₁ H ₃₂ N ₃ 0 ₈ F: Theoretical 491.2517 [M + NH 4] ⁺ , Found: 491.2523. ¹ H NMR (CDCl ₃ ) δ 1.5 (s, 18H), 1.9 (m, 1H), 2.1 (m, 3H), 2.3 (s, 3H), 3.7 (s, 3H), 4.2 (d, 2H), 4.8 (m, 1 H), 5.0 (dt, 1 H, J = 36 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −116.5 (dt, 1F, J = 38 Hz).
[542]
[543] EX-4H) The product of EX-4G (390 mg, 0.82 mmol) was dissolved in 20 mL of 25% HOAc aqueous solution containing 4 mL of methanol, and Zn dust (482 mg, 7.42 mmol) was added in two portions. The mixture was stirred for 3 hours while sonicating. Zn was removed by filtration through a pad of celite and the pad was washed with water. The filtrate was evaporated to dryness to afford crude product, which was purified by reverse phase HPLC. The portion containing the desired product was collected and combined and concentrated. The product was obtained as a colorless oil as a mixture of trifluoroacetate salts. ¹⁹ F NMR contained only the desired Z-isomer.
[544] 30% is a mono-Boc protected product: C ₁₅ H ₂₆ N ₃ 0 ₄ F HRMS: found 332.1986 [M + H] ⁺ , found 332.2001; 70% are di-Boc protected products: HRMS of C ₂₀ H ₃₄ N ₃ 0 ₆ F: found 432.2510 [M + H] ⁺ , found 432.2503. ¹ H NMR of the di-Boc product (D ₂ O) δ 1.3 (s, 18H), 1.8 (m, 1H), 2.1 (m, 3H), 2.1 (s, 3H), 3.6 (s, 3H), 3.9 (d, 2H), 4.9 (dt, vinyl, 1H, J = 37 Hz). ¹⁹ F NMR (D ₂ O) δ −117.3 (dt, 1F, J = 37 Hz).
[545] Example 4) Mono- and di-Boc products of EX-4H were dissolved in 80 mL of 6N HCl and the solution was heated with reflux for 1 hour, at which time LCMS analysis indicated the reaction was complete. Excess HCl and water were removed in vacuo to yield the desired (2S, 5Z) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, 3 as a pale yellow hygroscopic foam. Hydrochloride, dihydrate product 150 mg (50%, combined yields of two steps) were obtained.
[546] HRMS of C ₉ H ₁₆ N ₃ 0 ₂ F: requires 218.1305 [M + H] ⁺ , found 218.1290. ¹ H NMR (D ₂ O) δ 1.3 (s, 18H), 1.9 (m, 2H), 2.1 (m, 2H), 2.1 (s, 3H), 3.8 (t, 1H), 3.9 (d, 2H) , 4.9 (dt, vinyl, 1H, J = 37 Hz). ¹⁹ F NMR (D ₂ O) δ −117.3 (dt, 1F, J = 37 Hz). Analysis of C ₉ H ₁₆ N ₃ 0 ₂ F · 3HCl · 2H ₂ 0: Theoretical C, 29.81; H, 6.39; N, 11.59; Found C, 29.80; H, 6. 11; N, 11.20.
[547] Example 5
[548]
[549] (2R, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate
[550]
[551] EX-5A) Trimethylsilyl chloride is added dropwise to a cooled solution of D-glutamic acid dissolved in methanol at 0 ° C. The resulting clear colorless solution is stirred at room temperature until thin layer chromatography analysis shows no starting material remaining. The reaction is then cooled to 0 ° C. and triethylamine is added to form a white precipitate. Di-tert-butyldicarbonate is added and the mixture is allowed to warm to room temperature. After 3 hours the solvent is removed and diethyl ether is added. The solution is filtered and the filter cake is rinsed with additional diethyl ether. The filtrate is concentrated to give the desired mono-Boc diester product which is used in the next step without further purification.
[552]
[553] EX-5B) To a solution of the crude product of EX-5A dissolved in acetonitrile, 4-dimethylaminopyridine and di-tert-butyldicarbonate are added at room temperature. The resulting mixture is stirred at room temperature until thin layer chromatography analysis shows that most of the starting material is consumed. The solvent is removed in vacuo and the resulting residue is purified by flash column chromatography on silica gel to give the desired di-Boc protected diester product.
[554]
[555] EX-5C) The DIBAL solution is added dropwise to a cold solution of EX-5B dissolved in anhydrous diethyl ether at -78 ° C. After 30 minutes at −78 ° C., the solution is quenched with water and warmed to room temperature. The resulting hazy mixture is diluted with ethyl acetate, dried over MgSO ₄ and filtered through a pad of celite. The filtrate is concentrated and the resulting residue is purified by flash column chromatography on silica gel to give the desired aldehyde product.
[556]
[557] EX-5D) n-butyllithium is added to a cooled (-78 ° C) solution of triethyl 2-fluorophosphonoacetate dissolved in THR. The mixture is stirred at -78 ° C to give a light yellow solution. Next, a solution of the product of EX-5C dissolved in THF is added by syringe and the resulting mixture is stirred at −78 ° C. until thin layer chromatography analysis shows no starting material remains. The reaction is quenched with saturated aqueous NH ₄ Cl at −78 ° C. The organic layer is collected and the aqueous layer is extracted with diethyl ether. The combined organics are washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is then purified by flash column chromatography on silica gel to give the desired fluoro olefin product.
[558]
[559] EX-5E) To the solution of EX-5D dissolved in methanol, solid NaBH ₄ is added little by little at room temperature. The reaction is stirred at ambient temperature until thin layer chromatography analysis shows that most of the starting material is consumed. The reaction is quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic layers are combined, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired allyl alcohol product.
[560]
[561] EX-5F) To a mixture of EX-5E, polymer-supported triphenylphosphine and 3-methyl-1,2,4-oxadiazolin-5-one dissolved in THF is added dropwise dimethylazodicarboxylate. The reaction mixture is stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The mixture is filtered through celite and the filtrate is concentrated. The resulting yellow oil is partitioned between methylene chloride and water. The organic layer is separated, washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired protected E-allyl amidine product.
[562]
[563] EX-5G) The product of EX-5F is dissolved in methanol and acetic acid dissolved in water. Zinc dust is added and the mixture is stirred with sonication until HPLC analysis shows that little starting material remains. Zn dust from the reaction mixture is filtered through celite and the filtrate is concentrated. This crude material is purified by reverse phase HPLC column chromatography. The portions containing the product are combined and concentrated to give the desired acetamidine product as the trifluoroacetate salt.
[564] Example 5) A solution of EX-5G dissolved in 6.0N HCl is refluxed for 1 hour. The solvent is removed in vacuo. The resulting solid was dissolved in water and concentrated repeatedly from 1.0N HCl to remove all remaining TFA salts, thereby removing (2R, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) Amino] -5-heptenic acid, dihydrochloride product.
[565] Example 6
[566]
[567] (2S, 5E / Z) -2-amino-5,6-difluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride
[568]
[569] EX-6A) To the solution of EX-1C dissolved in methylene chloride containing 1 equivalent of tin (II) chloride is added ethyl diazoacetate at room temperature. Immediate gas evolution is observed as the mixture is stirred at room temperature. When the reaction is complete in thin layer chromatography analysis, the mixture is quenched with HCl and extracted with methylene chloride. The combined organic layers are dried, filtered and purified by column chromatography to give the desired beta-ketoester product.
[570]
[571] EX-6B) The solution of the product of EX-6A dissolved in N-methyl-2-pyrrolidinone is cooled to −78 ° C. and 1 equivalent of DAST is added. The resulting mixture is allowed to slowly warm up to room temperature. The mixture is quenched and concentrated when the reaction is complete in thin layer chromatography analysis. The resulting residue is extracted with methylene chloride. The combined organic layers are dried, filtered and filtered by column chromatography to give the desired difluoro olefin product as a mixture of E- and Z-isomers.
[572]
[573] EX-6C) To the solution of the product of EX-6B dissolved in methanol, solid NaBH ₄ is slowly added at room temperature. The reaction is stirred at ambient temperature until thin layer chromatography analysis shows that most of the starting material is consumed. The reaction is quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic layers are combined, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired difluoroallyl alcohol product as a mixture of E- and Z-isomers.
[574]
[575] EX-6D) To the mixture of the product of EX-6C dissolved in THF, a polymer-supported triphenylphosphine and 3-methyl-1,2,4-oxadiazolin-5-one, dropwise addition of dimethylazodicarboxylate do. The reaction is stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The mixture is filtered through celite and the filtrate is concentrated. The resulting oil is partitioned between methylene chloride and water. The organic layer is separated, washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired protected difluoro allyl amidine as a mixture of E- and Z-isomers.
[576]
[577] EX-6E) Zinc dust is added to a solution of the product of EX-6D dissolved in aqueous methanol and 25% acetic acid solution, and the mixture is sonicated with sonication until HPLC analysis shows that little starting material remains. Zinc dust from the reaction mixture is filtered through celite and the filtrate is concentrated. This crude material is purified by reverse phase HPLC column chromatography. The portions containing the product are combined and concentrated to give the desired difluoro allyl acetamidine trifluoroacetate product as a mixture of E- and Z-isomers.
[578] Example 6) A solution of the product of EX-6E dissolved in 6.0N HCl is refluxed for 1 hour. The solvent is removed in vacuo. The resulting solid is dissolved in water and concentrated repeatedly from 1.0 N HCl to remove any remaining TFA salt. (2S, 5E / Z) -2-amino-5,6-difluoro-7-[(1-iminoethyl) -amino] -5-heptenic acid desired as a mixture of E- and Z-isomers upon completion , Dihydrochloride product is obtained.
[579] Example 7
[580]
[581] (2S, 5E / Z) -2-Amino-5-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride
[582]
[583] EX-7A) The solution of EX-1C dissolved in THF and excess diethyl (trimethylsilyl) phosphite is heated with reflux until no starting material remains in thin layer chromatography analysis or ³¹ P NMR. . The solution is then cooled to room temperature and concentrated in vacuo. The resulting residue is then dissolved in aqueous methanol containing a small amount of p-toluenesulfonic acid and heated with reflux until thin layer chromatography analysis or ³¹ P NMR indicates no starting material remains. The solution is cooled and concentrated and the residue partitioned with ethyl acetate and water. The combined organics are washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired hydroxymethylphosphonate product.
[584]
[585] EX-7B) Excess DAST is added to a solution of the product of EX-7A dissolved in methylene chloride, previously cooled to -78 ° C. The resulting mixture is stirred at −78 ° C. and then slowly warmed to room temperature and stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The reaction is quenched by addition of a small amount of water. The organic layer is washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired fluoromethylphosphonate product.
[586]
[587] EX-7C) n-butyllithium hexane solution is added to a cooling (-78 ° C) solution of the product of EX-7B dissolved in THF. The mixture is stirred at −78 ° C. for 20 minutes to form a light yellow solution, followed by the addition of a cold (−78 ° C.) solution of ethyl glyoxalate dissolved in THF. The resulting mixture is stirred at −78 ° C. until thin layer chromatography analysis shows no starting material remains. The reaction is quenched with saturated aqueous NH ₄ Cl at −78 ° C. The organic layer is collected and the aqueous layer is extracted with diethyl ether. The combined organics are washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired fluoro olefin product as a mixture of E- and Z-isomers.
[588]
[589] EX-7D) To the solution of the product of EX-7C dissolved in methanol is added solid NaBH ₄ in portions at room temperature. The reaction is stirred at ambient temperature until thin layer chromatography analysis shows that most of the starting material is consumed. The reaction is quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic layers are combined, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired fluoroallyl alcohol product as a mixture of E- and Z-isomers.
[590]
[591] EX-7E) To the mixture of the product of EX-7D dissolved in THF, polymer-supported triphenylphosphine and 3-methyl-1,2,4-oxadiazolin-5-one, dropwise addition of dimethylazodicarboxylate do. The reaction is stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The mixture is filtered through celite and the filtrate is concentrated. The resulting oil is partitioned between methylene chloride and water. The organic layer is separated, washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired protected fluoroallyl amidine product as a mixture of E- and Z-isomers.
[592]
[593] EX-7F) Zinc dust is added to a solution of the product of EX-7E dissolved in methanol and 25% acetic acid aqueous solution, and the mixture is sonicated with sonication until HPLC analysis shows that little starting material remains. Zinc dust from the reaction mixture is filtered through celite and the filtrate is concentrated. This crude material is purified by reverse phase HPLC column chromatography. The portions containing the product are combined and concentrated to give the desired fluoro allyl acetamidine trifluoroacetate product as a mixture of E- and Z-isomers.
[594] Example 7) A solution of the product of EX-7F dissolved in 6.0N HCl is refluxed for 1 hour. The solvent is removed in vacuo. The resulting solid is dissolved in water and concentrated repeatedly from 1.0 N HCl to remove any remaining TFA salt. (2S, 5E / Z) -2-amino-5-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride product as desired as a mixture of E- and Z-isomers upon completion Get
[595] Example 8
[596]
[597] (2S, 5E / Z) -2-Amino-5-methyl-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride
[598]
[599] EX-8A) Methyl Grignard reagent solution is added to a cooled (-78 ° C) solution of the product of EX-1C dissolved in anhydrous THF. The reaction is then slowly warmed to room temperature and stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The reaction is quenched by addition of a small amount of saturated aqueous ammonium chloride. The mixture is concentrated and partitioned with ethyl acetate and water. The organic layer is washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired methyl alcohol product.
[600]
[601] EX-8B) To a solution of the product of EX-8A dissolved in methylene chloride, N-methylmorpholine-N-oxide and powdered 4 ′ molecular sieves are added at room temperature. The resulting mixture is then treated with tetra-n-propyl ammonium perruthenate and stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The mixture is concentrated and the residue is purified by flash column chromatography on silica gel to give the desired methyl ketone product.
[602]
[603] EX-8C) n-butyllithium is added to a cooled (-78 ° C) solution of triethyl 2-fluorophosphonoacetate dissolved in THF. The mixture is stirred at -78 ° C to give a light yellow solution. Next, a solution of the product of EX-8B dissolved in THF is added by syringe and the resulting mixture is stirred at −78 ° C. until thin layer chromatography analysis shows no starting material remains. The reaction is then quenched with saturated aqueous NH ₄ Cl at −78 ° C. The organic layer is collected and the aqueous layer is extracted with diethyl ether. The combined organics are washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired fluoro-methyl-substituted olefin product as a mixture of E- and Z-isomers.
[604]
[605] EX-8D) Solid NaBH ₄ is added in portions to the solution of the product of EX-8C dissolved in methanol at room temperature. The reaction is stirred at ambient temperature until thin layer chromatography analysis shows that most of the starting material is consumed. The reaction is quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic layers are combined, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired fluoro-methyl-substituted allyl alcohol product as a mixture of E- and Z-isomers.
[606]
[607] EX-8E) To the mixture of the product of EX-8D dissolved in THF, a polymer-supported triphenylphosphine and 3-methyl-1,2,4-oxadiazolin-5-one, dropwise addition of dimethylazodicarboxylate do. The reaction is stirred at room temperature until thin layer chromatography analysis shows no starting material remains. The mixture is filtered through celite and the filtrate is concentrated. The resulting oil is partitioned between methylene chloride and water. The organic layer is separated, washed with water and brine, dried over MgSO ₄ , filtered and concentrated. This crude material is purified by flash column chromatography on silica gel to give the desired protected fluoro-methyl substituted allyl amidine product as a mixture of E- and Z-isomers.
[608]
[609] EX-8F) Zinc dust is added to a solution of the product of EX-8E dissolved in aqueous methanol and 25% acetic acid solution, and the mixture is sonicated with sonication until HPLC analysis shows that little starting material remains. Zinc dust from the reaction mixture is filtered through celite and the filtrate is concentrated. This crude material is purified by reverse phase HPLC column chromatography. The portions containing the product are combined and concentrated to give the desired fluoro-methyl substituted allyl acetamidine trifluoroacetate product as a mixture of E- and Z-isomers.
[610] Example 8) A solution of the product of EX-8F dissolved in 6.0N HCl is refluxed for 1 hour. The solvent is removed in vacuo. The resulting solid is dissolved in water and concentrated repeatedly from 1.0 N HCl to remove any remaining TFA salt. Desired (2S, 5E / Z) -2-amino-5-methyl-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid as a mixture of E- and Z-isomers upon completion , Dihydrochloride product is obtained.
[611] Example 9
[612]
[613] (2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate
[614]
[615] EX-9A) To a solution of THF (45 mL) of the product of EX-1C (5.0 g, 11.5 mmol) was added dropwise a solution of red-Al (5.22 mL, 17.4 mmol) dissolved in 5.6 mL THF over 30 minutes under nitrogen. did. Internal temperature was kept below -10 degreeC. After 5 minutes the reaction was quenched with 33.7 mL 1.3 M Na.K tartrate. Toluene (11 mL) was added to the mixture to better separate. The organic layer was washed with 33.7 mL of 1.3 M Na.K tartrate and then with brine (40 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. 3.8 g (84%) of pale yellow oil as a crude product were used directly in the next step.
[616] LCMS: m / z = 414.2 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.48 (s, 18H), 1.95 (m, 1H), 2.1 (m, 1H), 2.2 (m, 1H), 2.35 (t, 1H), 3.7 (s, 3H), 4.25 (m, 2H), 4.8 (m, 1H), 5.15 (dt, 1H, J = 20 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −119.1 (d, 0.02F, J = 37 Hz, 2% Z-isomer), −111.8 (d, 0.98F, J = 24 Hz, 98% E-isomer).
[617]
[618] EX-9B) To a solution of the product of EX-9A (50.0 g, 0.128 mol) dissolved in 500 mL of methylene chloride was added triethylamine (18.0 g, 0.179 mol) at -10 ° C. A solution of methanesulfonyl chloride (17.5 g, 0.153 mol) dissolved in 50 mL methylene chloride was added slowly while maintaining the temperature at -10 ° C. The reaction was stirred at −10 ° C. for 45 minutes, at 45 minutes thin layer chromatography (50% ethyl acetate hexane solution) and LCMS analysis showed that most of the starting material was consumed. The reaction was quenched with 600 mL of 1.0 M citric acid and extracted with ethyl acetate (2 × 400 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. 70 g of crude oil, yellow, was used directly for the next step.
[619] LCMS: m / z = 492.2 [M + Na].
[620]
[621] EX-9C) Potassium 3-methyl-1,2,4-oxadiazolin-5-onate (28.7 g, in a solution of EX-19B product (70.0 g, 0.128 mol) dissolved in 400 mL of dimethyl formamide at room temperature 0.192 mol) was added. The reaction was stirred at room temperature for 2.5 hours, at 2.5 hours thin layer chromatography (30% ethyl acetate hexane solution) and LCMS analysis showed that the starting material was consumed. The reaction was diluted with 400 mL of water and extracted with ethyl acetate (5x400 mL). The organic layers were combined, washed with 400 mL water, 400 mL brine, dried over MgSO ₄ , filtered and concentrated. 70 g of crude yellow oil was purified by flash column chromatography on silica gel eluting with 1: 4 ethyl acetate: hexanes to give 38 g (63%) of a slightly yellow oil.
[622] EX-9D) Several duplicated EX-9Cs were combined and purified by HPLC column chromatography on a Merck silica gel MODCOL column at a flow of 550 mL / min as a 60:40 MtBE: heptane isocratic eluent. A second purification of 63 g recovered was purified by HPLC column chromatography on a Chiral Pack-AD column at a flow of 550 mL / min as 10:90 A: B (A: 100% ethanol, B: 100% heptane) isocratic elution. did. The portions containing the product were combined and concentrated to give 41 g (68%) of the desired protected L, E-allyl amidine product as clear oil. ^{According to 19} F NMR and chiral chromatography it contained only the desired L- and E-isomers.
[623] LCMS: m / z = 496.2 [M + Na] ⁺ . [M + NH ₄ ] ⁺ .
[624] HRMS of C ₂₁ H ₃₂ FN ₃ O ₈ : Theory 491.2507 [M + NH ₄ ] ⁺ , found 491.2517. ¹ HNMR (CDCl ₃ ) δ 1.48 (s, 18H), 1.85 (m, 1H), 2.2 (m, 3H), 2.25 (s, 3H), 3.64 (s, 3H), 4.25 (m, 2H), 4.8 (m, 1 H), 5.3 (dt, 1 H, J = 20 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −110.8 (q, 1F, J = 20 Hz).
[625]
[626] EX-9E) The product of EX-9D (22.5 g, 0.047 mol) was dissolved in 112 mL of methanol. Agitation was vigorously started and 225 mL of 40% acetic acid aqueous solution was added followed by zinc dust (11.5 g, 0.177 mmol). The stirring reaction was refluxed for 2.5 hours (approx. 60 ° C.) and at 2.5 hours HPLC analysis showed that most of the starting material was consumed. The reaction was cooled and Zn was filtered through celite from the reaction mixture and the celite was washed well with additional methanol. The filtrate and methanol wash were combined and concentrated. The resulting oily white solid was washed with methylene chloride (2x500 mL) and filtered through a pad of celite and further washed with 500 mL methylene chloride and filtered. The filtrates were combined and concentrated to give a pale yellow oil. 39 g of crude yellow pale yellow oil was purified by stop filtration on 200 mL silica gel eluting with 80: 19: 1 methanol: methylene chloride: acetic acid to give 13 g (83%) of the desired product.
[627] LCMS: m / z = 432.3 [M + H] ⁺ . 1 [M + H] ⁺ .
[628] HRMS of C ₁₅ H ₂₆ FN ₃ O ₄ : Theory 332.1986 [M + H] ⁺ , found 332.1982. ¹ H NMR (CD ₃ 0D) δ 1.42 (s, 9H), 1.7 (m, 1H), 1.9 (m, 1H), 2.17 (m, 2H), 2.22 (s, 3H), 3.3 (m, 1H) , 3.7 (s, 3H), 4.2 (d, 2H), 5.1 (dt, vinyl, 1H, J = 21 Hz). ¹⁹ F NMR (CD ₃ 0D) δ −110.83 (m, 1F, J = 21 Hz).
[629] Example 9) A solution of EX-1E (22 g, 0.066 mol) dissolved in 750 mL of 6.0N HCl was refluxed for 45 minutes. The solvent was removed in vacuo. The resulting solid was dissolved in water three more times and concentrated. The crude material was eluted with isocratic eluting by pumping 100% B for 30 minutes by reverse phase HPLC column chromatography on a YMC ODS-AQ column and then eluting with A with a 0-100% gradient for 10 minutes and 100% A for 20 minutes. It was washed and purified by elution over 60 minutes (A: 100% acetonitrile, B: 100% H ₂ O with 0.0025% acetic acid). The portions containing the product were combined and concentrated to give 3.5 g (68%) of the desired acetamidine product as dihydrochloride, which was the desired (2S, 5E) -2-amino-6-fluoro-7-[(1- Iminoethyl) amino] -5-heptenic acid, containing only the dihydrochloride product and obtained as a white solid. Melting point was 51.5-56.3 ° C. ^{According to 19} F NMR it contained only the desired E-isomer.
[630] LCMS: m / z = 218.1 [M + H] ⁺ . HRMS of C ₉ H ₁₆ FN ₃ 0 ₂ : requires 218.1305 [M + H] ⁺ , found: 218.1325. ¹ H NMR (D ₂ 0) δ 1.8 (m, 2H), 2.05 (m, 2H), 2.1 (s, 3H), 3.7 (t, 1H), 4.00 (d, 2H), 5.3 (dt, vinyl, 1H, J = 21 Hz). ¹⁹ F NMR (D ₂ O) δ −109.9 (m, 1F, J = 20 Hz). [a] ₅₈₉ = +15.3 (C, 0.334, (H ₂ O)). [α] ₃₆₅ = +52.8 (C, 0.334, (H ₂ 0))
[631] Example 10
[632]
[633] (2S, 5E) -2-Amino-6-fluoro-7-[(1-hydroxyiminoethyl) amino] -5-heptenic acid
[634]
[635] EX-10A) Gas phase HCl was bubbled into a stirring (0 ° C.) solution of the product of EX-9C (14 g, 30.0 mmol) dissolved in 100 mL of methanol for 5 minutes. The resulting dark yellow solution was stirred for another 30 minutes and at 30 minutes HPLC showed complete consumption of starting material. The resulting mixture was neutralized with saturated NaHCO ₃ to pH = 8 and the product extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated to afford the desired amino ester product as dark yellow oil, which was used for the next step.
[636] LCMS: m / z = 274 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ ) δ 1.8 (m, 4H), 2.25 (s, 3H), 3.42 (bm, 1H), 3.80 (s, 3H), 4.4 (dd, 2H), 5.40 (dt, vinyl, 1H , J = 21 Hz). ¹⁹ F NMR (CDCl ₃ ) δ −110.38 (m, 1F, J = 21 Hz).
[637] Example 10) A solution of EX-10A (8 g, 30 mmol) dissolved in 70 mL 2.5 N NaOH was stirred for 10 minutes and at 10 minutes HPLC analysis indicated complete consumption of starting material. The resulting solution was neutralized to pH = 7-8 with 12N HCl (approx. 50 mL) and concentrated. The resulting slurry was washed with methol and filtered to remove salts and then concentrated to brownish oil. The crude material was eluted with isocratic eluting by pumping 100% B for 30 minutes by reverse phase HPLC column chromatography on a YMC ODS-AQ column and then eluting with A with a 0-100% gradient for 10 minutes and 100% A for 20 minutes. It was washed and purified by elution over 60 minutes (A: 100% acetonitrile, B: 100%). The portions containing the product were combined and concentrated to give 1.0 g (14%) of the desired product as a white solid. The product was recrystallized from hot water and isopropyl alcohol and collected by filtration to obtain pure (2S, 5E) -2-amino-6-fluoro-7-[(1-hydroxyiminoethyl) as a white crystalline solid. Amino] -5-heptenic acid was obtained. Melting point was 198.00-200.00 ° C.
[638] LCMS: m / z = 234.1 [M + H] ⁺ . ¹ H NMR (D ₂ 0) δ 1.8 (m, 4H), 2.05 (m, 2H), 3.6 (t, 1H), 3.9 (d, 2H), 5.2 (dt, vinyl, 1H, J = 21 Hz). ¹⁹ F NMR (D ₂ O) δ −112.1 (m, 1F, J = 20 Hz). Anal of C ₉ H ₁₆ FN ₃ 0 ₃ : Theory C, 46.35; H, 6.91; N, 18.02; 0, 20.58. Found C, 46.44; H, 6. 95; N, 17.94; O, 20.78. Chiral Assay> 97.7%: CrownPak CR (+) (A: aqueous HClO ₄ , pH = 1.5) at 0.8 mL / min as isocratic elution with 100% A.
[639] Example 11
[640]
[641] (2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -N- (1H-tetrazol-5-yl) 5-heptenamide, dihydrochloride
[642]
[643] EX-11A) The product of EX-9C (6.1 g, 0.013 mol) was dissolved in 4 mL methanol. Vigorous stirring was started and 10 mL of 6N HCl was added. The stirring reaction was refluxed for 18 hours (approximately 60 ° C.) and at 18 hours HPLC analysis showed that most of the starting material was consumed. The reaction was cooled and concentrated to 3.3 g (100%) of orange oil.
[644] LCMS: m / z = 282 [M + Na] ⁺ .
[645]
[646] EX-11B) The product of EX-11A (3.3 g, 0.013 mol) was dissolved in 12 mL of 1: 1 H ₂ O: dioxane. Stirring was started and triethylamine (1.95 g, 0.019 mol) was added. The reaction was cooled to 0 ° C. and di-tert-butyldicarbonate (3.4 g, 0.016 mol) was added. The reaction was allowed to warm to room temperature, at which time acetonitrile (4 mL) was added to dissolve the solids. The reaction was stirred for 18 hours at room temperature and at 18 hours HPLC analysis showed that most of the starting material was consumed. The reaction was quenched with 1.ON KHS0 ₄ (25 mL), extracted with ethyl acetate ( ₃ × 50 mL) and the organic layer was dried over MgSO ₄ and concentrated. 3.5 g of crude black oil was purified by flash chromatography eluting with 4: 95: 1 methanol: methylene chloride: acetic acid to yield 2.4 g (52%) of the desired product as a pale yellow oil. LCMS: m / z = 382 [M + Na] ⁺ .
[647]
[648] EX-11C) The product of EX-HE (2.4 g, 0.007 mol) was dissolved in 13 mL of THF. Stirring was started and 5-aminotetrazole monohydrate (0.83 g, 0.008 mol) was added followed by 1,3-diisopropylcarbodiimide (1.0 g, 0.008 mol). The resulting mixture was stirred for 3 hours at room temperature and at 3 hours HPLC showed that most of the starting material was consumed. 12 mL water was added to the reaction and THF was removed by vacuum distillation. Ethanol (30 mL) was added and the reaction heated with reflux. After 15 minutes of reflux, the reaction was cooled to −10 ° C. at which time the desired product precipitated out of solution. The product was collected by filtration to give 1.25 g (50%) of a white solid. LCMS: m / z = 449 [M + Na] ⁺ .
[649]
[650] EX-11D) The product of EX-11C (1.0 g, 0.0023 mol) was dissolved in 5 mL of methanol. Vigorous stirring was started and 10 mL of 40% acetic acid aqueous solution was added followed by zinc dust (0.5 g, 0.008 mol). The stirring reaction was refluxed for 1.5 hours (approx. 60 ° C.) and at 1.5 hours HPLC analysis showed that most of the starting material was consumed. The reaction was cooled and Zn was filtered through celite from the reaction mixture and the celite was washed well with additional methanol. The filtrate and methanol wash were combined and concentrated. The resulting oily white solid was eluted with isocratic eluting by pumping 100% B for 30 minutes by reverse phase HPLC column chromatography on a YMC ODS-AQ column, eluting with A with a 0-100% gradient for 10 minutes and 100 minutes for 20 minutes. It was washed with% A and eluted over 60 minutes to purify (A: 100% acetonitrile, B: 100% H ₂ O with 0.0025% acetic acid). The portions containing the product were combined and concentrated to give 0.390 g (44%) of the desired acetamidine product as a white solid. LCMS: m / z = 407.3 [M + Na].
[651] Example 11) The product of EX-11D (0.30 g, 0.780 mmol) was dissolved in 5 mL of concentrated HOAc. To this was added 1 mL of 4N HCl in dioxane. The reaction was stirred at rt for 5 min. The solvent was removed in vacuo. The resulting solid was dissolved in water three more times and concentrated. HPLC showed amount of starting material. The solid was dissolved in 1N HCl and stirred for 3 hours, at 3 hours HPLC showed that most of the starting material was consumed. The solution was concentrated to give 290 mg (98%) of the desired acetamidine product as dihydrochloride.
[652] LCMS: m / z = 285.1 [M + H].
[653] Biological data
[654] Some or all of the following assays are used to demonstrate nitric oxide synthase inhibitory activity of the compounds of the present invention and to demonstrate useful pharmaceutical properties.
[655] Let Carrageenan Foot Edema Test
[656] The carrageenan paw edema test is a useful assay for evaluating the anti-inflammatory properties of the compounds of the present invention. The carrageenan paw edema test is essentially performed using materials, reagents and procedures as described by Winter et al. (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Daurey rats are selected from each group so that the average body weight is as similar as possible. The rats are kept in free access to water for 16 hours before testing. The rats are orally administered only compound (1 mL) or excipient suspended in excipients containing 0.5% methylcellulose and 0.025% surfactant. After 1 hour, 0.1 mL of a solution of 1% carrageenin / sterile 0.9% saline is injected by injection under the sole of the foot and the volume of the injected foot is measured with a preliminary flowmeter connected to a pressure transducer equipped with a digital indicator. Three hours after carrageenan injection, the volume of the foot is measured again. Average foot swelling in the drug-treated animals is compared to the average foot swelling in the placebo-treated animals and the percent inhibition of edema is measured (Otterness and Bliven, laboratory model for testing NSAIDs, Non-steroidal Anti- Inflammatory Drugs, (J. Lombardino, ed. 1985). Percent inhibition is expressed as percent reduction from control foot volume measured in this process.
[657] Citrulline Analysis for Nitric Oxide Synthase
[658] A nitric oxide synthase (NOS) activity L- [2,3- ³ H] - it can be determined by Morning sintering the conversion of citrulline (Bredt and ^{Snyder, - L- [2,3- 3 H} ] arginine Proc. Natl. Acad Sci. USA, 87, 682-685, 1990 and Moore et al. J. Med. Chem., 39, 669-672, 1996). Human inducible NOS (hiNOS), human endothelial constitutive NOS (hecNOS) and human neuronal constitutive NOS (hncNOS) were cloned from RNA extracted from human tissue, respectively. The cDNA of human induced NOS (hiNOS) is isolated from a λcDNA library made of RNA extracted from colon samples of patients with ulcerative colitis. The cDNA of human endothelial constitutive NOS (hecNOS) was isolated from a λcDNA library made of RNA extracted from human umbilical vein endothelial cells (HUVEC), and the cDNA of human neuronal constitutive NOS (hncNOS) was extracted from human cerebellum Isolate from a λcDNA library made of extracted RNA. Recombinant enzymes are expressed in Sf9 insect cells using baculovirus vectors (Rodi et al., The
[659] Biology of Nitric Oxide, Pt. 4: enzymatics, biochemistry and immunology; Moncada, S., Feelisch, M., Busse, R., Higgs, E., Eds .; Portland Press Lt., London, 1995; pp 447-450). Enzyme activity is isolated from soluble cell extracts and partially purified by DEAE-Sepharose chromatography. To measure NOS activity, 10 μl of enzyme was added to 40 μl of 50 mM Tris (pH 7.6) with or without test compound, 50 mM Tris (pH 7.6), 2.0 mg / mL bovine serum albumin, 2.0 mM DTT 50 μl of the reaction mixture containing 60 μM L-arginine containing 4.0 μm CaCl 2, 20 μM FAD, 100 μM tetrahydrobiopterin, 0.4 mM NADPH and 0.9 μC of L- [2,3- ³ H] -arginine Initiate the reaction. The final concentration of L-arginine in the assay is 30 μΜ. For hecNOS or hncNOS, calmodulin is included at a final concentration of 40-100 nM. After 15 minutes incubation at 37 ° C., a Dowex 50W X-8 cation exchange resin suspension (1 part resin, 3 parts buffer) suspended in stop buffer containing 10 mM EGTA, 100 mM HEPES, pH 5.5 and 1 mM L-citrulline was added. To terminate the reaction. After mixing the resin is allowed to settle and L- [2,3-3H] -citrulline formation is measured by counting the supernatant aliquots with a liquid scintillation counter. The results are reported in Table I as IC ₅₀ values of the compounds for hiNOS, hecNOS and hncNOS.
[660] Human cartilage explant analysis
[661] The bone pieces are rinsed twice with Dulbeccos 'phosphate buffered saline (GibcoBRL) and once with Dulbeccos' modified Eagles medium (GibcoBRL) and placed in a Petri dish with minimal essential medium (MEM) (GibcoBRL) containing no phenol red. Cartilage is cut into small explants weighing approximately 15-45 mg and one or two grafts per well are placed in 96 or 48 well culture plates with 200-500 μl culture medium per well. Culture medium is minimally essential medium (eagle) with custom modified L-arginine, L-glutamine, and salt of Earle (GibcoBRL) prepared without phenol red or custom-modified L-arginine, insulin, ascorbic acid, L-glutamine And serum-free Neuman and Tytell (GibcoBRL) medium prepared without phenol red. To induce nitric oxide synthase, 100 μM L-arginine (Sigma), 2 mM L-glutamine, 1X HL-1 supplement (BioWhittaker), 50 mg / ml ascorbic acid (Sigma) and 150 pg / ml recombination prior to using both Supplement with human IL-1β (RD system). The compound is then added to 10 μl aliquots and the explants are incubated at 37 ° C. with 5% CO ₂ for 18-24 hours. Next, the daily supernatant is discarded and replaced with fresh culture medium containing recombinant human IL-1β and the compound and incubated for another 20 to 24 hours. This supernatant is analyzed for nitrite by fluorometric analysis (Misko et al., Anal. Biochem., 214, 11-16, 1993). All samples are performed four times. Unstimulated controls are cultured in medium without recombinant human IL-1β. IC ₅₀ values (Table 1) are determined by plotting the percent inhibition of nitrite production at six different concentrations of inhibitor.
[662]
[663] In vivo analysis
[664] Letts can be treated by intraperitoneal injection of 1 to 12.5 mg / kg of endotoxin (LPS) with or without oral administration of a nitric oxide synthase inhibitor. Plasma nitrite / nitrate levels can be measured at 5 hours post treatment. The results can be used to indicate that administration of nitric oxide synthase inhibitors reduces the rise in plasma nitrite / nitrate levels, a reliable marker of nitric oxide production induced by endotoxin. As shown in Table II, Example 1 ((2S, 5E) -2-amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride) is a plasma nitrite Inhibited the increase in LPS-induced / nitrate levels, and the observed ED ₅₀ value was <0.1 mg / kg, demonstrating the ability to inhibit inducible nitric oxide synthase activity in vivo.
[665]
[666] Raw Cell Nitrite Analysis
[667] To induce NOS, RAW 264.7 cells can be plated to confluence in 96 well tissue culture plates grown overnight (17 hours) in the presence of LPS. Wells in rows 3-6 may be untreated and used as a control for subtracting nonspecific backgrounds. Media can be removed from each well and cells washed twice with Kreb-Ringers-Hepes (25 mM, pH 7.4) with 2 mg / ml glucose. Next, incubate with 50 μl of buffer containing L-arginine (30 μM) +/− inhibitor for 1 h on ice. The assay can be initiated by warming the plate for 1 hour at 37 ° C. in a water bath. The production of nitrite by intracellular iNOS will be linear with time. To terminate the cell assay, a plate of cells is placed on ice and the nitrite-containing buffer is transferred and analyzed using fluorescence for nitrite already published for nitrite. T. P. Misko et al., Analytical Biochemistry, 214, 11-16 (1993).

权利要求:
Claims (109)
[1" claim-type="Currently amended] A compound having a structure corresponding to formula (I) or a pharmaceutically acceptable salt thereof.
Formula I

(here:
R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, wherein the heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl , Dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroaryl Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, Arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dish Nocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, Diaalkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaalkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxy Optionally substituted with a moiety selected from the group consisting of phosphonoalkyl, dialcoxoxyphosphonoalkyl, guanidino, amidino and acylamino.)
[2" claim-type="Currently amended] A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure corresponding to formula (II).
Formula II

Wherein R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl; R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul Ponyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroa Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono Optionally substituted with a moiety selected from the group consisting of alkyl, dialcoxylphosphonoalkyl, guanidino, amidino, and acylamino.)
[3" claim-type="Currently amended] A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure corresponding to formula III.
(Formula 3)

Wherein R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, aiylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl ami Dosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroaryl Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono Optionally substituted with a moiety selected from the group consisting of alkyl, dialcoxiphosphonoalkyl, guanidino, amidino and acylamino.)
[4" claim-type="Currently amended] The method of claim 1,
R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo,
R ² is fluorine.
[5" claim-type="Currently amended] The method of claim 1,
R ¹ is H;
R ² is fluorine.
[6" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is halo; R ² is halo.
[7" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is fluorine; R ² is fluorine.
[8" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is fluorine; R ² is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[9" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is fluorine; R ¹ is H, characterized in that the compound.
[10" claim-type="Currently amended] A compound according to claim 1, wherein said compound is an E isomer.
[11" claim-type="Currently amended] The compound of claim 1, wherein the compound is a Z isomer.
[12" claim-type="Currently amended] The compound of claim 1, wherein the compound is an R enantiomer at the 2 position.
[13" claim-type="Currently amended] The compound of claim 1, wherein the compound is an S enantiomer at the 2 position.
[14" claim-type="Currently amended] The compound of claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.
[15" claim-type="Currently amended] 15. A pharmaceutically acceptable salt according to claim 14, having at least one anionic counterion.
[16" claim-type="Currently amended] 16. The pharmaceutical composition of claim 15, wherein the anionic counterion is selected from the group consisting of halides, carboxylates, sulfonates, sulfates, phosphates, phosphonates, resin-bound anions and nitrates. Acceptable salts.
[17" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is a halide.
[18" claim-type="Currently amended] 18. The pharmaceutically acceptable salt of claim 17, wherein the halide is chloride.
[19" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is a carboxylate.
[20" claim-type="Currently amended] The method of claim 19, wherein the carboxylate is formate, acetate, propionate, trifluoroacetate, succinate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL Glutamate, D-glutamate, L-glutamate, glycerate, succinate, steric, DL-tartarate, D-tartarate, L-tartarate, (±) -mandelate, (R)-( -)-Mandelate, (S)-(+)-mandelate, citrate, catenate, maleate, malonate, benzoate, DL-maleate, D-maleate, L-maleate, hemi-mal Latex, 1-adamantane acetate, 1-adamantanecarboxylate, flavianate, sulfonoacetate, (±) -lactate, L-(+)-lactate, D-(-)-lactate, Pamoate, D-alpha-galacturonate, glycerate, DL-state, D-state, L-state, DL-homostate, D-homocy State, L-homocystate, DL-cysteate, D-cysteate, L-cysteate, (4S) -hydroxy-L-proline, cyclopropane-1, 1-dicarboxylate, 2 , 2-dimethylmalonate, squarate, tyrosine anion, proline anion, fumarate, 1-hydroxy-2-naphthoate, phosphonoacetate, carbonate, bicarbonate, 3-phosphonopropio A pharmaceutically acceptable salt, characterized in that it is selected from the group consisting of Nate, DL-pyroglutamate, D-pyroglutamate, and L-pyroglutamate.
[21" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is a sulfonate.
[22" claim-type="Currently amended] The method of claim 21 wherein the sulfonate is methanesulfonate, toluenesulfonate, benzenesulfonate, trifluoromethylsulfonate, ethanesulfonate, (±) -camphorsulfonate, naphthalenesulfonate, lR-(-) -Camphorsulfonate, 1S-(+)-camphorsulfonate, 2-mesitylenesulfonate, 1,5-naphthalenedisulfonate, 1,2-ethanedisulfonate, 1,3-propanedisulfonate Pharmaceutically acceptable, which is selected from the group consisting of 3- (N-morpholino) propane sulfonate, biphenylsulfonate, isethionate, and 1-hydroxy-2-naphthalenesulfonate. salt.
[23" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is sulfate.
[24" claim-type="Currently amended] The pharmaceutically acceptable salt of claim 23, wherein the sulfate is selected from the group consisting of sulfate, monopotassium sulfate, monosodium sulfate and hydrogen sulfate.
[25" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is sulfamate.
[26" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is phosphate.
[27" claim-type="Currently amended] 27. The composition of claim 26 wherein the phosphate consists of phosphate, dihydrogen phosphate, potassium hydrogen phosphate, dipotassium phosphate, potassium phosphate, sodium hydrogen phosphate, disodium phosphate, sodium phosphate, calcium phosphate, and hexafluorophosphate. Pharmaceutically acceptable salts, characterized in that it is selected from the group.
[28" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is phosphonate.
[29" claim-type="Currently amended] 29. The pharmaceutically acceptable salt of claim 28, wherein the phosphonate is selected from the group consisting of vinylphosphonate, 2-carboxyethylphosphonate and phenylphosphonate.
[30" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is a resin-bound anion.
[31" claim-type="Currently amended] 31. The pharmaceutically acceptable salt of claim 30, wherein the resin-binding anion is selected from the group consisting of resins comprising polyacrylates and sulfonated poly (styrene divinylbenzenes).
[32" claim-type="Currently amended] 17. The pharmaceutically acceptable salt of claim 16, wherein the anionic counterion is nitrate.
[33" claim-type="Currently amended] 16. The pharmaceutically acceptable salt of claim 15, wherein the anion is selected from the group consisting of DL-ascorbate, D-ascorbate, and L-ascorbate.
[34" claim-type="Currently amended] 15. A pharmaceutically acceptable salt according to claim 14, having at least one cationic counterion.
[35" claim-type="Currently amended] 35. The pharmaceutically acceptable salt of claim 34, wherein the cationic counterion is selected from the group consisting of ammonium cations, alkali metal cations, alkaline earth metal cations, transition metal cations, resin-bound cations.
[36" claim-type="Currently amended] 36. The pharmaceutically acceptable salt of claim 35, wherein the cationic counterion is an ammonium cation.
[37" claim-type="Currently amended] 37. The method of claim 36, wherein the ammonium cation is selected from the group consisting of ammonium, methyl ammonium, dimethylammonium, trimethylammonium, tetramethylammonium, ethanolammonium, dicyclohexylammonium, guanidinium, and ethylenediammonium cations. Pharmaceutically acceptable salts.
[38" claim-type="Currently amended] 36. The pharmaceutically acceptable salt of claim 35, wherein the cationic counterion is an alkali metal cation.
[39" claim-type="Currently amended] The pharmaceutically acceptable salt of claim 38, wherein the alkali metal cation is selected from the group consisting of lithium cations, sodium cations, potassium cations, and cesium cations.
[40" claim-type="Currently amended] 36. The pharmaceutically acceptable salt of claim 35, wherein the cationic counterion is an alkaline earth metal cation.
[41" claim-type="Currently amended] 41. The pharmaceutically acceptable salt of claim 40, wherein the alkaline earth metal cation is selected from the group consisting of beryllium cations, magnesium cations, and calcium cations.
[42" claim-type="Currently amended] 36. The pharmaceutically acceptable salt of claim 35, wherein the cationic counterion is a transition metal cation.
[43" claim-type="Currently amended] 43. The pharmaceutically acceptable salt of claim 42, wherein the transition metal cation is a zinc cation.
[44" claim-type="Currently amended] 36. The pharmaceutically acceptable salt of claim 35, wherein the cationic counterion is a resin-bound cation.
[45" claim-type="Currently amended] 45. The pharmaceutically acceptable salt of claim 44, wherein the resin-binding cation is a cationic functionally poly (styrene divinylbenzene) resin.
[46" claim-type="Currently amended] 46. The pharmaceutically acceptable salt of claim 45, wherein the resin-binding cation is an aminated poly (styrene divinylbenzene) resin.
[47" claim-type="Currently amended] 45. The pharmaceutically acceptable salt of claim 44, wherein the resin-binding cation is a cationic functionalized polyacrylic resin.
[48" claim-type="Currently amended] 45. The pharmaceutically acceptable salt of claim 44, wherein the resin-binding cation is an aminated polyacrylic resin.
[49" claim-type="Currently amended] A compound or pharmaceutically acceptable salt thereof, characterized by having a structure corresponding to formula (IV).
Formula IV

Wherein R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo.)
[50" claim-type="Currently amended] The compound of claim 49, wherein R ¹ is halo; R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo.
[51" claim-type="Currently amended] The compound of claim 49, wherein R ¹ is halo; R ² is selected from the group consisting of H, F and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[52" claim-type="Currently amended] The method of claim 49,
R ¹ is fluorine;
R ² is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo.
[53" claim-type="Currently amended] The method of claim 49,
R ¹ is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted by one or more halo;
R ² is fluorine.
[54" claim-type="Currently amended] The method of claim 49,
R ¹ is H;
R ² is fluorine.
[55" claim-type="Currently amended] 50. The compound of claim 49, wherein said compound is an E isomer.
[56" claim-type="Currently amended] 50. The compound of claim 49, wherein said compound is a Z isomer.
[57" claim-type="Currently amended] 50. The compound of claim 49, wherein said compound is an R enantiomer at the 2-position.
[58" claim-type="Currently amended] 50. The compound of claim 49, wherein said compound is an S enantiomer at the 2-position.
[59" claim-type="Currently amended] A compound or salt thereof characterized by having a structure corresponding to formula VII.
Formula VII

Wherein R ⁵ is selected from the group consisting of H, F and methyl;
R ⁶ is selected from the group consisting of H, F and methyl;
Provided that either R ⁵ or R ⁶ is F.
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ ;
Wherein R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and a heterocyclic ring wherein at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur, said heterocyclic heteroarylamino , N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio , Nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul Ponyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroa Sulfinyl, heteroarylsulfonyl, alkane oil, alkenyl oil, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkan oil, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylal Kenyl, heteroaryl alkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicaralkoxyalkyl, cyanocycloalkyl, dicyano Cicle Alkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, dialralcock Siphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaalkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialcoxoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphono Optionally substituted with a moiety selected from the group consisting of alkyl, dialcoxylphosphonoalkyl, guanidino, amidino and acylamino;
Q is H, and the nitrogen protecting moiety.)
[60" claim-type="Currently amended] A compound characterized in that it is selected from the group consisting of:
(2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5E / Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5Z) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid;
(2S, 5Z) -2-Amino-6-fluoro-7- [(l-iminoethyl) amino] -5-heptenic acid;
(2R, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5E / Z) -2-Amino-5, 6-difluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5E / Z) -2-Amino-5-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid;
(2S, 5E / Z) -2-Amino-5-methyl-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid; (2S, 5E) -2-Amino-5, 6-difluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5Z) -2-Amino-5, 6-difluoro-7-[(1-iminoethyl) amino] -5-heptenic acid;
(2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -N- (1H-tetrazol-5-yl) 5-heptenamide,
(2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate;
(2S, 5E / Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5Z) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, trihydrochloride, dihydrate;
(2R, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate;
(2S, 5E / Z) -2-Amino-5, 6-difluoro-7-[(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5E / Z) -2-Amino-5-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5E / Z) -2-Amino-5-methyl-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5E) -2-Amino-5, 6-difluoro-7- [(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride;
(2S, 5Z) -2-Amino-5, 6-difluoro-7- [(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride; And
(2S, 5E) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -N- (lH-tetrazol-5-yl) 5-heptenamide, dihydrochloride.
[61" claim-type="Currently amended] (2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid.
[62" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5heptenic acid.
[63" claim-type="Currently amended] (2S, 5Z) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid.
[64" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid.
[65" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5-methyl-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid.
[66" claim-type="Currently amended] (2R, 5E) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid.
[67" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5, 6-difluoro-7- [(1-iminoethyl) amino] -5-heptenic acid.
[68" claim-type="Currently amended] (2S, 5E) -2-amino-6-fluoro-7-[(l-iminoethyl) amino] -N- (1H-tetrazol-5-yl) 5-heptenamide, dihydrochloride.
[69" claim-type="Currently amended] (2S, 5E) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate.
[70" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5heptenic acid, dihydrochloride.
[71" claim-type="Currently amended] (2S, 5Z) -2-Amino-6-fluoro-7-[(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride.
[72" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5-fluoro-7-[(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride.
[73" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5-methyl-6-fluoro-7-[(1-iminoethyl) amino] 5-heptenic acid, dihydrochloride.
[74" claim-type="Currently amended] (2R, 5E) -2-Amino-6-fluoro-7- [(1-iminoethyl) amino] -5-heptenic acid, dihydrochloride, monohydrate.
[75" claim-type="Currently amended] (2S, 5E / Z) -2-Amino-5, 6-difluoro-7- [(l-iminoethyl) amino] -5-heptenic acid, dihydrochloride.
[76" claim-type="Currently amended] (2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -N- (1Htetrazol-5-yl) 5-heptenamide, dihydrochloride.
[77" claim-type="Currently amended] (2S, 5E) -2-Amino-6-fluoro-7-[(1-iminoethyl) amino] -N- (1H- tetrazol-5-yl) 5-heptenamide.
[78" claim-type="Currently amended] A subject in need of such treatment or prevention comprising administering to a subject in need thereof such a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for treatment or prophylaxis. To treat or prevent an inflammation-related condition in a child.
Formula I

(here:
R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently composed of heterocyclic rings selected from oxygen, nitrogen and sulfur; The heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy , Hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amido Dosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl Thio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl oil, alkenoyl, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkanyl oil, alkyl, alkenyl, alkynyl, alkylenedioxy, Haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, Arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, Dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acyl Chel, dialkoxyphosphonoalkyl, dialralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialralcockoxyphosphonoalkylamino Is optionally substituted with a moiety selected from the group consisting of phosphonoalkylamino, dialkoxyphosphonoalkyl, dialralcoxiphosphonoalkyl, guanidino, amidino and acylamino.)
[79" claim-type="Currently amended] 79. The method of claim 78, wherein said inflammation related condition is an arthritis state.
[80" claim-type="Currently amended] 80. The method of claim 79, wherein said arthritis condition is osteoarthritis.
[81" claim-type="Currently amended] 80. The method of claim 79, wherein said arthritis condition is rheumatoid arthritis.
[82" claim-type="Currently amended] 80. The method of claim 78, wherein said inflammation related condition is postoperative inflammation.
[83" claim-type="Currently amended] 83. The method of claim 82, wherein said postoperative inflammation is associated with ophthalmic surgery.
[84" claim-type="Currently amended] 84. The method of claim 83, wherein the ophthalmic surgery is cataract surgery.
[85" claim-type="Currently amended] 79. The method of claim 78, wherein said inflammation related condition is associated with an infection.
[86" claim-type="Currently amended] 86. The method of claim 85, wherein said infection is sepsis.
[87" claim-type="Currently amended] 84. The method of claim 83, wherein said infection is caused by a virus.
[88" claim-type="Currently amended] 79. The method of claim 78, wherein said inflammation related condition is inflammatory bowel syndrome.
[89" claim-type="Currently amended] 79. The method of claim 78, wherein said inflammation related condition is caused by injury.
[90" claim-type="Currently amended] 79. The method of claim 78, wherein said inflammation related condition is lung inflammation.
[91" claim-type="Currently amended] 93. The method of claim 90, wherein said pulmonary inflammation is due to cystic fibrosis.
[92" claim-type="Currently amended] A subject in need of such treatment or prevention comprising administering to a subject in need thereof such an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for treatment or prophylaxis. How to treat or prevent malignant tumors in the.
Formula I

(here:
R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently composed of heterocyclic rings selected from oxygen, nitrogen and sulfur; The heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy , Hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amido Dosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl Thio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl oil, alkenoyl, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkanyl oil, alkyl, alkenyl, alkynyl, alkylenedioxy, Haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, Arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, Dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acyl Chel, dialkoxyphosphonoalkyl, dialralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialralcockoxyphosphonoalkylamino Is optionally substituted with a moiety selected from the group consisting of phosphonoalkylamino, dialkoxyphosphonoalkyl, dialralcoxiphosphonoalkyl, guanidino, amidino and acylamino.)
[93" claim-type="Currently amended] 93. The method of claim 92, wherein said cancer is an epithelial cell-induced tumor.
[94" claim-type="Currently amended] 95. The method of claim 93, wherein said epithelial cell-induced tumor is gastrointestinal cancer.
[95" claim-type="Currently amended] 95. The method of claim 94, wherein said epithelial cell-induced tumor is colon cancer.
[96" claim-type="Currently amended] 95. The method of claim 93, wherein said epithelial cell-induced tumor is lung cancer.
[97" claim-type="Currently amended] 95. The method of claim 93, wherein said epithelial cell-induced tumor is prostate cancer.
[98" claim-type="Currently amended] 95. The method of claim 93, wherein said epithelial cell-induced tumor is cervical cancer.
[99" claim-type="Currently amended] 95. The method of claim 93, wherein said epithelial cell-induced tumor is breast cancer.
[100" claim-type="Currently amended] 93. The method of claim 92, wherein said malignant tumor is mesenchymal tissue induced.
[101" claim-type="Currently amended] A method of treating intoxication in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Formula I

(here:
R ¹ is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo;
R ⁷ is selected from the group consisting of H and hydroxy;
J is selected from the group consisting of hydroxy, alkoxy and NR ³ R ⁴ , wherein;
R ³ is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
R ⁴ is selected from the group consisting of H and at least one member of the ring is carbon and from 1 to 4 heteroatoms are independently composed of heterocyclic rings selected from oxygen, nitrogen and sulfur; The heterocycle is heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaraloxy, cycloalkoxy, cycloalkenyloxy , Hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amido Dosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl Thio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl oil, alkenoyl, aroyl, heteroaroyl, arkanyl oil, heteroarkanyl oil, haloalkanyl oil, alkyl, alkenyl, alkynyl, alkylenedioxy, Haloalkylenedioxy , Cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxy Alkyl, aryl, aralkyl, aryloxy, aralkyloxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, Arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, Dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acyl Chel, dialkoxyphosphonoalkyl, dialralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, dialralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, dialralcockoxyphosphonoalkylamino Is optionally substituted with a moiety selected from the group consisting of phosphonoalkylamino, dialkoxyphosphonoalkyl, dialralcoxiphosphonoalkyl, guanidino, amidino and acylamino.)
[102" claim-type="Currently amended] 102. The method of claim 101, wherein said addiction is alcoholism.
[103" claim-type="Currently amended] 102. The method of claim 101, wherein said addiction is nicotine addiction.
[104" claim-type="Currently amended] A compound having a structure corresponding to formula IV or a pharmaceutically acceptable salt thereof.
Formula IV

Wherein R ¹ is selected from the group consisting of H and halo;
R ² is selected from the group consisting of H, halo and alkyl optionally substituted by one or more halo;
Provided that at least one of R ¹ or R ² contains halo.)
[105" claim-type="Currently amended] 107. The method of claim 104, wherein R ¹ is halo; R ² is selected from the group consisting of H and halo.
[106" claim-type="Currently amended] 107. The compound of claim 104, wherein R ¹ is selected from the group consisting of H and F; R ² is halo.
[107" claim-type="Currently amended] 105. The method of claim 104, wherein R ¹ is fluorine; R ² is selected from the group consisting of H and C ₁ -C ₃ alkyl optionally substituted with one or more halo.
[108" claim-type="Currently amended] 105. The method of claim 104,
R ¹ is fluorine
R ² is H, characterized in that the compound.
[109" claim-type="Currently amended] 105. The method of claim 104,
R ¹ is fluorine;
R ² is fluorine.

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JP2003530435A|2003-10-14|

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AU5539101A|2001-10-30|

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NZ521879A|2004-12-24|

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EP1282413A4|2004-12-01|

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WO2001078719A1|2001-10-25|

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US6465686B2|2002-10-15|

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EA200201054A1|2003-06-26|

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ZA200208169B|2003-10-10|

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AR032318A1|2003-11-05|

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CN1437468A|2003-08-20|

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BR0110143A|2005-01-11|

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US20020049202A1|2002-04-25|

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:
2000-04-13|Priority to US19703200P

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2000-04-13|Priority to US60/197,032

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2001-04-13|Application filed by 파마시아 코포레이션

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2003-05-22|Publication of KR20030040202A

优先权:

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申请号 | 申请日 | 专利标题

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US19703200P| true| 2000-04-13|2000-04-13|

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US60/197,032|2000-04-13|