CA2234641A1 - Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases - Google Patents
Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases Download PDFInfo
- Publication number
- CA2234641A1 CA2234641A1 CA002234641A CA2234641A CA2234641A1 CA 2234641 A1 CA2234641 A1 CA 2234641A1 CA 002234641 A CA002234641 A CA 002234641A CA 2234641 A CA2234641 A CA 2234641A CA 2234641 A1 CA2234641 A1 CA 2234641A1
- Authority
- CA
- Canada
- Prior art keywords
- aryl
- phenyl
- group
- hydrogen
- mono
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
Abstract
Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These diseases and disorders include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn, eczema or psoriasis and respiratory conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid arthritis, septic arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis.
Description
W O 97/16430 PCTrUS96/17447-~ TII~ F OF THE INVENTION
HEXAHYDRO-5-IMINO- 1,4-~ l ~ OAZEPINE DERIVATIVES AS
INHIBITORS OF NITRIC OXIDE SYNTHASES
This application is directed to inhibitors of nitric oxide synthase, and in particular cyclic amidines.
Nitric Oxide in Biology.
The emergence of nitric oxide (NO), a reactive, inorganic radical gas as a molecule contributing to important physiological and pathological processes is one of the major biological revelations of recent 15 times. This molecule is produced under a variety of physiological and pathological conditions by cells me~ tin~ vital biological functions.
Examples include endothelial cells lining the blood vessels; nitric oxide derived from these cells relaxes smooth rnuscle and regulates blood pressure and has significant effects on the function of circ~ tin~ blood 20 cells such as platelets and neutrophils as well as on smooth muscle, both of the blood vessels and also of other organs such as the airways. In the brain and elsewhere nitric oxide serves as a n~urotl~nsmitter in non-adrenergic non-cholinergic neurons. In these instances nitric oxide appears to be produced in small amounts on an int~rmittent basis in 25 response to various endogenous molecular sign~l~. In the immlm~ system nitric oxide can be synthesized in much larger amounts on a protracted basis. Its production is inflllce-l by exogenous or endogenous infl~mm~tory stimuli, notably endotoxin and cytokines elaborated by cells of the host defense system in response to infectious and 30 infl~mm~tory stimuli. This induced production results in prolonged nitric oxide release which contributes both to host defense processes such as the killing of bacteria and viruses as well as pathology associated with acute and chronic infl~mm~tion in a wide variety of diseases. The discovery that nitric oxide production is mediated by a unique series of three closely 35 related enzymes, named nitric oxide synth~es, which utilize the amino W O 97/16430 PCT~US96/17447 -acid ar~ ine and molecular oxygen as co-substrates has provided an underst~ntlin~ of the biochemistry of this molecule and provides distinct ph~rm~ological tal~ e~s for the inhibition of the synthesis of this mediator, which should provide ~ c~nt beneficial effects in a wide variety of diseases.
Nit~ic Oxidç SyIlthases Nitric oxide and L-citrulline are formed from L-arginine via 10 the dioxygenase activity of specific nitric oxide synthases (NOSs) in m~mm~ n cells. In this reaction, L-arginine, ~2 and NADPH are cosubstrates while FMN, FAD and tetrahydrobiopterin are cofactors.
NOSs fall into two distinct classes, con.~tit~ltive NOS (cNOS) and inducible NOS (iNOS) . Two constitutive NOSs have been identified.
15 They are:
(i) a con~iLulive, Ca++/calmodulin dependent enzyme, located in the endothelium and elsewhere (ecNOS or NOS 3), ~hat releases NO in response to receptor or physical stimnl~tion, (ii) a constitutive, Ca++/calmodulin dependent enzyme, located in ~e brain (ncNOS or NOS 1) and elsewhere, that releases NO in response to receptor or physical stirn~ tion, The third isoform identified is inducible NOS (iNOS or NOS 2):
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a large number of other cells by endotoxin and cytokines. Once expressed, this inducible NO
synthase produces NO in relatively large amounts for long periods of time.
Spectral studies of both the mouse macrophage iNOS and rat brain ncNOS have shown that these enzymes (which have been classified as P-450-like enzymes from their CO-difference spectra) contain a heme moiety. The structural ~imilz~rity between NOS and the P-450Mavoprotein complex suggests that the NOS reaction mech~ni~m may be ~imil~r to P-450 hydroxylation and/or peroxidation. This indicates that NOS belongs to a class of flavohemeproteins which contain both heme and flavin binding regions within a single protein in contrast to 5 the mul~iploteill NADPH oxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.
Distinct Functions of NO Produced by Different Nitric O~cide Syn~ases.
The NO released by the constitutive enzymes (NOS 1 and NOS 3) acts as an autocoid me~ ting a number of physiological responses. Two distinct cDNAs accounting for the activity of NOS 1 and NOS 3 in man have been cloned, one for NOS 1 (Nakane et. al., FEBS
Letters, 316, 175-182, 1993) which is present in the brain and a number of peripheral tissues, the other for an enzyme present in endoth~ m (NOS 3) (Marsden et. al., FEBS Letters, 307, 287-293, 1992). This latter enzyme is critical for production of NO to m~int~in vasorel7~x~tion. A
second class of enzyme, iNOS or NOS 2, has been cloned from human liver (Geller et. al., PNAS, 90, 3491-5, 1993), and identified in more than a dozen other cells and tissues, including smooth muscle cells, chondrocytes, the kidney and airways. As with its coull~el~all from the murine macrophage, this enzyme is induced upon exposure to cytokines such as g~mm:~ interferon (IFN-~), interl~nkin-l~ (IL-l,B), tumor necrosis factor (INF-a) and LPS (lipopolysaccharide). Once induced, iNOS
expression continlles over a prolonged period of time. The enzyme does not require exogenous calmodulin for activity.
Endothelium derived relaxation factor (EDRF) has been shown to be produced by NOS 3 (~oncada et. al., Pharmacol. Reviews, 43, 109-142, 1991). Studies with substrate analog inhibitors of NOS have ~ 30 shown a role for NO in regulating blood pressure in ~nim~ and blood flow in man, a function attributed to NOS 3. A transgenic mouse deficient in functional NOS 3 was shown to be hypertensive, thus validating the role of NO synthesis by NOS 3 in the regulation of blood pressure (Huang et al., Nature, 377, 239-242, 1995). NO has also been W O 97/16430 PCT~US96/17447-shown to be an effector of the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6, 3051-64, 1992) for fighting tumour cells and invading microorg~ni~m~ (Wright et al., Card. Res., 26 ,48-57, 1992 and Moncada et al., Pharmacological Review, 43, 109-142, 1991). It also 5 appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue fl~m~ge, may result largely from ~e effects of NO syntht-.si7.o-1 by the NO~ 2~
NO generated by NOS 2 has been implicated in the pathogenesis of infl~mm~tory diseases. In experiment~l ~nim~
10 hypotension induced by LPS or TNF-a can be reversed by NOS
inhibitors and reiniti~te~l by L-arginine (Kilbourn et. al., PNAS, 87, 3629-32, 1990). Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis (Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96--S100, 1992) and IL-2 therapy in cancer patients (Hibbs et. al., J. Clin. Invest., 89, 867-77, 1992). NOS 2 is implicated in these responses, and thus the possibility exists that a NOS inhibitor would be effective in ameliorating cytokine-intl-~cerl hypotension. Recent studies in ~nim~l models have suggested a role for NO in the pathogenesis of infl~mm~tion and pain and NOS inhibitors have been shown to have beneficial effects on some aspects of the infl~mm~tion and tissue changes seen in models of infl~mm~tory bowel disease, (Miller et. al., J.
Pharmacol. Exp. Thcer., 264, 11- 16, 1990) and cerebral ischemia and arthritis (Ialenti et. al., Br. J. Pharrnacol ., 110, 701-6, 1993; Stevanovic-Racic et al., Arth. & Rheum., 37, 1062-9, 1994). Moreover transgenic mice deficient in NOS 1 show t1imini~hed cerebral ischemia (Huang et.
al., Science, 265, 1883-5, 1994) and transgenic mice deficient in NOS 2 exhibit enhanced survivability in a model of LPS-in~ ce-l shock (MacMicking et al. CeU 81, 641-650, 1995) and Wei et al. Nature 375, 408-411, 1995)).
Further conditions where there is an advantage in inhibiting NO production from L-arginine include therapy with cytokines such as TNF, IL- 1 and IL-2 or therapy with cytokine-inducing agents, for example 5, 6-dimethylx~ntllenone acetic acid, and as an adjuvant to short term immlmosuppression in ~ansplant therapy. In addition, compounds .
W O 97/16430 PCTrUS96/17447 -S
- which inhibit NO synthesis may be of use in reducing the NO
concentration in patients suffering from infl~mm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition, for example adult respiratory distress syndrome (ARDS) and S myocarditis.
There is also evidence that an NO synthase enzyme may be illvolved in the de~eneration of cartila e which t~kes place i~
autoimmlme and/or infl~mm~tory conditions such as arthritis, rheumatoid ~lli~iS, chronic bowel disease and systemic lupus erythematosis (SLE).
10 It is also thought that an NO synthase enzyme may be involved in insulin-dependent diabetes mellitus. Therefore, a yet further aspect of the present invention provides cyclic amidine derivatives or salts thereof in the manufacture of a medicament for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term immllnosuppression in transplant 15 therapy, for the treatment of patients suffering from infl~mm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition.
SUMMARY OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
R R R R ~ b and ph~rm~ceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated ~ e~es and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and infl~mm~tion. These diseases and disorders 30 include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in in cancer patients, cachexia, immunosuppression W O 97/16430 PCT~US96/17447 such as in transplant therapy, autoimmllne andlor infl~n~m~tory indications including sunburn, eczema or psoriasis and respiratoIy conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, 5 infl~mm~tory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid alLllliLis, septic a~ iLis, c~hronic or inflammatoly bowel disease, ulcerative colitis~ Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-10 dependent diabetes mellitus and cystic fibrosis. Compounds of FormulaI are also usful in the treatment of hypoxia, hy~ell.alic oxygen convulsions and toxicity, dementia, Alzheimer's ~ e~e~ Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, Korsakoff's disease, 15 imbecility related to cerebral vessel disorder, NO me~i~te~l cerebral trauma and related sequelae, ischernic brain edema (stroke), sleepîng disorders, eating disorders such as anorexia, schizophrenia, depression, pre-menstrual syndrome (PMS), urinary incontin~n~e~ an~iety, drug and alcohol addiction, pain, migraine, emesis, tumor growth, immune 20 complex cli.ces~se, as immllnosupressive agents, acute allograft rejection, infections caused by invasive microorg~ni~m~ which produce NO and for preventing or reversing tolerance to opiates and diazepines.
Dl~TA~T Fr) DESCRIPTION OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
X
R,, R2, R3, R4 ~"' b~ R5 30 or a ph~ ceutically acceptable salt thereof wherein:
side a or side b has a double bond, WO 97/16430 PCTrUS96/17447-~ X is selected from 0, S(O)m, NH, and NR6, wherein R6 is selected from C1 12alkyl, C1 12alkyl-carbonyl, C 1- 12aLkyloxy-carbonyl, C 1-1 2aLkYlamino-carbonyl Cl l2alkyl-sulfonyl and Cl-l2aL~yl~mino-sulfonyl wherein said S Cl 12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1 6alkoxy, ~3~mino, a.nd hal misO, 1 or2;
Rl, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) C 1- 12alkoxy, (c) Cl 12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono Cl l2alkyl~rnin(, (e) (di-C l l2alkyl)amino, (f) C 1-12alkylcarbon (g) Cl 12alkyl, (h) C2 12alkenyl, (i) C2 12aL~ynyl, (j) C5 locycloalkyl~
(k) heteroCs locycloalkyl,whereintheheteroCs 10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) rul~llyl, (S) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) ox~ olyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, ~l.5~ pyrr~lyl~
(17) isoquinolyl, (18) tetrazolyl, . 10 (19) thi~ 701yl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) Cl 12alkYl-C(O)NH, (o) C1 12alkoxy-C(O)NH, (p) C1 12alkylamino-C(O)NH, (q) C1 12alkyl-S(0)2NH, (r) C1 12aLkyl~mino-C(0), (S) c1-12aLkylamino-s(o)2~
(t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imid~7:olyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(0) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imic1~7.olyl~ and triazolyl, (y) phenylamino-S(0)2, (z) hydroxy, (aa) amino, (ab) oxo, W O 97/16430 PCT~US96/17447 -(ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexylorCl 6alkyl, each of (b) to (y) being optionally mono or di- substit~lte-l, the substituents being independently selected from (1) hydroxy, (O)~lH5 (3) -NR7Rg, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C 1-6aL~Yl, (4) -NR7C(O)R8, (6) -NR7C(O)NHRg, (S) -NR7C(O)ORg ,where Rg is selected from phenyl, benzyl, cyclohexyl or C1 6alkyl, (7) -NR7S(0)2Rg, (8) -OR7, (9) -C(O)ORg, (10) -C(O)NR7R8, (1 1) -C(O)R7, (12) -S(O)kR7, (13) -S(0)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -CF3, (16) C(=NR7)-NHR8, (17) hetero C5 locycloaL~yl,wherein the hetero C5 10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, - (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, CA 02234641 l99X-04-09 WO 97/16430 PCT~US96/17447-(f~ pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and S (j) triazolyl, or when two members of the group Rl, ~2, R3 a~d R4 inclu.ding the optional substituents present thereon reside on the same carbon atom of Formula I, or two of the group Rl, R2, R3 and R4 including the optional substituents present thereon reside on adjacent atoms of Formula I, said two members rnay optionally be joined, such that together with the carbon atom to which they are ~tt~h~l there is formed a saturated or lln~tllrated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally co... l~;.. i.. ~e: up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2, R3 and R4 including the optional substituents present thereon resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6, such that together with the N
on which R6 resides and the carbon on which said member resides there is formed a saturated or lln~ rated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally cont~ininf~ up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and br~nchP-l C1 12aLkYl, optionally mono or di-substitllte-1, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, ~ (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) -CF3, (9) phenyl, optionally mono or di-substi~te~l with hydroxy, halo, Cl~aLtcyl, or Cl 4alkoxy, (c) -C(O)NRloRl 1, whe~ Rlo and Rl 1 are each independently hydrogen~ phe~ylJ cyclohe~yl~ -s(c))2NR7R~ or option~y substituted C 1-6aLkyl~ wherein the substituent is selected from (1) -NRl2Rl3~ wherein R12 and R13 are each independently H, Cl 6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)oRl2~
(4) -S(O)kR12, where k is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionallysubstituted Cs locycloaLkyl wherein cycloalky; and cycloalkyl substituents are as defined above, (9) hetero C5 10cycloalkyl, wherein the heteroCslocycloalkyl optionally contains 1 or 2 heteroato~s selected from S, O and N, (d) -C(O)R 1 1, (e) -C(~)ORl 1, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
Within this embodiment there is a genus of compounds wherein Rl, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, S (c) amino, (d) cyano, (e~ ~luoro, chlQro~ bromo, and iodo7 (f) trifluoromethyl, (g) C1 6alkyl, (h) C1 6aLkoxy, (i) C1-6alkylthio, (j) Cl 6alkylcarbonyl, (k) mono- and di-C l 6aLkylamino, (1) aryl, where aryl is phenyl and naph~yl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, ~3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substit~lte~l, the substituents being independently selected from (1) hydroxy, (2) C1 4alkyl, (3) C1 3alkoxy, (4) amino, (5) mono-anddi-C1 6aLkylamino, (6) carboxyl, (7) Cl 3alkylthio, (8) C1 3alkyl-S(O)k-, where k is 1 or 2, (9) Cl 4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, ) OX09 and (12) amidino, 10 R5 is selected from the group consisting of (a) hydrogen, (b) C1 6aLkylcarbonyl, (c) arylcarbonyl, wherein the aryl group is phenyl, (d) arylcarbonyl-aminocarbonyl, wherein the aryl group is phenyl and naphthyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group con~i~tins!: of (1) hydrogen, (2) C1 6alkyl, (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring cont~ining 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1 3alkoxy, (3) amino, (4) mono-anddi-Cl 6aLkYlamino, (5) carboxyl, (6) C1 3alkylthio, W O 97/16430 PCT~US96/17~47-(7) C1 3aLkyl-S(O)k-, where k is 1 or 2, (8) C1 4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (1 1) amidino.
Within this genus there is a class of compounds wherein Rl, R2, R3 and R4 are each indepenc1ently selected ~rom the group 10 consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1 4alkyl, (h) C 1 -4aL~oxy, (i) C1 4aLkylthio, and (j) mono-anddi-C1 4aLkyl~n-int, Rs is selected from the group consisting of (a) hydrogen (b) R6R7N-so2-NH-c(=o)-~ optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) Cl 4alkyl, and (3) aryl, wherein the aryl group is phenyl, and said substituents are independently selected from (1) hydroxy, (2) Cl 3aLkoxy, (3) amino, (4) mono-anddi-Cl 6aLkYlarnino, (5) carboxyl, -CA 0223464l l998-04-09 (6) Cl 3alkylthio, and (7) halo selected from fluoro, chloro, and - bromo.
S Within this class there is a sub-class of compounds wherein wherein E~2 is hydrogen or methyl-R4 is hydrogen or methyl;
Rl and R3 are each independently selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3; and 15 Rs is hydrogen.
Illustrating the invention are:
(a) hexahydro-5-imino-( lH)- 1 ,4-diazepine dihydrochloride, (b) hexahydro-5-imino-1,4-thiazepine hydrochloride (c) hexahydro-5-imino-1,4-oxazepine hydrochloride, (d) hexahydro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride, (e) hexahydro-S-imino-6-propyl- 1 ,4-thiazepine hydrochloride, (f~ hexahydro-5-imino-7-methyl- 1 ,4-thiazepine hydrochloride, (g) hexahydro-S-imino-2-methyl- 1 ,4-thiazepine hydrochloride, (h) hexahydro-S-imino-6-(3-methyl-2-n-butenyl)- 1,4-thiazepine hydrochloride, (i) hexahydro-S-imino-3-(3-methyl-2-n-butenyl)- 1,4-thiazepine hydrochloride, (i) hexahydro-S-imino-6-(2-methyl-propyl)- 1,4-thiazepine hydrochloride, W O 97/16430 PCT~US96/17447-(k) hexahydro-5-imino-3-(2-methyl-propyl)- 1,4-thiazepine hydrochloride, (1) hexahydro-5-imino-6-methyl- 1 ,4-thiazepine hydrochloride, (m) hexahydro-5-imino-3-methyl- 1 ,4-thiazepine hydrochloride, ~n~ hex~hydro-5-imino-3-ethyl-1,4-~ia~epine hydrochloride, (o) hexahydro-S-imino-3-butyl- 1 ,4-thiazepine hydrochloride, (p) hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1,4-thiazepine hydrochloride, (q) (~:)-trans-decahydro-4-imino-benzo[b]- 1 ,4-thiazepine acetic acid salt., (r) hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt, (s) hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt, (t) hexahydro-5-imino- 1 -methyl-( 1 H)- 1 ,4-diazepine hydrochloride, and pharmaceutically acceptable salts thereof.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C1 6aLkyl including methyl, 25 ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Simil~rly, C1 6aLkoxy is intended to include aLkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. F.x~mples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, 30 cyclohexyloxy, and the like. Likewise, C1 6 aLkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups inclll~le methylthio, ~r~ylLhio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
W O 97/16430 PCT~US96/17447-Heteroaryl includes furan, benzofuran, thiophene, pyrrole, indole, isoxazole, isothiazole, pyra_ole, oxazole, benzoxazole, thiazole, imidazole, benzimidazole, 1,2,3-oxadiazole, 1,2,3-thi~ 7ole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thi~ 7ole, 1,3,4-triazole, 1,2,5-5 oxadiazole, 1,2,5-thi~ 7ole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-tri~7.ine, 1,2,4,5-~e.trzt7in~.~ tet~azole, an.d the like.
As appreciated by those of skill in the art, the depiction X
R1, R2. R3, R4 ~ b, R5 is intented to indicate that substihlent~ Rl, R2, R3 and R4 may each independently reside at any available position on the ring structure of figure I.
Illustrative of the situation wllel~ill two members of R 1. R2, R3 and 15 R4 are joined together to form a ring or one member is joined together with R6 to form a ring include the following:
--~" N ' R5 ~" N ~ R5 R1 ~
~ R2 R1 ~ ~
- S ~ N ~' N--R5 R ~--N'~i' , R5 W O 97/16430 PCT~US96/17447 -~> R1 R~ R3 C~ ~ R2 ~--N~N--R5 ~ N ~N, R5 As outlined in the sllmm~ry of the invention, the compounds of the in.~t~nt invention are useful in the treatment of a number of NOS
S implic~qte.l diseases. The implication of these diseases is well documented in the li~ela~ule. For example, with regard to psoriasis, see Ruzicka et. al., J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen et.
al., Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm., 103:435(1994); with regard to uveitis, see Mandia et. al., Invest 10 Opthalmol., 35: 3673-89 (1994); with regard to type 1 diabetes, see Eisieik & Leijel~r~ , Diabetes & Metabolism, 20: 116-22 (1994) or Kroncke et. al., BBRC, 175: 752-8 (1991) or Welsh et. al., Endocrinol., 129: 3167-73 (1991); with regard to septic shock, see Petros et. al., Lancet,338: 1557-8 (l991),Thiemermann ~ Vane, Eur. J. Ph~ rol., 15 211: 172-82 (1992), or Evans et. al., Infec. Imm., 60: 4133-9 (1992), or Schillin~ et. al., Intensive Care Med, 19: 227-231 (1993); with regards to pain, see Moore et. al., Brit. J. Ph~ ol., 102: 198-202 (1991), or Moore et. al, Brit. J. Pharmacol., 108: 296-97 (1992) or Meller et. al., Europ. J. Pharmacol., 214: 93-6 (1992) or Lee et. al., NeuroReport, 3:
20 841-4 (1992); with regard to migraine, see Olesen et. al., TrPS, 15: 149-153 (1994); with regard to rhenm~toitl arthritis, see Kaurs & Halliwell, FEBS Letters, 350: 9-12 (1994); with regard to osteoarthritis, see Stadler et. al., J. Immunol., 147: 3915-20 (1991); with regard to infl~rnm~tory bowel disease, see Miller et. al., Lancet, 34: 465-66 (1993) or Miller et.
25 al., J. Ph~ rol. Exp. Ther., 264: 11-16 (1993); with regard to asthma, see Hamid et. al., Lancet, 342: 1510-13 (1993) or Kharitonov, et. al., Lancet, 343: 133-5 (1994); with regard to Tmmllne complex diseases, see Mllllig~n et. al., Br. J. Ph~rm~col., 107: 1159-62 (1992); with regard to ~ multiple sclerosis, see Koprowski et. al., PNAS, 90: 3024-7 (1993); with regard to ischemic brain edema, see Nagafuji et. al., Neurosci., 147: 159-- 62 (1992) or Buisson et. al., Br. J. Ph~rrn~col., 106: 766-67 (1992) or Trifileffl et. al., Europ. J. Pharmacol., 218: 197-8 (1992); with regard to toxic shock syndrome, see Zembowicz & Vane, PNAS, 89: 2051-55 (1992); with regard to heart failure, see Winlaw et. al., Lancet, 344: 373-4 (1994~ with regard to ulçeF~ive colitis~ see ~Bou~ton-Sm-~h e~. al.5 Lancet 342: 338-40 (1993); and with regard to atherosclerosis, see White et. al., PNAS, 91: 1044-8 (1994); with regard to glomerulonephritis, see Muhl et. al., Br. J. Pharmcol., 112: 1-8 (1994); with regard to paget's e~e and osteoporosis, see Lowick et. al., J. Clin. Invest., 93: 1465-72 (1994) or Evans et al., Clin. Orthopaedics & Related Res., 312: 275-294 (1995); with regard to infl~mm~tory sequelae of viral infections, see Koprowski et. al., PNAS, 90: 3024-7 (1993); with regard to retiniti~7 see Goureau et. al., BBRC, 186: 854-9 (1992); with regard to oxidant in~ ced lung injury, see Berisha et. al., PNAS, 91, 744-9 (1994); with regard to eczema, see Ruzica, et al., J. Invest. Derm., 103, 395(1994); with regard to acute allograft rejection, see Devlin, J. et al., Transplantation, 58, 592-595 (1994); with regard to infection caused by invasive microorg~ni~m~
which produce NO, see Chen, Y. and Rosazza, J.P.N., Biochem. Biophys.
Res. Comm., 203:1251-1258(1994); and with regard to tumor growth, see Jenkins et al., PNAS, 92, 4392-4396 (1995).
The ph~rm~eutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~rm~eutically acceptable salt, thereof, and may also contain a pharm~c elltically acceptable carrier and optionally other therapeutic ingredients. The term "ph~rm~eutically acceptable salts" refers to salts prepared from ph~rm~ceutically acceptable non-toxic acids or bases including inorganic bases and organic bases. Salts derived from inorganic acids include alllminllm, ammonium, calcium, copper, ferric, ferrous, lil~liulll, m~gnesium, m~n~nic salts, m~ng~nous~ potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, m~gnesium, potassium, and sodium salts. Salts derived from ph~T rn~eutically acceptable organic non-toxic bases include salts of W O 97/16430 PCT~US96/17447-primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic arnines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- -dibenzylethylene~ min~--, diethyl~min~, 2-diethyl~minoethanol, 2-S dimethylaminoeth~n~-l, ethanolamine, ethylene~ min~, N-ethylmorpholine, N-ethylpiperidine, glllc~n~ine, glucos~mine, histidine, hyd~abamine~ isop~opylamine, lysine~ methylglllca~ e, moIE~holiIle, piperazine, piperidine, polyamine resins, procaine, purines, theol,r~ e, triethyl~mine, trimethyl~mine, L~ yl~min~., trometh~mine, and the 10 like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pha~naceutically acceptable salts.
The ph~ reutical compositions cont~ining the active ingredient of the instant invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be plep~ed 20 according to any method known to the art for the m~n~lf~c~ture of ph~ eutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and p~l~t~ble preparations. Tablets 25 contain the active ingredient in admixture with non-toxic ph~ ceutically acceptable excipients which are suitable for the manufacture of tablets. I~ese excipients may be for exannple, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; gran~ tin~ and ~ ntegrating agents, for 30 example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay ~ integration and absorption in the gastrointestinal tract and thereby provide a sllct~in~.rl action over a longer WO 97/16430 PCT~US96/17447-~ period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. I~ey may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control rele2se S Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for e~ample, calcium carbollate~ calcillm phosphate or kaolin$ or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium ~l~in~te, polyvinyl-pyrrolidone, gum tr~c~nth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hept~-lec~t-thylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be form~ ted by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, ses~me oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral W O 97/16430 PCT~US96/17~47-preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active 5 ingredient in admixture with a dispersing or wefflng agent, suspending agent and one or more preservatives. Suitable dispersing or wetting a~ents and suspçndimg agents are e~empli~ied by those ~eady mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The ph~ eutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occur~ing phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be form~ ted with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The ph~rm~ell~ical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. I~is suspension may be formlll~ted according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable L,l~a,ation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-but~ne diol.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be W O 97/16430 PCT~US96/17447-employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be ~flmini~tered in the form of a suppositories for rectal ~lmini~tration of the drug. These S compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary tempelalures but liquid at th~ rect3~ temperature and wil~ therefore melt in th~ rect~ to re~ea~e the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or 10 suspensions, etc., cont~ining the compound of Formula I are employed.
(Por purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 15 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, infl~mm~tion may be effectively treated by the ~-lmini.~tration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 20 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of ~1mini~tration. Por example, a form~ tion intended for the oral ~lrnini~tration of hnm~n~
25 may contain from 0.5 mg to 5 g of active agent compounded with an a~lc,~liate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 30 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general h~lth, sex, diet, time of ~(1mini.stration, W O 97/16430 PCT~US96/17447 -route of ~1mini.ctration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Assay Protocol for NOS activity NOS activity is measured as the formation of L-[2,3,4,5-3H~Citrulline from L-r2~3~4~s-3H~ inine~ The incubatic!n buf~er ~100 uL) contained; 100 mM TES, pH 7.5, 5 uM FAD, 5 uM FMN, 10 uM
BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ug/mL calmodulin (bovine), 1 uM L-Arg, 0.2 uCi L-[2,3,4,5-3H]Arg, and the inhibitor in aqueous DMSO (max. 5 %). The reaction is initi~ted by addition of enzyme. Incubations are performed at room temperature for 30 ..~ .les and stopped by the addition of an equal volume of quenching buffer consisting of 200 mM sodium citrate, pH 2.2, 0.02% sodium azide.
15 Reaction products are separated by passing through a cation exchange resin and qll~ntit~ted as cpm by scintill~tion colmtin~. Percent inhibition is calculated relative to enzyme incubated without inhibitor according to:
% inhibition = 100 x (cpm L-t2,3,4,5-3H]Cit with inhibitor / cpm L-[2,3,4,5-3H~Cit without inhibitor).
Illustrative of the utility of the compounds of Formula I is the ability of such compounds to inhibit NO synthase as shown in Table 1 and as measured by the assay described above:
-WO 97/16430 PCT~US96/17447-~ Table 1. Inhibition of Nitric Oxide Syn~ase Isozymes Example iNOS ecNOS ncNOS
Number (Icso~ uM) (Icso~ uM) (ICso~ uM) ~50 >50 >50 2 <10 >10 <10 3 ~5(~ ~5~ ~ ~0 4 <l <50 <10 > 50 > 50 > 50 6 <l0 <l0 <l 7 <10 <10 <l 8 >50 >50 >50 9 <l >50 <50 < 50 > 50 > 50 11 <1 >50 <10 12 > 50 < 50 < l0 13 <1 <10 <10 14 <1 <50 <l0 <1 >50 <10 16 <1 <50 <l0 17 >50 >50 >50 18 <1 <10 <1 19 <10 <50 <10 <50 >50 >50 -W O 97/16430 PCT~US96/17447 -Methods of Synthesis The compounds of the present invention can be prepared according to the following methods.
5 Scheme 1.
Ph ~oc H
(~ a ~ ~) b, ~ c H N H
O O O
A ~
Boc Boc H
d ~) e N H H
D ~ E
Reaction conditions:
a) H2 40 psi, Pd(OH)2/C, EtOH, HOAc, 4 hr; b) (t-C4HsO2C)20, NaCI, NaOH, CHCI3, reflux, 4hr; c) (CH3)30BF4, CH2CI2, RT, overnight; d) NH4CI, EtOH, reflux, 4 hr; e) HCI, ethyl acetate, RT, overnight.
As shown in Scheme 1, hexahydro-1-(phenylmethyl)-(SH)-1,4-diazepin-5-one A (prepared as described by T. Irikura, CAS
84:31153r, 83:179149u) is reacted under hydrogen atmosphere at 40 psi in the presence of palladium hydroxide catalyst in e~anol and acetic acid to give hexahydro-SH- 1,4-diazepin-5-one B as the acetic acid salt.
Reaction with di-t-butyl dicarbonate in the presence of sodium chloride and sodium hydroxide gives 1-(tert-butyloxycarbonyl)-hexahydro-(5H)-. CA 02234641 1998-04-09 W O 97/16430 PCTrUS96/17447 -1,4-diazepin-5-one C. The imino ether D is formed from C by reaction with Meenvein's salt (trimethyloxonium fluoroborate). The amidine E is obtained by reaction of D with ammonium chloride in refluxing ethanol.
The amine protecting group in E is removed by reaction with hydrogen 5 chloride in ethyl acetate to give the desired amidine F as the dihydrochloride salt.
Scheme 2 a H H
A S NH HCI
Reaction conditions:
a) NH3, HgCI2, THF
An alternative preparation of the ~mi~1inP functionality is shown in Scheme 2. A thioamide A is reacted directly with ammonia in the presence of mercuric chloride to give the 5-imino-1,4-diazepine B.
CA 02234641 l99X-04-09 W O 97/16430 PCT~US96/17447-Scheme 3 when X = S
H
O N~ O
OH
A ~ C
~/when X = O
~-~? d ~
S NH HCI
D E
Re~.:tiG, I co, l~liliol)s:
a) NH20H - HCI, NaOH, EtOH; b) n-BuLi, TsCI; Et3N, aq.
dioxane; c) Lawesson's reagent, tol, 90~C; d) Me30BF4, iPr2NEt, CH2CI2; NH4CI, EtOH, reflux 1,4-Oxa- and thiazepine analogs are prepared by 5 methodology outline in Scheme 3. A ketone derivative A is converted to its corresponding oxime B by reaction with hydroxyl~mint~ in ethanol.
Ring expansion of B via a Beckm~nn rearrangement of the O-tosyl-oxime formed by reaction of ~ with with butyl lithium and p-toluenesulfonyl chloride gives hexahydro-1,4-heteroazepin-5-one C.
10 When X = S, the amide in C is converted to the thioamide D by reaction with Lawesson's reagent. Reaction of D with Meer~,veinls salt to form the imino-thioether followed by reaction with ammonium chloride gives the hexahydro-5-imino-1,4-heteroazepine E. Alternatively, when X = O in C, reaction with Meerwein's salt followed by ammonium chloride gives E
HEXAHYDRO-5-IMINO- 1,4-~ l ~ OAZEPINE DERIVATIVES AS
INHIBITORS OF NITRIC OXIDE SYNTHASES
This application is directed to inhibitors of nitric oxide synthase, and in particular cyclic amidines.
Nitric Oxide in Biology.
The emergence of nitric oxide (NO), a reactive, inorganic radical gas as a molecule contributing to important physiological and pathological processes is one of the major biological revelations of recent 15 times. This molecule is produced under a variety of physiological and pathological conditions by cells me~ tin~ vital biological functions.
Examples include endothelial cells lining the blood vessels; nitric oxide derived from these cells relaxes smooth rnuscle and regulates blood pressure and has significant effects on the function of circ~ tin~ blood 20 cells such as platelets and neutrophils as well as on smooth muscle, both of the blood vessels and also of other organs such as the airways. In the brain and elsewhere nitric oxide serves as a n~urotl~nsmitter in non-adrenergic non-cholinergic neurons. In these instances nitric oxide appears to be produced in small amounts on an int~rmittent basis in 25 response to various endogenous molecular sign~l~. In the immlm~ system nitric oxide can be synthesized in much larger amounts on a protracted basis. Its production is inflllce-l by exogenous or endogenous infl~mm~tory stimuli, notably endotoxin and cytokines elaborated by cells of the host defense system in response to infectious and 30 infl~mm~tory stimuli. This induced production results in prolonged nitric oxide release which contributes both to host defense processes such as the killing of bacteria and viruses as well as pathology associated with acute and chronic infl~mm~tion in a wide variety of diseases. The discovery that nitric oxide production is mediated by a unique series of three closely 35 related enzymes, named nitric oxide synth~es, which utilize the amino W O 97/16430 PCT~US96/17447 -acid ar~ ine and molecular oxygen as co-substrates has provided an underst~ntlin~ of the biochemistry of this molecule and provides distinct ph~rm~ological tal~ e~s for the inhibition of the synthesis of this mediator, which should provide ~ c~nt beneficial effects in a wide variety of diseases.
Nit~ic Oxidç SyIlthases Nitric oxide and L-citrulline are formed from L-arginine via 10 the dioxygenase activity of specific nitric oxide synthases (NOSs) in m~mm~ n cells. In this reaction, L-arginine, ~2 and NADPH are cosubstrates while FMN, FAD and tetrahydrobiopterin are cofactors.
NOSs fall into two distinct classes, con.~tit~ltive NOS (cNOS) and inducible NOS (iNOS) . Two constitutive NOSs have been identified.
15 They are:
(i) a con~iLulive, Ca++/calmodulin dependent enzyme, located in the endothelium and elsewhere (ecNOS or NOS 3), ~hat releases NO in response to receptor or physical stimnl~tion, (ii) a constitutive, Ca++/calmodulin dependent enzyme, located in ~e brain (ncNOS or NOS 1) and elsewhere, that releases NO in response to receptor or physical stirn~ tion, The third isoform identified is inducible NOS (iNOS or NOS 2):
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a large number of other cells by endotoxin and cytokines. Once expressed, this inducible NO
synthase produces NO in relatively large amounts for long periods of time.
Spectral studies of both the mouse macrophage iNOS and rat brain ncNOS have shown that these enzymes (which have been classified as P-450-like enzymes from their CO-difference spectra) contain a heme moiety. The structural ~imilz~rity between NOS and the P-450Mavoprotein complex suggests that the NOS reaction mech~ni~m may be ~imil~r to P-450 hydroxylation and/or peroxidation. This indicates that NOS belongs to a class of flavohemeproteins which contain both heme and flavin binding regions within a single protein in contrast to 5 the mul~iploteill NADPH oxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.
Distinct Functions of NO Produced by Different Nitric O~cide Syn~ases.
The NO released by the constitutive enzymes (NOS 1 and NOS 3) acts as an autocoid me~ ting a number of physiological responses. Two distinct cDNAs accounting for the activity of NOS 1 and NOS 3 in man have been cloned, one for NOS 1 (Nakane et. al., FEBS
Letters, 316, 175-182, 1993) which is present in the brain and a number of peripheral tissues, the other for an enzyme present in endoth~ m (NOS 3) (Marsden et. al., FEBS Letters, 307, 287-293, 1992). This latter enzyme is critical for production of NO to m~int~in vasorel7~x~tion. A
second class of enzyme, iNOS or NOS 2, has been cloned from human liver (Geller et. al., PNAS, 90, 3491-5, 1993), and identified in more than a dozen other cells and tissues, including smooth muscle cells, chondrocytes, the kidney and airways. As with its coull~el~all from the murine macrophage, this enzyme is induced upon exposure to cytokines such as g~mm:~ interferon (IFN-~), interl~nkin-l~ (IL-l,B), tumor necrosis factor (INF-a) and LPS (lipopolysaccharide). Once induced, iNOS
expression continlles over a prolonged period of time. The enzyme does not require exogenous calmodulin for activity.
Endothelium derived relaxation factor (EDRF) has been shown to be produced by NOS 3 (~oncada et. al., Pharmacol. Reviews, 43, 109-142, 1991). Studies with substrate analog inhibitors of NOS have ~ 30 shown a role for NO in regulating blood pressure in ~nim~ and blood flow in man, a function attributed to NOS 3. A transgenic mouse deficient in functional NOS 3 was shown to be hypertensive, thus validating the role of NO synthesis by NOS 3 in the regulation of blood pressure (Huang et al., Nature, 377, 239-242, 1995). NO has also been W O 97/16430 PCT~US96/17447-shown to be an effector of the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6, 3051-64, 1992) for fighting tumour cells and invading microorg~ni~m~ (Wright et al., Card. Res., 26 ,48-57, 1992 and Moncada et al., Pharmacological Review, 43, 109-142, 1991). It also 5 appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue fl~m~ge, may result largely from ~e effects of NO syntht-.si7.o-1 by the NO~ 2~
NO generated by NOS 2 has been implicated in the pathogenesis of infl~mm~tory diseases. In experiment~l ~nim~
10 hypotension induced by LPS or TNF-a can be reversed by NOS
inhibitors and reiniti~te~l by L-arginine (Kilbourn et. al., PNAS, 87, 3629-32, 1990). Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis (Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96--S100, 1992) and IL-2 therapy in cancer patients (Hibbs et. al., J. Clin. Invest., 89, 867-77, 1992). NOS 2 is implicated in these responses, and thus the possibility exists that a NOS inhibitor would be effective in ameliorating cytokine-intl-~cerl hypotension. Recent studies in ~nim~l models have suggested a role for NO in the pathogenesis of infl~mm~tion and pain and NOS inhibitors have been shown to have beneficial effects on some aspects of the infl~mm~tion and tissue changes seen in models of infl~mm~tory bowel disease, (Miller et. al., J.
Pharmacol. Exp. Thcer., 264, 11- 16, 1990) and cerebral ischemia and arthritis (Ialenti et. al., Br. J. Pharrnacol ., 110, 701-6, 1993; Stevanovic-Racic et al., Arth. & Rheum., 37, 1062-9, 1994). Moreover transgenic mice deficient in NOS 1 show t1imini~hed cerebral ischemia (Huang et.
al., Science, 265, 1883-5, 1994) and transgenic mice deficient in NOS 2 exhibit enhanced survivability in a model of LPS-in~ ce-l shock (MacMicking et al. CeU 81, 641-650, 1995) and Wei et al. Nature 375, 408-411, 1995)).
Further conditions where there is an advantage in inhibiting NO production from L-arginine include therapy with cytokines such as TNF, IL- 1 and IL-2 or therapy with cytokine-inducing agents, for example 5, 6-dimethylx~ntllenone acetic acid, and as an adjuvant to short term immlmosuppression in ~ansplant therapy. In addition, compounds .
W O 97/16430 PCTrUS96/17447 -S
- which inhibit NO synthesis may be of use in reducing the NO
concentration in patients suffering from infl~mm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition, for example adult respiratory distress syndrome (ARDS) and S myocarditis.
There is also evidence that an NO synthase enzyme may be illvolved in the de~eneration of cartila e which t~kes place i~
autoimmlme and/or infl~mm~tory conditions such as arthritis, rheumatoid ~lli~iS, chronic bowel disease and systemic lupus erythematosis (SLE).
10 It is also thought that an NO synthase enzyme may be involved in insulin-dependent diabetes mellitus. Therefore, a yet further aspect of the present invention provides cyclic amidine derivatives or salts thereof in the manufacture of a medicament for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term immllnosuppression in transplant 15 therapy, for the treatment of patients suffering from infl~mm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition.
SUMMARY OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
R R R R ~ b and ph~rm~ceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated ~ e~es and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and infl~mm~tion. These diseases and disorders 30 include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in in cancer patients, cachexia, immunosuppression W O 97/16430 PCT~US96/17447 such as in transplant therapy, autoimmllne andlor infl~n~m~tory indications including sunburn, eczema or psoriasis and respiratoIy conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, 5 infl~mm~tory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid alLllliLis, septic a~ iLis, c~hronic or inflammatoly bowel disease, ulcerative colitis~ Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-10 dependent diabetes mellitus and cystic fibrosis. Compounds of FormulaI are also usful in the treatment of hypoxia, hy~ell.alic oxygen convulsions and toxicity, dementia, Alzheimer's ~ e~e~ Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, Korsakoff's disease, 15 imbecility related to cerebral vessel disorder, NO me~i~te~l cerebral trauma and related sequelae, ischernic brain edema (stroke), sleepîng disorders, eating disorders such as anorexia, schizophrenia, depression, pre-menstrual syndrome (PMS), urinary incontin~n~e~ an~iety, drug and alcohol addiction, pain, migraine, emesis, tumor growth, immune 20 complex cli.ces~se, as immllnosupressive agents, acute allograft rejection, infections caused by invasive microorg~ni~m~ which produce NO and for preventing or reversing tolerance to opiates and diazepines.
Dl~TA~T Fr) DESCRIPTION OF THE INVENTION
The invention disclosed herein encompasses compounds of Formula I
X
R,, R2, R3, R4 ~"' b~ R5 30 or a ph~ ceutically acceptable salt thereof wherein:
side a or side b has a double bond, WO 97/16430 PCTrUS96/17447-~ X is selected from 0, S(O)m, NH, and NR6, wherein R6 is selected from C1 12alkyl, C1 12alkyl-carbonyl, C 1- 12aLkyloxy-carbonyl, C 1-1 2aLkYlamino-carbonyl Cl l2alkyl-sulfonyl and Cl-l2aL~yl~mino-sulfonyl wherein said S Cl 12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1 6alkoxy, ~3~mino, a.nd hal misO, 1 or2;
Rl, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) C 1- 12alkoxy, (c) Cl 12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono Cl l2alkyl~rnin(, (e) (di-C l l2alkyl)amino, (f) C 1-12alkylcarbon (g) Cl 12alkyl, (h) C2 12alkenyl, (i) C2 12aL~ynyl, (j) C5 locycloalkyl~
(k) heteroCs locycloalkyl,whereintheheteroCs 10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) rul~llyl, (S) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) ox~ olyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, ~l.5~ pyrr~lyl~
(17) isoquinolyl, (18) tetrazolyl, . 10 (19) thi~ 701yl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) Cl 12alkYl-C(O)NH, (o) C1 12alkoxy-C(O)NH, (p) C1 12alkylamino-C(O)NH, (q) C1 12alkyl-S(0)2NH, (r) C1 12aLkyl~mino-C(0), (S) c1-12aLkylamino-s(o)2~
(t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imid~7:olyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(0)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(0) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imic1~7.olyl~ and triazolyl, (y) phenylamino-S(0)2, (z) hydroxy, (aa) amino, (ab) oxo, W O 97/16430 PCT~US96/17447 -(ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexylorCl 6alkyl, each of (b) to (y) being optionally mono or di- substit~lte-l, the substituents being independently selected from (1) hydroxy, (O)~lH5 (3) -NR7Rg, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C 1-6aL~Yl, (4) -NR7C(O)R8, (6) -NR7C(O)NHRg, (S) -NR7C(O)ORg ,where Rg is selected from phenyl, benzyl, cyclohexyl or C1 6alkyl, (7) -NR7S(0)2Rg, (8) -OR7, (9) -C(O)ORg, (10) -C(O)NR7R8, (1 1) -C(O)R7, (12) -S(O)kR7, (13) -S(0)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -CF3, (16) C(=NR7)-NHR8, (17) hetero C5 locycloaL~yl,wherein the hetero C5 10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, - (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, CA 02234641 l99X-04-09 WO 97/16430 PCT~US96/17447-(f~ pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and S (j) triazolyl, or when two members of the group Rl, ~2, R3 a~d R4 inclu.ding the optional substituents present thereon reside on the same carbon atom of Formula I, or two of the group Rl, R2, R3 and R4 including the optional substituents present thereon reside on adjacent atoms of Formula I, said two members rnay optionally be joined, such that together with the carbon atom to which they are ~tt~h~l there is formed a saturated or lln~tllrated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally co... l~;.. i.. ~e: up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2, R3 and R4 including the optional substituents present thereon resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6, such that together with the N
on which R6 resides and the carbon on which said member resides there is formed a saturated or lln~ rated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally cont~ininf~ up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and br~nchP-l C1 12aLkYl, optionally mono or di-substitllte-1, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, ~ (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) -CF3, (9) phenyl, optionally mono or di-substi~te~l with hydroxy, halo, Cl~aLtcyl, or Cl 4alkoxy, (c) -C(O)NRloRl 1, whe~ Rlo and Rl 1 are each independently hydrogen~ phe~ylJ cyclohe~yl~ -s(c))2NR7R~ or option~y substituted C 1-6aLkyl~ wherein the substituent is selected from (1) -NRl2Rl3~ wherein R12 and R13 are each independently H, Cl 6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)oRl2~
(4) -S(O)kR12, where k is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionallysubstituted Cs locycloaLkyl wherein cycloalky; and cycloalkyl substituents are as defined above, (9) hetero C5 10cycloalkyl, wherein the heteroCslocycloalkyl optionally contains 1 or 2 heteroato~s selected from S, O and N, (d) -C(O)R 1 1, (e) -C(~)ORl 1, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
Within this embodiment there is a genus of compounds wherein Rl, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, S (c) amino, (d) cyano, (e~ ~luoro, chlQro~ bromo, and iodo7 (f) trifluoromethyl, (g) C1 6alkyl, (h) C1 6aLkoxy, (i) C1-6alkylthio, (j) Cl 6alkylcarbonyl, (k) mono- and di-C l 6aLkylamino, (1) aryl, where aryl is phenyl and naph~yl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, ~3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substit~lte~l, the substituents being independently selected from (1) hydroxy, (2) C1 4alkyl, (3) C1 3alkoxy, (4) amino, (5) mono-anddi-C1 6aLkylamino, (6) carboxyl, (7) Cl 3alkylthio, (8) C1 3alkyl-S(O)k-, where k is 1 or 2, (9) Cl 4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, ) OX09 and (12) amidino, 10 R5 is selected from the group consisting of (a) hydrogen, (b) C1 6aLkylcarbonyl, (c) arylcarbonyl, wherein the aryl group is phenyl, (d) arylcarbonyl-aminocarbonyl, wherein the aryl group is phenyl and naphthyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group con~i~tins!: of (1) hydrogen, (2) C1 6alkyl, (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring cont~ining 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1 3alkoxy, (3) amino, (4) mono-anddi-Cl 6aLkYlamino, (5) carboxyl, (6) C1 3alkylthio, W O 97/16430 PCT~US96/17~47-(7) C1 3aLkyl-S(O)k-, where k is 1 or 2, (8) C1 4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (1 1) amidino.
Within this genus there is a class of compounds wherein Rl, R2, R3 and R4 are each indepenc1ently selected ~rom the group 10 consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1 4alkyl, (h) C 1 -4aL~oxy, (i) C1 4aLkylthio, and (j) mono-anddi-C1 4aLkyl~n-int, Rs is selected from the group consisting of (a) hydrogen (b) R6R7N-so2-NH-c(=o)-~ optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) Cl 4alkyl, and (3) aryl, wherein the aryl group is phenyl, and said substituents are independently selected from (1) hydroxy, (2) Cl 3aLkoxy, (3) amino, (4) mono-anddi-Cl 6aLkYlarnino, (5) carboxyl, -CA 0223464l l998-04-09 (6) Cl 3alkylthio, and (7) halo selected from fluoro, chloro, and - bromo.
S Within this class there is a sub-class of compounds wherein wherein E~2 is hydrogen or methyl-R4 is hydrogen or methyl;
Rl and R3 are each independently selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3; and 15 Rs is hydrogen.
Illustrating the invention are:
(a) hexahydro-5-imino-( lH)- 1 ,4-diazepine dihydrochloride, (b) hexahydro-5-imino-1,4-thiazepine hydrochloride (c) hexahydro-5-imino-1,4-oxazepine hydrochloride, (d) hexahydro-5-imino-3-propyl- 1 ,4-thiazepine hydrochloride, (e) hexahydro-S-imino-6-propyl- 1 ,4-thiazepine hydrochloride, (f~ hexahydro-5-imino-7-methyl- 1 ,4-thiazepine hydrochloride, (g) hexahydro-S-imino-2-methyl- 1 ,4-thiazepine hydrochloride, (h) hexahydro-S-imino-6-(3-methyl-2-n-butenyl)- 1,4-thiazepine hydrochloride, (i) hexahydro-S-imino-3-(3-methyl-2-n-butenyl)- 1,4-thiazepine hydrochloride, (i) hexahydro-S-imino-6-(2-methyl-propyl)- 1,4-thiazepine hydrochloride, W O 97/16430 PCT~US96/17447-(k) hexahydro-5-imino-3-(2-methyl-propyl)- 1,4-thiazepine hydrochloride, (1) hexahydro-5-imino-6-methyl- 1 ,4-thiazepine hydrochloride, (m) hexahydro-5-imino-3-methyl- 1 ,4-thiazepine hydrochloride, ~n~ hex~hydro-5-imino-3-ethyl-1,4-~ia~epine hydrochloride, (o) hexahydro-S-imino-3-butyl- 1 ,4-thiazepine hydrochloride, (p) hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1,4-thiazepine hydrochloride, (q) (~:)-trans-decahydro-4-imino-benzo[b]- 1 ,4-thiazepine acetic acid salt., (r) hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt, (s) hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt, (t) hexahydro-5-imino- 1 -methyl-( 1 H)- 1 ,4-diazepine hydrochloride, and pharmaceutically acceptable salts thereof.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C1 6aLkyl including methyl, 25 ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Simil~rly, C1 6aLkoxy is intended to include aLkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. F.x~mples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, 30 cyclohexyloxy, and the like. Likewise, C1 6 aLkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups inclll~le methylthio, ~r~ylLhio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
W O 97/16430 PCT~US96/17447-Heteroaryl includes furan, benzofuran, thiophene, pyrrole, indole, isoxazole, isothiazole, pyra_ole, oxazole, benzoxazole, thiazole, imidazole, benzimidazole, 1,2,3-oxadiazole, 1,2,3-thi~ 7ole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thi~ 7ole, 1,3,4-triazole, 1,2,5-5 oxadiazole, 1,2,5-thi~ 7ole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-tri~7.ine, 1,2,4,5-~e.trzt7in~.~ tet~azole, an.d the like.
As appreciated by those of skill in the art, the depiction X
R1, R2. R3, R4 ~ b, R5 is intented to indicate that substihlent~ Rl, R2, R3 and R4 may each independently reside at any available position on the ring structure of figure I.
Illustrative of the situation wllel~ill two members of R 1. R2, R3 and 15 R4 are joined together to form a ring or one member is joined together with R6 to form a ring include the following:
--~" N ' R5 ~" N ~ R5 R1 ~
~ R2 R1 ~ ~
- S ~ N ~' N--R5 R ~--N'~i' , R5 W O 97/16430 PCT~US96/17447 -~> R1 R~ R3 C~ ~ R2 ~--N~N--R5 ~ N ~N, R5 As outlined in the sllmm~ry of the invention, the compounds of the in.~t~nt invention are useful in the treatment of a number of NOS
S implic~qte.l diseases. The implication of these diseases is well documented in the li~ela~ule. For example, with regard to psoriasis, see Ruzicka et. al., J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen et.
al., Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm., 103:435(1994); with regard to uveitis, see Mandia et. al., Invest 10 Opthalmol., 35: 3673-89 (1994); with regard to type 1 diabetes, see Eisieik & Leijel~r~ , Diabetes & Metabolism, 20: 116-22 (1994) or Kroncke et. al., BBRC, 175: 752-8 (1991) or Welsh et. al., Endocrinol., 129: 3167-73 (1991); with regard to septic shock, see Petros et. al., Lancet,338: 1557-8 (l991),Thiemermann ~ Vane, Eur. J. Ph~ rol., 15 211: 172-82 (1992), or Evans et. al., Infec. Imm., 60: 4133-9 (1992), or Schillin~ et. al., Intensive Care Med, 19: 227-231 (1993); with regards to pain, see Moore et. al., Brit. J. Ph~ ol., 102: 198-202 (1991), or Moore et. al, Brit. J. Pharmacol., 108: 296-97 (1992) or Meller et. al., Europ. J. Pharmacol., 214: 93-6 (1992) or Lee et. al., NeuroReport, 3:
20 841-4 (1992); with regard to migraine, see Olesen et. al., TrPS, 15: 149-153 (1994); with regard to rhenm~toitl arthritis, see Kaurs & Halliwell, FEBS Letters, 350: 9-12 (1994); with regard to osteoarthritis, see Stadler et. al., J. Immunol., 147: 3915-20 (1991); with regard to infl~rnm~tory bowel disease, see Miller et. al., Lancet, 34: 465-66 (1993) or Miller et.
25 al., J. Ph~ rol. Exp. Ther., 264: 11-16 (1993); with regard to asthma, see Hamid et. al., Lancet, 342: 1510-13 (1993) or Kharitonov, et. al., Lancet, 343: 133-5 (1994); with regard to Tmmllne complex diseases, see Mllllig~n et. al., Br. J. Ph~rm~col., 107: 1159-62 (1992); with regard to ~ multiple sclerosis, see Koprowski et. al., PNAS, 90: 3024-7 (1993); with regard to ischemic brain edema, see Nagafuji et. al., Neurosci., 147: 159-- 62 (1992) or Buisson et. al., Br. J. Ph~rrn~col., 106: 766-67 (1992) or Trifileffl et. al., Europ. J. Pharmacol., 218: 197-8 (1992); with regard to toxic shock syndrome, see Zembowicz & Vane, PNAS, 89: 2051-55 (1992); with regard to heart failure, see Winlaw et. al., Lancet, 344: 373-4 (1994~ with regard to ulçeF~ive colitis~ see ~Bou~ton-Sm-~h e~. al.5 Lancet 342: 338-40 (1993); and with regard to atherosclerosis, see White et. al., PNAS, 91: 1044-8 (1994); with regard to glomerulonephritis, see Muhl et. al., Br. J. Pharmcol., 112: 1-8 (1994); with regard to paget's e~e and osteoporosis, see Lowick et. al., J. Clin. Invest., 93: 1465-72 (1994) or Evans et al., Clin. Orthopaedics & Related Res., 312: 275-294 (1995); with regard to infl~mm~tory sequelae of viral infections, see Koprowski et. al., PNAS, 90: 3024-7 (1993); with regard to retiniti~7 see Goureau et. al., BBRC, 186: 854-9 (1992); with regard to oxidant in~ ced lung injury, see Berisha et. al., PNAS, 91, 744-9 (1994); with regard to eczema, see Ruzica, et al., J. Invest. Derm., 103, 395(1994); with regard to acute allograft rejection, see Devlin, J. et al., Transplantation, 58, 592-595 (1994); with regard to infection caused by invasive microorg~ni~m~
which produce NO, see Chen, Y. and Rosazza, J.P.N., Biochem. Biophys.
Res. Comm., 203:1251-1258(1994); and with regard to tumor growth, see Jenkins et al., PNAS, 92, 4392-4396 (1995).
The ph~rm~eutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~rm~eutically acceptable salt, thereof, and may also contain a pharm~c elltically acceptable carrier and optionally other therapeutic ingredients. The term "ph~rm~eutically acceptable salts" refers to salts prepared from ph~rm~ceutically acceptable non-toxic acids or bases including inorganic bases and organic bases. Salts derived from inorganic acids include alllminllm, ammonium, calcium, copper, ferric, ferrous, lil~liulll, m~gnesium, m~n~nic salts, m~ng~nous~ potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, m~gnesium, potassium, and sodium salts. Salts derived from ph~T rn~eutically acceptable organic non-toxic bases include salts of W O 97/16430 PCT~US96/17447-primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic arnines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- -dibenzylethylene~ min~--, diethyl~min~, 2-diethyl~minoethanol, 2-S dimethylaminoeth~n~-l, ethanolamine, ethylene~ min~, N-ethylmorpholine, N-ethylpiperidine, glllc~n~ine, glucos~mine, histidine, hyd~abamine~ isop~opylamine, lysine~ methylglllca~ e, moIE~holiIle, piperazine, piperidine, polyamine resins, procaine, purines, theol,r~ e, triethyl~mine, trimethyl~mine, L~ yl~min~., trometh~mine, and the 10 like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pha~naceutically acceptable salts.
The ph~ reutical compositions cont~ining the active ingredient of the instant invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be plep~ed 20 according to any method known to the art for the m~n~lf~c~ture of ph~ eutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and p~l~t~ble preparations. Tablets 25 contain the active ingredient in admixture with non-toxic ph~ ceutically acceptable excipients which are suitable for the manufacture of tablets. I~ese excipients may be for exannple, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; gran~ tin~ and ~ ntegrating agents, for 30 example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay ~ integration and absorption in the gastrointestinal tract and thereby provide a sllct~in~.rl action over a longer WO 97/16430 PCT~US96/17447-~ period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. I~ey may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control rele2se S Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for e~ample, calcium carbollate~ calcillm phosphate or kaolin$ or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium ~l~in~te, polyvinyl-pyrrolidone, gum tr~c~nth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hept~-lec~t-thylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be form~ ted by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, ses~me oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral W O 97/16430 PCT~US96/17~47-preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active 5 ingredient in admixture with a dispersing or wefflng agent, suspending agent and one or more preservatives. Suitable dispersing or wetting a~ents and suspçndimg agents are e~empli~ied by those ~eady mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The ph~ eutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occur~ing phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be form~ ted with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The ph~rm~ell~ical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. I~is suspension may be formlll~ted according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable L,l~a,ation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-but~ne diol.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be W O 97/16430 PCT~US96/17447-employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be ~flmini~tered in the form of a suppositories for rectal ~lmini~tration of the drug. These S compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary tempelalures but liquid at th~ rect3~ temperature and wil~ therefore melt in th~ rect~ to re~ea~e the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or 10 suspensions, etc., cont~ining the compound of Formula I are employed.
(Por purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 15 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, infl~mm~tion may be effectively treated by the ~-lmini.~tration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 20 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of ~1mini~tration. Por example, a form~ tion intended for the oral ~lrnini~tration of hnm~n~
25 may contain from 0.5 mg to 5 g of active agent compounded with an a~lc,~liate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 30 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general h~lth, sex, diet, time of ~(1mini.stration, W O 97/16430 PCT~US96/17447 -route of ~1mini.ctration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Assay Protocol for NOS activity NOS activity is measured as the formation of L-[2,3,4,5-3H~Citrulline from L-r2~3~4~s-3H~ inine~ The incubatic!n buf~er ~100 uL) contained; 100 mM TES, pH 7.5, 5 uM FAD, 5 uM FMN, 10 uM
BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ug/mL calmodulin (bovine), 1 uM L-Arg, 0.2 uCi L-[2,3,4,5-3H]Arg, and the inhibitor in aqueous DMSO (max. 5 %). The reaction is initi~ted by addition of enzyme. Incubations are performed at room temperature for 30 ..~ .les and stopped by the addition of an equal volume of quenching buffer consisting of 200 mM sodium citrate, pH 2.2, 0.02% sodium azide.
15 Reaction products are separated by passing through a cation exchange resin and qll~ntit~ted as cpm by scintill~tion colmtin~. Percent inhibition is calculated relative to enzyme incubated without inhibitor according to:
% inhibition = 100 x (cpm L-t2,3,4,5-3H]Cit with inhibitor / cpm L-[2,3,4,5-3H~Cit without inhibitor).
Illustrative of the utility of the compounds of Formula I is the ability of such compounds to inhibit NO synthase as shown in Table 1 and as measured by the assay described above:
-WO 97/16430 PCT~US96/17447-~ Table 1. Inhibition of Nitric Oxide Syn~ase Isozymes Example iNOS ecNOS ncNOS
Number (Icso~ uM) (Icso~ uM) (ICso~ uM) ~50 >50 >50 2 <10 >10 <10 3 ~5(~ ~5~ ~ ~0 4 <l <50 <10 > 50 > 50 > 50 6 <l0 <l0 <l 7 <10 <10 <l 8 >50 >50 >50 9 <l >50 <50 < 50 > 50 > 50 11 <1 >50 <10 12 > 50 < 50 < l0 13 <1 <10 <10 14 <1 <50 <l0 <1 >50 <10 16 <1 <50 <l0 17 >50 >50 >50 18 <1 <10 <1 19 <10 <50 <10 <50 >50 >50 -W O 97/16430 PCT~US96/17447 -Methods of Synthesis The compounds of the present invention can be prepared according to the following methods.
5 Scheme 1.
Ph ~oc H
(~ a ~ ~) b, ~ c H N H
O O O
A ~
Boc Boc H
d ~) e N H H
D ~ E
Reaction conditions:
a) H2 40 psi, Pd(OH)2/C, EtOH, HOAc, 4 hr; b) (t-C4HsO2C)20, NaCI, NaOH, CHCI3, reflux, 4hr; c) (CH3)30BF4, CH2CI2, RT, overnight; d) NH4CI, EtOH, reflux, 4 hr; e) HCI, ethyl acetate, RT, overnight.
As shown in Scheme 1, hexahydro-1-(phenylmethyl)-(SH)-1,4-diazepin-5-one A (prepared as described by T. Irikura, CAS
84:31153r, 83:179149u) is reacted under hydrogen atmosphere at 40 psi in the presence of palladium hydroxide catalyst in e~anol and acetic acid to give hexahydro-SH- 1,4-diazepin-5-one B as the acetic acid salt.
Reaction with di-t-butyl dicarbonate in the presence of sodium chloride and sodium hydroxide gives 1-(tert-butyloxycarbonyl)-hexahydro-(5H)-. CA 02234641 1998-04-09 W O 97/16430 PCTrUS96/17447 -1,4-diazepin-5-one C. The imino ether D is formed from C by reaction with Meenvein's salt (trimethyloxonium fluoroborate). The amidine E is obtained by reaction of D with ammonium chloride in refluxing ethanol.
The amine protecting group in E is removed by reaction with hydrogen 5 chloride in ethyl acetate to give the desired amidine F as the dihydrochloride salt.
Scheme 2 a H H
A S NH HCI
Reaction conditions:
a) NH3, HgCI2, THF
An alternative preparation of the ~mi~1inP functionality is shown in Scheme 2. A thioamide A is reacted directly with ammonia in the presence of mercuric chloride to give the 5-imino-1,4-diazepine B.
CA 02234641 l99X-04-09 W O 97/16430 PCT~US96/17447-Scheme 3 when X = S
H
O N~ O
OH
A ~ C
~/when X = O
~-~? d ~
S NH HCI
D E
Re~.:tiG, I co, l~liliol)s:
a) NH20H - HCI, NaOH, EtOH; b) n-BuLi, TsCI; Et3N, aq.
dioxane; c) Lawesson's reagent, tol, 90~C; d) Me30BF4, iPr2NEt, CH2CI2; NH4CI, EtOH, reflux 1,4-Oxa- and thiazepine analogs are prepared by 5 methodology outline in Scheme 3. A ketone derivative A is converted to its corresponding oxime B by reaction with hydroxyl~mint~ in ethanol.
Ring expansion of B via a Beckm~nn rearrangement of the O-tosyl-oxime formed by reaction of ~ with with butyl lithium and p-toluenesulfonyl chloride gives hexahydro-1,4-heteroazepin-5-one C.
10 When X = S, the amide in C is converted to the thioamide D by reaction with Lawesson's reagent. Reaction of D with Meer~,veinls salt to form the imino-thioether followed by reaction with ammonium chloride gives the hexahydro-5-imino-1,4-heteroazepine E. Alternatively, when X = O in C, reaction with Meerwein's salt followed by ammonium chloride gives E
15 directly.
~ 29 ~
Scheme 4 RO2C RO2C~ CO2R ~ Co2R
O O
A B
¦ d where R2 = H ¦ c ~R3 [~X CO2R
O O O
E E D
N'OH O O
Q H
~h,i\~
R2 ~ ~ 2 J K
Reaction con.lilions:
a) NaOR, Et2o; b) MnO2, CHC13, reflux, c) Cu212, (R2)Li, CH3SCH3, d) NaH
(R3~X, DMF; e) when R = al!yl, (Ph3P)4Pd(o)~ rllo~ e, THF; f) H2NOH - HCI, NaOH, EtOH; g) n-BuLi, Tsc~l, ~t20; Et3N aq. dioxane- h) Lav.e.,son's ,~agenl, separate po-ciilional isomers; i) Me30gF4, iPr2NEt, CH2CI2; NH4CI, EtOH.
More highly substituted hexahydro-5-imino- 1,4-5 heteroazepines may be prepared according to methodology olltlin.o.-l in Scheme 4. Diester ~ is cyclized via a Dieckm~nn condensation to keto-ester B. Treatment of B with a strong base such as sodium hydride followed by addition of an aLkylating agent such as n-propyl iodide will give E (where R2 is hydrogen and R3 is n-propyl). Alternatively, keto-ester ~ may be oxidized by m~n~nese dioxide to form the a,~-S lm~ lrated keto-ester C. A substituent R2 is introduced via a Michael reaction with an organo-cuprate reagent to form I~. Alkylation of P with (R3)X in the presence of a strong base will form E (R~ and R3 are not hydrogen). Deesterification-decarboxylation of E will form E. By procedures outlined in Scheme 3, F is converted to ~mi~les H and I via 10 Beckm~nn rearrangement of oxime G. Since the Beckm~nn rearrangement can occur with migration to either side of the oxime, the two amides H and I may be formed. These amides H and I may be separated chromatographically at this point or, ~ltem~tively, may be subsequently converted to their respective thioamides by reaction with 15 Lawesson's reagent and then separated. Reaction of the thio~mi~es from H and E with Meerwein's salt followed by treatment with ammonium chloride will give substituted hexahydro-5-irnino-1,4-heteroazepines 1 and K. When X is nitrogen, a a~p.~pliate amine protecting group (eg., tert-butyloxycarbonyl) may be employed in the reaction sequence.
W O 97/16430 PCTrUS96/17447 -Scheme 5 Rz ~OH R2~~H R2 a b ~ ~ c,d . N--Boc R3~ NH2 R3~--N--Boc R3 E~ ~
X C 02H R3X ~ f R3 N H2 HCI N ~
o ~2 E
R~S ~ R~S
S NH HCI
E G
Reaction conditions:
a) (t-C4Hg0)2CO, NaHCO3, CH2CI2; b) Ph3P, (i-C3H702C)2N2,THF;
C) HS(CH2)2C O2H~ CsCO3, DMF; d) HCI, EtOAc;
e) 1-ethyl-3-(~dimethylaminopropyl) carbodiimide, 1 -hydroxy-7-azaben~ul, - 'e, N-methyl" ,o"~holine;
f) Lawesson's reagent, tol, 90~C; g) Me30BF4, (i-C3H7)2NC2H5, CH2CI2;
h) NH4CI, EtOH, reflux .
S More highly substituted hexahydro-5-imino-1,4-heteroazepines may also be prepared according to methodology olltlinP-l in Scheme 5. Briefly, the amine functionality in aminoalcohol A is protected to give B. Mitsunobu conditions will cyclize B to form aziridine C. The aziridine ring in C is opened wi~ ,B-mercaptopropionic acid followed by treatment with hydrochloric acid in ethyl acetate to yield W O 97/16430 PCT~US96/17447 -amino acid D. Reaction of D under st~n-l~rd peptide bond forrninp reactions gives lactam E. Reaction with Lawesson's reagent gives the thiol~ t~m F which is converted to 5-imino-1,4-thiazepine Gby previously described conditions.
The invention will now be illustrated by the ~ollowing non-limiting examples in wh;ch, unless state~ otherwise:
all operations were carried out at room or ambient 10 ternpel~lu~c;, that is, at a temperature in the range 18-25~C; evaporation ofsolvent was carried out using a rotary evaporator under re~ ce~l pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60~C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points 15 are uncorrected and 'd' indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with di~er~llt melting points in some p,~al~Lions; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, 20 nuclear magnetic resonance (NMR) spectrometry or microanalytical data;
yields are given for illustration only; when given, NM~ data is in the form of delta (~) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 400 MHz or 500 MHz using the indicated solvent;
25 conventional abbreviations used for signal shape are: s. singlet; d.
doublet; t. triplet; m. multiplet; br. broad; etc.: in addihon "Ar" .si~nifies an aromatic signal; chemical symbols have their usual mÇ~ning.~; the following abbreviations have also been used v (volume), w (weight), b.p.
(boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g 30 (gram(s)), mg (milligrarns(s)), mol (moles), mmol (millimoles), eq (equivalent(s)) .
W O 97/16430 PCT~US96117447 -N ~
Hexahydro-5-imino-( lH)- 1.4-diazepine dihydrochloride.
S Step A: Hexahydro-(5H)-1.4-diazepine-5-one acetic acid salt.
l-Benzylhexahydro-(5H)-1,4-diazepine-5-one (1.5 g, 7.34 mmol) was dissolved in 12 mL of ethanol and 6 mL of acetic acid. After addition of 150 mg of 20% p~ ium hydroxide on carbon, the mixture was shaken under 40 psi of hydrogen for 4 h. The resulting mixture was centrifuged and the supern~t~nt was filtered through a 0.45 micron membrane filter.
The catalyst was washed with ethanol (3 x 10 mL), and the combined filtrate was conce~ ted in vacuo to give a yellow oil which began to crystallize. Swirling with 2 mL of methanol and 1 mL of ethyl acetate facilitated the cryst~lli7~tion, and evaporation of the solvent in vacuo gave 1.23 g (96%) of hexahydro-(5H)- 1,4-diazepin-5-one acetic acid salt as light yellow crystals.
lH NMR (400 MHz, CD30D): o 3.44-3.40 (m, 2H), 3.19-3.15 (m, 2H), 3.15-3.11 (m, 2H), 2.74-2.70 ( m, 2H), 1.94 (s, 3H).
Mass spectrum: m/z = 115 (M+l, 100%).
Step B: l-(tert-Butoxycarbonyl)hexahydro-(5H)-1~4-diazepin-5-one.
A mixture of hexahydro-(5H)- 1,4-diazepin-5-one acetic acid salt (200 mg, 1.15 mmol), di-tert-butyldicarbonate (277 mg, 1.27 mmol) and sodium chloride (460 mg, 7.93 mmol) in 2.0 mL of chloroform was stirred and 2.5 N aqueous sodium hydroxide (460 uL, 1.15 mmol) was le~l The mixture was heated to reflux for 4 h, and then extracted with 3xlO mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, ~lec~nt~-1 and evaporated in vacuo to give 219 mg (89%) of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one as a white solid.
lH NMR (400 MHz, CD30D): ~ 3.60-3.53 (m, 4H), 3.28-3.25 (m, 2H), 2.61-2.56 (m, 2H), 1.47 (s, 9H).
Mass spectmm: m/z = 215 (~+1~ 100%).
Anal. calcd for CloH18N203: C, 56.32; H, 8.04; N, 13.14. Found: C, 55.92; H, 8.48; N, 13.00.
Step C: l-(tert-Butoxycarbonyl)-2.3~6~7-tetrahydro-5-methoxy-(lH)-1~4-diazepine.
Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of l-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl ~cet~t~ The organic layer was separated and the aqueous layer was extracted with 3 x 10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85~) of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-S-methoxy-(1H)-1,4-diazepine as a yellow liquid.
lH NMR(400 MHz, CD30D): ~ 3.58 (s, 3H), 3.53-3.45 (rn, 6H), 2.63-2.59 (m, 2H), 1.46 (s, 9H).
Mass spectrum: m/z= 129.
Step D: 1 -(tert-Butoxycarbonyl)-hexahydro-S-imino-( lH)- 1 diazepine hydrochloride .
W O 97/16430 PCT~US96/17447-- A mixture of l-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-metho~y-(lH)-1,4-diazepine (170 mg, 0.75 mmol) and ammonium chloride (40.1 mg, 0.75 mmol) in 2.0 mL of anhydrous ethanol was refluxed for 3 h. The solvent was then removed in vaCuo and residue was lli~ulated with 3 x 10 S mL of ether to give 174 mg of 1-(tert-butoxycarbonyl)-hexahydro-5-imino-(1H)-1,4-diazepine hydrochloride as a light yellow solid.
lH NMR (400 MHz,CD30D): o 3.71-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.55-3.50 (m, 2H), 2.90-2.86 (m, 2H), 1.47 (s, 9H).
Mass spectrum: m/z = 214 (M+l, 100%).
Step E: Hexahydro-5-Imino-(1H)-1~4-diazepine dihydrochloride.
Hydrogen chloride gas (2.0 g, 55 mmol) was bubbled into 15 mL of ethyl ~ret~t~ at 0 ~C over 3 min. 1-(tert-Butoxycarbonyl)-5-iminohexahydro-(1H)-1,4-diazepine hydrochloride (85 mg, 0.34 mmol ) was added and mixture was stirred at room overnight. Removal of solvent and hydrogen chloride in vacuo gave 60 mg (95%) of hexahydro-5-imino-(1H)-1,4-diazepine dihydrochloride as a yellow solid.
lH NMR (400 MHz, CD30D): o 3.84-3.80 (m, 2H), 3.55-3.50 (m, 2H), 3.43-3.39 (m, 2H), 3.21-3.16 (m, 2H).
Mass spectrum: m/z = 114 (M - 2HCl + 1, 100%).
Anal. calcd for CsH13N3Cl2: C, 32.27; H, 7.04; N, 22.58; Cl, 38.10.
Found: C, 32.09; H, 7.04; N, 21.67; Cl, 38.05.
FX~MPLE 2 H~
NH HCI
Hexahydro-5 -imino- 1.4-thiazepine hydrochloride Step A: 4-Oximino-tetrahydrothio~yr~ll To a stirring solution of solution of tetrahydrothiopyran-4-one (4.9 g, 42.1 mmol) and hydroxyl~rnin~ hydrochloride ~5.9 g~ 84 mnnol~ in 35 mlL
of ethanol at 0 ~C was added a solution of sodium hydroxide (3.38 g, 84.5 mmol) dissolved in 13 mL water. The reaction mixture was warmed to room temperature and stirred for an additional 2 h. The ethanol was removed in vacuo and the aqueous solution extracted with ether (2 X 250 mL). The etheral layer was washed with with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give crude oxime which was recryst~lli7e~1 lS from hexane/ether to give 4. 66 g of 4-oximino-tetrahydrothiopyran.
IH NMR (500 MHz, CDCl3): o 9.43 (brs, lH), 2.86 (m, 2H), 2.78(m, 2H), 2.73 (m, 2H), 2.56 (m, 2H).
13C NMR (125 MHz, CDC13): o 158.24, 33.94, 29.75, 28.38, 26.78.
Step B: Tetrahydro-(2H)-1.4-thiazepin-S-one To a solution of 4-oximino-tetrahydrothiopyran (1.0 g, 7.6 mmol) in 20 mL of dry ether under nitrogen atmosphere at 0 ~C was added n-butyllithium (S.0 mL of a 1.6 M solution in hexane, 8.0 mmol). The resulting white suspension was stirred at 0 ~C for one hour at which point a solution of p-toluenesulfonyl chloride (1.52 g, 8.0 mmol) in 10 mL
ether was added and the reaction mixture stirred for 4 h at 5 ~C. The solvent was removed in vacuo and then the residue was treated with 20 mL of 70% dioxane cont~ining five drops of trie~ylamine and stirred for 24 h at room temperature. The solvent was removed in vacuo and the residue was extracted with methylene chloride. The methylene chloride layer was washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and W O 97/16430 PCT~US96/17447 -- the product purified by flash column chromatography on silica gel eluted with hexane/ethyl acetate (7 :3) to give 0.13 g of hexahydro-(1H)-1,4-thiazepin-5-one.
S lH N~IR (S00 MHz, CDCl3): o 6.92 (brs, lH), 3.61 (m, 2H), 2.92(m, 2H), 2.74 (m, 2H), 2.70 (m, 2H).
13C NMR (125 I~HZ;t CDC13 ): ~ 177~76, 45.88, 40.95, 31 54, 24~61.
Step C: Tetrahydro-(2H)-1 ~4-thiazepin-S-thione To a solution of tetrahydro-(2H)- 1,4-thiazepin-S-one (0.335 g, 2 mmol) in S mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide]
(0.971 g, 2.4 mmol) and the mixture was stirred at 90~C for 30 mins.
lS Evaporation of the solvent in vacuo followed by purification by flash column chromatography on siIica gel eluted with methylene chloride:
ethyl acetate (19: 1) gave 0. 365 g of tetrahydro-(2H)-1,4-thiazepin-S-thione.
lH NMR (500 MHz, CDC13): o 9.19 (brs, lH), 3.80 (m, 2H), 3.44 (m, 2H), 2.78 (m, 2H), 2.71 (m, 2H).
13C NMR (125 MHZ, CDCl3 ): ~ 208.90, 50.39, 49.02, 29.54, 25.86.
Step D: Hexahydro-S-imino-1.4-thiazepine hydrochloride To a solution of tetrahydro-(2H)-1,4-thiazepin-S-thione (90 mg, O.S
mmol) in 2 mL of dry methylene chloride at room temperature was added trimethyloxonium tetrafluoroborate (Meerwein's salt) (88 mg, 0.6 mmol) followed by diisopropylethyl~min~ (77 mg, 0.6 mmol). The resulting mixtllre was stirred at room temperatere for 2 h. The methylene chloride layer was washed with water, saturated sodium chloride solution and ~ dried over anhydrous m~gnesium sulfate. The solvent was rernoved in vacuo to give the crude imino-ether which was subsequently treated with ammonium chloride (0. 017 g) in 3 mL of ethanol and h~te-l at 80 ~C for WO 97/16430 PCT~US96/17447-15 h. Evaporation of ethanol followed by trituration of the oil with ethyl acetate and ether gave 53 mg of hexahydro-5-imino-1,4-thiazepine hydrochloride as a white solid.
IH NMR (500 MHz, D2O): ~ 3.81 ( m, 2H), 3.11 (m, 2H), 2.84 (m, 2H), 2.76 (m, 2H).
13C NM:R (125 MHz5 D20?: ~i 46 88~ 35r52~ 28 847 23 74 Mass spectrum: m/z--131 (M~l).
N ~
NH HCI
Hexahydro-S-imino-1.4-oxazepine hydrochloride.
Step A: 4-Oximino-tetrahydropyran Employing the procedure described in F.x~rnple 2, step A, tetrahydropyran-4-one was converted to 4-oximino-tetrahydropyran.
IH NMR (500 MHz, CDC13): ~ 3.82 (m, 2H), 3.77 (m, 2H), 2.68 (m, 2H), 2.39 (m, 2H).
Step B: Tetrahydro-(2H)-1.4-oxazepin-5-one Employing the procedure in Example 2, step B, 4-oximino-tetrahydropyran was converted to tetrahydro-(2H)-1,4-oxazepin-5-one.
WO 97/16430 PCT~US96/17447 -- lH NMR (500 MHz, CDC13): ~i 7.07 (brs, lH), 3.79 (m, 2H), 3.75(m, 2H), 3.34 (m, 2H), 2.69 (m, 2H).
13C NMR (125 MHZ, CDC13): ~ 177.94, 71.61, 65.52, 44.74, 41.01.
5 Step C: Hexahydro-5-imino-1.4-oxazepine. hydrochloride Fmploying the procedure in Example 2y step ~ tetr~d~ 2~1,4-oxazepin-5-one was reacted with Meerwien's salt and ammonium chloride to form hexahydro-5-imino-lH-1,4-oxazepine, hydrochloride.
lH NMR (500 MHz, D2O): o 3.89 ( m, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 2.96 (m, 2H).
3C NMR (125 MHz, D2O): o 69.54, 64.92, 46.12, 35.42. MS: m/z =
115.1 (M+).
(~
H
NH HCI
Hexahydro-5-imino-3-propyl-1.4-thiazepine hydrochloride.
Step A: Tetrahydrothiopyran-4-one-3-carboxylic acid~ allyl ester.
A mixture of 3,3'-thiodi~ ionic acid (17.82 g, 10 mmol), allyl alcohol (20.4 mL, 30 mmol) and p-toluenesulfonic acid (0.750 g) in 100 mL of toluene was refluxed for 8 h in a Dean-Stark apparatus to azeotropically remove water. The reaction mixture was quenched with saturated solution of sodium bicarbonate and the toluene layer was se~al~led and washed with saturated sodium chloride solution and dried over anhydrous m~gn~.sium sulfate. The solvent was removed in vacuo and gave approxim~t~ly 20 g of crude 3,3'-thiodi~r~ionic acid, diallyl ester. This material was suf~lciently pure by NMR and was used in the subsequent reaction.
s To a ~ixl~le of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL
of dly ether at r~om temperatllre was added allyl ?llcohol (2.25g, 38.7 mmol) in a dlo~vise m~nner. The result~nt mixture was stirred for 15 min. A solution of 3,3'-thiodipropionic acid, diallyl ester (S.0 g, 19.3 10 mmol) in 10 mL ether was slowly added and the mixture refluxed for S h.
The reaction was cooled to room temperalule and then quenched with water and the pH adjusted to 4 with lN HCl. The e~er layer was separated and the aqueous layer was extracted with e~er (2 X 100 mL).
The combined etheral layer was washed with sautrated sodium chloride 15 solution and dried over anhydrous m~gnPsium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (9: 1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
lH NMR (S00 MHz, CDC13): ~ 12.48 (s, lH), 5.95 (m, lH), 5.35 (m, 2H), 4.68 (m, 2H), 3.38 (s, 2H), 2.78 (t, J--6 Hz, 2H), 2.60 (t, J = 6.1 Hz, 2H).
13C NMR (125 MHZ, CDC13): o 172. 80, 131.91, 118.48, 65.32, 30.95, 24.75, 23.58.
Step B: 3-Propyl-tetrahydrothiopyran-4-one-3-carboxylic acid. allyl ester.
A solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (1.0 g, 5 mmol) in 1 mL of dimethylform~mi~le was added to a stirred mixture of sodium hydride (60% in oil, 0.22 g, 5.5 mmol) and l-iodopropane (0.934 g, 5.5 mmol) in 2.5 mL of dimethylform~mide at 0 ~C. The reaction mixture was warmed to room temperature and stirred overnight.
The reaction mixture was diluted with water and extracted with ether.
- The etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (19 :1) to give 0.277 g of 3-propyl-S tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
lH NMR (500 MHz~ CDCl~ 5.93 (m, lH)~ 5.27-5.38 ~m, 2H,), 4.70(m, 2H), 3.33-2.73 (m, 6H), 1.96-1.20(m, 4H), 0.93 (t, J = 6.3 Hz, 3H).
lO 13C NMR (125 MHZ, CDC13): ~ 205.44, 170.83, 131.36, 119.10, 66.05, 63.14, 43.33, 38.66, 36.66, 30.93, 18.01, 14.48.
Step C: 3-Propyl-tetrahydrothiopyran-4-one.
15 To a stirred solution of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.272 g, 1.1 mmol) in 5.0 mT . dry tetrahydrofuran at room temperature was sllcces.cively added morpholine (0.979 g, 1.12 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.055 mmol). Stirring was contimle~l until the thin layer chromatography 20 indicated the completion of reaction at which point the reaction mixture was evaporated and the crude product was purified by flash column chromatography on silica gel eluted eluted with hexane: ether (19: 1) to give 0.163 g of 3-propyl-tetrahydrothiopyran-4-one.
lH NMR (500 MHz, CDC13): ~ 3.02-2.94 (m, 7H), 1.88-1.29 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHZ, CDC13): o 210.61, 52.77, 43.82, 35.92, 31.58, 31.06, 20.19, 14.13.
Step D: 4-Oximino-3-propyl-tetrahydrothiopyran.
Employing the procedure described in Example 2, step A, 3-propyl-tetrahydrothiopyran-4-one was reacted with hydroxyl~n~ine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
Step E: Tetrahydro-3-propyl-(2H)-1.4-thiazepin-5-one and S tetrahydro-6-propyl-(2H)- 1.4-thiazepin-5-one.
Employin~s thç procedllre described in E~ample 2, s1ep B,4-oximino-3-propyl-tetrahydrothiopyran was converted to a 3: 1 mixture of tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-one and tetrahydro-6-propyl-(2H)-1,4-10 thiazepin-5-one.
Step F: Tetrahydro-3-propyl-(2H)-1.4-thiazepin-5-thione.
Employing the procedure described in Example 2, step C, the mixtllre of 15 tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-one and tetrahydro-6-propyl-(2H)- 1,4-thiazepin-5-one was reacted with Lawesson's reagent to yield the corresponding thio~n~icles. The 3-n-propyl isomer was isolated and puri~led by flash column chromatography on silica gel eluted with methylene chloride: hexanes (1:1) to yield tetrahydro-3-propyl-(2H)-1,4-20 thiazepin-5-thione as a single compound.
H NMR (500 MHz, CDC13): o 8.06 (brs, lH), 3.95 (m, lH), 3.58 (m, lH), 3.30 (m, lH), 2.85 (m, lH), 2.73 (m, 2H), 2.56(m, lH), 1,71-1.42 (m, 4H), 0.97 (t, J = 7.3 Hz, 3H).
25 13C NMR (125 MHZ, CDC13): o 208.08, 61.95, 48.61, 37.70, 34.41, 25.75, 19.24, 13.68.
Step G: Hexahydro-5-imino-3-propyl-1.4-thiazepine hydrochloride.
30 Employing the procedure described in Example 2, step D, tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-thione was reacted with Meerwein's salt and ammonium chloride to yield hexahydro-5-imino-3-propyl- 1,4-thiazepine, hydrochloride.
W O 97/16430 PCT~US96/17447 -H NMR (500 MHz, CD30D): ~ 3.93 ( m, 2H), 3.23-2.62 (m, 6H), 1.68-1.47(m, 4H), 0.98 (t, 3H, J = 7 Hz).
~ 13C NMR (125 MHZ, CD30D): o 170.96, 58.65, 36.54, 34.99, 34.10, 23.36, 18.87, 12.68. MS: m/z = 173.1 (M+l).
s NH ~
NH HCI
Hexahydro-5-imino-6-propyl-1.4-thiazepine hydrochloride.
The 6-propyl thio~mitle isomer isolated from Example 4, Step F was 15 reacted with Meerwein's salt and ammonium chloride according to the procedure described in Example 2, Step D to yield hexahydro-5-imino-6-propyl-1,4-thiazepine, hydrochloride.
lH NMR (500 MHz, CD30D) 3.75 (m, 2H), 3.18 (m, lH), 2.95 (dd, lH), - 20 2.82 (m, lH), 2.73 (m, 2H), 1.87 (m, 2H), 1.50 (m, lH), 1.39 (m, lH), 0.99 (t, 3H).
Mass spectrum: m/z = 173 (M+l) ~S ~CH3 H~
NH HCI
WO 97/16430 PCT~US96/17447 -Hexahydro-5-imino-7-methyl-l.~thiazepine hydrochloride.
Step A: 2.3-Dihydrothiopyran-4-one-3-carboxylic acid. allyl ester.
s To a solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester ~E~ample 4~ step A) (2.:~ g, 11 5 mmol,~ in lOQ ~l, dr~ chlorQform at room temperature was added activated m~ng~nese dioxide (10 g, 115 mmol) and the resulting mixture was refluxed for S h. The reaction 10 mixture was filtered and evaporated. The the rem~ining residue was purified by flash column chromatography on silica gel eluted with hexane : ethyl ~et~te (7 :3) to give 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.988 g).
lH NMR (500 MHz, CDC13): o 8.49 (s, IH), 5.97 (m, iH), 5.41-5.25 (m, 2H), 4.70 (m, 2H), 3.29 (m, 2H), 2.82 (m, 2H).
3C NMR (125 MHZ, CDCl3): o 189.26, 162.68, 156.42, 131.97, 125.20, 118.61, 65.75, 37.83, 27.29.
Step B: 2-Methyl-tetrahydrothio~yl~u.-4-one-3-carboxylic acid. allyl ester.
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide / 4.0 mL dimethylsulfide and 4.0 mL
methyllithium/ether at -78 ~C) at -78 ~C was added a solution of 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.61~nol) in ~lim~tllyl~lllfitle (5 mL). The resulting yellow-colored solution was sitrred for 30 min. at the same temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperature for and 1 h. The reaction mixtllre was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous m~ sium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane: ether (4: 1) to -W O 97/16430 PCT~US96/17447-~ give 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol: keto tautomers.
lH NMR (S00 MHz, CDC13): ~ 12.67 (s, lH), 5.94 (m, lH), 5.35-5.27 S (m, 2H), 4.70 (m, 2H), 3.09-2.50(m, 6H), 1.52 (d, J = 6.9 Hz, 3H).
13C NMR (125 MHZ, CDCl3): ;j 173. 02, 131.86, 119.50, 66.71, 65.33, 42.66~ 30~767 ?3~9~S7 20.02 Step C: 2-Methyl-tetrahydrothiopyran-4-one Employing the procedure described in Example 4, step C, 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester was decarboxylated to form 2-methyl-tetrahydrothiopyran-4-one.
lS Step D: Hexahydro-S-imino-7-methyl-1.4-thiazepine hydrochloride.
Employing the procedures described in Fx~n~ple 4, steps D through G, 2-methyl-tetrahydrothiopyran-4-one was converted to hexahydro-S-imino-7-methyl-1,4-thiazepine, hydrochloride lH NMR (S00 MHz, D20): ~ 3.78 (d, lH, J = lS Hz), 3.62 (dd, lH, J =
lS, 7 Hz), 3.05 (m, 2H), 2.87 (m, 2H), 2.10 (m, lH), 1.21 (d, 3H, J = 7 Hz).
13C NMR (125 MHz, CD30D): ~ 51.87, 36.76, 34.73, 22.12, 17.34.
Mass spectrum: m/z = 145.1 (M+l).
and hexahydro-S-imino-2-methyl-1,4-thiazepine hydrochloride (see Fx~n~ple 7).
CA 02234641 l99X-04-09 W O 97/16430 PCT~US96/17447-CH
N
NH HCI
~lexahydro-~-iminQ-2-rnethyl- 1.4-thiazepine hydrochloride.
5 Hexahydro-5-imino-2-methyl- 1,4-thiazepine hydrochloride was prepared according to the procedures described in Example 6.
lH NMR (500 MHz, CD30D): ~ 3.80 (ABq, 2H), 3.30 (m, lH), 3.12 (m, 2H), 2.80 (ABq, 2H), 1.39 (d, 3H, J = 7 Hz).
lO 13C NMR (125 MHz, CD30D) ~ 46.62, 42.25, 32.51, 28.01, 20.26.
Mass spectrum: m/z = 145.2 (M+l).
E~AMPLE 8 H ( NH HCI
Hexahydro-5-imino-6-(3-methyl-2-n-butenyl)- 1.4-thiazepine hydrochloride.
Employing the procedures described in Fx~mrle 4, but sub~ u~ g l-bromo-3-methyl-2-n-butene for l-iodopropane in step B, the 6-positional isomer was separated from the 3-positional isomer (see Fx~mrle 9) as its respective thioamide by flash column chromatography .
25 Subsequently, reaction with Meerwein's salt and ammonium chloride as W O 97/16430 PCT~US96/17447-described in Fx~mple 2, step D gave hexahydro-5-imino-6-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): ~ 5.10 (m, lH), 4.15, (m, lH), 3.79 (m, lH), 1.75 (s, 3H), 1.71 (s, 3H).
Mass spectrum: m/z = 199.2 (M+l).
S
~N ~
NH HCI
Hexahydro-5-imino-3-(3-methyl-2-n-butenyl)- 1.4-thiazepine hydrochloride.
Employing the procedures described in Ex~mple 4, but substituting l-bromo-3-methyl-2-n-butene for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 8) by flash column chromatography as its respective thio~mide.
20 Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 5.17 (br t, lH), 3.96 (ABq, 2H), 3.22 (m, lH), 3.09 (m, lH), 2.45 (m, 2H), 1.75 (s, 3H), 1.70 (s, 3H).
13C NMR (125 MHZ, CD30D) o 118.04, 59.14, 35.09, 33.38, 32.93, 24.63, 23.36, 16.81.
Mass spectrum: m/z = 199.2 (M+l).
W O 97/16430 PCT~US96/17447 -NH~
NH HCI
s Hexahydro-5-imino-6-(2-methyl-propyl)-1~4-thiazepine hydrochloride Employing the procedures described in Example 4, but substihl1inp~
isobutyl iodide for l-iodopropane in step B, the 6-positional isomer was 10 separated from the 3-positional isomer (see Example 11) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Fx~mple 2, step D gave hexahydro-5-imino-6-(2-methyl-propyl)-1,4-thiazepine hydrochloride.
H NMR (500 MHz, CD30D): o 3.77 (t, 2H), 3.25 (m, lH), 2.95 (d of d, lH), 2.83 (m, lH), 2.73 (m, 2H), 1.87 (m, lH), 1.70 (m, 2H), 1.01 (d, 3H), 0.99 (d, 3H)-Mass spectrum: ~ = 187.2 FXAM[PLE 1 1 H
NH HCI
Hexahydro-5-imino-3-(2-methyl-propyl)-1.4-thiazepine hydrochloride W O 97/16430 PCT~US96/17447 -Employing the procedures described in Fx~mrle 4, but sub~ u~ g isobutyl iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 10) as its respective 5 thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Fx~mple 2, step D gave hexahydro-5-imino-?i-~2-methyl-propyl)-1i4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 3.95 (m, lH), 3.25 (m, lH), 3.10 (m, lH), 2.87 (m, lH), 2.80 (m, lH), 2.73 (d, lH), 2.65 (d of d, lH), 1.76 (m, lH), 1.69 (m, lH), 1.5 (m, lH), 0.98 (t, 6H) Mass spectrum: m/z = 187.2 ~H ~--NH HCI
Hexahydro-5 -imino-6-methyl- 1 ~4-thiazepine hydrochloride .
Employing the procedures described in Example 4, but sub~
methyl iodide for l-iodopropane in step B, the 6-positional isomer was 25 separated from the 3-positional isomer (see Example 13) as its respective thi~mide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-6-methyl- 1,4-thiazepine hydrochloride.
W O 97/16430 PCT~US96/17447-lH NMR (500 MHz, CD30D): ~ 3.78 (t, 2H), 3.4 (m, lH), 2.82 (m, 2H), 2.72 (m, 2H), 1.42 (d, 3H) Mass spectrum: m/z = 145.0 FxAMpLE 13 H ~
NH HCI
10 Hexa~ydro-5-imino-3-methyl-1.4-thiazepine hydrochloride.
Employing ~e procedures described in Example 4, but sub~
methyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 13) as its respective 15 thioamide by ~ash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-methyl- 1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 4.07 (m, lH), 3.19 (m, lH), 3.04 (m, lH), 2.80 (m, 2H), 2.69 (m, 2H), 11.39 (d, 3H) Mass spectrum: ~ = 145.1 H
NH HCI
Hexahydro-5-imino-3-ethyl-1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting ethyl 5 iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently? reaction witl~ eerwein's ~alt ~cl ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-ethyl-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 3.87 (m, lH), 3.23 (m, lH), 3.06 (m, lH), 2.80 (m, 2H), 2.64 (d of d, 2H), 1.75 (m, 2H), 1.04 (t, 3H).
Mass spectrum: m/z = 159.1 H
NH HCI
20 Hexahydro-5-imino-3-butyl-1.4-thiazepine. hydrochloride.
E~ploying the procedures described in Example 4, but sub~LiLuLhlg butyl iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column 25 chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-butyl-1,4-thiazepine, hydrochloride.
lH NMR (500 MHz, CD30D): ~ 3.90 (m, lH), 3.23 (m, lH), 3.02 (m, lH), 2.80 (m, 2H), 2.63 (d of d, lH), 1.70 (m, 3H), 1.40 (m, 4H), 0.94 (t, 3H)-Mass spectrum: m/z = 187.2 s H
NH HCI
Hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1 ~4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substitlltin~ 3-15 bromo-2-methylpropene for l-iodo~r~palle in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(2-methyl-3-propenyl)-1,4-thiazepine 20 hydrochloride.
lH NMR (500 MHz, CD30D): o 4.85 (s, lH), 4.75 (s, lH), 4.13 (m, lH), 3.28 (m, lH), 3.12 (m, lH), 2.88 (m, lH), 2.82 (m, lH), 2.78 (d, lH), 2.66 (d of d, lH), 2.45 (m, 2H), 1.78 (s, 3H).
25 Mass spectrum: m/z = 185.1 l--"'",~S~
(+) H ~
(~)-trans-Decahydro-4-imino-benzolbl-1.4-thiazepine acetic acid salt.
Step A: (+)-trans-2-(tert-Butoxycarbonylamino)-cyclohexanol To a vigoursly stirring solution of trans-2-aminocyclohexanol hydrochloride (5.5 g, 36 mmol) in 100 m L methylene chloride and saturated sodium bicarbonate solution (1: 1) at 0 ~C was added di-tert-butylcarbonate (13.09 g, 60 mmol). The resulting heterogeneous mixture wSle wa.r.mA.ed to the r~omA tem.pera~.lre a~,d s~ed o~er~ht ~le methylene chloride layer was washed with brine, dried and evoporated.
The solid obtained was triturated with hexane and filtered to give 5.86 g (96%) of (+)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol.
H NMR (500 MHz, CDC13): o 4.61(brs, lH), 3.27 (m, lH), 2.73 (brs, lH), 2.02-1.69 (m, 4H), 1,45 (s, 9H), 1.42-l.O9(m, 4H).
13C NMR (125 MHz, CDCl3): ~ 75.42, 56.62, 34.22, 31.84, 28.43, 27.48, 24.78, 24.11.
Step B: (+)-7-(tert-Butoxycarbonyl)-7-aza-bicyclo-r4.1.0l-cycloheptane To a stirring mixture of (+)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol ( 4.08 g, 20 mmol) and triphenylphosphine (10.49 g, 40 mmol) in 50 mL of tetrahydrofuran at 0 ~C was slowly added diisopropyl azodicarboxylate (8.08 g, 40 mmol). The reaction mixture was warmed to the room temperature and stirred until the TLC indicated the disappearence of the starting alcohol ( appro. 2- 4 hrs). The tetrahydrofuran was evaparated in vacuo and the crude product was O 97/16430 PCT~US96/17447-p~se~l through a silica gel column and eluted with hexane/methylene chloride (1:1) to give 3.18 g (85%) of the desired ~)-7-(tert-butoxycarbonyl)-7-aza-bicyclo-[4.1.0]-cycloheptane as an oil.
lH NMR (500 MHz, CDC13): ~ 2.55 (m, 2H), 1.93-1.75 (m, 4H), 1.45 (s, 9H), 1.44- 1.21 (m, 4H).
13C NMR (125 MHz. CDC13): o 80.62, 36.96? 28.04~ 23.80, 19.93.
Step C: (+)-trans-2-amino-1-r2-(carboxy)ethylthiol-cyclohexane hydrochloride ~t)-7-(tert-Butoxycarbonyl)-7-aza-bicyclo-[4.1.0]- cycloheptane (0.5 g, 2.68 mmol) was dissolved in 2 mL dimethylform~mide and ,B-mer~o~ ionic acid (0.318 g, 3 mmol). After the addition of cesium carbonate (1.95 g, 6 mmol), the mixture was stirred at 60 ~C until the TLC indicated the full con~u~ lion of starting m~teri~l (appro. 4 hrs).
The reaction mixture was diluted with water, the pH was adjusted to 4 (with 2.4 M HCl) and finally extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the crude (+)-trans-2-(tert-butocycarbonylamino)-1-[2-(carboxy)ethylthio]-cyclohexane, which was not purified but taken to the next stage.
The crude from the above was dissolved in 10 ml e~yl acetate saturated with hydrogen chloride and stir at room temperature. The white precipitate that resulted was filtered and dried under vacuo yielding 0.636 g of (+)-trans-2-amino-1-[2-(carboxy)ethylthio]-cycloht-x~n~.
lH NMR (500 MHz, D20): ~ 3.20 (m, lH), 2.81-2.65 (m, 3H), 2.24 (m, 2H), 1.79-1.2 (m, 8H).
Step D: (+)-trans-Decahydro-4-oxo-benzorb~ 4-thiazepine To (+)-trans-2-amino-1-[2-(carboxy)ethylthio]-cyclohexane hydrochloride (0.240 g, 1 mmol) dissolved in 2 mT of dimethylform~mide at 0 ~C was successively added 1-ethyl-3-(3-WO 97/16430 PCT~US96/17447-~ dinnethylaminopropyl) carbo~liimic1e (0.356 g, 1.2 mmol), 1-hydroxy-7-azabenzotriazole (0.164 g, 1.2 mmol) and then finally N-methylmorpholine (0.252 g, 2.5 mmol). After stirring for an additional S
mins., the reaction mixture was warmed to room temperature and stirred overnight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride.
T~e solvent layer W?lS ~ashed ~ith brine~ d~ied an~l evapor~tçd to giYe the crude which was purified by silica column and eluted with hexane/ethylacetate (7: 3 + 5% methanol) to give 0.102 g (55%) of (+)-trans-decahydro-4-oxo-benzo[b]-1,4-thiazepane as white solid.
1H NMR (500 MHz, CDCl3): o 5.66 (s, lH), 3.46 (m, lH), 2.98-2.64 (m, 5H), 2.05-1.74 (m, 4H), 1.39-1.21 (m, 4H).
13C NMR (125 MHz, CDCl3): ~ 175.94, 58.07, 46.78, 40.50, 33.77, 31.70, 25.32, 24,67, 24.52.
Step E: (+)-trans-Decahydro-4-thioxo-benzorb~ 4-thiazepine To a solution of (+)-trans-decahydro-4-oxo-benzo[b]-1,4-thiazepane (0.100 g, 0.54 mmol) in 5 mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (0. 328 g, 0.81 mmol) and the mixture was stirred at 90 ~C for 30 mins. Evaporation of the solvent in vacuo followed by purification by flash column chromatography on silica gel eluted with methylene chloride: ethyl acetate (19: 1) gave 0. 083 g (77%) of (+)-trans-decahydro-4-thioxo-benzo[b]- 1 ,4-thiazepine.
1H NMR (500 MHz, CDCl3): o 7.70 (brs, lH), 3.72 (m, lH), 3.65 (m, lH), 3.23 (m, lH), 2.96 (m, lH), 2.77-2.65 (m, 2H), 2.14-1.25 (m, 8H).
13C NMR (125 MHZ, CDCl3 ): ~ 63.26, 48.42, 44.43, 33.73, 31.41, 26.45, 25.06, 24.3 1.
Step F: (+)-trans-Decahydro-4-imino-benzolb1-1.4-thiazepine acetic acid salt.
= - =. .
To a solution of (+)-trans-decahydro-4-thioxo-benzo[b]-1,4-thiazepane (25 mg, 0.12 mmol) in 2 mL of dry methylene chloride at room tempeLaLule was added trimethyloxonium tetrafluoroborate (Meelweill's 5 salt) (24 mg, 0.16 mmol). I~e resulting mixt~re was stirred at roonn temperatere overni~ht The reaction mixture was quenched with saturated solution of sodium bica~orlate solution and stir for S mins. Tlle methylene chloride layer was washed with water, saturated sodium chloride solution and dried over anhydrous m~ne.sium sulfate. The 10 solvent was removed in vacuo to give the crude imino-ether which was subsequently treated with ammonium chloride (14 mg) in 4 mL of ethanol and heated at 80 ~C for 4 h. Evaporation of ethanol followed by purification by column chromatography and elution with acetonitrile:
water: acetic acid (90:5:5) gave 21.8 mg (+)-trans-decahydro-4-irnino-15 berlzo[b]-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, D20): ~ 3.68 (m, lH), 3.64 (m, lH), 3.26-2.83 (m, 4H), 2.06-1.23 (m, 8H).
13C NMR (125 MHZ, CDCl3 ): ~ 58.72, 45.32, 33.96, 31.85, 31,76, 20 25.00, 23.95, 21.47.
Mass spectrum: m/z = 185.1 (M+) H
Hexahydro-5-imino-3(S)-propyl-1~4-thiazepine~ acetic acid salt Step A: Tetrahydro-3(S)-propyl-(2H)-1.4-thiazepine-5-thione W O 97/16430 PCTrUS96/17447 -The title compound was prepared employing the procedure in Example 17, Steps A to E and starting from ~norvalinol instead of (+)-trans-2-aminocyclohexanol.
s Step B: Hexahydro-5-imino-3(S~-propyl-1.4-thiazepine acetic acid To a solution of tetrahydro-3(S)-propyl-(2H)-1,4-thiazepine-5-thione (42 mg, 0.22 mmol) in 5 mL tetrahy~lorLuan and saturated with ammonia gas at 60 ~C was added mercuric chloride (73.3 mg, 0.27 mmol). The stream of ammonia gas was bubbled for another 10 mins. at the same temperature. After stirrin~ for 2 h, the reaction mixture was filtered and the filtrate was evaporated. The crude compound was then purified by column chromatography and eluted with acetonitrile: water: acetic acid (90:5:5) giving 31.5 mg of hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, CD30D): ~ 3.93 ( m, lH), 3.30-2.61 (m, 6H), 1.72-1.40 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz).
13C NMR (125 MHZ, CD30D): ~ 58.58, 36.42, 34.95, 34.09, 23.33, 18.87, 12.61.
Mass spectrum: m/z = 173.1 (M+1).
(R)- S
H
Hexahydro-5-imino-3(R)-propyl-1.4-thiazepine acetic acid salt Step A: Tet~ahydro-3(R)-propyl-(2H)-1.4-thiazepine-5-thione The title compound was prepared employing the procedure in Fx~mple 17, Steps A-E and starting from D-norvalinol in~te~fl of (+)-trans-2-aminocyclohexanol.
Step B: Hexahydro-5-imino-3(R)-propyl-1.4-thiazepine acetic salt 10 Employing the procedure 19, step B, tetrahydro-3(R)-propyl-(2H)-1,4-thiazepine-5-thione (40 mg, 0.21 mmol) was converted to 37.4 mg of hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, CD30D): d 3.93 ~ m, lH), 3.29-3.02 (m, 2H), 2.87-15 2.61 (m, 4H), 1.73-1.41 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz). 13C NMR
(125 MHZ, CD30D): d 58.60, 36.43, 34.96, 34.10, 23.35, 18.87, 12.63.
Mass spectrum: ~ = 173.1 (M+l).
N ~
NH (HC1)2 Hexahydro-5-imino- 1 -methyl- lH- 1.4-diazepine hydrochloride.
Employing the method of Foloppe et al. (M.P. Foloppe, S. Rault, and M.
Robba, Tetrahedron Lett. 1992, 33, 2803-2804), a solution of hexahydro-l-methyl-(SH)-1,4-diazepin-5-thione (R. Guryn, Polish J. Chem. 1~87, 61, 259-262) (100 mg, 0.694 mmol) in tetrahydrofuran (5.0 mL) was W O 97/16430 PCTrUS96/17447 -_ 59 _ ~ warmed in a SS ~C oil bath as ammonia was bubbled into the solution.
Mercuric chloride (207 mg, 0.764 mmol) was added in one portion, and the mixture quickly became black. After 20 min, the introduction of ammonia was discontinued and the "~i x~ e was stirred at room S ternpera~ul~ for 1 h. The mixture was then centrifuged and the supern~t~nt was decanted. The pellet was resuspended in tetrahydrofuran (3 ml,~ ~ the mix1ure was centrifilged~ and the snpernat~nt was decanted.
This was repeated with 2 x 3 mL of tetrahydrofuran and then 3 x 3 mT . of methanol. The methanol extracts were combined, filtered through a 0.45 10 micron membrane, and evaporated to give 131 mg of white solid. Based on the combustion analysis for carbon, this material contained 92 mg (82% yield) of hexahydro-5-imino- 1 -methyl-( lH)- 1,4-diazepine hydrochloride salt.
lS lH NMR (400 MHz, CD30D): o 3.56-3.52 (m, 2H), 2.88 (dd, 2H, J = 6 Hz, 3 Hz), 2.79-2.71 (m, 2H), 2.71-2.63 (m, 2H), 2.43 (s, 3H).
Mass spectrum: m/z = 128 (M - HCl + 1).
Anal. calc'd. for C6H14N3Cl-1.23 NH4Cl: C, 31.1; H, 8.40; N, 25.5;
Cl, 34.1. Found: C, 31.08; H, 8.16; N, 23.41; Cl, 34.06.
~ 29 ~
Scheme 4 RO2C RO2C~ CO2R ~ Co2R
O O
A B
¦ d where R2 = H ¦ c ~R3 [~X CO2R
O O O
E E D
N'OH O O
Q H
~h,i\~
R2 ~ ~ 2 J K
Reaction con.lilions:
a) NaOR, Et2o; b) MnO2, CHC13, reflux, c) Cu212, (R2)Li, CH3SCH3, d) NaH
(R3~X, DMF; e) when R = al!yl, (Ph3P)4Pd(o)~ rllo~ e, THF; f) H2NOH - HCI, NaOH, EtOH; g) n-BuLi, Tsc~l, ~t20; Et3N aq. dioxane- h) Lav.e.,son's ,~agenl, separate po-ciilional isomers; i) Me30gF4, iPr2NEt, CH2CI2; NH4CI, EtOH.
More highly substituted hexahydro-5-imino- 1,4-5 heteroazepines may be prepared according to methodology olltlin.o.-l in Scheme 4. Diester ~ is cyclized via a Dieckm~nn condensation to keto-ester B. Treatment of B with a strong base such as sodium hydride followed by addition of an aLkylating agent such as n-propyl iodide will give E (where R2 is hydrogen and R3 is n-propyl). Alternatively, keto-ester ~ may be oxidized by m~n~nese dioxide to form the a,~-S lm~ lrated keto-ester C. A substituent R2 is introduced via a Michael reaction with an organo-cuprate reagent to form I~. Alkylation of P with (R3)X in the presence of a strong base will form E (R~ and R3 are not hydrogen). Deesterification-decarboxylation of E will form E. By procedures outlined in Scheme 3, F is converted to ~mi~les H and I via 10 Beckm~nn rearrangement of oxime G. Since the Beckm~nn rearrangement can occur with migration to either side of the oxime, the two amides H and I may be formed. These amides H and I may be separated chromatographically at this point or, ~ltem~tively, may be subsequently converted to their respective thioamides by reaction with 15 Lawesson's reagent and then separated. Reaction of the thio~mi~es from H and E with Meerwein's salt followed by treatment with ammonium chloride will give substituted hexahydro-5-irnino-1,4-heteroazepines 1 and K. When X is nitrogen, a a~p.~pliate amine protecting group (eg., tert-butyloxycarbonyl) may be employed in the reaction sequence.
W O 97/16430 PCTrUS96/17447 -Scheme 5 Rz ~OH R2~~H R2 a b ~ ~ c,d . N--Boc R3~ NH2 R3~--N--Boc R3 E~ ~
X C 02H R3X ~ f R3 N H2 HCI N ~
o ~2 E
R~S ~ R~S
S NH HCI
E G
Reaction conditions:
a) (t-C4Hg0)2CO, NaHCO3, CH2CI2; b) Ph3P, (i-C3H702C)2N2,THF;
C) HS(CH2)2C O2H~ CsCO3, DMF; d) HCI, EtOAc;
e) 1-ethyl-3-(~dimethylaminopropyl) carbodiimide, 1 -hydroxy-7-azaben~ul, - 'e, N-methyl" ,o"~holine;
f) Lawesson's reagent, tol, 90~C; g) Me30BF4, (i-C3H7)2NC2H5, CH2CI2;
h) NH4CI, EtOH, reflux .
S More highly substituted hexahydro-5-imino-1,4-heteroazepines may also be prepared according to methodology olltlinP-l in Scheme 5. Briefly, the amine functionality in aminoalcohol A is protected to give B. Mitsunobu conditions will cyclize B to form aziridine C. The aziridine ring in C is opened wi~ ,B-mercaptopropionic acid followed by treatment with hydrochloric acid in ethyl acetate to yield W O 97/16430 PCT~US96/17447 -amino acid D. Reaction of D under st~n-l~rd peptide bond forrninp reactions gives lactam E. Reaction with Lawesson's reagent gives the thiol~ t~m F which is converted to 5-imino-1,4-thiazepine Gby previously described conditions.
The invention will now be illustrated by the ~ollowing non-limiting examples in wh;ch, unless state~ otherwise:
all operations were carried out at room or ambient 10 ternpel~lu~c;, that is, at a temperature in the range 18-25~C; evaporation ofsolvent was carried out using a rotary evaporator under re~ ce~l pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60~C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points 15 are uncorrected and 'd' indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with di~er~llt melting points in some p,~al~Lions; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, 20 nuclear magnetic resonance (NMR) spectrometry or microanalytical data;
yields are given for illustration only; when given, NM~ data is in the form of delta (~) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 400 MHz or 500 MHz using the indicated solvent;
25 conventional abbreviations used for signal shape are: s. singlet; d.
doublet; t. triplet; m. multiplet; br. broad; etc.: in addihon "Ar" .si~nifies an aromatic signal; chemical symbols have their usual mÇ~ning.~; the following abbreviations have also been used v (volume), w (weight), b.p.
(boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g 30 (gram(s)), mg (milligrarns(s)), mol (moles), mmol (millimoles), eq (equivalent(s)) .
W O 97/16430 PCT~US96117447 -N ~
Hexahydro-5-imino-( lH)- 1.4-diazepine dihydrochloride.
S Step A: Hexahydro-(5H)-1.4-diazepine-5-one acetic acid salt.
l-Benzylhexahydro-(5H)-1,4-diazepine-5-one (1.5 g, 7.34 mmol) was dissolved in 12 mL of ethanol and 6 mL of acetic acid. After addition of 150 mg of 20% p~ ium hydroxide on carbon, the mixture was shaken under 40 psi of hydrogen for 4 h. The resulting mixture was centrifuged and the supern~t~nt was filtered through a 0.45 micron membrane filter.
The catalyst was washed with ethanol (3 x 10 mL), and the combined filtrate was conce~ ted in vacuo to give a yellow oil which began to crystallize. Swirling with 2 mL of methanol and 1 mL of ethyl acetate facilitated the cryst~lli7~tion, and evaporation of the solvent in vacuo gave 1.23 g (96%) of hexahydro-(5H)- 1,4-diazepin-5-one acetic acid salt as light yellow crystals.
lH NMR (400 MHz, CD30D): o 3.44-3.40 (m, 2H), 3.19-3.15 (m, 2H), 3.15-3.11 (m, 2H), 2.74-2.70 ( m, 2H), 1.94 (s, 3H).
Mass spectrum: m/z = 115 (M+l, 100%).
Step B: l-(tert-Butoxycarbonyl)hexahydro-(5H)-1~4-diazepin-5-one.
A mixture of hexahydro-(5H)- 1,4-diazepin-5-one acetic acid salt (200 mg, 1.15 mmol), di-tert-butyldicarbonate (277 mg, 1.27 mmol) and sodium chloride (460 mg, 7.93 mmol) in 2.0 mL of chloroform was stirred and 2.5 N aqueous sodium hydroxide (460 uL, 1.15 mmol) was le~l The mixture was heated to reflux for 4 h, and then extracted with 3xlO mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, ~lec~nt~-1 and evaporated in vacuo to give 219 mg (89%) of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one as a white solid.
lH NMR (400 MHz, CD30D): ~ 3.60-3.53 (m, 4H), 3.28-3.25 (m, 2H), 2.61-2.56 (m, 2H), 1.47 (s, 9H).
Mass spectmm: m/z = 215 (~+1~ 100%).
Anal. calcd for CloH18N203: C, 56.32; H, 8.04; N, 13.14. Found: C, 55.92; H, 8.48; N, 13.00.
Step C: l-(tert-Butoxycarbonyl)-2.3~6~7-tetrahydro-5-methoxy-(lH)-1~4-diazepine.
Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of l-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl ~cet~t~ The organic layer was separated and the aqueous layer was extracted with 3 x 10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85~) of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-S-methoxy-(1H)-1,4-diazepine as a yellow liquid.
lH NMR(400 MHz, CD30D): ~ 3.58 (s, 3H), 3.53-3.45 (rn, 6H), 2.63-2.59 (m, 2H), 1.46 (s, 9H).
Mass spectrum: m/z= 129.
Step D: 1 -(tert-Butoxycarbonyl)-hexahydro-S-imino-( lH)- 1 diazepine hydrochloride .
W O 97/16430 PCT~US96/17447-- A mixture of l-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-metho~y-(lH)-1,4-diazepine (170 mg, 0.75 mmol) and ammonium chloride (40.1 mg, 0.75 mmol) in 2.0 mL of anhydrous ethanol was refluxed for 3 h. The solvent was then removed in vaCuo and residue was lli~ulated with 3 x 10 S mL of ether to give 174 mg of 1-(tert-butoxycarbonyl)-hexahydro-5-imino-(1H)-1,4-diazepine hydrochloride as a light yellow solid.
lH NMR (400 MHz,CD30D): o 3.71-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.55-3.50 (m, 2H), 2.90-2.86 (m, 2H), 1.47 (s, 9H).
Mass spectrum: m/z = 214 (M+l, 100%).
Step E: Hexahydro-5-Imino-(1H)-1~4-diazepine dihydrochloride.
Hydrogen chloride gas (2.0 g, 55 mmol) was bubbled into 15 mL of ethyl ~ret~t~ at 0 ~C over 3 min. 1-(tert-Butoxycarbonyl)-5-iminohexahydro-(1H)-1,4-diazepine hydrochloride (85 mg, 0.34 mmol ) was added and mixture was stirred at room overnight. Removal of solvent and hydrogen chloride in vacuo gave 60 mg (95%) of hexahydro-5-imino-(1H)-1,4-diazepine dihydrochloride as a yellow solid.
lH NMR (400 MHz, CD30D): o 3.84-3.80 (m, 2H), 3.55-3.50 (m, 2H), 3.43-3.39 (m, 2H), 3.21-3.16 (m, 2H).
Mass spectrum: m/z = 114 (M - 2HCl + 1, 100%).
Anal. calcd for CsH13N3Cl2: C, 32.27; H, 7.04; N, 22.58; Cl, 38.10.
Found: C, 32.09; H, 7.04; N, 21.67; Cl, 38.05.
FX~MPLE 2 H~
NH HCI
Hexahydro-5 -imino- 1.4-thiazepine hydrochloride Step A: 4-Oximino-tetrahydrothio~yr~ll To a stirring solution of solution of tetrahydrothiopyran-4-one (4.9 g, 42.1 mmol) and hydroxyl~rnin~ hydrochloride ~5.9 g~ 84 mnnol~ in 35 mlL
of ethanol at 0 ~C was added a solution of sodium hydroxide (3.38 g, 84.5 mmol) dissolved in 13 mL water. The reaction mixture was warmed to room temperature and stirred for an additional 2 h. The ethanol was removed in vacuo and the aqueous solution extracted with ether (2 X 250 mL). The etheral layer was washed with with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give crude oxime which was recryst~lli7e~1 lS from hexane/ether to give 4. 66 g of 4-oximino-tetrahydrothiopyran.
IH NMR (500 MHz, CDCl3): o 9.43 (brs, lH), 2.86 (m, 2H), 2.78(m, 2H), 2.73 (m, 2H), 2.56 (m, 2H).
13C NMR (125 MHz, CDC13): o 158.24, 33.94, 29.75, 28.38, 26.78.
Step B: Tetrahydro-(2H)-1.4-thiazepin-S-one To a solution of 4-oximino-tetrahydrothiopyran (1.0 g, 7.6 mmol) in 20 mL of dry ether under nitrogen atmosphere at 0 ~C was added n-butyllithium (S.0 mL of a 1.6 M solution in hexane, 8.0 mmol). The resulting white suspension was stirred at 0 ~C for one hour at which point a solution of p-toluenesulfonyl chloride (1.52 g, 8.0 mmol) in 10 mL
ether was added and the reaction mixture stirred for 4 h at 5 ~C. The solvent was removed in vacuo and then the residue was treated with 20 mL of 70% dioxane cont~ining five drops of trie~ylamine and stirred for 24 h at room temperature. The solvent was removed in vacuo and the residue was extracted with methylene chloride. The methylene chloride layer was washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and W O 97/16430 PCT~US96/17447 -- the product purified by flash column chromatography on silica gel eluted with hexane/ethyl acetate (7 :3) to give 0.13 g of hexahydro-(1H)-1,4-thiazepin-5-one.
S lH N~IR (S00 MHz, CDCl3): o 6.92 (brs, lH), 3.61 (m, 2H), 2.92(m, 2H), 2.74 (m, 2H), 2.70 (m, 2H).
13C NMR (125 I~HZ;t CDC13 ): ~ 177~76, 45.88, 40.95, 31 54, 24~61.
Step C: Tetrahydro-(2H)-1 ~4-thiazepin-S-thione To a solution of tetrahydro-(2H)- 1,4-thiazepin-S-one (0.335 g, 2 mmol) in S mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide]
(0.971 g, 2.4 mmol) and the mixture was stirred at 90~C for 30 mins.
lS Evaporation of the solvent in vacuo followed by purification by flash column chromatography on siIica gel eluted with methylene chloride:
ethyl acetate (19: 1) gave 0. 365 g of tetrahydro-(2H)-1,4-thiazepin-S-thione.
lH NMR (500 MHz, CDC13): o 9.19 (brs, lH), 3.80 (m, 2H), 3.44 (m, 2H), 2.78 (m, 2H), 2.71 (m, 2H).
13C NMR (125 MHZ, CDCl3 ): ~ 208.90, 50.39, 49.02, 29.54, 25.86.
Step D: Hexahydro-S-imino-1.4-thiazepine hydrochloride To a solution of tetrahydro-(2H)-1,4-thiazepin-S-thione (90 mg, O.S
mmol) in 2 mL of dry methylene chloride at room temperature was added trimethyloxonium tetrafluoroborate (Meerwein's salt) (88 mg, 0.6 mmol) followed by diisopropylethyl~min~ (77 mg, 0.6 mmol). The resulting mixtllre was stirred at room temperatere for 2 h. The methylene chloride layer was washed with water, saturated sodium chloride solution and ~ dried over anhydrous m~gnesium sulfate. The solvent was rernoved in vacuo to give the crude imino-ether which was subsequently treated with ammonium chloride (0. 017 g) in 3 mL of ethanol and h~te-l at 80 ~C for WO 97/16430 PCT~US96/17447-15 h. Evaporation of ethanol followed by trituration of the oil with ethyl acetate and ether gave 53 mg of hexahydro-5-imino-1,4-thiazepine hydrochloride as a white solid.
IH NMR (500 MHz, D2O): ~ 3.81 ( m, 2H), 3.11 (m, 2H), 2.84 (m, 2H), 2.76 (m, 2H).
13C NM:R (125 MHz5 D20?: ~i 46 88~ 35r52~ 28 847 23 74 Mass spectrum: m/z--131 (M~l).
N ~
NH HCI
Hexahydro-S-imino-1.4-oxazepine hydrochloride.
Step A: 4-Oximino-tetrahydropyran Employing the procedure described in F.x~rnple 2, step A, tetrahydropyran-4-one was converted to 4-oximino-tetrahydropyran.
IH NMR (500 MHz, CDC13): ~ 3.82 (m, 2H), 3.77 (m, 2H), 2.68 (m, 2H), 2.39 (m, 2H).
Step B: Tetrahydro-(2H)-1.4-oxazepin-5-one Employing the procedure in Example 2, step B, 4-oximino-tetrahydropyran was converted to tetrahydro-(2H)-1,4-oxazepin-5-one.
WO 97/16430 PCT~US96/17447 -- lH NMR (500 MHz, CDC13): ~i 7.07 (brs, lH), 3.79 (m, 2H), 3.75(m, 2H), 3.34 (m, 2H), 2.69 (m, 2H).
13C NMR (125 MHZ, CDC13): ~ 177.94, 71.61, 65.52, 44.74, 41.01.
5 Step C: Hexahydro-5-imino-1.4-oxazepine. hydrochloride Fmploying the procedure in Example 2y step ~ tetr~d~ 2~1,4-oxazepin-5-one was reacted with Meerwien's salt and ammonium chloride to form hexahydro-5-imino-lH-1,4-oxazepine, hydrochloride.
lH NMR (500 MHz, D2O): o 3.89 ( m, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 2.96 (m, 2H).
3C NMR (125 MHz, D2O): o 69.54, 64.92, 46.12, 35.42. MS: m/z =
115.1 (M+).
(~
H
NH HCI
Hexahydro-5-imino-3-propyl-1.4-thiazepine hydrochloride.
Step A: Tetrahydrothiopyran-4-one-3-carboxylic acid~ allyl ester.
A mixture of 3,3'-thiodi~ ionic acid (17.82 g, 10 mmol), allyl alcohol (20.4 mL, 30 mmol) and p-toluenesulfonic acid (0.750 g) in 100 mL of toluene was refluxed for 8 h in a Dean-Stark apparatus to azeotropically remove water. The reaction mixture was quenched with saturated solution of sodium bicarbonate and the toluene layer was se~al~led and washed with saturated sodium chloride solution and dried over anhydrous m~gn~.sium sulfate. The solvent was removed in vacuo and gave approxim~t~ly 20 g of crude 3,3'-thiodi~r~ionic acid, diallyl ester. This material was suf~lciently pure by NMR and was used in the subsequent reaction.
s To a ~ixl~le of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL
of dly ether at r~om temperatllre was added allyl ?llcohol (2.25g, 38.7 mmol) in a dlo~vise m~nner. The result~nt mixture was stirred for 15 min. A solution of 3,3'-thiodipropionic acid, diallyl ester (S.0 g, 19.3 10 mmol) in 10 mL ether was slowly added and the mixture refluxed for S h.
The reaction was cooled to room temperalule and then quenched with water and the pH adjusted to 4 with lN HCl. The e~er layer was separated and the aqueous layer was extracted with e~er (2 X 100 mL).
The combined etheral layer was washed with sautrated sodium chloride 15 solution and dried over anhydrous m~gnPsium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (9: 1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
lH NMR (S00 MHz, CDC13): ~ 12.48 (s, lH), 5.95 (m, lH), 5.35 (m, 2H), 4.68 (m, 2H), 3.38 (s, 2H), 2.78 (t, J--6 Hz, 2H), 2.60 (t, J = 6.1 Hz, 2H).
13C NMR (125 MHZ, CDC13): o 172. 80, 131.91, 118.48, 65.32, 30.95, 24.75, 23.58.
Step B: 3-Propyl-tetrahydrothiopyran-4-one-3-carboxylic acid. allyl ester.
A solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (1.0 g, 5 mmol) in 1 mL of dimethylform~mi~le was added to a stirred mixture of sodium hydride (60% in oil, 0.22 g, 5.5 mmol) and l-iodopropane (0.934 g, 5.5 mmol) in 2.5 mL of dimethylform~mide at 0 ~C. The reaction mixture was warmed to room temperature and stirred overnight.
The reaction mixture was diluted with water and extracted with ether.
- The etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (19 :1) to give 0.277 g of 3-propyl-S tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
lH NMR (500 MHz~ CDCl~ 5.93 (m, lH)~ 5.27-5.38 ~m, 2H,), 4.70(m, 2H), 3.33-2.73 (m, 6H), 1.96-1.20(m, 4H), 0.93 (t, J = 6.3 Hz, 3H).
lO 13C NMR (125 MHZ, CDC13): ~ 205.44, 170.83, 131.36, 119.10, 66.05, 63.14, 43.33, 38.66, 36.66, 30.93, 18.01, 14.48.
Step C: 3-Propyl-tetrahydrothiopyran-4-one.
15 To a stirred solution of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.272 g, 1.1 mmol) in 5.0 mT . dry tetrahydrofuran at room temperature was sllcces.cively added morpholine (0.979 g, 1.12 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.055 mmol). Stirring was contimle~l until the thin layer chromatography 20 indicated the completion of reaction at which point the reaction mixture was evaporated and the crude product was purified by flash column chromatography on silica gel eluted eluted with hexane: ether (19: 1) to give 0.163 g of 3-propyl-tetrahydrothiopyran-4-one.
lH NMR (500 MHz, CDC13): ~ 3.02-2.94 (m, 7H), 1.88-1.29 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHZ, CDC13): o 210.61, 52.77, 43.82, 35.92, 31.58, 31.06, 20.19, 14.13.
Step D: 4-Oximino-3-propyl-tetrahydrothiopyran.
Employing the procedure described in Example 2, step A, 3-propyl-tetrahydrothiopyran-4-one was reacted with hydroxyl~n~ine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
Step E: Tetrahydro-3-propyl-(2H)-1.4-thiazepin-5-one and S tetrahydro-6-propyl-(2H)- 1.4-thiazepin-5-one.
Employin~s thç procedllre described in E~ample 2, s1ep B,4-oximino-3-propyl-tetrahydrothiopyran was converted to a 3: 1 mixture of tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-one and tetrahydro-6-propyl-(2H)-1,4-10 thiazepin-5-one.
Step F: Tetrahydro-3-propyl-(2H)-1.4-thiazepin-5-thione.
Employing the procedure described in Example 2, step C, the mixtllre of 15 tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-one and tetrahydro-6-propyl-(2H)- 1,4-thiazepin-5-one was reacted with Lawesson's reagent to yield the corresponding thio~n~icles. The 3-n-propyl isomer was isolated and puri~led by flash column chromatography on silica gel eluted with methylene chloride: hexanes (1:1) to yield tetrahydro-3-propyl-(2H)-1,4-20 thiazepin-5-thione as a single compound.
H NMR (500 MHz, CDC13): o 8.06 (brs, lH), 3.95 (m, lH), 3.58 (m, lH), 3.30 (m, lH), 2.85 (m, lH), 2.73 (m, 2H), 2.56(m, lH), 1,71-1.42 (m, 4H), 0.97 (t, J = 7.3 Hz, 3H).
25 13C NMR (125 MHZ, CDC13): o 208.08, 61.95, 48.61, 37.70, 34.41, 25.75, 19.24, 13.68.
Step G: Hexahydro-5-imino-3-propyl-1.4-thiazepine hydrochloride.
30 Employing the procedure described in Example 2, step D, tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-thione was reacted with Meerwein's salt and ammonium chloride to yield hexahydro-5-imino-3-propyl- 1,4-thiazepine, hydrochloride.
W O 97/16430 PCT~US96/17447 -H NMR (500 MHz, CD30D): ~ 3.93 ( m, 2H), 3.23-2.62 (m, 6H), 1.68-1.47(m, 4H), 0.98 (t, 3H, J = 7 Hz).
~ 13C NMR (125 MHZ, CD30D): o 170.96, 58.65, 36.54, 34.99, 34.10, 23.36, 18.87, 12.68. MS: m/z = 173.1 (M+l).
s NH ~
NH HCI
Hexahydro-5-imino-6-propyl-1.4-thiazepine hydrochloride.
The 6-propyl thio~mitle isomer isolated from Example 4, Step F was 15 reacted with Meerwein's salt and ammonium chloride according to the procedure described in Example 2, Step D to yield hexahydro-5-imino-6-propyl-1,4-thiazepine, hydrochloride.
lH NMR (500 MHz, CD30D) 3.75 (m, 2H), 3.18 (m, lH), 2.95 (dd, lH), - 20 2.82 (m, lH), 2.73 (m, 2H), 1.87 (m, 2H), 1.50 (m, lH), 1.39 (m, lH), 0.99 (t, 3H).
Mass spectrum: m/z = 173 (M+l) ~S ~CH3 H~
NH HCI
WO 97/16430 PCT~US96/17447 -Hexahydro-5-imino-7-methyl-l.~thiazepine hydrochloride.
Step A: 2.3-Dihydrothiopyran-4-one-3-carboxylic acid. allyl ester.
s To a solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester ~E~ample 4~ step A) (2.:~ g, 11 5 mmol,~ in lOQ ~l, dr~ chlorQform at room temperature was added activated m~ng~nese dioxide (10 g, 115 mmol) and the resulting mixture was refluxed for S h. The reaction 10 mixture was filtered and evaporated. The the rem~ining residue was purified by flash column chromatography on silica gel eluted with hexane : ethyl ~et~te (7 :3) to give 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.988 g).
lH NMR (500 MHz, CDC13): o 8.49 (s, IH), 5.97 (m, iH), 5.41-5.25 (m, 2H), 4.70 (m, 2H), 3.29 (m, 2H), 2.82 (m, 2H).
3C NMR (125 MHZ, CDCl3): o 189.26, 162.68, 156.42, 131.97, 125.20, 118.61, 65.75, 37.83, 27.29.
Step B: 2-Methyl-tetrahydrothio~yl~u.-4-one-3-carboxylic acid. allyl ester.
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide / 4.0 mL dimethylsulfide and 4.0 mL
methyllithium/ether at -78 ~C) at -78 ~C was added a solution of 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.61~nol) in ~lim~tllyl~lllfitle (5 mL). The resulting yellow-colored solution was sitrred for 30 min. at the same temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperature for and 1 h. The reaction mixtllre was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous m~ sium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane: ether (4: 1) to -W O 97/16430 PCT~US96/17447-~ give 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol: keto tautomers.
lH NMR (S00 MHz, CDC13): ~ 12.67 (s, lH), 5.94 (m, lH), 5.35-5.27 S (m, 2H), 4.70 (m, 2H), 3.09-2.50(m, 6H), 1.52 (d, J = 6.9 Hz, 3H).
13C NMR (125 MHZ, CDCl3): ;j 173. 02, 131.86, 119.50, 66.71, 65.33, 42.66~ 30~767 ?3~9~S7 20.02 Step C: 2-Methyl-tetrahydrothiopyran-4-one Employing the procedure described in Example 4, step C, 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester was decarboxylated to form 2-methyl-tetrahydrothiopyran-4-one.
lS Step D: Hexahydro-S-imino-7-methyl-1.4-thiazepine hydrochloride.
Employing the procedures described in Fx~n~ple 4, steps D through G, 2-methyl-tetrahydrothiopyran-4-one was converted to hexahydro-S-imino-7-methyl-1,4-thiazepine, hydrochloride lH NMR (S00 MHz, D20): ~ 3.78 (d, lH, J = lS Hz), 3.62 (dd, lH, J =
lS, 7 Hz), 3.05 (m, 2H), 2.87 (m, 2H), 2.10 (m, lH), 1.21 (d, 3H, J = 7 Hz).
13C NMR (125 MHz, CD30D): ~ 51.87, 36.76, 34.73, 22.12, 17.34.
Mass spectrum: m/z = 145.1 (M+l).
and hexahydro-S-imino-2-methyl-1,4-thiazepine hydrochloride (see Fx~n~ple 7).
CA 02234641 l99X-04-09 W O 97/16430 PCT~US96/17447-CH
N
NH HCI
~lexahydro-~-iminQ-2-rnethyl- 1.4-thiazepine hydrochloride.
5 Hexahydro-5-imino-2-methyl- 1,4-thiazepine hydrochloride was prepared according to the procedures described in Example 6.
lH NMR (500 MHz, CD30D): ~ 3.80 (ABq, 2H), 3.30 (m, lH), 3.12 (m, 2H), 2.80 (ABq, 2H), 1.39 (d, 3H, J = 7 Hz).
lO 13C NMR (125 MHz, CD30D) ~ 46.62, 42.25, 32.51, 28.01, 20.26.
Mass spectrum: m/z = 145.2 (M+l).
E~AMPLE 8 H ( NH HCI
Hexahydro-5-imino-6-(3-methyl-2-n-butenyl)- 1.4-thiazepine hydrochloride.
Employing the procedures described in Fx~mrle 4, but sub~ u~ g l-bromo-3-methyl-2-n-butene for l-iodopropane in step B, the 6-positional isomer was separated from the 3-positional isomer (see Fx~mrle 9) as its respective thioamide by flash column chromatography .
25 Subsequently, reaction with Meerwein's salt and ammonium chloride as W O 97/16430 PCT~US96/17447-described in Fx~mple 2, step D gave hexahydro-5-imino-6-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): ~ 5.10 (m, lH), 4.15, (m, lH), 3.79 (m, lH), 1.75 (s, 3H), 1.71 (s, 3H).
Mass spectrum: m/z = 199.2 (M+l).
S
~N ~
NH HCI
Hexahydro-5-imino-3-(3-methyl-2-n-butenyl)- 1.4-thiazepine hydrochloride.
Employing the procedures described in Ex~mple 4, but substituting l-bromo-3-methyl-2-n-butene for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 8) by flash column chromatography as its respective thio~mide.
20 Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 5.17 (br t, lH), 3.96 (ABq, 2H), 3.22 (m, lH), 3.09 (m, lH), 2.45 (m, 2H), 1.75 (s, 3H), 1.70 (s, 3H).
13C NMR (125 MHZ, CD30D) o 118.04, 59.14, 35.09, 33.38, 32.93, 24.63, 23.36, 16.81.
Mass spectrum: m/z = 199.2 (M+l).
W O 97/16430 PCT~US96/17447 -NH~
NH HCI
s Hexahydro-5-imino-6-(2-methyl-propyl)-1~4-thiazepine hydrochloride Employing the procedures described in Example 4, but substihl1inp~
isobutyl iodide for l-iodopropane in step B, the 6-positional isomer was 10 separated from the 3-positional isomer (see Example 11) as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Fx~mple 2, step D gave hexahydro-5-imino-6-(2-methyl-propyl)-1,4-thiazepine hydrochloride.
H NMR (500 MHz, CD30D): o 3.77 (t, 2H), 3.25 (m, lH), 2.95 (d of d, lH), 2.83 (m, lH), 2.73 (m, 2H), 1.87 (m, lH), 1.70 (m, 2H), 1.01 (d, 3H), 0.99 (d, 3H)-Mass spectrum: ~ = 187.2 FXAM[PLE 1 1 H
NH HCI
Hexahydro-5-imino-3-(2-methyl-propyl)-1.4-thiazepine hydrochloride W O 97/16430 PCT~US96/17447 -Employing the procedures described in Fx~mrle 4, but sub~ u~ g isobutyl iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 10) as its respective 5 thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Fx~mple 2, step D gave hexahydro-5-imino-?i-~2-methyl-propyl)-1i4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 3.95 (m, lH), 3.25 (m, lH), 3.10 (m, lH), 2.87 (m, lH), 2.80 (m, lH), 2.73 (d, lH), 2.65 (d of d, lH), 1.76 (m, lH), 1.69 (m, lH), 1.5 (m, lH), 0.98 (t, 6H) Mass spectrum: m/z = 187.2 ~H ~--NH HCI
Hexahydro-5 -imino-6-methyl- 1 ~4-thiazepine hydrochloride .
Employing the procedures described in Example 4, but sub~
methyl iodide for l-iodopropane in step B, the 6-positional isomer was 25 separated from the 3-positional isomer (see Example 13) as its respective thi~mide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-6-methyl- 1,4-thiazepine hydrochloride.
W O 97/16430 PCT~US96/17447-lH NMR (500 MHz, CD30D): ~ 3.78 (t, 2H), 3.4 (m, lH), 2.82 (m, 2H), 2.72 (m, 2H), 1.42 (d, 3H) Mass spectrum: m/z = 145.0 FxAMpLE 13 H ~
NH HCI
10 Hexa~ydro-5-imino-3-methyl-1.4-thiazepine hydrochloride.
Employing ~e procedures described in Example 4, but sub~
methyl iodide for 1-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer (see Example 13) as its respective 15 thioamide by ~ash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-methyl- 1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 4.07 (m, lH), 3.19 (m, lH), 3.04 (m, lH), 2.80 (m, 2H), 2.69 (m, 2H), 11.39 (d, 3H) Mass spectrum: ~ = 145.1 H
NH HCI
Hexahydro-5-imino-3-ethyl-1.4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substituting ethyl 5 iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently? reaction witl~ eerwein's ~alt ~cl ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-ethyl-1,4-thiazepine hydrochloride.
lH NMR (500 MHz, CD30D): o 3.87 (m, lH), 3.23 (m, lH), 3.06 (m, lH), 2.80 (m, 2H), 2.64 (d of d, 2H), 1.75 (m, 2H), 1.04 (t, 3H).
Mass spectrum: m/z = 159.1 H
NH HCI
20 Hexahydro-5-imino-3-butyl-1.4-thiazepine. hydrochloride.
E~ploying the procedures described in Example 4, but sub~LiLuLhlg butyl iodide for l-iodopropane in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column 25 chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-butyl-1,4-thiazepine, hydrochloride.
lH NMR (500 MHz, CD30D): ~ 3.90 (m, lH), 3.23 (m, lH), 3.02 (m, lH), 2.80 (m, 2H), 2.63 (d of d, lH), 1.70 (m, 3H), 1.40 (m, 4H), 0.94 (t, 3H)-Mass spectrum: m/z = 187.2 s H
NH HCI
Hexahydro-5-imino-3-(2-methyl-3-propenyl)- 1 ~4-thiazepine hydrochloride.
Employing the procedures described in Example 4, but substitlltin~ 3-15 bromo-2-methylpropene for l-iodo~r~palle in step B, the 3-positional isomer was separated from the 6-positional isomer as its respective thioamide by flash column chromatography . Subsequently, reaction with Meerwein's salt and ammonium chloride as described in Example 2, step D gave hexahydro-5-imino-3-(2-methyl-3-propenyl)-1,4-thiazepine 20 hydrochloride.
lH NMR (500 MHz, CD30D): o 4.85 (s, lH), 4.75 (s, lH), 4.13 (m, lH), 3.28 (m, lH), 3.12 (m, lH), 2.88 (m, lH), 2.82 (m, lH), 2.78 (d, lH), 2.66 (d of d, lH), 2.45 (m, 2H), 1.78 (s, 3H).
25 Mass spectrum: m/z = 185.1 l--"'",~S~
(+) H ~
(~)-trans-Decahydro-4-imino-benzolbl-1.4-thiazepine acetic acid salt.
Step A: (+)-trans-2-(tert-Butoxycarbonylamino)-cyclohexanol To a vigoursly stirring solution of trans-2-aminocyclohexanol hydrochloride (5.5 g, 36 mmol) in 100 m L methylene chloride and saturated sodium bicarbonate solution (1: 1) at 0 ~C was added di-tert-butylcarbonate (13.09 g, 60 mmol). The resulting heterogeneous mixture wSle wa.r.mA.ed to the r~omA tem.pera~.lre a~,d s~ed o~er~ht ~le methylene chloride layer was washed with brine, dried and evoporated.
The solid obtained was triturated with hexane and filtered to give 5.86 g (96%) of (+)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol.
H NMR (500 MHz, CDC13): o 4.61(brs, lH), 3.27 (m, lH), 2.73 (brs, lH), 2.02-1.69 (m, 4H), 1,45 (s, 9H), 1.42-l.O9(m, 4H).
13C NMR (125 MHz, CDCl3): ~ 75.42, 56.62, 34.22, 31.84, 28.43, 27.48, 24.78, 24.11.
Step B: (+)-7-(tert-Butoxycarbonyl)-7-aza-bicyclo-r4.1.0l-cycloheptane To a stirring mixture of (+)-trans-2-N-(tert-butoxycarbonyl)-cyclohexanol ( 4.08 g, 20 mmol) and triphenylphosphine (10.49 g, 40 mmol) in 50 mL of tetrahydrofuran at 0 ~C was slowly added diisopropyl azodicarboxylate (8.08 g, 40 mmol). The reaction mixture was warmed to the room temperature and stirred until the TLC indicated the disappearence of the starting alcohol ( appro. 2- 4 hrs). The tetrahydrofuran was evaparated in vacuo and the crude product was O 97/16430 PCT~US96/17447-p~se~l through a silica gel column and eluted with hexane/methylene chloride (1:1) to give 3.18 g (85%) of the desired ~)-7-(tert-butoxycarbonyl)-7-aza-bicyclo-[4.1.0]-cycloheptane as an oil.
lH NMR (500 MHz, CDC13): ~ 2.55 (m, 2H), 1.93-1.75 (m, 4H), 1.45 (s, 9H), 1.44- 1.21 (m, 4H).
13C NMR (125 MHz. CDC13): o 80.62, 36.96? 28.04~ 23.80, 19.93.
Step C: (+)-trans-2-amino-1-r2-(carboxy)ethylthiol-cyclohexane hydrochloride ~t)-7-(tert-Butoxycarbonyl)-7-aza-bicyclo-[4.1.0]- cycloheptane (0.5 g, 2.68 mmol) was dissolved in 2 mL dimethylform~mide and ,B-mer~o~ ionic acid (0.318 g, 3 mmol). After the addition of cesium carbonate (1.95 g, 6 mmol), the mixture was stirred at 60 ~C until the TLC indicated the full con~u~ lion of starting m~teri~l (appro. 4 hrs).
The reaction mixture was diluted with water, the pH was adjusted to 4 (with 2.4 M HCl) and finally extracted with methylene chloride. The solvent layer was washed with brine, dried and evaporated to give the crude (+)-trans-2-(tert-butocycarbonylamino)-1-[2-(carboxy)ethylthio]-cyclohexane, which was not purified but taken to the next stage.
The crude from the above was dissolved in 10 ml e~yl acetate saturated with hydrogen chloride and stir at room temperature. The white precipitate that resulted was filtered and dried under vacuo yielding 0.636 g of (+)-trans-2-amino-1-[2-(carboxy)ethylthio]-cycloht-x~n~.
lH NMR (500 MHz, D20): ~ 3.20 (m, lH), 2.81-2.65 (m, 3H), 2.24 (m, 2H), 1.79-1.2 (m, 8H).
Step D: (+)-trans-Decahydro-4-oxo-benzorb~ 4-thiazepine To (+)-trans-2-amino-1-[2-(carboxy)ethylthio]-cyclohexane hydrochloride (0.240 g, 1 mmol) dissolved in 2 mT of dimethylform~mide at 0 ~C was successively added 1-ethyl-3-(3-WO 97/16430 PCT~US96/17447-~ dinnethylaminopropyl) carbo~liimic1e (0.356 g, 1.2 mmol), 1-hydroxy-7-azabenzotriazole (0.164 g, 1.2 mmol) and then finally N-methylmorpholine (0.252 g, 2.5 mmol). After stirring for an additional S
mins., the reaction mixture was warmed to room temperature and stirred overnight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride.
T~e solvent layer W?lS ~ashed ~ith brine~ d~ied an~l evapor~tçd to giYe the crude which was purified by silica column and eluted with hexane/ethylacetate (7: 3 + 5% methanol) to give 0.102 g (55%) of (+)-trans-decahydro-4-oxo-benzo[b]-1,4-thiazepane as white solid.
1H NMR (500 MHz, CDCl3): o 5.66 (s, lH), 3.46 (m, lH), 2.98-2.64 (m, 5H), 2.05-1.74 (m, 4H), 1.39-1.21 (m, 4H).
13C NMR (125 MHz, CDCl3): ~ 175.94, 58.07, 46.78, 40.50, 33.77, 31.70, 25.32, 24,67, 24.52.
Step E: (+)-trans-Decahydro-4-thioxo-benzorb~ 4-thiazepine To a solution of (+)-trans-decahydro-4-oxo-benzo[b]-1,4-thiazepane (0.100 g, 0.54 mmol) in 5 mL of dry toluene was added Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (0. 328 g, 0.81 mmol) and the mixture was stirred at 90 ~C for 30 mins. Evaporation of the solvent in vacuo followed by purification by flash column chromatography on silica gel eluted with methylene chloride: ethyl acetate (19: 1) gave 0. 083 g (77%) of (+)-trans-decahydro-4-thioxo-benzo[b]- 1 ,4-thiazepine.
1H NMR (500 MHz, CDCl3): o 7.70 (brs, lH), 3.72 (m, lH), 3.65 (m, lH), 3.23 (m, lH), 2.96 (m, lH), 2.77-2.65 (m, 2H), 2.14-1.25 (m, 8H).
13C NMR (125 MHZ, CDCl3 ): ~ 63.26, 48.42, 44.43, 33.73, 31.41, 26.45, 25.06, 24.3 1.
Step F: (+)-trans-Decahydro-4-imino-benzolb1-1.4-thiazepine acetic acid salt.
= - =. .
To a solution of (+)-trans-decahydro-4-thioxo-benzo[b]-1,4-thiazepane (25 mg, 0.12 mmol) in 2 mL of dry methylene chloride at room tempeLaLule was added trimethyloxonium tetrafluoroborate (Meelweill's 5 salt) (24 mg, 0.16 mmol). I~e resulting mixt~re was stirred at roonn temperatere overni~ht The reaction mixture was quenched with saturated solution of sodium bica~orlate solution and stir for S mins. Tlle methylene chloride layer was washed with water, saturated sodium chloride solution and dried over anhydrous m~ne.sium sulfate. The 10 solvent was removed in vacuo to give the crude imino-ether which was subsequently treated with ammonium chloride (14 mg) in 4 mL of ethanol and heated at 80 ~C for 4 h. Evaporation of ethanol followed by purification by column chromatography and elution with acetonitrile:
water: acetic acid (90:5:5) gave 21.8 mg (+)-trans-decahydro-4-irnino-15 berlzo[b]-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, D20): ~ 3.68 (m, lH), 3.64 (m, lH), 3.26-2.83 (m, 4H), 2.06-1.23 (m, 8H).
13C NMR (125 MHZ, CDCl3 ): ~ 58.72, 45.32, 33.96, 31.85, 31,76, 20 25.00, 23.95, 21.47.
Mass spectrum: m/z = 185.1 (M+) H
Hexahydro-5-imino-3(S)-propyl-1~4-thiazepine~ acetic acid salt Step A: Tetrahydro-3(S)-propyl-(2H)-1.4-thiazepine-5-thione W O 97/16430 PCTrUS96/17447 -The title compound was prepared employing the procedure in Example 17, Steps A to E and starting from ~norvalinol instead of (+)-trans-2-aminocyclohexanol.
s Step B: Hexahydro-5-imino-3(S~-propyl-1.4-thiazepine acetic acid To a solution of tetrahydro-3(S)-propyl-(2H)-1,4-thiazepine-5-thione (42 mg, 0.22 mmol) in 5 mL tetrahy~lorLuan and saturated with ammonia gas at 60 ~C was added mercuric chloride (73.3 mg, 0.27 mmol). The stream of ammonia gas was bubbled for another 10 mins. at the same temperature. After stirrin~ for 2 h, the reaction mixture was filtered and the filtrate was evaporated. The crude compound was then purified by column chromatography and eluted with acetonitrile: water: acetic acid (90:5:5) giving 31.5 mg of hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, CD30D): ~ 3.93 ( m, lH), 3.30-2.61 (m, 6H), 1.72-1.40 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz).
13C NMR (125 MHZ, CD30D): ~ 58.58, 36.42, 34.95, 34.09, 23.33, 18.87, 12.61.
Mass spectrum: m/z = 173.1 (M+1).
(R)- S
H
Hexahydro-5-imino-3(R)-propyl-1.4-thiazepine acetic acid salt Step A: Tet~ahydro-3(R)-propyl-(2H)-1.4-thiazepine-5-thione The title compound was prepared employing the procedure in Fx~mple 17, Steps A-E and starting from D-norvalinol in~te~fl of (+)-trans-2-aminocyclohexanol.
Step B: Hexahydro-5-imino-3(R)-propyl-1.4-thiazepine acetic salt 10 Employing the procedure 19, step B, tetrahydro-3(R)-propyl-(2H)-1,4-thiazepine-5-thione (40 mg, 0.21 mmol) was converted to 37.4 mg of hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt.
lH NMR (500 MHz, CD30D): d 3.93 ~ m, lH), 3.29-3.02 (m, 2H), 2.87-15 2.61 (m, 4H), 1.73-1.41 (m, 4H), 0.97 (t, 3H, J = 7.3 Hz). 13C NMR
(125 MHZ, CD30D): d 58.60, 36.43, 34.96, 34.10, 23.35, 18.87, 12.63.
Mass spectrum: ~ = 173.1 (M+l).
N ~
NH (HC1)2 Hexahydro-5-imino- 1 -methyl- lH- 1.4-diazepine hydrochloride.
Employing the method of Foloppe et al. (M.P. Foloppe, S. Rault, and M.
Robba, Tetrahedron Lett. 1992, 33, 2803-2804), a solution of hexahydro-l-methyl-(SH)-1,4-diazepin-5-thione (R. Guryn, Polish J. Chem. 1~87, 61, 259-262) (100 mg, 0.694 mmol) in tetrahydrofuran (5.0 mL) was W O 97/16430 PCTrUS96/17447 -_ 59 _ ~ warmed in a SS ~C oil bath as ammonia was bubbled into the solution.
Mercuric chloride (207 mg, 0.764 mmol) was added in one portion, and the mixture quickly became black. After 20 min, the introduction of ammonia was discontinued and the "~i x~ e was stirred at room S ternpera~ul~ for 1 h. The mixture was then centrifuged and the supern~t~nt was decanted. The pellet was resuspended in tetrahydrofuran (3 ml,~ ~ the mix1ure was centrifilged~ and the snpernat~nt was decanted.
This was repeated with 2 x 3 mL of tetrahydrofuran and then 3 x 3 mT . of methanol. The methanol extracts were combined, filtered through a 0.45 10 micron membrane, and evaporated to give 131 mg of white solid. Based on the combustion analysis for carbon, this material contained 92 mg (82% yield) of hexahydro-5-imino- 1 -methyl-( lH)- 1,4-diazepine hydrochloride salt.
lS lH NMR (400 MHz, CD30D): o 3.56-3.52 (m, 2H), 2.88 (dd, 2H, J = 6 Hz, 3 Hz), 2.79-2.71 (m, 2H), 2.71-2.63 (m, 2H), 2.43 (s, 3H).
Mass spectrum: m/z = 128 (M - HCl + 1).
Anal. calc'd. for C6H14N3Cl-1.23 NH4Cl: C, 31.1; H, 8.40; N, 25.5;
Cl, 34.1. Found: C, 31.08; H, 8.16; N, 23.41; Cl, 34.06.
Claims (18)
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, X is selected from O, S(O)m, NH, and NR6, wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2;
R1, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) C1-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl, (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, (16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, or when two members of the group R1, R2, R3 and R4 reside on the same carbon atom of Formula I, or two of the group R1, R2, R3 and R4 reside on adjacent atoms of Formula I, said two members along with the optional substihutents thereon may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2, R3 and R4 resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6 along with the optional subtstituents thereon, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or optionally substituted C1-6alkyl, wherein said substituent is selected from (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (d) -C(O)R11, (e) -C(O)OR11, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, X is selected from O, S(O)m, NH, and NR6, wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2;
R1, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) C1-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl, (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, (16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, or when two members of the group R1, R2, R3 and R4 reside on the same carbon atom of Formula I, or two of the group R1, R2, R3 and R4 reside on adjacent atoms of Formula I, said two members along with the optional substihutents thereon may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2, R3 and R4 resides on an atom adjacent to the N on which R6 resides, said member may optionally be joined with R6 along with the optional subtstituents thereon, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or optionally substituted C1-6alkyl, wherein said substituent is selected from (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (d) -C(O)R11, (e) -C(O)OR11, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
2. A compound according to Claim 1 wherein R1, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro, bromo, and iodo, (f) trifluoromethyl, (g) C1-6alkyl, (h) C1-6alkoxy, (i) C1-6alkylthio, (j) C1-6alkylcarbonyl, (k) mono- and di-C1-6alkylamino, (l) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono-and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl, (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (11) amidino.
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono-and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl, (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (11) amidino.
3. A compound according to Claim 2 wherein R1, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1-4alkyl, (h) C1-4alkoxy, (i) C1-4alkylthio, and (j) mono- and di-C1-4alkylamino, R5 is selected from the group consisting of (a) hydrogen, (b) R6R7N-SO2-NH-C(=O)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-4alkyl, and (3) aryl, wherein the aryl group is phenyl, and said substituents are independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, and (7) halo selected from fluoro, chloro, and bromo.
4. A compound according to Claim 3 wherein R2 is hydrogen or methyl;
R4 is hydrogen or methyl;
R1 and R3 are each independently selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3; and R5 is hydrogen.
R4 is hydrogen or methyl;
R1 and R3 are each independently selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3; and R5 is hydrogen.
5. A compound according to Claim 1 wherein or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, X is selected from O, S(O)m, NH, and NR6, wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2, R1 and R2 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) Cl-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, an d triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, (16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituted being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or C1-6alkyl, said C1-6alkyl optionally substituted by (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12.
(3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substitutedL C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (d) -C(O)R11, (e) -C(O)OR11, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
side a or side b has a double bond, X is selected from O, S(O)m, NH, and NR6, wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2, R1 and R2 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) Cl-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, an d triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, (16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituted being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or C1-6alkyl, said C1-6alkyl optionally substituted by (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12.
(3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substitutedL C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (d) -C(O)R11, (e) -C(O)OR11, (f) aryl, selected from phenyl or naphthyl, (g) cyclohexyl.
6. A compound according to Claim 5 wherein R1 and R2 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro, bromo, and iodo, (f) trifluoromethyl, (g) C1-6alkyl, (h) C1-6alkoxy, (i) C1-6alkylthio, (j) C1-6alkylcarbonyl, (k) mono-and di-C1-6alkylamino, (l) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono- and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, brorno, and iodo, (10) oxo, and (11) amidino.
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono- and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, brorno, and iodo, (10) oxo, and (11) amidino.
7. A compound according to Claim 6 wherein R1 and R2 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1-4alkyl, (h) C1-4alkoxy, (i) C1-4alkylthio, and (j) mono- and di-C1-4alkylamino, R3 and R4 reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a sahurated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) R6R7N-SO2-NH-C(=O)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-4alkyl, and (3) aryl, wherein the aryl group is selected from phenyl, and said substituents are independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono- and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, and (7) halo selected from fluoro, chloro, and bromo.
8. A compound according to Claim 7 wherein R1 and R2 are each independently selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3, R3 and R4 reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, R5 is hydrogen.
9. A compound according to Claim 1 or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, X is NR6.
wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2, R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) C1-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9, where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, ( 16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or C1-6alkyl, said C1-6alkyl optionally substituted by (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionaJly substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (e) -C(O)R11, (f) -C(O)OR11, (g) aryl, selected from phenyl or naphthyl, (h) cyclohexyl.
side a or side b has a double bond, X is NR6.
wherein R6 is selected from C1-12alkyl, C(O)C1-12alkyl, C(O)OC1-12alkyl, C(O)NHC1-12alkyl, S(O)2C1-12alky and S(O)2NHC1-12alkyl wherein said C1-12alkyl group being optionally mono or di- substituted by substituents being independently selected phenyl, C1-6alkoxy, amino, and halo;
m is 0, 1 or 2, R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) C1-12alkyl-C(O)NH, (o) C1-12alkoxy-C(O)NH, (p) C1-12alkylamino-C(O)NH, (q) C1-12alkyl-S(O)2NH, (r) C1-12alkylamino-C(O), (s) C1-12alkylamino-S(O)2, (t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl, and pyridyl, (v) phenylamino-C(O)NH, (w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl, (x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, and triazolyl, (y) phenylamino-S(O)2, (z) hydroxy, (aa) amino, (ab) oxo, (ac) C(O)OR7, R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl or C1-6alkyl, (4) -NR7C(O)R8 (6) -NR7C(O)NHR8, (5) -NR7C(O)OR9, where R9 is selected from phenyl, benzyl, cyclohexyl or C1-6alkyl (7) -NR7S(O)2R9, (8) -OR7, (9) -C(O)OR9, (10) -C(O)NR7R8, (11) -C(O)R7, (12) -S(O)kR7, (13) -S(O)2NR7R8, (14) halo selected from F, Cl, Br and I, (15) -trifluoromethyl, ( 16) -C(=NR7)-NHR8, (17) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (18) aryl, selected from phenyl or naphthyl, (19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl, (b) isooxazolyl, (c) isothiazolyl, (d) oxadiazolyl, (e) oxazolyl, (f) pyridyl, (g) tetrazolyl, (h) thiazolyl, (i) thienyl, and (j) triazolyl, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR7R8, (4) -OR7, (5) -C(O)OR7, (6) -S(O)kR7, (7) halo selected from F, Cl, Br and I, (8) trifluoromethyl, (9) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, -S(O)2NR7R8 or C1-6alkyl, said C1-6alkyl optionally substituted by (1) -NR12R13, wherein R12 and R13 are each independently H, C1-6alkyl, phenyl or benzyl, (2) -OR12, (3) -C(O)OR12, (4) -S(O)kR12, where m is 0, 1 or 2, (5) halo selected from F, Cl, Br and I, (6) optionaJly substituted aryl wherein aryl and aryl substituents are as defined above, (7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (9) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (e) -C(O)R11, (f) -C(O)OR11, (g) aryl, selected from phenyl or naphthyl, (h) cyclohexyl.
10. A compound according to Claim 9 wherein R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro, bromo, and iodo, (f) trifluoromethyl, (g) C1-6alkyl, (h) C1-6alkoxy, (i) C1-6alkylthio, (j) C1-6alkylcarbonyl, (k) mono-and di-C1-6alkylamino, (l) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroalkyl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono- and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono-and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (11) amidino.
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono- and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) C1-6alkylcarbonyl, (c) aroyl, wherein the aroyl group is benzoyl, (d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl, (e) R6R7N-SO2-NH-C(=O)-, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-6alkyl (3) aryl, wherein the aryl group is selected from phenyl, and (4) R6 and R7 may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen, each of (b) to (e) being mono- or di- substituted the substituents being independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono-and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, (7) C1-3alkyl-S(O)k-, where k is 1 or 2, (8) C1-4alkoxycarbonyl, (9) halo selected from fluoro, chloro, bromo, and iodo, (10) oxo, and (11) amidino.
11. A compound according to Claim 10 wherein R1, R2 and R3 are each independently selected from the group consistingof (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1-4alkyl, (h) C1-4alkoxy, (i) C1-4alkylthio, and (j) mono- and di-C1-4alkylamino, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S, R5 is selected from the group consisting of (a) hydrogen, (b) R6R7N-SO2-NH-C(=O)-, optionally mono or di-substituted, wherein R6 and R7 are independently selected from the group consisting of (1) hydrogen, (2) C1-4alkyl, and (3) aryl, wherein the aryl group is selected from phenyl, and said substituents are independently selected from (1) hydroxy, (2) C1-3alkoxy, (3) amino, (4) mono-and di-C1-6alkylamino, (5) carboxyl, (6) C1-3alkylthio, and (7) halo selected from fluoro, chloro, and bromo.
12. A compound according to Claim 11 wherein R1 is hydrogen or methyl;
R2 is hydrogen or methyl;
R3 is selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S; and R5 is hydrogen.
R2 is hydrogen or methyl;
R3 is selected from (a) hydrogen, (b) methyl, ethyl, propyl or butyl, (c) chloro, (d) -CN, and (e) -CF3, R4 resides on an atom adjacent to the N on which R6 resides, and R4 is joined with R6, such that together with the N on which R6 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5 or 6 atoms, said monocycle optionally containing one or 2 hetero atoms selected from N, O or S; and R5 is hydrogen.
13. A compound according to Claim 1 selected from the group consisting of (a) hexahydro-5-imino-(1H)-1,4-diazepine dihydrochloride, (b) hexahydro-5-imino-1,4-thiazepine hydrochloride (c) hexahydro-5-imino-1,4-oxazepine hydrochloride, (d) hexahydro-5-imino-3-propyl-1,4-thiazepine hydrochloride, (e) hexahydro-5-imino-6-propyl-1,4-thiazepine hydrochloride, (f) hexahydro-5-imino-7-methyl-1,4-thiazepine hydrochloride, (g) hexahydro-5-imino-2-methyl-1,4-thiazepine hydrochloride, (h) hexahydro-5-imino-6-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride, (i) hexahydro-5-imino-3-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride, (j) hexahydro-5-imino-6-(2-methyl-propyl)-1,4-thiazepine hydrochloride, (k) hexahydro-5-imino-3-(2-methyl-propyl)-1,4-thiazepine hydrochloride, (l) hexahydro-5-imino-6-methyl-1,4-thiazepine hydrochloride, (m) hexahydro-5-imino-3-methyl-1,4-thiazepine hydrochloride, (n) hexahydro-5-imino-3-ethyl-1,4-thiazepine hydrochloride, (o) hexahydro-5-imino-3-butyl-1,4-thiazepine hydrochloride, (p) hexahydro-5-imino-3-(2-methyl-3-propenyl)-1,4-thiazepine hydrochloride, (q) (~)-trans-decahydro-4-imino-benzo[b]-1,4-thiazepine acetic acid salt., (r) hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt, (s) hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt, (t) hexahydro-5-imino-1-methyl-(1H)-1,4-diazepine hydrochloride, and pharmaceutically acceptable salts thereof.
14. A compound according to Claim 1 of the formula wherein R4 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro, bromo, and iodo, (f) trifluoromethyl, (g) C1-6alkyl, (h) C1-6alkoxy, (i) C1-6alkylthio, (j) C1-6alkylcarbonyl, (k) mono-and di-C1-6alkylamino, (l) aryl, where aryl is phenyl and naphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and (o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono-and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino,
(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5) pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from (1) hydroxy, (2) C1-4alkyl, (3) C1-3alkoxy, (4) amino, (5) mono-and di-C1-6alkylamino, (6) carboxyl, (7) C1-3alkylthio, (8) C1-3alkyl-S(O)k-, where k is 1 or 2, (9) C1-4alkoxycarbonyl, (10) halo selected from fluoro, chloro, bromo, and iodo, (11) oxo, and (12) amidino,
15. A compound according to Claim 14 wherein R4 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e) fluoro, chloro or bromo, (f) trifluoromethyl, (g) C1-4alkyl, (h) C1-4alkoxy, (i) C1-4alkylthio, and (j) mono- and di-C1-4alkylamino.
16. A pharmaceutical composition for treating a nitric oxide synthase mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of the compound according to Claim 1.
17. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of the compound of Claim 1.
18. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of the compound of Claim 13.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US717295P | 1995-11-01 | 1995-11-01 | |
| US60/007,172 | 1995-11-01 | ||
| US901295P | 1995-12-21 | 1995-12-21 | |
| US60/009,012 | 1995-12-21 | ||
| GBGB9605162.8A GB9605162D0 (en) | 1996-03-12 | 1996-03-12 | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
| GBGB9605700.5A GB9605700D0 (en) | 1996-03-19 | 1996-03-19 | Hexahydro-5-imino,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
| GB9605162.8 | 1996-03-19 | ||
| GB9605700.5 | 1996-03-19 | ||
| PCT/US1996/017447 WO1997016430A1 (en) | 1995-11-01 | 1996-10-28 | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2234641A1 true CA2234641A1 (en) | 1997-05-09 |
Family
ID=27451425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002234641A Abandoned CA2234641A1 (en) | 1995-11-01 | 1996-10-28 | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0861238A4 (en) |
| JP (1) | JP3188715B2 (en) |
| AU (1) | AU700078B2 (en) |
| CA (1) | CA2234641A1 (en) |
| WO (1) | WO1997016430A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2136661C1 (en) * | 1993-10-21 | 1999-09-10 | Джи Ди Сирл энд Ко. | Amidino-derivatives, their use and pharmaceutical composition |
| WO1996033175A1 (en) * | 1995-04-20 | 1996-10-24 | G.D. Searle & Co. | Cyclic amidino agents useful as nitric oxide synthase inhibitors |
| US5981556A (en) * | 1997-07-22 | 1999-11-09 | G.D. Searle & Co. | 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors |
| JP4204657B2 (en) * | 1997-12-05 | 2009-01-07 | 有限会社ケムフィズ | Diabetes prevention and treatment |
| DE19806348A1 (en) * | 1998-02-12 | 1999-08-19 | Schering Ag | 3,4-dihydroquinoline derivatives and their use in medicinal products |
| US6489323B1 (en) | 1998-06-10 | 2002-12-03 | G.D. Searle & Co. | Heterobicyclic and tricyclic nitric oxide synthase inhibitors |
| SE9901530D0 (en) * | 1999-04-28 | 1999-04-28 | Astra Pharma Prod | Novel compounds |
| US6344473B1 (en) | 2000-08-07 | 2002-02-05 | G.D. Searle & Co. | Imidazoles useful as nitric oxide synthase inhibitors |
| EP2085400A1 (en) | 2008-01-29 | 2009-08-05 | Sanofi-Aventis | Substituted heteroarylamide oxazepinopyrimidone derivatives |
| EP2090578A1 (en) | 2008-01-29 | 2009-08-19 | Sanofi-Aventis | Substituted arylamide diazepinopyrimidone derivatives for the treatment of neurodegenerative diseases caused by abnormal activity of GSK3-beta |
| EP2090579A1 (en) | 2008-01-29 | 2009-08-19 | Sanofi-Aventis | Substituted heteroarylamide diazepinopyrimidone derivatives |
| EP2085399A1 (en) | 2008-01-29 | 2009-08-05 | Sanofi-Aventis | substituted arylamide oxazepinopyrimidone derivatives |
| EP2138488A1 (en) | 2008-06-26 | 2009-12-30 | sanofi-aventis | 4-(pyridin-4-yl)-1H-[1,3,5]triazin-2-one derivatives as GSK3-beta inhibitors for the treatment of neurodegenerative diseases |
| EP2138493A1 (en) | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidone derivatives |
| EP2138495A1 (en) | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted pyrimido[2,1-a]isoquinolin-4-one derivatives |
| EP2138492A1 (en) | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidin-4-one derivatives |
| EP2138494A1 (en) | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted alkyl pyrimidin-4-one derivatives |
| EP2138498A1 (en) | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted tricyclic derivatives against neurodegenerative diseases |
| EP2138485A1 (en) | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted N-Oxide pyrazine derivatives |
| KR20220105661A (en) * | 2019-11-26 | 2022-07-27 | 길리애드 사이언시즈, 인코포레이티드 | Methods and intermediates for preparing MCL1 inhibitors |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH422793A (en) * | 1961-07-20 | 1966-10-31 | Wander Ag Dr A | Process for the preparation of 11-basic substituted dibenzo (b, f) (1,4) thiazepines |
| US3444169A (en) * | 1966-01-17 | 1969-05-13 | American Cyanamid Co | Process for 11 - aminodibenz(b,f)(1,4)oxazepines and analogous thiazepines |
| SU629879A3 (en) * | 1974-11-26 | 1978-10-25 | Лилли Индастриз Лимитед, (Фирма) | Method of obtaining thieno(1,5)-benzodiazepines or salts thereof |
| AT355025B (en) * | 1974-11-29 | 1980-02-11 | Sandoz Ag | METHOD FOR PRODUCING NEW 5-AMINO-7-PHENYL-2,3-DIHYDRO-1H-1,4-DIAZEPINE |
| US4761411A (en) * | 1983-05-18 | 1988-08-02 | Hoechst-Roussel Pharmaceuticals Inc. | Dihydrobenzopyrrolobenzodiazepines useful for treating pyschoses |
| RU2136661C1 (en) * | 1993-10-21 | 1999-09-10 | Джи Ди Сирл энд Ко. | Amidino-derivatives, their use and pharmaceutical composition |
| US5629322A (en) * | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
-
1996
- 1996-10-28 AU AU75287/96A patent/AU700078B2/en not_active Ceased
- 1996-10-28 CA CA002234641A patent/CA2234641A1/en not_active Abandoned
- 1996-10-28 JP JP51753197A patent/JP3188715B2/en not_active Expired - Fee Related
- 1996-10-28 WO PCT/US1996/017447 patent/WO1997016430A1/en not_active Application Discontinuation
- 1996-10-28 EP EP96937836A patent/EP0861238A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP3188715B2 (en) | 2001-07-16 |
| WO1997016430A1 (en) | 1997-05-09 |
| AU7528796A (en) | 1997-05-22 |
| JPH11501327A (en) | 1999-02-02 |
| EP0861238A1 (en) | 1998-09-02 |
| EP0861238A4 (en) | 2000-03-01 |
| AU700078B2 (en) | 1998-12-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6372733B1 (en) | Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases | |
| CA2234641A1 (en) | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases | |
| US5629322A (en) | Cyclic amidine analogs as inhibitors of nitric oxide synthase | |
| EP0054951B1 (en) | Dibenz(b,f)(1,4)oxazepine derivatives, process for preparing the same, and pharmaceutical compositions comprising the same | |
| KR100305989B1 (en) | Inhibitors of farnesyl-protein transferases and pharmaceutical compositions comprising them | |
| Srivastava et al. | Synthesis and biological evaluation of 4-thiazolidinone derivatives as potential antimycobacterial agents | |
| WO1996014842A1 (en) | Substituted heterocycles as inhibitors of nitric oxide synthase | |
| EP2252596B1 (en) | Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings | |
| JP4637584B2 (en) | Novel lactams and their use | |
| MX2008013137A (en) | Organic compounds. | |
| WO2008079836A2 (en) | Macrocyclic factor viia inhibitors useful as anticoagulants | |
| EP2374454B1 (en) | Hemiasterlin derivatives and uses thereof in the treatment of cancer | |
| CA2097465A1 (en) | Pyrazinoindoles | |
| US7351721B2 (en) | Amino acid derivatives and pharmaceutical composition comprising, as active ingredients, them | |
| CA2721433A1 (en) | Cysteine and cystine bioisosteres to treat schizophrenia and reduce drug cravings | |
| CA2218360A1 (en) | Nitric oxide synthase inhibitors derived from cyclic amidines | |
| AU2002332640B2 (en) | Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment | |
| EP1664088A2 (en) | Hemiasterlin derivatives and uses thereof | |
| IE840927L (en) | 1,5-benzothiazepines | |
| AU2002332640A1 (en) | Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment | |
| WO2001055118A1 (en) | Benzene-fused heterocycle derivatives and drugs containing the same as the active ingredient | |
| NZ258889A (en) | 3-alkylamino-1,5-benzoxazepin- (and benzothiazepin-) 4-one derivatives and pharmaceutical compositions | |
| HU208420B (en) | Process for producing compounds with analgesic activity for the central nerve systhem and process for producing pharmaceutical activity containing them | |
| GB2065105A (en) | Dibenzazepines | |
| GB2307911A (en) | Substituted saturated aza heterocycle inhibitors of nitric oxide synthase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |