AU712995B2 - Nitric oxide synthase inhibitors derived from cyclic amidines - Google Patents
Nitric oxide synthase inhibitors derived from cyclic amidines Download PDFInfo
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- AU712995B2 AU712995B2 AU57454/96A AU5745496A AU712995B2 AU 712995 B2 AU712995 B2 AU 712995B2 AU 57454/96 A AU57454/96 A AU 57454/96A AU 5745496 A AU5745496 A AU 5745496A AU 712995 B2 AU712995 B2 AU 712995B2
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Description
WO 96/35677 PCT/US96/06831 Nitric Oxide Synthase Inhibitors Derived from Cyclic Amidines This application is a continuation-in-part of U.S. Serial No. 08/438,321, filed May 10, 1995, the contents of which are herein incorporated by reference.
Field of the Invention The present invention relates to amidino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use in therapy, in particular their use as nitric oxide synthase inhibitors.
Background of the Invention It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amyl nitrite, glyceryl trinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacoloyv, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews. 43, 109-142 (1991).
It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve WO 96/35677 PCTIUS96/06831 systemic hypotension such as toxic shock and therapy with certain cytokines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A- 0446699.
It has recently become apparent that there are at least three types of NO synthase as follows: a constitutive, Ca+/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines.
Once expressed this inducible NO synthase synthesizes NO for long periods.
The NO released by the constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms.
It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase.
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis. Accordingly, 2 WO 96/35677 PCT/US96/06831 further conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, inflammatory bowel disease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest), and other CNS disorders mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors for example nicotine and eating disorder.
Further conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy. Further conditions in which there is an advantage in inhibiting NO production from Larginine include autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or ARDS or inflammatory bowel disease, or asthma, cardiovascular ischemia, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, and diabetes.
Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective in that they inhibit both the constitutive and the inducible NO synthase. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible S 35 thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
Thus, while non-selective NO synthase inhibitors have 3
I
WO 96/35677 PCT/US96/06831 therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use.
W094/12165, W094/14780, WO93/13055, EP0446699A1 and U.S.
Patent No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
Summary of the Invention In accordance with the present invention novel amidino derivatives are provided. These novel inhibitor compounds can be represented by the following chemical formula
R
"-Ix N R9
R
7
N
R
8
(I)
and salts, and pharmaceutically acceptable esters and prodrugs thereof, wherein:
R
1 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkyloxy, thioalkoxy, cycloalkyl, heterocyclyl, and aryl, which may optionally be substituted by lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, 4 and salts, and pharmaceutically acceptable esters thereof, wherein:
R
1 is selected from hydrogen, hydroxy, C 1 -Cl 0 -alkyl, C 2 -0 10 -alkenyl, C- 2 -Clo-alkynyl, alkyloxy, thioalkoxy, C 3 -Cl 0 -Cycloalkyl, heterocyclyl, and aryl, which may optionally be substituted by 0 1 -0 10 -alkyl, C 2 -0 10 -alkenyl, 0 2 -Cl 0 alkynyl, C 3 -0 10 -cycloalkyl, 04-Clo-heterocyclyl, hydroxy, 0 1 -0 10 -alkoxy, aryloxy, halogen, thiol, Cl-0 10 -thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, CONR 1 0
R
1 1
S(O)R
10
S(O)
2
R
10 S0 2
NR
0
R
11
PO(OR'
0 )(0R 11 amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, Cl-0 10 -alkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, 0 1 -0 10 -alkoxy, S(O)R 10
S(O)
2
R
10 amidino, guanidino; X =NR 2 S, SO, SO 2
(CH
2
CH=CH;
p 0 to 6; A =NR 3 0, S, SO, SO 2 (CHz)q, CH=CH; q 0 to 6; B NR 4 0, S, So, SO 2
(CH
2
CH=CH;
v 0 to 6; R hydrogen, 0 1 -Clo-alkyl, aryl, C 4 -0 10 -heterocyclyl; R 3= hydrogen, Cl-0 10 -alkyl, aryl, C 4 -Cloheterocyclyl; R~ 4 hydrogen. Cl-Cl 10 -alkyl, aryl, C 4 -0 10 ,-heterocyclyl; 2 34 :::wherein only one of X, A, and B, may be selected from NR ,NR 3 or NR, respectively, 0, S, SO, or SO 2
R
5 R5, R 7 are independently selected from hydrogen, Cl-Cl 0 -alkyl, C 2 -Cloalkenyl, 02-Cia- ?~.alkynyl, C 4 -0 10 -heterocyclyl, hydroxy, 0 1 -0 10 -alkoxy, thiol, C 1 -0 10 -thioalkoxy, S(O)R 9
S(O)
2
R
9 halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxyl, cartoalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonyl- ::*aminoalkyl, haloalkyl, S0 2
NR
0
R
1 wherein all said substitutions may be optionally 36 substituted with one or more of the following: 0 1 -Clo-alkyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, Cl-Clo-alkoxy;
R
6 may optionally be taken together to form an C 3
-C
10 -alicyclic hydrocarbon, 07ZCC0htrccy or C4-Ci,~ aromatic hydrocarbon and said optionally formed ring may be nally substituted with one or more of the following: 0 1 -0 10 -alkyl, 0 2
-C
10 )-alkenyl, 0 2 -Cloalkynyl which may be optionally substituted with carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and 0 1 -0 10 -alkoxy; R" hydrogen, hydroxy, alkyloxy;
R
9 hydrogen, hydroxy, alkyloxy; R0= hydrogen, O 1 -Clc 0 -alkyl, alkylaryl, aryl; hydrogen, 0 1 -0 10 )-alkyl, alkylaryl, aryl;
R
10 and R 11 taken together, may be alkylene, resulting in a N-containing heterocycle; wherein aryl wherever occuring means a 5- or 6-membered single aromatic radical which may-include 0-4 heteroatoms; with the proviso that when A is (CH2)q and B is (CH 2 then only one of R 1 and R' can be hydrogen; with the proviso that when R' is 0 1 -0 10 -alkyl, C 2 -Clo-alkenyl, 0 2 -Clo-alkynyl, alkyloxy, or thioalkoxy, R' is not substituted by C 3 -0 1 -CYcloalkyl,
C
4
-C
10 heterocyclyl, and aryl, unless one A, or B is NR 2 SO, SO 2 with the proviso that when A and B are(CH 2 )p or CH=CH, and R' is C 1 -0 10 alkyl, C2-ClOalkenyl, 0 2 -0 10 -alkynyl, alkyloxy, or thioalkoxy,
R
1 is not substituted by C 3 -Cl 0 -cycloalkyl, P* 4-010 -heterocyclyl, or aryl and R 5 and R 6 are not H; with the further proviso that when A or B is N, at least one of R 1
R
5
R
6 and R 7 is not H; ::with the further proviso that when X is (0H 2 A is (CH2)q, and p+q is 2, and B is N, R 4 is not alkyl;, with the -further proviso that when X is (CH 2 A is (CH2)q, p-fl is 3, IRS, R6, and R are each H, B is not SO 2 with the further proviso that when x is CH 2 and B is (CH2)v, then A :cannot be 0, S, NHl or (CEHI)q unless R1, R 5
R
6 and R7are not hydrogen; with the further proviso that when X is (CH 2 A is (CH2)q, B is (CH 2 and p+q+v is 3, or one of B is CH=CH and p+q is 1, then none of R 5 R3, and R 7 can be a 0 1 -0 10 ,-alkyl, C2-OCIC alkenyl, C 2 -0 10 -alkynyl, C3-Cia-cycloalkyl, or aryl at position 5, and no more than one of R', SYTII 5 R 6 and R 7 can be alkoxy or cycloalkoxy at the WO 96/35677 PCTIUS96/06831 In another broad aspect, the present invention is directed to inhibiting nitric oxide synthesis in a subject in need of such inhibition or treatment by administering a compound of Formula which preferentially inhibits the inducible isoform of nitric oxide synthase over the constitutive isoform of nitric oxide synthase, in a nitric oxide synthesis inhibiting amount to such subject.
The invention further relates to a pharmaceutical composition comprising a compound from Formula Compounds and compositions defined above have usefulness as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form.
Conditions in which there is an advantage in inhibiting NO production from L-arginine in disorders mediated by nitric oxide including amongst others, systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
Further conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or inflammatory bowel disease, cardiovascular ischemia, diabetes, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, hyperalgesia (allodynia) cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest) and other CNS disorder mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors for example nicotine and eating disorder.
The present invention includes compounds of formula in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic 7 WO 96/35677 PCT/US96/06831 acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of nonpharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, lactic, acetic, succinic, fumaric, maleic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and the like.
(See, for example, S. M. Berge et al., Pharmaceutical Salts, J.
Pharm. Sci., 1977, 66, 1-19.) Salts of the compcunds of formula can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
While it may be possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. According to a further aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, inhalation, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with 8 WO 96/35677 PCT/US96/06831 liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring onl the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
-9- WO 96/35677 PCT/US96/06831 Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Formulations for inhalation administration where the active ingredient is inhaled into the lungs either as a mist or coadministered with an inert carrier agent.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day.
The dose range for adult humans is generally from 0.005 mg to g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of formula are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age 10 WO 96/35677 PCT/US96/06831 and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
As utilized herein, the term "lower alkyl", alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term "lower alkenyl" refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include propylenyl, buten-l-yl, isobutenyl, pentenylen-l-yl, 2-2-methylbuten-l-yl, 3methylbuten-l-yl, hexen-l-yl, hepten-l-yl, and octen-1-yl, and the like.
The term "lower alkynyl" refers to an unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl, propynyl, butyn-lyl, butyn-2-yl, pentyn-l-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-l-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
The term "alicyclic hydrocarbon" or "cycloalkyl" means a aliphatic radical in a ring with 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbon atoms. Examples of suitable alicyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
The term "aromatic hydrocarbon" means aromatic radical with 4 to about 16 carbon atoms, preferably 6 to about 12 carbon 11 WO 96/35677 PCT/US96/06831 atoms, more preferably 6 to about 10 carbon atoms. Exarmles of suitable aromatic hydrocarbon radicals include phenyl, naphthyl, and the like.
The term '"aryl" as used herein means 5- and 6-membered single-aromatic radicals which may include from zero to four heteroatoms. Representative aryls include phenyl, thienyl, furanyl, pyridinyl, (is)oxazoyl and the like.
The term DCM means dichloromethane.
The term DEAD means diethyl azodicarboxylate.
The term DIBAL-H means diisobutylaluminum hydride.
The term DMAP means dimethylaminopyridine.
The term DMSO means dimethylsulfoxide.
The term EDC means l-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride.
The term "heterocyclyl radical" means a saturated or unsaturated cyclic hydrocarbon radical including aromatic systems with 4 to about 10 carbon atoms, preferably about 5 to about 6; wherein 1 to about 4 carbon atoms are replaced by nitrogen, oxygen, sulfur, or carbonyl. The "heterocyclic radical" may be fused to an aromatic hydrocarbon radical.
Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, indolyl, thienyl, furanyl, tetrazolyl, 2pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolinyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like.
12 WO 96/35677 PCT/US96/06831 The term HOBT means N-hydroxybenzotriazole.
The term "lower alkoxy", alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms.
Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term "lower thioalkoxy", alone or in combination, means an alkyl thioether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms.
Examples of suitable alkyl thioether radicals include thiomethoxy, thioethoxy, thio-n-propoxy, thio-i-propoxy, thio-nbutoxy, thio-iso-butoxy, thio-sec-butoxy, thio-tert-butoxy and the like.
The term alkoxycarbonyl as used herein means an alkoxy group, as defined above, having a carbonyl group attached.
The term "halogen" means fluorine, chlorine, bromine or iodine.
The term MCPBA means m-chloroperbenzoic acid.
The term NMM means N-methylmorpholine.
The term NMMO means 4-methylmorpholine N-oxide.
The term "prodrug" refers to a compound that is made more active in vivo.
The term sulfinyl means SO.
The term sulfonyl means S0 2 The term TEA means triethylamine.
The term TMSN 3 means azidotrimethylsilane.
13 WO 96/35677 PCT/US96/06831 As used herein, reference to "treatment" of a patient is intended to include prophylaxis.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
Compounds of the present invention can exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, Eand Z-geometric isomers, R- and S-enantiomers, diastereomers, disomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
Disclosed are eleven general synthetic processes useful in the preparation of the compounds of the present invention.
14 WO 96/35677 Scheme 1: PCTJUS96/06831
CO
2 ,Me R 7 z Z halide)
R
6 A. B CO 2 Me R 7 k OH R e R
R
1 dx
Q
RK
6 .x 0 6> R A-B ,c Z- R a, b
R
1 R6
-B
1'm Z- R' fi g h 0
R
R
1
N
B/77 R R 6 R 5 NH .HCI 6 NH R A
AB'
NH .HCI NH a) Mg, TEF; b) Cul, -30 OC; c) -30 00 to 0 OC or d) DMSO, oxalyl chloride, CI{2C12, -70 e) Et 3 N, -70 0 C to 0 00; f) NH20H, NaGAc, EtOH; g) PhSO 2 Cl, NaOH, H 2 0, acetone; h) MeiO'
BF
4 i) NH 4 Cl; j) 1(2003 or NaH, DMF; k) NaCN, DMSO, H 2 0, heat 1) DMF, L- R! (where L'-Rl is CH 2 =CH-CO-Rl); m) 1N LiOH, MeOH.
15 WO 96/35677 WO 9635677PCTJUS96/06831 Scheme 2: R AB 0 R m b R A7
HO,
5 N Rm x
Y
RR
R 7
C
Rm 0 RnB Y R-7AR6 NH .HC1 'K N* n
A
RmNH
.HCI
RR
(Y CN, CO0alkyl, N0 2
SO
2 alky.,
SO
2
NH
2 S0 2 NRlOR 1 1 heteroaryl) R= H, alkyl, cycloalkyl, aryl, heterocycle R= H, alkyl, aryl, heterocycle Rm and Rn may be taken together to form a ring a) solvent (benzene); b) NH 2 OH, NaQAc, EtOH; c) PhSO 2 Cl, NaOH, H 2 0, acetone; d) Me 3
O'BF
4
CH
2 C1 2 e) NH 4 Cl, MeOH.
16 WO 96/35677 Scheme 3: PCTIUS96/06831 a b OR
R
HCI d (R alkyl or aryl) a) Base, R 1
CH
2
NO
2 b) H 2 RaNi, 55*C c) Me 3
O'BF
4 CH-,C1 2 d) NH 4 C1, MeOH Scheme 4: 02>, a R
R
1 b Ri OMe
NO
2 R 7
C
d ,e 6 'Rl a) R 5
COR
6 base; b) Base, R 7 CH-)Co 2 Me; c) H 2 /RaNi, 55'C; d) Me 3
O'BF
4
CH
2 C1 2 e) NH 4 Cl, MeOH.
17 WO 96/35677 Scheme PCTIUS96/06831 0 a R 7 NH b R 6
CO
2 Me
(OH
2 9 N 'YOCH, Ph 0 (Ph =phenyl)
C
CO
2 Me
NYOCH
2 Ph d 002 Me
NYOCH
2 Ph 0
.HCJ.
C0 2 Me pNH 2 HC2.
NH HCJ.
C0 2 Me
.OCH
2 Ph a) DBU, Z-a-phosphonoglycine trimethyl ester; b) H 2 [Rh( (COD) (RR-DIPAMP) I]+BF 4 (antipod catalyst can be used); C) Me 3 0+ BF 4
CH
2 Cl 2 d) NH 4 Cl,MeOH; e) H 2 Pd/C.
i8 WO 96/35677 WO 9635677PCTIUS96/06831 Scheme 6: 0
NH
R
5
R
b 0 HC N>KO2,-- Me I
R
5 Me 0H .1I Me
A/,I
R
5
R
6 Me s, Me c f em Me ,I
R
5
R
:1 NH .HC1 g Ha,, NH
R
5
R
a) (t-butylOCO) 2 0, DMAP, THF; b) LiHMDS, HMPA, THF, (1S) (1O-camphorsulfonyl)oxazirid-ne or (iR) (l-camphorsul1onyl) oxazir-4dine; c) t-butyldirnethy'Silyl chloride, imidazole, DMF; d) 4 2
CH
3 CN; e) Me-zO-SF 4
CH
2 Ci 2 f)N 4 Cl, MO; g (butyl) 4 NF, MeOH.
19 WO 96/35677 WO 9635677PCTfUS96/06831 Scheme 7: t 0 O~ d I e 0 0 f -w CN COOK i N.
OTs m-
NHZ
COOMe
NHZ
e 1n 2) p 3) q
-IM
NH
m N-Z 1 )r 2)j H NH MeC' a) NaH/THF; b) BrCH2CN/THF; c) Ethylene glycol/p-toluenesulfonic acid/toluene; d) LiA1H4/Et2O; e) Carbobenzoxy chloride/tf) p-Toluenesulfonyl chloride/CH2C12/pyridine; g) 20 WO 96/35677 PTU9/63 PCTIUS96/06831 KC.N/acertonitr4 le; h) KOH/ethyiene glyco7 i MeI/nMF/'NaHCO3-; j) H2 Pd/MeOi; k) B2H6,,THF; nn) HCl,'AcOH/H 2 0; ni) NH2OH; p) Benzenesulfony. chloride' 1:20/acet one NaOH; q) Trimethyloxonium terrafluoroborate; r) NH4C1/MeOH; Scheme 8: 7 R 71N BOc co d I k~
BOC
\Si 0I e f MeO'
Z
0 g
N
I
N-Z
H
.N-H
21 WO 96135677 PCTIUS96/06831 a) (t-butYlOCO) 2 0, DMAP, THF; b) LiHMDS, HMPA, THF, camphorsulfonyl)oxaziridine or (iR) (l-camphorsulfonyl) oxaziridine; c) t-butyJldimethylsilyl chloride, imidazole, DMF; d) Mg(ClO4)2 CH3CN; e) Me3O+ BF4g, CH2C12; f) NH4C1, MeOH; g) (butyl)4NtF-,MeQH; h) H2, Pd/c.
-22- WO 96135677 WO 9635677PCT1US96/06831 Scheme 9: 0 x C0 2 Et ab 0 0 0 OCN x d A7BC 2 t A-I. B C0 2 Et xC, 0
NH
1\
OH
A B R 7 e 0 0
H
x I
OH
f 0 0
NHZ
B OTs For E=CH 2 0 0
NZ
For E=CHCH 2 g O 0 NHZ h A-I B
N
O 0
-,NHZ
A .B
R
7 i 0 NHZ E*I A-1. B CO e R 7 j O 0
NH
For either E= CH 2 or E= CH 2
CH
2 O 0 x A-1 B ENZ
R
0 n x A-1 B E'NZ
R
n
A-[B
23 WO 96/35677 WO 9635677PCTIUS96/06831 Scheme 9 (continued) HO, 0 ZN- E0 ;E -NZ NHAlN x I/ E s B} NZ
R
7 O~e Zq ZN.E O~e /7 x E
NHNNN
EI
BA BH B Z 7 x t zI a)R N7/T F b7 ArH C H c t y e e gl c l p t l e e u f acd/ouee;d L~l4EtO e) Crezx cHlie baNoH/waterNH HCI p-ouNslENHCl N C C/a)cH/H2; b) NrH2O/H; Eyenezllptlenesulfonylcird/H0NO;q Trimethyloxoniufl tetrafluoroborate; r) NH4Cl/MeOH-;s) H 2 /Pd/C.
24 WO 96/35677 Scheme PCTIUS96/06831 0
INH
A,
E
.NZ
a N K I f/13-tNZ b Me c Me d f Me 1 0 Me Me I OMe MeFt
NZ
a) (t-butylOCO) 2 0, DMAP, THF; b) LiHMDS, HMPA, TEF, (1O-carphorsulfonyl)oxaziridine or (1O-camphorsulfoiyl) oxaziridine; c) t-butyldinethylsi.y chloride, imiidazole, DMF; d) Mg(Cl0 4 )2 CH 3 CN; e) Me-OBF 4 L, CH 2 Cl2); f) NH 4 Cl, MeOH; g) (butyl) 4 MeOH; h) H 2 Pd/C.
25 WO 96/35677 PCT/US96/06831 Scheme 11: a R alkyl, cycloalkyl, aryl, heterocycle,
CH
2
CH(NH
2
)CO
2
H
Rm H, alkyl, cycloalkyl, aryl, heterocycle Rn H, alkyl, cycloalkyl, aryl, heterocycle
R
m and R n may be taken together to form a ring Z leaving group n 1-4 m 1-4 b, c or d, e, f or n SNH Rm R
R
R H a) catalytic hydrogenation; b) RCHO; c) reduction; d) CH2=C(NHZ)CO 2 Me; e) reduction; f) hydrolysis Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
All experiments were performed under either dry nitrogen or argon. All solvents and reagents were used without further purification unless otherwise noted. The routine work-up of the reactions involved the addition of the reaction mixture to a mixture of either neutral, or acidic, or basic aqueous solutions and organic solvent. The aqueous layer was extracted 26 WO 96/35677 PCT/US96/06831 n times with the indicated organic solvent. The combined organic extracts were washed n times with the indicated aqueous solutions, dried over anhydrous Na 2 S0 4 filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography were achieved with conditions described by Still. (Still, W. Kahn, Mitra, A. Rapid Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., 1978, 43, 2923-2925.) The hydrochloride salts were made from 1N HC1, HC1 in ethanol (EtOH), 2 N in MeOH, or 6 N HC1 in dioxane. Thin layer chromatograms were run on 0.25 mm EM precoated plates of silica gel 60 F254. High performance liquid chromatograms (HPLC) were obtained from C-8 or C-18 reverse phase columns which were obtained from several vendors. Analytical samples were dried in an Abderhalden apparatus at either 56'C or 78'C. 1 H NMR spectra were obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometer with tetramethylsilane as an internal standard. 13 C NMR were obtained from a Varian spectrometer at 125.8 MHz with tetramethylsilane as an internal standard.
27 WO 96/35677 PCT/US96/06831 Example 1 2,2,6-trimethylcyclohexanone, oxime
N
O H
H
3 C CH 3
H
3
C
A Sample of 2,2,6-trimethylcyclohexanone (Aldrich, 4.9 g, 39.0 nmol) was combined with hydroxylamine hydrochloride (NH2OH HC1, 3.6 g, 52.4 mmol) and sodium acetate (NaOAc, 5.2 g, 62.9 mmol) in a mixture of ethanol (EtOH, 35 mL) and water (25 mL). This mixture was refluxed for 5 h under a nitrogen atmosphere. After the reaction was cooled to room temperature and stirred for an additional 5 days, all solvent was removed under reduced pressure.
The residue was partitioned between ethyl acetate (EtOAc) and water and the organic phase was washed with 1 x 75 mL of saturated NaC1 (brine), dried over Na2SO4, and stripped of all solvent under reduced pressure. This provided 5.0 g of the title compound as a white solid. This material showed a retention time of 9.6 min (100% purity by peak area integration) on a Shimadzu GC-14A gas chromatograph (GC) with a 0.25 mm x 25 M methyl, 5% phenylsilicone column using helium as the carrier gas and a temperature program starting at 55 'C and increasing 10 '/minute up to 200 The NMR and IR spectra were also consistent with the assigned structure.
Elemental analysis: C9H17NO 0.1 H20 (MW 157.04) C H N Calculated: 68.83 11.04 8.92 Found: 69.00 11.00 8.85 28 WO 96/35677 PCTIUS96/06831 Example 2 Isomer-A: hexahydro-3,3,7-trimethyl-2H-azepin-2-one Isomer-B: hexahydro-3,7,7-trimethyl-2H-azepin-2-one C H 3 CH3
CH
3 O 0 N N H H 3 C H
H
3 C
CH
3 Isomer-A Isomer-B A 4.9 g (34.3 mmol) sample of the title material of Example 1 was added to a dropping funnel containing 6 mL of 80% H2S04. After using a stirring rod to obtain a turbid solution, this mixture was added dropwise (10 min) to 5 mL of 80% H2S04 stirred magnetically and maintained at 120 OC with an external oil bath. Within minutes of the start of addition an exotherm was noted and the temperature of the reaction rose to 160 OC before cooling again to 120 OC. Ten minutes later the flask was removed from the bath and allowed to cool to room temperature. The product mixture was diluted with water (20 mL) and brought to pH 6 with concentrated This solution was further diluted with 75 mL of water and extracted with 3 x 75 mL of CH2C12. The combined organic phase was washed with 1 x 50 mL of brine, dried (Na2SO4), filtered, and stripped of all solvent under reduced pressure. The oily residue (2.9 g, 56%) is separated by HPLC on silica gel to yield the title products.
29 WO 96/35677 PCT/US96/06831 Example 3 3,4,5,6-tetrahydro-7-methoxy-2,6,6-trimethyl-2H-azepine
CH
3
CH
3 SOMe
N
SH
3
C
To a magnetically stirred slurry of trimethyloxonium tetrafluoroborate (Lancaster, 0.30 g, 2.0 mmol) and 3A molecular sieves (2 g) in CH2C12 (15 mL) under argon (Ar) was added the Isomer-A product of Example 2 (0.31 g, 1.5 mmol). This mixture was stirred at room temperature for 3 days before it was diluted with mL of CH2C12 and partitioned between 40 mL of saturated KHCO3 and 50 mL of EtOAc. The organic phase was separated, dried over Na2S04, filtered, and stripped of all solvent under reduced pressure to provide the crude title product as a pale yellow oil.
This material was chromatographed on a short path Merck flash silica column eluting with EtOAc/n-hexane The title pale yellow liquid product (308 mg, 93%) had a GC retention time of 15.5 min (100%) under the conditions of Example 1 and NMR and IR spectra consistent with the indicated product.
Example 4 3,4,5,6-tetrahydro-7-methoxy-2,2,6-trimethyl-2H-azepine
CH
3 SOMe
N
H
3
CH
3 The Isomer-B product of Example 2 is reacted with trimethyloxor.n.i tetrafluoroborate by the method of Example 3 to produce the title material.
30 WO 96/35677 PCTUS96/06831 Example hexahydro-3,3, 7 -trimethyl-2H-azepin-2-imine, monohydrochloride
CH
3
CH
3
NH
N
H .HC1
H
3
C
The title product of Example 3 (0.30 g, 1.4 mmol) and 0.06 g (1.1 mmol) of ammonium chloride (NH4C1) were refluxed in 13 mL of methanol (MeOH) under a nitrogen atmosphere for 19 h. After cooling the reaction to room temperature, it was filtered, stripped of all solvent under reduced pressure, and partitioned between mL of water and 7 mL of CH2C1 2 The organic and aqueous phases were separated and the aqueous phase was washed with a 25 mL portion of EtOAc before it was lyophilized to provide 0.24 g (92%) of the white solid title material.
Example 6 hexahydro-3,7, 7 -trimethyl-2H-azepin-2-imine, monohydrochloride
CH
3
NH
N
H
3 C H .HCI
CH
3 The product of Example 4 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
31
N
WO 96/35677 PCT/US96/06831 Example 7 3,3,5,5-tetramethylcyclohexanone, oxime
N.OH
A sample of 3,3,5,5-tetramethylcyclohexanone (Aldrich, 6.2 g, 40.0 mmol) was converted to the title compound by the method of Example 1 using 5.6 g (80.0 mmol) of hydroxylamine hydrochloride and 6.7 g (82.0 mmol) of NaOAc in a mixture of 60 mL of EtOH and 60 mL of water. The procedure produced 7.5 g (100%) of the title material as a white solid.
Example 8 hexahydro-4,4,6,6-tetramethyl-2H-azepin-2-one 0
N
H
A sample of the product of Example 7 (7.5 g, 44.4 mmol) was converted to the title compound by the method of Example 2 using 11 mL of 80% H2S0 4 The procedure produced 5.6 g of the title material as a pale yellow tacky solid.
32 WO 96/35677 WO 9635677PCTIUS96/06831 Example 9 3,4,5, 6-tetrahydro-7-nethoxy-3 5-tetramethyl-2H-azeiri-e /OMe
N
The title product of Example 8 (845 mg, 5.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (962 mg, 5.0 mmol) by the method of Example 3 to yield 815 mg (100%) of the title material.
Example hexahydro-4, 4,6, 6-tetramethyl-2H-azepin-2-imine, monohydrochloride
NH
H HC The product of Example 9 (110 mg, 0.6 nmmol) in 3.5 mL of MeOH was reacted with ammonium chloride (32 mg, 0.6 mmol) by the method of Example 5 to yield 90 mg of the title material.
ERMS (El) calcd for C10H20N2 m/e 168.163, found m/e 168.162.
1 H NMR (CD3OD) 8 3. 21 2H) 2. 62 2H) 1. 54 2H) 1. 1 (s, 6H), 1.01 6H).
Elemental analysis: ClOH2ON2 -HCl 0.3 H20 0.25 NH4Cl (MW 223.52) Calculated: Found: 53.74 53.71
H
10.19 9.66
N
14. 10 13 .99 Cl 19.83 19.59 33 WO 96/35677 PCT/US96/06831 Example 11 Tetrahydro-4H-pyran-4-one, oxime
,OH
N
0 Tetrahydro-4H-pyran-4-one (5.0 g, 0.05 mole), hydroxylamine hydrochloride (5.2 g, 0.075 mole) and sodium acetate (13.6 g, 0.1 mole) were refluxed in ethanol (30 mL)/H20 (20 mL) overnight. Contents were allowed to cool and concentrated in vacuo to remove the ethanol. The aqueous solution left was extracted with CH2C12 which was dried (MgSO4) and concentrated in vacuo leaving the title material as a white solid (5.4 g).
1H NMR (CDC13): 6 9.15 (br, 1H); 3.85-3.70 4H); 2.72 2.60 2H); 2.40 2.35 2H).
Example 12 tetrahydro-1,4-oxazepin-5(2H)-one 0 N 0
H
To the title material of Example 11 (5.4 g, 0.047 mole) in acetone (30 mL) at 0 °C was added lN sodium hydroxide. Benzene sulfonyl chloride (6 mL, 0.047 mole) in acetone (10 mL) was added dropwise with magnetic stirring. Contents were stirred hours and concentrated in vacuo to remove the acetone. The aqueous solution was extracted with CH2C12 (2 x 150 mL), dried (MgS04) and concentrated in vacuo leaving an amber oil/solid 34 WO 96/35677 PCT/US96/06831 (2.2 The residue was crystallized from hexanes to give the title material as a white solid (1.37 g).
1H NMR (CDC1 3 6 6.90 (br, 1H); 3.82 3.70 4H); 3.38 3.30 2H); '2.75 2.65 2H).
Example 13 tetrahydro-l,4-oxazepin-5(2H)-imine, trifluoroacetate salt N NH
H
*TFA
The title material of Example 12 (960 mg, 0.008 mole) and trimethyloxonium tetrafluoroborate (1.5 g, 0.01 mole) were mixed in CH2C12 (50 mL) and stirred 72 hours. Contents were concentrated in vacuo and the residue was dissolved in methanol mL). Anhydrous ammonia was bubbled through for 15 minutes.
Contents were stoppered and stirred overnight. After concentrating in vacuo, the residue was partitioned between CH2C12 and water. The aqueous layer was purified by C-18 reverse phase chromatography eluting with 100% H20 (0.05% TFA) to give the title material as a white solid (730 mg).
1H NMR (D20): 8 3.78 3.72 2H); 3.68 3.63 2H); 3.49 3.44 2H); 2.85 2.80 2H).
35 WO 96/35677 PCT/US96/06831 Example 14 1-(5,6-dihydro-2H-pyran-4-yl)pyrrolidine
N
O
Tetrahydro-4H-pyran-4-one (5.0 g, 0.05 mole) and pyrrolidine (4.6 mL, 0.055 mole) were refluxed in benzene (50 mL) with a Dean Stark trap to collect water for 2 hours. Contents were concentrated in vacuo leaving a thick amber oil (7.6 g) which was distilled on a kugelrohr apparatus at 40 'C (0.1 mm) to give the title material as a clear colorless oil (5.9 g).
1H NMR (CDC13): 8 4.28 4.20 2H); 4.20 4.13 1H); 3.88 3.78 2H); 3.07 2.95 4H); 2.35 2.22 2H); 1.90 1.80 4H).
Example 3-(2-Butenyl)tetrahydro-4H-pyran-4-one The title material of Example 14 (23 g, 0.15 mole) and crotyl bromide (15.4 mL, 0.15 mole) were mixed in benzene (200 mL) and stirred 72 hours. Water (50 mL) was added and stirred 2 hours.
The benzene layer was removed and the aqueous layer was extracted with EtOAc (150 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo leaving an oil 36 WO 96/35677 PCT/US96/06831 (20.8 The oil was chromatographed on silica gel elu=ing with 5% EtOAc/hexanes to give the title material as a colorless oil (12.3 g).
1H NMR (CDC13): 6 5.52 5.25 2H); 4.20 4.07 2H); 3.82 3.70 1H); 3.50 3.40 1H); 2.68 2.40 4H); 2.03 1.90 1H); 1.65 J 6 Hz, 3H).
Example 16 3-(2-Butenyl)tetrahydro-4H-pyran-4-one, oxime HO, "N To the title material of Example 15 (13.0 g, 0.084 mole) and hydroxylamine hydrochloride (6.5 g, 0.093 mole) in methanol (100 mL) was added dropwise anhydrous pyridine (8.1 mL, 0.1 mole) in methanol (50 mL). Contents were stirred overnight. Contents were concentrated in vacuo and the residue was partitioned between CH2C12 and water. The CH2C12 layer was dried (MgSO4) and concentrated in vacuo leaving the title material as an oil (19.5 g).
1H NMR (CDC13) as a mixture of syn and anti oximes: 8 8.85 (br, [5.80 5.25, 5.20 4.85 4.20 2.90 (m, 2.80 2.00 4H); [1.63 J 6 Hz), 1.20 0.90 (m) 37 WO 96/35677 PCT/US96/06831 Example 17 3-(2-Butenyl)tetrahydro-1,4-oxazepin-5(2H)-one 0 N 0
H
To the title material of Example 16 (5.0 g, 0.03 mole) in acetone (30 mL) at 0 'C was added 1N sodium hydroxide (30 mL).
Benzene sulfonyl chloride (3.8 mL, 0.03 mole) in acetone (10 mL) was added dropwise and after the reaction came, to room temperature, it was stirred overnight. The contents were concentrated in vacuo to remove acetone and the aqueous solution left was extracted with CH2C12 (2 x 150 mL). The CH2C12 extracts were combined, dried (MgS04), and concentrated in vacuo leaving an oil. Hexane was added to the oil, the resulting white solid was filtered and recrystallized from EtOAc/hexane to give the title material as a white solid (812 mg). From the mother liquor was isolated additional title material plus its other regeoisomer, 6-(2-Butenyl)tetrahydro-1,4-oxazepin-5(2H)one, which was separated by chromatography.
1H NMR (CDC13): 6 5.75 (br, 1H); 5.70 5.50 1H); 5.40 5.23 1H); 4.00 3.80 2H); 3.72 3.52 2H); 3.40 3.30 1H); 2.95 2.80 1H); 2.60 2.55 1H); 2.30 2.15 1H); 2.10 1.95 1H); 1.70 J 6 Hz, 3H).
38 WO 96/35677 PCT/US96/06831 Example 18 3-(2-Butenyl)tetrahydro-l,4-oxazepin-5(2H)-imine, trifluoroacetate salt 0 N NH
H
.TFA
To the title material of Example 17 (612 mg, 3.6 mmol) in CH2C12 mL) was added trimethyloxonium tetrafluoroborate (540 mg, 3.6 mmol) and contents were stirred overnight. After concentrating in vacuo, the residue was dissolved in methanol mL) and anhydrous ammonia was bubbled through the solution.
Contents were stoppered and stirred 72 hours. Contents were concentrated in vacuo and the residue was purified by C-18 reverse phase chromatography eluting with a CH3CN/H 2 0 gradient (0.05 TFA) to give the title material as a white solid (404 mg).
Mass spectral analysis for C 9
H
16
N
2 0: M H 169.
1H NMR (CDC13): 8 9.7 (br, 2H); 8.9 (br, 1H); 5.70 5.54 (m, 1H); 5.40 5.25 1H); 4.03 3.92 1H); 3.90 3.80 (m, 1H); 3.76 3.58 2H); 3.46 3.32 1H); 3.04 2.76 (m, 2H); 2.42 2.18 2H); 1.67 J 6 Hz, 3H).
39 WO 96/35677 PCT/US96/06831 Example 19 l-Methyl-4-piperidin-4-one, oxime, monohydrochloride
OH
N
N
S .HCI To a slurry of 1-methyl-4-pyridone (10 mL, 0.08 mole) and hydroxylamine hydrochloride (6.1 g, 0.088 mole) in methanol (100 mL) was added anhydrous pyridine (7.8 mL, 0.097 mole) in methanol (50 mL) dropwise. Contents were stirred overnight and the title material was filtered as a white solid (9.2 More of the title material was recovered from the methanol filtrate (7.7 g).
1H NMR (D20): 8 3.70 2.90 5H); 2.80 3H); 2.60 2. 2H); 2.40 2.10 1H).
Example hexahydro-l-methyl-5H-l,4-diazepin-5-one
N
N 0
H
To the title material of Example 19 (9.2 g, 0.056 mole) in acetone (50 mL) at 0 °C was added dropwise 1N sodium hydroxide.
After stirring 5 minutes, benzene sulfonyl chloride (7.1 mL) in acetone (5 mL) was added dropwise. Contents were stirred 72 hours, coming to room temperature. Contents were concentrated 40 WO 96/35677 PCTIUS96/06831 in vacuo to remove the acetone, the aqueous solution was made basic with IN sodium hydroxide and lyophilized leaving a solid.
The solid was triturated with CH2C12 and filtered. The CH2C12 was concentrated in vacuo leaving the title material as a solid (4.9 g).
1H NMR (CDC13): S 6.85 (br, 1H); 3.30 3.20 2H); 2.65 2.40 6H); 2.35 3H).
Example 21 hexahydro-l-methyl-5H-l,4-diazepin-5-imine, trifluoroacetate salt N NH
H
.TFA
The 5-0xo-2,3,4,5,6,7-hexahydro-1,4-diazepine product of Example 20 was treated with Me30+BF4 in CH 2 C12 and stirred overnight.
After concentrating in vacuo, the residue was dissolved in methanol and anhydrous ammonia was bubbled through the solution.
The contents were stirred overnight and concentrated in vacuo.
The residue was purified by C-18 reverse phase chromatography to give the title product.
Mass spectral analysis for C 6
H
13
N
3 M'H 128.
IH NMR (DMSO-d6): 5 9.80 9.40 1H); 9.40 1H); 9.10 (s, 1H); 8.60 1H); 3.70 2.85 8H); 2.80 3H).
Example 22 41 WO 96/35677 PTU9I63 PCTfUS96/06831 tetrahydro-3- (2-methoxyethyl) -4H-pyran-4-one Me The title compound of Example 14 is reacted with bromoethyl methyl ether by the method of Example 15 to generate the title compcund.
42 WO 96/35677 PCT/US96/06831 Example 23 tetrahydro-3-(2-methoxyethyl)-4H-pyran-4-one, oxime
HO%
N
Me 0 The title compound of Example 22 is reacted with hydroxylamine by the method of Example 16 to generate the title compound.
Example 24 Isomer-A: tetrahydro-3-(2-methoxyethyl)-1,4-oxazepin-5(2H)-one Isomer-B: tetrahydro-6-(2-methoxyethyl)-1,4-oxazepin-5(2H)-one 0 0. H II 0 N T i_0 Isomer A Isomer B The title compound of Example 23 is reacted with benzenesulfonyl chloride by the method of Example 17 to generate the title compounds. The isomers are separated by column chromatography.
43 WO 96/35677 PCT/US96/06831 Example 2,3,6,7-tetrahydro-3-(2-methoxyethyl)-5-methoxy-l,4 -oxazeoine Me o N
O
N
-0 The Isomer A of Example 24 is reacted with trimethyloxonium tetrafluoroborate in methylene chloride by the method of Example 3 to generate the title compound.
Example 26 2,3,6,7-tetrahydro-6-(2-methoxyethyl)-5-methoxy-1,4-oxazepine OMe 0 The isomer B of Example 24 is reacted with trimethyloxonium tetrafluoroborate in methylene chloride by the method of Example 3 to generate the title compound.
44 WO 96/35677 PCTIUS96/06831 Example 27 tetrahydro-3-(2-methoxyethyl)-1,4-oxazepin-5(2H)-imine, monohydrochloride .HC1
HN
The product of Example 25 is reacted with ammonium chloride in methanol by the method of Example 4 to generate the title compound.
Example 28 tetrahydro-6-(2-methoxyethyl)-1,4-oxazepin-5(2H)-imine, monohydrochloride .HCI NH
HN-
0 The product of Example 26 is reacted with ammonium chloride in methanol by the method of Example 4 to generate the title compound.
45 WO 96/35677 PCT/US96/06831 Example 29 4,4-dimethyl-5-pentylpyrrolidin-2-imine, monohydrochloride
HCI
H
HN N Example 29A Ethyl 3 3 -dimethylacrylate (4.9 g, 38 mmol) was mixed with nitrohexane (5.0 g, 38 mmol), 1M tetrabutylammoniumfluoride (in THF, 38 mL) and heated at 40 °C for 24 hours. The reaction mixture was diluted with diethyl ether, washed with brine, followed by water. Purification by chromatography on silica gel yielded the product, methyl 3,3dimethyl-4-nitrononanoate (6.6 g, 67%).
Example 29 B) The product of Example 29 A (5.6 g, 24 mmol) in absolute MeOH was hydrogenated over RaNi at 55 *C and 60 psi for 24h. The reaction product was purified by column chromatography to yield 4,4-dimethyl-5-pentylpyrrolidin-2-one (2.63 g, Example 29 C) The product of Example 29 B (2.63 g, 14.3 mmol) was treated with trimethyloxonium tetrafluoroborate (2.56 g, 17.4 mmol) in DCM (20 mL) by the method of Example 3, to yield 3,4-dihydro-5methoxy-3,3-dimethyl-2-pentyl-2H-pyrrole (2.0 g, 71%).
Example 29) A solution of the title product of Example 29 C g, 10 mmol) in MeOH (30 mL) was reacted with ammonium chloride (529 mg, 9.9 mmol) by the method of Example 5 followed by chromatography on reverse phase HPLC.
46 WO 96/35677 PCTUS96/06831 Example 5-pentyl-4,4-bis(trifluoromethyl)pyrrolidin-2-imine, monohydrochloride
HCI
H H N N
CF
3
CF
3 Example 30 A) Ethyl 4,4,4-trifluoro-3-(trifluromethyl)crotonate g, 38 mmol) was mixed with nitrohexane (5.0 g, 38 mmol), potassium carbonate (5.3 g, 38 mmol) and Aliquat 336 (20 drops).
The mixture was sonicated at room temperature. When the reaction, monitored by was complete the mixture was acidified with HC1 (1 N) and the aqueous phase extracted with ether. Purification by chromatography on silica gel yielded the product, methyl 4-nitro- 3 3 -bis(trifluoromethyl)nonanoate (3 g, 21%).
Example 30 B) The product of Example 30 A in absolute MeOH is hydrogenated over RaNi at 55'C and 60 psi for 24h. The reaction product is purified by column chromatography to yield 5-pentyl-4,4bis(trifluoromethyl)pyrrolidin-2-one.
Example 30 C) The product of Example 30 B is treated with trimethyloxonium tetrafluoroborate in DCM (20 mL) by the method of Example 3, to yield 3, 4 -dihydro-5-methoxy-2-pentyl-3,3bis(trifluoromethyl)-2H-pyrrole.
Example 30) A solution of the title product of Example 30 C in MeOH (30 mL) is reacted with ammonium chloride by the method of Example 5 followed by chromatography on reverse phase HPLC to generate the title material.
47 WO 96/35677 PCTIUS96/06831 Example 31 ethyl 2 -imino-4-methyl-5-pentylpyrrolidine-3-carboxylate, monohydrochloride
.HCI
H
HN N
-I^
0 Example 31 A) The diethyl ethylidenemalonate (6.4 g, 33 mmol) is mixed with nitrohexane (5 g, 38 mmol), potassium carbonate (2 g) and Aliquat 336 (10 drops). The mixture is sonicated at room temperature. When the reaction, monitored by is complete the mixture is acidified with HC1 (1 N) and the aqueous phase extracted with ether. Purification by chromatography on silica gel yields the product, diethyl 2-(l-methyl-2-nitroheptyl)propane-l,3-dioate.
Example 31 B) The product of Example 31 A in absolute EtOH is hydrogenated over RaNi at 55 'C and 60 psi for 24h. The reaction product is purified by column chromatography to yield ethyl 4methyl-2-oxo-5-pentylpyrrolidine-3-carboxylate.
Example 31 C) The material 31 B is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3, to yield ethyl 3,4-dihydro-5-methoxy-2-pentyl-2H-pyrrole-3-carboxylate.
Example 31) A solution of the title product of Example 31 C in MeOH is reacted with ammonium chloride by the method of Example followed by chromatography on reverse phase HPLC to generate title material.
48 WO 96/35677 PCT/US96/06831 Example 32 2 -imino- 4 -methyl-5-pentylpyrrolidine-3-carboxylic acid, monohydrochloride .HCI
H
HN N
HO
0 Example 32 A) A solution of the title product of Example 31 B in MeOH 2N NaOH is stirred 6h followed by lyophilization. The resulting solid is dissolved in water and EtOAc containing benzylbromide added. The mixture is shaken in a separatory funnel.
The organic solution is separated, dried and evaporated. The residue is purified by column chromatography to yield phenylmethyl 4-methyl-2-oxo-5-pentylpyrrolidine-3-carboxylate.
Example 32 B) The product of Example 32 A is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3, to yield phenylmethyl 3, 4 -dihydro-5-methoxy-3-methyl-2-pentyl- 2 H-pyrrole-4-carboxylate.
Example 32 C) A solution of the title product of Example 32 B in MeOH is reacted with ammonium chloride by the method of Example followed by chromatography on reverse phase HPLC to generate phenylmethyl 2 -imino- 4 -methyl-5-pentyl-3-carboxylate.
Example 32) A solution of product of Example 32 C in absolute MeOH is hydrogenated over Pd/C. The reaction product is purified by chromatography on reverse phase HPLC to generate title material.
49 WO 96/35677 PCTIUS96/06831 Example 33 a-amino-4-hydroxy-5-imino-3-(trifluoromethyl)pyrrolidine-2butanoic acid, monohydrochloride .HC1 H
.HCI
HN N NH 2
OH
OH
HO CF 3 0 Example 33 A) The ethyl 4 ,4,4-trifluoromethyl crotonate (10 mmol) and 2 2 -nitroethyl)-l,3-dioxolane (12 mmol) are reacted with, potassium carbonate (5 mmol) and Aliquat 336 (3 drops), by the method of Example 14. Purification by chromatography on silica gel yields ethyl y-nitro-- (trifluoromethyl)-1,3-dioxolane-2pentanoate.
Example 33 B) The product of Example 33 A in MeOH is hydrogenated over RaNi at 55'C and 60 psi for 6h. The reaction product is purified by column chromatography to yield 5-[(1,3-dioxolan-2yl)methyl]-4-(trifluoromethyl)pyrrolidin-2-one as a mixture of diasteromers.
Example 33 C) The product of Example 33 B is treated with di-tbutyldicarbonate and DMAP in THF and refluxed for 2 h. The solvent is removed and the product is purified by column chromatography to yield 1,1-dimethylethyl 3 -dioxolan-2-yl)methyl]-5-oxo-3- (trifluoromethyl)pyrrolidine-l-carboxylate.
Example 33 D) The product of Example 33 C.with HMPA (1 equivalent) in THF at -70 'C is treated with Lithium hexamethyl disilazide (1.2 equivalents, 1M in THF). The solution is allowed to warm to -40 °C then cooled to -70 and a solution of camphor sulfonyl oxaziridine in THF is added. The solution is stirred at -40 "C for 2h then quenched onto saturated NH4C1. The solution is then extracted with EtOAc. The organics are combined. The solvent is removed and the product is purified by column chromatography to yield 1,1-dimethylethyl 2-[(1,3-dioxolan-2-yl)methyl]-4-hydroxy-5oxo-3-(trifluoromethyl)pyrrolidine-l-carboxylate.
50 WO 96/3S677 PCT/US96/06831 Example 33 E) The product of Example 33 D is treated with NaH and benzylbromide in THF. The product is purified by column chromatography to yield 1,1-dimethylethyl 2-[(1,3-dioxolan-2yl)methyl]-5-oxo-4-(phenylmethoxy)-3-(trifluoromethyl)pyrrolidine- 1-carboxylate.
Example 33 F) The product of Example 33 E in MeOH is treated with HC1 (IN) to yield 5-oxo-4-(phenylmethoxy)-3- (trifluoromethyl)pyrrolidine-2-acetaldehyde which is used directly in the next step.
Example 33 G) To a solution of product of Example 33 F and Z-aphosphonoglycine trimethyl ester in CH2C1 2 is added DBU. The solution is stirred for 2h The solvent is removed and the product is purified by column chromatography to yield methyl 4 -[5-oxo-4- (phenylmethoxy)-3-(trifluoromethyl)pyrrolidin-2-yl]-2- [[(phenylmethoxy)carbonyl]amino]- 2 -butenoate.
Example 33 H) The product of Example 33 G is hydrogenated with [Rh(COD)(R,R-DIPAMP)]+ BF4-. The solvent is removed and the product is purified by column chromatography to yield methyl a-[[(phenylmethoxy)carbonyl]amino]-4-(phenylmethoxy)-3- (trifluoromethyl)pyrrolidine-2-butanoate.
Example 33 I) The product of Example 33 H is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3, to yield methyl 3 4 [[(phenylmethoxy)carbonyl]amino]-4-(phenylmethoxy)-3- (trifluoromethyl)-2H-pyrrole-2-butanoate.
Example 33 J) A solution of the title product of Example 33 I in MeOH is reacted with ammonium chloride by the method of Example followed by chromatography on reverse phase HPLC to yield methyl imino-a-[[(phenylmethoxy)carbonyl]amino]-4-(phenylmethoxy)-3- (trifluoromethyl)pyrrolidine-2-butanoate, monohydrochloride.
Example 33) The product of Example 33 J in absolute MeOH is hydrogenated over Pd/C for 24h. The reaction product is purified by chromatography on reverse phase HPLC to yield 33.
51 WO 96/35677 PCT/US96/06831 Example 34 hexahydro-2-imino-4methyl-7-( 2 -propenyl) -lH-azepin--3-ol Me
OH
N NH
H
HCI
Example 34 A) A THF solution of hexahydro-4-methyl.7-(2propenyl)-2H-azepin-2-one is treated with di-t-butyldicarbonate and dimethylalninopyridine (DMAP, 1 eq) to generate the Boc protected lactam, 1, 1-dimethylethyl hexahydro-4-methyl-2oxo 7 2 -propenyl) -lH-azepine-l-carboxylate.
Example 34B) To the product of Example 34 A above dissolved in THF and cooled to a low temperature is added hexaxnethylphosphoramide (HMPA, 1 eq) followed by lithium hexamethyldisilylazide (LHMDS, 1.1 eq). To this is added 1.2 equivalents of either (lS) -(camphorsulfonyl) -oxaziridine or (lR) -(camphorsulfonyl) -oxaziridine to generate a chromatographically separable mixture of diastereomers Isomer-A 1, 1-dimethylethyl hexahydro-3R-hydroxy-4-methyl2oxo-7-(2propenyl)-lHi-azepine-l-carboxylate or Isomer-B l,l-dimethylethyl hexahydro-3S-hydroxy-4-methyl- 2 -oxo-7-( 2 -propenyl) -lH-azepine-lcarboxylate.
Example 34 C) A product or product mixture from Example 34 B above dissolved in DMF is treated with imidazole (2 eg) and tbutyldimethylsilyl chloride yielding ll-dimethylethyl dimethylethyl) dimethylsilyloxy] hexahydro-4-methyl2oxo-7-(2propenyl) -lH--azepine-l-carboxylate.
Example 34 D) To a product or product mixture from Example 34 C above dissolved in acetonitrile and warmed to around 50 'C is added magnesium perchlorate [Mg(Cl04)2, 0.2 eq] generating 3- 1-dimethylethyl) dimethylsilyloxylhexahydro.4mety- 2 0
X
0 2 -propenyl) 2 H-azepin-2-one.
Example 34 E) The product or a product mixture from Example 34 D above is treated with trimethyloxonium tetrafluoroborate in CH2Cl 2 52- WO 96/35677 PCT/US96/06831 by the method of Example 3, to yield dimethylethyl)dimethylsilyloxy]-3,4,5,6-tetrahydro-7-methoxy-5methyl-2H-azepine.
Example 34 F) A solution of the title product or a product mixture of Example 34 E in MeOH is reacted with ammonium chloride by the method of Example 5 to generate dimethylethyl)dimethylsilyloxy]hexahydro-4-methyl-7-( 2 -propenyl)- 2H-azepin-2-imine, monohydrochloride. This material is treated with a source of fluoride ion and the crude product chromatographed on reverse phase HPLC to yield the title material.
Example 6-butyl-3-hydroxy-4-methylpiperidin-2-imine, monohydrochloride Me
OH
N NH
H
.HCI
Example 35 A) A THF solution of 6-butyl-4-methylpiperidin-2-one is treated with di-t-butyldicarbonate and dimethylaminopyridine (DMAP, 1 eq) to generate the Boc protected lactam, 1,1dimethylethyl 2-butyl-4-methyl-6-oxopiperidine-l-carboxylate.
Example 35 B) To the product of Example 35 A above dissolved in THF and cooled to a low temperature is added hexamethylphosphoramide (HMPA, 1 eq) followed by lithium hexamethyldisilylazide (LHMDS, 1.1 eq). To this is added 1.2 equivalents of either (lS)-(+)-(camphorsulfonyl)-oxaziridine or (1R)-(-)-(camphorsulfonyl)-oxaziridine to generate chromatographically separable mixture of diastereomers Isomer-A I,l-dimethylethyl 6-butyl-3R-hydroxy-4-methyl-2-oxopiperidine-lcarboxylate or Isomer-B l,l-dimethylethyl 6-butyl-3S-hydroxy-4methyl- 2 -oxopiperidine-l-carboxylate.
Example 35 C) A product or product mixture from Example 35 B above dissolved in DMF is treated with imidazole (2 eq) and tbutyldimethylsilyl chloride yielding 1,1-dimethylethyl 6-butyl- 53 WO 96/35677 PCT/US96/06831 3-[(1,1-dimethylethyl)dimethylsilyloxy]-4-methyl-2oxopiperidine-l-carboxylate.
Example 35 D) To a product or product mixture from Example 35 C above dissolved in acetonitrile and warmed to around 50 'C is added magnesium perchlorate [Mg(Cl0 4 0.2 eq] generating 6butyl-3-[(l,l-dimethylethyl)dimethylsilyloxy]- 4 -methylpiperidin- 2-one.
Example 35 E) The product or a product mixture from Example 35 D above is treated with trimethyloxonium tetrafluoroborate in CH2C1 2 by the method of Example 3, to yield dimethylethyl)dimethylsilyloxy]-6-ethoxy-2,3,4,5-tetrahydro-4methylpyridine.
Example 35 F) A solution of the title product or a product mixture of Example 35 E in MeOH is reacted with ammonium chloride by the method of Example 5 to generate 6-butyl-3-[(l,ldimethylethyl)dimethylsilyloxy]- 4 -methylpiperidin-2-imine. This material is treated with a source of fluoride ion and the crude product chromatographed on reverse phase HPLC to yield the title material.
Example 36 6-imino-2,4-dimethylpiperidine-3-methanamine, dihydrochloride CH3 .HC1
H,N
H
3 C N NH H .HC1 6-amino-2,4-dimethylpyridine-3-carbonitrile (1.5 g) and platinum oxide (500 mg) in ethanol (30 mL) and conc HC1 (1 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen at 55 'C for 48 hours. The contents were filtered and the filtrate concentrated in vacuo leaving a waxy solid.
Trituration with ethanol gave the title material as a white solid (191 mg).
54 WO 96/35677 PCT/US96/06831 Mass spectral analysis for C 8
H
17
N
3 M+H 156 1 H NMR (D20): S 3.63 3.40 2H); 3.20 3.07 1H); 2.72 2.60 1H); 2.40 2.25 1H); 2.05 1.90 2H); 1.25 (d, J 6 Hz, 3H); 1.00 J 6 Hz, 3H).
Example 37 4,6,6-trimethylpiperidine-2-imine, trifluoroacetate salt
CH
3 H3C4:
H
H
3 C N NH
H
3
C
H .CF 3
CO
2
H
Example 37 A) A solution of 2,2,4-trimethylcyclopentanone g, 44 mmol) in 35 mL EtOAc/25 mL of water was refluxed with hydroxylamine hydrochloride (4.6 g, 66 mmoles) and sodium acetate trihydrate (10.8 g, 79 mmol) for 4 hrs under nitrogen.
After the solvent was removed by evaporation, the residue was redissolved in 100 mL of EtOAc, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and stripped of all solvent to give 5.6 g of the white powder, 2,2,4-trimethylcyclopentanone oxime. FAB/MS: (MH+)=142.
Example 37 B) The product of Example 37 A was dissolved in mL of acetone and 50 mL of 1 N sodium hydroxide at 0 oC.
Benzenesulfonyl chloride (7.8 g, 44 mmol) was added over 5 min.
The reaction mixture was allowed to warm up and stirred for 18 hrs until complete as determined by shift in HPLC retention time (Vydac C-18, linear gradient 5 to 75 acetonitrile/0.05 TFA in water/0.05 TFA over 20 min). The solvent was removed by evaporation and the residue redissolved in 100 mL EtOAc, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and stripped of all solvent by evaporation.
The crude semisolid material was purified on Waters Deltapak C- 55 WO 96/35677 PCTIUS96/06831 18 using a linear gradient from 10 to 15 acetonitrile(0.05 TFA) in water (0.05 TFA) over 20 min. The lyophilized product, 4,6,6-trimethylpiperidin-2-one, was a tan semisolid, 0.47 g. FAB/MS: (MH+)=142.
Example 37 C) To the product of Example 37 B (3.3 mmol) in mL CH2C12 was added trimethyloxonium tetrafluoroborate (0.6 g, mmol). After stirring 18 hrs, the reaction mixture was diluted with an additional 10 mL of CH2C12, washed with a saturated aqueous potassium carbonate solution, dried over magnesium sulfate, and stripped of all solvent to generate 2,3,4,5-tetrahydro-6-methoxy-2,2,4-trimethylpyridine.
Example 35) The product of Example 37 C was dissolved in 25 mL of methanol and refluxed with ammonium chloride for 3 hrs. The solvent was removed by evaporation and the residue oil was dissolved in 25 mL of EtOAc, washed with water, and stripped of all solvent under reduced pressure to produce the crude product.
The material was purified on Waters Deltapak C-18 using a linear gradient of 5% to 70% acetonitrile(0.05 TFA) in water (0.05 TFA) over 30 min. and lyophilized to give 0.075 g white powder title material. FAB/MS: (MH+)=141.
1H NMR (CDC13): 6 10.4 (bs, 1H); 9.7 (bs, 1H); 7.5 (bs, 1H); 2.6 1H); 2.0 2H); 1.8 2H); 1.4 3H); 1.3 3H); 1.1 3H).
Example 38 4,4,6-trimethylpiperidin-2-imine, trifluoroacetate salt
H
3 C CH 3
H
3 C N NH
H
.CF
3
COH
Example 38 A) A solution of 2,4,4-trimethylcyclopentanone g, 44 mmol) in 35 mL ethyl acetate/25 mL water was refluxed with hydroxylamine hydrochloride (4.6 g, 66 mmol) and sodium acetate 56 WO 96/35677 PCT/US96/06831 :rihydrate (10.8 g, 79 mmol) for 4 hrs under nitrogen. Removed solvent by evaporation, redissolved in 100 mL ethyl acetate and washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then removed solvent to give 6.2 g of 2,4,4-trimethylcyclopentanone oxime as a white powder. FAB/MS: (MH+)=142.
Example 38 B) The product of Example 38 A was dissolved in mL acetone and 50 mL 1 N sodium hydroxide at 0 OC.
Benzenesulfonyl chloride was then added (7.8 g, 44 mmol) over min. The reaction mixture was allowed to warm up and stir for 18 hrs until complete, as determined by the shift in HPLC retention time (Vydac C-18, linear gradient 5 to 75 acetonitrile/0.05 TFA in water/0.05 TFA over 20 min). The solvent was removed by evaporation and the residue was redissolved in 100 mL EtOAc, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and stripped of all solvent by evaporation. The semisolid product was purified on a Waters Deltapak C-18 using a linear gradient from 10% to 15% acetonitrile(0.05 TFA) in water (0.05 TFA) over 20 min. The lyophilized product, 6,4,4-trimethylpiperidin- 2-one, was a tan semisolid, 0.75 g. FAB/MS: (MH+)=142.
Example 38 C) To the product of Example 38 B (5.3 mmol) in mL CH2C12 was added trimethyloxonium tetrafluoroborate (0.9 g, mmol). After stirring 18 hrs, the reaction mixture was diluted with an additional 15 mL of CH2C12, washed with saturated aqueous potassium carbonate solution, dried over magnesium sulfate, and stripped of all solvent to give 0.69 g of 2,3,4,5-tetrahydro-6-methoxy-2,4,4-trimethylpyridine as an oil.
Example 38) The product of Example 38 C was dissolved in 25 mL of methanol and refluxed with ammonium chloride (0.25 g, 4.6 mmol) for 3 hrs. The solvent was removed by evaporation and the residue oil was dissolved in 25 mL EtOAc, washed with water, and stripped of all solvent. The residue was purified on a Waters Deltapak C-18 using a linear gradient of 5% to 70% acetonitrile (0.05 TFA) in water (0.05 TFA) over 30 min. and lyophilized to give 0.66 g of the title material as a white powder. FAB/MS: (MH+)=141.
57 WO 96135677 WO 9635677PCTIUS96/06831 H? NMR CCDC13): 5 10.4 Cbs, 1H); 9.5 (bs, 1H); 8.1 (bs, 1H); 3.8 Cm, 1iN); 2.3 2H); 1.75 Cd, 2H); 1.3 3H); 1.1 Cs, 3H); 3H).
Example 39 3- C2-butenyl)hexahydro-5-imine-l, 4-oxazepin-6-ol, trifluoroacetate salt N N H
H
TFA
Isomer A Example 39 A) A sample of the 3-(2-Buten-l-yl)-5-oxo- 2,3,4,5..6,7-hexahydro-1,4-oxazepine product of Example 17 (6.6 g, 39 inmol), di-t-butyl dicarbonate C17.5 g, 80 mmol) and 4dimethylaminopyridine (200 mg) were ref luxed in anhydrous THF rnL) overnight. The contents were allowed to cool, diluted with EtOAc, and washed with 5% aqueous NaHCO 3 dried over MgSO 4 and concentrated in vacuo leaving an oil C(12.9 The oil was purified by chromatography on silica gel eluting with EtOAc/hexanes to give 4-N-Boc-3- C2-buten-l-yl) 2,3,4,5,6,7-hexahydro-l,4-oxazepine as a colorless oil C3.7 g).
Example 39 B) To the 4-N-Boc-3-C2-buten-1-yl)-5-oxo- 2.3,4,5,6,7-hexahydro-1,4-oxazepine product of Example 39 A C3.1 g, 12 inmol) in anhydrous TI-F (60 mL) at -78 0 C was added dropwise lithium bis~trimethylsilyl)amide C1M in TEF, 12 mL) keeping the temperature below -70 The contents were allowed to warm to -40 'C and then cooled back to -78 A solution of (1S)-(+)-(10-camphorsulfonyl)oxaziridine C3.0 g, 13 rnmol) in THF m.L) was added dropwise. The contents were warmed to -25 'C and stirred 3 hours before pouring into saturated NH 4 Cl and extracting with EtOAc. The EtOAc layer was dried-over MgSO 4 and concentrated in vacuo to provide 4-N-Boc-3-(2-buten-1-yl)-6- 58 WO 96/35677 PCT/US96/06831 hydroxy-5-oxo-2,3,4,5,6, 7 -hexahydro-l,4-oxazepine as a waxy solid.
Example 39 C) The 4 -N-Boc-3-(2-buten-l-yl)-6-hydroxy-5-oxo- 2,3,4,5,6, 7 -hexahydro-l,4-oxazepine product of Example 39 B (600 mg), t-butyldimethylsilyl chloride (2.0 imidazole (1.6 g) and anhydrous THF (50 mL) were stirred overnight. The contents were partitioned between EtOAc and water. The EtOAc layer was dried over MgSO 4 and concentrated in vacuo to generate an oil.
This oil was chromatographed on silica gel eluting with EtOAc/hexanes to give 4-N-Boc-3-(2-buten-l-yl)-6-(tbutyldimethylsilyloxy)-5-oxo-2,3,4,5,6,7-hexahydro-l, 4 -oxazepine as an oil (400 mg).
Example 39 D) The 4 -N-Boc-3-(2-Buten-l-yl)-6-(tbutyldimethylsilyloxy)-5-oxo-2,3,4,5,6,7-hexahydro-l, 4 -oxazepine product of Example 39 C (400 mg, 1 mmol) and magnesium perchlorate (45 mg) were heated at 50 OC in CH 3 CN (25 mL) for 3 hours. The contents were allowed to cool and were partitioned between EtOAc and water. The EtOAc layer was dried over MgSO 4 and concentrated in vacuo leaving 3-(2-Buten-l-yl)-6-(tbutyldimethyl-silyloxy)-5-oxo-2,3,4,5,6,7-hexahydro-l,4oxazepine as an oil (300 mg).
Example 39) The 3 2 oxo- 2 3 4 ,5,6, 7 -hexahydro-1,4-oxazepine product of Example 39 D (300 mg, 1 mmol) and Me30+BF 4 (150 mg, 1 mmol) were stirred in
CH
2 C1 2 overnight. The contents were concentrated in vacuo, the residue dissolved in methanol, and anhydrous ammonia bubbled into the solution. The reaction was stoppered and stirred overnight. The contents were concentrated in vacuo leaving a yellow oil (366 mg). The oil was purified by C-18 reverse phase chromatography eluting with a CH 3
CN/H
2 0 to give the title products of this Example 39 (isomer A 16 mg) and Example (isomer B, 11 mg) as oils.
Mass spectral analysis for C 9
H
16
N
2 0 2 M+H 185- 1H NMR (D 2 8 5.60 5.42 1H); 5.35 5.20 1H); 4.75 4.60 1H); 3.95 3.50 5H); 2.35 2.20 2H); 1.60 1.45 3H) 59 WO 96/35677 WO 9635677PCT/US96/06831 Example 3- (2-butenyl)hexahydro-5-imine-l,4-oxazepin-6-ol, trifluoroacetate salt
.TFA
Isomer B The crude product oil of Example 39 was purified by C-l8 reverse phase chromatography eluting with a CH 3
CN/H
2 0 to give the title products of Example 39 and title product of Example 40 (isomer B, 11 mng).
Mass spectral analysis for CqH 16
N
2 0 2 M'H =185 1H NMR (D 2 8 5.65 5.45 (in, 1H); 5.35 -5.20 (mn, 1H); 4.90 4.75 (in, 1H); 3.90 3.45 (mn, 4H); 3.35 3.20 (mn, 1H); 2.25 2.05 (in, 2H); 1.60 1.45 3H).
Example 41 6- (2-butenyl)hexahydro-l, 4-oxazepin-5-imine, trifluoroacetate salt H
NH
TFA
The title material was prepared according to the procedure of Example 18, using the 6-(2-Butenyl)tetrahydro-l,4-oxazepin- 5(2H)-one isolated in Example 17.
60 WO 96/35677 PCTIUS96106831 Mass spectral analysis for Cq1-1 6
N
2 0: M+H- 169.
1H MR (D 2 6 5.65 5.50 (in, 1H); 5.40 -5.20 (mn, 1H); 3.95 3.25 (in, 6N); 2.80 2.60 (mn, 1H); 2.50 2.30 (mn, 2H); 1.60 1.50 (mn, 3H).
61- WO 96/35677 PCT/US96/06831 Example 42 3-butylhexahydro-1,4-oxazepin-5-imine, trifluoroacetate salt 2 NH
H
.TFA
The product of Example 18 (1.3 g, 4.6 mmole), 5% rhodium/carbon (400 mg), ethanol (30 mL) and glacial acetic acid (30 mL) were shaken on a Parr hydrogenator at 55 psi of hydrogen overnight.
The reaction contents were filtered and the filtrate was concentrated in vacuo leaving an oil (1.1 The oil was purified by C-18 reverse phase chromatography eluting with a
CH
3
CN/H
2 0 to give the title product as an oil (701 mg, 54% yield).
Mass spectral analysis for C 9
H
18
N
2 0: M+H 171.
iH NMR (CDC1 3 8 9.90 1H); 9.50 1H); 8.90 1H); 4.00 3.40 6H); 3.00 2.70 2H); 1.80 1.20 6H); 1.00 0.80 3H).
Example 43 hexahydro-5-imino-l,4-oxazepine-3-ethanamine, bis(trifluoroacetate) salt
H
2 N H NH .2TFA Example 43 A) To 2-nitroethanol (Aldrich, 50 mL, 0.7 mol) in
CH
2 C12 (50 mL) was added dropwise acetyl chloride (53.3 mL, 0.75 mol) in CH 2 C1 2 (50 mL). The contents were stirred overnight, 62 WO 96/35677 PCT/US96/06831 washed with water, dried over MgSO 4 and concentrated in vacuo leaving l-acetyl-2-nitroethanol as a light yellow oil (86 g).
Example 43 B) A sample of tetrahydropyran-4-one (Aldrich, 30 g, 0.3 mol) and morpholine (Aldrich, 30.5 mL, 0.35 mol) were refluxed in benzene (500 mL) for 3 hr with a Dean Stark trap to collect the water. The contents were allowed to cool and were concentrated in vacuo. The residue was dissolved in acetonitrile (250 mL) and added dropwise to a solution of the 1acetyl-2-nitroethanol product of Example 48 A (46.6 g, 0.35 mol) in acetonitrile (250 mL) at -20 OC. The reaction contents were stirred overnight coming to room temperature and concentrated in vacuo. The residue was partitioned between Et20 and water. The ether layer was dried over MgSO 4 and concentrated in vacuo leaving an oil. The oil was distilled on a Kugelrohr apparatus at 100 OC (0.1 mm) to give 2 -nitroethyltrahydropyran-4-one as an oil which partially solidified (20.9 g).
Example 43 C) The 2 -Nitroethyltetrahydropyran-4-one product of Example 43 B, hydroxylamine-0-sulfonic acid, and formic acid are refluxed for 0.5 hr. The contents are allowed to cool and concentrated in vacuo. The residue is partitioned between
CH
2 Cl 2 and water. The CH 2 C1 2 layer is dried over MgSO 4 and concentrated in vacuo. The residue is purified by C-18 reverse phase chromatography to give 3 -(2-nitroethyl)-5-oxo-2,3,4,5,6,7hexahydro-1,4-oxazepine.
Example 43 D) To the 3 -(2-nitroethyl)-5-oxo-2,3,4,5,6,7hexahydro-1,4-oxazepine product of Example 43 C in CH 2 C12 mL) is added Me30+BF4- and the contents are stirred overnight.
After concentrating in vacuo, the residue is dissolved in methanol (25 mL) and anhydrous ammonia is bubbled through the solution. Contents are stoppered and stirred 72 hours.
Contents are concentrated in vacuo and the residue is purified by C-18 reverse phase chromatography eluting with a CH 3
CN/H
2 0 gradient (0.05% TFA) to give 3 2 2,3,4,5,6,7-hexahydro-l,4-oxazepine.
Example 43) A sample of the 3 2 2,3,4,5,6,7-hexahydro-l,4-oxazepine product of Example 43 C and palladium black in ethanol are shaken at 55 psi hydrogen on a Parr hydrogenation apparatus overnight. The contents are filtered and the filtrate is concentrated in vacuo. The residue -63-- WO 96/35677 PCT/US96/06831 is purified by C-18 reverse phase chromatography to give the title compound.
Example 44 3 a-methoxy- 4 a-methyl-5a-pentylpyrrolidin-2-imine, monohydrochloride MeO CHs HN N
HCI
HH
Example 44 was prepared from Example 45e, iodomethane, and sodium hydride. The synthesis of Example 44 is completed in the manner described in Example Example 2 -imino-4a-methyl-5a-pentyl-3a-pyrrolidinol, monohydrochloride H H .HC1 H Example 45A) To a stirring solution of methyl crotonate (3.28 g, 32.8 mmol) and nitromethane (1.08 g, 16.0 mmol) in mL of CH 3 CN was added DBU (2.39 mL, 16.0 mL). After 72 h, the reaction was concentrated under reduced pressure. The residue was taken up in EtOAc. The EtOAc solution was washed with 0.5 N HC1 and brine, was dried over Na 2
SO
4 anhydrous, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 3.05 g.
WO 96/35677 PCT/US96/06831 Example 45B,C) Example 45A (34 g, 0.15 mol) was reduced under catalytic hydrogenation conditions using Raney Ni in MeOH. After heating the reaction mixture for 16 h at 55 °C, the solvent was removed under vacuum. The crude lactam was separated by column chromatography into the cis (45B) and trans (45C) lactam.
Example 45D) A stirring solution of Example 45B (20 g, 0.12 mol), (BocO) 2 0 (38.7 g, 0.18 mol), DMAP (14.4 g, 0.12 mol) in 500 mL of THF was heated at reflux for 3 h. After concentrating reaction under vacuum, the residue was taken up in EtOAc and washed with KHSO 4 and brine. The organic layer was dried over anhydrous Na2SO 4 filtered, and stripped. The crude product was purified by column chromatography to yield 31 g.
Example 45E) To a stirring solution of Example 45D (2.7 g, 9.9 mmol) and HMPA (1.8 g, 10.0 mmol) in 15 mL of THF cooled to -70 "C was added lithium hexamethyldisilazide (1.7 g, 10.0 mmol). After 20 min, the reaction was warmed to -40 'C and cooled again to -70 To the stirring reaction was added (R)-(-)-(camphorsulphonyl)oxaziridine (2.4 g, 10.4 mmol) in 7 mL of THF. After stirring at -70 "C for 30 min, the reaction was warmed to -30 'C and stirred an additional 2.5 h. To the reaction was added saturated NH 4 C1 solution followed by EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2
SO
4 filtered, and stripped. The crude product was purified by column chromatography to yield 1.3 g of 3hydroxylactam.
Example 45F) To a solution of Example 45E (1.3 g) in CH 2 C12 was added TFA (6 mL). After 2 h, the reaction was concntrated under vacuum to give 0.85 g of product.
Example 45G) To a stirring solution of Example 45F (0.85 g, 4.6 mmol) and imidazole (0.35 g, 4.6 mmol) in 15 mL was added t-butyldimethylsilylchloride (0.70 g, 4.6 mmol). After 18 h, the reaction mixture was concentrated under high vacuum. To the residue was added EtOAc. The organic layer was washed with KHCO 3 solution, H 2 0, and brine, dried over anhydrous Na2SO 4 filtered, and stripped to yield 1.1 g of product.
Example 45H) A solution of Example 45G (1.1 g, 3.7 mmol) and trimethyloxonium tetrafluoroborate (0.6 g, 4.7 mmol) in 30 mL WO 96/35677 PCT/US96/06831 was stirred for 72 h at ambient temperature. After removing solvent under vacuum, the residue was dissolved in EtOAc.
The organic layer was washed with KHCO 3 solution and brine, dried over anhydrous Na 2
SO
4 filtered, and stripped to yield 1 g of product.' Example 451) Example 45H (I g) in MeOH was treated with NH4C1 (0.3 g) under 12 Kbar of pressure. The reaction was concentrated under vacuum. The residue was taken up in
CH
2 C1 2 filtered, and stripped to give 0.8 g of product.
Example 45) To a solution of Example 451 (0.8 g) in 40 mL of MeOH was added 10 mL of 1 N HC1. After 1.5 h, the reaction mixture was concentrated under vacuum. The residue was partitioned between 0.05 N HC1 and CH 2 Cl 2 The aqueous layer stripped. The residue was purified by chromatography on a reverse phase C-18 column to give two alcohols. The first eluting was Example 46 and the second eluting was Example Elemental analysis: CIOH20N 2 0-l HC1 -0.2 H 2 0 (MW=224.35) C H N Cl Calculated: 53.80 9.61 12.49 15.80 Found: 53.80 9.47 12.14 15.46 Example 46 2-imino-4(X-methyl-5-pentyl-3-pyrrolidinol, monohydrochloride HO1 HN .HCI
H
The synthesis and isolation of Example 46 was described in Example Elemental analysis: CIOH20N 2 0-l HC1 -0.2 H 2 0 (MW=224.35) C H N Cl Calculated: 53.80 9.61 12.49 15.80 Found: 53.78 9.37 12.14 15.78 -66- WO 96/35677 PCT/US96/06831 Example 47 2-imino-5a-pentyl-43-(trifluoromethyl)-3a-pyrrolidinol, monohydrochloride H F3 HN
N
.HC1 H Example 47A) A suspension of ethyl 4,4,4-trifluorocrotonate (10.0 g, 59 mmol), 1-nitrohexane (7.86 g, 60 mmol), K 2 C0 3 (4.1 and Aliquot 336 6 drops) was sonicated for 5 h. To the reaction was added Et 2 0 (200 mL). The reaction mixture was filtered, extracted with brine, dried over Na 2
SO
4 (anhydrous), filtered, and concentrated under reduced pressure to give a yellow liquid. The product was purified by column chromatography to give 13.8 g Example 47B,C) A solution of Example 47A (13.0 g) in MeOH was reduced under catalytic hydrogenation conditions (60 psi, using Raney nickel. The reaction was heated for 8 h to effect cyclization after reduction of the nitro group.
After concentration of the reaction mixture under reduced pressure, the residue was purified by column chromatography to give 9.0 g of a light yellow liquid. A second column was run to separate the cis (47B) and trans lactam (47C).
Example 47D) Example 47C was treated in the manner described in Example 45D and following to prepare Example 47.
Elemental analysis: C10H17N2F 3 0 1 HC1 (MW=274.71) C H N C1 Calculated: 43.72 6.60 10.20 12.91 Found: 43.62 6.44 10.15 12.73 -67- WO 96/35677 PCT1US96/06831I Exam-ple 43 h-exahydro-5-imirlo-f-phenyl1, 4 -oxazepine-3-ethanamine, bis (tri4fluoroacetate) salt
H
2 N Na NH
H
2TFA The title product is prepared according to the procedure of Example 43, using P-nitrostyrene instead of l-acetyl-2rnitroethanol to afford the title product.
Example 49 N-34dhdo2-yrl5y~exhdo5iio14oaeie3 ethanamine, bis (trifluoroacetate) salt
N
7
N
H
H
2TFA Example 43 is allowed to react with 2 -rnethoxypyrroline to afford zhe title product.
E~xample (hexahydro-5-imino-l,4-oxazepin-3>yl)ethyl]aminolalanine, -:ris (l:rifluoroacetate) salt 68- WO 96 3 5677 PCT/US96/06831 .3TFA O
HO
2 NN
NH
H
NH
NH
2 Example 50 A) Example 43 is allowed to react with N-CBZdehydroalanine methyl ester to afford the protected title produc=.
Example 50) Removal of the CBZ protecting group from Example A by hydrogenation followed by acid hydrolysis affords the title product.
Example 51 3-[[2-(hexahydro-5-imino-1,4 -oxazepin-3-yl)-2phenylethyl]amino]alanine, tris(trifluoroacetate) salt .3TFA O HO H N H
H"H
NH2 Example 51 A) Example 48 is allowed to react with N-CBZdehydroalanine methyl ester to afford the protected title product.
Example 51) Removal of the CBZ protecting group from example 51a by hydrogenation followed by acid hydrolysis affords the title product.
Example 52 2-(hexahydro-5-imino-1,4-oxazepin-3-yl)cyclohexanamine, bis(trifluoroacetate) salt WO 96/35677 PCTJ[JS96/06831
NH
2 a
H
H
.2TFA :he title product is prepared by the method of Example 43 using z-nitrocyclohexanol in place of 2-nitroethanol.
WO 96/35677 PCTJUS96/06831 Example 53 f-cyclopropylhexahydro-5-imino1, 4 -oxazepine-3-ethanamine, bis (tri-fluoroacetate) salt
H
2
N
.2TFA Example 53 A) 2 -nitro-2-cyclopropylethanol is prepared from cyclopropylcarboxaldehyde via the Henry reaction.
Example 53) The title product is prepared by the method of Example 43 using the 2 -nitro-2-cyclopropylethanol product of Example 53 A in place of 2 -nitroethanol.
Example 54 QX-ethylhexahydro5iminopmethyl1 4 -oxazepine-3-ethanamine, bis (trifluoroacetate) salt
H
2 N Ha 2TFA The title product is prepared by the method of Example 43 using 3 -nitro-4-hydroxypentane in place of 2 -nitroethanol.
Example 2- (hexahydro-.5-imino-1, 4 -oxazepin--3-yl) cyclohexanamine, bis (tr.4fluoroacetate) salt -71- WO 96135677 WO 9635677PCTIUS96/0683 1
NH
2 a
H
H
.2TFA E~xamnple 55 A) Tetrahydropyran-4-one is allowed to react with onitrobenzyl bromide under basic conditions to give 2-(onitrobenzyl) tetrahydropyran-4-one.
Example 55 B) The 2 -(o-nitrobenzyl)tetrahydropyran-4-one product of Example 55 A is carried on as in Example 43c-d to give 3 -(o-nitrobenzyl)-5-imino-2,3,4,5,6,7-hexahydro.1,4oxazepine.
Example 55) The 3 -(o-nitrobenzyl)-5-imino-2,3,4,5,6,7hexahydro-l..4-oxazepine product of Example 55 A is reduced under hydrogen atmosphere utilizing platinum oxide catalyst to afford the title product.
Example 56 hexahydro-5-imino-3- (2-thienyl) 4-oxazepine-3-ethanamine, bis (trifluoroacetate) salt
H
2 N Na NH
H
I2TFA The title material is prepared according to the procedure of E.xample 48 using l-nitro-2-(2-thiophenyl)ethene.
Example 57 c-aminohexahydro-5-imino-J3-(2-thienyl) -1,4-oxazepine-3-proranc--z acid, bis(trifluoroacetate) salt -72- WO 96/35677 PCTIUS96/06831
H
2
N'
.2TFA Example 58 x- (arinomethyl)hexahydro-5-imino-1, 4 -oxazepine-3-methanol, bis (trifluoroacetate) salt
H
2 N Na NH
H
OH
2TFA Example 59 8-imino-3,7-diazaspiro[5.6]dodecan-9-ol, dihydrochioride
NH
.2HC1 (Spiro- 4 -piperidinyl-N-Z)cap~rolactam is treated as descr-ibed in Example 34 to give the title compound.
Example 3 2 -aminoethyl)hexahydro-5-imino-,4oxazepin.6-ol, bis (tri fluoroacetate) salt -73- WO 96/35677 PCT1US96/06831 Examnple 60 A) The product of Example 430 i -s reacted as in Example 39 to afford 3- 2 -nitroethyl)hexahydro-.5im no-inlA oxazepin-6-ol.
7xaxnple 60) 3 2 -nitroethy)hexahydro5...inin14-oxazeD.G6-l -s reduced as in Example 43 to afford the title compound.
Example 61 2 -pyrrolidinylidene)aminolethyl] -1,4oxazepin-6-ol, bis (trifluoroacetate) salt 0OH N N H
H
N
H
N
The product of Example 60 is reacted as in Example 49 to afford the title compound.
Example 62 2 -amino hentylehydrhexahydro-1,4-~oxazpin 6 1 ol 'bis(trifluoroacetate) salt -74-
I
WO 96/35677 WO 9635677PCT/US96/0683 I
H
2
N'
Example 62 A) 3-(2-Nitro-l-phenylethyl)-5-oxo-2,3,4,5,6,7hexahydro-l,4-oxazepine is prepared as in Example 43, using1nitrostyrene instead of l-acetyl-2-nitroethanol.
Example 62 B) 3-(2-Nitro-l-phenylethyl)-5-oxo-2,3,4,5,6,7hexahydro-1..4-oxazepine is reacted as in Example 39 to afford 3- (2-nitro--1-phenylethyl) -6-hydroxy-5-imino-2,3,4, 5, 6,7-hexahydro- 1, 4-oxazepine.
Example 62) 3-(2-Nitro-1-phenylethyl) 2,3,4,5,6,7-hexahydro-1,4-oxazepine is reduced as in Example 43 to afford the title compound.
Example 63 W± 2-imino-4L- (trifluoromethyl) -51-pentylpyrrolidin-3t-o1 HO
CF
3
H
Example 63 is synthesized and isolated from Example 47.
Example 64 ±)2-imino-43- (trifluoromethyl) -51-pentylpyrrolidin,-3a-oI WO 96/35677 WO 9635677PCTJUS96/0683 I H HOI Example 64 is prepared from Example 4-7B in the manner described in Example 47.
Example 2-i-mino-4x- (trifluoromethyl) -5ax-pentylpyrrolidi-n-3ax-oI HO
CF
3 HN:
N
H HOI Example 65 is prepared from Example 47B in the manner described in Example 47.
Example 66 ()2-imino-4p-methyl-5aX-pentylpyrrolidin-3ax-ol HO 1CH 3 HN N H HOI =xam-ole 66 iS prepared from Example 450 in the manner describDed in Example 1 Example 67 irino-4cL-methyl- 5P-pentylpyrrol idin-3cx-ol -76- WO 96/35677 WO 9635677PCTJUS96/0683 I HO
OH
3 H HOI E.xample 67 is prepared from Example 45C in the manner described in Example Example 68 ±)5c-(3-aminopropyl)2-imino-4cx-methylpyrrolidin-3ax-ol, dihydrochioride HO
OH
3 HNI17.NH 2
HN
Example 69 (3-aminobutyl) -2-imino-4a-methylpyrrolidin-3z-ol, dihydrochloride HO
OH
3
NH
2 HN-
N
H
HOI
Example camino 4c-hydroxy- 5- imino 3 -methylpyrro 1idine- 2 abutanol, dihydrochioride 77- WO 96/35677 WO 9635677PCTIUS96/06831 HO
OH
3
NH
2 HN
N
H HCI OH Example 71 methyl a-amino 4-hydroxy- 5 -imino -3 ccmethylpyrro 1idine 2cx-butanoate, dihydrochioride HO
OH
3
NH
2 HN N HOI COOMe
H
Example 72 2 -imino- 4 a-methyl-5cX-pentylpyrrolidin3..amine, dihydrochioride
H
2
CH
3
HN
N
C
HHC
amle72 is prepared from Example 45E and Boc 2 NH by Mitsunobu reaction conditions. The synthesis of Example 72 ;s completed in the manner described in Example Example 73 5S-mino-4a-methyl-2cx-pentiylpyrrolidin-3cx-ol, mLonohydroch.'.oride -78B- WO 96/35677 PCTIUS96/0683 1
H
3 0 OH HN N
NHHCI
Example 74 (±5-imino-3a,4a-dimethylpyrroiin2aXpropanamine, dihydroc'Loride HA0
OH
3 HN: NH 2
HN
0 Example 2 -imino-4a-methyl-5sa-pentylpyrroidine3axcarboxylic acid, ronohydrochloride HOOC
OH
3 HN N H
HCI
Example 76 2 -imino-4a-methyl-5a-pentylpyrrolidine-3a.methanol, monohydrochioride
HOH
2 C
OH
3
HN
N
C
HHC
-79- WO 96/35677 WO 9635677PCT/US96/06831 Example 77 3 -i 4 ,5-dihydro-'LH-imidazo -2-y1)propyl] 2 -irn-,ino-4cirethylPyrrolidin-3 cL-al, dihydrochloride Example 78 5Qx-[3-(lH-imidazl-2-yl)prpyl-2imino4x methylpyrrolidin-3 a-al, dihydrochiaride HO CH1 H N
N
NN
NHHCI
Example 79 5 ax-[ 3 -amino-3-(lH-imidazl-2yl)propyl-2imino-4ax methylzDyrrolidin-3aX-ol, trihydrochloride HO
OH
3
HN
H N H HOI
NH
2 Example ()2-imina-4cL-methyl-5a- [3- (phenylmeth'-yl) amino Iproayl] yrrolidin-3a-ol, dihydrachloride WO 96/35677 PCT/US96/06831 HO H
H
3
SHN
HHCI
H
Example 80 A) cis and trans-5-[(1,3-dioxolan-2-yl)methyl]-4- (methyl)pyrrolidin-2-one was prepared in the manner described in R. Ohrlein, W. Schwab, R. Ehrler, V. Jager, Synthesis 1986, 535-538) starting with l,l-dimethoxy-3-nitropropane and methyl crotonate.
Example 80 B,C) Example 80 A was reduced under catalytic hydrogenation conditions using Raney Ni in MeOH. After heating the reaction mixture for 16 h at 55 the solvent was removed under vacuum. The crude lactam was separated by column chromatography into the cis (80 B) and trans lactam.
Example 80 D) A stirring solution of Example 80 B (BocO) 2 0, DMAP in THF is heated at reflux for 3 h. After concentrating reaction under vacuum, the residue is taken up in EtOAc and washed with KHSO 4 and brine. The organic layer is dried over anhydrous Na 2
SO
4 filtered, and stripped. The crude product is purified by column chromatography.
Example 80 E) To a stirring solution of Example 80 D and HMPA in THF cooled to -70 'C is added lithium hexamethyldisilazide. After 20 min, the reaction is warmed to -40 'C and cooled again to -70 To the stirring reaction is added (R)-(-)-(camphorsulphonyl)oxaziridine in THF. After stirring at -70 'C for 30 min, the reaction is warmed to -30 'C and stirred an additional 2.5 h. To the reaction is added saturated NH 4 C1 solution followed by EtOAc.
The organic layer is washed with brine, dried over anhydrous Na2SO 4 filtered, and stripped. The crude product is purified by column chromatography to yield 1.3 g of 3-hydroxylactam.
Example 80 F) To a stirring solution of Example 80 E in CHC1 is added H.0 and TFA. After stirring for 2 h, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in EtOAc. The organic layer is washed with a -81- WO 96 3 5677 PCT/US96/06831 minimum of saturated NaHCO 3 dried over MgS04, filtered, and concentrated under reduced pressure to recover crude aldehyde.
Example 80 G) To a sirring solution of Example 80 F in MeOH is added NaBH 3 CN. The reaction is maintained at pH 4 by the addition of HOAc. After stirring for three days, the reaction mixture is concentrated under vacuum. To the residue is added N HC1 and EtOAc. After separating the layers, the aqueous phase is neutralized with NaHCO 3 and extracted with EtOAc.
After concentrating the organic phase, the residue is treated with 1 N HC1 and lyophilized. The resulting solid is purified by reverse phase column chromatography on a C-18 column.
Example 80 H) The product of Example 80 G is treated with trimethyloxonium tetrafluoroborate in CH2C12 as described in Example Example 80) A solution of the product of Example 80 H in MeOH is reacted with ammonium chloride by the method of Example followed by chromatography on reverse phase HPLC to generate the title material.
Example 81 4c-methyl-5c-pentyl-3a-(methylthio)pyrrolidin-2-imine, monohydrochloride MeS
H
3 HN N H
HCI
H
Biological Data The activity of the above listed compounds as NO synthase inhibitors has been determined in the following assays: Citrulline Assay for Nitric Oxide Svnthase -82- WO 96/35677 PCT/US96/06831 Nitric oxide synthase (NOS) activity was measured by mo-niori-g the conversion of [3H]-arginine to 3 H]-citrulline (Bred: and Snyder, Proc. Natl. Acad. Sci. 87, 682-635, 1990 and Misko et al, Eur. J. Pharm., 233, 119-125, 1993). Human inducible NOS'(hiNOS), human endothelial constitutive
NOS
(hecNOS) and human neuronal constitutive NOS (hncNOS) were each cloned from RNA extracted from human tissue. The cDNA for human inducible NOS (hiNOS) was isolated from a kcDNA library made from RNA extracted from a colon sample from a patient with ulcerative colitis. The cDNA for human endothelial constitutive NOS (hecNOS) was isolated from a kcDNA library made from RNA extracted from human umbilical vein endothelial cells (HUVEC) and the cDNA for human neuronal constitutive NOS (hncNOS) was isolated from a XcDNA library made from RNA extracted from human cerebellum obtained from a cadaver. The recombinant enzymes were expressed in Sf9 insect cells using a baculovirus vector (Rodi et al, in The Biology of Nitric Oxide. Pt. 4: Enzymoloqv.
Biochemistry and Immunolov:; Moncada, Feelisch, Busse, Higgs, Eds.; Portland Press Ltd.: London, 1995; pp 447- 450). Enzyme activity was isolated from soluble cell extracts and partially purified by DEAE-Sepharose chromatography. To measure NOS activity, 10 L of enzyme was added to 40 IL of mM Tris (pH 7.6) in the presence or absence of test compounds and the reaction initiated by the addition of 50 4L of a reaction mixture containing 50 mM Tris (pH 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaC12, 20 4M FAD, 100 .LM tetrahydrobiopterin, 0.4-2.0 mM NADPH and 60 iM L-arginine containing 0.9 4Ci of L-[2,3- 3 H]-arginine. The final concentration of L-arginine in the assay was 30 4M. For hecNOS, and hncNOS, calmodulin was included at a final concentration of 40-100 nM. Following incubation at 370 C for 15 minutes, the reaction was terminated by addition of 300 4L of cold stop buffer containing 10 mM EGTA, 100 mM HEPES, pH 5.5 and 1 m-M citrulline. :3H]-Citrulline was separated by chromatography on Dowex 50W X-8 cation exchange resin and radioactivity determined with a liquid scintillation counter. Results are reported in Table I as the IC50 values of compounds for hiNOS, hecNOS and hncNOS. Compounds giving less than 50% inhibition at 100 uM were reported as having IC50 values of >100 4M and compounds -83- WO 96/35677 PCTJUS96/06831I giving greater t-han 50% inhibit-ion az 100 4aM were reported as avingr IC50 values of <100 PtM.
-84- 35 WO 96/35677 PCT1US96106831 The -F:7Llowirig Examples were assayed with- the following results.
Table I
IC
5 0 (14M] Example hiNos hecNOS hncNOS ±0 >100 13 <100 <100 <100 18 <100 >100 >100 21 >100 >100 >100 36 >100 37 <100 <100 <100 38 >100 <100 <100 39 <100 >100 <100 40 <100 >100 <100 41 >100 >100 >100 42 <100 >100 <100 44 >100 >100 >100 <100 >100 <100 46 <100 >100 <100 47 <100 >100 <100 hiNOS refers to human inducibDle NOS WO 96/35677 PCT/US96/06831 necNOS refers to human endothelial constitutive
NOS
nncNOS refers to human neuronal constitutive
NOS
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
-86-
Claims (4)
1. A compound having the formula: R and salts, and pharmaceutically acceptable esters thereof, wherein: 9 99 R 1 is selected from hydrogen, hydroxy, 0 1 -0 10 -alkyl, 0 2 -Cl 0 -alkenyl, C 2 -0 10 -alkynyl, alkyloxy, thioalkoxy, C3-Clo-Cycloalkyl, heterocyclyl, and aryl, which may optionally be substituted by 0 1 -0 10 -alkyl, 0 2 -C 10 )-alkenyl, C 2 -0 10 -alkynyl, 0 3 -C 10 -cycloalkyl, 04-Clo7-heterocyclyl, hydroxy, Cl-Clo-alkoxy, aryloxy, halogen, thiol, C 1 -C 10 -thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, ::alkylaminoaryl, acylamino, carboxy, carboxyalkyl, CONR P S(O)R' 0 S(O) 2 R' 0 ~:SO 2 NR 10 R' 1 P O(0R 10 amidino, guanidlino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, C, -Clo-alkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, *carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, 0 1 -C 10 -alkoxy, S(O)R 10 S(0) 2 R'O, amidino, guanidino; 9* .2tJ 9999
9. *9 .9 9. *9 9 9 X =N P 2 os, p 0 to 6; A =NR, OS' q =0 to 6; B NR 4 v 0 to 6; 2 R hydrogen, R 3 hydrogen, P 4 =hydrogen. SO, S02, (CHOP, CH=t-l; SO, S0 2 (OH 2 CH=CH; SO, SO 2 (CH 2 X, CH=CH; Cl-0 10 -alkyl, aryl, 0 1 -0 10 -alkyl, aryl, Ci-Clo-alkyl, aryl, 0 4 -0 10 -heterocyclyi; 04-Cloheterocyclyl; 04-Clo-heterocyclyl; wherein only one of X, A, and B, may be selected from NR 2 NR or NR respectively, 0, S, SO, or SO 2 R6 R 7are independently selected from hydrogen, 0 1 -Cio-alkyl, C2-Cloalkenyl, C2_Cj2- alkynyl, 04-Clo-heterocyclyl, hydroxy, Cl-Cl 10 -alkoxy, thiol, Cl-Cio-thioalkoxy, S(O)R 9 halogen, nitro, amino, alkylamino, dialkylarnino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxyl, car-boalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonyl- aminoalkyl, haloalkyl, S0 2 NR 10 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: C 1 -C 10 alkyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, Cl-Clo-alkoxy;- R6, may optionally be taken together to form an 0 3 -Clo-alicyclic hydrocarbon. C 4 -0 10 -heterocyclyl or 04-016 aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more of the following: 0 1 -0 10 -alkyl, C2-0i 0 -alkenyl, 0 2 -Cloalkynyl which may be optionally substituted with carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and Cl-Clo-alkoxy; 2Q.R yrgn hdoy lyoy R'5 hydrogen, hydroxy, alkyloxy; R 10 hydrogen, Cl-Clo-alkyl, alkylaryl, aryl; R" hydrogen, Cl-C 10 -alkyl, alkylaryl, aryl; R 10 and R' 1 taken together, may be alkylene, resulting in a N-containing heterocycle; 0**wherein aryl wherever occuring means a 5- or 6-membered single aromatic radical which :::may-include 0-4 heteroatoms; *with the proviso that when A is (CH 2 and B is (CH 2 then only one of R 5 R 5 and R 7 :.can be hydrogen;, with the proviso that when R' is Cl-0 10 )-alkyl, C2-0 10 -alkenyl, 0 2 -C 10 -alkynyl, alkyloxy, or thioalkoxy, R' is not substituted by 0 3 -0 10 ,-cycloalkyl, 0 4 -Cl 0 heterocyclyl, and aryl, unless one A, or B is NR 0, S, SO, SO 2 with the proviso that when A and B are(CH 2 )p or CH=CH, and R 1 is Cl-0 10 alkyl, 02-010- alkenyl, 02-Clo-alkynyl, alkyloxy, or thioalkoxy, R 1 is not substituted by 0 3 -C, 0 -cycloalkyl, -heterocyclyl, or aryl and R 5 and R 6 are not H; with the further proviso that when A or B is N, at least one of R 5 R and R 7 is not H; with the further proviso that when X is (CH 2 A is (CH2)q, and p~-q is 2, and B is N, R 4 is not alkyl; with the further proviso that when X is (CH 2 A is (CH2)q, p+q is 3, R 1 R 5 R's, and R 7 are each H, B is not S0 2 with the further proviso that when X is CR 2 and B is (CH 2 then A cannot be 0, S, NH or (CR 2 q unless R 1 R 5 R 6 and R 7 are not hydrogen; with the further proviso that when X is (CH 2 A is (CH2)q, B is (CH 2 and p+q+v is 3, or one of B is CH=CH and p+q is 1, then none of R6, and R 7can be a C 1 -Clo-alkyl, C2-CO1O- alkenyl, C 2 -0 10 -alkynyl, C3-Clo-cycloalkyl, or aryl at position 5, and no more than one of R 1 RR 6 and R 7 can be alkoxy or cycloalkoxy at the The compound as recited in Claim 1 wherein: R1 is selected from hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, thioalkoxy, C 3 -0 10 -cycloalkyl, and 0 4 -Clo-heterocyclyl, which may optionally be substituted by Cj- C 10 -alkyl, C 2 -Clo-alkenyl, C 2 -Clo-alkynyl, cycloalkyl, heterocyclyl, aryf, hydroxy, Cl-0 10 -alkoxy, aryloxy, halogen, thiol, lower thioalkoxy, amino, alkylamino, aminoalkyl, aminoaryl, carboxy, 0 .carboxy(alkyl, CONR 0 R 1 SO 2 NRU(R amidino, gua'nidino; wherein all said substitutions :may be optionally substituted with one or more of the following: halogen, 0 1 -0 10 -alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, Cl-0 10 -alkoxy, amidino, guanidino; X NR', 0, S, (CH 2 CH0CH; p~ p=O0to 4; A NR 3 0, S, SO, S0 2 (CH2)q, CH=CH-, q 0 to 4; B NR 4 0, S, So, SO 2 (CH 2 CH=CH; v =0 to 4; R 2 hydrogen, Cl-Clo-alkyl, aryl, C4-C1O)-heterocyclyl; R3= hydrogen, Cl-Clo-alkyl, ar-Yl, C4-Cloheterocyclyi; R4= hydrogen, Cl-0 10 -alkyl, aryl, C4-Cloheterocycdyp- R 6 R 7 are independently selected from hydrogen, Ci-0 10 -alkyl, 02-ClO)-alkenyl, C 2 -Cl 10 -alkynyl, C4-Clo-heterocyclyl, hydroxy, Cl-Clo-alkoxy, thiol, Ci-Cla-thioaikoxy, amino, alkylamnino, aminoalkyl, arylamino, aminoaryl, carboxyl, carboalkoxy, carboaryloxy, amino- carbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, haloalkyl, SO 2 NR"l, wherein all said substitutions may be optionally substituted with one or more of the following: Cl-Clo-alkyl, halogen, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carbo- alkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, C 1 -Clo-alkoxy; R6, may optionally be taken together to form a 03-Clo-alicyclic hydrocarbon, or 04-ClO)-heterocyclyl; ?.Ra hydrogen or hydroxy; n:.R 9 hydrogen; R1 hydrogen or Cl-Co 1 -alkyl; and R' 1 hydrogen or Ci-0 10 -alkyl. 3. The compound as recited in Claim 1 wherein: R' is- selected from hydrogen, hydroxy, 0 1 -Clo-alkyl, C2-Clo-alkenyl, C 2 -0 10 -alkynyl, *4:alkyloxy, thioalkoxy, C,3-Clo-cycloalkyl, and O4-ClO-heterocyclyi, which may optionally be' :::substituted by Ci-C 10 -alkyl, C2-Clo-alkenyl, 0 2 -Clo-alkynyl, halogen, 0 3 -0 10 -cycloalkyl, C4-C10- aryl, hydroxy, Ci-Clo-alkoxy, aryloxy, amino, alkylamino, aminoalkyl, aminoaryl, :::carboxy, carboxyalkyl, SO 2 NR 10 'R' 1 amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, Cl-C 10 -alkyl, or amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, 0 1 -C 10 -alkoxy, amidino, guanidino; X (CH 2 CH=CH;- p 0 to 3; RAA NR 3 0, S, (CH 2 CH=CH- q 0 to 3; B =NR 4 0, S, (CH 2 CH=CH; v =0 to 3; R 3 hydrogen, Cl-Cl 0 -alkyl, aryl, C 4 -0 10 -heterocyclyl; R 4 hydrogen, Cl-0 10 -alkyl, aryl, C 4 -0 10 -heterocyclyl; R 5 R'3 R 7 are independently selected from hydrogen, Cl-Cl 0 -alkyl, C 2 -Clo-alkenyl, 02-010- alkynyl, 0 4 -0 10 -heterocyclyl, hydroxy, 0 1 -C 10 -alkoxy, amino, alkylamino, aminoalkyl, aryl- amino, aminoaryl, carboxyl, carboalkoxy, carboaryloxy, aminocarbonylamino, S0 2 NR 0 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: Cl-0 10 -alkyl, halogen, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, 0 1 -0 10 -alkoxy; R8= hydrogen or hydroxy; R 9 hydrogen or hydroxy; R' hydrogen or 0 1 -Clo-alkyl; and hydrogen or C 1 -0 10 -alkyl. 4. The compound as recited in Claim 1 wherein: R 1 is selected from hydrogen, hydroxy, C 1 -0 10 -alkyl, C 2 -0 1 l,-alkenyl, C 2 -Clo-alkynyl,
24-- alkyloxy, thioalkoxy, Cr-Clo-cycloalkyl, and 0 4 -C 10 -heterocyclyl, which may optionally be substituted by CI-CT-alkyl, C 2 -Cl 0 -alkenyl, 0 2 -0 10 alkynyl, 0 3 -C 10 -cydloalkyl, C4-C1o.- heterocyclyl, aryl, hydroxy, 0 1 -0 10 -alkoxy, aryloxy, amino, alkylamino, aminoalkyl, aminoaryl, carboxy, carboxyalkyl, SO 2 NR 10 amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the .025 following: halogen, C 1 -Cj 0 -alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carbo- alkoxy, hydroxy, Cl-0 10 -alkoxy, amidino, guanidino; Xp= :A =NR oxygen, (CH2)q, CH=CH; q =O0to 3; 0, (CH 2 CH=CH; v 0 to 3; R 3 hydrogen, Cl-C 10 -alkyl, aryl, 0 4 -0 10 -heterocyclyi; R 5 R 6 RP 7 are independently selected from hydrogen, 0 1 -C 10 -alkyl, C 2 -0 10 -alkenyl, 02-0o alkynyl, C,-C 10 )-heterocyclyl, hydroxy, 0 1 -0 10 alkoxy, amino, alkylamino, aminoalkyl, aryl- -amino, aminoaryl, carboxyl, carboalkoxy, aminocarbonylamino, S0 2 NR 0 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: Ci-Cio- alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, lower alkoxy-, R a hydrogen or hydroxy; R= hydrogen or hydroxy; R 10 hydrogen or C 1 -Cl 0 -alkyl; and R 11 hydrogen or Cl-0 10 -alkyl. The compound as recited in Claim 1 wherein: R' is selected from hydrogen, hydroxy, CI-C 10 -alkyl, C 2 -Clo-alkenyl, alkyloxy, thioalkoxy. 0 3 -0 10 -cycloalkyl, and C 4 -0 10 -heterocyclyl, which may optionally be substituted by CI-C 10 -alkyl, 0 2 -C 10 alkenyl, halogen, aryl, hydroxy, Cl-Clo-alkoxy, aryloxy, amino, alkyl- amino, aminoalkyl, aminoaryl, carboxy, carboxyalkyl, S0 2 NR 1 amidino, guanidino. X =(0H 2 )p; p =0 to 3; A =NR 3 oxygen, (CH2)q, CH=CH; q =0 to 3; B =(CH2)V, CH=CH; 2M.. v 0 to 3, 3 =hydrogen, Cl-Clo-alkyl, any!, C 4 -C 1 -heterocycly!; R5 R6 R are independently selected from hydrogen, 0 1 -Clo-alkyl, C 2 -C 10 alkenyl, *C 4 -Cl 0 -heterocyclyl, hydroxy, C 1 -Cl 0 -alkoxy, amino, alkylamino, aminoalkyl, anylamino, 5. aminoaryl, carboxyl, c-arboalkoxy, aminocarbonylamino, S0 2 NR 0 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: C 1 -C 10 -alkyl, '00:4 *4 halQgen,.amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, ::Cl-Cl-alkoxy; R8 hydrogen or hydroxy; R 9 hydrogen or hydroxy; .0 R. hydrogen or 0 1 -C 10 alkyl; and 1 hydrogen or C 1 -0 10 -alkyl. 6. The compound as defined in Claim 1 wherein the compound is selected from the group consisting of hexahydro-3,37-timethyl-2H-azepin-2-imine, monohydrochloridel hexahydro-3,7,7-trimethyl-2H-azepin-2-imine, monohydrochloride; hexahydro-4,4, 6 6 tetramethyl-2H-azepin-2-imine, monohydrochloride; tetrahydro-1 ,4-oxazepin-5(2H)-inmine, trifluoroacetate salt; 3-(2-butenyl)tetrahydro- 1,4-oxazepin-5(2H)-imine, trifluoroacetate salt; hexahydro-1 -methyl-5H-1 ,4-diazepin-5-imine, trifl uo roacetate salt; tetrahydro-3- (2-methoxyethyl)-1 ,4-oxazepin-5(2H)-imine, monohydrochloride; tetra hydro-6-(2-methoxyethyl)-1, ,4-oxazepin-5(2 H)-imi ne, monohydrochloride; 4,4- a-amino-4-hydroxy-5-imino-3-(trifluoromethyl) pyrrolidine-2-butanoic acid, monohy- drochloride; h exahyd ro-2-i min o-4-m eth yl-7-(2-p rope nyl)- 1H-azepin-3-ol; 6-butyl-3-hydroxy-4- methyl piperidin-2-imine, monohydrochloride; 6-imino-2,4-dimethylpiperidine-3-methanamine, dihydrochioride; 4,6,6-trimethylpiperidine-2-imine, tnifluoroacetate salt; and 4,4,6-trimethylpiperidin-2-imine, trifluoroacetate salt. 7. A pharmaceutical composition comprising a compound having the formula Re A X R N< R 7 an atad hraetcal0cetbl sesteroween R'i*eetdfo hdoehdoy C-l0lyC.loakn. 2Cc-aknl lyoy :4 :amn al, and pam atically acpabeeter terofl, whren:O" ()RO substitutcycsomayybe andionally sebeticutyd whichomayooptionaolytbe followcyno,- nitrogeCl-l, amino, alkylamino, dialkylamino, aminoalkyl, dilyaminoalkyl, ayaio carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, lower alkoxy, S(0)R 10 S(O) 2 amidino, guanidino; X NR 2 0, S, SO, S02, (CH 2 CH=CH; p =0 to 6; A =NR 3 0, S, So, SO 2 (0H 2 CH=CH;, q 0 to 6; B =N N 4 SO, SO 2 (CH 2 CH=CH; v 0 to 6; R2= hydrogen, 0 1 -0 10 -alkyl, aryl, 0 4 -0 10 -heterocyclyl; R 3 hydrogen, 0 1 -0 10 -alkyl, aryl, 0 4 -Cloheterocycly; P 4 hydrogen, Cl-Clo-alkyl, aryl, C 4 -Clo-heterocyclyl; wherein only one of X, A, and B, may be selected from NR 2 NP 3 or NR 4 respectively, 0, 3, SO, or S0 2 R 5, RPs, R 7 are independently selected from hydrogen, 0 1 -C 10 alkyl, 02-ClO)-alkenyl, C2-C1o- alkynyl, 0 4 -Clo-heterocyclyi, hydroxy, 0 1 -Clo-alkoxy, thiol, Cl-0 10 thioalkoxy, S(O) P 9 S(O) 2 P 9 halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dial kylam inoal kyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonyl- **aminoalkyl, haloalkyl, SO 2 NP 10 P' 1 wherein all said substitutions may be optionally substituted with one or more of the following: Cl-Clo-alkyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, Cl-Clo-alkoxy; R5, P 3, may optionally be taken together to form an0- 1 lcci yrcarbon -ma n-lo.cylchyr n 0 4 -0 10 7heterocyclyl or a 0 4 -0 16 -aromatic hydrocarbon and said optionally formed ring may F be optionally substituted with one or more of the following: 0 1 -0 10 -alkyl, 0 2 -0 10 -alkenyl, 02-Cia alkynyl which may be optionally substituted with :carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy; P' hydrogen, hydroxy, alkyloxy; P9 hydrogen, hydroxy, alkyloxy; P 10 =hydrogen, Cl-Clo-alkyl, alkylaryl, aryl; R= hydrogen, C 1 -Clo-alkyl, alkylaryl, aryl; P' and PR 1 taken together, may be alkylene, resulting in a N-containing heterocycle: wherein aryl wherever occuring means a 5- or 6-membered single aromatic radical which may include 0 to 4 heteroatoms; with the proviso that when A is (0H 2 and B is (CH 2 then oniy one of R1, Rs, R 6 and R 7 can be hydrogen; with the proviso that when R' is C,-C 10 -alkyl, 0 2 -C 10 -alkenyl, 0 2 -0 10 -alkynyl, alkyloxy, or thioalkoxy, R' cannot be optionally substituted by C 3 -C 10 -cycloalkyl, C 4 -Clo-heterocyclyi, and aryl, unless one A, or B is NR 2 0, S, So, SO 2 with the proviso that when A and B are(CH 2 )p or CH=CH, and R' is 0 1 -C, 0 -alkyl, 0'2-Cia- alkenyl, C 2 -0 10 -alkynyl, alkyloxy, or thioalkoxy, R' is not substituted by 0 3 -Clo-cycloalkyl, 0 4 -Clo-heterocyclyl, or aryl and R5 and R6 are not H;, with the further proviso that when X=(0H 2 A=(0H, 2 B=(CH 2 p+q+v=3, then no more than one of R, R5, R6 and R 7can be alkyl, alkoxy, C 3 -0 10 -cycloalkyl or cycloalkoxy at the with further proviso that when X=(CH 2 A=(CH 2 B=(CH 2 p+q+v=3, and one of R 1 iswR 5 R6 and R 7 is an alkyl, C. 3 -Cl 0 -cycloalkyl or aryl group at the 5-position, then none of the remaining R 1 R 5 R's and R 7 can be a cyano, substituted amino, alkoxy or thioalkoxy at the with the further proviso that when x is CR 2 and 3 is (CH 2 then A *cannot be 0, S, NH or (CH 2 q unless R 1 R5, R6 and R 7 are not 3* hydrogen; togethe r with at least one non-toxic pharmaceutical acceptable carrier. 8. The composition as recited in Claim 7 wherein: R' is selected from hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, thioalkoxy, cycloalkyl, and heterocyclyl, which may optionally be substituted by C 1 -C 1 0 -alkyl., 0 2 -Cl 10 -alkenyl, C 2 -Clo-alkynyl, C3-Cla-cycloalkyl, 0 4 -Cloheterocyclyl, aryl, hydroxy, Ci-Cia)- alkoxy, aryloxy, halogen, thiol, 0 1 -Clo-thioalkoxy, amino, alkylamino, aminoalkyl, aminoaryl, carboxy, carboxyalkyl, CONR', S0 2 NR 0 R 11 amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, Cl-Cl 0 -alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, 'hydroxy, Cl-C 10 -alkoxy, amidino, guanidino; X =NR 2 0,S, (CHOP, CH=CH; p 0 to 4; A =NR 3 0,S, SO, SO 2 (CH2)q, CH=CH; q 0 to 4; B NR 4 0, S, So, SO 2 (CH 2 CH=CH; v =O0to 4; R 2 hydrogen, C,-Cio-alkyl, aryl, C 4 -0 10 heterocyclyl; R 3 hydrogen, C 1 -Clo-alkyl, aryl, C 4 -Cl-heterocyclyl; R 4 hydrogen, C 1 -0 10 -alkyl, aryl, C 4 -Cl-heterocyclyl; R 5 RG, R 7 are independently selected from hydrogen, 0 1 -C 10 -alkyl, C 2 -Cloalkenyl, 0 2 -0 10 -alkynyl, 0 4 -0 10 -heterocyclyl, hydroxy, C 1 -Clo-alkoxy, thiol, Cl-0 10 -thioalkoxy, amino, alkylamino, aminoalkyl, arylamino, aminoaryl, carboxyl, carboalkoxy, carboaryloxy, amino- carbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, haloalkyl, S0 2 NR 10 R" 1 wherein all said substitutions may be optionally substituted with one or more of the following: Cl-0 10 -alkyl, halogen, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, Cl-0 10 -alkoxy; R, R, may optionally be taken together to form a C 3 1 aiycchdrabor 0 4 -Clo-heterocyclyl; hydrogen or hydroxy; R9 =,hydrogen; Rl'=hydrogen or Cl-0 10 -alkyl; and hydrogen or CI-Clo- alkyl, 9. The composition as recited in Claim 7 wherein: R' is selected from hydrogen, hydroxy, Cl-0 10 alkyl, 0 2 -Clo-alkenyl, C 2 -Cl 0 -alkynyl, alkyloxy, thioalkoxy, C3rClO-cycloalkyl, and C4-Clo-heterocyclyl, which may optionally be substituted by 0 1 -C 10 -alkyl, 0 2 -Clo-alkenyl, 0 2 -Cl 0 -alkynyl, halogen, O 3 -CO 0 cycloalkyl, C 4 -C 10 -heterocyclyl, aryl, hydroxy, 0 1 -0 10 -alkoxy, aryloxy, amino, alkylamino, aminoalkyl, aminoaryl, carboxy, carboxyalkyl, SO 2 NR' 0 amidino, guanidino; wherein all said subtiutinsmay be optionally substituted with one or more of the following: halogen, 97 Cl-Clo-alkyl, or amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, Cj-0 10 -alkoxy, amidino, guanidino; X (OH 2 CH=CH; p=0 to3;- A =NR 0, S, (CH2)q, OH=CH; q 0 to 3; B NR 4 C, S, (OH 2 CH=CH; v 0 to 3,; R 3 hydrogen, Cl-C 10 -alkyl, aryl, C 4 -C 10 -heterocyclyl; R4= hydrogen, Cl-Clo-alkyl, aryl, 0 4 -C 10 -heterocyclyi; 6 7 R'3, R are independently selected from hydrogen, Cl-Clo-alkyl, 02-ClO)-alkenyl, C2-Clc- alkynyl, 0 4 -Cio-heterocyclyl, hydroxy, Cl-Clo-alkoxy, amino, alkylamino, aminoalkyl, aryl- amino, aminoaryl, carboxyl, carboalkoxy, carboaryloxy, aminocarbonylamino, S0 2 NR 0 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: Ci-Clo-alkyl, halogen, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, C-i-C 10 -alkoxy; 2t*Ra hydrogen or hydroxy; 9 hydrogen or hydroxy; 10 hydrogen or Cl-Cl 0 -alkyl; and R" hydrogen or Cl-Clo-alkyl. The compound as recited in Claim 8 wherein: R1 is selected from hydrogen, hydroxy, C 1 -C 10 alkyl, 02-Clo-alkenyl, C 2 -Cl 0 -alkynyl, *.*alkyloxy, thioalkoxy, C3-OlO-cycloalkyl, and C 4 -C 10 ,-heterocyclyl, which may optionally be substituted by Cl-Clo-alkyl, C 2 -Clo-alkenyl, C 2 -0 10 -alkynyl, Cr-Co--cycloalky, C4-ClO- S heterocyclyl, aryl, hydroxy, Cl-Clo-alkoxy, aryloxy, amino, alkylamino, aminoalkyl, aminoaryl, *::carboxy, carboxyalkyl, SO 2 NR OR 11 amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, Cl-Clo-alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, Cl-C 10 -alkoxy, amidino, guanidino;, X (CH 2 )p: p 0 to 3; RA NR oxygen, CHOCH; 98 q 0 to 3; B (CH 2 01-=0 H; v 0 to 3; R 3 hydrogen, C,-0 10 -alkyl, aryl, 0 4 -0 10 -heterocyclyl; R 5,R6, R 7are independently selected from hydrogen, Cl-0 10 -alkyl, 0 2 -0 10 -alkynyl, 04-Clo-heterocyclyl, hydroxy, 0 1 -0 10 -alkoxy, amino, alkylamino, aminoalkyl, arylamino, aminoaryl, carboxyl, carboalkoxy, aminoc-arbonylamino, S0 2 NR 0 R 1 wherein all said substitutions may be optionally substituted with one or more of the following: 0j-0jO- alkyl, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, Cj-Cj 0 alkoxy; R" hydrogen or hydroxy; R9= hydrogen or hydroxy; R hydrogen or 01-010- alkyl; and R 11 hydrogen or 0j-CjO- alkyl. 11. The composition as recited in Claim 7 wherein: R' is selected from hydrogen, hydroxy, 0 1 -0 10 -alkyl, 0 2 -0 10 -alkenyl, alkyloxy, thioalkoxy, 2iO* 0 3 -0 10 -cycloalkyl, and 0 4 -0 10 -heterocyclyi, which may optionally be substituted by C:0-0 10 -alkyl, 02-Clo-alkenyl, halogen, aryl, hydroxy, Cl-C 10 -alkoxy, aryloxy, amino, alkyl- amino, aminoalkyl, aminoaryl, carboxy, carboxyalkyl, SO 2 NRl 0 R 11 amidino, guanidino. (CH2)p; :i*p 0 to 3; NR', oxygen, (CH 2 OH=CH; q= 0 to 3; 8 (OH 2 CH=CH; v=0 to 3; R 3 =hydrogen, 0 1 -0 10 -alkyl, aryl, 04-Clo-heterocyclyl; R5, R5, R 7are independently selected from hydrogen, 0 1 -Clo-alkyl, C 2 -0 10 -alkenyl, 0 4 -0 10 -heterocyclyl, hydroxy, 0 1 -0 10 -alkoxy, amino, alkylamino, aminoalkyl, arylamino, aminoaryl, carboxyl, carboalkoxy, aminocarbonylamino, SO 2 NR' 0 R 11 wherein all said substitutions may be optionally substituted with one or more of the following: Cl-Clo-alkyl, halogen, amino, alkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, hydroxy, Ci-Cic- alkoxy; hydrogen or hydroxy; R 9 hydrogen or hydroxy; R'O hydrogen or C 1 -C 1 0 -alkyl; and R 1= hydrogen or C 1 -Clo-alkyl. 12. The composition as defined in Claim 11 wherein the compound is selected from the group consisting of hexahydro-3,3,7-trimethyl-2H-azepin-2-imine, monohydrochloride; hexahydro-3,7,7-trimethyl-2H-azepin-2-imine, monohydrochloride; hexahydro-4,4,6,6-tetramethyl-2H-azepin-2-imine, monohydrochioride; tetrahydro-1,4-oxazepin-5(2H)-imine, trifluoroacetate salt; 3-(2-butenyl)tetrahydro-1,4-oxazepin-5(2H)-imine, trifluoroacetate salt; hexahydro-1-methyl-5H-1,4-diazepin-5-imine, trifluoroacetate salt; tetrahydro-3-(2-methoxyethyl)-1,4-oxazepin-5(2H)-imine, monohydrochloride; tetrahydro-6-(2-methoxyethyl)-1,4-oxazepin-5(2H)-imine, monohydrochloride; a-amino-4-hydroxy-5-imino-3-(trifluoromethyl)pyrrolidine-2-butanoic acid, monohydrochloride; hexahydro-2-imino-4-methyl-7-(2-propenyl)- 1H-azepin-3-ol; 6-butyl-3-hydroxy-4-methylpiperidin-2-imine, monohydrochloride; 6-imino-2,4-dimethylpiperidine-3-methanamine, dihydrochloride; 4,6,6-trimethylpiperidine-2-imine, trifluoroacetate salt; and 4,4,6-trimethylpiperidin-2-imine, trifluoroacetate salt. 13. Use of a compound or salt or ester according to any one of claims 1-6, or a composition of any one of claims 7-12, for preparing a medicament for inhibiting nitric oxide synthesis in a subject in need of such inhibition. 14. Use of a compound or salt or ester according to any one of claims 1-6, or a composition of any one of claims 7-12, for preparing a medicament for selectively inhibiting nitric oxide synthesis produced by inducible nitric oxide synthase over nitric oxide produced by the endothelial constitutive form of nitric oxide synthase in a subject in need of such inhibition. Use of a compound or salt or ester according to any one of claims 1-6, or a composition of any one of claims 7-12, for preparing a medicament for lowering nitric oxide levels in a subject in need of such. 100 16. A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective an-cunt of a comp~ound or salt or ester according to any one of claims 1-6, or a composition of any one of claims 7-12.
517. A method of selectively inhibiting nitric oxide synthesis produced by inducible nitric oxide synthase over nitric oxide produced by the endothelial constitutive form of nitric oxide synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound or salt or ester according to any one of claims 1-6, or a composition of any one of claims 7-12. 18. A method of lowering nitric oxide levels in a subject in need of such by administering a therapeutically effective amount of a compound or salt or ester according to any one of claims 1-6, or a composition of any one of claim 7-12. DA D this 15th day of September 1999 G. D. SEAPLE CO., By its Patent Attorneys, E. F. WEUJTNGIGN CO., V.. (Brucef Welntn A/IkA/8972
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43832195A | 1995-05-10 | 1995-05-10 | |
| US438321 | 1995-05-10 | ||
| PCT/US1996/006831 WO1996035677A1 (en) | 1995-05-10 | 1996-05-09 | Nitric oxide synthase inhibitors derived from cyclic amidines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5745496A AU5745496A (en) | 1996-11-29 |
| AU712995B2 true AU712995B2 (en) | 1999-11-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU57454/96A Ceased AU712995B2 (en) | 1995-05-10 | 1996-05-09 | Nitric oxide synthase inhibitors derived from cyclic amidines |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0824523A1 (en) |
| JP (1) | JPH11511741A (en) |
| KR (1) | KR19990014671A (en) |
| CN (1) | CN1190390A (en) |
| AU (1) | AU712995B2 (en) |
| BR (1) | BR9608133A (en) |
| CA (1) | CA2218360A1 (en) |
| MX (1) | MX9708631A (en) |
| NZ (1) | NZ307950A (en) |
| TW (1) | TW415941B (en) |
| WO (1) | WO1996035677A1 (en) |
| ZA (1) | ZA963742B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043358A (en) | 1995-11-01 | 2000-03-28 | Merck & Co., Inc. | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
| GB9524526D0 (en) * | 1995-11-30 | 1996-01-31 | Zeneca Ltd | Chemical process |
| ES2205441T3 (en) * | 1997-01-09 | 2004-05-01 | G.D. SEARLE & CO. | ATTENTION OF THE OPOLIUM TOLERANCE BY INHIBITION OF THE INDEPENDENT NITRICAL OXIDE ROUTES SYNTHETIC IN THE TREATMENT OF PAIN. |
| NO310618B1 (en) * | 1997-04-10 | 2001-07-30 | Ono Pharmaceutical Co | Condensed piperidine compounds, their preparation and use, and preparations comprising such compounds |
| CA2333691A1 (en) * | 1998-06-10 | 1999-12-16 | G.D. Searle & Co. | Heterobicyclic and tricyclic nitric oxide synthase inhibitors |
| US6552052B2 (en) | 1998-06-10 | 2003-04-22 | Monsanto/G.D. Searle | Pyrrolo[2,1-c][1,2,4] thiadiazoles and Pyrollo[2,1-c][1,12,4]oxadiazoles useful as nitric oxide synthase inhibitors |
| SE9901530D0 (en) * | 1999-04-28 | 1999-04-28 | Astra Pharma Prod | Novel compounds |
| DE60110902T2 (en) | 2000-03-24 | 2006-04-27 | Pharmacia Corp., Chicago | AMIDINO COMPOUND AND SALTS USING THEREOF AS NITROGEN OF NITROGEN MONOXIDE SYNTHASE |
| US6545170B2 (en) | 2000-04-13 | 2003-04-08 | Pharmacia Corporation | 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| AR034120A1 (en) | 2000-04-13 | 2004-02-04 | Pharmacia Corp | HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-4,5, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND THE USE OF SUCH COMPOUND AND SUCH COMPOSITION IN THE MANUFACTURE OF A MEDICINAL PRODUCT TO INHIBIT OR MODULATE NITRIC ACID SYNTHESIS |
| US6956131B2 (en) | 2000-04-13 | 2005-10-18 | Pharmacia Corporation | 2-amino-3, 4 heptenoic compounds useful as nitric oxide synthase inhibitors |
| AR032318A1 (en) | 2000-04-13 | 2003-11-05 | Pharmacia Corp | HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-5,6; PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF NITRICAL SYNTHEASE OXIDE |
| AR030416A1 (en) | 2000-04-13 | 2003-08-20 | Pharmacia Corp | HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-3,4, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF SYNTHETIC NITRIC OXIDE |
| US6787668B2 (en) | 2000-04-13 | 2004-09-07 | Pharmacia Corporation | 2-amino-4,5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| US7012098B2 (en) | 2001-03-23 | 2006-03-14 | Pharmacia Corporation | Inhibitors of inducible nitric oxide synthase for chemoprevention and treatment of cancers |
| JPWO2003022309A1 (en) * | 2001-09-10 | 2004-12-24 | 小野薬品工業株式会社 | Allergic disease treatment |
| CN102573910B (en) * | 2009-06-12 | 2015-08-26 | 鹿特丹伊拉斯谟大学医疗中心 | For the targeted nano light medicine of cancer photodynamic therapy |
| EP2480086A4 (en) | 2009-09-25 | 2013-03-20 | N30 Pharmaceuticals Inc | Novel dihydropyrimidin-2(1h)-one compounds as s-nitrosoglutathione reductase inhibitors |
| ES2550939T3 (en) | 2010-07-16 | 2015-11-13 | Nivalis Therapeutics, Inc. | New dihydropyridin-2- (1H) -one compounds as S-nitrosoglutathione reductase inhibitors and neurocinin-3 receptor antagonists |
| US8906933B2 (en) | 2010-09-24 | 2014-12-09 | N30 Pharmaceuticals, Inc. | Dihydropyrimidin-2(1H)-one compounds as neurokinin-3 receptor antagonists |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2049582A (en) * | 1931-11-04 | 1936-08-04 | Rohm & Haas | Amidines |
| US3121093A (en) * | 1962-08-31 | 1964-02-11 | Rohm & Haas | Substituted iminopyrrolidines |
| EP0897912A1 (en) * | 1993-10-21 | 1999-02-24 | G.D. Searle & Co. | Amidino derivatives useful as nitric oxide synthase inhibitors |
| US5629322A (en) * | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
-
1996
- 1996-05-09 NZ NZ307950A patent/NZ307950A/en unknown
- 1996-05-09 AU AU57454/96A patent/AU712995B2/en not_active Ceased
- 1996-05-09 JP JP8534320A patent/JPH11511741A/en not_active Abandoned
- 1996-05-09 BR BR9608133A patent/BR9608133A/en not_active Application Discontinuation
- 1996-05-09 WO PCT/US1996/006831 patent/WO1996035677A1/en not_active Application Discontinuation
- 1996-05-09 CA CA002218360A patent/CA2218360A1/en not_active Abandoned
- 1996-05-09 EP EP96915767A patent/EP0824523A1/en not_active Withdrawn
- 1996-05-09 CN CN96195400A patent/CN1190390A/en active Pending
- 1996-05-09 KR KR1019970708012A patent/KR19990014671A/en not_active Application Discontinuation
- 1996-05-09 MX MX9708631A patent/MX9708631A/en unknown
- 1996-05-10 ZA ZA963742A patent/ZA963742B/en unknown
- 1996-08-06 TW TW085109538A patent/TW415941B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996035677A1 (en) | 1996-11-14 |
| MX9708631A (en) | 1998-02-28 |
| NZ307950A (en) | 1999-06-29 |
| KR19990014671A (en) | 1999-02-25 |
| AU5745496A (en) | 1996-11-29 |
| BR9608133A (en) | 1999-02-09 |
| ZA963742B (en) | 1997-07-09 |
| CA2218360A1 (en) | 1996-11-14 |
| TW415941B (en) | 2000-12-21 |
| CN1190390A (en) | 1998-08-12 |
| EP0824523A1 (en) | 1998-02-25 |
| JPH11511741A (en) | 1999-10-12 |
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